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LeBoit P. E., Burg G., Weedon D., Kurman R. J., Carcangiu M. L., El-Naggar A. K., Chan J.K.C .,
Sarasin A. (Eds): World Health Herrington C. S., Young R.H. (Eds): Gradis J. R, Takata T., Slootweg P.J.
Organization Classification of WHO Classification of Tumours (Eds): WHO Classification of Head
Tumours. Pathology and Genetics of Female Reproductive and Neck Tumours (4th edition).
of Skin Tumours (3rd edition). Organs (4th ed ition). IARC: Lyon 2014. IARC: Lyon 2017.
IARC Press: Lyon 2006. ISBN 978-92-832-2435-8 ISBN 978-92-832-2438-9
ISBN 978-92-832-2414-0
Bosman F. T., Carneiro F., Travis W. D., Brambi lla E., Burke A. P., Lloyd R. V., Osamura R. Y., Kloppel G.,
Hruban R.H., Theise N. D. (Eds): Marx A., Nicholson A.G. (Eds): Rosai J. (Eds): WHO Classification of
WHO Classification of Tumours of WHO Classification of Tumours of Tumours of Endocrine Organs
the Digestive System (4th edition). the Lung, Pleura, Thymus and Heart (4th ed ition). IARC: Lyon 2017 .
IARC: Lyon 2010. (4th edition). IARC: Lyon 2015. ISBN 978-92-832-4493-6
ISBN 978-92-832-2432-7 ISBN 978-92-832-2436-5
Lakhani S. R., El lis 1.0., Schnitt S. J., Moch H., Humphrey P.A., Swerdlow S. H., Campo E. , Harris N. L.,
Tan P.H., van de Vijver M.J. (Eds): Ulbright T. M., Reuter V. E. (Eds): Jaffe E.S., Pileri S.A., Stein H.,
WHO Classification of Tumours of the WHO Classification of Tumours of the Thiele J. (Eds): WHO Classification of
Breast (4th edition). IARC : Lyon 2012. Urinary System and Male Genital Tumours of Haematopoietic and Lym-
ISBN 978-92-832-2433-4 Organs (4th edition). IARC: Lyon 2016. phoid Tissues (Revised 4th ed ition).
ISBN 978-92-832-2437-2 IARC: Lyon 2017.
ISBN 978-92-832-4494-3
Fletcher C. D. M., Bridge JA, Louis D. N., Ohgaki H., Wiestler O.D.,
Hogendoorn P. C. W., Mertens F. (Eds): Cavenee W. K. (Eds):
WHO Classification of Tumours WHO Class ification of Tumours of
of Soft Tissue and Bone (4th edition). the Central Nervous System (Revised
IARC: Lyon 2013. 4th edition). IARC: Lyon 2016.
ISBN 978-92-832-2434-1 ISBN 978-92-832-4492-9
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'
'·
WHO
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~~
OMS
Edited by
Steven H. Swerdlow
Elias Campo
Nancy Lee Harris
Elaine S. Jaffe
Stefano A. Pi leri
Harald Stein
JOrgen Thiele
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WHO c lassif ication of tumours of haematopoietic and lymphoid ti ssues I edited by Steven H. Swerd low, El ias Campo,
Nancy Lee Harris, Elaine S. Jaffe, Stefano A. Pileri, Harald Stein, Jurgen Thiele . - Revised 4th ed ition.
10 WHO classification
WHO classification 11
12 WHO classification
Why classify? Classification is the language 130 pathologists and haematologists from The first component is the recognition that
of medicine; diseases must be described, around the world were involved in writing the underlying causes of these neoplasms
defined, and named before they can be the chapters. are often unknown and may vary. There-
diagnosed, treated, and stud ied. A con- It has now been more than 8 years since fore, the WHO approach to classification
sensus on definitions and terminology is the publication of the 4th edition, and nu- incorporates all available information -
essential for both clinical practice and in- merous basic and cl inical investigations morphology, immunophenotype, genetic
vestigation. A classification should contain have since led to many advances in the features, and clinical features - to define
diseases that are clearly defined, clinically fiel d that warrant an update to the clas- the diseases. The relative importance of
distinctive, and non-overlapping (i.e. mutu- sification. Important contributions have each of these features varies by disease,
ally exclusive), and that together constitute been made through the application of depending on the current state of know-
all known entities (i.e. are collectively ex- high-throughput genetic technologies ledge; there is no single gold standard by
haustive). A classification should provide such as gene expression profi ling and which all diseases are defined.
a basis for future investigation and should next-generation sequencing . These tech- The second important component of this
be able to incorporate new information as it nolog ies have led to new diagnostic tools classification process is the recognition
becomes available. Disease classification and have revealed new mechanisms of that the complexity of the field makes it
involves two distinct processes: class dis- tumorigenesis and new potential therapeu- impossible for any single expert or small
covery (the process of identifying catego- tic targets. Because the 4th edition of the group of experts to be completely au-
ries of diseases) and class prediction (the WHO classification of tumours series is not thoritative; for a classification to be widely
process of determining to which category yet complete (with several volumes yet to accepted, broad agreement is necessary.
individual cases belong). The work of pa- be released), the 5th edition cannot yet be Therefore, the WHO approach to clas-
tholog ists is essential for both processes. started, so the editors and authors have in- sification rel ies on building a consensus
The 2008 WHO classification of tumours stead undertaken a major update to the ex- on the definitions and nomenclature of
of the haematopoietic and lymphoid tis- isting 4th edition of the WHO classification the diseases among as many experts as
sues (4th edition) {3848) was a collabora- of tumours of the haematopoietic and lym- possible. We recognize that compromise is
tive project of the European Association phoid tissues. This process has involved essential for establishing a consensus, but
for Haematopathology and the Society for many of the original editors as well as an we believe that even an imperfect single
Hematopathology. It was a revision and additional three senior advisors special- classification is better than multiple com-
update of the 3rd edition {1820), which izing in myeloid neoplasms and two senior peting classifications.
was the first true worldwide consensus advisors with expertise in molecular and The final important component of this clas-
classification of haematological malignan- cytogenetic issues. Clinical advisory com- sification process is the understanding that
cies. The 4th edition had an eight-member mittee meetings were held regarding both although pathologists must take primary
steering committee composed of members myeloid and lymphoid neoplasms, as was responsibility for developing a classifica-
of both societies. Through a series of meet- done for prior editions. The key features of tion, the involvement of clinicians is also
ings and discussions, with input from both this revision have been summarized in re- essential, to ensure the classification's
societies, the steering committee agreed cent review articles {129A,3848A}. usefulness and acceptance in daily prac-
on a proposed list of diseases and chap- The WHO classification of tumours of hae- tice {1556). When the 3rd edition of the
ters and chose authors. As was done for matopoietic and lymphoid tissues is based WHO classification was publ ished , pre-
the 3rd edition , the advice of clinical hae- on the principles initially defined in the Re- vious proponents of other classifications of
matologists and oncologists was obtained vised European-American classification of haematological neoplasms agreed to ac-
to ensure that the classification would be lymphoid neoplasms (REAL), proposed by cept and use the new c lassification, end-
clinically useful {1556). Two clinical advi- the International Lymphoma Study Group ing decades of controversy over the clas-
sory committees were convened: one for (ILSG) {1557). In the WHO classification , sification of these tumours {338A,339,340,
myeloid neoplasms and other acute leu- these principles have also been applied to 1165, 1330A, 1643A,2412A,2836,331 OA}.
kaemias and one for lymphoid neoplasms. the classification of myeloid and histiocytic As stated above, there is no single gold
The meetings were organized around a se- neoplasms. The guiding principle of both standard by which all diseases are defined
ries of questions, which addressed topics the REAL and the WHO classification is in the WHO classification. Morphology is al-
such as disease definitions, nomenclature, the importance of defining 'real' diseases ways important; many diseases have char-
grading, and clinical relevance. The com- that can be recognized by pathologists acteristic or even diagnostic morphological
mittees were able to reach consensus on using the available techniques, and that features. lmmunophenotype and genetic
most of the questions posed, and much of appear to be distinct clinical entities. There features are also important aspects of the
the input from the committees was incor- are three important components of this definition of tumours of haematopoietic and
porated into the classification. More than process. lymphoid tissues, and the availabil ity of this
The 2001 WHO Classification of Tumours: current revision explicitly acknowledges decision-making and that also provides a
Pathology and Genetics of Tumours of that recurrent genetic abnormalities not flexible framework for integration of new
Haematopoietic and Lymphoid Tissues only provide objective criteria for rec- data.
{3rd edition) reflected a paradigm shift in ognition of specific entities but are also
the approach to the classification of my- vital for the identification of abnormal
eloid neoplasms {1 820). For the first time, gene products and pathways that are Prerequisites for the
genetic information was incorporated into potential therapeutic targets. Several classification of myeloid
diagnostic algorithms provided for the disease subgroups and sets of defining
neoplasms by WHO criteria
various entities. The publication was pref- criteria have been expanded to include
aced with a comment pred icting future not only neoplasms associated with chro- The WHO classification of myeloid neo-
revisions necessitated by rapidly emerg- mosomal abnormalities recognizable by plasms relies on the morp hological, cy-
ing genetic information relevant to the di- conventional karyotyping, but also those tochemical, and immunophenotypic fea-
agnosis and classification of myeloid ma- with gene mutations with or without a cy- tures of the neoplastic cells to establish
lignancies. The 4th edition (published in togenetic correlate. However, the impor- their lineage and degree of maturation,
2008) and the current 4th ed ition revision tance of careful clinical, morphological, and to determine whether the cellular
reflect the significant new molecular in- and immunophenotypic characterization appearance is cytologically normal, dys-
sights that have become available since of every myeloid neoplasm, and correla- plastic, or otherwise morphologically ab-
the publication of the 2001 edition. tion with the genetic findings, cannot be normal. The classification is based on cri-
The first entity described in th is volume, overemphasized . The discoveries of acti- teria applied strictly to initial specimens
chronic myeloid leukaemia, remains the vating JAK2 mutations and mutations in obtained prior to any therapy. Blast per-
prototype for the identification and clas- CALR and MPL have revolutionized the centages in the peripheral blood, bone
sification of myeloid neoplasms. This leu- diagnostic approach to myeloprol ifera- marrow, and other involved tissues re-
kaemia is recognized by its clinical and tive neoplasms (M PNs) {299,1831,2014, main of practical importance for catego-
morphological features, and its natural 2037,2099,2290,2823). However, these rizing myeloid neoplasms and determin-
progression is characterized by an in- mutations are not specific for any single ing their progression. Cytogenetic and
crease in blasts of myeloid, lymphoid, or clinical or morpholog ical MPN pheno- molecular genetic studies are required at
mixed myeloid- lymphoid immunophe- type, and some are also reported in cer- the time of diagnosis not only for recogni -
notype. It is always associated with the tain cases of myelodysplastic syndromes tion of specific genetically defined enti-
BCR-ABL1 fu sion gene, wh ich results in (MDSs), myelodysp lastic/myeloprolifera- ties, but also for establishing a basel ine
the production of an abnormal protein ty- tive neoplasms (M DS/MPNs), and acute against which follow-up studies can be
rosine kinase with enhanced enzymatic myeloid leukaemia (AML). Therefore, an interpreted to assess disease progres-
activity. This oncoprotein is sufficient to integrated, multimodality approach is sion. Given the integrated, multimodality
cause the disease and is also a target for necessary for the classification of all my- approach req uired for d iagnosing and
protein tyrosine kinase inhibitor therapy, eloid neoplasms. It is also critical to eluci- classifying these neoplasms, it is recom-
which has prolonged the lives of thou- date how molecular testing can be used mended that the various diagnostic stud-
sands of patients with this previously fatal to inform the diagnosis and treatment of ies be correlated with the c linical fi ndings
illness {1040). This successful integration myeloid malignancies, and to articulate and commun icated in a sing le integrated
of clinical, morphological, and genetic in- how these tests should be incorporated report. If a definitive classification cannot
formation embodies the goal of the WHO into clinical practice, on the basis of cur- be determined, the report should indicate
classification scheme. rent and evolving scientific evidence. why and provide guidance for add itional
In this revision, the combination of clini- With so much yet to be learned, there studies that may clarify the diagnosis.
cal, morphological, immunophenotypic, may be some missteps as trad itional For the purpose of achieving consist-
and genetic features continues to be approaches to categorization are fused ency, the following guidelines are recom-
used in an attempt to define disease enti- with more molecularly oriented classifi- mended for the evaluation of specimens
ties, such as chronic myeloid leukaemia, cation schemes. But the authors, senior when a myeloid neoplasm is suspected.
that are biologically homogeneous and advisors and editors of this revision of In this context, a standardized approach
clinically relevant - the same approach the WHO classification, as well as the to the processing, documentation, and
used in the 3rd and 4th editions of the clinicians who served as members of reporting of bone marrow findings is
classification. The previous classifica- its clinical advisory committees, have emphasized {2253). It is assumed that
tion schemes opened the door to includ- worked diligently to develop an updated, the evaluation wi ll be performed with full
ing genetic abnormalities as criteria for evidence-based classification that can knowledge of the clinical history and per-
classifying myeloid neoplasms, and the be used in daily practice for therapeutic tinent laboratory data.
Blasts
The percentage of myeloid blasts is very
important for the diagnosis and classi-
fication of myeloid neoplasms. In the
peripheral blood, the blast percentage
should be determined from a 200-cell
leukocyte differential count and in the
bone marrow, from a 500-cell count using
cellular bone marrow aspirate smears as
described above. The blast percentage
Fig. 1.01 Myelodysplastic syndrome. Bone marrow biopsies should be well fixed, and thin (3-4 µm) sections should determined from the bone marrow aspi-
be stained with H&E and/or Giemsa stain to enable optimal evaluation of histological details. rate should correlate with an estimate of
n AM L with from myeloblasts in MOS with excess NPM1, RUNX1, and CEBPA figure promi- it characterize myeloblasts.
ymphoblas- blasts or pure erythroid leukaemia, and nently in this revised classification. In alpha-naphthyl butyrate es-
1ic myeloid CD61 or CD42b staining often facil itates addition, many recently characterized alpha-naphthyl acetate es-
the myeloid the identification of abnormal megakaryo- somatic disease alleles (e.g. recurrent ' diffuse cytoplasmic activity
Jhoid blast cytes and megakaryoblasts. mutations in TET2 , ASXL 1, and ONMT3A) ts and monocytes. Lympho-
~50% ~20% no yes n/a AML with recurrent AML with recurrent genetic
genetic abnormality abnormality
> 80% immature erythroid < 20% no no• n/a AML, NOS; AML, NOS;
precursors with acute erythroid leukaemia pure erythroid leukaemia
> 30% proerythroblasts (pure erythroid subtype)
AML, acute myeloid leukaemia; BM, bone marrow; MOS, myelodysplastic syndrome; n/a, not applicable; NOS, not otherwise specified; PB, peripheral blood.
a Cases of AML with t(8;21)(q22;q22.1) resulting in the RUNX1-RUNX1T1 fusion protein, AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22) resulting in the CBFB-MYH11
fusion protein, or acute promyelocytic leukaemia with the PML·RARA fusion protein may rarely occur in this setting with < 20% blasts, and those diagnoses take
precedence over the diagnosis of either AML, NOS or MOS.
b Classify according to the myeloblast percentage of all BM cells and PB leukocytes, along with other MOS criteria.
proper classification to guide the clini- fied: single lineage versus multilineage this revision that affects MOS diagnosis
cal approach. The general features of dysplasia, ring sideroblasts, excess is in the diagnostic criteria for myeloid
MOS, as well as specific guidelines for blasts, or the defining del(5q) cytogenet- neoplasms in wh ich ?: 50% of the bone
their diag nosis and classification, are ic abnormality. No new disease entities marrow cells are erythroid precursors . In
outlined in Chapter 6, Mye/odysplastic have been introduced, but the diagnostic the original 4th edition WHO classifica-
syndromes: Overview (p. 98). criteria for some entities have been re- tion, erythroid/myeloid-type acute eryth-
In this revised WHO classification, new fined , as detailed in Table 6.01 (p. 101) in roid leukaemia (erythroleukaem ia) was
terminology has been introduced. In the the Myelodysplastic syndromes chapter diagnosed if blasts accounted for ?:20%
original 4th edition, MOS disease names and in the sections on each MOS entity. of the non-erythroid cells in the bone
included references to cytopenia or spe- MOS cases with multilineage dysplasia, marrow; if blasts accounted for < 20%
cific types of cytopenia (e.g. refractory ring sideroblasts, and no excess of blasts of the non-erythroid cells, the case was
anaemia). Although cytopenia is a sine or isolated del(5q) cytogenetic abnormal- considered to be MOS and subclassified
qua non of any MOS diag nosis, the WHO ity are now categorized as a subg roup of on the basis of the blast count among all
classification relies mainly on the degree MOS with ring sideroblasts rather than nucleated bone marrow cel ls. Due to the
of dysplasia and blast percentages for being grouped with MOS with multiline- apparent close biological relationship of
MOS classification; specific cytopenias age dysplasia lacking ring sideroblasts erythroleukaemia to MOS and the poor
have only a minor impact on classifica- as in the original 4th ed ition. MOS in chil- reproducibility and potential !ability of
tion. Moreover, the lineage(s) manifesting dren has features that differ from those of non-erythroid blast counts, and in an at-
significant morpholog ical dysplasia often most MOS in adults, and the provisional tempt to ach ieve consistency in express-
do not correlate with the specific cytope- entity refractory cytopenia of childhood ing blast percentages across al l myeloid
nias seen in individual MOS cases. For remains in this updated classification. neoplasms, non-erythroid blast counting
these reasons , the updated MOS names Although this entity is sti ll provisional, its has been eliminated from the diagnostic
do not refer to cytopenia. All diagnostic morphological features and distinction criteria for all myeloid neoplasms. For
entity names start with 'myelodysplastic from severe aplastic anaemia are now all cases (even those with ?:50% bone
syndrome', with further qualifiers speci- better defined. An important change in marrow erythroid cells), the bone mar-
Analysis Cytogenetic and molecular Next-generation sequencing The Cancer Genome Atlas (TCGA) project {545}
genetic analysis approaches
Class I
Class 2 - Nucleophosmin 1
Activated signalling
NPM1 mutations
Class I e.g. FLT3, KIT, and RAS mutations
Activated signalling
Class 3 - Tumour suppressor genes
e.g. FLT3, KIT, RAS mutations
e.g. TP53 and PHF6 mutations
Class II
Class 7 - Myeloid transcription factor genes
Transcription and differentiation
e.g. CEBPA, RUNX1 mutations
e.g. t(8;21), inv(16), t(15;17),
and CEBPA mutations Epigenetic modifiers
(so-called 'Class Ill') Class 8 - Cohesin complex genes
e.g. TET2, DNMT3A, and ASXL1 e.g. STAG2, RAD21, SMC1, SMC2 mutations
mutations
Class 9 - Spliceosome-complex genes
e.g. SRSF2, U2AF1, ZRSR2 mutations
used in the 4th edition proved flexible studies have shown no difference in de assigned to this category if they evolve
enough to incorporate the new entities novo cases with and without this find- from previously documented MOS, have
proposed by members of the WHO and ing {211,975,1145). Lastly, the provisional specific myelodysplasia-related cytoge-
clinical advisory committees. The origi- category of AML with mutated RUNX1 netic abnormalities, or exhibit morpho-
nal entities described in the subgroup has been added for de novo cases with logical multilineage dysplasia. However,
'acute myeloid leukaem ia with recurrent this mutation that are not associated with these features do not supersede therapy-
genetic abnormalities' remain (with only MOS-related cytogenetic abnormalities. related disease or the defined cytoge-
minor modifications), and two provisional This provisional category appears to rep- netic categories of AML. As mentioned
entities have been added. A new provi- resent a biolog ically distinct form of AML above, de novo cases with N PM1 or bi-
sional category, AML with BCR-ABL1, {1 274, 2627,3576,3897). AML with mu- allelic CEBPA mutation with no MOS-re-
has been added to recogn ize these rare tated FLT3 is not included as a separate lated cytogenetic abnormalities, but with
de novo cases {2082,2801,3740), which entity, because FL T3 mutation occurs multilineage dysplasia, are now classi-
may benefit from tyrosine kinase inhibi- across multiple AML subtypes; however, fied as either AML with mutated NPM1
tor therapy and must be distinguished the significance of this mutation shou ld or AML with biallelic mutation of CEBPA.
from blast transformation of chronic my- not be underesti mated, and it should be The cytogenetic abnormalities that de-
eloid leukaemia. AM Ls with mutated tested for in essentially all cases, includ- fine MOS-associated disease have also
NPM1 and CEBPA are now fu ll entities, ing those with NPM1 or CEBPA mutation been modified: del(9q), which does not
but a biallelic mutation is required for the or other recurrent genetic abnormali- appear to have prognostic significance
revised category now known as AM L ties. Broader gene panels are becom- in the setting of NPM1 or biallelic CEBPA
with biallelic mutation of CEBPA. Addi- ing increasingly available and are prob- mutation, has been removed from the list
tionally, multilineage dysplasia alone no ably indicated in most, if not all, types {1511,3562), as has monosomy 5; del(5q)
longer supersedes a diagnosis of AML of AML. Modifications have been made and unbalanced translocation involving
with mutated NPM1 or AML with bial- to the AML with myelodysplasia-related 5q remain {1559,4209).
lelic mutation of CEBPA, because recent changes subgroup. Cases should still be
Myeloproliferative neoplasms
Chronic myeloid leukaemia, BCR-ABL1-positive
Chronic neutrophilic leukaemia
Polycythaemia vera
Primary myelofibrosis
Essential thrombocythaemia
Chronic eosinophilic leukaemia, NOS
Myeloproliferative neoplasm, unclassifiable
. a iJ
Fig. 2.01 Splenomegaly in chronic myeloid leukaemia, BCR-ABL1-positive. A The gross appearance of the spleen is solid and uniformly deep red, although areas of infarction
may appear as lighter-coloured regions. B The red pulp distribution of the infiltrate usually compresses and obliterates the white pulp. C The leukaemic cells are present in the
splenic cords and sinuses. In this case the cells are shifted towards immature forms; care must be taken to assess the maturity of the cells in splenectomy specimen, because
enlarging spleens, particularly in the face of TKI therapy, may be associated with disease progression.
30 Myeloproliferative neoplasms
;::: 1000 x 109 /L; marked thrombocytope- Fig.2.02 Chronic myeloid leukaemia (CML), BCR-ABL1- positive (chronic phase). A Peripheral blood smear
nia is uncommon in CP {1662}. showing leukocytosis and neutrophilic cells at various stages of maturation; basophilia is prominent; no dysplasia is
Most cases of CML can be diagnosed present. B Bone marrow biopsy showing marked hypercellularity due to granulocytic proliferation. CThe megakar-
yocytes in CML are characteristically smaller than normal megakaryocytes. D Bone marrow aspirate smear shows
on the basis of peripheral blood findings expansion and maturation of the neutrophil lineage, increased basophils and a small 'dwarf' megakaryocyte, which is
combined with detection of the Ph chro- smaller than a normal megakaryocyte but larger than the micromegakaryocytes seen in myelodysplastic syndromes,
mosome and/or BCR-ABL 1 by cytoge- although micromegakaryocytes are sometimes seen in CML in the accelerated or myeloid blast phase.
netic and molecular genetic techniques.
However, bone marrow aspiration is es-
sential to ensure sufficient material for
a complete karyotype and for morpho-
logical evaluation to confirm the phase
of disease. Bone marrow biopsy is not
required to diagnose CML in most cases,
but should be done if the findings in the
peripheral blood are atypical or if a cel-
lular aspirate cannot be obtained {1662,
2911}.
In CP, bone marrow specimens are hyper-
cellular, with marked granulocytic prolif-
eration and a maturation pattern similar
to that in the blood, including expansion
at the myelocyte stage {822}. There is
no significant dysplasia. Blasts usually
account for < 5% of the marrow cells;
;::: 10% suggests advanced disease {817}.
The proportion of erythroid precu rsors is
usually significantly decreased. Mega-
karyocytes may be normal or slightly
decreased in number, but 40-50% of
cases exh ibit moderate to marked mega-
-· - ..·-
Fig. 2.03 Chronic myeloid leukaemia (CML), 8CR-A8L1-positive (chronic phase). A There may be morphological
. ...
variability in the initial bone marrow biopsy specimens of patients with CML. In this case there is a prominent increase
in the number of 'dwarf' megakaryocytes that are dispersed throughout the marrow. Such cases are sometimes re-
karyocytic proliferation {495,3976,3982}. ferred to as 'megakaryocyte-rich' CML. B Up to 30% of cases of CML may have reticulin fibrosis of variable degree
In CP, the megakaryocytes are smaller at presentation. C Pseudo-Gaucher cells in CML. Pseudo-Gaucher cells are commonly observed in the marrow
than normal and have hyposegmented aspirates of patients with CML. D They may also be appreciated as foamy or striated cells in marrow biopsy sections.
nuclei; they are referred to as 'dwarf' These histiocytes are secondary to increased cell turnover, are derived from the neoplastic clone and are easily
megakaryocytes, but are not true micro- distinguished from the 'dwarf' megakaryocytes seen in the lower middle margin of the photograph.
megakaryocytes such as those seen in
myelodysplastic syndromes {853,3982}. cher cel ls are common . These features cytes (5-10 cells in thickness) is common
Eosinophils and basophils are usually are mirrored in marrow biopsy sections, around the bone trabeculae, in contrast
increased in number, and pseudo-Gau- in wh ich a layer of immature granulo- to the normal th ickness of 2- 3 cells {853}.
32 Myeloproliferative neoplasms
.....
Fig.2.06 Chronic myeloid leukaemia, BCR-ABL1- positive (lymphoid blast phase). A Peripheral blood smear with numerous lymphoid-morphology blasts among leukaemic
myelocytes. B Bone marrow biopsy of the same case. C Marrow aspirate smear. By fiow cytometry, the blasts coexpressed CD19, CD10, CD22, terminal deoxynucleotidyl
transferase (TdT), and CD13, but there was no expression of MPO.
34 Myeloproliferative neoplasms
;_ ~-l: t(9;22)(q34;q11.2)
BCR-ABL1
e13a2
·. -·-·
e14a2
A
p210
DD
-- P-SIT
(SH2· blnd.) rho-GEF
MN
ijiiji\ ~
~
SH1 I
-/
I
B
Fig.2.10 Chronic myeloid leukaemia, BCR-ABL1- positive. A Schematic representation of the t(9;22) chromosomal translocation, the fusion mRNA transcripts encoded by
the BCR-ABL1 fusion gene generated in the changed chromosome 22 and the Philadelphia (Ph) chromosome, and the translated BCR-ABL1 fusion protein (p21 O) - whose
oncogenic properties are due primarily to its constitutively activated tyrosine kinase, encoded by the SH1 domain (indicated in red). Some of the other important functional domains
contributed by the BCR and ABL1 portions of the oncoprotein are also shown: the dimerization domain (DD); Y177, which is the autophosphorylation site crucial for binding to
GRB2; the phospho-serine/threonine (P-S/T) SH2-binding domain; a region homologous to Rho guanine nucleotide exchange factors (rho-GEF); the ABL1 regulatory SH3 and
SH2 domains; Y412, which is the major site of autophosphorylation within the SH1 kinase domain; nuclear localization signals (NLS); and the DNA-binding and actin-binding
domains. B Mechanism of action of BCR-ABL1 tyrosine kinase inhibitors. The physiological binding of ATP to its pocket allows BCR-ABL1 to phosphorylate selected tyrosine
residues on its substrates (left panel); a synthetic ATP mimic such as imatinib fits the pocket (right panel), but does not provide the essential phosphate group to be transferred
to the substrate. The downstream chain of reactions is then halted because. with its tyrosines in the unphosphorylated form, the substrate does not assume the necessary
conformation to ensure association with its effector.
0 .1
residues on its substrates. Interruption
Busulfan, 1983 -1994, 5-year survival 38%, 10-year survival 11%
of the oncogenic signal in this way is 0.0
effective for control of the disease, par- 0 2 4 6 8 10
ticularly when used early in CP. However,
Year after diagnosis
the emergence of subclones of leukae-
mic progenitor cells that have BCR-ABL 1 Fig.2.11 Chronic myeloid leukaemia (CML), BCR-ABL1-positive (chronic phase). Survival probabilities in CML over
point mutations that alter amino acids time as observed in five consecutive randomized treatment-optimization studies (1983-2014) of the German CML
Study Group using different treatment modalities, showing marked improvement in survival with tyrosine kinase
and prevent the binding of the inhibitor to
inhibitor therapy. Similar results have been published by other cooperative groups. From: Hehlmann R (1602).
the BCR-ABL1 kinase domain can lead
to drug resistance, particu larly in AP and
BP {122). The second and third genera- MECOM (also called EV/1), TET2, CBL, haematological findings (the Sokal score
tions of TKls (i.e. nilotini b, dasatinib, bo- ASXL1, IDH1, and IDH2, but their exact {3716) and EUTOS score {1582)) are also
sutinib, and ponatinib) can circumvent role (if any) in the transformation is un- valid, with low-risk patients responding
this form of drug failure in the presence known {2453,3743). The introduction to TKls sign ificantly better than high-risk
of most kinase domain mutations {4281). of genome-wide expression profi ling patients {207) Overall, the complete cy-
The molecular basis of transformation is by microarray technology has revealed togenetic response rate to first-line TKI
still largely unknown {2620}. Progression other candidate genes associated with is 70- 90%, with 5-year progression-free
is usually associated with clonal evolu- the advanced stages, and has also re- and overall survival rates of 80- 95%. A
tion; at the time of transformation to AP vealed similar gene expression patterns major molecular response (BCR-ABL 1
or BP, 80% of cases demonstrate cyto- in AP and BP, suggesting that the ge- < 0.1% on the international scale) and a
genetic changes in add ition to the Ph netic events leading to transformation in deeper molecular response (BCR-ABL1
chromosome, including an extra Ph chro- AP and BP occur in late CP or early AP :s;0.01%) are ach ieved faster and more
mosome, isochromosome 17q, and gain {4426). These studies have also shown frequently with second-generation TKls,
of chromosome 8 or 19, the so-called that progression to advanced-phase predicting that a condition of treatment-
major route karyotypic abnormalities. disease often shares biological features free remission wi ll be achieved in more
The presence of any of these abnormali- associated with resistance to TKI therapy patients than with imatinib. However, the
ties in the karyotype at the time of initial {3277) progression-free survival rate is on ly mar-
diag nosis of CML has been reported to ginally improved, and overall survival is
be an adverse prognostic finding, and Prognosis and predictive factors the same irrespective of the TKI used as
places a case in the AP category {1161}. In the current era of TKI therapy, the most first-line therapy. Today, few patients die
Genes reported to be altered in the trans- important prognostic indicator is response from leukaemia, and the overall survival
formed stages include TP53, RB1, MYC, to treatment at the haematological, cyto- is similar to that of the non-leukaemic
CDKN2A (also called p16/NK4a), NRAS, genetic, and molecular level. However, population {207,1602).
KRAS, RUNX1 (also called AML 1), the risk scores based on clinical and
36 Myeloproliferative neoplasms
Definition kaemia {391,2845}, but there is no reason present as well 14441,4501}. There may
Chronic neutrophilic leukaemia is a rare to postulate a relationship between the be bruising and purpura. A history of
myeloproliferative neoplasm character- two cond itions. Acute myeloid leukaemia bleeding from mucocutaneous surfaces
ized by sustained peripheral blood neu- has supervened in 3 cases of a chron ic or from the gastrointestinal tract is re-
trophilia, bone marrow hypercellularity neutrophilic leukaemia-like condition as- ported in 25- 30% of cases 11588,4501).
due to neutrophilic granulocyte prol ifera- sociated with a plasma cell neoplasm, Gout and pruritus are other possible fea-
tion, and hepatosplenomegaly. There but all 3 patients had been exposed to tures {4501 }. Serum vitamin 812 and uric
is no Philadelphia (Ph) chromosome or leukaemogenic drugs before the emer- acid are often elevated.
BCR-ABL1 fusion gene. The diagnosis gence of acute myeloid leukaemia {995,
requires exclusion of reactive neutrophilia 2294,4079). The association of a con- Imaging
and other myeloproliferative and myelo- dition resembling chronic neutrophilic Imaging may show enlargement of the
dysplastic/myeloproliferative neoplasms leukaemia with other neoplasms is also liver or spleen.
(Table 2.02, p. 38). likely to reflect a leukaemoid reaction.
Microscopy
ICD-0 code 9963/3 Localization The peripheral blood shows neutrophilia,
The peripheral blood and bone marrow with a white blood cell count ~25 x 109/L.
Epidemiology are always involved, and the spleen and The neutrophils are usually segmented,
The true incidence of chronic neutro- liver usually show leukaemic infiltrates. but there may also be a substantial in-
philic leukaemia is unknown; > 200 cas- However, any tissue can be infiltrated crease in band forms. In almost all cases,
es have been reported, but only about {4035,4441,4501 }. neutrophil precursors (promyelocytes,
150 of these meet the cu rrent diagnostic myelocytes, and metamyelocytes) ac-
criteria 1231}. In one study of 660 cases Clinical features count for < 5% of the white blood cells,
of chronic leukaemias of myeloid origin, The most constant clinical feature re- but occasionally they may account for
not a single case of chronic neutrophilic ported is splenomegaly, which may be as much as 10% {515,1094,1096A,1588,
leukaemia was observed 13642}. Chronic symptomatic. Hepatomegaly is usually 4441,4501). Myeloblasts are almost
neutrophilic leukaemia generally affects
older adu lts, but has also been reported
rarely in adolescents and young adults
{1588,4441,4501}. In 116 patients whose
age and sex were reported, the median
age at presentation was 66 years and the
male-to-female ratio was 1.6:1 {231).
Etiology
The cause of chronic neutrophilic leukae-
mia is unknown. Some cases have fol-
lowed cytotoxic chemotherapy 11095).
Its occurrence in a father and son has
been reported {2072}. In about a quarter
of reported cases of chronic neutrophilic
leukaemia or an apparently similar con-
dition, the neutrophilia was associated
with an underlying neoplasm, most often
multiple myeloma or monoclonal gam-
mopathy of undetermined significance.
The majority of such cases constitute a
neutrophilic leukaemoid reaction result-
ing from synthesis of g ranulocyte colony- ~ l ~ ~
Fig. 2.12 Chronic neutrophilic leukaemia. A Characteristic neutrophilia in a peripheral blood smear. B Toxic granu-
stimulating factor by neoplastic plasma
lation is commonly observed. C Bone marrow aspirate smear demonstrates neutrophil proliferation from myelocytes
cells. A very small number of patients ap- to segmented forms with toxic granulation, but no other significant abnormalities. D The bone marrow biopsy speci-
pear to have had both a plasma cell neo- men is hypercellular, showing a markedly elevated myeloid-to-erythroid ratio, with increased numbers of neutrophils,
plasm and true chronic neutrophilic leu- in particular mature segmented forms.
38 Myeloproliferative neoplasms
Polycythaem ia vera 39
40 Myeloproliferative neoplasms
Cl inical laboratory studies that facilitate lineages; i.e. there is a panmyelosis. cially noteworthy in the subcortical mar-
the diagnosis of PV include detection of The peripheral blood shows a mil d to row space, which is normally hypocel lular
JAK2 V617F or functionally similar mu- overt excess of normochromic, normo- (1329,3964). Panmyelosis accounts for
tations (e.g. JAK2 exon 12 mutations) cytic RBCs. If there is iron deficiency the increased haematopoietic cellularity,
(2603 ,3056,3929,3931,3932) and sub- due to bleeding, the RBCs may be hy- but increased numbers of erythroid pre-
normal erythropoietin levels (251,2602, pochromic and microcytic. Neutroph ili a cursors and megakaryocytes are often
2760,3677,3929). Endogenous erythroid and rarely basop hili a may be present. most prominent (1098,1329,3964,3978).
colony growth is no longer included as Occasional immature granulocytes may Using standardized prominent bone mar-
a minor diagnostic criterion, due to its be detectable, but circulating blasts are row features (3969,3973}, several groups
limited practicality {3932) ; it is time-con- generally not observed . have succeeded in identifying histo-
suming, unstandardized, restricted to Bone marrow cellularity is usually in- logical patterns that are characteristic
specialized institutions, and costly. creased (3975). Hypercellularity is espe- of WHO-defined PV, including so-called
Some cases (in particular cases in
JAK2 V617F-mutated patients with pro-
minent thrombocytosis and in itially low
haemoglobin levels and/or haematocrit)
can c linically mimic essential thrombo-
cythaemia at onset (249), despite show-
ing bone marrow histopathology char-
acteristic of PV and later increases in
the RBC parameters {1364,2152,3972).
Therefore, determination of JAK2 and
CALR mutation status alone (without mor-
pho logical examination) is not sufficient
to differentiate PV from JAK2-mutated
essential thrombocythaemia (3920).
Microscopy
In PV, the major features in the periph-
eral blood and bone marrow are attribut-
able to effective pro liferation in the eryth-
-
Fig. 2.17 Polycythaemia vera, post-polycythaemic myelofibrosis (post-PV MF) and myeloid metaplasia, splenectomy
specimen. The splenic enlargement in the post-polycythaemic phase is due mainly to extramedu llary haematopoiesis
that occurs in the splenic sinuses, as well as fibrosis and entrapment of platelets and haematopoietic cells in the
roid, granulocytic, and megakaryocytic splenic cords.
Polycythaemia vera 41
masked PV {251,1361,1364,3677.3964, with a minor increase in reticulin {3964). myelofibrosis, underscoring the value of
3972,3978,3983). Erythropoiesis is usu- Marrow sinuses are dilated and often bone marrow biopsy {1 1,253). Reactive
ally normoblastic, erythroid precursors densely filled by erythrocytes. It is usually nodular lymphoid aggregates are found
form large islets or sheets, and granu- possible to disti nguish PV from essential in as many as 20% of cases {3964,3969).
lopoiesis is morphological ly normal. thrombocythaemia, primary myelofi- In > 95% of cases, stainable iron is ab-
The proportion of myeloblasts is not in- brosis, and reactive erythrocytosis and sent in bone marrow aspirate and biopsy
creased. Megakaryocytes are increased thrombocytosis {1361,1380, 2147,2433, specimens {1 098,3978,3983).
in number (particularly in cases with an 3964,3983) on the basis of the char-
excess of platelets) and frequently dis- acteri stic histolog ical pattern of PV Spent phase and post-polycythaemic
play hypersegmented nuclei. Cases with (Table 2.04) {3969). Therefore, WHO has myelofibrosis (post-PV MF)
high platelet counts and low haemoglo- adopted bone marrow morphology as During the later phases of PV, erythro-
bin or haematocrit values may mimic es- one of the major diagnostic criteria for poiesis progressively decreases. As a re-
sential thrombocythaemia at onset {1364, PV {257,3932}. Reticu lin staining reveals sult, the RBC mass normalizes and then
2152,3972). Megakaryocytes tend to form a normal reticulin fibre network in about decreases, and the spleen further en-
loose clusters or lie close to the bone tra- 80% of cases, but the remainder may larges. Persistent leukocytosis occurring
beculae, and often show a signifi cant de- display increased reticulin and even mild at or around the time of progression to
gree of pleomorphism, resu lting in a mix- to moderate collagen fibrosis {11,253, post-PV MF has been reported to be as-
ture of sizes. Most of the megakaryocytes 496,1329,2105,3964,3983}. depending sociated with an overall more aggressive
exhibit normally folded or deeply lobed on the stage of disease at initial diag- course of disease {405). These changes
nuclei, and they usually lack significant nosis. Even a minor increase in reticulin are usually accompanied by correspond-
atypia, although a minority may show fibres (reticulin grade 1) {3975) at initial ing bone marrow alterations {407,1098,
bulbous nuclei and other nuclear abnor- presentation of PV has been associated 3511 ,3758). The most common pattern
malities, particularly when associated with a more rapid progression to post-PV of disease progression is post-PV MF
42 Myeloproliferative neoplasms
Polycythaemia vera 43
Definition Table 2.06 Diagnostic criteria for primary myelofibrosis, prefibrotic/early stage
Primary myelofibrosis (PMF) is a clon- The diagnosis of prefibrotic/early primary myelofibrosis requires that all 3 major criteria and
al myeloproliferative neoplasm (MPN) at least 1 minor criterion are met.
characterized by a proliferation of pre-
dominantly abnormal megakaryocytes Major criteria
and granulocytes in the bone marrow, 1. Megakaryocytic proliferation and atypia, without reticulin fibrosis grade > 1•, accompanied by
increased age-adjusted bone marrow cellularity, granulocytic proliferation, and (often) decreased
which in fully developed disease is asso-
erythropoiesis
ciated with reactive deposition of fibrous
2. WHO criteria for 8CR-A8L1-positive chronic myeloid leukaemia, polycythaemia vera,
connective tissue and with extramedul- essential thrombocythaemia, myelodysplastic syndromes, or other myeloid neoplasms are not met
lary haematopoiesis.
3. JAK2, CALR, or MPL mutation
There is a stepwise evolution from an
or
initial prefibrotic/early stage, character-
Presence of another clonal markerb
ized by hypercellular bone marrow with
or
absent or minimal reticulin fibrosis, to
Absence of minor reactive bone marrow reticulin fibrosis 0
an overt fibrotic stage with marked re-
ticulin or collagen fibrosis in the bone Minor criteria
marrow, and often osteosclerosis. The Presence of at least one of the following, confirmed in 2 consecutive determinations:
fibrotic stage of PMF is clinically char- - Anaemia not attributed to a comorbid condition
acterized by leukoerythroblastosis in the - Leukocytosis 2 11 x 109/L
- Palpable splenomegaly
blood (with teardrop-shaped red blood
- Lactate dehydrogenase level above the upper limit of the institutional reference range
cells), hepatomegaly, and splenomega-
ly. The diagnostic criteria for prefibrotic/ a See Table 2.09 (p.47).
early PMF (pre-PMF) are summarized in b In the absence of any of the 3 major clonal mutations, a search for other mutations associated with myeloid
Table 2.06 and those of overt (classic) neoplasms (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF381 mutations) may be of help in determin-
PMF in Table 2.07. ing the clonal nature of the disease.
c Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory
ICD-0 codes conditions, hairy cell leukaemia or another lymphoid neoplasm, metastatic malignancy, or toxic (chronic)
myelopathies.
Primary myelofibrosis 9961 /3
Primary myelofibrosis,
prefibrotic/early stage 9961/3
Primary myelofibrosis, lence of PMF is probably increasing, due fami lial predisposition to PMF {617,3418}.
overt fibrotic stage 9961/3 to earlier diagnosis (i.e. of pre-PMF) and
prolonged survival {615}. PMF affects Localization
Synonyms men and women nearly equally {3916}. The blood and bone marrow are al-
Chronic idiopathic myelofibrosis; myelofi- It occurs most commonly in the sixth to ways involved. In the later stages of the
brosis/sclerosis with myeloid metaplasia; seventh decades of life, and only about disease, extramedullary haematopoie-
agnogenic myeloid metaplasia; mega- 10% of overt PMF cases are diagnosed sis (also known as myeloid metaplasia)
karyocytic myelosclerosis; idiopathic in patients aged < 40 years {61 4}. Chi l- becomes prominent, particularly in the
myelofibrosis; myelofibrosis with myeloid dren are rarely affected {81,614}. spleen {267}, which harbours neoplastic
metaplasia; myelofibrosis as a result of stem cells {4255). In the initial stages, the
myeloproliferative disease Etiology number of randomly distributed CD34+
Exposure to benzene or ionizing radiation progenitors is slightly increased in the
Epidemiology has been documented in some cases bone marrow, but not in the peripheral
The estimated annual incidence of overt {998}. Rare fami lial cases of bone mar- blood. The frequency of bone marrow
PMF is 0. 5-1.5 cases per 100 000 popu- row fibrosis in young children have been CD34+ cells is inversely related to the
lation {2613,2764,3916,4010}. Valid data reported; how many of these constitute number of circulating CD34+ cells {2864,
on the incidence of pre-PMF are not MPNs is unknown, but at least some 3971); only in the later stages do they ap-
available, but data from reference cen- cases appear to constitute an autosomal pear in large numbers in the peripheral
tres suggest that the prefibrotic/early recessive inherited condition {3457}. In blood. This increase in the number of c ir-
stage accounts for 30- 50% of all PMF other families, with a somewhat older pa- culating CD34+ cells is a phenomenon
cases. There are few reliable estimates tient age at onset, the features have been largely restricted to overt PMF; it is not
of prevalence {2764,4010}. The preva- consistent with an MPN, suggesting a seen in non-fibrotic polycythaemia vera
44 Myeloproliferative neoplasms
'
arthritis and renal stones due to hyperuri-
caemia can also occur. Splenomegaly of
various degrees is detected in as many
Clinical - p<onounced thfOmboeylhemia - decrease in platelet oounts
as 90% of patients, and can be massive. - leukoelythroblastosis
Nearly 50% of patients have hepatomeg- presentation : :::: ~~=de~ine anemia - anemia
- no or borde~ine splenomegaly - splenomegaly
aly, depending on the stage of disease - normal or bordeltine increased LOH
tations in 8%. About 12% of cases are Fig.2.18 Primary myelofibrosis (PMF). Dynamics of the disease process, with haematological presentation and
triple-negative for mutations in JAK2, associated bone marrow fibrosis (MF) grading and relative survival rates.
CALR, and MPL {3920,3932,3933}. BM, bone marrow; LOH, lactate dehydrogenase; MMM, myelofibrosis with myeloid metaplasia.
Primary myelofibrosis 45
46 Myeloproliferative neoplasms
Primary myelofibrosis 47
~> '
~. ~
~-. .16;.l ~:,. •4 . . _/,/ '.~~~~
Fig.2.22 Primary myelofibrosis (PMF), overt fibrotic stage. A Bone marrow biopsy specimen showing hypocellularity, markedly dilated sinuses, and severe marrow fibrosis with
osteosclerosis, findings typical of advanced-stage PMF. B PMF with osteomyelosclerosis characterized by broad, irregular bone trabeculae, which can occupy as much as 50%
of the marrow space; fibrosis, cellular depletion, sinusoidal dilatation, and megakaryocytic proliferation are prominent in the intertrabecular areas.
Overt primary myelofibrosis matopoietic cells, showing mainly dense reported that interferon {744,3204} and
Most cases of PMF are initially diagnosed reticulin or collagen fibrosis, with small is- JAK1/JAK2 inhibitor {1563A,1798,1800,
in the overt fibrotic stage {264,613,3916}. lands of haematopoietic precursors situ- 1833,2543A,4316} therapy may delay or
In this stage, the bone marrow biopsy ated mostly with in the vascular sinuses. even reverse bone marrow fibrosis pro-
shows clear-cut reticulin or collagen fi- Associated with the development of my- gression across all aspects of the fibrotic
brosis (i.e. fibrosis grades 2 and 3) {2148, elofibrosis is a sig nificant proliferation of process (i.e. reticulin fibrosis, col lagen
3975), often associated with various de- vessels showing marked tortuosity and deposition, and osteosclerosis).
grees of collagen fibrosis and osteo- luminal distension, often also associated The development of monocytosis in PMF
sclerosis (see Table 2.10 and Table 2.11, with conspicuous intrasinusoidal haema- may indicate disease progression {404}
p. 47). The bone marrow may still be fo- topoiesis {438,2149,2642,2863). Osteoid In patients with a previously established
cally hypercellular, but is more often nor- seams or appositional new bone forma- diagnosis of PMF, the finding of 10-19%
mocellular or hypocellular, with patches tion in bud-like endophytic plaques may blasts in the peripheral blood and/or bone
of active haematopoiesis alternating with be observed {3965). In this osteosclerotic marrow and the detection by immunohis-
hypocellular regions of loose connective phase, the bone may form broad, irregu- tochemistry of an increased number of
tissue and/or fat. Foci of immature cells lar trabeculae that can occupy > 50% of CD34+ cells with cluster formation and/
may be more prominent, although my- the bone marrow space. or an abnormal endosteal location in the
eloblasts account for < 10% of the bone The development of overt fibrosis in PMF bone marrow {3965,3971} indicate an ac-
marrow cells {3965). Atypical mega- is related to disease progression {494, celerated phase of the disease, whereas
karyocytes are often the most conspicu- 3979,3980}, and is not significantly in- the finding of ~20% blasts is diagnostic
ous find ing; they occur in large clusters fluenced by standard cytoreductive of blast transformation. Patients with PMF
or sheets, often within dilated vascular treatment modalities (with the exception may rarely present initially in the acceler-
sinuses {494,3965). In some cases, the of allogeneic stem cell transplantation ated phase or blast phase.
bone marrow is almost devoid of hae- {2125,2864,3974)). However, it has been
48 Myeloproliferative neoplasms
Primary myelofibrosis 49
50 Myeloproliferative neoplasms
,. • I
.
_,,. _:;.e '
Fig. 2.24 Essential thrombocythaemia. A Peripheral blood smear. The major abnormality seen is marked thrombocytosis; the platelets show anisocytosis, but are often not
remarkably atypical. B Bone marrow aspirate smear showing increased number and size of the megakaryocytes. C Bone marrow aspirate smear. Note the deeply lobulated
megakaryocyte nuclei, as well as the large pools of platelets; aspirate smears fail to reveal the overall marrow architecture and distribution of the megakaryocytes, which can only
be seen on biopsy.
JAK2 and mutations of the gelsolin gene leukocytosis and erythrocytosis were normal platelet counts (adjusted for sex
(GSN) were recently reported in several unusual findings, as was an increased and race) {2265,3452,3469,3931 }. This
pedigrees of hereditary thrombocytosis serum level of lactate dehydrogenase; threshold value has also been adopted
{1677,3457). leukoerythroblastosis and poikilocytosis by the British Committee for Standards
were absent {254,3933,3977). in Haematology (BCSH) {1562). Although
Localization Previously, the platelet count threshold this lowered threshold will encompass
The bone marrow and blood are the prin- for the diagnosis of ET was :?:600 x 10 9 /L more cases of ET, it will also include
cipal sites of involvement. The spleen {2791}. However, given that some patients more cases of conditions that mimic
does not show significant extramedullary experience haemorrhagic or thrombotic ET {257,1380}; therefore, it is essential
haematopoiesis at the time of onset, but events at lower platelet counts {2265, that all diagnostic criteria for ET (see
is a sequestration site for platelets {1217, 3331,3469), several investigators have Table 2.12) are met in order to exclude oth-
1563}. convincingly argued for a lower platelet er neoplastic and non-neoplastic causes
count threshold for the diagnosis of ET, in of thrombocytosis {1380,3931 ,3932).
Clinical features order to avoid compromising the diagno- Bone marrow biopsy is particularly help-
More than half of all cases are asymp- sis in such cases. As a result, WHO has ful in excluding other myeloid neoplasms
tomatic at the time of diagnosis, dis- adopted the recommendation of a plate- associated with high platelet counts,
covered incidentally when an elevated let count threshold of :?:450 x 109 /L, a such as myelodysplastic syndromes as-
platelet count is found on a routine pe- value that exceeds the 95th percentile for sociated with isolated del(5q), myelodys-
ripheral blood count {254,1217,1378,
1563). The other half present with some
manifestation of vascular occlusion or
haemorrhage {566,1096,1215,3088,
3933}. Microvascular occlusion can lead
to transient ischaemic attacks, digital
ischaemia with paraesthesias, and gan-
grene {566,3088). Thrombosis of major
arteries and veins can also occur, and
ET can be a cause of splenic or hepatic
vein thrombosis as seen in Budd-Chiari
syndrome {1022,2012,3703). Bleed ing
occurs most commonly from mucosal
surfaces, such as in the gastrointestinal
tract and upper airway passages {1096,
1215,1378). In PVSG-defined ET, mild
splenomegaly is present in approximate-
ly 50% of cases at diagnosis and hepa-
•
..
.. . :. .:,,. .·=.... .
~~
..: i .: : ~
tomegaly in 15-20% {1563,2791,3927).
When the WHO criteria, which exclude
cases with thrombocytosis associated
f ..- •
..::.::··.
...
.
[ .
;.·•· .
with prefibrotic/early primary myelofibro- u • • .. le* ~
•• ~
- • - --
sis (pre-PMF), are used, minor palpable Fig. 2.25 Essential thrombocythaemia, bone marrow biopsy. A Normocellular bone marrow with an increased number
of large to giant megakaryocytes. BThere is no significant increase in erythropoiesis or granulopoiesis, as demonstrated
splenomegaly is seen in only 15-20% of
by naphthol AS-D chloroacetate esterase (CAE) staining: granulocytic cells are stained red by the reaction product.
ET cases {254,3917,3933,3977). In three C With periodic acid-Schiff (PAS) staining, the enlarged megakaryocytes demonstrate abundant amounts of mature
studies including almost 1500 WHO-de- cytoplasm and deeply lobulated and hyperlobulated (staghorn-like) nuclei. D The large to giant megakaryocytes may
fined cases of ET from various centres, be arranged in small, loose clusters.
Essential thrombocythaemia 51
52 Myeloproliferative neoplasms
Essential thrombocythaemia 53
Definition Table 2.14 Diagnostic criteria for chronic eosinophilic leukaemia, NOS
Chronic eosinophilic leukaemia (CEL)
1. Eosinophilia (eosinophil count~ 1.5 x 109/L)
not otherwise specified (NOS), is a mye-
loproliferative neoplasm (M PN) in which 2. WHO criteria for BCR-ABL1-positive chronic myeloid leukaemia, polycythaemia vera,
essential thrombocythaemia, primary myelofibrosis, chronic neutrophilic leukaemia, chronic
an autonomous, clonal proliferation of eo-
myelomonocytic leukaemia and BCR-ABL1-negative atypical chronic myeloid leukaemia are not met
sinoph il precursors results in persistently
3. No rearrangement of PDGFRA, PDGFRB or FGFR1, and no PCM1-JAK2,
increased numbers of eosinophils in the
ETV6-JAK2, or BCR-JAK2 fusion
peripheral blood, bone marrow, and pe-
ripheral tissues, with eosinophilia being 4. Blast cells constitute <20% of the cells in the peripheral blood and bone marrow, and inv(16)(p13.1q22),
t(16;16)(p1 3.1;q22), t(8;21)(q22;q22.1), and other diagnostic features of acute myeloid leukaemia are
the dominant haematological abnormal-
absent
ity. Organ damage occurs as a result of
5. There is a clonal cytogenetic or molecular genetic abnormality"
leukaemic infiltration or of the release of
or
cytokines, enzymes, or other proteins by Blast cells account for~ 2% of cells in the peripheral blood or~ 5% in the bone marrow
the eosinoph ils.
CEL, NOS excludes cases with a Phil-
a Because some clonal molecular genetic abnormalities (e.g. mutations in TET2, ASXL1, and DNMT3A) can
adelphia (Ph) chromosome; BCR-ABL 1 occur in a minority of elderly people in the absence of any apparent haematological abnormality, it is essential
fu sion; rearrangement of POGFRA , to exclude all possible causes of reactive eosinophilia before making this diagnosis solely on the basis of a
PDGFRB, or FGFR1; or PCM1-JAK2, molecular genetic abnormality in an elderly person.
ETV6-JAK2, or BCR-JAK2 fu sion .
In CEL, NOS the eosinophil count is
~ 1.5 x 109/L in the blood, and there are Table 2.15 Diagnostic criteria for myeloproliferative neoplasm (MPN), unclassifiable.
< 20% blasts in the peripheral blood and
The diagnosis of myeloproliferative neoplasm (MPN), unclassifiable, requires that either all 3 criteria are met.
bone marrow. For a diagnosis of CEL,
NOS to be made, there shou ld be evi- 1. Features of an MPN are present
dence for clonality of myeloid cells or an 2. WHO criteria for any other MPN, myelodysplastic syndrome", myelodysplastic/
increase in myeloblasts in the peripheral myeloproliferative" neoplasm, or BCR-ABL1-positive chronic myeloid leukaemia are not met
blood or bone marrow. However, in many
3. JAK2, CALR, or MPL mutation characteristically associated with MPN
cases it is impossible to prove clonal-
or
ity; in such cases, providing there is no
Presence of another clonal markerb
increase in blast cells, the diagnosis of
or
idiopathic hypereosinophilic syndrome Absence of a cause of reactive fibrosisc
(HES) is made. It is clinical ly important
to clearly distinguish between CEL, NOS
a Effects of any previous treatment, severe comorbidity, and changes during the natural progression of the
and idiopathic HES. Idiopathic HES is disease process must be excluded.
defined as eosinophilia (eosinophil count b In the absence of any of the 3 major clonal mutations, a search for other mutations associated with
~ 1.5 x 109/L) persisting for ~ 6 months myeloid neoplasms (e.g. ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF381 mutations) may be of help
for which no underlying cause can be in confirming the clonal nature of a suspected MPN, unclassifiable.
found, associated with signs of organ c Bone marrow fibrosis secondary to infection, autoimmune disorder or another chronic inflammatory condition,
involvement and dysfunction (759,4291}; hairy cell leukaemia or another lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathy.
there is no evidence of eosinophil clon-
ality. It is a diagnosis of exclusion, and
may include some cases of true eosino- 2.1 4, diagnosis of CEL, NOS requires common in men, with a reported median
philic leukaemia that cannot currently be integration of clinical, laboratory, and mo- age of occurrence in the seventh decade
recogn ized, as well as cases of cytokine- lecular features. of life (42498,1606). The epidemiologi-
driven eosinophilia due to the abnormal cal features of idiopathic cases of HES
release of eosinophil growth factors (e.g. ICD-0 code 9964/3 remain undefined.
IL2, IL3, and IL5) for unknown reasons
(226,759,3581,3759,4291}. If there is a Epidemiology Localization
similar unexplained hypereosinophilia Due to the previous difficulty in distin- CEL, NOS is a multisystemic disorder.
but with no evidence of tissue damage, guishing CEL from idiopathic HES, the The peripheral blood and bone marrow
the designation 'idiopath ic hypereosino- true incidence of these rare diseases is are always involved. Tissue infiltration by
philia' is appropriate. As outlined in Table unknown. CEL, NOS appears to be more eosinophils and the release of cytokines
54 Myeloproliferative neoplasms
with a history of persistent eosinophilia. Immature and mature eosinophils are present.
....
Fig. 2.29 Idiopathic hypereosinophilic syndrome. Blood smear from a patient with
cardiac failure, leukocytosis, and hypereosinophilia.
The cytogenetic analysis showed trisomy 10.
and humoral factors from the eosinophil tion, and rheumatological findings are {4249B}. Neutrophilia often accompanies
granules lead to tissue damage in a num- frequent manifestations {1606). the eosinophilia, and some cases show
ber of organs; the heart, lungs, central mild monocytosis, but do not meet all
nervous system (CNS), skin, and gastro- Microscopy the criteria for chronic myelomonocytic
intestinal tract are commonly involved. In CEL, NOS the most striking feature leukaemia. Mild basophilia has been re-
Splenic and hepatic involvement is also in the peripheral blood is eosinophi lia, ported. Blast cells may be present but
common {1606). mainly of mature eosinophils, with only account for < 20% of the cells.
small numbers of eosinophilic myelo- The bone marrow is hypercellular, due
Clinical features cytes and promyelocytes {2127). There in part to eosinophilic proliferation {481,
Eosinophilia is sometimes detected in- may be a range of eosinophil abnormali- 1606,2127). In most cases, eosinophil
cidentally in patients who are otherwise ties, including sparse granulation (with maturation is orderly (i.e. without a dis-
asymptomatic. In other cases, patients clear areas of cytoplasm), cytoplasm ic proportionate increase in myeloblasts).
experience constitutional symptoms vacuolation, nuclear hypersegmentation Charcot- Leyden crystals are often pres-
such as weight loss, night sweats, fever, or hyposegmentation, and increased ent. Erythropoiesis and megakaryocy-
fatigue, cough, angio-oedema, muscle size. Because these changes can be topoiesis are usually normal. Increased
pain, pruritus, and diarrhoea. The most seen in both reactive and neoplastic proportions of myeloblasts (::::2% in pe-
serious clinical findings relate to endomy- eosinophilia, they are not very helpful in ripheral blood or 5- 19% in bone marrow)
ocardial fibrosis, with ensuing restrictive determining whether a case is likely to support the diagnosis of CEL, NOS, as
cardiomegaly. Scarring of the mitral and be CEL, NOS {226). Occasional patients do dysplastic features in other cell line-
tricuspid valves leads to valvular regur- with CEL, NOS have cytologically normal ages {4249B}. Marrow fibrosis is seen in
gitation and the formation of intracardiac eosinophils, but the absence of eosino- about one third of cases, although severe
thrombi, which can embolize to the brain phil dysplasia generally favours reactive fibrosis is rare {481,4249B}.
or elsewhere. Cardiac failure can occur. eosinophilia {4249B}. Significant dys- Any tissue can show eosinophilic infiltra-
Peripheral neuropathy, CNS dysfunction, plasia in cells of other myeloid lineages tion, and Charcot-Leyden crystals are of-
pulmonary symptoms due to lung infiltra- supports the diagnosis of CEL, NOS ten present. Fibrosis is common, caused
56 Myeloproliferative neoplasms
Definition 3. Cases with convincing evidence of an lar to those of other MPNs. In early un-
The designation of myeloproliferative neo- MPN in which a coexisting neoplastic or classifiable disease, organomegaly may
plasm, unclassifiable (MPN-U) should be inflammatory disorder obscures some of be minimal or absent, but splenomegaly
applied only to cases that have definite the usual diagnostic clinical and/or mor- and hepatomegaly can be massive in
clinical, laboratory, molecular, and mor- pholog ical features {2147). advanced cases in which bone marrow
phological features of a myeloproliferative specimens are characterized by marked
neoplasm (MPN) but fail to meet the diag- ICD-0 code 9975/3 myelofibrosis and/or increased numbers
nostic criteria for any of the specific MPN of blasts {3978,3983). The haematologi-
entities, or that present with features that Epidemiology cal values are also variable, rangin g from
overlap between two or more of the MPN The exact incidence of MPN-U is un- mild leukocytosis to moderate or marked
categories (Table 2.15, p. 54). Most cases known, but some reports indicate that thrombocytosis, with or without accom-
of MPN-U fall into one of three groups: unclassifiable cases account for as many panying anaemia. Prominent cytope-
1. A subset of cases with so-called as 10-1 5% of all MPNs {3983). The rela- nia or myelodysplastic features should
masked I pre-polycythaem ic presentation tive frequency varies significantly ac- always prompt the definitive exclusion
of polycythaemia vera, prefibrotic/early cording to the experience of the diag- of MDS/MPN and myelodysplastic syn-
primary myelofibrosis, or early-phase nostician and the specific classification drome (MOS) {257,2147). Discrepancies
essential thrombocythaemia in which the system and criteria used {1361,1361A, between morphological and clinical fea-
characteristic features are not yet fully 1362,1363,2151,2348A,3978}. Careful tures are particularly common in cases
developed {1380,2147,2152} - a propor- evaluation of clinical, morphological, and presenting with otherwise unexplained
tion of cases presenting with portal or molecular features reduces the frequen- portal or splanchnic vein thrombosis
splanchnic vein thrombosis that fail to cy of unclassifiable cases to < 5% {257, {1103,1362).
meet the diagnostic criteria for any of the 1086,1361A,1799A,2147,2433}.
specific MPN entities may also be con- Exclusionary criteria
sidered to belong in this group {1103, Localization The presence of BCR-ABL 1 fusion; re-
1362); The blood and bone marrow are the ma- arrangement of PDGFRA, POGFRB, or
2. Advanced-stage MPN, in which pro- jor sites of involvement, but in advanced FGFR1; or PCM1-JAK2 fusion excludes
nounced myelofibrosis, osteosclerosis, stages the spleen and liver (i.e. the major the diagnosis of MPN-U. This diagnosis is
or transformation to a more aggressive sites of extramedullary haematopoiesis) also inappropri ate if clinical data sufficient
stage with increased blast counts and/or may be also affected. for proper classification are not available,
myelodysplastic changes obscures the if the bone marrow specimen is of inad-
underlying disorder {404,405,2151,3968, Clinical features equate quality or size for accurate evalua-
3978,3983}; or The clinical features of MPN-U are simi- tion {2147,2151,2152,3978,3983}, or if the
58 Myeloproliferative neoplasms
Mastocytosis
Cutaneous mastocytosis
Systemic mastocytosis
Mast cell sarcoma
62 Mastocytosis
Fig. 3.01 Cutaneous mastocytosis. A Numerous typical macular and maculopapular pigmented lesions of urticaria pigmentosa in a young child. B The skin lesions of all forms of
cutaneous mastocytosis may urticate when stroked (Darier's sign). A palpable wheal appears a few moments after the physical stimulation, due to the release of histamine from the
mast cells. CThickened, reddish, peau chagrine lesions characteristic of diffuse cutaneous mastocytosis, which occur almost exclusively in children.
Mastocytosis 63
C findings
1. Bone marrow dysfunction caused by neoplastic mast cell infiltration,
manifested by~ 1 cytopenia: absolute neutrophil count < 1.0 x 109/L, haemoglobin level < 10 g/dL,
and/or platelet count< 100 x 109/L
2. Palpable hepatomegaly with impairment of liver function, ascites and/or portal hypertension
3. Skeletal involvement, with large osteolytic lesions with or without pathological fractures (pathological
fractures caused by osteoporosis do not qualify as a C finding)
4. Palpable splenomegaly with hypersplenism
5. Malabsorption with weight loss due to gastrointestinal mast cell infiltrates
Fig. 3.05 Systemic mastocytosis. Skeletal lesions are
common in systemic mastocytosis. This X-ray shows
patchy osteosclerosis, osteoporosis and multiple lytic
lesions in the femur.
66 Mastocytosis
Bone marrow mastocytosis Smouldering systemic mastocytosis can occur. Skin lesions are found in most
In the bone marrow mastocytosis sub- In smouldering systemic mastocytosis, patients and the KIT D816V mutation is
type of indolent systemic mastocytosis, the mast cell burden is high, organo- almost invariably present; unlike in typi-
the burden of neoplastic mast cells is megaly is often found, and multilineage cal indolent systemic mastocytosis, the
usually low, and serum tryptase levels involvement is typically present. Although mutation is usually detectable in several
are often normal or nearly normal. the clinical course is often stable for many myeloid lineages and sometimes even
years, progression to aggressive system- in lymphocytes, reflecting multilineage
ic mastocytosis or mast cell leukaemia involvement by the neoplastic process
Systemic mastocytosis 67
68 Mastocytosis
Myeloid/lymphoid neoplasms
with eosinophilia and gene rearrangement
Myeloid/lymphoid neoplasms with
PDGFRA rearrangement
Myeloid/lymphoid neoplasms with
PDGFRB rearrangement
Myeloid/lymphoid neoplasms with
FGFR1 rearrangement
Myeloid/lymphoid neoplasms with PCM1-JAK2
PCM1-JAK2
l
These disorders can present as chronic trephine biopsy and CEL
likely
investigation for
myeloproliferative neoplasms (MPNs), FIP1L1·PDGFRA
8 ;
l ,c=J
related disorders usually present as
chronic eosinophilic leukaemia with ~
prominent involvement of the mast cell
lineage and sometimes the neutrophil
lineage. Less often, they present as
acute myeloid leukaemia or T-lympho- - Investigate
- -- --
for reactive
eosinophilia (including
blastic leukaemia/lymphoma, with ac- T-ce ll subsets) (if not
... Idiopathic HES
Cytochemistry
Cytochemical stains are not neces-
Serum vitamin 812 is markedly elevated Microscopy sary for diagnosis. The reduced granule
{4147}. FIP1L1-PDGFRA-associated CEL The most striking feature in the periph- content of the eosinophils can result in
is very responsive to imatinib; the FIP1 L1- eral blood is eosinophilia. Most of the reduced peroxidase content and inaccu-
PDGFRA fusion protein is 100 times as eosinophils are mature, with only small rate automated eosinophil counts.
sensitive as BCR-ABL1 {798}. numbers of eosinophil myelocytes or
Cytochemistry
The eosinophils, neutroph ils and mono-
cytes show the cytochemical reactions
expected for cells of these lineages.
lmmunophenotype
lmmunophenotypic analysis of the mast
cells has shown expression of CD2 and
CD25, which is also found in most cases
of mast cel l disease !4236}.
Cell of origin
The postulated cell of orig in is a pluri-
potent haematopoietic stem cell that
can give rise to neutrophils, mono-
cytes, eosinophils, probably mast cells
and (in some patients) B-cell lineage
lymphoblasts.
Genetic profile
Fig. 4.04 Myeloid neoplasm with eosinophilia and rearrangement of PDGFRB. A Bone marrow trephine biopsy Cytogenetic analysis usually shows
section from a patient with t(5;12) shows a marked increase in eosinophils. B Peripheral blood smear from a patient t(5;12)(q32;p13.2), with the translocation
with t(5;12) shows numerous abnormal eosinophils, at lower (B) and higher (C) magnification. Eosinophils accounted resulting in ETV6-PDGFRB gene fusion
for 40% of the leukocytes. {1398} (previously called TEL-PDGFRB).
In one patient, ETV6-PDGFRB fusion
is not indicated when no 5q31 -33 break- cases. Tissue infiltration by eosinophils resulted from a four-way translocation:
point is found by conventional cytoge- and the release of cytokines, humoral t(1 ;12;5;12)(p36;p13.2;q32;q24) {835);
netic analysis, because almost all cases factors or granule contents by eosino- in another, the fusion occurred in asso-
reported to date in which 20 metaphases ph ils can contribute to tissue damage in ciation with ins(2;12)(p21;q13;q22) {883}.
were available for examination have had several organs. The 5q breakpoint is sometimes as-
a cytogenetically detectable abnormality. signed to 5q31 and sometimes to 5q33,
Clinical features although the gene map locus of PDGFRB
ICD-0 code 9966/3 Most patients have splenomegaly and is 5q32.
some have hepatomegaly. Some patients Not all translocations characterized
Synonyms have skin infiltration and some have car- as t(5;12)(q31-33;p12) lead to ETV6-
Chronic myelomonocytic leukaemia with diac damage lead ing to cardiac failure. PDGFRB fusion. Cases without a fusion
eosinophilia associated with t(5;12); mye- Serum tryptase may be mildly or moder- gene are not assigned to this category
loid neoplasms with PDGFRB rearrange- ately elevated. The vast majority of pa- of MPN and, importantly, are not likely
ment; myeloid neoplasms associated tients who have been treated with imatin- to respond to imatinib; in such cases,
with PDGFRB rearrangement ib have been found to be responsive. an alternative leukaemogen ic mecha-
nism is upregulation of interleukin 3
Epidemiology Microscopy (IL3) {799} Therefore, RT-PCR using
This neoplasm is considerably more The white blood cell count is increased. primers su itable for all known break-
common in men than in women (male-to- There may be anaemia and thrombocy- points is recommended for confirma-
female ratio: 2:1) and occurs over a wide topenia. There is a variable increase in tion of ETV6-PDGFRB {850}, but if mo-
age range (8- 72 years), with peak inci- neutrophils, eosinophils, monocytes and lecular analysis is not avai lable, a trial
dence in middle-aged adults and a me- eosinophil and neutrophil precursors. of imatinib is justified in patients with an
dian age of onset in the late 40s {3776). Rarely, there is a marked increase in ba- MPN associated with t(5;1 2). Due to the
sophils {4236). large number of potential partner genes,
Localization The bone marrow is hypercellular as a re- molecular analysis to demonstrate variant
MPN associated with t(5;12)(q32;p13.2) sult of active granulopoiesis (neutrophi lic fusion genes is only feasible after a trans-
is a multisystem disorder. The periph- and eosinophilic). Bone marrow treph ine location has been shown by cytogenetic
eral blood and bone marrow are always biopsy may show an increase in mast analysis. If subsequent monitoring of
involved. The spleen is enlarged in most cells, which may be spindle-shaped treatment response is planned, the fusion
Myelodysplastic/myeloproliferative neoplasms
Chronic myelomonocytic leukaemia
Atypical chronic myeloid leukaemia,
BCR-ABL 1-negative
Juvenile myelomonocytic leukaemia
Myelodysplastic/ myeloproliferative neoplasm with
ring sideroblasts and thrombocytosis
Myelodysplastic/ myeloproliferative neoplasm,
unclassifiable
Synonyms • Myeloproliferative neoplasms (MPN) can be associated with monocytosis or it can develop during the course
of the disease; such cases can mimic CMML. In these rare instances, a documented history of MPN excludes
Chronic myelomonocytic leukaemia, type I;
CMML, whereas the presence of MPN features in the bone marrow and/or MPN-associated mutations (in
chronic myelomonocytic leukaemia, type JAK2, CALR or MPL) tends to support MPN with monocytosis rather than CMML.
II; ch ronic myelomonocytic leukaemia in b Blasts and blast equivalents include myeloblasts, monoblasts and promonocytes. Promonocytes are monocytic
transformation (obsolete); chronic myelo- precursors with abundant light-grey or slightly basophilic cytoplasm with a few scattered fine lilac-coloured
monocytic leukaemia, NOS granules, finely distributed stippled nuclear chromatin, variably prominent nucleoli and delicate nuclear folding
or creasing. Abnormal monocytes, which can be present in both the peripheral blood and the bone marrow,
Epidemiology are excluded from the blast count (see Introduction and overview of the classification of myeloid neoplasms,
Fig. 1.04, p.18).
There are few reliable incidence data for
c In the appropriate clinical context, mutations in genes often associated with CMML (e.g. TET2, SRSF2,
CMML; in some epidemiological surveys , ASXL1 and SETBP1) support the diagnosis. However, some of these mutations can be age-related or present
CMML has been grouped with chronic in other neoplasms; therefore, these genetic findings must be interpreted with caution.
myeloid leukaemias and in others it has
82 Myelodysplastic/myeloproliferative neoplasms
Microscopy
Peripheral blood monocytosis is the
hallmark of CMML. By definition, the
monocyte count is always 2 1 x 109 / L;
it is usually 2-5 x 109 /L, but can ex-
ceed 80 x 10 9/L {2517,2653). Mono-
cytes shou ld account for 2 10% of the
leukocytes {339). In general, the mono-
cytes are mature and have unremark-
able morphology, but they can exhibit
unusual nuclear segmentation or c hro-
matin patterns and abnormal granulation
{2092). Those with abnormal granulation
are best termed abnormal monocytes,
a designation used to describe mono-
cytes that are immature but have denser
chromatin, more nuclear convolutions
and folds, and more abundant grey-
ish cytoplasm than do promonocytes
and monoblasts (see Introduction and
overview of the classification of myeloid
neoplasms, Fig. 1.04, p. 18). Blasts and
promonocytes may also be seen, but if
they account for 220% of the leukocytes,
the diagnosis is acute myeloid leukaemia may have complications related to the biopsy or on marrow aspirate smears.
(AML; acute myelomonocytic leukaemia degranulation of the eosinophils. These Cytochemical and immunohistochemi-
or acute monocytic leukaemia) rather hypereosinoph ilic cases of CMML can cal studies that facilitate the identifica-
than CMM L. Other changes in the blood closely resemble cases of myeloid neo- tion of monocytes and their precursors
are variable. The WBC count may be plasms with eosinophilia associated with are strongly recommended when the
normal or slightly decreased with neu- specific genetic abnormalities, which diagnosis of CMML is suspected {2985,
tropenia, but in half or more of all cases are classified and discussed separately 2987). Dysgranulopoiesis, similar to
it is increased due to both monocytosis from CMML (see Mye/oid/lymphoid neo- that in the blood, is present in the bone
and neutrophilia {1 334,2517,2978). Neu- plasms with PDGFRB rearrangement, marrow of most patients with CMML.
trophil precursors (promyelocytes and p. 75). Mild anaemia, often normocytic Dyserythropoiesis (e.g. megaloblastoid
myelocytes) usually account for< 10% of but sometimes macrocytic, is common. changes, other abnormal nuclear fea-
the leukocytes {339}. Dysgranulopoiesis, Platelet counts vary, but moderate throm- tures and ring sideroblasts) may also be
including the formation of neutrophils with bocytopenia is often present. Atypical, observed, but is usually mild {1334,2517,
hyposegmented or abnormally segment- large platelets and nucleated red blood 2653). Micromegakaryocytes and/or
ed nuclei or abnormal cytoplasmic gran- cell precursors may be seen {1338, 2517). megakaryocytes with hyposegmented
ulation, is present in most cases, but may The bone marrow is hypercellular in nuclei are found in as many as 80% of
be less prominent in patients with leuko- > 75% of cases, but normocellular speci- cases {1338,2517, 2653).
cytosis than in those with a normal or low mens are also seen {2653,2985,3805). Unlike in chronic myeloid leukaemia,
WBC count {2092,2517). In some cases, Hypocellularity is very rare. One recent pseudo-Gaucher cells are usually ab-
it may be difficult to distinguish between study on the histological assessment of sent. A mild to moderate increase in the
hypogranu lar neutrophils and dysplastic marrow found that < 5% of CMML cases number of reticulin fibres is seen in the
monocytes. Mild basophi lia is sometimes were hypocellular and 84% were hyper- bone marrow in nearly 30% of cases
present. Eosinophils are usually normal or cellular {3554). {2538). Careful attention to morphologi-
slightly increased in number, but in some Granulocytic proliferation is often the cal features and other disease-specific
cases eosinophilia is striking . CMML with most striking fin ding in the bone marrow, clinicopatholog ical findings may be
eosinophilia can be diagnosed when the but an increase in erythroid precursors needed to distinguish CMML from MPN
criteria for CMML are met and the eo- may also be seen {339,2653). Mono- associated with monocytosis {404,1 097).
sinophi l count in the peripheral blood is cytic proliferation is invariably present, The presence of one of the characteristic
~ 1 .5 x 10 9 /L. Patients with this diagnosis but can be difficult to recognize in the MPN driver mutations (in JAK2, CALR or
~
Fig. 5.05 Chronic myelomonocytic leukaemia. A Some degree of fibrosis may be seen in as many as 30% of cases; this bone marrow biopsy specimen shows streaming of cells
suggestive of underlying reticulin fibrosis, the presence of which was confirmed by reticulin silver staining (B).
86 Myelodysplastic/myeloproliferative neoplasms
Definition Table 5.02 Diagnostic criteria for atypical chronic myeloid leukaemia, BCR-ABL1-negative (aCML)
Atypical chronic myeloid leukaemia,
- Peripheral blood leukocytosis ~ 13 x 109/L, due to increased numbers of neutrophils and their precursors
BCR-ABL1-negative (aCML) is a leukae-
(i.e. promyelocytes, myelocytes and metamyelocytes), with neutrophil precursors constituting
mic disorder with myelodysplastic as well ~ 10% of the leukocytes
as myeloproliferative features present at
- Dysgranulopoiesis, which may include abnormal chromatin clumping
the time of initial diagnosis (Table 5.02). It
- No or minimal absolute basophilia; basophils constitute <2% of the peripheral blood leukocytes
is characterized by principal involvement
- No or minimal absolute monocytosis; monocytes constitute< 10% of the peripheral blood leukocytes
of the neutrophil lineage, with leukocyto-
- Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia,
sis resulting from an increase of morpho- with or without dysplasia in the erythroid and megakaryocytic lineages
log ically dysplastic neutrophils and their - < 20% blasts in the blood and bone marrow
precursors. However, multilineage dys- - No evidence of PDGFRA, PDGFRB or FGFR1 rearrangement, or of PCM1-JAK2
plasia is common, and reflects the stem- - WHO criteria for 8CR-A8L1-positive chronic myeloid leukaemia, primary myelofibrosis, polycythaemia vera,
cell origin of this entity. The neoplastic or essential thrombocythaemia2 are not met
cells do not have BCR-ABL 1 fusion;
rearrangement of PDGFRA, PDGFRB or a Myeloproliferative neoplasms (MPNs), in particular those in accelerated phase and /or in post-polycythaemia
FGFR1, or PCM1-JAK2 Therapy-related vera or post-essential thrombocythaemia myelofibrosis, if neutrophilic, may simulate aCML. A history of
cases with features of aCM L are dis- MPN, the presence of MPN features in the bone marrow, and/or MPN-associated mutations (in JAK2, CALR
or MPL) tend to exclude the diagnosis of aCML; conversely, the diagnosis is supported by the presence of
cussed separately (see Therapy-related
SETBP1 and /or ETNK1 mutations. CSF3R mutation is uncommon and, if detected, should prompt careful
myeloid neoplasms, p. 153). morphological review to exclude an alternative diagnosis of chronic neutrophilic leukaemia or another
myeloid neoplasm.
ICD-0 code 9876/3
Synonyms been reported in teenagers {447,1621, times to thrombocytopenia; for other pa-
Atypical chron ic myeloid leukaemia, Phil- 2143, 2517,4248). The reported male-to- tients, the primary symptoms are related
adelphia ch romosome-negative (Ph1-); female ratio varies, but in larger series it to splenomegaly {447,1621, 2143,2517).
atypical chronic myeloid leukaemia, is approximately 1:1 {447,1621,2143,2517,
BCR!ABL 1-negative 4248). Microscopy
The white blood cell count is always
Epidemiology Localization ~ 13 x 10 9/ L (339), but median values
The exact incidence of aCML is unknown, The peripheral blood and bone marrow of 24-96 x 109/L have been reported,
but it is estimated that there are only are always involved; splen ic and hepatic and some patients have white blood cell
1-2 aCML cases for every 100 cases of involvement is also common. counts of >300 x 109/ L {447,1621,2143,
BCR-ABL1-positive chronic myeloid leu- 2517,4248). Blasts are usually < 5% and
kaemia {2987,4248). Patients with aCM L always < 20% of peripheral blood leuko-
tend to be elderly. In the few series re- Clinical features cytes. Neutrophil precursors (promye-
ported to date, the median patient age at There are only a few reports of the clinical locytes, myelocytes, and metamyelo-
diagnosis is in the seventh or eighth dec- features of aCML. Patients usually have cytes) co nst i tute ~ 10% of the leukocytes.
ade of life, although the disease has also symptoms related to anaemia or some- The absolute monocyte count may be
Cytochemistry
No specific cytochemical abnormalities
have been reported to date, although
the use of esterase stains or immuno-
histochemistry to exclude a significant
monocytic component can faci litate the
exclusion of chronic myelomonocytic leu-
kaemia. Neutrophil alkaline phosphatase
scoring is rarely done; the scores can be
low, normal, or high, and are therefore not
useful for distinguishing this entity from
BCR-ABU-positive chronic myeloid leu-
kaemia {2143,2517).
lmmunophenotype
No specific immunophenotypic charac-
teristics have been reported to date. Like
esterase cytochemistry, immunohisto-
chemistry for CD14 or CD68R on biopsy
sections may facilitate the identification
of monocytes; the finding of sign ificant
a •
Fig. 5.08 Atypical chronic myeloid leukaemia, BCR-ABL I-negative. A The bone marrow biopsy shows hyper- marrow monocytosis should call into
cellularity, due to granulocytic proliferation. B Note the increased number of megakaryocytes, with small, abnormal question a diagnosis of aCML. In some
forms. From the biopsy alone, the morphology would be difficult to differentiate from that of BCR-ABL1- positive cases with decreased megakaryocytes,
chronic myeloid leukaemia. C Dysplasia in the granulocytic and megakaryocytic lineages is evident on the bone CD61 or CD42b immunohistochemistry
marrow aspirate smear.
may facilitate the identification of dys-
increased, but the percentage of periph- cursors. The myeloid-to-erythroid ratio is megakaryopoiesis. CD34 can facilitate
eral blood monocytes is < 10%. Basophil- usually > 10:1, reflecting the increased the identification of blasts.
ia may be observed but is not prominent granulopoiesis and the decreased eryth-
{339,447,1621,2517,4248). One of the ropoiesis, but in some cases erythroid Cell of origin
major features that characterize aCML precursors account for > 30% of the mar- A bone marrow haematopoietic stem cell
is dysgranulopoiesis, which may be pro- row cel ls. Dyserythropoiesis is present
nounced. Acquired Pelger-Huet anom- in about 40% of cases {339,447,4248) Genetic profile
aly or other nuclear abnormalities, such Dysgranulopoiesis is invariably present, Karyotypic abnormalities are reported
as hypersegmentation with abnormally and the changes in the neutrophil lineage in as many as 80% of cases. The most
clumped nuclear chromatin or bizarrely observed in the bone marrow are similar common abnormalities are gain of chro-
segmented nuclei, abnormal cytoplas- to those in the blood. Megakaryopoie- mosome 8 and del(20q), but abnormali-
mic granularity (usually hypogranularity) sis is usually quantitatively normal or in- ties of chromosomes 13, 14, 17, 19 and 12
and multiple nuclear projections, may creased, but is sometimes decreased; are also common {447,1621,2517). Rare-
be observed in the neutrophils. Mod- there is often evidence of dysmegakary- ly, cases is which the neoplastic cells
erate anaemia is common, and the red opoiesis, including micromegakaryo- have an isolated isochromosome 17q
blood cells may show changes indica- cytes and small megakaryocytes with have featu res of aCML, although most
tive of dyserythropoiesis. The platelet hypolobated nuclei {447,1621). Blasts fulfil the criteria for chronic myelomono-
count is variable, but thrombocytopenia may be moderately increased in number, cytic leukaemia {2594). There is no BCR-
is common {339,1621,2517). Careful mor- but are always < 20%; large sheets or ABL1 fusion. Cases with rearrangement
pholog ical examination of the peripheral clusters of blasts are not present. Mar- of POGFRA, PDGFRB or FGFR1, or with
blood is crucial for distinguishing this en- row fibrosis (usually mild) is seen in some PCM1-JAK2, are also specifically ex-
tity from chronic neutrophilic leukaemia cases at the time of diag nosis; in others, it cluded. In the past, some cases of t(8;9)
{4248}, which lacks dysplastic features in appears later in the course of the disease. (p22;p24) with PCM1-JAK2 fusion were
the neutrophils and has< 10% circulating diagnosed as aCML {436,3337}, but
immature myeloid cells. There are also Variant such cases are now grouped with other
differences in the frequency of associ- Most cases reported as the syndrome of eosinophilic neoplasms associated with
ated mutations (see Genetic profile). abnormal chromatin clumping can in fact specific chromosomal rearrangements,
The bone marrow is hypercellular due to be considered a variant of aCML {460, and are discussed separately (see Mye-
an increase of neutrophils and their pre- 1178,1766). These cases are character- loid/lymphoid neoplasms with PCM1 -
88 Myelodysplastic/myeloproliferative neoplasms
Definition as girls. Approximately 15% of cases twins {3093}. The association between
Juvenile myelomonocytic leukaemia occur in infants with Noonan syndrome- NF1 and JMML has long been estab-
(JMML) is a clonal haematopoietic dis- like disorder (which is caused by a CBL lished {581,2872,3804). In ch ildren with
order of childhood characterized by a mutation) {2381 }, and 10% occur in ch il- NF1 (un like in adults with the disorder),
proliferation principally of the granulo- dren with neurofibromatosis type 1 (NF1) the risk of developing myeloid malig-
cytic and monocytic lineages. Blasts {2872}. nancy (main ly JMM L) is reported to be
and promonocytes account for < 20% 200-500 times that in the general pae-
of the white blood cells in the peripheral Etiology diatric popu lation {2872). Occasionally,
blood and bone marrow. Erythroid and The cause of JMML is unknown. Rare infants with Noonan syndrome develop
megakaryocytic abnormalities are often cases have been reported in identical a JMML-like disorder, which resolves
present {88,507,2662}. BCR-ABL1 fusion
is absent, whereas mutations involving Table 5.03 Diagnostic criteria for juvenile myelomonocytic leukaemia; modified from Locatelli F and Niemeyer CM {2377}
genes of the RAS pathway are character-
Clinical and haematological criteria (all 4 criteria are required)
istic. The diagnostic criteria are listed in
- Peripheral blood monocyte count :z: 1 x 109/L
Table 5.03. - Blast percentage in peripheral blood and bone marrow of< 20%
- Splenomegaly
ICD-0 code 9946/3 - No Philadelphia (Ph) chromosome or BCR-ABL1 fusion
Genetic criteria (any 1 criterion is sufficient)
Synonym - Somatic mutation• in PTPN11, KRAS or NRAS
Juvenile chronic myelomonocytic - Clinical diagnosis of neurofibromatosis type 1 or NF1 mutation
leukaemia - Germline CBL mutation and loss of heterozygosity of CBL b
Other criteria
Epidemiology Cases that do not meet any of the genetic criteria above must meet the following criteria
The annual incidence of JMML is estima- in addition to the clinical and haematological criteria above:
ted to be approximately 0.13 cases per - Monosomy 7 or any other chromosomal abnormality
100 000 ch ildren aged 0-14 years. It or
accounts for < 2-3% of all leukaemias - :z: 2 of the following:
in chi ldren, but for 20-30% of all cases - Increased haemoglobin F for age
of myelodysplastic and myeloprolifera- - Myeloid or erythroid precursors on peripheral blood smear
tive diseases in patients aged < 14 years - Granulocyte-macrophage colony-stimulating factor (also called CSF2) hypersensitivity in colony assay
- Hyperphosphorylation of STATS
{1585,3092). Patient age at diagnosis
ranges from 1 month to early adoles-
a If a mutation is found in PTPN11, KRAS or NRAS it is essential to consider that it might be a germline
cence, but 75% of cases occur in chil- mutation and the diagnosis of transient abnormal myelopoiesis of Noonan syndrome must be considered.
dren aged <3 years {2415,2872). Boys b Occasional cases have heterozygous splice-site mutations.
are affected nearly twice as frequently
Localization
The peripheral blood and bone marrow
always show evidence of myelomono-
cytic proliferation. Leukaemic infiltration Fig. 5.09 Juvenile myelomonocytic leukaemia. A The bone marrow aspirate smear usually reflects the changes
of the liver and spleen is found in virtually noted in the blood, but the monocyte component may be difficult to distinguish from other marrow cells in Wright-
all cases. The lymph nodes, skin, respira- Giemsa-stained preparations. B Combined alpha-naphthyl butyrate esterase and naphthol AS-D chloroacetate
tory system, and gut are other common esterase (CAE) reaction identifies the granulocytic (blue) and monocytic (brown) components; a few cells contain
sites of involvement, although any tissue both blue and brown reaction products.
can be infiltrated {2415,2872).
normal karyotype {2872). Other features cytosis consists mainly of neutrophils,
Clinical features include polyclonal hypergammaglob- with some immature cells (e.g. promye-
Most patients present with constitutional ulinaemia and the presence of autoan- locytes and myelocytes) and monocytes.
symptoms or evidence of infection {241 5, tibodies {2872). In vitro hypersensitivity Blasts (including promonocytes) usu-
2872). There is generally marked hepato- of JMML myeloid progenitors to granu- ally account for < 5% of the white blood
splenomegaly. Occasionally, spleen size locyte-macrophage colony-stimulating cells, and always < 20%. Eosinophilia
is normal at diagnosis but rapidly increas- factor (also called CSF2) {1100) is a and basophilia are observed in a minor-
es thereafter. About half of all patients hallmark of the disease, and served as ity of cases. Nucleated red blood cells
have lymphadenopathy, and leukaemic an important diagnostic tool before the are often seen. Red blood cell changes
infiltrates may give rise to markedly en- discovery of the five canonical RAS path- include macrocytosis (particularly in pa-
larged tonsils. Dry cough, tachypnoea way mutations (in PTPN11 , NRAS, KRAS, tients with monosomy 7), but normocytic
and interstitial infiltrates on chest X-ray NF1 and CBL), which now allow molecu- red blood cells are more common; micro-
are signs of pulmonary infi ltration. Gut lar diagnosis in approximately 85% of cytosis due to iron deficiency or acquired
infiltration may predispose patients to all JMML cases, greatly facilitating the thalassaemia phenotype {1680} may be
diarrh oea and gastrointestinal infections. diagnosis. In RAS pathway mutation- seen as well. Platelet counts vary, but
Signs of bleeding are common, and negative cases, disorders with a clinical thrombocytopenia is typical and may be
about a quarter of all patients have skin and haematological picture mimicking severe {2415, 2872,3093).
rashes (eczematous eruptions or indura- that of JMM L, such as infection (2481), Bone marrow findings alone are not diag-
tions with central clearing). Cafe-au-lait Wiskott- Aldrich syndrome (eczema- nostic. The bone marrow aspirate and bi-
spots might be indicative of an underly- th rom bocytope nia-i mmunodeficie ncy opsy are hypercellular with granulocytic
ing germline condition such as NF1 or syndrome) {4436) and malignant infantile proliferation, although in some patients
Noonan syndrome-like disorder {2528, osteopetrosis {3811}, must be excluded. erythroid precursors may predominate
2874). JMML rarely involves the central {2872,3093). Monocytes in the bone
nervous system (CNS), although a small Microscopy marrow are often less prominent than in
number of patients with CNS myeloid The peripheral blood is the most impor- the peripheral blood, general ly account-
sarcoma and ocular infiltrates have been tant specimen for diagnosis. It typically ing for 5- 10% of the bone marrow cells.
descri bed {2872). shows leukocytosis and thrombocyto- Blasts (including promonocytes) account
A notable feature of many JMML cases penia, and often anaemia {2415,2872). for < 20% of the bone marrow cells, and
is markedly increased synthesis of hae- The median reported white blood cell Auer rods are never present. Dysplasia
moglobin F, particularly in cases with a counts are 25-30 x 109/L. The leuko- is usually minimal; however, dysgranu-
A
••
90 Myelodysplastic/myeloproliferative neoplasms
malignancies (including JMML) {2102, heart defects, and a variety of abnormali- haemoglobin F levels at diagnosis are the
2871,3316}. ties in other organs. Heterozygous ger- main clinical predictors of short survival
NF1, the first syndrome found to be as- mline mutations in PTPN11, SOS1, RAF1, {2872,3093).
sociated with a germline mutation in KRAS, NRAS and other components of JMML with KRAS or NRASmutation gen-
the RAS pathway, can manifest in early the RAS pathway {811} are recognized, erally has an aggressive course, with
childhood with cafe-au-lait spots, JMML, with PTPN11 mutations accounting for early haematopoietic stem cell trans-
plexiform neurofibromas, optic pathway about half of the cases {3317). As many plantation needed. In a few infants with
tumours, and bone lesions (3314). In as 10% of children with Noonan syn- KRAS or NRAS alterations, long-term
children with NF1, the risk of developing drome develop a transient myelopro- survival in the absence of therapy has
JMML is estimated to be 200- 350 times liferative disorder in early infancy {217, been observed; these chi ldren had low
the risk in children without the syndrome 2871 }. The vast majority of patients with haemoglobin F levels, normal or moder-
(3804). For about half of the patients with Noonan syndrome/myeloproliferative ately decreased platelet counts, and no
JMM L and NF1, a positive fam ily history disorder harbour germline PTPN11 mu- subclonal mutations {2377,3801 ). There
is known . In most affected ch ildren, the tations predicted to result in a weaker are similarities between JMML with KRAS
clinical diagnosis of NF1 can be made gain-of-function effect than the somatic or NRAS mutation and RAS-associated
at the time of leukaemic presentation; PTPN11 mutations found in children with autoimmune leukoproliferative disorder
JMML may be the first manifestation of JMML {2103}. The abnormal myelopoie- (RALD) {530). JMML and RALD show
NF1 in some of these infants {3801}. Pa- sis in Noonan syndrome/myeloprolifera- overlapping clinical and laboratory fea-
tients with Noonan syndrome-l ike disor- tive disorder is ben ign in most infants, tures (with the exception of the leukope-
der exh ibit a variable Noonan syndrome- but about 10% of these children acquire nia seen in RALD). However, long-term
like phenotype, with a high frequen cy clonal chromosomal abnormalities and follow-up suggests that RALD has an in-
of neurological features and pigmented develop JMML {21 7,2871). dolent clinical course, unlike most cases
skin lesions {2528,2874, 3817). Suscepti- of JMML with RAS mutations {530)
bility for JMML in children with germline Prognosis and predictive factors Most ch ildren with JMM L and germline
CBL mutation is high, although the small JMML with somatic PTPN11 mutation CBL mutations experience spontaneous
number of patients precludes more pre- or occurring in children with NF1 is in- regression of JMML with persistence of
cise risk estimation {2528}. variably rapidly fatal if left untreated. The uniparental disomy of the CBL locus in
Noonan syndrome is the most common median survival time without al logeneic haematopoietic cells. Occasionally, sec-
RASopathy, with an incidence of 1 case haematopoietic stem cell transplantation ondary genetic alterations occu r that re-
per 1000-2500 births {3317). It is char- is about 1 year. Low platelet count, pa- sult in an aggressive clinical course.
acterized by a typical facial appearance, tient age > 2 years at diagnosis and high
92 Myelodysplastic/myeloproliferative neoplasms
Definition Table 5.04 Diagnostic criteria for myelodysplastic/myeloproliferative neoplasmwith ring sideroblasts and thrombocytosis
Myelodysplastic/myeloproliferative neo- - Anaemia associated with erythroid-lineage dysplasia, with or without multilineage dysplasia;
plasm (MOS/MPN) with ring sideroblasts <:: 15% ring sideroblasts", < 1% blasts in the peripheral blood and< 5% blasts in the bone marrow
and thrombocytosis (MOS/MPN-RS-T) - Persistent thrombocytosis, with platelet count <::450 x 109/L
is a subtype of MOS/MPN character-
- SF3B1 mutation or, in the absence of SF3B1 mutation, no history of recent cytotoxic or growth factor therapy
ized by the presence of thrombocytosis that could explain the myelodysplastic / myeloproliferative featuresb
(;::450 x 109/L) and < 1% blasts in the
- No BCR-ABL1 fusion; no rearrangement of PDGFRA, PDGFRB or FGFR1; no PCM1-JAK2
peripheral blood and associated with and no t(3;3)(q21 .3;q26.2), inv(3)(q21 .3q26.2), or de1(5q)c
ring sideroblasts accounting for ;:: 15%
- No history of myeloproliferative neoplasm, myelodysplastic syndrome (except myelodysplastic syndrome
of erythroblasts, dyserythropoiesis and with ring sideroblasts), or other myelodysplastic/myeloproliferative neoplasm
< 5% blasts in the bone marrow {1499,
1890,3104,3862}.
a <:: 15% ring sideroblasts is a required criterion even if SF381 mutation is detected.
In the original 4th edition of the WHO b The diagnosis of myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis is
classification, refractory anaemia with strongly supported by the presence of SF3B1mutation together with a JAK2 V617F, CALR or MPL mutation.
ring sideroblasts associated with marked c In a case that otherwise meets the diagnostic criteria for myelodysplastic syndrome with isolated del(5q).
thrombocytosis (RARS-T) was proposed
as a provisional entity to encompass
cases with the clinical and morpho- tions. By convention, these cases would Clinical features
logical features of myelodysplastic syn- be considered to constitute disease pro- The clinical features of MOS/MPN-RS-T
drome with ring sideroblasts (MOS-RS) gression of MOS, and would therefore be greatly overlap those seen in MOS-RS
but also with thrombocytosis associated excluded from the MOS/MPN category and the BCR-ABL1-negative MPN cat-
with abnormal megakaryocytes similar to (see Table 5.04); however, given the lack egories, in particular essential thrombo-
those seen in BCR-ABL1- negative my- of prog nostic difference, it might be most cythaemia. Anaemia is always present,
eloproliferative neoplasms {1499,1890}. appropriate to group these cases with but at the time of clinical presentation, pa-
More recently, MOS/MPN-RS-T has the rest of the cases of MOS/MPN-RS- tients with MOS/MPN-RS-T tend to have
become a well-characterized , distinct T. Therapy-related cases with features higher haemoglobin levels, white blood
MOS/MPN overlap entity, particu larly of MOS/MPN-RS-T are diagnosed as cell (WBC) counts, and platelet counts
following the discovery of a strong asso- therapy-related myeloid neoplasms and than do patients with MOS-RS, with simi-
ciation with SF381 mutations, wh ich are are discussed separately (see Therapy- lar mean corpuscular volumes. In con-
often concurrent with the JAK2 V617F related myeloid neoplasms, p. 153). trast, patients with MOS/MPN-RS-T have
mutation and less commonly with MPL lower haemog lobin levels, WBC counts,
or CALR mutation {409,594,1310,2461, ICD-0 code 9982/3 and platelet counts , but higher mean cor-
2464,3103,3339,3344, 3569,3575,3773, puscular volumes than do patients with
3862.4249}. Synonym essential thrombocythaemia {463}.
Cases that fulfil the diagnostic criteria for Refractory anaemia with ring sideroblasts
MOS with isolated del(5q) or that have associated with marked thrombocytosis Microscopy
t(3;3)(q21. 3;q26.2) or inv(3)(q21.3;q26.2) The peripheral blood typically shows
cytogenetic abnormalities are excluded Epidemiology normochromic macrocytic or normo-
from this category, as are cases with a A median patient age at the time of dia- cytic anaemia. The red blood cells in
BCR-ABL 1 fusion gene. If there has been gnosis of 74 years has been reported, the blood smear may show anisocytosis,
a prior diagnosis of an MPN without ring wh ich is higher than that observed in often with a dimorphic pattern. Circulat-
sideroblasts, or if there is evidence that MPN such as essential thrombocythae- ing blasts are absent or rare (accounting
the ring sideroblasts might be a conse- mia. A slight female prevalence has been for < 1% of the cells). Thrombocytosis
quence of therapy or might reflect dis- consistently reported across studies (;:: 450 x 109/L) is one of the defining fea-
ease progression of a case that meets {462.463}. tures. The platelets often display anisocy-
the criteria for another well-defined MPN, tosis, ranging from tiny forms to atypical
this designation should not be used. It is Localization large or giant platelets. Bizarrely shaped
unclear how to best categorize the rare The peripheral blood and bone marrow or agranular platelets may be seen, but
cases that initially present as MOS-RS are always involved. Splenomegaly has are uncommon. The WBC count and leu-
and later evolve to MOS/MPN-RS-T upon been reported in about 40% of cases , kocyte differential count are usually nor-
acquisition of a JAK2 V617F mutation and hepatomegaly can also occur {3861). mal, although a borderline elevation in
{2461) or other MPN-associated muta- the WBC count can occur.
94 Myelodysplastic/myeloproliferative neoplasms
Genetic profile
There are no cytogenetic or molecular
genetic findings specific for this group.
The Philadelphia (Ph) chromosome
and the BCR-ABL 1 fusion gene should
always be excluded prior to making the
diagnosis of MOS/MPN-U. Cases with re-
arrangements of PDGFRA, PDGFRB, or
FGFR1 or with PCM1-JAK2, are excluded
from this category as well.
The appropriate categorization of cases
associated with isolated isochromo-
some 17q is uncertain. A proportion of
cases meet the criteria for chronic myelo-
monocytic leukaemia, BCR-ABL 1-nega-
tive atypical chronic myeloid leukaemia,
MPN in accelerated or blast phase, MOS
or acute myeloid leukaemia, but other
cases may be appropriately categorized
as MOS/MPN-U {1220,1912,2594}.
Relatively high frequencies of TET2,
NRAS, RUNX1, CBL, SETBP1 and ASXL 1
mutations have been reported in several
studies {2610,4248,4502}. In diagnosti-
- ~neoplasm, unclassifiable. A case associated with isolated isochromo-
Fig. 5.15 Myelodysplastic/myeloproliferative
some 17q. A Bone marrow core biopsy showing hypercellularity with increased dysplastic megakaryocytes and
increased immature cells. B Bone marrow aspirate smear showing increased blasts and dysplastic granulocytes
cally difficult cases, the presence of one
or more of these mutations in the appro- with pseudo-Pelger-Huet nuclei (Wright-Giemsa). C Bone marrow aspirate showing dysplastic non-lobated mega-
karyocytes (Wright-Giemsa).
priate clinicopathological context may
help to confirm a suspected diagnosis.
SF381 mutation should prompt careful talion be classified as MOS with isolated had a median overall survival of 21.8
exclusion of MOS/MPN-RS-T, includ- del(5q) rather than included in the MOS/ months and leukaemia-free survival of
ing rare instances of disease progres- MPN-U category. 18.9 months {4248). Prognosis is vari-
sion from MOS with ring sideroblasts. Cases with MOS/MPN features that har- able, with its uncertainty further com-
Although cases that meet the criteria for bour one of the types of driver mutations pounded by inadequate representation
MOS with isolated del(5q) are excluded, seen in classic MPN (i.e. JAK2, MPL or of the subgroup in commonly used prog-
a small proportion of such cases with a CALR mutations) most likely constitute nostic scoring systems, including the
combined del(5q) and JAK2V617F muta- MPN with features of disease progres- International Prognostic Scoring System
tion have been reported to have prolifera- sion. However, if a chronic phase has not (IPSS) and Revised IPSS (IPSS-R) {401 1).
tive features in the bone marrow associ- been previously detected or cannot be As with other MOS/MPN overlap disor-
ated with higher median platelet counts documented and therefore the underly- ders, the treatment for patients with MOS/
{1759). However, it is unclear whether ing MPN cannot be confirmed, then the MPN-U is based on therapies used for
their clinical presentation or progno- designation of MOS/MPN-U is justified. MOS or MPN and is guided by symptoms
sis is any different from that of the MOS and/or cytopenias {4011 }. Growth factors
with isolated del(5q) and wildtype JAK2 Prognosis and predictive factors (erythropoiesis- and granulopoiesis-stim-
{3101 ,3717). Until more evidence is pub- There is very limited information avail- ulating agents) can alleviate cytopenias,
lished, it is recommended that cases with able about this rare subgroup. In a re- whereas leukocytosis can be managed
combined del(5q) and JAK2 V617F mu- cent study, patients with MOS/M PN-U with cytoreductive therapies.
96 Myelodysplastic/myeloproliferative neoplasms
Myelodysplastic syndromes
Myelodysplastic syndrome with single lineage dysplasia
Myelodysplastic syndrome with ring sideroblasts
Myelodysplastic syndrome with multilineage dysplasia
Myelodysplastic syndrome with excess blasts
Myelodysplastic syndrome with isolated del(5q)
Myelodysplastic syndrome, unclassifiable
Childhood myelodysplastic syndrome
Refractory cytopenia of childhood
Definition
The myelodysplastic syndromes (MOS)
are a group of clonal haematopoietic
stem cell diseases characterized by cy-
topenia, dysplasia in one or more of the
major myeloid lineages, ineffective hae-
matopoiesis, recurrent genetic abnor-
malities and increased risk of developing
acute myeloid leukaemia (AML) {340,
592,4151}. There is an increased degree ~ ~
of apoptosis within the bone marrow pro- Fig. 6.01 Parvovirus B19 infection. Bone marrow smear Fig. 6.02 Arsenic poisoning. Bone marrow smear from
genitors, which contributes to the cyto- shows marked erythroid hypoplasia, with occasional a 47-year-old man with pancytopenia being chronically
pen ias {439}. Cytopenia in at least one giant erythroblasts with dispersed chromatin and fine exposed to arsenic; there is marked dyserythropoiesis.
haematopoietic lineage is required for a cytoplasmic vacuoles.
diagnosis of MOS. The recommended The morphological hallmark of MOS is the number of cytopenias at presentation,
thresholds for cytopenias established dysplasia in one or more myeloid line- the number of myeloid lineages manifest-
in the original International Prognostic ages. Dysplasia may be accompanied by ing dysplasia, the presence of ring side-
Scoring System (IPSS) for risk stratifica- an increase in myeloblasts in the periph- roblasts, and the blast percentages in
tion (haemoglobin concentration < 10 g/ eral blood and/or bone marrow, but the the blood and bone marrow. In the cur-
dL, platelet count < 100 x 109 /L, and blast percentage is always < 20%, wh ich rent classification , only one cytogenetic
absolute neutrophil count < 1.8 x 10 9/L is the requisite threshold recommended abnormality, del(5q), is used in the defini-
{1442,1442A}), have traditionally been for the diagnosis of AML. It is important tion of a specific MOS subtype. Mutation
used to define cytopenias for MOS di- to recognize that the threshold of 20% of one gene, SF3B1, is closely associ-
agnosis and most MOS patients will blasts distinguishing AM L from MOS ated with MOS with ring sideroblasts as
have a cytopenia below at least one of does not reflect a therapeutic mandate well as with one of the MOS/MPN sub-
these thresholds. However, a diagnosis to treat cases with 2': 20% blasts as acute types: MOS/MPN with ring sideroblasts
of MOS may still be made in patients leukaemia. Recu rrent cytogenetic abnor- and thrombocytosis.
with milder degrees of anaemia (haemo- malities are present in 40-50% of cases, Althoug h progression to AML is the nat-
globin < 13g/dL in men or < 12g/dL in whereas acquired somatic gene muta- ural course in many cases of MOS, the
women) or thrombocytopenia (platelets tions are seen in the vast majority of MOS percentage of patients who progress
< 150 x 109 / L) if definitive morphologic cases at diagnosis. varies substantially across the subtypes,
and/or cytogenetic findings are present The MOS category encompasses several with a higher probability of progression
{1444A,4179}. In determining whether distinct subtypes, wh ich are defined by in subtypes with increased myeloblasts
a patient is cytopenic, it is important to
be cognizant of each laboratory's lower
reference range and to take into account
conditional variants of these values, such
as due to ethnicity and sex. These are
particularly important considerations in
patients with a borderline low neutro-
phil count {229}. Persistent neutrophilia,
monocytosis, erythrocytosis or thrombo-
cytosis in a patient with cytopenias and
dysplastic morphology generally war-
rants classification as a myelodysplastic/
myeloproliferative neoplasm (MOS/MPN)
or myeloproliferative neoplasm rather
than MOS. However, thrombocytosis
(platelet count 2':450 x 109/L) is allowed
in MOS with isolated del(5q) or with inv(3) Fig. 6.03 Antifolate chemotherapy effect. Bone marrow smear from a 57-year-old woman who received several
(q21.3q26.2) or t(3;3)(q21 .3;q26.2). chemotherapeutic agents for breast carcinoma, including folic acid antagonists, showing transient marked
dyserythropoiesis and megaloblastic changes.
98 Myelodysplastic syndromes
Etiology
Primary or de novo MOS occurs without a
known history of chemotherapy or radia-
tion exposure. Possible etiolog ies for pri-
mary MOS include benzene exposure (at
levels well above the minimum allowed
by most government agencies), cigarette
smoking (at least in part also due to ben-
A .....
Fig. 6.05 Granulocyte colony-stimulating factor (G-CSF) therapy effect. A Blood smear from a patient on G-CSF,
zene in cigarette smoke), exposure to ag- showing a neutrophil with a bilobed nucleus and increased azurophilic granulation and a myeloblast (B).
Characteristics of dysplasia
Oyserythropoiesis manifests principally
as nuclear alterations, including budding,
internuclear bridging, karyorrhexis and
multinuclearity. Megaloblastoid changes
are often present in MOS, but alone they
-Fig. 6.06 Myelodysplastic syndrome with
n multilineage dysplasia and a complex karyotype including del(17p). are insufficiently specific to firmly estab-
Dysgranulopoiesis is evident on these blood smears, showing three neutrophils with bilobed nuclei (pseudo- Pelger- lish dyserythropoiesis. Cytoplasmic
Huet anomaly) (A) and a neutrophil with a non-segmented nucleus (B). features include formation of ring side-
roblasts, vacuol ization and aberrant pe-
As a general precaution, no patient nosed with MOS either; this condition has riodic acid-Schiff (PAS) positivity (either
should be diagnosed with MOS if the been termed 'clonal haematopoiesis of diffuse or granular). Oysg ranu lopoiesis
clinical and drug history is unknown, indeterminate potential' {3772). is characterized primarily by nuclear hy-
and no case of MOS shou ld be reclassi- Cases of MOS without an increase in posegmentation (pseudo-Pelger-Huet
fied while the patient is on growth factor blasts are recognized as manifesting ei- anomaly) or hypersegmentation, cyto-
therapy, including erythropoietin. Certain ther single lineage dysplasia or multilin- plasmic hypogranularity, pseudo-Che-
drugs, infections, metabolic deficiencies eage dysplasia. In most cases of MOS diak-Higashi granules and small size
and immune disorders can cause both with single lineage dysplasia, the dyspla- {1387). Megakaryocyte dysplasia is
cytopenias and morphological dyspla- sia is confined to the erythroid lineage. characterized by micromegakaryocytes,
sia; these possible secondary etiolo- Single lineage dysplasia can also affect non-lobated nuclei in megakaryocytes
gies must be carefully considered prior the granulocytic lineage or megakaryo- of all sizes, and multiple widely sepa-
to rendering a diagnosis of MOS (see cytes, but this is much less common rated nuclei {1388}; however, the finding
Differential diagnosis). Unexplained, than dysplasia isolated to erythroid cells of multiple widely separated nuclei is of
persistent cytopenia in the absence of {450,2423). In MOS with multilineage limited specificity for MOS, unless the
dysplasia should not be interpreted as dysplasia, significant dysplastic features nuclei are rounded and rough ly similar in
MOS unless certain specific cytogenetic are recognized in two or more lineages. size. Megakaryocytic dysplasia is read -
abnormalities are present (see Genetic The recommended requisite percent- ily apparent in bone marrow sections,
profile below and Table 6.03, p. 104). age of erythroid and granulocytic cells and both biopsy and aspirate specimens
Persistent cytopenia without dysplasia manifesting dysplasia to be considered should be evaluated. The morphological
and without one of the specifi c cytoge- significant is :::: 10% {3404). Significant manifestations of dysplasia in each line-
netic abnormalities should be diagnosed megakaryocyte dysplasia is defined as age are summarized in Table 6.02. Auer
as idiopathic cytopenia of undetermined :::: 10% dysplastic megakaryocytes based rods are considered to be evidence of
significance, and the patient's haemato- on evaluation of ::::30 megakaryocytes in MOS with excess blasts regardless of
logical and cytogenetic status should be smears or sections; however, some stud- the blast percentage. Cases of MOS with
carefu lly monitored {4106,4336). Patients ies suggest that a 30- 40% threshold for < 5% blasts in the bone marrow and< 1%
with MOS-associated clonal gene muta- megakaryocyte dysplasia may provide in the peripheral blood may rarely have
tions identified in haematopoietic cells greater specificity {947,1309,2567). Mi- Auer rods, and such cases are associ-
but without significant dysplasia on bone cromegakaryocytes and multinucleated ated with an adverse prognosis {4328}.
marrow examination should not be diag- megakaryocytes with separated nuclei
MOS-MLO 2-3 1-3 <15%/<5%b BM <5%, Any, unless fulfils all criteria for
PB <1%, MDS with isolated del{5q)
no Auer rods
MOS-RS
MDS-RS-SLD 1-2 ;::15%/;::5%b BM <5%, Any, unless fulfils all criteria for
PB <1%, MDS with isolated de1(5q)
no Auer rods
MDS-RS-MLD 2- 3 1-3 ;::15%/;::5%b BM <5%, Any, unless fulfils all criteria for
PB <1%, MDS with isolated del(5q)
no Auer rods
MOS with isolated del{Sq) 1-3 1-2 None or any BM <5%, del(5q) alone or with
PB <1%, 1 additional abnormality, except
no Auer rods loss of chromosome 7 or del{7q)
MOS-EB
MDS-EB-1 1- 3 1-3 None or any BM 5- 9% or PB 2- 4%, Any
BM< 10% and PB <5%,
no Auer rods
MDS-EB-2 1- 3 1-3 None or any BM 10- 19% or PB 5- 19% Any
or Auer rods,
BM and PB <20%
MOS·U
with 1% blood blasts 1-3 1-3 None or any BM <5%, Any
PB= 1%c,
no Auer rods
with SLD and pancytopenia 3 None or any BM <5%, Any
PB <1%,
no Auer rods
based on defining 0 1-3 <15%d BM <5%, MOS-defining abnormality"
cytogenetic abnormality PB <1%,
no Auer rods
Differential diagnosis and other factors can also cause myelo- tation causes rin g sideroblast formation.
A major difficulty in the diagnosis of MOS dysplastic changes in any of the haema- The antibiotic cotrimoxazole and the im-
is the determination of whether the pres- topoietic lineages. These factors include munosuppressants tacrolimus and my-
ence of morphological dysplasia and vitamin 81 2 and folic acid deficiency, cophenolate mofetil can cause marked
cytopen ia is due to a clonal disorder or essential element deficiencies (such as neutrophil hyposegmentation, often in-
is the result of another factor. Oysplasia, copper deficiency), exposure to heavy distinguishable from the changes seen in
even if prominent, is not in itself defini- metals (in particular arsenic, lead and MOS. In some patients on multiple drugs
tive evidence of a clonal process. Some toxic levels of zinc) and exposure to sev- or with multiple comorbidities, it may be
dysplastic features, such as micromega- eral commonly used drugs and biolog i- difficult to identify the cause of dysplastic
karyocytes, are strongly associated with cal agents (439}. lsoniazole treatment in changes (1991,3867). Oysplastic chang-
MOS (947), but several nutritional, toxic the absence of vitamin 86 supplemen- es can also be encountered in otherwise
•-
Megaloblastoid changes
siently in the peripheral blood; the bone
Cytoplasmic
Ring sideroblasts marrow blast percentage is generally
Vacuolization
Periodic acid-Schiff (PAS) positivity
Dysgranulopoiesis
normal in such cases, but is transiently in-
creased in some cases. Hypothyroidism,
infections, autoimmune disorders, par-
....
J
lmmunophenotype
The immunophenotypic abnormalities
that have been described in MOS hae-
matopoietic cells compared with normal
haematopoiesis are abnormal quantity
and aberrant phenotypes of progenitor
cells; aberrant immunophenotypic pro-
Fig. 6.10 Myelodysplastic syndrome with multilineage files of maturing granulocytic, erythroid Fig. 6.11 Dysplastic megakaryocyte. Bone marrow
dysplasia. Dysgranulopoiesis is present in the bone and monocytic cells; and a decrease smear from a case of myelodysplastic syndrome with
marrow aspirate smear, including hypogranular neutro- of haematogones {63,1856,2555,2935, single lineage dysplasia shows a binucleated mega-
phils with pseudo-Pelger-Huet anomaly. 3895). Abnormal myeloid maturation karyocyte with separated round nuclei.
patterns include asynchrony of CD15
in some cases of aplastic anaemia) are and CD16 on granulocytes; altered ex- screening panels have also been applied
helpful in this distinction {342,945,947). pression of CD13 in relation to CD11 b or {4,259,945,1856,2933,3287). but may
MOS-associated somatic mutations have CD16; and aberrant expression of CD56 be less sensitive and less specific than
been reported to occur in as many as one and/or CD7 on progenitors, granulocytes larger panels.
third of patients with aplastic anaemia or monocytes. Decreased side-scatter of
{4440). lmmunosuppressive therapies granulocytes can also be seen. In eryth- Cell of origin
used to treat aplastic anaem ia have been roid cells, an increased coefficient of vari- The postulated cell of origin is a haema-
used with some degree of success in this ation and decreased intensity of CD71 or topoietic stem cell.
MOS subgroup {439,2334,3698,4447, CD36 expression are highly associated
4448). When considering the diagnosis with MOS {2563}. There is generally good Genetic profile
of hypoplastic MOS, it is important to ex- correlation between the percentage of Cytogenetic studies play a major role in
clude acute marrow injury due to a toxin, blasts as determined by morphological the eval uation of patients with MOS in re-
infection or an autoimmune disorder. examination of the bone marrow aspi- gard to prognosis, determination of clon-
rate smear or touch imprint, immunohis- ality {1442,3551,2971} and recognition of
Myelodysplastic syndrome with fibrosis tochemistry of the bone marrow biopsy cytogenetic correlates with morphological
Significant degrees of myelofibrosis (i.e. section and flow cytometry (CD34+ cells) and clinical features. MOS with isolated
corresponding to grade 2 or 3 of the {1994). However, in some cases there del(5q), i.e. either with a del(5q) alone or
WHO grading scheme) {3975) are ob- may be significant discordance due to with one add itional abnormality other than
served in 10-15% of MOS cases, and marrow fibrosis or haemodiluted sam- loss of chromosome 7 or del(7q), is a spe-
these cases have been referred to as ples; therefore, percentages of CD34+ cific MOS subtype in this classification. It
MOS with fibrosis (MDS-F) {2201}. Sig- cells as determined by flow cytometry occurs more often in women and is char-
nificant fibrosis does not define a spe- cannot replace the morphological differ- acterized by megakaryocytes with non-lo-
cific MOS subtype in this classification. ential count. Nevertheless, the finding of bated or hypolobated nuclei, macrocytic
However, many of the cases with fibrosis CD34+ myeloid progenitors accounting anaemia, normal or increased platelet
have an excess of blasts, and significant for > 2% of nucleated cells has been re- count, and a favourable clinical course.
fibrosis is associated with an aggressive ported to be of adverse prognostic sig- Loss of 17p is associated with MOS or
clinical course in MOS, independent of nificance in MOS {2555A,2556}. AM L with pseudo- Pelger- Huet anomaly,
the blast count {942,1261 ). MDS-F cases Flow cytometry findings alone are not small vacuolated neutrophils, TP53 muta-
with excess blasts may erroneously be sufficient to establish a primary diagnosis tion and an unfavourable clinical course;
diagnosed as low-grade MOS based of MOS in the absence of definitive mor- it is most common in therapy-related MOS
only on the blast count determined from phological and/or cytogenetic findings. A {2187). Complex karyotypes (;:>:3 abnor-
the bone marrow aspirate, which is usu- series of consensus guidelines has been malities) typically include abnormalities of
ally diluted with peripheral blood. In this published by the European LeukemiaNet chromosomes 5 and/or 7, such as del(5q),
fibrotic group, as in other cases of MOS (ELN) MOS working group regard ing the loss of 5q, loss of chromosome 7 and
with inadeq uate aspirates, accu rate blast use of flow cytometry in the diagnos- del(7q); these are generally associated
determination requires a bone marrow bi- tic work-up of patients with MOS {3223, with an unfavourable clinical course. Sev-
opsy, and immunohistochemical studies 4117,4118,4305), including a summary of eral other cytogenetic findings appear to
for CD34 may prove invaluable. Unlike the reported aberrations associated with be associated with characteristic morpho-
the myeloproliferative neoplasm entity MOS and how to report the results {2463, logical abnormalities; for example, isolat-
primary myelofibrosis, MDS-F is usually 3223,4119}. Aberrant findings in at least ed del(20q) is associated with dysmega-
not associated with splenomegaly, leu- three tested features and at least two karyopoiesis and thrombocytopenia, and
koerythroblastosis or intrasinusoidal hae- cell compartments have been reported inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)
matopoiesis and typically exhibits MDS- to be highly associated with an MOS or is associated with abnormal megakaryo-
type megakaryocyte morphology (i.e. MDS/MPN diagnosis in several stud- cytes and may be associated with throm-
micromegakaryocytes), other dysplastic ies {3221,3223,4063,4119}. More limited bocytosis. {446,1500,2142,3392}.
bone marrow blast percentage in all survival prediction in the IPSS-R {1444) lower-risk cases and at time points after
MOS diagnoses, so that the IPSS-R can Another risk-stratification scheme used the initial diagnosis {2462).
be app lied . Five IPSS-R risk groups are to predict outcome in MOS is the WHO Accumulating data indicate that both
defined , on the basis of the total score Classification-based Prognostic Scoring number and type of individual gene
of the parameters listed in Table 6.06: System (WPSS), which incorporates ad- mutations are strongly associated with
very low, low, intermediate, high and very ditional variables of transfusion require- disease outcome in MOS. The addi-
high. The IPSS-R is significantly better at ment and morpholog ical dysplasia (sin- tion of mutation data improves the abil-
pred icting survival and evolution to AML gle lineage vs multilineage) that are not ity of existing risk-stratification schemes
than the original IPSS {4219). Consid- included in the IPSS-R. The WPSS may such as the IPSS to predict prognosis in
eration of patient age further improves be particularly useful when applied to MOS {311,312). Many commonly mutated
•.... 'I
'~
A ~ a ..L'I • JI '- ;;..< t •. ~
Fig. 6.12 Myelodysplastic syndrome with fibrosis (MDS-F). A Bone marrow biopsy from a case of MDS with excess blasts and fibrosis shows several micromegakaryocytes.
B Reticulin of a marrow biopsy from a case of MDS with fibrosis reveals a marked increase in reticulin fibres.
Myelodysplastic syndromes
Myelodysplastic syndrome with MOS-SLO was called refractory cytope- agnostic conclusion. The defining feature
single lineage dysplasia nia with unilineage dysplasia, and was of this type of MOS is ;::: 10% dysplastic
divided into three subtypes: refractory cells in one myeloid lineage. Cases with
Brunning R.D. Thiele J. anaemia, refractory neutropenia and re- erythroid dysplasia only and ;::: 15% ring
Hasserjian R.P. Hellstrbm- fractory thrombocytopenia. This subclas- sideroblasts (or ;:::5% ring sideroblasts
Porwit A. Lindberg E. sification has been controversial; some in the presence of SF381 mutation) are
Bennett J.M . List A.F. stud ies have demonstrated no clear cor- classified as MOS with rin g sideroblasts
Orazi A. relation between lineage cytopenia and and single lineage dysplasia (MOS-RS-
lineage dysplasia and no significant dif- SLO). If SF3B1 mutation status is un-
ferences in survival between the three known, it is recommended that cases
Definition subtypes {1503,2423,2568,4179). How- with 5- 14% ring sideroblasts and single
The category of myelodysplastic syn- ever, other stud ies have found some su r- lineage dysplasia be classified as MOS-
drome (MOS) with single lineage dyspla- vival differences {449,251 1}. Given these SLO. As in the 2008 classification, it is
sia (MOS-SLO) encompasses the MOS conflicting find ings and the inconsisten- recommended that cases with single
cases that present with unexplained cies between lineage cytopenia and line- lineage dysplasia and pancytopenia be
cytopenia or bicytopenia, with ;::: 10% age dysplasia, we recommend that cas- categorized as MOS, unclassifiable.
dysplastic cells in one myeloid lineage. es of MOS presenting with single lineage As noted in the Overview section (p. 98),
Most patients present with persistent un- cytopenia or bicytopenia and unilineage the recommended thresholds for de-
explained anaemia or bicytopenia; some dysplasia be classified as MOS-SLO, fining cytopenias are haemoglobin
present with persistent unexplained neu- without additional subclassification. concentration < 10 g/dl , absolute neu-
tropenia or thrombocytopenia {2423). The presenting lineage dysplasia and trophil cou nt < 1.8 x 10 9 /L and plate-
In the 2008 edition of this classification, cytopenias(s) should be noted in the di- let count < 100 x 10 9 / L, as per the ri sk
Clinical features
The presenting symptoms are generally
related to the type of cytopenia. The cyto-
..
-
Fig. 6.15 Myelodysplastic syndrome with single lineage
dysplasia. Peripheral blood smear from a 56-year-old
man shows granulocytic dysplasia. The neutrophil in the
nophenotypic features of erythropoietic
precursors can be found by flow cytom-
etry analysis {944,1994,3223). In a frac-
tion of these cases, flow cytometry also
penias are unresponsive to haematinic upper right is normal-appearing, with well-granulated detects aberrant immunophenotypic
therapy but may respond to growth fac- cytoplasm and a normally segmented nucleus. The features in the myelomonocytic compart-
tors (1707). neutrophil in the lower left is dysplastic, with moderately ment or in precursors (259,946,1994,
hypogranular cytoplasm and occasional Dahle bodies;
3223) These patients should be reas-
the nucleus shows retarded segmentation. Approxi-
Microscopy mately half of the neutrophils were dysplastic. sessed and closely observed for devel-
In the peripheral blood, the red blood opment of multi lineage dysplasia (3223).
cells are usually normochromic and nor-
mocytic or normochromic and macro- but account for < 15% of the erythroid Cell of origin
cytic. Unusually, there is anisochromasia precursors. If the proportion of ring si- A haematopoietic stem cell
or dimorphism with populations of both deroblasts is 25% but < 15% and there
normochromic and hypochromic red is SF3B1 mutation, the case should be Genetic profile
blood cel ls; this finding is more common classified as MDS-RS-SLD. If the SF3B1 Cytogenetic abnormalities may be ob-
in MOS with ring sideroblasts. Anisocyto- mutation status is unknown, the case served in as many as 50% of cases
sis and poikilocytosis range from absent shou ld be classified as MDS-SLD. (1341 ,2423} Several acquired clonal
to marked. Neutrophil dysplasia can manifest as chromosomal abnormalities may be
As noted, circulating blasts are rarely small size, dense chromatin, variable observed, but although useful for es-
seen, and if present, account for < 1% degrees of nuclear hyposegmentation, tablish ing a diag nosis of MOS, they are
of the peripheral blood leukocytes. The pseudo-Pelger-Huet changes, and ab- not specific. The abnormal ities gener-
presence of any blasts should call into normalities of granulation (either agranu- ally associated with MDS-SLD include
question the diagnosis of MDS-SLD; as larity or hypogranularity). Less common- del(20q), gain of chromosome 8, and
previously stated, the presence of 1% ly, large granules resembling those found abnormalities of chromosomes 5 and 7;
blasts on two successive examinations in Chediak-H igashi syndrome may be del(20q) has been reported in patients
warrants categorization of the case as seen . Nuclear hypersegmentation may with MDS-SLD (as well as MDS-MLD)
MOS, unclassifiable. also be noted. presenting with thrombocytopenia (446,
In cases of MDS-SLD with dyserythro- The principal manifestations of mega- 1500,3526). This finding may be useful in
poiesis, the erythroid precursors in the karyocytic dysplasia include hypolobat- distinguishing MOS from immune-medi-
bone marrow can vary from markedly ed or bilobed nuclei, multiple separated ated thrombocytopenia.
decreased to markedly increased. Dys- nuclei, and micromegakaryocytes; mi- Somatic driver mutations have been
erythropoiesis varies in degree, but is cromegakaryocytes are considered to identified in 60-70% of cases of MDS-
always present in 2 10% of the nucleated be the most reliable and reproducible SLD. The underlying mutations affect a
erythroid precursors. There may be a evidence of megakaryocytic dyspla- haematopoietic stem cell and are pres-
shift to more immature cells. The primary sia {1338,2568,4179). Megakaryocytic ent in all lineages despite the limitation
manifestation of dyserythropoiesis is in dysplasia may be more apparent in bone of dysplastic findings to one lineage
the nucleus. There may be nuclear bud- marrow sections than smears, and its {4354} TET2 and ASXL1 appear to be
ding, internuclear chromatin bridging, conspicuousness is increased by immu- the most commonly mutated genes in
multinuclearity, megaloblastoid changes nohistochemical reactions and PAS stain. MDS-SLD (1 513). However, mutations
or karyorrhexis. Megaloblastoid nuclear The assessment of megakaryocytic dys- in other DNA methylation genes, splic-
changes are best evaluated in the poly- plasia should be based on examination ing factors, RAS pathway genes, cohe-
chromatic and orthochromatic stages of of 230 megakaryocytes. A threshold sion complex genes and RUNX1 are
development because of the normally of ;:>: 10% dysplastic megakaryocytes less common than in MDS-MLD and
fine chromatin pattern in the nuclei of is recommended for the diagnosis of MOS with excess blasts {2465). SF3B1
proerythroblasts and basophilic erythro- megakaryocytic dysplasia. However, mutation is rare. Cases with features of
blasts. Dysplastic cytoplasmic features some experts have found thresholds of MDS-SLD, an SF3B1 mutation, and <5%
include impaired haemoglobinization, 30-40% dysplastic megakaryocytes to ring sideroblasts should be diagnosed
vacuolization, and periodic acid-Schiff be more reliable for distinguishing nor- as MDS-SLD, whereas cases with fea-
(PAS) positivity (either diffuse or granu- mal from dysplastic bone marrow (1338, tures of MDS-SLD, an SF3B1 mutation,
lar). Ring sideroblasts may be present, 2568,947). The bone marrow is typically and 25% ring sideroblasts shou ld be
- -
Fig. 6.16 Myelodysplastic syndrome with ring sideroblasts and single lineage dysplasia. A Blood smear with dimorphic red blood cells and macrocytes. B Bone marrow aspirate
smear showing marked erythroid proliferation, with a dysplastic binucleated form. C Iron stain of bone marrow aspirate showing numerous ring sideroblasts.
stained aspirate smears, ~ 15% (or ~5% if Cell of origin raid cells provided an SF381 mutation is
SF3B1 mutation has been documented) A haematopoietic stem cell present. Cases of MOS-RS with < 15%
of the red blood cell precursors are ring ring sideroblasts tend to have a lower
sideroblasts, as defined by ~5 iron gran- Genetic profile SF3B1 mutant allele burden than do cas-
ules encircling one third or more of the Mutation in the spliceosome gene SF3B1 is es with ~ 15% ring sideroblasts, but they
nucleus {2778). The bone marrow biopsy frequent in MOS-RS, being present in 80- appear to have a similar prognosis {2466,
specimen is normocellular to markedly hy- 90% of MDS-RS-SLD cases and 30- 70% 3099).
percellular, usually with marked erythroid of MDS-RS-MLD cases {593,2464,3104). Clonal chromosomal abnormalities are
proliferation. Megakaryocytes are normal Mutations in other splicing factor genes seen in 5-20% of cases of MDS-RS-
in number and morphology. In MDS-RS- (e.g. SRSF2, U2AF1 and ZRSR2) are pres- SLD; when present, they typically involve
MLD, in addition to ring sideroblasts and ent in < 10% of MOS-RS cases and are a single chromosome {448,1333,1335).
erythroid lineage dysplasia, there is signif- mutually exclusive with the SF381 muta- Cytogenetic abnormalities are seen in
icant dysplasia (~ 10% dysplastic forms) in tion {2464,4433). Additional mutations in about half of MDS-RS-MLD cases and
one or two non-erythroid lineages. Aside TET2 and DNMT3A, genes affecting DNA more often include high-risk abnorm-
from the presence of ring sideroblasts, the methylation, are associated with SF3B1 alities such as loss of chromosome 7
morphological features of MDS-RS-MLD mutation and are more frequent in MDS- {1341,2467,2940).
are generally similar to those of MOS with RS-M LD than in MDS-RS-SLD {2464). In
multilineage dysplasia. cases with multiple mutations, SF3B1 mu- Prognosis and predictive factors
Ring sideroblasts are often observed tation tends to be present at the highest Approximately 1-2% of cases of M DS-
in other types of MOS and can also be allele burden and is stable during disease RS-SLD evolve to acute myeloid leukae-
seen in other myeloid neoplasms, in- progression, suggesting that it is an early mia. The reported median overall survival
cluding acute myeloid leukaemia {1333, event in the disease pathogenesis {593, is 69 to 108 months (943,1335). Overall
1891). For example, cases of MOS with 1513,2337,4354). survival is 28 months in MDS-RS-MLD
ring sideroblasts that have excess blasts A diagnosis of MOS-RS can be made if (similar to that in MOS with multilineage
in the peripheral blood or bone marrow ring sideroblasts constitute ~5% of eryth- dysplasia), and approximately 8% of cas-
are classified as MOS with excess blasts,
and cases that fulfil the criteria for MOS
with isolated del(5q) should be classified 100
as such, even if ring sideroblasts and/or
SF3B1 mutation are present.
80
Non-neoplastic causes of ring sidero-
blasts, including alcohol, toxins (e.g. lead (ij
>
·~
and benzene), drugs (e.g. isoniazid), cop- :::J
60
--'-- RCMD with ~15% RS
per deficiency (which may be induced "'
'E
by zinc administration), and congenital ~ 40
Ql
--'-- RARS
sideroblastic anaemia must be excluded a..
{55). Unlike in MOS-RS, patients with
congenital sideroblastic anaemia tend to 20
present at a much younger age and with
microcytic (rather than macrocytic) anae- 0
mia {2940). 0 100 200 300 Months
Fig. 6.17 Myelodysplastic syndrome with ring sideroblasts (MOS-RS). Survival curves based on long-term follow-up
lmmunophenotype of 167 patients with MOS-RS with single lineage dysplasia and >15% ring sideroblasts (formerly called refractory
In MOS-RS, aberrant immunophenotypic anaemia with ring sideroblasts, RARS) and 318 patients with MOS-RS with multilineage dysplasia (formerly called
features of erythropoietic precursors may refractory cytopenia with multilineage dysplasia, RCMO) with <!: 15% ring sideroblasts (RS), showing inferior survival
be found by flow cytometry analysis {944). of patients with MOS-RS with multi lineage dysplasia (P = 0.00005); data from the Ousseldorf MOS registry.
Synonym
Refractory cytopenia with multilineage
dysplasia
~J ....... ~
Fig. 6.21 Myelodysplastic syndrome with isolated de1(5q). A Bone marrow section showing numerous megakaryocytes of various sizes, several with non-lobated nuclei. B Bone
marrow aspirate smear showing two megakaryocytes with non-lobated, rounded nuclei.
,,..,, ......
~-X!'
• ~
,., .. ,.\, ')- .-~v·'~
...{ ~
Fig. 6.25 Refractory cytopenia of childhood (RCC). A Bone marrow aspirate smear showing abnormal nuclear
adipocytosis of bone marrow spaces; the few scattered segmentation of an erythropoietic precursor cell and a small megakaryocyte with a bi lobed nucleus. B Bone marrow
cellsaremainlylymphocytes, plasma cells, macrophages, biopsy showing a cluster of proerythroblasts without maturation.
mast cells and occasional mature myeloid cells.
Definition are generally considered to be rare, but failed stem cell engraftment, poor graft
Myelodysplastic syndromes (MOSs) and as recognition grows, they may be found function, and donor-derived leukaemias.
acute myeloid leukaemia (AML) present to be more common than is currently re- Therefore, it is critical to distinguish mye-
primarily as sporad ic diseases and typi- alized. Because the hereditary basis for loid neoplasms that arise as a conse-
cally occur in older adults. However, it these neoplasms is only beginning to be quence of germline predisposition from
has become increasingly apparent that understood, it is likely that more disor- those that arise spontaneously or are
some cases of myeloid neoplasms, in ders will be identified and that many of secondary to environmental or chemical
particular MOS and AML, occur in asso- the currently recognized disorders will exposures.
ciation with inherited or de novo germline become more clearly defined. This chapter discusses the major mye-
mutations characterized by specific The recognition and diagnosis of myeloid loid neoplasms with germline predisposi-
genetic and clinical findings. The most malignancies that arise from a germline tion. The discussion focuses on myeloid
established of these disorders are those mutation is critical for the proper clinical neoplasms, but lymphoid neoplasms
that occur in the setting of well-defined management and long-term follow-up of and solid tumours also occasionally
inherited syndromes that exhibit add- affected individuals. Even if a patient has occur in these same ped igrees, and are
itional non-haematological findings and not developed malignancy, the presence mentioned when relevant. There is in-
often present in childhood, such as the of additional organ dysfunction and ab- creasing evidence to support germline
bone marrow failure syndromes (includ- normalities in platelet number and func- mutations with predisposition to lympho-
ing Fanconi anaemia) and the telomere tion warrant clinical management. For blastic leukaemia {1734,3134,3630); this
biology disorders (e.g. dyskeratosis example, patients with germline RUNX1, is discussed in the sections on T- and B-
congenita, see Table 7.01) {2866,3613, ANKRD26, or ETV6 mutations can bleed lymphoblastic leukaemias / lymphomas.
3800). However, we have become in- out of proportion to their platelet cou nts The familial myeloid neoplasms included
creasingly aware of additional autosomal and may require anticipatory transfusion in this chapter are categorized into three
dominant disorders with predisposition of normal platelets prior to invasive pro- groups (Table 7.01). The first group in-
to MOS/AML. Some patients with these cedures or childbirth. Individuals in these cludes myeloid neoplasms associated
disorders initially present with a myeloid families benefit greatly from genetic with germline mutations of CEBPA or
neoplasm, whereas others have a pre- counselling from counsellors with train- DDX41, with a clinical picture dominat-
existing disorder or organ dysfunction. ing in fami lial haematopoietic disorders. ed by either MOS or AML and with no
Some of the first cases to be described Because the cl inical management of pa- other significant organ dysfunction or
were AM L with germline-mutated CEBPA tients with malignant myeloid disorders pre-existing disorder. The second group
and MOS/AML with germline mutations often involves allogeneic haematopoietic consists of myeloid neoplasms associ-
in RUNX1 and a pre-existing familial stem cell transplantation, careful donor ated with germline mutations of RUNX1,
platelet disorder, but the list of these dis- selection is critical in these families, to ANKRD26, or ETV6 in which affected pa-
orders is expanding (Table 7.01) {854, avoid re-introduction of the deleterious tients have a pre-existing platelet disor-
1390,301 5,4301}. Myeloid neoplasms mutation. Inadvertent use of affected der. The third category includes myeloid
associated with predisposing mutations donor stem cel ls has resulted in poor or neoplasms with predisposing mutations
Epidemiology
The frequency of myeloid neoplasms
associated with genetic predisposition is
unknown, but they are considered rare.
Some germl ine mutations are associated haematological malignancy. It is particu- exhib it early dysplastic features that are
with pre-existing non-neoplastic haema- larly important to include detailed ques- stable and may not progress to MOS or
tological disorders or organ dysfunction tioning about personal and family history AML for decades. These include the fa-
that may present during childhood or in including bleeding history as described milial disorders in which dysmegakaryo-
young adults. The neoplasms can pre- in Tab le 7.02; documentation may be poiesis accompanies thrombocytopen ia
sent in any age group, often in children facilitated by genetic counse lling with a secondary to germline ANKRD26 or
and young adults but also in older indi- counsellor familiar with inherited haema- ETV6 mutations. It is recommended that
viduals, depend ing on the specific gene to logical malignancies (757). these cases not be considered neoplas-
mutation. tic un less additional signs of neoplasia
Microscopy and immunophenotype develop (e.g. increased blasts, increa-
Etiology The morphology of the neoplasm sing marrow ce llularity in the presence
The etiology of these neoplasms is re la- depends on its subtype (MOS or AML). of persisting cytopenias, increasing
ted to the underlying germline mutations. In many instances, the morphology has cytopenias, and /or the presence of ad-
In some instances, the development of not been defined in detail or the num- ditional cytogenetic or molecular geneti c
the myeloid neoplasm has been found to ber of cases described is limited. There abnormalities to suggest progression
be associated with additional molecular is no known morphological finding spe- to MDS/AML). Diagnosis of the child-
and /or cytogenetic events. cific for any neoplasm with an underlying hood syndromic disorders can also be
germline mutati on, but some findings challenging . For example, patients with
Clinical features (e.g. bone marrow hypocellularity, dys- Fanconi anaemia often have a clinical
There are no clinical features spec ific to plasia, and the presence of Auer rods) course with fluctuating clonal haema-
myeloid neoplasms with a predispos ing characteristic of certain mutations are topoiesis that can be difficult to distin-
germ line mutation. However, many of described here. The neoplasms have guish from overt MOS (78,79). Close co l-
the germline mutations are associated a myeloid immunophenotype. Some of laboration of pathologists and clinicians
with non-neoplasti c haematolog ical dis- these disorders exh ibit distincti ve blood with clinical geneti cists and /or ce rtified
orders, organ dysfu nction, or inherited and bone marrow morphology at base- geneti c counsellors is esse nti al for ad-
syndromic disorders that correlate with line, before the development of overt dressing these chall enges.
the specific gene involved and often neoplasia. The presence of a genetic Another challenge is that the genetic
manifest before the myeloid neoplasm predispos ition does not in itself place a pred isposition may not be known or iden-
develops. case into the category of a myeloid neo- tified at the time of diagnos is of the first
Recognition of the presence of a germ- plasm until the appearance of standard myeloid neoplasm within a family, which is
line predisposition syndrome requires diagnostic features of MOS, AML, or often class ified as a sporadic neoplasm.
familiarity with the currently defined syn- other myeloid malignancy. In general, When the germline mutation becomes
dromes and their clinical features. Guide- the diagnostic criteria for the germline known, the diagnosis can be modified .
lines recommend conducting a comp lete predispos ition disorders are the same as For examp le, after a germline mutation is
fam ily history in the context of a compre- those for sporad ic cases; however, the identified, a diagnos is of AML cou ld be
hensive medical history and physical ex- diagnosis of MOS may be chal leng ing in mod ified to AML with germline CEBPA
amination of all patients diagnosed with a some cases. For example, some cases mutation. Similarly, myeloid neoplasms
Myeloid neoplasms with germline pred isposition and pre-existing platelet disorders 125
Fanconi anaemia AR: MOS, AML MOS: 7% Bone marrow failure, Screening:
FAN CA AML: 9% low birth weight, chromosomal breakage analysis
XLR: short stature, Gene sequencing for relevant
FANCB, FANCC, radial anomalies, mutations
BRCA2 (FANCD1), congenital heart disease,
FANCD2, microphthalmia,
FANCE, FANCF, FANCG, ear anomalies, deafness,
FANG/, BR/Pt (FANCJ), renal malformations,
FANCL, FANCM, hypogonadism,
PALB2 (FANCN), cafe-au-lait spots,
RAD51C, SLX4 (BTBD12) solid tumours
Severe congenital AD: MOS,AML 21-40% HAX1: Gene sequencing for relevant
neutropenia ELANE, CSF3R, GF/1 neurodevelopmental mutations
AR: G6PC3:
HAX1, G6PC3 cardiac and other
XLR:
WAS
Shwachman-Diamond AR: MOS, AML, ALL 5-24% Preceding isolated Gene sequencing for SBDS
syndrome SBDS neutropenia, mutations
pancreatic insufficiency,
short stature,
skeletal abnormalities
including metaphyseal
dysostosis
Telomere biology XLR: MOS,AML 2-30% Nail dystrophy, Telomere length measurement by
disorders DKC1 abnormal skin and fiow-FISH
including dyskeratosis AD: pigmentation, If abnormal, gene sequencing
congenita and TERT, TERC, TINF2, oral leukoplakia, for relevant mutations
syndromes RTEL1 pulmonary fibrosis,
due to TERC or TERT hepatic fibrosis,
AR: squamous cell carcinoma
mutation
NOP10, NHP2, WRAP53,
RTEL1, TERT, CTC1
patients develop MOS with a high risk B cells, and NK cells; lymphoedema; and peak incidence in adolescence. In
of evolution to AML or development of and/or other cl inical manifestations of most ch il dren with germline GATA2muta-
CMML {3755). Concurrent ASXL1 mu- GATA2 mutation may po int to the dia- tion, MOS appears to be sporadic, with-
tations have bee n reported in many gnosis. However, some patients with out a fam ily history of myeloid leukaem ia
patients with monosomy 7, some of germline GATA2 mutation present with or other GATA2-re lated symptoms {4342).
whom have a germ li ne GATA2 mutation MOS/AML without these clues. In MOS in GATA2-mutant MOS can be heralded by
{514,2656,4303}. MOS/AML develops in ch ildren and adolescents, GATA2 muta- anaemia, neutropenia, or thrombocy-
approximately 70% of affected ind ividu- tion accounts for 15% of advanced MOS topenia. Characteristic morphological
als, at a med ian patient age of 29 years cases and 7% of all MOS cases {4342). features are bone marrow hypocellu-
{2656). It is high ly prevalent among patients with larity and multi lineage dysplasia (most
The cli nical history of immunodeficiency monosomy 7, with 37% of such patients prominent in the megakaryocyte line-
associated with reduced monocytes, harbouring GATA2 germline mutations, age), including micromegakaryocytes
Myeloid neoplasms with germline predisposition associated with other organ dysfunction 127
Introduction tion of 200 AML cases found an average with a high rate of complete rem ission
of 13 mutations per case of AML, with and favourable long-term outcome.
Acute myeloid leukaemia with balanced at least 23 recurrent mutations identi-
translocations/ inversions fied {545) These discoveries and others ICD-0 code 9896/3
The recurrent genetic abnormalities in have identified at least eight distinct cat-
acute myeloid leukaem ia (AM L) are as- egori es of mutations in AM L, which are Synonyms
sociated with distinctive clinicopatho- discussed in more detail in Chapter 1 Acute myeloid leukaem ia, t(8;21)
logical features and have prognostic (Introduction and overview of the classi- (q22;q22); acute myeloid leukaemia,
significance. Those most commonly fication of the myeloid neoplasms, p. 15). AML1(CBF-alpha)/ETO; acute mye-
identified are balanced abnormalities: The current WHO classification recog- loid leukaemia with t(8;21)(q22;q22),
t(8;21)(q22;q22.1 ), inv(16)(p13.1q22) or nizes AML with mutated NPM1 and RUNX1 -RUNX1T1
t(16;16)(p13.1 ;q22), t(15;1 7)(q24.1 ;q21.2), AM L with biallelic mutation of CEBPA as
and t(9;11)(p21.3;q23.3) {511,1236,1465, specific AML classification categories Epidemiology
1466,3701). Most of these structural (entities), and AML with mutated RUNX1 The t(8;21)(q22;q22.1) is found in 1-5%
chromosomal rearrangements create a as a provisional entity. However, many of cases of AML, usually in younger pa-
fusion gene encoding a chimeric protein other mutations also occur in AML, and tients and in cases with features of AM L
that is required, but usually not sufficient, some that have prognostic significance, with granulocytic maturation.
for leukaemogenesis {3746). Many of such as FLT3 internal tandem duplication
these disease groups have characteristic (FLT3-ITD) and KIT mutations, may be Clinical features
morphological and immunophenotypic mutated in specific AML types. Tumour manifestations, such as myeloid
features {126}. Many other balanced Next-generation sequencing panels sarcoma, may be present at presenta-
translocations and inversions also recur are now available to screen for a large tion. In such cases the initial bone mar-
in AML, but are uncommon. Several of number of mutations in AML. Table 8.02 row aspiration may show a low number
these occur more common ly in paedi- (p. 146) summarizes the more common of blast cells.
atric patients, and are summarized in gene mutations in AML. It is beyond the
Table 8.01. scope of this classification to discuss Microscopy
AM L with t(8;21)(q22;q22.1 ), AML with each prognostically significant mutation The common morphological featu res in-
inv(16)(p13.1q22) or t(16;16)(p13.1;q22), in AM L individually, and the significance clude the presence of large blasts with
and acute promyelocytic leukaemia of some mutations is sti ll unclear. Some abundant basophilic cytoplasm, often
with PML-RARA are considered to be combinations of gene mutations (e.g. containing numerous azurophilic gran-
acute leukaemias without regard to blast NPM1 mutation and FLT3-ITD in normal- ules and perinuclear clearing (hofs). In
cell count. It is controversial whether al l karyotype AML) appear to cluster within many cases, a few blasts show very large
cases with t(9;1 1)(p21.3;q23.3), t(6;9) certain disease categories {9,545); the granules (pseudo- Chediak- Higashi gran-
(p23 ;q34.1), inv(3)(q21.3q26.2), t(3;3) prognostic significance of these muta- ules), suggesting abnormal fusion . Auer
(q21.3;q26.2), or t(1 ;22)(p13.3;q13.1) as tions and combinations of mutations is rods are frequently found and appear as
well as AML with the BCR-ABL1 fusion discussed within the various sections a single long and sharp rod with tapered
should be categorized as AM L when the throughout this volume. ends; they may be detected in mature
blast cell count is< 20%. Therapy-related neutroph ils. In addition to the large blast
myeloid neoplasms may also have the cells, some smaller blasts, predom inant-
balanced translocations and inversions Acute myeloid leukaemia ly in the peripheral blood, may be found.
described in this section, but these with t(B;21)(q22;q22.1); Promyelocytes, myelocytes, and mature
should be diagnosed as therapy-related neutrophils with variable dysplasia are
RUNX1-RUNX1T1
myeloid neoplasms, with the associated present in the bone marrow. These cells
genetic abnormality noted. Definition may show abnormal nuclear segmenta-
Acute myeloid leukaemia (AML) with tion (e.g . pseudo- Pelger-Huet nuclei)
Acute myeloid leukaemia with t(8; 21)(q22;q22.1) resulting in RUNX1- and/or cytoplasmic staining abnormali-
gene mutations RUNX1T1 is an AM L showing predom i- ties, including homogeneous pink cyto-
It is now understood that, in add ition to nantly neutrophilic maturation. The bone plasm in neutrophils. However, dysplasia
translocations and inversions, gene mu- marrow and peripheral blood show large of other cell lines is uncommon; erythro-
tations are also common in AM L {9,545 , myeloblasts with abundant basophilic blasts and megakaryocytes usually have
1074,3095,3651). The Cancer Genome cytoplasm, often containing azurophilic normal morphology. A monocytic compo-
Atlas (TCGA) Research Network evalua- granules. This type of AML is associated nent is usually minimal or absent. Eosino-
Chromosomal tranalocatlona
Translocation Gene fusions Frequency in Age group predilection Comments and References
children and adults, Prognosis
respectively
phil precursors are frequently increased, is reported in some cases; mast ce ll infil- lmmunophenotype
but they do not exh ibit the cytological trates may be masked by the acute leu- Most cases of AML with t(8;21) display
or cytochem ical abnormalities charac- kaemia infiltration of the bone marrow at a characteristic immunophenotype, with
teristic of AML with inv(16)(p13.1q22) diagnosis {1868). Rare cases with a bone a subpopulation of blast cells showing
or t(16;16)(p13.1 ;q22); basophils and/or marrow blast percentage < 20% occur; high-intensity expression of CD34, HLA-
mast ce ll s are sometimes present in ex- these should be class ified as AML rather DR, MPO, and CD13, but relatively weak
cess. Concurrent systemic mastocytosis than myelodysplastic syndrome. expression of CD33 {2002,3224). There
Epidemiology
Either inv(16)(p13.1q22) or t(16;16)
(p13.1;q22) is found in 5 - 8% of younger
patients with AML; the frequen cy is lower
- ...._
in older ad ults.
Fig. 8.01 Acute myeloid leukaemia with t(8;21 ) Fig. 8.02 Myeloid sarcoma with t(8;21)(q22;q22.1).
(q22;q22.1). Bone marrow blasts showing abundant Biopsy of an orbital mass from a child with acute myeloid
granular cytoplasm with perinuclear clearing and large leukaemia with t(8;21)(q22;q22.1); eosinophil precursors Clinical features
orange-pink granules/globules in some blasts. are scattered within the predominant blast population. Myeloid sarcoma may be present at
initial diagnosis or at relapse and may
are usually signs of neutrophilic differen- More than 70% of cases show additional constitute the only evidence of relapse
tiation, with subpopulations of cells show- chromosome abnormalities, such as loss in some patients. The white blood cell
ing neutrophilic maturation demonstrated of a sex chromosome or del(9q) with loss count at diagnosis is significantly higher
by CD15 and/or CD65 expression. Pop- of 9q22. K/Tmutations occur in 20-30% in AM L with inv(16)(p13.1q22) or t(16;16)
ulations of blasts showing maturation of cases {3078). Secondary cooperating (p13.1;q22) than in cases with t(8;21)
asynchrony (e.g. coexpressing CD34 mutations of KRAS or NRAS are com- (q22;q22.1) {2502,3559).
and CD15) are sometimes present. mon, occurring in 30% of paediatric and
These leukaemias frequently express the 10-20% of adult CBF-associated leu- Microscopy
lymphoid markers CD19 and PAX5, and kaemias {1 392,3077}. ASXL1 mutations In AML with inv(16)(p13 .1q22) or t(16;16)
may express cytoplasm ic CD79a {1738, occur in approximately 10% of patients, (p13.1;q22), in addition to the usual
2034,3996}. In t(8;21) AML, PAX5 is not mostly adults; ASXL2 mutations occur in morphological features of acute myelo-
directly activated by RUNX1 -RUNX1T1, 20-25% of patients of all ages {2657) monocytic leukaemia, the bone marrow
but expression requ ires constitutive shows a variable number of eosinophils
MAPK signalling {3322). Some cases Prognosis and predictive factors (usually increased, but sometimes <5%)
are TdT-positive, but TdT expression is AM L with t(8;21)(q22;q22.1) is usually at all stages of maturation, without sig-
generally weak. CD56 is expressed in a associated with a high rate of complete nifi cant maturation arrest. The most strik-
fraction of cases and may have adverse remission and long-term disease-free ing abnormalities involve the immature
prognostic significance {221,1777). The survival when treated with intensive con- eosinophilic granules, mainly evident
adverse prognostic significance of CD56 solidation therapy (e.g. high-dose cytara- at the late promyelocyte and myelocyte
may be due to higher CD56 expression in bine) {393,1466). Some factors appear to stages. The abnormalities are usually
cases with K/T mutations {894). adversely affect prognosis, including the not present at later stages of eosinophil
presence of KIT mutations in adults and maturation. The eosinophilic granu les are
Postulated normal counterpart CD56 expression {221,3078). Therapeu- often larger than those normally present
A haematopoietic progen itor cell with the tic trials investigating mutant KIT in this in immature eosinophils, are purple-violet
potential to differentiate along granulo- AML type are under way. in colour, and in some cells are so dense
cytic and monocytic lineages that they obscure the cell morphology.
The mature eosinophils occasionally
Genetic profile Acute myeloid leukaemia with show nuclear hyposegmentation. Auer
The genes for both heterodimeric com- inv(16){p13.1q22) or t(16;16) rods may be observed in myeloblasts.
ponents of core-binding factor (CBF), Neutrophils in the bone marrow are usu-
{p13.1;q22); CBFB-MYH11
RUNX1 (also called AML 1 and CBFA) ally sparse, with a decreased number of
and CBFB, are involved in rearrange- Definition
ments associated with acute leukaemias Acute myeloid leukaemia (AML) with
{3746). The t(8;21)(q22;q22.1 ) involves inv(16)(p13.1 q22) or t(16; 16)(p13.1;q22)
RUNX1, wh ich encodes the alpha subunit resulting in CBFB-MYH1 1 is an AML that
of CBF, and RUNX1T1 (ETO) {1032,2321, usually shows monocytic and granulo-
3149} The RUNX1-RUNX1T1 fusion tran- cytic differentiation and characteristically
script is consistently detected in patients an abnormal eosinophil component in
with t(8;21)(q22;q22.1) AML. The CBF the bone marrow {2236,2513,3746).
transcription factor is essential for hae-
matopoiesis; transformation by RUNX1- ICD-0 code 9871/3
RUNX1T1 likely results from transcrip-
tional repression of normal RUNX1 target Synonyms Fig. 8.03 Acute myeloid leukaemia with inv(16)
genes via aberrant recruitment of nuclear Acute myeloid leukaemia, t(16;1 6) (p13.1q22). Abnormal eosinophils, one with large baso-
transcriptional co-repressor complexes. (p1 3;q11); acute myeloid leukaemia, philic coloured granules, are present.
• •
•
IXI
•
~ I
nl 16 inv(16)
A
Fig. 8.04 Acute myeloid leukaemia with inv(16)(p13.1q22). A The inversion results from the breakage and rejoining of bands 16p13.1 and 16q22; G-banded normal chro-
mosome 16 (nl) and inv(16) are shown. B Dual-colour FISH, with the 5' region of CBFB labelled in red and the 3' region in green; in a normal chromosome 16, the 5' and
3' reg ions are contiguous, resulting in a single yellow or overlapping red/green signals; the inv(16) splits the CBFB locus, resu lting in separate red and green signals; both inter-
phase cel ls have one normal chromosome 16 and one inv(16).
mature neutrophils. The peripheral blood granulocytic lineage (positive for CD13, tions are suboptimal. Therefore FISH and
is not different from that in other cases CD33, CD15, CD65, and MPO) and the RT-PCR methods may be necessary at
of acute myelomonocytic leukaemia; eo- monocytic lineage (positive for CD14, diagnosis to document the genetic al-
sinoph il s are not usually increased, but CD4, CD11b, CD11c, CD64, CD36, and teration. Secondary cytogenetic abnor-
an occasional case has been reported lysozyme). Maturation asynchrony is malities occur in approximately 40% of
with abnormal and increased eosinophils often seen. Coexpression of CD2 with cases, with gains of chromosomes 22
in the peripheral blood. Most cases with myeloid markers has been frequently and 8 (each occurring in 10-15% of cas-
inv(16)(p13.1q22) have abnormal eosino- documented, but it is not specific for this es), del(7q), and gain of chromosome 21
phils, but in some cases they are rare diagnosis. (in -5% of cases) most common ly ob-
and difficu lt to find. Occas ional cases served (2502). Trisomy 22 is fair ly spe-
with this genetic abnormality lack eosino- Postulated normal counterpart cific for inv(16)(p13.1q22) cases, be ing
philia, show only granulocytic matura- A haematopoietic progenitor cell with the rarely detected with other primary aber-
tion without a monocytic component, or potential to differentiate along granulo- rations in AML, whereas gain of chromo-
show only monocytic differentiation. In cytic and monocytic lineages some 8 is commonly seen in patients with
some cases , the blast percentage is at other primary aberrations. Rare cases
the 20% threshold or occasionally lower. Genetic profile of AM L and chronic myeloid leukaem ia
Cases with inv(16)(p13.1q22) or t(16;16) The inv(16)(p13.1q22) found in the vast with both inv(16)(p13 .1q22) and t(9;22)
(p13.1 ;q22) and < 20% bone marrow majority of this subtype and the less (q34.1;q11.2) have been reported, and
blasts should be diagnosed as AM L. common t(16; 16)(p13.1;q22) both result this finding in chronic myeloid leukaemia
in the fusion of CBFB at 16q22 to MYH11 is usually associated with the accelerat-
Cytochemistry at 16p13.1 (3650). MYH11 codes for a ed or blast phase of the disease {4379).
The naphthol AS-D ch loroacetate ester- smooth muscle myosin heavy chain {871). Secondary gene mutations are very com-
ase (CA E) reaction, which is normally CBFB codes for the beta subunit of core- mon in this AML type; present in> 90% of
negative in eosinophils, is characteristi- bind ing factor (CBFB), a heterodimeric cases . Mutations of KIT (most commonly
cally faintly positive in the abnormal eosin- transcription factor known to bind the en- in exons 8 and 17) occur in 30- 40% of
ophils. Such a reaction is not seen in eo- hancers of the T-cell receptor, cytokine cases {3078). Mutations of NRAS (in 45%
sinoph il s of AM L with t(8;21)(q22;q22.1). genes, and othe r genes. Th e CB FB subu - of cases) , KRAS (in 13%), and FLT3 (in
At least 3% of the blasts show MPO re- nit heterodimerizes with RUNX1 (CBFA2), 14%) have also been reported {3076).
activity. The monoblasts and promono- the gene product of RUNX1, which is one ASXL2 mutations, although common in
cytes usually show non -specif ic esterase of the genes involved in AML with t(8;21) AML with t(8;21), are uncommon in AM L
reactivity, although it may be weaker than (q22 ;q22.1). Occasionally, cytological with inv(16) or t(16 ;16) {2657).
expected or eve n absent in some cases. features of AML with abnormal eos ino-
phils may be present without karyotypic Prognosis and predictive factors
lmmunophenotype evidence of a chromosome 16 abnor- Like AML with t(8;21)(q22;q22.1),
Most of these leukaemias are charac- mality, but with CBFB-MYH11 neverthe- AML with inv(16)(p13.1q22) or t(16;16)
terized by a complex immunopheno- less demonstrated by molecular genetic (p13.1;q22) is associated with a high rate
type, with the presence of multiple blast stud ies (2775,3432}. By conventional of complete rem iss ion and favourable
populations: immature blasts with hig h cytogenetic analysis, inv(16)(p13.1q22) overall survival when treated with inten-
CD34 and KIT (CD117) expression and is a subtle rearrangement that may be sive conso li dation therapy (e.g . high -
populations differentiating towards the overlooked when metaphase prepara- dose cytarabine) (1466,2772).
Clinical features
Both hypergranular and microgranular
APL are frequently associated with dis-
seminated intravascular coagu lation and
increased fibrinolysis (454,3519). Co-
Fig. 8.05 Acute promyelocytic leukaemia. A Hypergranular type; in bone marrow smear, there are several abnormal
agulopathy is associated with significant
promyelocytes, with intense azurophilic granulation; bundles of numerous Auer rods are seen in some of the
early death rates in APL patients (3282}. promyelocytes. B Microgranular variant; in peripheral blood smear, there are several abnormal promyelocytes with
In microg ranular APL, unlike hypergranu- lobed, almost cerebriform nuclei; the cytoplasm contains numerous small azurophilic granules; other cells appear
sparsely granular.
nl 15 der(15) 15 17
nl 17 der(17)
i I
t( 15; 17)(q22;q12)
A
Fig. 8.08 Acute promyelocytic leukaemia with t(15; 17)(q24.1;q21.2). A The translocation results from the breakage and rejoining of bands 15q22 and 17q12; G-banded normal
(nl) chromosomes 15 and 17 and the derivatives der(15) and der(17) are shown. B Dual-colour FISH with probes for PML (15q22) and RARA (17q12) demonstrates the presence
of a PML-RARA fusion resu lting from the 15;17 translocation; each of the three interphase cells has a separate red (PML) signal, a separate green (RARA) signal, and a yel low or
overlapping red/green signal, consistent with the presence of PML-RARA fus ion.
Epidemiology
The t(1 ;22)(p13.3;q13.1) is an uncommon
.
abnormality in AML, occurring in < 1%
of all cases. It occurs most commonly
in infants without trisomy 21 (Down syn -
drome), with a female predominance. -
Some cases are congenital {232}. Fig. 8.13 Acute myeloid leukaemia (megakaryoblastic) with t(1;22)(p13.3;q13.1). A Bone marrow section from
a 3.5-month-old chi ld shows extensive replacement of marrow by blast cells in areas arranged into clusters and
aggregates surrounded by fibrotic stroma. B Bone marrow smear contains a heteromorphic population of blasts.
Clinical features C High magnification of the specimen shows blasts without differentiating features.
Most of the balanced translocations and
inversions discussed in this chapter are medium-sized to large blasts (12-18 µm) lmmunophenotype
more common in adult AML than in pae- with a round, sli ghtly irregular, or indent- The megakaryoblasts express one or
diatric cases. However, AML with t(1 ;22) ed nucleus with fine reticular chromatin more of the platelet glycoproteins: CD41
(p13.3;q13.1) is a de nova AML restrict- and 1- 3 nucleoli. The cytoplasm is ba- (glycoprotein Ilb/II la), CD61 (glycopro-
ed to infants and young chi ldren (aged sophilic, often agranular, and may show tein Illa), and CD42b (glycoprotein lb).
~ 3 years), with most cases occurring in distinct blebs or pseudopod formation. The myeloid-associated markers CD13
the first 6 months of life (median patient Micromegakaryocytes are common, but and CD33 may also be pos itive. CD34,
age: 4 months). The vast majority of cas- dysplastic features of granulocytic and CD45, and HLA-DR are often negative;
es present with marked organomegaly, erythroid cells are not usually present. CD36 is characteristically positive but not
most commonly hepatosplenomegaly. The bone marrow is usually normocel- specific. Blasts are negative with MPO
Patients also have anaem ia and usually lu lar to hypercellular, with reticulin and antibodies. Lympho id markers and TdT
have thrombocytopenia and a moderate- collagenous fibrosis usual ly present. Due are not expressed . Cytoplasm ic expres-
ly elevated white blood cell count. to the often dense fibros is, the pattern of sion of CD41 or CD61 is more spec ific
bone marrow infiltration may mimic that of and sensitive than is surface staining.
Microscopy a metastatic tumour {357,567}. The pres-
The peripheral blood and bone marrow ence of fibrosis may cause difficulties in Postulated normal counterpart
blasts of AML with t(1;22)(p13.3;q13.1) establish in g the presence of ~20% blast A myeloid progenitor ce ll with predomi-
are similar to those of acute megakaryo- cells in the bone marrow based on the nant megakaryocytic differentiation
blastic leukaemia (one of the subtypes aspirate; correlation with bone marrow
of AML, NOS). Smal l and large mega- biopsy findings may be crucial. Genetic profile
karyoblasts may be present and they Cases should show karyotypic evidence
may be admixed with more morpholog- Cytochemistry of t(1 ;22)(p13.3;q13.1) or molecular ge-
ically undifferentiated blast cells with Cytochem ical stainin g for Sudan Black B netic evidence of RBM15-MKL1 fusion.
a high N:C ratio, resembling lympho- and MPO is consistently negative in the In most cases, t(1;22)(p13.3;q13 .1) is the
blasts. The megakaryoblasts are usually megakaryoblasts. sole karyotypic abnormality. This translo-
Synonym
Acute myeloid leukaemia with cytoplas-
mic nucleophosmin Fig. 8.14 Acute myeloid leukaemia with mutated NPM1 and myelomonocytic features. A Bone marrow biopsy shows
complete replacement by large blasts with abundant cytoplasm and folded nuclei. B and C Leukaemic cells are
CD34-negative (B) and show aberrant cytoplasmic expression of NPM1 (C). D Expression of nucleolin (also called
Epidemiology
C23) is restricted to the nucleus.
NPM1 mutation is one of the most com-
mon recurrent genetic lesions in AML both acute myelomonocytic and acute mia. Multilineage dysplasia, as seen in
{470,1075,1149,1150,3958,4185}, and is monocytic leukaemia and NPM1 mu- many cases of AML with myelodyspla-
relatively specific for AML; it occurs in tation {1149,1150); notably, 80-90% sia-related changes (AML-MRC), is ob-
2-8% of childhood cases and 27% - 35% of acute monocytic leukaemias show served in almost a quarter of cases of
of adult cases overall, as well as in NPM1 mutation. However, NPM1 muta- de nova AML with mutated NPM1. These
45-64% of adult cases with a normal kar- tions are also detected in AML with and cases usually have a normal karyotype,
yotype {470,590,749,1149,3958,4185). without maturation and in pure erythroid and the blast cells are CD34-negative.
There is a female predominance. leukaemia. The bone marrow is usually markedly hy-
The diagnosis relies on the identifica- percellular. In the setting of NPM1 muta-
Clinical features tion of the genetic lesion by molecular tion, this type of dysplasia does not result
Patients with AML with mutated NPM1 techniques and/or immunoh istochem ical in a worse prognosis, and its presence
often have anaemia and thrombocyto- detection in paraff in sections of aberrant does not eliminate a diagnosis of AML
penia, and often have higher white blood cytoplasmic expression of NPM1 {1150). with mutated NPM1 {975,1145).
cell and platelet counts than seen with lmmunostaining with anti-NPM1 antibod-
other AML types {1075). Cases may show ies reveals involvement of two or more lmmunophenotype
extramedu llary involvement; the most fre- bone marrow lineages (mye loid, mono- AML with mutated NPM1 is character-
quently affected sites are gingiva, lymph cytic, erythroid, megakaryocytic) in the ized by high CD33 expression and vari-
nodes, and skin. vast majority of cases {3083}. The vari- able (often low) CD13 expression. KIT
ability of bone marrow cell types show- (CD117), CD123, and CD110 expres-
Microscopy ing NPM1 mutation accounts for the wide sion are common {2889}. HLA-DR is
There is a strong association between morphological spectrum of this leukae- often negative. Two major subgroups of
Fig. 8.15 Multilineage invo lveme nt in acute myeloid leukaemia with mutated NPM1. A Bone marrow biopsy shows massive replacement by myeloid blasts with maturation; there
are also megakaryocytes and occasional immature erythroid cells (arrow). B Bone marrow biopsy of a minimally differentiated case shows occasional immature glycophorin-
positive erythroid cells. C Myeloid blasts and immature erythroid ce lls (arrow) show cytoplasmic expression of NPM1.
* - Mutations ofTryptophans 288 and 290 diagnosis of AML with biallelic mutation
of CEBPA (especially in younger patients)
Fig. 8.17 Acute myeloid leukaemia with mutated NPM1. Mutations usually occur at exon 12 of the NPM1 gene; the should raise concern and prompt inves-
first-identified NPM1 mutations (mutations A to F) are shown {1149); mutation A is the most frequent, accounting for tigation for the possibility of a germline
70-80% of cases; all mutations result in common changes at the C-terminus (COOH) of the wildtype NPM1 (NPM) mutation with predisposition to develop
protein; these changes (asterisk) consist of replacement of tryptophan(s) at positions 288 and 290 and creation of a AM L (see Mye/oid neoplasms with germ-
new nuclear export signal (NES) motif; both changes are responsible for the increased nuclear export and aberrant
line predisposition, p.121).
cytoplasmic accumulation of mutant NPM1.
Microscopy
A 8 AML with biallelic mutation of CEBPA has
100 100
P<0.0001 P<0.0001 no distinctive morphological features, but
the vast majority of cases have features
~00
of AML either with or without maturation
~ NPM1m"'IFLT3-ITD"eg
-~ 00 {1052,1429,1668}.
(/)
Multilineage dysplasia is reportedly pres-
~ CEBPAm"'
ic. 40
ent in 26% of cases of de novo AML with
l1J
Qi
mutated CEBPA (similar to in AML with
"'20 20
others mutated NPM1), with no adverse prog-
others
nostic significance {211). Therefore, in
the setting of biallelic CEBPA mutations,
0 1 2 3 4 5
•
Time [months]
7 8 9 10 0 1 2 3 4 s s 7
Time [months]
a 9 10
this type of dysplasia no longer excludes
a case from this category.
c NPM1mut/FL T3-ITD'eg D others
100
P=0.71
100
P=0.003 lmmunophenotype
In earlier studies that did not distinguish
~80 between single and double mutations in
<ii
.2: Donor CEBPA, leukaemic blasts were reported
~ '°
(/)
to usually express one or more of the
"!!! No-Donor Donor myeloid-associated antigens (CD13,
~ 40
c.
.!!!
CD33, CD65, CD11b, and CD15). There
"
"' 20
was usually expression of HLA-DR and
CD34 by most blasts. CD? was present
No-Donor
in 50-73% of cases, whereas expression
0 1 2 3 4 5 6
Time [months1
7 8
• 10 0 1 2 3 4 5
Time [months]
6 7 8 9 10
of CD56 or other lymphoid antigens was
uncommon {372,1776,2341). In contrast,
Fig. 8.18 Prognosis of acute myeloid leukaemia (AML) according to NPM1, FLT3, and CEBPA mutations. The geno- cases with biallelic mutation of CEBPA
types NPM1mut1 FLT3-ITDneg and CEBPAmut are favourable prognostic markers (A and B). For univariate donor versus
are reported to have a higher frequency
no-donor analysis on relapse-free survival for AML with normal karyotype in first complete remission, according to
genotype, the donor group was defined by the availability of an HLA-matched related donor. As evidenced by the of HLA-DR, CD?, and CD15 expression
results of this analysis in cases with the favourable genotype NPM1mut1 FLT3-ITDneg (C) and those with the adverse and a lower frequency of CD56 expres-
genotypes FLT3-1TDP 0 ' and NPM1w 1/CEBPAw1/ FLT3-ITDneg (D), only cases with adverse genotypes (D) benefit from sion than are cases with a single mutation
allogeneic stem cell transplantation. From Schlenk RF et al. {3560). {1705,2341). Monocytic markers such as
ITD, internal tandem duplication; mut, mutant; neg, negative; pos, positive; wt, wildtype. CD14 and CD64 are usually absent.
.. P• .2
••
P< .0001 1 u
I •.
r·M t..
I i ..'"
P• .05
IP•.5 r·.... '""""'
P< .0001
~
u
j ..". . .... t P• .034
OJ OJ P= .05
FLT3n'DINPM1 914 ......, P • .001
'" "
P"<JJOOl
O '--~~~~~~~~----c~
0 10 ~ liO 4:1 50 80
n.n. (monlha)
10 IO IO 100
P' • .CM
XI 40 ~ IO
Tl'fle{monlh&)
10
P" < .0001
.. .. .. .,
Time (monlhl) "
., .. "'
Fig. 8.19 Significance of CEPBA mutation type in acute myeloid leukaemia. A Kaplan-Meier overall survival curves for cases with CEBPA double mutations (CEBPAdm), single
mutations (CEBPA5m) and wildtype (CEBPAY-1). Band C. Kaplan-Meier overall survival curves for CEBPA"mcases (B) and CEBPAY-1 cases (C) with four genotypes: FLT3 internal
tandem duplication (FLT3-ITD) and mutant NPM1 (FLT31T0/NPM1mutant), FLT3-ITD and wildtype NPM1 (FLT31TD!NPM1w1), wildtype FLT3 and mutant NPM1 (FLT3w1/NPM1mutant), and
wildtype FLT3 and NPM1 (FLT3w1/NPM1w1) {3908).
* P value by global log-rank test.
KIT mutation t(8;21 )(q22;q22.1) Significantly shorter DFS {3063A}, RFS {408A}, EFS {408A,2016A,3576B}, and OS
{408A,523A,2016A,3063A,3095,3576B} and higher CIR (3078} and RI {523A} for patients
with KIT mutation (especially in exon 17) than for patients with wildtype KIT
In series from the USA {3207A} and Taiwan, China {3653A}, no significant difference in
CRR {3207A}, DFS {3207A}, EFS {3653A}, RR {3207A,3653A}, or OS {3207A,3653A}
between paediatric patients with and without KIT mutation; in a Japanese study,
significantly shorter DFS and OS and higher RR for paediatric patients with KIT mutation
(especially in exon 17) than for those with wildtype KIT {3657A}
KIT mutation inv(16)(p13.1q22)/t(16;16)(p13.1;q22) In most studies, no significant difference in RI {523A}, RFS {408A), PFS {1876A}, EFS
{408A}, or OS {408A,523A,1876A,3076,3095} between patients with and without KIT
mutation, or in EFS {2016A} or OS {2016A} between patients with and without KIT mutation
in exon 17 at codon 0816
In single studies, shorter RFS (3076} for patients with KIT mutation (especially in exon 8),
higher RR {564A} for patients with exon 8 KIT mutation, and higher CIR and shorter OS
(3078} for patients with exon 17 KIT mutation than for patients with wildtype KIT
In paediatric studies, no significant difference in CRR {3207A}, DFS {3207A}, EFS {3653A},
RR {3207A,3653A}, or OS {3207A,3653A} between patients with and without KIT mutation
FLT3-ITD Normal karyotype Significantly shorter DFS {372,4307A,4307C}, CRD {345A,1259A}, and OS
{345A,372,1259A,4307C} for patients with FLT3-ITD than for patients without FLT3-ITD
No significant difference in CRR between patients with and without FLT3-ITD
{345A,372,4307A,4307C}
FLT3-ITD with no expression Normal karyotype Significantly shorter DFS and OS for patients with FLT3-ITD and no expression of
ofwildtype FLT3 wildtype FLT3 than for patients without FLT3-ITD {4307A}
FLT3-ITD Various abnormal and normal Among younger patients (aged < 60 years), significantly shorter OS for patients with
karyotypes combined FLT3-ITD than for patients without FLT3-ITD (3095}
FLT3-ITD mutant level Various abnormal and normal Increasingly worse RR and OS (but not CRR) with increasing FLT3-ITD mutant level (i.e.
karyotypes combined the proportion of total FLT3 alleles accounted for by FLT3-ITD) in a comparison of mutant
levels in 4 subsets of patients: without FLT3-ITD, with low (1 -24%) FLT3-ITD mutant level,
with intermediate (25-50%) mutant level, and with high (>50%) mutant level (1278}
Biallelic CEBPA mutation Normal karyotype Significantly higher CRR (3908} and DFS (1705} and longer RFS (3908}, EFS (3908},
and OS (1052,1705,3908} for patients with double CEBPA mutation than for patients with
wildtype CEBPA
Biallelic CEBPA mutation Various abnormal and normal Significantly longer DFS (1705,3022}, EFS (4368}, and OS (1429,1705,3022,4368} for
karyotypes combined patients with double CEBPA mutation than for patients with wildtype CEBPA or
single CEBPA mutation
Single CEBPA mutation Normal karyotype Significantly lower CRR (3908} and shorter DFS (1705} and OS (1705} for patients with
single CEBPA mutation than for patients with double CEBPA mutation
NPM1 mutation Normal karyotype In some studies, significantly higher CRR (3577} and longer DFS (3958}, RFS (1075), and
EFS (3577) for patients with NPM1 mutation than for patients with wildtype NPM1; in other
studies, no significant difference in CRR {258A,408C}, RFS {258A,408C,3577}, or EFS
{258A,408C} between patients with and without NPM1 mutation
No consistently observed significant difference in OS between patients with and
without NPM1 mutation {258A,408C,1075,3577,3958}
Among older patients (aged ~ 60 years), significantly better CRR, DFS, and OS for patients
with NPM1 mutation than for patients with wildtype NPM1 (310)
NPM1 mutation & FLT3-ITD Normal karyotype Significantly better CRR (3560}, EFS (3577), RFS (1075,3560}, DFS (3958}, and OS
(1075,3560,3577,3958} for patients with NPM1 mutation without FLT3-ITD than for patients
with NPM1 mutation and FLT3-ITD or with wildtype NPM1 with or without FLT3-ITD
RUNX1 mutation Normal karyotype Significantly lower CRR (2627}; higher resistant disease rate (1274}; and shorter DFS
(2627,3897}, EFS (1274,2627,3576}, and OS (2627,3576,3897} for patients with RUNX1
mutation than for patients with wildtype RUNX1
RUNX1 mutation Non-complex karyotype (i.e. 1 Significantly shorter EFS and OS for patients with RUNX1 mutation than for patients with
or 2 abnormalities and a normal wildtype RUNX1 (3576)
karyotype combined)
KMT2A-PTD Normal karyotype No difference in CRR, DFS, or OS between patients with and without KMT2A-PTD,
either among younger patients (aged < 60 years) receiving intensive treatment including
autologous stem cell transplantation (43070) or among older patients (aged ;?: 60 years)
(43078)
In earlier studies, significantly worse CRD (but not CRR or OS) {526A,1075A} and
higher RR or risk of death during CR (3560) for patients with KMT2A-PTD than for patients
without KMT2A-PTD
KMT2A-PTD Various abnormal and normal Among younger patients (aged < 60 years), significantly shorter OS for patients with
karyotypes combined KMT2A-PTD than for patients without KMT2A-PTD (3095)
WT1 mutation Normal karyotype Significantly lower CRR {4197A}; higher resistant disease rates {4197A), RR {33438), and
CIR {4197A}; and shorter DFS {3078A}, RFS {4197A}, EFS {21048), and OS {3078A} for
patients with WT1 mutation than for patients with wildtype WT1
Among younger patients (aged S60 years), significantly worse CRR, RFS, and OS for
patients with WT1 mutation and FLT3-ITD than for patients with WT1 mutation
without FLT3-ITD {12748)
In studies in Europe {16688} and the USA {1646A}, significantly worse CRR {16688}, EFS
{1646A,16688}, and OS {1646A,16688) for paediatric patients with WT1 mutation than for
those with wildtype WT1; in a Japanese study {3513A}, no significant difference in
DFS or OS
WT1 mutation Various abnormal and normal Significantly worse RR and OS for patients with WT1 mutation than for patients with
karyotypes combined wildtype WT1 {33438); no significant difference in EFS (21048}
In studies in Europe (16688} and the USA {1646A}, significantly worse resistant disease
rates {16688}, CIR (16688}, EFS {1646A,16688}, and OS {1646A,16688} for paediatric
patients with WT1 mutation than for those with wildtype WT1; in a Japanese study {3513A},
no significant difference in DFS or OS
TET2 mutation Normal karyotype No significant difference in CRR {864A,1274A,2648C}, DFS {2648C}, RFS {864A,1274A},
EFS {1274A,2648C}, or OS {864A,1274A,2648C,4290A} between patients with and without
TET2 mutation
Significantly worse CRR {2648C}, DFS {2648C}, RR {4290A}, EFS {2648C,4290A}, and OS
{2648C} for patients with TET2 mutations classified in the ELN favourable genetic groupc
{but not those in the intermediate-I groupc) than for patients with wildtype TET2; one study
{1274A}, reported higher CRR for younger patients (aged s 60 years) with TET2 mutations
classified in the ELN intermediate-I genetic groupc (but not those in the favourable groupc)
than for those with wildtype TET2
Significantly worse RR {4290A}, EFS {4290A}, and OS {3998A} for patients with TET2 and
NPM1 mutation without FLT3-ITD than for patients with wildtype TET2; similarly, TET2
mutation was associated with shorter RFS and OS in younger patients (aged s 60 years)
with FLT3-ITD {864A} and with shorter OS in patients with NPM1 mutation {3998A}
TET2 mutation Various abnormal and normal Among younger patients (aged S60 years), no significant difference in CRR, RFS, EFS,
karyotypes combined or OS between patients with and without TET2 mutation {1274A}
ASXL1 mutation Normal karyotype Significantly worse CRR {2648A}, DFS {2648A}, EFS {2648A,3576A}, and OS
{2648A,3576A} for patients with ASXL1 mutation than for patients with wildtype ASXL1
Among older patients (aged ;?: 60 years), significantly worse CRR, DFS, EFS, and OS for
patients with ASXL1 mutation classified in the ELN favourable genetic groupc {but not those
in the intermediate-I genetic groupc) than for patients with wildtype ASXL1 {2648A}
ASXL1 mutation Various abnormal and normal Significantly worse CRR {748A,3079,3232A}, RFS (3079), and OS {748A,3079,
karyotypes combined 3095,3232A} for patients with ASXL1 mutation than for patients with wildtype ASXL1
ASXL1 mutation Intermediate-risk karyotypeb Significantly shorter EFS and OS for patients with ASXL1 mutation than for patients with
wildtype ASXL1 {3576A}
DNMT3A mutation Normal karyotype In some studies, significantly worse CRR {3987A), DFS {2501E}, EFS {3343A},
and OS {3343A,3987A} for patients with DNMT3A mutation (R882 or non-R882) than
for patients with wildtype DNMT3A; in other studies, no difference in CRR {1274C}, RFS
{1274C,3987A}, EFS {1274C}, or OS {1274C}
Among younger patients (aged s: 60 years) with NPM1 mutation, significantly shorter EFS and
OS for patients with DNMT3A mutation (mainly R882) than for patients with
wildtype DNMT3A {3343A}
Among younger patients (aged s: 60 years), significantly shorter RFS and OS for patients
with DNMT3A mutation (mainly R882) classified in the ELN intermediate-I genetic groupc than
for patients with wildtype DNMT3A; no difference in outcome between patients with and without
DNMT3A mutation classified in the favourable genetic groupc {1274C}
Among younger patients (aged 560 years) with either NPM1 mutation without FLT3-ITD or
biallelic CEBPA mutation, significantly shorter EFS and OS for patients with DNMT3A mutation
than for patients with wildtype DNMT3A {3343A}
DNMT3A R882 mutation Normal karyotype Among older patients (aged ~ 60 years), significantly shorter DFS and OS for patients with
DNMT3A R882 mutation than for patients with wildtype DNMT3A {2501E}
Non-R882 DNMT3A mutation Normal karyotype Among younger patients (aged <60 years), significantly shorter DFS for patients with
non-R882 DNMT3A mutation than for patients with wildtype DNMT3A {2501E}
DNMT3A mutation Various abnormal and normal Among younger patients (aged s: 60 years), significantly higher CRR but no significant
karyotypes combined difference in RFS, EFS, or OS for patients with DNMT3A mutation (R882 and non-R882
combined) than for patients with wildtype DNMT3A {1274C}
IDH1 mutation Normal karyotype No significant difference in CRR (4088,2501D}, DFS {2501 D}, RR {4088), or OS (4088,2501 D}
between patients with IDH1 mutation and patients with wildtype IDH1 and IDH2
IDH1 R132 mutation Normal karyotype Among patients with NPM1 mutation without FLT3-ITD, significantly shorter DFS for patients
with IDH1 R132 mutation than for patients with wildtype IDH1 and IDH2 {2501 D}
Among patients with NPM1 or CEBPA mutation without FLT3-ITD, significantly higher RR and
shorter OS for patients with IDH1 R132 mutation than for patients with wildtype IDH1 {4088)
IDH2 mutation Normal karyotype No significant difference in CRR, RFS, or OS between patients with and without IDH2 mutation
(mostly R140); this was also true in a subset of patients with NPM1 mutation without
FLT3-ITD {39878)
IDH2 R172 mutation Normal karyotype Significantly worse CRR (4088,25010), RR {4088), and OS (4088) for patients with IDH2 R172
mutation than for patients with wildtype IDH2
IDH2 R140 mutation Normal karyotype No significant difference in CRR, DFS, or OS between patients with IDH2 R140 mutation and
patients with wildtype IDH1 and IDH2 {2501 D}
IDH2 R140Q mutation Various abnormal and normal Among younger patients (aged < 60 years), significantly longer OS for patients with IDH2
karyotypes combined R140Q mutation than for patients with wildtype IDH2 (3095)
IDH1 and IDH2 mutations Normal karyotype Significantly shorter DFS and OS for patients with IDH1 or IDH2 mutation than for patients with
combined wildtype IDH1 and IDH2 {2889A}
Among younger patients (aged s: 60 years), no significant difference in CRR, RFS, or OS
between patients with IDH1 or IDH2 mutation and patients with wildtype IDH1 and IDH2; but
in a subset of patients with NPM1 mutation without FLT3-ITD, significantly shorter RFS for
patients with IDH1 or IDH2 mutation than for patients with wildtype IDH1 and IDH2 {30788)
IDH1 and IDH2 mutations Various abnormal and normal Among younger patients (aged s: 60 years), no significant difference in CRR, RFS, or OS
combined karyotypes combined between patients with IDH1 mutation or with either IDH1 or IDH2 mutation and patients with
wildtype IDH1 and IDH2 {30788)
TP53 alteration (mutation or loss) Complex karyotype Significantly shorter RFS, EFS, and OS for patients with TP53 alteration than for patients with
(~ 3 abnormalities)d wildtype TP53 {3462A}
TP53 mutation Complex karyotype No significant difference in CRR, DFS, or OS between patients with and without TP53 mutation
(~ 5 abnormalities) {439A}
TP53 mutation Abnormalities of chromosome 5, Significantly shorter OS for patients with TP53 mutation than for patients with wildtype TP53
7, or 17 and/or complex karyotype {439A}
(~5 abnormalities)
BAALC expression Various abnormal and normal No significant difference in CIR {1620A}, EFS {1620A}, or OS {1620A,3763A} between
karyotypes combined paediatric patients with high and low BAALC expression; in one study {3763A},
high expression was associated with significantly shorter EFS
ERG expression Normal karyotype Significantly worse CRR {2501C,26488}, DFS (26488}, EFS {2501C}, CIR {2501A}, and
OS {2501A,26488,3594C} for patients with high ERG expression in blood {2501A,2501C}
or bone marrow (26488} than for patients with low expression
No significant difference in CIR, EFS, or OS between paediatric patients with high and low
ERG expression {1620A}
ERG expression Various abnormal and normal No significant difference in CIR, EFS, or OS between paediatric patients with high and low
karyotypes combined ERG expression {1620A}
MN1 expression Normal karyotype Significantly lower CRR {2217A,35948}; higher RR {1631A}; and shorter RFS {1631A},
EFS (35948}, and OS {1631A,2217A} for patients with high MN1 expression than for
patients with low expression
DNMT38 expression Normal karyotype Among older patients (aged ~ 60 years), significantly lower CRR and shorter DFS and OS
for patients with high DNMT3B expression than for patients with low expression {2870A}
SPARC expression Normal karyotype Among younger patients (aged < 60 years), significantly lower CRR and shorter DFS and
OS for patients with high SPARC expression than for patients with low expression {50A}
MECOM expression Normal karyotype Among younger patients (aged ::; 60 years), significantly shorter EFS for patients with high
MECOM (EV/1) expression than for patients with low expression {1479A}
MECOM expression Various abnormal and normal Among younger patients (aged ::; 60 years), significantly lower CRR and shorter RFS and
karyotypes combined EFS for patients with high MECOM (EV/1) expression than for patients with low expression
{1479A}
MECOM expression Intermediate-risk karyotypeb Among younger patients (aged ::; 60 years), significantly shorter RFS and EFS for patients
with high MECOM (EV/1) expression than for patients with low expression {1479A}
MIR181A expression Normal karyotype Among younger patients (aged < 60 years), significantly better CRR and OS for patients
with high MIR181A expression than for patients with low expression {3594A}
MIR3151 expression Normal karyotype Among older patients (aged ~ 60 years), significantly shorter DFS and OS for patients with
high MIR3151 expression than for patients with low expression {1085A}
MIR3151 expression Intermediate-risk karyotypeb Significantly shorter DFS and OS and higher CIR for patients with high MIR3151 expression
than for patients with low expression (9748}
MIR155 expression Normal karyotype Significantly lower CRR and shorter DFS and OS for patients with high MIR155 expression
than for patients with low expression {25018}
Definition Table 8.03 Diagnostic criteria for acute myeloid leukaemia with myelodysplasia-related changes (AML-MRC)
Acute myeloid leukaemia with myelodys- The diagnosis of AML-MRC requires that the following 3 criteria are met.
plasia-related changes (AM L-MRC) is an
acute leukaemia with ;::: 20% peripheral 1 ~ 20% blood or marrow blasts
blood or bone marrow blasts with mor- 2 Any of the following:
pholog ical features of myelodysplasia, or - History of myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm
occurring in patients with a prior history · Myelodysplastic syndrome-related cytogenetic abnormality (Table 8.04)
of a myelodysplastic syndrome (MOS) or • Multilineage dysplasia•
myelodysplastic/myeloproliferative neo-
3 Absence of both of the following:
plasm (MOS/MPN), with MOS-related
cytogenetic abnormalities; the specific - Prior cytotoxic or radiation therapy for an unrelated disease
- Recurrent cytogenetic abnormality as described in Acute mye/oid leukaemia with recurrent
genetic abnormalities characteristic of
genetic abnormalities (p. 130)
acute myeloid leukaemia (AML) with re-
current genetic abnormalities are absent. 8 Multilineage dysplasia alone is insufficient for a diagnosis of AML-MRC in a de nol/O case of AML with
Patients should not have a history of prior mutated NPM1 or biallelic mutation of CEBPA (see text for details).
cytotoxic or radiation therapy for an unre-
lated disease. Therefore, there are three
possible reasons for classifying a case transformation, and may have clinical be- Microscopy
as this subtype (Table 8.03): AML arising haviour more similar to that of MOS than Most cases in this category of AM L have
from previous MOS or MOS/MPN, AML that of AML {1590}. Some authors rec- morphological evidence of multilineage
with an MOS-related cytogenetic abnor- ommended categorizing such cases as dysplasia, which must be assessed on
mality and AML with multilineage dyspla- a favourable prognostic subtype of AML well-stained smears of peripheral blood
sia. A given case may be classified as (1590). However, this recommendation is and bone marrow. For an AM L to be clas-
this subtype for one, two or all three of controversial. The National Comprehen- sified as having myelodysplasia-related
these reasons. sive Cancer Network (NCCN) Clinical changes based on morphology, dyspla-
Practice Guidelines for Myelodysplas- sia must be present in ::::50% of the cells
ICD-0 code 9895/3 tic Syndromes, which endorse using in at least two haematopoietic cell lines.
the WHO classification system, recom- Oysgranulopoiesis is characterized by
Synonyms mend that cases with 20-29% marrow neutrophils with hypogranular cytoplasm,
Acute myeloid leukaem ia with multiline- blasts and a stable clinical course for hyposegmented nuclei (pseudo-Pelger-
age dysplasia; acute myeloid leukaemia ::::2 months be considered as either MOS Huet anomaly) or bizarrely segmented
with prior myelodysplastic syndrome or AML, in order for such cases to be eli- nuclei. In some cases, these features
gible for treatment as either entity {1443}. can be more readily identified on periph-
Epidemiology Several important findings support this eral blood than bone marrow smears.
AML-MRC occurs mainly in elderly pa- recommendation: (1) patients with 20- Oyserythropoiesis is characterized by
tients, and is rare in chi ldren {1595,2261}. 29% marrow blasts have previously been megaloblastosis, karyorrhexis, and nu-
Although the definitions of multilineage included in and benefited from major clear irregularity, fragmentation or multi-
dysplasia in the literature vary, this cat- therapeutic trials for MOS {1183,1796); (2) nucleation. Ring sideroblasts, cytoplas-
egory appears to account for 24 to 35% survival and disease evolution were simi- mic vacuoles and periodic acid- Schiff
of all cases of AM L {132,885,1514,2682, lar in the MOS patient groups with 10- (PAS) positivity are additional features of
4276,4416). 19% and 20-29% marrow blasts {1444}; dyserythropoiesis. Oysmegakaryopoie-
and (3) molecular and cytogenetic fea- sis is characterized by micromegakaryo-
Clinical features tures have been reported to be similar cytes and normal-sized or large mega-
AML-MRC often presents with severe between these two patient groups (210}. karyocytes with non-lobated or multiple
pancytopen ia. Some cases with 20-29% Molecular genetic factors (rather than nuclei. Oysplastic megakaryocytes may
blasts, especially cases ari sing from strictly morphological or historical fac- be more readily appreciated in sections
MOS or in ch ildhood, may be slowly pro- tors) have helped refine the diagnosis of than on smears (132,1270).
gressive. Such cases, with relatively sta- MOS-type AML; a set of gene mutations Some cases lack sufficient non-blast
ble peripheral blood counts for weeks or defines a subset of de nova AML cases, bone marrow elements to adequately
months, are categorized by the French- including those that evolved from MOS, assess for multilineage dysplasia; oth-
American-British (FAB) classification as with clinical features and therapeutic re- ers have sufficient non-blast cells but do
refractory anaemia with excess blasts in sponses highly specific for MOS (2351}. not meet the criteria described above for
Clinical features
Two subsets of t-MNs are generally
recogn ized c linically {1976,2221,3119,
3435,3709}. The more common occurs
5- 1O years after exposure to alkylating
agents and/or ionizing radiation . These
cases often present with an MOS with
marrow failure and one or more cytope-
I
nias, although a minority present with
Fig. 8.22 Therapy-related acute myeloid leukaemia (t-AML) with t(9;11 )(p22;q23). This patient developed t-AML < 1
t-MDS/MPN or overt t-AML. This subset year following initiation of therapy for osteosarcoma, which included both alkylating agents and topoisomerase II
is commonly associated with unbalanced inhibitors.
loss of genetic material, often involving
chromosomes 5 and/or 7, as well as com- acute leukaemia associated with multi- may be designated as t-MDS or t-AML
plex karyotypes and mutations or loss of lineage dysplasia {130,2654,3709,41 54, depending on the blast percentage, but
TP53. The second t-MN subset accounts 4479). There is commonly an elic ited whether the percentage of blasts is prog-
for 20- 30% of cases, has a shorter latent history of prior therapy with alkylating nostically sig nificant in this group with
period (1 - 5 years), and follows treatment agents and/or radiation therapy, and MOS-related features is unclear {208 ,
with agents that interact with DNA topoi- cytogenetic studies often reveal abnor- 1211 ,2124,3686,4479). About half of the
somerase II (topoisomerase II inhibitors). malities of chromosomes 5 and/ or 7 or cases that present with a myelodysplas-
Most cases in this subset do not have a complex karyotype, often associated tic phase have < 5% bone marrow blasts,
a myelodysplastic phase but present with mutated TP53 {2351,3253,3652). but they often exhibit poor-risk cytogenet-
with overt acute leukaemia, often as- The peripheral blood shows one or more ics {2654,3686). The diagnosis of t-MDS,
sociated with a balanced c hromosomal cytopenias. Anaemia is almost always t-AML, or t- MDS/MPN should include the
translocation . Althoug h it may be useful present and red blood cell morphology assoc iated cytogenetic abnormalities.
to consider t-MN cases as being either is usually characterized by macrocytosis In 20- 30% of cases, the first manifesta-
alkylating agent/radiation-related or and poikilocytosis. Dysplastic c hanges tion of a t-MN is overt acute leukaemia
topoisomerase II inhibitor-related, many in the neutrophi ls include abnormal nu- without a preceding myelodysplastic
patients have received multiple types of clear segmentation and hypogranular phase {2654,3435,3709}. These cases
therapy, and the boundaries between cytoplasm. Basophilia is freq uently pre- often occur following topoisomerase 11 in-
these two categories are therefore not sent. The bone marrow may be hypercel- hibitor therapy, and most are associated
always clear {1976). Most cases of t-MN lular, normocellular, or hypocellular, and with recurrent balanced chromosomal
present within 10 years of the most recent reticu li n fibrosis is common {852,2654). translocations, which freq uently involve
exposure, and the origin of AML in cases Dysg ranulopoiesis and dyserythropoie- 11q23 (KMT2A, previous ly called MLL)
with very long latent periods may be un- sis are usually present. Most cases show or 21q22.1 (RUNX1) and have a morphol-
related to therapy {1420}. dysplastic megakaryocytes with non- ogy resembling that of de nova acute
lobated or hypolobated nuclei or widely leukaemia associated with these same
Microscopy separated nuclear lobes. Cases present- c hromosomal abnormalities, although
Most patients present with an MOS or ing with myelodysplasia and cytopenias a few such cases p resent as MOS or
i9V00o~""000 00 ~: -C ~- .
o o 0 o o o J'o,••'·
o ooo ·o 00 o o 0
o o ooOo o oooo .•
~o.Q 0 0 o oo o00 oo0 .·
o o
go
o0 o 0°0 0 ~a ol .··
0 o,. oo o •
100 0 00 00 0 0 o 0 0 c
A0_ o_ _o__ o~" _o 1 • ... ..
Fig. 8.23 Therapy-related myelodysplastic syndrome /acute myeloid leukaemia. This 42-year-old man was treated with ABVD chemotherapy (i.e. doxorubicin, bleomycin, vin-
blastine, and dacarbazine) for classic Hodgkin lymphoma, then relapsed 16 months later and was given salvage chemotherapy and radiotherapy; 2 years later, he presented with
pancytopenia in the peripheral blood (A) and a bone marrow aspirate (B) and bone marrow biopsy (C) showed increased blasts and multilineage dysplasia. The karyotype was
complex and included loss of chromosomes 5 and 7.
Fig. 8.28 Acute myelomonocytic leukaemia. A Blood smear shows a myeloblast, a monoblast, and promonocytes. B Bone marrow smear shows myeloblasts and several more-
mature monocytes, including promonocytes. C Non-specific esterase reaction on a bone marrow smear reveals several positive cells; the non-reacting cells are predominantly
myeloblasts and neutrophil precursors.
Fig. 8.31 Acute monocytic leukaemia, testicular infiltration. A and B The monocytic cells have relatively abundant Epidemiology
cytoplasm and very dispersed chromatin. Pure erythroid leukaemia is extremely
rare. It can occu r at any age, including in
nant lymphoma or soft tissue sarcomas. Cell of origin childhood. It can occur de nova, but more
Occasional cases resemble prolympho- The postulated cell of origin is a haemato- often occurs as progression of a prior
cytic leukaemia; they are readily distin- poietic stem cel l. myelodysplastic syndrome or as therapy-
guished by immunophenotyping and related disease (2371,4247). Therapy-
cytochemistry. The major differential dia- Genetic profile related cases should be diagnosed as
gnoses of acute monocytic leukaemia Myeloid-associated, non-specific cyto- therapy-related myeloid neoplasms.
include chron ic myelomonocytic leukae- genetic abnormalities are present in
mia, acute myelomonocytic leukaemia, most cases. The t(8;16)(p11. 2;p13.3) Clinical features
and microgranular acute promyelocytic can be associated with acute monocytic The clinical features are not unique,
leukaemia. These can be distinguished leukaemia or acute myelomonocytic leu- but profound anaemia and circu lating
by careful examination of well-stained kaemia and in most cases is associated erythroblasts are common .
smears. The differential diagnosis with with haemophagocytosis (in particu lar
chron ic myelomonocytic leukaemia is erythrophagocytosis) by leukaemic cells Microscopy
critical; it relies on the proper identifica- and with coagulopathy (972,3768}. Pure erythroid leukaemia is character-
tion of promonocytes and their inclusion ized by the presence of medium-sized
as blast equivalents. The abnormal pro- to large erythroblasts, usually with round
myelocytes in acute promyelocytic leu- Pure erythroid leukaemia nuclei, fi ne chromatin, and one or more
kaemia show intense MPO and naphtha! nucleoli (proerythroblasts); the cyto-
AS-0 chloroacetate esterase (CAE) posi- Definition plasm is deeply basophilic and agranular
tivity, whereas the monocytes are weakly Pure erythroid leukaemia is a neoplas- and frequently contains vacuoles , which
reactive or negative. tic proliferation of immature cells (und if- often give a positive period ic acid-Schiff
ferentiated or proerythroblastic in ap- (PAS) reaction. Occasionally, the blasts
lmmunophenotype pearance) committed exclusively to the are smal ler, with scanty cytoplasm, and
Flow cytometry shows that these leukae- erythroid lineage (> 80% of the bone can resemble the lymphoblasts of lymph-
mias variably express the myeloid antigens marrow cells are erythroid, with z30% oblastic leukaemia. The cells are nega-
CD13, CD33 (often very bright), CD15, and proerythroblasts), with no evidence of tive for MPO and Sudan Black B staining;
CD65. There is generally expression of at a significant myeloblastic component they show reactivity with alpha-naphthyl
least two markers characteristic of mono- (2095,2281,2371). acetate esterase, acid phosphatase, and
cytic differentiation, such as CD14, CD4, Cases previously classified as erythro- PAS (with PAS, usually in a block-like
CD11b, CD11c, CD64 (bright), CD68, leukaemia (erythroid/myeloid type) on staining pattern). In bone marrow biopsy
CD36 (bright), and lysozyme. CD34 is the basis of counting myeloblasts as a sections of pure erythroid leukaemia,
positive in only 30% of cases, whereas percentage of non-erythroid cells when the cel ls appear undifferentiated and
KIT (CD11 7) is more often expressed. erythroid precursor cells constituted
Most cases are positive for HLA-DR. z50% of the marrow cells are now clas-
MPO can be expressed in acute mono- sified on the basis of the total bone mar-
cytic leukaemia and less often in mono- row or peripheral blood blast cell count.
blastic leukaemia. Aberrant expression Such cases are classified as myelodys-
of CD? and/or CD56 is found in 25-40% plastic syndrome with excess blasts if
of cases. By immunohistochemistry in blasts constitute < 20% of all marrow or
paraffin-embedded bone marrow biopsy blood cells, and usually as acute myeloid
specimens and in extramedullary myeloid leukaemia (AML) with myelodysplasia-re-
(monoblastic) sarcomas, MPO and CAE lated changes if blasts constitute z20%
are typically negative but can be weakly of the cells, irrespective of the erythroid
positive. Lysozyme is often positive, but is precursor cell count.
Fig. 8.32 Pure erythroid leukaemia.
also expressed in AML lacking monocytic smear with numerous very immature erythroid precur-
differentiation. CD68 (PGM1) and CD163 ICD-0 code 9840/3 sors; these cells have cytoplasmic vacuoles, which oc-
are often positive. casionally coalesce.
Epidemiology
Acute megakaryoblastic leukaemia is an
uncommon disease, accounting for < 5%
of cases of AM L. It occurs in both adults
and children.
Clinical features
•l
Fig. 8.34 Pure erythroid leukaemia. A Bone marrow smear shows four abnormal proerythroblasts; the erythroblasts Patients present with cytopen ias (often
are large, with finely dispersed chromatin, prominent nucleoli, and cytoplasmic vacuoles, some of which are thrombocytopenia), although some may
coalescent. B The cytoplasm of the proerythroblasts shows intense globular periodic acid-Schiff (PAS) staining. have thrombocytosis. Dysplastic features
Microscopy
The megakaryoblasts are usually medi-
um-sized to large blasts (12-18 µm) with ....
Fig. 8.36 Acute megakaryoblastic leukaemia. Bone marrow smear (A) and bone marrow section (B) from a
-
a round, slightly irregular, or indented 22-month-old child, with complete replacement by poorly differentiated blasts.
nucleus with fine reticular chromatin and
1-3 nucleoli. The cytoplasm is basophilic,
often agranular, and may show distinct
blebs or pseudopod formation. In some
cases, the blasts are predominantly small
with a high N:C ratio, resembling lympho-
blasts; large and small blasts may be
present in the same patient. Occasional-
ly, the blasts occur in small clusters. Cir-
culating micromegakaryocytes, mega-
karyoblast fragments, dysplastic large
platelets, and hypogranular neutrophils Fig. 8.37 Acute megakaryoblastic leukaemia A Bone marrow smear shows two megakaryoblasts, which are large
may be present. Micromegakaryocytes cells with cytoplasmic pseudopod formation; portions of the cytoplasm are zoned, with granular basophilic areas and
should not be counted as blasts. In some clear cytoplasm; nucleoli are unusually prominent. B The cytoplasm of the megakaryoblasts is intensely reactive with
patients, because of extensive bone mar- antibody to CD61 (platelet glycoprotein Illa).
row fibrosis resulting in so-called dry tap,
the percentage of bone marrow blasts is esterase (CAE), and MPO is consistent- megakaryoblastic leukaemia, acute pan-
estimated from the bone marrow biopsy. ly negative in the megakaryoblasts; the myelosis with fibros is, and AML-MRC can
Imprints of the biopsy may also be useful. blasts may give a positive periodic acid- be problematic. In such cases, careful
Although acute megakaryoblastic leu- Schiff (PAS) reaction, show reactivity for immunohistochemical analysis of bone
kaemia can be associated with extensive acid phosphatase, and show punctate or marrow biopsy can be particularly help-
fibrosis, this is not an invariable finding. focal non-specific esterase reactivity. ful {2991}.
The histopathology of the biopsy speci-
men varies; some cases have a uniform Differential diagnosis lmmunophenotype
population of poorly differentiated blasts The differential diagnosis includes mini- The megakaryoblasts express one or
and others have a mixture of poorly dif- mally differentiated AML, AML-MRC, more of the platelet glycoproteins: CD41
ferentiated blasts and maturing dysplas- acute panmyelosis with myelofibrosis, (glycoprotein lib/Illa), CD61 (glycopro-
tic megakaryocytes. Various degrees of lymphoblastic leukaemia, pure eryth- tein Illa), and CD42b (glycoprotein lb).
reticu lin fibrosis can be present. ro id leukaemia, blastic transformation The myeloid-associated markers CD13
of chronic myeloid leukaemia, and the and CD33 may be positive. CD34, the
Cytochemistry blast phase of any other myeloprolifera- panleukocyte marker CD45, and HLA-
Cytochemical staining with/for Sudan tive neoplasm. In blastic transformation DR are often negative, especially in chil-
Black B, naphthol AS-0 chloroacetate of chronic myeloid leukaemia and the dren; CD36 is characteristically positive
blast phase of any other myeloprolifera- but not specific . Blasts are negative with
tive neoplasm, there is usually a history MPO antibody and with other markers
of a chronic phase, and splenomegaly is of granulocytic differentiation. Lymphoid
an almost invariable finding . Some meta- markers and TdT are not expressed,
static tumours in the bone marrow, in but there may be aberrant expression of
particular in children (e.g. alveolar rhab- CD?. Cytoplasmic expression of CD41 or
domyosarcoma), may resemb le acute CD61 is more spec ific and sensitive than
megakaryoblastic leukaemia. In general, is surface staining, due to possible ad-
acute megakaryoblastic leukaemia con- herence of platelets to blast cells, which
..
Fig. 8.35 Acute megakaryoblastic leukaemia. Bone
marrow biopsy section showing virtually complete
stitutes a proliferation predominantly of
megakaryoblasts, whereas acute pan-
myelosis is characterized by a trilineage
proliferation of granulocytes, megakaryo-
can be misinterpreted as positive staining
on flow cytometry. In cases with fibrosis,
immunophenotyping on bone marrow
trephine biopsy sections is particularly
replacement by a population of blasts; one micromega- cytes, and erythroid precursors. In some important for diagnosis. Megakaryocytes
karyocyte can be seen. cases, the distinction between acute (and in some cases megakaryoblasts)
can be recognized by a positive reac- Acute basophilic leukaemia may be vacuolation of the cytoplasm.
tion with antibodies to von Willebrand Immature forms can be seen, but mature
factor, the platelet glycoproteins (CD61 Definition basophils are usually sparse. Dysplastic
and CD42b), and LAT; the detection of Acute basophilic leukaemia is an acute features in the erythroid precursors may
platelet glycoproteins is most lineage- myeloid leukaemia (AML) in which the be present. Electron microscopy shows
specific, but detection is highly depend- primary differentiation is to basoph ils. that the granules have features charac-
ent on the procedures used for fixation Acute basophilic leukaemia does not fulfil teristic of basophil precursors; they con-
and decalcification. the criteria for inclusion in any of the pre- tain an electron-dense particulate sub-
viously described groups (i.e. AM L with stance, are internally bisected (e.g. have
Cell of origin recurrent genetic abnormalities, AML a theta character), or contain crystalline
The postu lated cell of orig in is a with myelodysplasia-related changes, or material arranged in a pattern of scrolls
haematopoietic stem cell. therapy-related AML). or lamellae (which is more typical of mast
cells) {3148}. The most characteristic
Genetic profile ICD-0 code 9870/3 cytochem ical reaction is metachromatic
There is no unique chromosomal abnor- staining with toluidine blue. The blasts
mality associated with acute megakary- Synonym usually show a diffuse pattern of staining
oblastic leukaemia in adults. Complex Basophilic leukaemia (no longer used) with acid phosphatase, and in some cas-
karyotypes typical of myelodysplastic es show periodic acid- Schiff (PAS) pos-
syndrome, inv(3)(q21 .3q26.2), and t(3;3) Epidemiology itivity in large blocks; the blasts are often
(q21 .3q26.2) can all be associated with Acute basoph ilic leukaemia is a very rare negative for naphthol AS-D chloroacetate
megakaryoblastic/ megakaryocytic dif- disease, with a relatively small number esterase (CAE), Sudan Black B staining,
ferentiation {873,2964), but such cases of reported cases. It accounts for < % of MPO, and non-specific esterase. The
should be assigned to other categories of cases of AML. lack of CAE reactivity can be helpful in
AML (see Acute myeloid leukaemia with distinguishing blasts of acute basophilic
recurrent genetic abnormalities, p. 130). Clinical features leukaemia from mast cells {1360}. Bone
In young males with mediastinal germ As with other acute leukaemias, patients marrow biopsy shows diffuse replace-
cell tumours and acute megakaryoblas- present with features related to bone ment by blast cells.
tic leukaemia, several cytogenetic abnor- marrow failure and may or may not have
malities have been observed; of these, circulating blasts. Cutaneous involve- Differential diagnosis
isochromosome 12p is particu larly char- ment, organomegaly, lytic lesions, and The differential diagnosis includes the
acteristic {633,2990). symptoms related to hyperhistaminaemia blast phase of a myeloproliferative
may be present. neoplasm; other AM L subtypes with
Prognosis and predictive factors basophilia, such as AML with t(6;9)
The prognosis of this category of acute Microscopy (p23;q34.1); AM L with BCR-ABL1; mast
megakaryoblastic leukaemia is usually The circulating peripheral blood and cell leukaemia; and (more rarely) a sub-
poorer than that of other AML types, bone marrow blasts are medium-sized, type of lymphoblastic leukaemia with
AML (megakaryoblastic) with t(1;22) with a high N:C ratio; an oval, round, or prominent coarse granules. The clinical
(p13.3;q13.1) {1050,2964), and acute irregular nucleus characterized by dis- features and cytogenetic pattern distin-
megakaryoblastic leukaemia in Down persed chromatin, and 1-3 prominent nu- guish cases presenting de nova from
syndrome. cleoli. The cytoplasm is moderately baso- those resu lting from transformation of
philic and contains a variable number of chronic myeloid leukaemia and from oth-
coarse basophilic granules that are pos- er AM L subtypes with basophilia. Immu-
itive with metachromatic staining; there nological markers distinguish between
lmmunophenotype
Leukaemic blasts express myeloid mark-
ers such as CD13 and CD33; are usually
positive for CD123, CD203c, and CD11b;
and are negative for other monocytic
markers and KIT (CD117) {3761). Blasts
may express CD34. Unlike normal baso-
phils, they may be positive for HLA-DR
but are negative for KIT. lmmunopheno-
typic detection of abnormal mast cells
expressing KIT, mast cell tryptase, and
CD25 distingu ishes mast cell leukaemia
from acute basophilic leukaemia. Blasts
usually express CD9. Some cases are
positive for membrane CD22 and/or
TdT. Other membrane and cytoplasmic
lymphoid-associated markers are usually
negative {2322,3762).
Genetic profile
No consistent chromosomal abnormal -
ity has been identified, but a recurrent
t(X;6)(p11 .2;q23.3) resulting in MYB-
GATA 1 appears to occur in male infants
with acute basophi li c leukaemia {872, .....• .
•.r I .. ~ •
3260} Other cytogenetic abnormalities Fig. 8.39 Acute panmyelosis with myelofibrosis. A Marrow trephine imprint shows several megakaryocytes with hy-
reported in acute basophilic leukaemia posegmented nuclei and blast forms. B The marrow is markedly hypercellular, with increased fibrosis and a hetero-
include t(3;6)(q21;p21) and abnormalities geneous mixture of cells that include numerous dysplastic megakaryocytes. C Reticulin staining shows marked
involvin g 12p {1710,1711} . AML with t(6;9) marrow fibrosis. D lmmunohistochemistry for CD34 shows an increase in blast cells.
(p23;q34.1) is specifically excluded, as
are cases assoc iated with BCR-ABL 1. changes, or therapy-related acute mye- only minimal splenomegaly. The clinical
loid leukaemia. evolution is usually rapidly progressive
Prognosis and predictive factors {3986}.
There is little information on survival with ICD-0 code 9931/3
th is rare type of acute leukaemia. The Microscopy
cases observed have generally been as- Synonyms The peripheral blood shows pancyto-
sociated with a poor prognosis. Acute panmyelosis, NOS; acute (malig- penia, which is usually marked. The
nant) myelofibrosis; acute (malignant) red blood cells show no or minimal an-
myelosclerosis, NOS; malignant myelo- isopoikilocytosis and variable macrocy-
Acute panmyelosis with sc lerosis; acute myelofi bros is; acute my- tosis; rare erythroblasts can be seen, but
mye/ofibrosis elosclerosis, NOS teardrop-shaped cells (dacryocytes) are
not observed. Occasional neutrophil pre-
Definition Epidemiology cursors, including blasts, may be seen .
Acute panmyelosis with myelofibrosis APMF is a very rare form of AML. It oc- Dysplastic changes in myeloid cells are
(APMF) is an acute panmyeloid pro lifera- curs de nova and is primarily a disease frequent, but the criteria for AML with
tion with increased blasts (;:::20% of ce ll s of adults, but has also been reported in myelodysp lasia-related changes are not
in the bone marrow or peripheral blood) children. met. Abnormal plate lets may be noted.
and accompanying fibrosis of the bone Bone marrow asp iration is frequently un-
marrow {307,2991,3831}. APMF does not Clinical features successful; either no bone marrow can
fulfil the criteria for inclusion in any of the Patients are acutely sick at presentation, be obtained or the specimen is subopti-
previous ly described groups; i.e. acute with severe constitutional symptoms in- mal . Bone marrow biopsy supplemented
myeloid leukaemia (AML) with recurrent cluding weakness and fatigue. Fever and with immunohistochem istry is required
genetic abnormalities, acute myeloid bone pain are also common. Pancyto- for diagnosis {3837,3986}. The bone mar-
leukaemia with myelodysplasia-related penia is always present. There is no or row is hypercellul ar and shows, within a
Localization
A lmost any site in the body can be in-
vo lved; the most freq uentl y affected are
the skin, lymph nodes, gastro intestinal
tract, bone, soft tissue, and testes {1144,
3177). In< 10% of cases, myeloid sarco-
ma presents at multip le anatom ical sites
{1 144,3177) .
Fig. 8.40 Myeloid sarcoma. The tumour consists of blasts with scant cytoplasm and round-oval nuclei with finely
Clinical features dispersed chromatin and minute but distinct nucleoli. Mitotic figures are numerous. Neoplastic cells strongly express
Myeloid sarcoma occurs in the absence MPO (inset).
-·
Fig. 8.41 Myeloid sarcoma. On skin biopsy with staining
for NPM1, leukaemic cells infiltrating the derma show, in
addition to the expected nuclear positivity, aberrant cy-
and von Willebrand factor. C099 staining
is positive in more than half of all cases,
with no association with a specific sub-
Fig. 8.42 lnterphase FISH with CBFB dual-colour break-
apart rearrangement probe shows splitting of the gene:
one red and one green signal appear separately in the
type. About 20% of myeloid sarcomas
toplasmic expression of NPM1, which indicates the pres- nucleus, and the normal CBFB allele appears as a fused
show variable degrees of C056 expres-
ence of NPM1 mutation; cells of the overlying epidermis red/green signal.
show a nuclear-restricted positivity for NPM1.
sion, irrespective of their myeloid, myelo-
monocytic, or monoblastic profile. Foci of
Differential diagnosis plasmacytoid dendritic cell differentiation involving the skin, and 75% of these cas-
The major differential diagnosis is with (C0123+, C0303+, but C056-) are oc- es have monocytic features {2419). The
malignant lymphoma. The diagnosis of casionally detected, more often in cases t(8;21)(q22;q22) observed in paediatric
myeloid sarcoma is validated by the re- with inv(16) {4424). About 16% of tu- series seems to be less frequent in adult-
sults of cytochemical and/or immunophe- mours stain for NPM1 at the nuclear and hood {516,3177,3596). lnv(16) or amplifi-
notypic analyses. These allow the dis- cytoplasmic level; this indicates the pres- cation of CBFB has been linked to breast,
tinction of myeloid sarcoma from B- and ence of NPM1 mutations {1144). Excep- uterus, or intestinal involvement and pos-
T-lymphoblastic leukaemia/lymphoma, tionally, aberrant antigenic expressions sible foci of plasmacytoid dendritic cell
Burkitt lymphoma, diffuse large B-cell (cytokeratins, B-cell or T-cell markers, or differentiation (60,2475,3177). Trisomy 8
lymphoma, small round cell tumours (in CD30) are observed (2295 ,3177). Cases and KMT2A-MLLT3 fusion seem to
particular in children), and blastic plas- that meet the criteria for mixed-pheno- have a higher incidence in myeloid sar-
macytoid dendritic cell neoplasm (3177). type acute leukaemia are not classified coma involving the skin or breasts (60,
Myeloid sarcoma must be distinguished as myeloid sarcoma. Flow cytometric 3177,4373}. In one series, FLT3 internal
from non-effacing extramedullary blastic analysis on cell suspensions reveals pos- tandem duplication (FLT3-ITO) was ob-
proliferations, which can occur in AML or itivity for C013, C033, KIT, and MPO in served in< 15% of cases {111 ).
in conjunction with acute transformation tumours with myeloid differentiation, and
of MPN, MOS, or MOS/MPN, as well as for C014, C0163, and C011c in mono- Prognosis and predictive factors
from extramedullary haematopoiesis fol - blastic tumours. Clinical behaviour and response to thera-
lowing the administration of growth fac- py do not seem to be influenced by age,
tors that can produce pseudotumoural Postulated normal counterpart sex, anatomical site(s) involved, type of
masses in virtually every part of the body A haematopoietic stem cell presentation (with or without clinical his-
(2915,3177). Nodular accumulations of tory of AML, MOS, MOS/M PN, or MPN),
mature haematopoietic cel ls can occur Genetic profile therapy-relatedness, histological fea-
in advanced-stage MPN . Although they By FISH and/or cytogenetics, chromo- tures, immunophenotype, or cytogenetic
may clinically mimic myeloid sarcoma, somal aberrations are detected in about findings (3177) Radiotherapy or surgery
the often trilineage haematopoiesis and 55% of cases. They include mono- is sometimes used upfront in patients
the lack of a significant blast component somy 7; trisomy 8; KMT2A rearrange - who need debulking or rapid symptom
confirm a diagnosis of extramedullary ment; inv(16); trisomy 4; monosomy 16; relief (238,4424) Patients who undergo
haematopoiesis (myeloid metaplasia) loss of 16q, Sq , or 20q; and trisomy 11 allogeneic or autologous bone marrow
and exclude myeloid sarcoma {3177, (3177). About 16% of cases carry NPM1 transplantation seem to have a higher
3232). mutations, as evidenced by aberrant cy- probability of prolonged survival or cure
toplasmic NPM1 expression (1144,1149}. {452,3177); in one study, the 5-year over-
lmmunophenotype Such cases frequently have myelomono- all survival rate among 51 patients with
On immunohistochemistry in paraf- cytic or monoblastic morphology, CD34 myeloid sarcoma treated with allogeneic
fin sections, tumours with a more im- negativity, normal karyotype, and mutual bone marrow transplantation was 47%
mature myeloid profi le express C033, exclusivity with MOS or MPN (1144,1149). (706}.
C034, C068 (KP1 but not PGM1), and Interestingly, next-generation sequenc-
KIT (C0117). Staining for TdT, MPO, and ing studies show a much higher (> 50%)
C045 is inconsistent (1144,2039,3177, prevalence of NPM1 mutations in AML
·- .......
Fig. 8.44 Myeloid leukaemia associated with Down syndrome in a 2-year-old child. A The peripheral blood and bone marrow smears contained multiple blasts, as illustrated
in this bone marrow smear; many of the blasts contained numerous coarse basophilic, coloured granules, which were MPO-negative; cytogenetic study showed trisomy 8 in
addition to trisomy 21. B Bone marrow trephine biopsy from the same patient shows numerous blasts and occasional megakaryocytes, including one with a unilobed nucleus.
C Numerous cells are immunohistochemically reactive for CD61 , including obvious megakaryocytes and several smaller cells.
Blastic plasmacytoid
dendritic cell neoplasm
Definition commonly observed: an isolated (one or seen. Cytopenias (espec ially thrombo-
Blastic plasmacytoid dendritic cell neo- few) purplish nodule type (accounting for cytopenia) can occur at diagnosis and
plasm (BPOCN) is a clinically aggres- two thirds of cases), an isolated (one or in a minority of cases is severe, indicat-
sive tumour derived from the precursors few) bruise-like papule type, and a dis- ing bone marrow failure {1 209} Follow-
of plasmacytoid dend ritic cells (POCs, seminated type with purplish nodules ing initial response to c hemotherapy,
also called professional type I interferon- and/or papules and/or macules {820, relapses invariably occur, involving skin
producing cel ls or plasmacytoid mono- 1887). Isolated nodules are preferentially alone or skin and other sites , including
cytes), with a high frequency of cutane- found on the head and lower limbs and soft tissue and the CNS. In most cases, a
ous and bone marrow involvement and can be > 10 cm in diameter. The isolated fulminant leukaemic phase ultimately de-
leukaemic dissemination . bruise-like papu le type is clinically very velops {1209). About 10-20% of cases
challenging. The disseminated type is the of BPOCN are associated with or devel-
ICD-0 code 9727/3 most characteristic clinical presentation. op into other myeloid neoplasms, most
In some patients lacking skin involve- commonly chronic myelomonocytic leu-
Synonyms ment and with leukaemic presentation, kaemia, but also MOS or acute myeloid
Blastic NK-cell lymphoma (obsolete); the diagnosis is made based on periph- leukaemia (AML) {1 209,1618,2004,3151,
agranular C04+ NK leukaemia (obso- eral blood or bone marrow analyses. Re- 3332,4206).
lete); blastic NK leukaemia/lymphoma gional lymphadenopathy at presentation BPOCN must be distinguished from
(obsolete); agranular C04+ C056+ hae- is common (seen in 20% of cases). Pe- mature plasmacytoid dendritic cell pro-
matodermic neoplasm/tumour ripheral blood and bone marrow involve- liferation (MPOCP), in wh ich POCs are
ment can be minimal at presentation, but morphologically mature and CD56-neg-
Epidemiology invariably develops with progression of ative. Th is condition may be associated
This rare form of haematolog ical neo- disease. Oral mucosa! infiltration may be with cutaneous lesions (rash, macules
plasm has no known racial or ethnic
predilection. The male-to-female ratio is
3.3:1. Most patients are elderly, with a
mean/median patient age at diagnosis
of 61-67 years, but this neoplasm can
occur at any age, including in children
{1209,1812).
Etiology
There are currently no clues to the etiolo-
gy of BPOCN, but its association with my-
elodysplastic syndrome (MOS) in some
cases may suggest a related pathogen-
esis. There is no association with EBV.
Localization
The disease tends to involve multiple
sites, most commonly the skin (involved
in 64- 100% of cases), followed by the
bone marrow and peripheral blood (in
60-90%) and lymph node (in 40-50%)
{2525,3151).
Clinical features
Skin manifestations are the most frequent
clinical presentation of typical cases of
BPOCN, and the diagnosis is made on
skin biopsy. Patients usually present with Fig. 9.01 Blastic plasmacytoid dendritic cell neoplasm. A Skin tumour and plaques. B The neoplastic cells are
asymptomatic solitary or multiple lesions. medium-sized, with fine chromatin and scanty cytoplasm, reminiscent of undifferentiated blasts. C Massive dermal
Three types of presentation are most infiltrate diffusely involves the dermis and extends into subcutaneous fat, but spares the epidermis.
Microscopy
BPDCN is characterized by a diffuse,
monomorphous infiltrate of med ium-
sized blast cells resembling either lymph-
oblasts or myeloblasts. Nuclei have ir-
regular contours, fine chromatin, and one
to several small nucleoli . The cytop lasm
is usually scant and appears greyish-
blue and agranu lar on Giemsa staining.
Mitoses are variable in number, and the
Ki-67 proliferation index is 20-80%; an-
gioinvasion and coagulative necrosis are
absent {820,1887,2004,3182}.
In cutaneous infiltrates, the dermis is usu-
ally massively involved, with extens ion to
the subcutaneous fat; the epidermis and
adnexa are spared, with rare exceptions
{820}. Lymph nodes are diffusely involved
in the interfollicular areas and medulla,
whereas B cell follicles are often spared.
Bone marrow biopsy shows either a mild
interstitial infiltrate (detectable only by im-
munophenotyping) or massive replace-
ment; res idual haematopoietic tissue may
exhibit dysplastic features, especially in
Fig. 9.02 Blastic plasmacytoid dendritic cell neoplasm. The neoplastic cells show immunoreactivity for CD4 (A), CD56
megakaryocytes {3151}. On peripheral (B), CD123 (C), TCL 1A (D), CD303 (E), BCL 11A (F).
blood and bone marrow smears, tumour
ce ll s may show cytoplasmic microvacu-
oles localized along the ce ll membrane does not rule out the diagnosis if other
and pseudopodia; granules and crystals PDC-associated antigens (in particular
are absent {1209}. CD123, TCL1A, or CD303) are expressed
{53,406 ,1887}. Tumours that have some
Cytochemistry immunophenotypic features of BPDCN
The neoplastic cells in BPDCN are may be better class ified as one of the
negative with alpha-naphthyl butyrate subtypes of acute leukaemia of ambigu-
esterase, naphthol AS-D ch loroacetate ous lineage. CD68 (an antigen typically
esterase (CAE), and MPO cytochem ical expressed strongly on normal PDCs) is
reactions {300,1209,2004,3332}. detected in 50- 80% of cases, in the form
of smal l cytoplasm ic dots {3151,3157}. Of
lmmunophenotype the lymp hoid and myeloid-associated
The tumour cells express CD4, CD43, antigens, CD7 and CD33 are re latively
CD45RA, and CD56, as well as the PDC- commonly expressed; some cases
assoc iated antigens CD123 (IL3 alpha- show express ion of CD2, CDS, CD36 , may also express other antigens that are
chain receptor), CD303, TCL1A, CD2AP, CD38, and CD79a, whereas CD3, CD13, usually negative in normal PDCs, such
and SPIB and the type I interferon- de- CD16, CD19, CD20, LAT, lysozyme, and as BCL6, IRF4, and BCL2 {820} (with
pendent molecule MX1 {107,406,1618, MPO are negati ve. Granzyme B, wh ich BCL2 potentially acting against tumour
1887, 2497,2702,3151,3152, 3157,3182, is found in normal PDCs, has also been ce ll apoptosis {3520}). In addition, S100
3248,3332}. Recently, the TCF4 (E2-2) demonstrated on flow cytometry im- protein is expressed in 25-30% of all
transcription factor, which is essential munophenotyping and mRNA analysis cases {1887}, and even more frequently
to drive PDCs development, was found in BPDCN {663,1410}, but it is typically in paed iatric cases {1847,1849}; the zonal
to represent a faithful diagnostic mark- negative on tissue sections, as are oth- distribution of this antigen and its vari-
er for BPDCN {6058}. In about 8% of er cytotoxic molecules such as perforin ab le expression in tumour ce ll s may re-
cases, CD4 or CD56 is negative, which and TIA1. In addition to CD56, BPDCN flect divergent subclones with maturation
along the dendritic cell pathway {1847, can share morphological and immuno- assays {329,664), gene expression pro-
1887). TdT is positive in about one third of phenotypic features with BPOCN (es- filing {987,3520), and the tumour-derived
cases, with expression in 10-80% of the pecially AML with monocytic differen- cell lines {2437,2828) all point towards
cells {985,1887,2497,2546,3152,3153). tiation, which can express CD4, CD56, derivation from the precursors of a spe-
Occasional cases express KIT (C011 7). and CD123 {987,3157,4206)), extensive cial subset of dendritic cel ls: PDCs {597,
C034 is negative on sections {663,820, immunohistochemical and/or genetic 1476,3739). In humans, these cells are
1977,3151,3153,4065), but has been analysis is necessary before a defini- distinguished by their production of large
found by flow immunophenotyping in tive diagnosis of BPOCN can be made. amounts of type I interferon {598); they
17% of cases, all invariably associated BPOCNs must also be distinguished have been known by many names, such
with other-li neage CD34+ blasts {2525). from MPOCPs associated with other my- as lymphoblasts, T-cell- associated plas-
EBV antigens and EBV-encoded small eloid neoplasms, which are predominant- ma cells, plasmacytoid T cells, and plas-
RNA (EBER) are negative. ly found in lymph nodes, skin, and bone macytoid monocytes {11 29).
The identification of BPOCN by flow marrow. MPOCPs consist of nodules or Recent gene expression profil ing studies
cytometry benefits from gate and inten- irregular aggregates composed of cells have revealed that the neoplastic cells
sity evaluation criteria {663,1209,1303, morphologically similar to normal POCs; show a gene expression signature similar
1410,4058,4065). BPOCN is character- these nodules can be very numerous, to that of resting normal PDCs and closer
ized by high levels of CD123 and weak are sometimes confluent, and may show to that of myeloid than of lymphoid pre-
expression of CD45 (blast gate); in ad- prominent apoptosis. The PDCs in these cursors {3520). The immunophenotypic
dition, C036, CD304, and LI LRB4 (also nodules generally have the same phe- heterogeneity with regard to TdT and the
called ILT3), but not CD141, are ex- notype as their normal counterparts, al- association with myeloid disorders sug-
pressed {4058,4065). The absence of lin- though in occasional cases aberrant sin- gest a multilineage potential for some
eage-associated antigens, together with gle or multiple antigen expression (e.g . cases.
positivity for CD4, CD45RA, CD56, and of CD2, CD5, C07, C010, C013, CD14, Furthermore, recent data obtained by
C0123, is considered a unique pheno- CD15, and/or C033) has been reported TCF4 (E2-2) Ch lP-seq data and gene ex-
type virtually pathognomonic of BPOCN {333,869,2497,4191,4206}. Most impor- pression changes following TCF4 knock-
{4058); C0303 positivity has the highest tantly, C056 is negative in most cases, down revealed the similarity between
diagnostic score within a panel of mark- or shows only focal and weak reactivity normal PDCs, BPDCN cell lines and
ers used for BPOCN identification {1303}. {11 30,4206}. The POCs in MPOCP have primary BPOCN, distinguishing BPOCN
Subgroups of tumours may be identified a low Ki-67 proliferation index (< 10%) from AML lines {605B}.
on the basis of mutually exclusive expres- and lack TdT. Their neoplastic nature and
sion of antigens, such as TdT/C0303 relatedness with the associated myeloid Genetic profile
{1846), TdT/S100 {1887), and C034/KIT/ neoplasm have been evidenced by the T-cell and B-cell receptor gene mutations
CD56 {2525). These subgroups may demonstration of identical clonal chro- are usually germline {3151,3332), except
correspond to diverse levels of matura- mosomal abnormalities in the two cellular in a few cases that show T-cell receptor
tion and may be associated with differ- components {684,3177,4191}. gamma rearrangement, possibly due to
ent clinical presentations {2525), but their clonal bystander T cells {53,3151). Two
prognostic significance remains unclear. Cell of origin/normal counterpart thirds of patients with BPDCN have an
Among the antigens generally overex- The cell of origin is a haematopoietic abnormal karyotype. Specific chromo-
pressed by BPOCN blasts, CD123 could stem cell; the normal counterpart is the somal aberrations are lacking, but com-
serve as a therapeutic target of engin- precursor of PDCs. plex karyotypes are common; six major
eered monoclonal antibodies {108,506 , Data on antigen {663,664,1410,1618,1812, recurrent chromosomal abnormalities
1248,2877). 1846,3152,3157) and chemokine recep- have been recognized, involving 5q21
Because other haematological neoplasms tor expression {329), in vitro functional or 5q34 (seen in 72% of cases), 12p13
••
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.5?'
a,
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en
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A B
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CD45 PERCP CVTOPL ASMIC MPO FITC
blast s
CHAPTER 10
.
. .,
. ..
~
.: .. .. .."'•
:~
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a,
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0
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en - . . - ... E
VI
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-
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(.)
F
liilih I I i ii "I
CD45 PerCP cMPO FITC
Definition 'acute bilineage (or bilineal) leukaemia' specif ied, irrespective of whether one
Acute leukaemias of ambiguous line- has been applied to MPALs containing or more than one population of blasts is
age are leukaem ias that show no clear separate popu lations of blasts of more seen.
evidence of differentiation along a single than one lineage. The term 'biphenotyp ic Some well-defined myeloid leukaemia
lineage. They include acute undifferenti- leukaemia' has typically been reserved entities have immunophenotypic features
ated leukaemias, which show no lineage- for MPALs co ntain in g a sing le popu lation that mig ht suggest that they be class ified
specific antigens , and mixed-phenotype of blasts coexp ressing anti gens of more as B/myeloid or T/myel o id leukaemia.
acute leukaemias (MPALs), which have than one lineage {1539, 2257,2578 ,3830}, However, the MPAL group, as defined
blasts that express antigens of more than but is sometimes used more broadly to in this volume, excludes cases that can
one li neage to such a degree that it is not also encompass bilin eage leukaemias. be c lassified (e ither by genetic or clin i-
possible to assign the leukaem ia to any In thi s vo lu me, the term 'm ixed -pheno- cal features) in another category, such
one lineage with certainty. MPALs can type acute leukaemia' is app li ed to this as cases with the recurrent genetic ab-
contain distinct blast popul ations each group in general; the more specifi c term s normaliti es t(8;21), inv(1 6), or PML-RARA
of a different li neage, one popu lation with 'B/myeloid leukaemia' and 'T/mye loid fusion , wh ich are associated with ac ute
mu ltiple antigen s of different li neages on leukaemia', as defi ned below, refer to mye loid leukaem ia (AM L); cases with
the same cells, or a combination. The leukaem ias containing the two lineages t(8;2 1) exp ress multi ple B-ce ll marke rs
amb iguity of antigen express ion most of-
ten involves mye loid antigens coexisting
with either T-cel l or B-cell antigens, but
rare cases of amb iguity of assignment
between B-cell and T-cell lineages also
'w'BCs
occ ur. Leukaemia with well-def ined line-
age engagement but express ing one or
more antigens associated with a different r--
:::c u
lineage should be considered acute leu- I
a..
u -<(
kaemia with aberrant antigen expression Ci..
-<( v
rather than MPAL. ![')
I'<')
v c
c u
Epidemiology u
Ambiguous-lineage leukaemias are rare ,
accounting for < 4% of all acute leukae-
mia cases. Many cases that have been
reported as undifferentiated leukaem ia SSC-H CD 19 PE-CF594
can in fact be demonstrated to be leu-
kaemias of unusual lineages, and many
cases that have been reported as biphe-
I{)
notypic acute leukaemias may in fact be
acute lymphoid or myeloid leukaemias u==~ I.LI
Ci..
I
I.LI ~
with cross-lineage antigen express ion ; Ci.. a-.
therefore, the true frequency of ambig- r-- r--
c
uous-lineage leukaemias may be even uQ
c
lower than reported. These leukaemias u
occur in both children and adults, but
more frequently in adults , although some
subtypes of MPAL may be more com mon
in children {2013,3013}. CD13 PE-Cy7 cMPO FITC
Terminology
Historically, there has been confusion re-
Fig. 10.01 B/myeloid mixed-phenotype acute leukaemia. Flow cytometry reveals a dominant, relatively homogene-
garding the terminology and definitions ous blast population (red) with bright CD34 and CD19, and little to no expression of myeloid antigens CD117 and
of all ambiguous-lineage leukaemias CD13. The CD79a vs MPO plot is more heterogeneous, with the brighter CD79a (i.e. more lymphoid) population
and in particu lar the MPALs. The term expressing little or no MPO, and the MPO-positive cel ls lacking CD79a. Courtesy Dr B. Wood.
Epidemiology
Th is rare leukaemia is more common
in child ren than in adu lts. Like ALL and
acute myeloid leukaemia with KMT2A re-
arrangements, this leukaemia is relatively
more common in infancy {2013,3013).
Clinical features
Patients present similarly to other pa-
tients with acute leukaemia. As with other
Fig. 10.02 B/myeloid mixed-phenotype acute leukaemia with t(9;22)(q34.1;q11.2). The blasts vary from small
lymphoid-appearing blasts to large blasts with dispersed chromatin, prominent nucleoli, and a moderate amount of
acute leukaemias with KMT2A transloca-
pale cytoplasm. tions, high white blood cell counts are
common.
blood ce ll counts, sim il ar to patients with mixed blast crisis shou ld be considered
Philadelphia (Ph) chromosome-positive in the differential diagnosis, espec ial ly if Microscopy
lymphoblastic leukaemia. there are two distinct lymphoid and mye- These leukaemias typically show a dimor-
loid blast popu lations. Many cases have phic blast popu lation, with some blasts
Microscopy additional cytogenetic abnormalities, clearly resembling monoblasts and oth-
Many cases show a dimorphic blast and complex karyotypes are common. ers resembling lymphoblasts. However,
population, with some blasts resembl in g some cases have no distin guishing fea-
lymphoblasts and others myeloblasts, Prognosis and predictive factors tures and appear on ly as und ifferenti-
although other cases have no distin- Th is type of leukaemia has a poor prog- ated blast cells. Cases in wh ich the entire
guish ing features. Cases generally do nosis, which appears to be worse than blast population appears monoblastic
not show sign ificant myeloid maturation; that of other MPALs {2013}, in particul ar are more likely to be acute myeloid leu-
caution should be exercised when mak- in adu lts {2583}. kaem ia with a KMT2A trans location, but
ing th is diagnosis in a case of myeloid It is unclear whether the prognosis is this diagnosis requ ires flow cytometry to
leukaemia with maturation that also ex- worse than that of Ph chromosome- pos- exclude the presence of a small lympho-
presses lymphoid markers, because itive lymphob lastic leukaemia. Some blastic popu lation.
such a pattern can also be seen in the data suggest that treatment with tyrosine
blast phase of CML. kinase inhibitors may improve outcome lmmunophenotype
as is seen in lymphoblastic leukaemia In most cases, it is possib le to recognize
lmmunophenotype with BCR-ABL1 {1973,3659). There are a lymphoblast popu lation with a CD19+,
The great majority of cases have blasts no known biolog ical factors that pred ict CD10-, pro-B (B-ce ll precursor, B-1) im-
that meet the criteria for B-ce ll and whether patients with this leukaemia will munophenotype, frequently positive for
myeloid lin eage, as described above, do better or worse with therapy. CD15. Expression of other B-ce ll mark-
although some cases have T-cell and ers, such as CD22 and CD79a, is often
myeloid blasts. Triphenotypic cases have weak. Cases also fulfil the criteria for
also rarely been reported. Mixed-phenotype acute myeloid lineage as defined above, most
leukaemia with t(v;11q23.3); common ly via demonstration of a sepa-
Postulated normal counterpart KMT2A-rearranged rate popu lation of myeloid (usually mono-
The postu lated normal counterpart is a blastic) leu kaemic cells {3013,4279). Co-
multipotent haematopoietic stem ce ll . Definition expression of MPO on lymp hoid blasts
There is no evidence that this leukaemia Mixed-phenotype acute leukaemia is rare. Because KMT2A translocations
derives from a different cell than do other (MPAL) with t(v; 11 q23.3) fulfils the criteria can also produce T-ALL, it is theoretically
cases of Ph chromosome-positive acute for MPAL and has blasts with a transloca- poss ible that T/mye loid leukaemias with
leukaemia. tion involving KMT2A (previously call ed t(v;11q23.3) could occur, although no
MLL). Many cases of lymphoblastic leu- such cases have been reported.
Genetic profile kaemia (ALL) with KMT2A translocations
All cases have either t(9;22) detected by express myeloid-associated antigens, Genetic profile
conventional karyotyp ing or the BCR- but such cases should not be considered All cases have rearrangements of
ABL1 translocati on detected by FISH or MPAL unless they fulfil the specific crite- KMT2A, with the most common part-
PCR. The p190 fu sion transcript is more ria noted above. ner gene being AFF1 (AF4) on chromo-
common than the p210 transcript {4256). some 4 band q21.3 {560,3013}. Trans-
If the p210 transcript is present, CML in a ICD-0 code 9807/3 locations t(9;11) and t(11;19) have also
A~>·::.>
often treated differently than are patients
diagnosed with ALL with KMT2A translo-
cations, but there is no evidence that this ...,
Q.
(.)
Q.
<
is necessary or beneficial. N
N ..
··:. .... . 17>
s
\. ("
I .:. ~: · ·' . 0
(.)
.
Fig.10.05 T/myeloid mixed-phenotype acute leukaemia, NOS. There is a dimorphic population of blasts, with many
small lymphoblasts. Larger blasts also have a high nuclear:cytoplasmic ratio, fine chromatin and inconspicuous nucleoli.
directed and lymphoid-directed therapies
have been tried {3447,4347), and some
patients may respond to one or the other.
Mixed-phenotype acute
leukaemia, not otherwise
• I
·..
'•, ;
,.
, •,• 0 ~
specified, rare types
8
l,l
Definition
In some documented cases of leukae-
~ mia, the leukaemic blasts show clear-cut
c[
0
.... evidence of both T-cell and B-cell line-
ti age commitment as defined above. This
A is a very rare phenomenon, with a fre-
I iiiiiiij quency that is likely even lower than has
typically been reported in the literature
{2583). As strictly applied, the European
Group for the Immunological Characteri-
zation of Leukemias (EGIL) criteria for bi-
~ phenotypic leukaemia (i.e. scores > 2 in
.,...
Q.
more than one lineage), which assign a
Cl
(.) 2-point value to CD79a expression {331,
332} may overestimate the incidence of
B-/T-leukaemia, because CD79a can
be detected in T-lymphoblastic leukae-
mia with some antibodies {1584). For
the purpose of assigning B-cell lineage
blasts
to a case of T-lymphoblastic leukaemia,
(.)
Q.
CD79a and CD10 should not be consid-
< ered evidence of B-cell differentiation.
"'
Cl
(.) There have also been a few cases with
.· ·...' ',·
,!,!
evidence of trilineage (B-cell, T-cell, and
. . .. . ~
.!!
myeloid lineage) assignment. Overall,
- •.. ···:··~·. :. : a.
~
(.) there are too few cases with these char-
F acteristics for any specific statements to
be made about clinical features, genetic
lesions, or prognosis.
To date, there have been no reports of
Fig. 10.06 T/myeloid mixed-phenotype acute leukaemia, NOS: flow cytometry in several cases, with gating on all mixed B- or T-cell and megakaryocytic or
cells (A,C,E) and on blasts (B,D,F), and with normal T-cells superimposed in violet. A and B So-called bilineage mixed B- or T-cell and eryth roid leukae-
leukaemia, with two separate populations of T-cell (blue) and myeloid (green) blasts; the side scatter (SSC) mias. It has been postulated that eryth-
versus CD45 histogram shows that (A) the myeloid and T-cell populations have distinct light-scattering profiles. roid and megakaryocytic lineages are
B The cCD3 expression on the T-cell blasts is comparable in intensity to that on the residual normal T-cells.
the earliest to branch off from the pluri-
C and D So-called biphenotypic leukaemia, with a single population of blasts (red) coexpressing cCD3 and MPO;
there is a wide range of cCD3 expression intensity, but the brightest blasts are about as bright as the normal T-cells. potent haematopoietic stem cell, leaving
E and F Leukaemia in which both coexpression (red) and separate populations of T-cell (blue) and myeloid (green) progenitor cells with T-cell, B-cell, and
blasts can be seen; neither the term 'biphenotypic' nor the term 'bilineage' readily fits this case. myeloid potential {1803}; therefore, neo-
Naiv~~ ~<>
B-cel~
Progenitor
B-cell
~~AG
Extrafollicular { - \ 1' Memory B-cells
Pre-B-cell
B-blast V Marginal zone
Shoo-I_, l• rd #J
plasma cell ... a / ""
I
"
......... " "
... _...
Precursor 8-cell neoplasms Pre-GC neoplasm
'------ GC neoplasms Post-GC neoplasms
B lymphoblastic Mantle cell lymphoma Follicular lymphoma
leukaemia/lymphoma Burkitt lymphoma Marginal zone & MALT lymphomas
DLBCL (some) Lymphoplasmacvtic lymphoma
Hodgkin lymphoma CLL/SLL, DLBCL(some)
Plasma cell myeloma
Fig. 11.02 Normal 8-cell differentiation and its relationship to major 8-cell neoplasms. 8-cell neoplasms correspond to various stages of normal 8-cell maturation, although the
normal cell counterparts are unknown in some instances. Precursor 8 cells, which mature in the bone marrow, may undergo apoptosis or develop into mature na'ive 8 cells, which,
following exposure to antigen (AG) and blast transformation, may develop into short-lived plasma cells or enter the germinal centre (GC), where somatic hypermutation and heavy-
chain class switching occur. Centroblasts, the transformed cells of the GC, either undergo apoptosis or develop into centrocytes. Post-GC cells include both long-lived plasma
cells and memory/marginal-zone 8 cells. Most 8 cells are activated within the GC, but T-ce ll-independent activation can take place outside the GC and probably also leads to
memory-type 8 cells. Monocytoid 8 cells, many of which lack somatic hypermutation, are not illustrated . The red bars indicate IGH gene rearrangement and the blue bars IG light
chain gene rearrangement; the black insertions in red and blue bars indicate somatic hypermutation {3848).
CLL/SLL, chronic lymphocytic leukaemia/small lymphocytic lymphoma; D, surface lgD; DL8CL, diffuse large 8-cell lymphoma; FDC, follicular dendritic cell; M, surface lgM;
MALT, mucosa-associated lymphoid tissue.
scribed germinal centre markers include of the late primary or secondary immune correspond to pro liferating cells and are
LM02 and HGAL. LM02 is expressed in response {2428). BCL6 also undergoes clinically aggressive tumours .
haematopoietic precursors in the bone somatic mutation in the germinal centre, Centrob lasts mature to centrocytes,
marrow, but appears to be specific for but at a lower frequency than do the IG and these cells are seen predominantly
germinal centre B cells in normal reac- genes {3084). Ongoing IGV gene mu- in the light zone of the germinal centre.
tive lymphoid tissues {2840}; it lacks this tation with intraclonal diversity is a hall- Centrocytes express slg that has an al-
specificity in lymphoid neoplasms {35). mark of germinal centre ce ll s, and both tered antibody-comb in ing site compared
HGAL (also called GCET2) rs expressed IGV gene and BCL6 mutations serve as with that of their progenitors, due to both
in germinal centre B cells and germinal markers of cells that have been through somatic mutations and heavy-chain
centre- derived malignancies {3043). the germinal centre. Most diffuse large class switching. Centrocytes with muta-
In the germinal centre, somatic hyper- B-cell lymphomas (DLBCLs) are com- tions that result in increased affinity are
mutation occurs in the IGV genes; these posed of cells that at least in part resem- rescued from apoptosis and re-express
mutations can result in a non-functional ble centrob lasts and have mutated IGV BCL2 {2427). Through interaction with
gene or a gene that produces antibody genes, consistent with a derivation from surface molecules on follicular dendritic
with lower or higher affinity for antigen. cells that have been exposed to the ger- cells and T cells (e.g. CD23 and CD40
Also in the germinal centre, some cells minal centre. Burkitt lymphoma cells are ligand), centrocytes switch off BCL6
switch from lgM production to lgG or lgA BCL6-positive and have mutated IGH expression {584,3199} and differenti-
production. Through these mechanisms, genes, and are therefore also thought ate into either memory B cells or plasma
the germinal centre reaction gives rise to to correspond to a germ inal centre blast ce ll s {2427). BCL6 and IRF4 (also called
the higher-affinity lgG or lgA antibodies cell. Both Burkitt lymphoma and DLBCL MUM1) are reciprocally expressed, with
Pro-B Pre-B Immature Mature Germinal Memory B Plasma cell T-ce!l lymphomas: Lymphocyte
B naive B centre B (Marginal zone) differentiation and function
1mt T lymphocytes arise from a bone mar-
I co1o row precursor that undergoes maturation
I LM02 and acq uisition of function in the thymus
CD19
gland. Antigen-specific T cells mature in
the thymic cortex. T cells recogn izing self
I CD79A
I PAX6 peptides are eliminated via apoptosis, in
.............-- 1co20 a process mediated by cortical epithe-
I CD23 lial cells and thymic nurse cel ls. Corti-
cal thymocytes have an immature T-cell
I CD38 I CD38 CD38 phenotype and express TdT, CD1a, CD3,
~ CDS, and CD?. CD3 is first expressed in
~
-=---===- I IRF41MOM1 the cytoplasm, prior to complete T-cell
receptor (TR) gene rearrangement and
BLIMP1 I export to the cell membrane. Cortical thy-
XBP1 I mocytes are initially double-negative for
CD138 I CD4 and CDS. These antigens are coex-
pressed in maturing thymocytes; more-
Fig. 11.03 B-cell differentiation. B cells go through various stages of differentiation as they mature from pro-B cells mature T cel ls express only CD4 or CDS.
to plasma cells. The antigen-dependent phase of differentiation usually begins in the germinal centre, where B cells
encounter antigen. Red bar in nucleus indicates heavy chain gene rearrangement; blue bar indicates light chain re-
These various stages of T-cell maturation
arrangement; black boxes connote somatic hypermutation. Cells coloured in yellow have not encountered antigen, as are reflected in T-lymphob lastic leukae-
opposed to antigen-dependent stages shown in violet. Modified from Swerdlow SH et al. {3848). mia/lymphoma.
BCR, B-cell receptor; D, surface lgD; M, surface lgM; SHM, somatic hypermutation. Medullary thymocytes have a phenotype
similar to that of mature T cells of the pe-
IRF4 being positive in late centrocytes Post-germinal centre memory B cells ripheral lymphoid organs. There are two
and plasma cells {1141, 34S3}. IRF4 plays circulate in the peripheral blood and classes of T cells: alpha beta T cells and
a critical role in downregulating BCL6 account for at least some of the cells in gamma delta T cells {3S50}. This distinc-
expression {34S3}. Recent studies indi- the follicular marginal zones of lymph tion is based on the structure of the T-cell
cate that MYC plays an important role in nodes, spleen, and mucosa-associated receptor. The alpha beta and gamma
germinal centre formation (1020). MYC lymphoid tissue (MALT). Marginal-zone delta chains are each composed of a
is upregulated upon interaction of na·ive B cells of this compartment typically ex- variable portion and a constant portion.
B cells with antigen and T cells by the press pan- B-cell antigens and surface They are both associated with the CD3
action of BCL6, and is essential for ger- lgM (with only low levels of lgD), and lack complex, which contains gamma, delta,
minal centre formation. In normal reactive both CDS and CD10 (3749,4124). Plasma and epsilon chains. NK cel ls do not have
lymph nodes, staining for MYC highlights cells produced in the germinal centre en- a complete T-cel l receptor complex; ac-
a population of centrocytes in the light ter the peripheral blood and home to the tivated NK cells express the epsilon and
zone of the germinal centre, and is re- bone marrow. They contain predominant- zeta chains of CD3 in the cytoplasm.
pressed in the dark zone. However, MYC ly lgG or lgA; they lack slg and CD20 but They express CD2, CD?, and sometimes
is re-induced in a subset of light-zone B express IRF4, CD79a, CD3S, and CD13S. CDS, but not surface CD3. They also typ-
cells (centrocyes), allowing re-entry into Both memory B cells and long-lived plas- ically express CD16 and CDS6, variably
the dark zone and maintenance of the ma cells have mutated IGV genes, but do express CDS?, and contain cytoplasmic
germinal centre reaction (1020). Follicu- not continue to undergo mutation. Post- cytotoxic granule proteins. NK cells kill
lar lymphomas are tumours of germinal germinal centre B cells retain the ability their targets through antibody-dependent
centre B cells (centrocytes and centro- to home to tissues in which they have cell-mediated cytotoxicity or a second
blasts) in which the germinal centre cells undergone antigen stimulation, probably mechanism involving killer activation re-
fail to undergo apoptosis, in most cases through surface integrin expression, so ceptors and inhibitory killer-cell immuno-
due to a chromosomal rearrangement, that B cells that arise in MALT tend to re- globulin-like receptors. Because NK cells
t(14;1S), that prevents the normal switch- turn there, whereas B cells that arise in do not rearrange the TR genes, antibod-
ing off of BCL2 expression. Centrocytes the lymph nodes home to nodal sites and ies to the various killer-cel l immunoglobu-
usually predominate over centroblasts, bone marrow {SOS}. Marginal zone lym- lin-like receptors can be used for analysis
and these neoplasms tend to be indolent. phomas of the MALT type, splenic type, of clonality in NK-cell proliferations.
~~~ - eeeeeee
innate immune system {1816). Lymphoid
neoplasms derived from innate lymphoid
cells include aggressive NK-cell leukae-
Prothy Subcapsular Cortical Thymocyte Medullary Peripheral T-eell Follicular T-reg Th1 Th2 Th17
mocyte Thymocyte Thymocye T-helper mia, systemic EBV-positive T-cell lym-
I CD341 phoma of childhood, hepatosplen ic gam-
\IDT I====-==-. ma delta T-cell lymphoma, and gamma
I CD10
delta T-cell lymphomas often arising in
cutaneous and mucosa\ sites.
I co3 cvtoplasmic I co3 sulface Gamma delta T cells usually lack expres-
sion of CD4 and CDS, as well as CDS. A
I CD1a subpopulation expresses CDS. Gamma
jFOXP3j lTBX21ilGATA3j jRORCj delta T cells account for < 5% of all nor-
lco2sl ~mD ~ mal T cells and have a restricted distribu-
[ill [0 I TNFa. I tion, being found mainly in the splenic red
pulp, intestinal epithelium, and other epi-
thelial sites. These sites are more com-
Fig. 11.04 T-cell differentiation. T cells mature in the thymus gland and then leave to occupy peripheral lymphoid monly affected by gamma delta T-cell
tissues. T-cell receptor (TR) genes are shown schematically with a solid red bar indicating absence of rearrangement. lymphomas, which are otherwise rela-
The black boxes in the red bars reflect the rearrangements of the TR genes. The double red lines on the cell mem- tively rare {150,1299,3850). Gamma delta
brane represent the expressed T-cell receptor complex. Antigen dependent maturation leads to the different T-cell T cells have a restricted range of antigen
subsets, also illustrated in Fig. 11 .05. The phenotypes of several key T-cell subsets are illustrated:
recognition, and serve as a first line of
T follicular helper (TFH), T regulatory (T-reg), T helper 1 (Th1), T helper 2 (Th2), and T helper 17 (Th17).
Modified and updated from {3848).
defence against bacterial peptides, such
as heat shock proteins {3850) They are
often involved in responses to mycobac-
Central lymphoid tissue Peripheral lymphoid tissue terial infections and in mucosa\ immunity.
Precursor T-cells Peripheral (mature) T- and NK-cells
The T cells of the adaptive immune sys-
tem, which are heterogeneous and func-
tionally complex, include na·1ve, effector
(regulatory and cytotoxic), and memory
T cells. T-cell lymphomas of the adap-
tive immune system present primarily in
adults and are mainly nodal in origin, in
contrast with the extranodal T-cell lym-
phomas of the innate immune system
{1816). CD4+ T cells are primarily regu-
latory, acting via cytokine production;
based on their cytokine secretion pro-
files, CD4+ T cells are divided into two
major types: T helper 1 (Th1) cells and
T helper 2 (Th2) cells. Th1 cells secrete
IL2 and interferon gamma, but not IL4,
IL5, or IL6. In contrast, Th2 cells secrete
Follicle
IL4, IL5, IL6, and IL10 {3850). Th1 cells
T lymphoblastlc
lymphoma/leukaemia Peripheral (mature) T·cell and NK-cell lymphomasneukaemlas provide help mainly to other T cells and to
macrophages, whereas Th2 cells provide
Fig. 11.05 T-cell differentiation. T-cell neoplasms correspond to various stages of normal T-cell maturation. Mature help mainly to B cells, in the production
T cells include alpha beta and gamma delta T cells, both of which mature in the thymus gland. Recently recognized of antibod ies {1758A}. CD4+ T cells can
T-cell subsets include the various types of CD4+ effector T cells, including T helper 1 (Th1), T helper 2 (Th2), T regula- act both to help and to suppress immune
tory (Treg), T helper 17 (Th17), and T follicular helper (TFH) cells. Modified and updated from {3848).
responses, and consist of multiple sub-
Ag, antigen; FDC, follicular dendritic cell.
populations only recently recognized. For
Toll-like receptors play a role in cell-cell also play a role in the adaptive immune example, T regulatory (Treg) cells have
interactions and signall ing. They play a system {2284). diverse functions, including suppressing
critical role in the recognition of infectious The lymphomas of the innate immune immune responses to cancer and limit-
agents, initiating signalling through NF- system are predominantly extranodal ing inflammatory responses in tissues
kappaB . They function most prominently in presentation, mirroring the distribu- {2403,4350). Recent studies have iden-
in innate immune responses, but they tion of the functional components of this tified transcription factors, TBX21 (also
LPL +/ -, + -/+ +•
SMZL +, -!+
HCL +, - + +! - +
FL +, - +/- - /+ + - /+ b
MCL +, - + + +
BL +, - + -!+ n/ a + - !+
a The plasma cell components of LPL and MALT lymphoma are IRF4+.
b Some grade 3A and 3B FLs are IRF4+.
c Some DLBCLs are CD5+. Other B-cell neoplasms can sometimes be CD5+, including LPL, MALT and FL.
d DLBCLs of germinal centre-B-ceU type express CD10 and BCL6.
• DLBCLs of activated B-cell type are typically IRF4+
1815,2199}. Hepatosplenic T-cell lym- Principles of classification classic Hodgkin lymphoma (CHL). Simi-
phoma of gamma delta origin has muta- The classification of lymphoid neoplasms larly, CD56 is a characteristic feature of
tions in STAT5B in approximately 35% of is based on all available information to nasal NK/T-cell lymphoma, but it can
cases {2869), and the same mutation is define disease entities {1557). Having also be found in other T-cell lymphomas,
recurrent in gamma delta T-cell lympho- sufficient tissue for this multiparameter in plasma cell neoplasms, and in non-
mas involving the gastrointestinal tract approach is critical. Great caution is ad- lymphoid cells such as blastic plasmacy-
and skin {2160}. The JAK/STAT path- vised when core needle biopsies are used toid dendritic cell neoplasms. {173,315,
way is implicated in many form s of T-cell for the primary diagnosis of lymphoma; 746,987,4357). Within a given disease
lymphoma, including anaplastic large fine-needle aspi ration is generally inad- entity, variation in immunophenotypic
cell lymphoma (both ALK-positive and equate for this purpose. Morphology and features can be seen. For example, most
ALK-negative) and monomorphic epithe- immunophenotype are sufficient for the hepatosplenic T-cell lymphomas are of
liotropic intestinal T-cell lymphoma {836, diagnosis of most lymphoid neoplasms. the gamma delta T-cell phenotype, but
2807). However, no one antigenic marker is spe- some cases are of alpha beta T-cel l
Other genetic tools have also been ap- cific for any neoplasm, and a combination derivation. Likewise, some follicular lym-
plied in the study of mature lymphoid of morphological features and a panel of phomas are CD10-negative. An aberrant
neoplasms. These include comparative antigenic markers are necessary for cor- immunophenotype may suggest or help
genomic hybridization and more sensitive rect diagnosis. Most B-cell lymphomas to confirm a diagnosis of malignancy
techniques of array-based copy-number have characteristic immunophenotypic {1815).
profiling, both of which can identify areas profil es that are very helpful in diagnosis. Although lineage is a defining feature of
of deletion or amplification within the However, immune profiling is somewhat most lymphoid malignancies, in recent
genome. Gene expression microarrays less helpful in the subclassification of T- years there has been an increasing ap-
can interrogate the expression of thou- cell lymphomas. preciation of lineage plasticity with in the
sands of genes at the RNA level, helping Although certain antigens are common ly haematopoietic system. Lineage switch
to elucidate pathways of activation and associated with specific disease enti- or demonstration of multiple lineages
transformation {877,878,884,1208,1775, ties, these associations are not entirely is most often encountered in immature
2719,3409,3538). Most recently, studies disease-specific. For example, CD30 is a haematolymphoid neoplasms, but also
have begun to explore changes at the universal feature of anaplastic large cell can be seen rarely in mature lymphomas
epigenetic level that control the expres- lymphoma, but can also be expressed in {772,1172,1536}.
sion of multiple genes {2352, 3528}. other T-cell and B-cell lymphomas and in
Definition lymphoma with recurrent genetic abnor- 6000 per year {1 603), with approximately
B-lymphoblastic leukaemia/ lymphoma malities (p. 203). 80-85% being of precursor B-cell pheno-
(B-ALL/LBL) is a neoplasm of precur- type {1501,3358).
sor lymphoid cells committed to the B- ICD-0 code 9811 /3 B-LBL constitutes about 10% of lympho-
eel! lineage, typically composed of small blastic lymphomas (LBLs); the remainder
to medium-sized blast cells with scant Synonyms are ofT-cell lineage {419}. In one literature
cytoplasm, moderately condensed to Pro-B lymphoblastic leukaemia; com- review, approximately 64% of 98 reported
dispersed chromatin, and inconspicu- mon precursor B-lymphoblastic leukae- cases were in patients aged < 18 years
ous nucleoli, involving bone marrow and mia; pre-B lymphoblastic leukaemia; {2448}. One report indicated a male pre-
blood (B-ALL) and occasionally present- pre-pre-B lymphoblastic leukaemia; dominance {2345}.
ing with primary involvement of nodal or common lymphoblastic leukaemia; pre-
extranodal sites (B-LBL). By convention, cursor B-cell lymphoblastic lymphoma; Etiology
the term lymphoma is used when the pro- precursor B-cell lymphoblastic leukae- The etiology of B-ALL/LBL is unknown.
cess is confined to a mass lesion with no mia, NOS; B-cell acute lymphoblastic There is an increased risk of B-ALL in
or minimal evidence of blood and mar- leukaemia children with Down syndrome and other
row involvement. With extensive marrow constitutional genetic disorders {4494).
and blood involvement, the appropriate Epidemiology Genome-wide association studies have
term is B-ALL. If a patient presents with ALL is primarily a disease of children; 75% shown increased risk of B-ALL associ-
a mass lesion and lymphoblasts in the of cases occu r in ch ildren aged< 6 years. ated with certain single nucleotide poly-
marrow, the distinction between leukae- The estimated annual incidence world- morphisms (SNPs) of genes including
mia and lymphoma is arbitrary {2792). wide is 1- 4.75 cases per 100 000 popu- GATA3, ARID58, IKZF1, CE8PE, and
In many treatment protocols, a value of lation {3327). The estimated number of CDKN2A / 8 {3051,3133}. However, true
> 25% marrow blasts is used to define new cases in the USA is approximately familial ALL is rare, with some kindreds
leukaemia. Unlike with myeloid leukae-
mias, there is no agreed-upon lower limit
for the proportion of blasts required to
establish a diagnosis of lymphoblastic
leukaemia (ALL). In general, the diag-
nosis should be avoided when there are
< 20% blasts. Presentations of ALL with
low blast counts are uncommon; there
is no compelling evidence that failure to
treat a patient when there are < 20% mar-
row lymphoblasts has an adverse effect
on outcome.
... ....... --
Fig. 12.01 B-lymphoblastic leukaemia. A Bone marrow smears showing several lymphoblasts with a high
nuclear:cytoplasmic ratio and variably condensed nuclear chromatin. B B-cell lymphoblasts containing numerous
coarse azurophilic granules.
Exclusionary criteria
The term B-ALL should not be used to
indicate Burkitt leukaemia/lymphoma.
Furthermore, some cases of B-ALL/LBL
have specific recurrent genetic abnor-
malities that are associated with distinc-
tive clinical and phenotypic properties,
have important prognostic implications,
or demonstrate other evidence that they
are mutually exclusive of other entities.
.. .. ..
These cases should not be classified
as B-ALL/ LBL, NOS, but rather accord- .- ....
Fig. 12.02 Benign B-cell precursors (haematogones) in bone marrow. A Increased haematogones in bone marrow
ing to their genetic abnormal ities. There
biopsy section may resemble lymphoblasts. B Bone marrow aspirate smear with increased haematogones, from an
are currently nine genetical ly defined B- 8-year-old boy, shows lymphoid cells with a high nuclear:cytoplasmic ratio and homogeneous nuclear chromatin;
ALL/ LBLs, which are further described nucleoli are not observed or are indistinct. These cells resemble the lymphoblasts in lymphoblastic leukaemia of
in section 8 -lymphoblastic leukaemia/ childhood.
Fig.12.03 B-lymphoblastic lymphoma in skin. A Neoplastic cells diffusely infiltrate the dermis but spare the epidermis. B Higher magnification of the same case shows
lymphoblasts surrounding a blood vessel.
described having mutations in PAX5 children. Marrow and blood involvement Cytochemistry
{3630}, ETV6 {4435}, and TP53 {3226). may be present, but by definition the pro- Cytochemistry seldom contributes to the
TP53 mutation, as discussed below, portion of lymphoblasts in the marrow is diagnosis of ALL. Lymphoblasts are nega-
shows a specific association with low < 25% {2345,2448). tive for MPO. Granules, if present, may
hypodiploid B-ALL {1929}. Some translo- stain light grey with Sudan Black B but are
cations associated with ALL have been Microscopy less intense than myeloblasts. Lympho-
detected in neonatal specimens long In smear and imprint preparations, the blasts may show periodic acid-Schiff
before the onset of leukaemia, and mo- lymphoblasts in B-ALL/ LBL vary from (PAS) positivity, usual ly in the form of
nozygotic twins with concordant leukae- small blasts with scant cytoplasm, con- coarse granules. They may react with non -
mia frequently share genetic abnormali- densed nuclear chromatin, and indis- specific esterase, with a multifocal punc-
ties (1428,2731). However, these findings tinct nucleoli to larger cells with moder- tate or Golgi region pattern that shows
are thought to reflect somatic mutations ate amounts of light-blue to bluish-grey variable inhibition with sodium fluoride.
occurring in one twin and shared via in cytop lasm (occasionally vacuolated),
utero circulation rather than constitutional dispersed nuclear chromatin, and mul- lmmunophenotype
genetic lesions. tiple variably prominent nucleoli. The The lymphoblasts in B-ALL/LBL are
nuclei are round or show convolutions. almost always positive for the B-cell
Localization Coarse azurophilic granules are pres- markers CD19, cCD79a, and cCD22;
By definition, the bone marrow is involved ent in some lymphoblasts in approxi- although none of these by itself is spe-
in all cases class ified as B-ALL, and mately 10% of cases. In some cases, the cific, their positivity in combination or at
the peripheral blood is usually involved. lymphoblasts have cytoplasmic pseudo- high intensity strongly supports the diag-
Extramedullary involvement is common, pods (hand-mirror cells). Normal B-cell nosis. The lymphoblasts are positive for
with particular predilection for the cen- precursors (haematogones) can mimic CD10, surface CD22, CD24, PAX5, and
tral nervous system (CNS), lymph nodes, lymphoblasts, but they typically have TdT in most cases, whereas CD20 and
spleen, liver, and testes. The most frequent even higher nuclear:cytoplasmic ratios, CD34 expression is variable; CD45 may
sites of involvement in B-LBL are the skin, more-homogeneous chromatin, and no be absent and if present is nearly always
soft tissue, bone, and lymph nodes {354, discernible nucleoli. more dimly expressed than on mature
2345,2448). Mediastinal masses are un- In bone marrow biopsies, the lympho- B cells. The myeloid -associated antigens
common (354,2448,3506}. blasts in B-ALL are relatively uniform CD13 and CD33 may be expressed and
in appearance, with round to oval, in- the presence of these myeloid markers
Clinical features dented, or convo luted nuclei . Nucleoli
Most patients with B-ALL present w ith range from inconspicuous to prominent.
evidence and consequences of bone The chromatin is finely dispersed. The
marrow failure: thrombocytopenia, anae- number of mitotic figures varies. LBL is
mia, and/or neutropenia. The leukocyte generally characterized by a diffuse or
count may be decreased, normal, or (less common ly) paracortical pattern of
markedly elevated. Lymphadenopathy, involvement of lymph node. A single-fil e
hepatomegaly, and splenomegaly are pattern of infiltration of soft tissue is com-
frequent. Bone pain and arthralgias may mon. Mitotic figures are usually numer-
be prominent symptoms. Patients pre- ous, and in some cases there may be a
senting with B-LBL are usually asymp- focal so-called starry-sky pattern. The
tomatic, and most have limited-stage morpholog ical features of B-lymphoblas- Fig. 12.04 B-lymphoblastic leukaemia. lmmunohisto-
disease. Head and neck presentations tic and T-lymphoblastic proliferations are chemical demonstration of nuclearTdT in a bone marrow
are particularly common, especially in indistinguishable. biopsy.
Fig. 12.07 B-lymphoblastic leukaemia/lymphoma with t(v;11q23.3); KMT2A-rearranged. FISH study using a break-
apart probe for KMT2A (previously called MLL); the normal KMT2A gene [MLL(1 1q23)] appears as juxtaposed red B-lymphoblastic
and green signals or sometimes a yellow signal; the translocation is demonstrated by separation of the red and green leukaemia/lymphoma with
probes (MLLsp). t(12;21)(p13.2;q22. 1);
Synonym blastic populations, a finding that can be ETV6-RUNX1
B-lymphoblastic leukaemia/ lymphoma confirmed by immunophenotyping; such
with t(v;11q23); MLL-rearranged cases should be considered B/ myeloid Definition
leukaemias. B-lymphoblastic leukaemia /lymphoma
Epidemiology (B-ALL/LBL) with t(12;21 )(p13.2;q22.1)
B-ALL with KMT2A rearrangement is the lmmunophenotype is a neoplasm of lymphoblasts commit-
most common leukaemia in infants aged Cases of B-ALL with KMT2A rearrange- ted to the B-cel l lineage in wh ich the
< 1 year. It is less common in older child- ments, especially t( 4;1 1), typically have a blasts harbour a translocation between
ren and then becomes increasingly com- C019+, CD10- , CD24-, pro-B immuno- ETV6 (also called TEL ) on chromo-
mon with age into adu lthood. phenotype, and are also positive for some 12 and RUNX1 (also called AML1)
CD15 {1712,3066). The NG2 homologue on chromosome 21.
Etiology encoded by CSPG4 is also characteris-
Although the specific etiology of leukae- tically expressed and is relatively specific. ICD-0 code 9814 / 3
mia with KMT2A translocations is un-
known, this rearrangement may occur Genetic profile Synonym
in utero, with a short latency between The KMT2A gene on chromo- B acute lymphoblastic leukaemia /
the translocation and development of some 11q23.3 is a promiscuous onco- lymphoma with t(12;21 )(p13;q22),
disease. Evidence for this includes the gene, with > 100 fusion partners. Trans- TEL/ AML 1 ( ETV6-RUNX1)
fact that these leukaemias are frequent locations involving th is gene can be
in very young infants, as well as the fact detected by standard karyotyping stud- Epidemiology
that this translocation has been identified ies or by FISH with a break-apart probe This leukaemia is not seen in infants, but
in neonatal blood spots of patients who directed against the KMT2A gene. PCR is common in children, accounting for
subsequently develop leukaemia {1277). can be used to identify major transloca- about 25% of cases of B-ALL in that age
tion partners, but a negative PCR resu lt group. It decreases in frequency with age
Clinical features cannot exclude an alternative fusion part- to the point that it is rare in adu lthood.
Patients with this leukaemia typically ner. The most common partner gene is
present with very high wh ite blood cell AFF1 (AF4) on chromosome 4q21. Other Clinical features
counts: frequently > 100 x 109 IL. There common partner genes include MLLT1 The presenting features are generally
is also a high frequency of CNS involve- (ENL) on chromosome 19p13 and MLLT3 similar to those seen in patients with
ment at diagnosis. Although organ in- (AF9) on chromosome 9p21.3. KMT2A- other Alls.
volvement may be seen, pure lymphoma- MLLT1 fusions are also common in T-
tous presentations are not typical. ALL, whereas fusions between KMT2A Microscopy
and MLLT3 are more typical ly associ- There are no unique morphological or cy-
Microscopy ated with acute myeloid leukaemia. Leu- tochemical features that distinguish this
There are no unique morphological or kaemias with KMT2A rearrangement are entity from other types of ALL.
cytochemical features that distinguish frequently associated with overexpres-
this entity from other types of ALL. In sion of FLT3 {149). In contrast to nearly lmmunophenotype
some cases of leukaemias with KMT2A all other categories of B-ALL, B-ALL with Blasts have a CD19+, CD10+ phenotype
rearrangement, it may be possible to rec- KMT2A rearrangement in infants has very and are most often C034 positive; other
ognize distinct lymphoblastic and mono- few associated additional mutations, with phenotypic features, including near or
Fig. 12.08 B-lymphoblastic leukaemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1. FISH study using
B-lymphoblastic
probes against RUNX1 (AML1) (red) and ETV6 (TEL) (green). The normal genes appear as isolated red or green leukaemia/lymphoma with
signals, and the fusion gene (arrows) appears as a yellow signal. hyperdiploidy
complete absence of CD9, CD20, and expression signature {4423). The ETV6-
CD66c {421,914,1712), are relatively spe- RUNX1 translocation is considered to be Definition
cific. Myeloid-associated antigens, es- an early lesion in leukaemogenesis, as B-lymphoblastic leukaemia/ lymphoma
pecially CD13, are frequently expressed evidenced by studies of neonatal blood (B-ALL/LBL) with hyperdiploidy is a
(283}. spots that have shown the presence neoplasm of lymphoblasts committed
of the translocation in ch il dren who de- to the B-ce ll lineage whose blasts con-
Cell of origin velop leukaemia many years later {4311}. tain > 50 chromosomes (usually < 66),
This leukaemia appears to derive from a There is evidence that the translocation is typically without translocations or other
B-cell progenitor rather than a haemato- necessary but not sufficient for the devel- structural alterations. There is contro-
poietic stem cell {580} opment of leukaemia {4311 }. versy as to whether the specific chromo-
somal additions, rather than the specific
Genetic profile Prognosis and predictive factors number of chromosomes, should be part
The ETV6-RUNX1 translocation results B-ALL with the ETV6-RUNX1 transloca- of the definition {1554,3284,3835).
in the production of a fusion protein that tion has a very favourable prognosis, with
probably acts in a dominant negative cure seen in > 90% of children, especially ICD-0 code 9815/3
fashion to interfere with normal function of if they have other favourable risk factors .
the transcription factor RUNX1. Th is leu - Relapses often occur much later than do Synonyms
kaemia appears to have a unique gene those of other types of ALL . Because this Hyperdiploid acute lymphoblastic leu-
kaemia; high hyperdiploid acute lympho-
blastic leukaemia; acute lymphoblastic
leukaemia with favourable trisomies
Epidemiology
This leukaemia is common in children,
accounting for about 25% of cases of
B-ALL in this age group. It is not seen
in infants , and decreases in frequency
10 11 12
among older ch il dren. It is uncommon in
adulthood, accounting for about 7- 8% of
cases of B-ALL in adults {2771}.
Clinical features
13 14 15 16 ' 18
The presenting features are generally
similar to those seen in patients with oth-
er Alls.
.> ;t ~-
19 20 21 22 x y Microscopy
There are no unique morphological or cy-
55,XX,+ X,+4,+6,+10,+14,+17 ,+18,+21,+21 tochemical features that distinguish this
Fig. 12.09 B-lymphoblastic leukaemia with hyperdiploidy. G-banded karyotype showing 55 chromosomes, including entity from other types of ALL.
trisomies of chromosomes 4, 10, and 17 and tetrasomy 21. There are no structural abnormalities.
Genetic profile
The TCF3-PBX1 translocation results in
the production of a fusion protein that
has an oncogenic role as a transcrip-
tional activator, and also likely interferes
with the normal function of the transcrip-
tion factors coded by TCF3 and PBX1
{2243}. The functional fusion gene re-
sides on chromosome 19, and there may
be loss of the derivative chromosome 1 in
some cases, resulting in an unbalanced
Fig.12.10 B-lymphoblaslic leukaemia with t(5;14)(q31.1;q32.1); IGH/ IL3. Bone marrow smear showing a population translocation. Gene expression profil-
of typical lymphoblasts along with numerous mature eosinophils. The granule distribution in some of the eosinophils ing studies have identified a signature
is unusual, but this is not a consistent factor. unique to this lesion {4423}. An alterna-
tive TCF3 translocation, t(17;19), occurs
Microscopy B-lymphoblastic in rare cases of ALL involving the HLF
Blasts in this neoplasm have the typi- leukaemia/lymphoma with gene on chromosome 17 and is associ-
cal morphology of lymphoblasts, but the ated with a dismal prognosis. Therefore,
t(1;19)(q23;p13.3);
striking finding is an increase in circulat- demonstration of a TCF3 rearrangement
ing eosinoph ils. This is a reactive popula- TCF3-PBX1 by itself is not a diagnostic criterion for
tion and not part of the leukaemic clone. this leukaemia.
Definition A subset of B-ALL cases, most common-
lmmunophenotype B-lymphoblastic leukaemia/ lymphoma ly hyperdiploid B-ALLs, have a karyotypi-
Blasts have a CD19+, CD10+ pheno- (B-ALL/LBL) with t(1;19)(q23;p13.3) is a cally identical t(1 ;19) that involves neither
type. The finding of even small numbers neoplasm of lymphoblasts committed to TCF3 nor PBX1, and should not be con-
of blasts with this phenotype in a patient the B-cell lineage in which the blasts har- fused with th is entity.
with eosinophilia strongly suggests this bour a translocation between TCF3 (also
diagnosis. known as E2A ) on chromosome 19 and Prognosis and predictive factors
PBX1 on chromosome 1. In early stud ies, B-ALL with TCF3-PBX1
Genetic profile was associated with a poor prognosis,
The unique characteristics of this neo- ICD-0 code 9818/3 but this is now readily overcome with
plasm derive from a functional re- modern intensive therapy. However,
arrangement between the IL3 gene on Epidemiology there may be an increased relative risk
chromosome 5 and an IGH gene on This leukaemia is relatively common in of CNS relapse in these patients {1850}.
chromosome 14, resulting in constitu- ch ildren, accounting for about 6% of cas- Many treatment protocols no longer re-
tive overexpression of IL3 {1463}. Other es of B-ALL. It is less common in adults. quire identification of this genetic lesion;
than eosinophilia, the functional con- the importance of identifying it as a dis-
sequences of this rearrangement are Clinical features tinct entity is controversial, although the
not well understood. The abnormality is The presenting features are generally findings of unique immunophenotypic
typical ly detected by conventional karyo- similar to those seen in patients with and genetic features support its inclusion
typing; it can also be detected by FISH, other Alls. as a distinct entity.
although appropriate probes are not
widely available. Microscopy
There are no unique morphological or
Prognosis and predictive factors cytochemical features that distinguish
The prognosis is not considered to be this entity from other types of ALL.
different from that of other types of ALL,
although there are too few cases to be lmmunophenotype
certain. Blast percentage at diagnosis is Blasts typically have a pre-B phenotype,
not known to be a predictive factor. with positivity for CD19, CD10, and cy-
toplasmic mu heavy chain, although not
all cases of pre-BALL have the t(1;19).
Fig. 12.11 T-lymphoblastic leukaemia. A Blood smear. The lymphoblasts vary in size from large cells to small cells with a very high N:C ratio. B Bone marrow biopsy section
showing mitotic activity in the lymphoblasts.
Etiology small lymphoblasts with very condensed abnormality involving the FGFR1 gene
One study reported a set of T-ALL cas- nuclear chromatin and no evident nucle- (see Myeloid/lymphoid neoplasms with
es in monozygotic twins that shared the oli to larger blasts with finely dispersed FGFR1 rearrangement, p. 77) {15,1760}.
same TR gene rearrangement {1235}, chromatin and relatively prominent nucle-
suggesting an in utero origin of the ear- oli. Nuclei range from round to irregular to Cytochemistry
liest genetic lesions. convoluted. Cytoplasmic vacuoles may T-lymphoblasts frequently show focal
be present. Occasionally, blasts of T-ALL acid phosphatase activity in smear and
Localization may resemble more mature lymphocytes; imprint preparations, although this is not
The bone marrow is involved in all cases in such cases , immunophenotypic stud- specific.
of T-ALL. Unlike in B-ALL, aleukaemic ies may be required to distinguish this
presentations in the setting of bone mar- disease from a mature (peripheral) T-cell lmmunophenotype
row replacement are uncommon. T-LB L leukaemia. The lymphoblasts in T-ALL/LBL are usu-
frequently shows mediastinal (thymic) In bone marrow sections, the lympho- ally TdT-positive and variably express
involvement, although it may involve any blasts have a high N:C ratio, a th in nucle- CD1a, CD2, CD3, CD4, CD5, CD?, and
lymph node or extranodal site. The skin, ar membrane, finely stippled chromatin, COB. Of these markers, CD? and CD3
tonsils, liver, spleen, CNS, and testes and inconspicuous nucleoli. The number (cytoplasmic) are most often positive,
may be involved, althoug h presentation of mitotic figures is reported to be higher but only CD3 is considered lineage
at these sites without nodal or mediasti- in T-ALL than in B-ALL. In T-LBL, the specific. CD4 and CDS are frequently
nal involvement is uncommon. lymph node generally shows complete coexpressed on the blasts, and CD10
effacement of architecture and involve- may be positive; however, these immu-
Clinical features ment of the capsu le. Partial involvement nophenotypes are not specific for T-ALL,
T-ALL typically presents with a high leu- in a paracortical location with sparing of because CD4 and CDS double positivity
kocyte count, and often with a large me- germinal centres may occur. Sometimes, can also be seen in T-cell prolymphocytic
diastinal mass or other tissue mass. Lym- a multinodular pattern is produced due leukaemia and CD10 positivity in periph-
phadenopathy and hepatosplenomegaly to stretching of the fibrous framework, eral T-cell lymphomas (most commonly
are common. For a given leukocyte count mimicking follicular lymphoma. A starry- angioimmunoblastic T-cell lymphoma).
and tumour burden, T-ALL often shows sky effect may be present, sometimes In addition to TdT and CD34, CD1a and
relative sparing of normal bone marrow mimicking Burkitt lymphoma, although CD99 may help to indicate the precur-
haematopoiesis compared to B-ALL. the nucleoli and cytoplasm are typically sor nature of T-lymphoblasts {3373}. In
T-LBL frequently presents with a mass in less prominent in T-LBL. The blasts can 29- 48% of cases, there is nuclear stain-
the anterior mediastinum, often exhibiting have round or convoluted nuclei. Mitotic ing for TAL1 , but this does not necessar-
rapid growth and sometimes presenting figures are often numerous. In the thy- ily correlate with presence of TAL 1 gene
as a respiratory emergency. Pleural effu- mus, there is extensive replacement of alteration {695,931 }.
sions are common. the thymic parenchyma and permeative CD79a positivity has been observed in
infiltration of the surrounding fibroadi- approximately 10% of cases {3188). One
Microscopy pose tissue. or both of the myeloid-associated an-
The lymphoblasts in T-ALL/LBL are mor- Cases with histological finding s of T-LBL tigens CD13 and CD33 are expressed
phologically indistinguishable from those with a significant infiltrate of eosinophils in 19-32% of cases {1998,4088}. KIT
of B-ALL/LBL. In smears, the cells are of among the lymphoma cells may be as- (CD117) is positive in occasional cases;
medium size with a high N:C ratio; there sociated with eosinophilia, myeloid hy- such cases have been associated with
may be a considerable size range, from perplasia, and an 8p11.2 cytogenetic activating mutations of FLT3 {3027). The
presence of myeloid markers does not (TR) genes, and there is simultaneous as a result of a cryptic interstitial deletion
exclude the diagnosis of T-ALL/LBL, nor presence of IGH gene rearrangements in at chromosome 1p32 {467,1 596,1837).
does it indicate T /myeloid mixed-pheno- approximately 20% of cases {31S7,3S60}. Aberrant TAL1 expression interferes with
type acute leukaemia. differentiation and proliferation by inhib-
Many markers characteristic of immature Cytogenetic abnormalities and iting the transcriptional activity of TCF3
T cells, such as CD?, CD2, and even CD5 oncogenes (also called E47) and TCF12 (also called
and cCD3-epsilon, may also be seen in An abnormal karyotype is found in HEB) {2919). Other important transloca-
NK-cell precursors. Therefore, it can be 50-70% of cases of T-ALL/LBL {1426, tions in T-ALL include t(10;11)(p13;q14),
very difficult to distinguish the rare true 1534). The most common recurrent cy- which results in PICALM-MLLT10 (also
NK-cell ALL/LBL from T-ALL that ex- togenetic abnormality involves the al- called CALM-AF10) and is found in 10%
presses only immature markers. CD56 pha and delta TR loci at 14q11.2, the of cases, and translocations involving
expression, although characteristic of beta locus at 7q35, and the gamma lo- KMT2A (also called MLL) , which occur in
NK cells, does not exclude T-cell leu- cus at 7p14-15, with a variety of partner S% of cases , most often with the partner
kaemia. T-ALL/LBL has previously been genes {1426,1534). In most cases, these MLLT1 (also called ENL ) at 19p13 {1426};
stratified into four stages of intrathymic translocations lead to a dysregulation of both result in activation of HOXA genes
differentiation according to the antigens transcription of the partner gene by jux- {2614). It has been proposed that T-ALL
expressed {332}: (1) pro-T /T-1, (2) pre- taposition with the regulatory region of be divided into four distinct, non-overlap-
T /T-11, (3) cortical T/ T-111, and (4) medul- one of the TR loci. The most commonly ping genetic subgroups based on spe-
lary T /T-IV. Many cases previously clas- involved genes include the transcrip- cific translocations that lead to aberrant
sified as pro-T or pre-T would now meet tion factors TLX1 (also called HOX11) expression of ( 1) TAL or LMO genes, (2)
the criteria for early T-cell precursor ALL at 10q24, which is involved in 7% of TLX1, (3) TLX3, and (4) HOXA genes, re-
(see next section). Like normal thymo- childhood and 30% of adu lt cases, and sulting in arrest of T-cell maturation at dis-
cytes, T-ALL of the cortical T stage often TLX3 (also called HOX11L2) at 5q35, tinct stages of thymocyte development
has a double-positive (CD4+, CDS+) im- which is involved in 20% of childhood {2614,4143). The TLX1 group appears
munophenotype together with CD1a posi- and 10-15% of adult cases {1426). Other to have a relatively favourable prognosis
tivity, whereas the medullary T stage ex- transcription factors that may be involved {11S9}. Another group, characterized by
presses either CD4 or CDS. Some studies in translocations include MYC at Sq24.1 , overexpression of LYL 1, may correspond
have shown a correlation between the TAL1at1p32, LM01 (also called RBTN1) more closely to early T-cell precursor
stages of T-cell differentiation and surviv- at 11p15, LM02 (also called RBTN2) at ALL {2614).
al. T-ALL tends to have a more immature 11p13, and LYL1 at 19p13 {S97,1426}. Deletions also occur in T-ALL. The most
immunophenotype than does T-LBL, but The cytoplasmic tyrosine kinase LCK important is del(9p), resulting in loss of
the groups overlap {42S7}. at 1p34.3-35 can also be involved in a the tumour suppressor gene CDKN2A
translocation. In many cases, transloca- (an inhibitor of the cyclin-dependent ki-
Postulated normal counterpart tions are not detected by karyotyping nase COK4) , which occurs at a frequen-
A T-cell progenitor (T-ALL) or a thymic but only by molecular genetic studies. cy of about 30% by cytogenetics, and a
lymphocyte (T-LBL) For example, the TAL 1 locus is altered greater frequency by molecular testing.
by translocation in about 20-30% of This leads to loss of G1 control of the
Genetic profile cases of T-ALL, but a t(1 ;14 )(p32;q1 1) cell cycle.
Antigen receptor genes translocation can be detected in only About 50% of cases have activating muta-
T-ALL/ LBL almost always shows clonal about 3% of cases. Much more often, tions involving the extracellular heterodi-
rearrangements of the T-cell receptor TAL1 is fused to ST!L (also called SIL) merization domain and /or the C-terminal
Definition Early in their development, NK-cell pro- wider availab ility of more specific NK-cell
NK-lymphoblastic leukaemia/lymphoma genitors express no specific markers markers, including panels of antibodies
has been very difficult to define, and {1255), or express markers that overlap against killer-cell immunoglobulin-like re-
there is considerable confus ion in the with those seen in T-ALL, including CD?, ceptors, will help clarify th is disease, but
literature. Contri buting to th is confus ion CD2, and eve n CD5 and cCD3-eps il on until then, NK-ALL/ LBL is best consid-
is the fact that many cases reported as {3757); therefore, distinguish ing between ered a provisional entity. The diagnosis
NK-leukaemia due to express ion of CD56 T-ALL and NK-cell tumours can be dif- of precursor NK-ALL/LBL may be con -
(NCAM) are now recognized to in fact be ficu lt. More-mature but more-specific sidered in a case that expresses CD56
blasti c plasmacytoid dendritic ce ll neo- markers such as CD16 are rarely ex- along with immature T-associated mark-
plasms {3151,3152}. Similarly, the e ntity pressed in any acute leukaem ia; some ers such as CD? and CD2, and even
known as mye loid/NK acute leukaemia markers that might be co nsidered re la- in cluding cCD3, provided that the case
{3599,3841}, which has been suggested tive ly specific but that are still expressed lacks B-cell and mye loid markers, TCR
to be of precursor NK-cell orig in {3000}, on NK-cell progenitors (e.g. CD94 and IG genes are in the germline con -
has a primitive immunophenotype indis- and CD161 {1255)) are not commonly figuration {1975,2070,3000}, and blastic
ti nguishable from that of acute myeloid tested. Some we ll- characterized cases plasmacytoid dendritic cell neoplasm
leukaemia with minimal differentiation. of NK precursor tumours with lympho- has bee n exc luded.
Until further evidence emerges, these matous presentations that expressed
should be considered as cases of acute NK-specific CD94 1A transcripts have
myeloid leukaemia. been described {2338). It is hoped that
Fig.13.01 Chronic lymphocytic leukaemia I small lymphocytic lymphoma (CLL/SLL). A Bone marrow trephine section illustrating a nodular pattern of infiltration. B Bone marrow
trephine section illustrating an interstitial pattern of lymphocytic infiltration. C Peripheral blood. The CLL lymphocytes are small and round, with distinct clumped chromatin.
Smudge cells are commonly seen.
in proliferation centres independently of can have very similar, if not identical, Cytogenetic abnormalities and
gene alterations {2047,2123). immunoglobu lin sequences, a phenom- oncogenes
enon that is present in 30% of all CLL CLL has no specific genetic markers.
Postulated normal counterpart cases and termed 'BCR stereotypy' {28). About 80-90% of the cases have cy-
An antigen-experienced mature CD5+ BCR signal ling is more active in CLL with togenetic abnormalities detected by
B cell with mutated or unmutated IGHV unmutated IGHV genes {4483), where- FISH or copy-number arrays {1073,2469,
genes {721} as other cases, in particular those with 3244). The most common alterations are
mutated IGHV genes, have a response deletions in 13q14.3 (miR-16-1 and miR-
Genetic profile resembling anergy. CLL 8-cell recep- 15a; present in -50% of cases) and tri-
Antigen receptor genes tors have been shown to recognize both somy 12 or partial trisomy 12q13 (pres-
IGHV gene usage in CLL is highly foreign and self antigens, including the ent in -20%); less commonly, there is
skewed; IGHV genes are mutated (i.e. possibility of the monoclonal immuno- deletion in 11q22-23 (ATM and B/RC3),
< 98% identity with the germline) in 50- globu lin recogn izing itself on the same or 17p13 (TP53) , or 6q21 {1073,1510,4469}.
70% of cases and unmutated (i.e. ::::98% an adjacent cell (so-called autonomous The distribution of these abnormalities
identity) in 30-50% {863,1528). Patients signalling) {1072). varies depending on the IGHV mutation
status (see Table 13.01). High-resolution
genomic arrays have helped to refine and
expand the known DNA copy-number al-
terations, identifying gains in 2p (present
in 7% of cases) and 8q24 (MYC; in 3%),
as well as losses of 14q (in 4%), among
others {1079,2469,3244). Chromosomal
translocations in CLL are uncommon, but
t(14;18)(q32;q21), resulting in IGH/BCL2,
.
CD70APC
t 1U
CDH flTC
.
CD4J APCH7
can be found , most likely as a secondary
change, in 2% of cases, usually with mu-
tated IGHV. Translocations involving the
13q14 region , present in 2% of cases, are
•'-,.. associated with miR-16-1 and miR-15a
. :··= .'
:;
·... deletions {3244,3247). The t(14;19)
(q32;q13) translocation, resulting in IGH/
BCL3, is present in occasional cases of
CLL with unmutated IGHV genes {1730).
Complex rearrangements withi n sin-
• 111 1U 11W H• • 11l
CDHtPE L••llitl• PE gle chromosomes (chromoth ripsis) and
among chromosomes have been identi-
fied in 2% of cases, mainly with unmu-
Fig.13.05 Chronic lymphocytic leukaemia. lmmunophenotype of CLL (orange), normal B cells (blue), and T cells
tated IGHV genes and frequently in asso-
(green) by flow cytometry. CLL cells have weak expression of CD22, CD79b (top-left plot), and CD20 (top-middle
plot); coexpression of CDS(top-middle plot) and CD43 (top-right plot); strong expression of CD200 (bottom-left plot) ciation with TP53 mutations {1079, 3244).
and CD23 (bottom-middle plot); negative FMC7 (bottom-middle plot); and restricted expression of dim kappa light The most commonly mutated genes, af-
chain (bottom-right plot). fected in 3- 15% of cases, are NOTCH1,
c.,"'
.······
als aged < 40 years and S0-7S% among .,
f:
a..
40
Hematology Clinic Series
90-year-old individuals {13S3,2876, ., (Lymphocytosis)
3320}. It has been reported that virtually .2:
-;;; 20 ...·····
all CLLs are preceded by MBL, although :; ....·
not all MBL progresses to CLL {1167).
E
::J
(..)
0
....···-·
Some patients have counts that oscillate 0.01 0.1 10 100 1000 10000
between MBL and CLL for some time.
Absolute Number of Neoplastic B-cells
CLL-type MBL must be further classified
on the basis of the size of the monoclonal Fig.13.09 Low-count and high-count chronic lymphocytic leukaemia (CLL)-type monoclonal B-cell lymphocytosis
population, as low-count (< O.S x 10 9 /L) (MBL). The cumulative percentage of cases according to the absolute number of clonal B cells in studies of individuals
or high-count (~0.Sx 10 9 /L) MBL. Low- from the general population with a normal blood count (dotted line) and in series of individuals referred for clinical
count MBL has some biological dif- haematology investigations, usually with current or prior lymphocytosis (solid line). There is a marked difference
in the clonal B-cell count in CLL-type MBL in cases from population studies versus cl inical haematology series. In
ferences from high-count MBL and population studies, the median clonal B-cell count is 1/µL, with 95% of cases having< 56/µL (white background). In
CLL, and does not seem to progress, clinical haematology series, the median is 2939/µL, with 95% of cases having >447/µL (dark-grey background). Very
whereas high-count MBL has biological few cases from either series have a clonal B-cell count within the same range as polyclonal B-cell levels in individuals
features identical to those of low-stage with no detectable abnormal B cells (light-grey background). From Rawstron AC et al. {3321).
(Rai stage 0) CLL, and progresses to
frank leukaemia requiring therapy at an otherwise have MBL may constitute a to rule out a specific lymphoid neoplasm
annual rate of 1-2% (1167,3319,3666}. nodal equivalent of MBL rather than small (1949). Some cases have aberrant karyo-
The higher the MBL count, the more lymphocytic lymphoma {1369}. types involving chromosome 7q, and as
likely there will be progression. The ad- MBL with an atypical CLL phenotype ex- many as 17% may eventually develop
verse prognostic indicators identified in presses CD19, CDS, CD20 (bright), and sp lenomegaly, suggesting a relation-
patients with CLL are also associated moderate to bright surface immunoglob- ship to splen ic marginal zone lymphoma
with progression from MBL to CLL and ulin. CD23 may be negative. It is critical (4390). Some very similar cases with a
shorter time to treatment (1949,1992}. to exclude the possibility of mantle cell low rate of progression may have a mono-
MBL cases usually have mutated IGHV lymphoma or other B-cell lymphoma in typ ic B-cell count >S x 10 9 /L, therefore
genes (present in 7S-90% of cases) these cases. not fulfilling the criteria for MBL (4390).
and may carry the same chromosomal MBL with a non-CLL phenotype is char- Some cases of diffuse large B-ce ll lym-
abnormalities and somatic mutations as acterized by CDS- (or CDS(d im) in 20% phoma with simultaneous MBL with a
CLL, including NOTCH1, SF381, ATM, of cases), CD19+, CD20+ B cells with CLL or non-CLL phenotype are clonally
and TP53 aberrations, although at lower moderate to bright surface immunoglob- related (2468}.
frequencies (1992,3244). Nodal infiltra- ulin expression {13S3,3631}. Some of
tion by CLL-type cells without apparent these clonal expans ions may be transient ICD-0 codes
proliferation centres in individuals without and self-lim ited. Add itional phenotypic MBL, CLL-type 9823/1
lymphadenopathy > 1.S cm on CT who and cytogenetic studies are mandatory MBL, non-CLL-type 9S91/1
Definition Localization
Splenic marginal zone lymphoma (SMZL) The tumour involves the spleen and
is a 8-cell neoplasm composed of small splenic hilar lymph nodes, the bone mar-
lymphocytes that surround and replace row, and often the peripheral blood. The
the splenic white pulp germinal centres, liver may also be involved. Peripheral
efface the follicle mantle, and merge with lymph nodes are not typically involved
a peripheral (marginal) zone of larger {347,2691}.
cells, including scattered transformed
blasts; both small and larger cells infiltrate Clinical features
the red pulp. Splenic hilar lymph nodes Patients present with splenomegaly,
and bone marrow are often involved; lym- sometimes accompanied by autoim-
phoma cells are frequently found in the mune thrombocytopenia or anaem ia and Fig.13.13 Splenic marginal zone lymphoma.
Peripheral blood conta ining tumour cells with polar villi
peripheral blood as villous lymphocytes. a variable presence of peripheral blood
(villous lymphocytes).
villous lymphocytes. The bone mar-
ICD-0 code 9689/3 row is regularly involved, but peripheral
lymphadenopathy and extranodal infil- protein, but marked hyperviscosity and
Synonyms tration are extreme ly uncommon. About hypergammag lobulinaemia are uncom-
Splenic 8-cell marginal zone lymphoma; one third of patients have a small para- mon {347,2691). An association with
sp lenic lymphoma with vi llous lympho- hepatitis C virus has been described in
cytes; sp lenic lymphoma with circulating southern Europe {135,1620).
villous lymphocytes (no longer used)
Macroscopy
Epidemiology Gross examination of the spleen reveals
SMZL is a rare disorder, accounting for marked expansion of the wh ite pu lp and
< 2% of lymphoid neoplasms {148), but it infiltration of the red pu lp.
may account for most cases of otherwise
unclassifiable chronic lymphocytic leu- Microscopy
kaemias that are CDS-negative. Most pa- In the splen ic white pulp, a central zone
tients are aged > 50 years, with a median of small round lymp hocytes surrounds or,
age of 67-68 years. The incidence rates Fig.13.12 Splenic marginal zone lymphoma. more commonly, replaces reactive ger-
among males and females are equal {347, Gross photograph of spleen showing marked expansion minal centres, with effacement of the nor-
1999,4388). of the white pulp and infiltration of the red pulp. mal follicle mantle {1783,2691). This zone
merges with a peripheral zone of small to are a helpful feature, although they are however, such a specimen is often not
medium-sized cells with more dispersed sometimes observed in other lymphomas available.
chromatin and abundant pale cytoplasm, 11242). When lymphoma cells are present
which resemble marginal zone cells, and in the peripheral blood, they are usually lmmunophenotype
interspersed transformed blasts. The characterized by short polar villi. Some Tumour cells express surface lgM and
red pulp is always infiltrated, with smal l may appear plasmacytoid 12622). usually lgO. They are positive for C020
nodules of the larger cells and sheets of and C079a and negative for C05, C010,
the small lymphocytes, which often in- Differential diagnosis C023, C043, and annexin A1 {1783,
vade sinuses. Epithelioid histiocytes may The differential diagnosis includes other 2579). C0103 is usually negative, and
be present in the lymphoid aggregates. small B-cell lymphomas/leukaemias, in- cyclin 0 1 is absent j3540}. Ki-67 staining
Some cases have a markedly predomi- cluding chronic lymphocytic leukaemia shows a distinctive targetoid pattern due
nant popu lation of the larger marginal (CLL), hairy cell leukaemia (HCL), mantle to an increased growth fraction in both
zone-like cells {1532,1793). Plasmacytic cell lymphoma, follicular lymphoma, and the germinal centre, if present, and the
differentiation may occur, and in rare cas- lymphoplasmacytic lymphoma. It is also marginal zone. The absence of cyc\in 01
es, clusters of plasma cells are present important to recog nize that many small B- and LEF1 is useful in excluding mantle
in the centres of the white pulp nodules. eel\ lymphomas (other than HCL, wh ich cell lymphoma and CLL, respectively.
In splenic hilar lymph nodes, the sinuses diffusely involves the red pulp) can have The absence of annexin A1 excludes
are dilated and lymphoma surrounds and slightly larger cells with pale cytoplasm HCL, and lack of C010 and BCL6 helps
replaces germinal centres, but the two when they involve the splenic marginal to exclude follicular lymphoma 13540). A
cell types, small lymphocytes and mar- zone, mimicking SMZL !3197). The nodu- group of C05+ SMZL cases has been
ginal zone cells, are often more intimately lar pattern on bone marrow biopsy ex- described, distinguished by a higher
admixed, without the formation of a dis- cludes HCL, but the morphological fea- lymphocytosis and diffuse bone marrow
tinct so-called marginal zone. In the bone tures on bone marrow examination may infiltration {285).
marrow, there is a nodular interstitial in- not be sufficient to distinguish between
filtrate cytologically similar to that in the the other small B-cell neoplasms. lmmu- Postulated normal counterpart
lymph nodes. Occasionally, neoplastic nophenotypic and molecular/cytogenetic A marginal-zone B cell that may or may
cells surround reactive follicles. lntrasinu- findings may also be very helpful, but the not demonstrate evidence of antigen
soidal lymphoma cells, which are more diagnosis can be rend ered most con- exposure
apparent after C020 immunostaining, fidently from a splenectomy specimen;
Genetic profile
Antigen receptor genes
JG heavy and light chain genes have
clonal rearrangements, and approxi-
mately half of the cases have somatic hy-
permutation. Bias in IGHV1-2*04 usage
has been found in 30% of SMZL cases,
suggesting that this tumour derives from
a highly selected B-cell population 162,
378). Stereotyped HCOR3 sequences,
specific for SMZL, support a potential
role of antigen selection in the pathogen-
esis of these lymphomas {4493).
Cytogenetic abnormalities and NOTCH2 is one of the most frequently Prognosis and predictive factors
oncogenes mutated genes in SMZL, mutated in ap- The clinical course is indolent, with a 10
SMZL lacks recurrent chromosomal proximate ly 10-25% of cases {771, 2006, year survival probab il ity from 67% to 95%
translocations, including transloca- 2532,3070,3203,3419). Although dia- {135,347,2266,2781,3956,3957,3768A}.
tions that are typical of other lymphoma gnostically useful, NOTCH2 mutations Response to chemotherapy of the type
types, such as the t(14;18)(q32;q21) are also seen in infrequent other small that is typically effective in other small B-
translocation affecting BCL2 in follicular B-cel l lymphomas {305,1945,2006, cell neoplasms is often poor, but patients
lymphoma; the t(11 ;14)(q13;q32) trans- 3419). KLF2 is somatically mutated in generally have haematological responses
location affecting CCND1 in mantle cell approximately 10-40% of SMZLs {771, to sp lenectomy and/or rituximab, with
lymphoma; and the t(11 ;18)(q21 ;q21), 3070,3203}, but these mutations are long -term survival {2266,3139A,3768A}
t(14;18)(q32;q21), and t(1 ;14)(p22;q32) also found in some other small B-cell Transformation to large B-cell lymphoma
translocations resulting in BIRC3/MALT1, neoplasms {3203). Mutations in both of occurs in 10-15% of cases {4388), and
IGH!MALT1, and IGH/BCUO juxtaposi- these genes have been associated with is usually associated with a shorter time
tion, respectively, in extranodal marginal SMZLs that have deletion in 7q. MYDBB to progression {2266,2781). Hepatitis C
zone lymphoma of mucosa-associated mutations are rare in SMZL, and may virus- positive cases have been reported
lymphoid tissue (MALT lymphoma). The therefore be a useful biomarker for the to respond to antiviral treatment using in-
absence of these abnormalities helps differentiation of SMZL from lymphop- terferon gamma, with or without ribavirin
distinguish SMZL from some of the lym- lasmacytic lymphoma in patho logically {1620,3955). Adverse clinical prognostic
phomas that can mimic it. A small num- challenging cases with evidence of plas- factors include a large tumour mass and
ber of SMZLs carry a recurrent t(2;7) macytic differentiation {2534,3070). The poor general health status {627). A clin ical
(p12;q21) trans location, wh ich activates fact that the most frequently mutated scoring system has been proposed that
the CDK6 gene through juxtaposition genes in SMZL (i.e. NOTCH2 and KLF2) incorporates haemoglobin concentration,
with the IGK locus {810} Approximately are physiologically involved in prolifera- platelet count, lactate dehydrogenase
30% of SMZLs show a heterozygous tion and commitment of mature B cells level, and presence of extrahilar lym-
deletion in 7q, wh ich is rarely found in to the marginal zone, points to homing phadenopathy {2696}. Although data are
other lymphoma subtypes {3362,3497). to the spleen compartment and marg inal limited, NOTCH2, KLF2, and in particular
The gene(s) targeted by the 7q deletion zone differentiation as the major pro- TP53 mutations have been reported to be
remain unknown, despite the combined grammes deregulated in this lymphoma. adverse prognostic indicators {3070).
investigation of genomic and transcrip- Congruently, SMZL has an expression
tomic profiles and mutation analys is of a signature characterized by the upregula-
number of cand idate genes {1254,3376, tion of genes be longing to the marginal
4268). Gain of 3q is present in a consid- zone differentiation programme {3455,
erable subset of cases . 4064).
tial so-called hairy projections on smears Spleen and other tissues planted by immunophenotypic/immuno-
{364,3638). Occasionally, the cytoplasm In the spleen, HCL infiltrates are found in histochemical techniques. When appro-
contains discrete vacuoles or rod-shaped the red pulp. The white pulp is typically priate air-dried unfixed slide preparations
inclusions that represent the ribosome atrophic. The cells characteristically fill are available, virtually all cases of HCL
lamellar complexes that have been identi- the red pulp cords . Red blood cell lakes, are found to contain at least some cells
fied by electron microscopy {3638). collections of pooled erythrocytes sur- with strong, granular cytoplasmic tartrate-
The diagnosis is best made on bone mar- rounded by elongated hairy cells, are the resistant acid phosphatase positivity;
row biopsy. The extent of bone marrow presumed consequence of disruption of weak staining is of no diagnostic utility.
effacement in HCL varies. The primary normal blood flow in the red pulp {364 ,
pattern is interstitial or patchy with some 3638). The liver may show infiltrates of lmmunophenotype
preservation of fat and haematopoietic el- hairy cells, predominantly in the sinu- The classic immunophenotypic profile of
ements. The infiltrate is characterized by soids. Lymph node infiltration may occur, HCL consists of bright monotypic surface
widely spaced lymphoid cells with oval or especially with advanced disease, and is immunoglobulin; bright coexpression of
indented nuclei, in contrast to the closely variably interfollicular/paracortical, with CD20, CD22, and CD11c; and expres-
packed nuclei of most other indolent lym- sparing of follicles and intact sinuses. sion of CD103, CD25, CD123, TBX21
phoid neoplasms involving the bone mar- (also called TBET), annexin A1, FMC?,
row. The abundant cytoplasm and promi- Cytochemistry CD200, and cyclin 01 {1153 ,1302,1896,
nent cell borders may produce a so-cal led The only cytochemical stain used in the 3643). Most cases of HCL lack both
fried-egg appearance. Mitotic figures are diagnosis is tartrate-resistant acid phos- CD5 and CD10, but CD10 expression is
virtually absent. When infiltration is mini- phatase, but the use of this technically reported in about 10-20% of cases and
mal, the subtle clusters of hairy cells can challenging stain has been largely sup- CD5 expression in about 0-2% {685,
be overlooked . In patients with advanced
disease, a diffuse solid infiltrate may be
evident. The obvious discrete aggregates
that typify bone marrow infiltrates of many
other chronic lymphoproliferative neo-
plasms are not a feature of HCL. An in-
crease in reticulin fibres is associated with
all hairy cell infiltrates in bone marrow and
other sites, and often results in a so-called
dry tap (i.e. failure to obtain aspirate on at-
tempted bone marrow aspiration). In some
cases, the bone marrow is hypocellular,
with a loss of haematopoietic elements,
in particular of the granulocytic lineage,
which can lead to an incorrect diagnosis
of aplastic anaemia. In such cases, im-
munostaining for a B-cell antigen such as
CD20 is essential for the identification of
an abnormal B-ce ll infiltrate, prompting
the use of immunohistochemical stains
more specific for HCL. In some cases, the
morphological appearance of HCL over-
laps with that of splenic marginal zone ~' • • i" ' .••~··...:;
Fig.13.20 Hairy cell leukaemia (HCL), bone marrow biopsy. A Low-magnification view showing a subtle diffuse
lymphoma or splenic B-cell lymphoma/ interstitial infiltrate of hairy cells. B Extensive diffuse interstitial infiltration by hairy cell leukaemia. Note the widely
leukaemia, unclassifiable, requiring corre- spaced oval nuclei and paucity of mitotic activity. C The so-called fried-egg appearance of hairy cells is evident on
lation with the immunophenotypic studies. high magnification. D Note the diffuse increase in reticulin fibres.
Genetic profile
Antigen receptor genes
Although exceptions have been report-
ed, the majority (> 85%) of c ases of HCL
demonstrate IGHV genes with somatic
hypermutation indicative of a post-ger-
minal centre stage of maturation {152,
Fig.13.21 Hairy cell leukaemia (HCL). A Hypocellular HCL with interstitial infiltrates in bone marrow biopsy. BCD20 586,3994) A unique feature of HCL is the
immunohistochemical staining highlights the subtle leukaemic infiltrate in this case. C Spleen shows red pulp infiltra- common coexpression of multiple c lon-
tion with numerous red blood cell lakes. D There is both portal and sinusoidal infiltration in the liver. ally related immunoglobulin isotypes,
suggesting arrest at some point during
isotype switching {3994).
Epidemiology
Splenic diffuse red pulp small SDRPL is a rare disorder, account-
8-cel/ /ymphoma ing for < 1% of non-Hodgkin lympho-
mas. It accounts for about 10% of the
Definition B-cell lymphomas diagnosed in sple-
Splenic diffuse red pulp small B-cell lym- nectomy specimens. Most patients are
phoma (SDRPL) is an uncommon lympho- aged > 40 years, and there is no sex
ma with a diffuse pattern of involvement predilection.
of the sp lenic red pulp by small mono-
morphous B lymphocytes. The neoplasm Localization
also involves bone marrow sinusoids and All cases are diagnosed at clinical
peripheral blood, commonly with a vil - stage IV, with spleen, bone marrow, and
Fig.13.23 Splenic diffuse red pulp small B-cell lympho-
lous cyto logy {1921,4043,4044). This is a peripheral blood involvement. Peripheral
ma. A Peripheral blood cytology with vil lous ce ll. B Re-
provisional entity that requires add itional lymph node involvement is only rarely ticu lin staining in spleen outlines the infiltration of red
molecular studies for defining its main reported. pulp cords and sinusoids. C Bone marrow intrasinusoi-
features and diagnostic markers. This dal infiltration highlighted by CD20 staining.
cryoglobul in aemia, or paraprotein depo- is usually composed predominantly of sidual germinal centres . There is a rela-
sition. Deposits of lgM may occur in the small lymphocytes admixed with variable tively monotonous proliferation of small
skin or the gastrointestinal tract, where numbers of plasma cells, plasmacytoid lymphocytes, plasma cells, and plasma-
they may cause diarrhoea. Coagulopa- lymphocytes, and often increased mast cytoid lymphocytes, with relatively few
thies may be caused by lgM bind in g to cells {2347,3016,3017). The plasma cells transformed cells. Dutcher bodies (PAS-
clotting factors, platelets, and fibrin. lgM may also form distinct clusters separate positive intranuc lear pseudoinclusions),
paraproteins are not diagnostic of either from the lymphoid component {2347, increased mast cells, and haemosiderin
LPL or WM, because they can also oc- 2736). Residual disease after treatment are also typical features. Other cases
cur in patients with other lymphoid neo- may demonstrate virtually all plasma show greater architectural destruction
plasms or without an overt neoplasm . A ce lls {2347,4157). A similar spectrum of and may have a vaguely follicular growth
minority of patients initi ally present with ce ll s as are present in the bone marrow pattern, more prominent residual ger-
an lgM-related disorder such as cryoglo- may be present in the peripheral blood, minal centres (even with follicular co lo-
bulinaemia or lgM monoclonal gammop- but the white blood cel l count is typi- nization), epithe li oid histiocyte clusters,
athy of undetermined significance (see cally lower than in chronic lymphocytic sometimes a much greater proportion of
below) and only later develop an overt leukaemia. plasma cells, and sometimes a paucity
LPL {621,2173,2752}. of frank plasma cells {3521,3851). The
Lymph nodes and other tissues presence of prom inent large transformed
Microscopy In the most classic cases, which are cells should raise the possib ility of either
Bone marrow and peripheral blood usually associated with WM, the lymph disease progression or a diagnosis other
Bone marrow involvement is character- nodes show retention of normal archi- than LPL. Proliferation centres like those
ized by a nodular, diffuse, and/or in- tectural features with dilated sinuses with seen in chronic lymphocytic leukae-
terstitial infiltrate, sometimes even with periodic acid-Schiff (PAS) positive mate- mia I small lymphocyti c lymphoma must
paratrabecular aggregates. The infi ltrate rial and sometimes small portions of re - be absent, and the presence of paler
'· .
Fig.13.28 Lymphoplasmacytic lymphoma with MYDBB L265P mutation and prominent follicular colonization, lymph node. A The lymph node has intact sinuses and a
monotonous lymphoplasmacytic proliferation with a somewhat follicu lar growth pattern. B CD21 immunohistochemical staining highlights the prominent infiltration of distorted
fo llicular structures by the lymphoma.
l.o21
Definition Table 13.03 Diagnostic criteria for lgM monoclonal may be required to identify the clonal
lgM monoclonal gammopathy of unde- gammopathy of undetermined significance; adapted population within the backg round of be-
termined significance (MGUS) is defined from the International Myeloma Working Group (IMWG) nign polytypic B cells (2924,3032,3034).
by a serum lgM paraprotein concen- updated criteria for the diagnosis of multiple myeloma When present, the clonal B-cell popula-
From: Rajkumar SV, et al. {3290).
tration < 30 g/L; bone marrow lympho- tion shows a non-specific phenotype
plasmacytic infiltration of < 10%; and • Serum lgM monoclonal protein similar to that of LPL (CD19+, CD20+,
no evidence of anaemia, constitutional concentration < 30 g/L CD5-, CD10-, and CD103-). The plas-
symptoms, hyperviscosity, lymphadeno- • Bone marrow lymphoplasmacytic infiltration ma cells in lgM MGUS lack expression of
pathy, hepatosplenomegaly, or other of <10% CD56 {3034).
end-organ damage that can be attribut- No evidence of anaemia,
ed to the underlying lymphoproliferative constitutional symptoms, hyperviscosity, Postulated normal counterpart
disorder {3290) lgM MGUS is a precur- lymphadenopathy, hepatosplenomegaly, B cells with somatic hypermutation of the
sor condition that may progress to overt or other end-organ damage that IGHV genes but without class switching
can be attributed to the underlying
lymphoma or primary amyloidosis. {2177)
lymphoproliferative disorder
Localization
The spleen, liver, bone marrow, and pe-
ripheral blood may be involved; periph-
eral lymphadenopathy is usually absent.
Clinical features
Most patients present with a slowly pro-
gressive disease resembling CLL. Mu
HCD differs from most cases of CL L in
the high frequency of hepatospleno-
megaly and the absence of peripheral
Complement· lymphadenopathy. Routin e serum prote in
CH2 } binding site electrophoresis is frequently normal. lm-
munoelectrophoresis reveals reactivity
to anti-mu in polymers of diverse sizes.
Although mu chain is not found in the
CH3 Fc-receptor- urine, Bence Jones light chains (particu-
} binding site larly kappa chains) are common (found in
COOH the urine in 50% of cases). Light chains,
COOH
although still produced in mu HCD, are
not assemb led into a complete immuno-
CDR,_,, complementarity-determining regions 1-3; C,, light chain constant region; COOH, C-terminus;
J,, light chain joining region; NH,, N-terminus; v,, light chain variable region. globulin protein, due to IGH gene aber-
rancies leading to truncated forms {242,
Fig.13.31 Structure of the immunoglobulin molecule in heavy chain disease. An immunoglobulin molecule is com- 4229,4230).
posed of two heavy chains (H) and two light chains (L), which are joined by disulfide bonds (S- S). The normal heavy
chain constant region has three constant domains: CH1 is responsible for binding to the light chain, CH2 for binding to Microscopy
complement, and CH3 for binding to Fe receptors. In the absence of an associated light chain, the CH1 domain binds The bone marrow contains vacuolated
to HSP78 and undergoes proteasomal degradation; thus, normal free heavy chains are not secreted. In heavy chain
plasma cells, which are typically admixed
diseases, non-contiguous deletions in the CH1 domain prevent both binding of the heavy chain to the light cha in and
degradation in the proteasome, and free heavy chains are secreted. Variably sized deletions also occur in the heavy with small, round lymphocytes similar to
chain diversity region (DH), the heavy chain joining region (J"), and the heavy chain variable region (VH). Reprinted CL L ce ll s.
with permission from Munshi NC et al. {2785).
Localization
The tumour may involve the lymph nodes,
Fig.13.32 Mu heavy chain disease. Bone marrow
Waldeyer ring , gastrointestinal tract and
aspirate shows predominantly plasma cells with other extranodal sites, bone marrow,
prominent cytoplasmic vacuolation. liver, spleen, and peripheral blood .
lmmunophenotype
The cells express CD79a and cytoplasmic
gamma chain and are negative for CD5
and CD10. CD20 is found on the lympho-
cytic component and CD138 on the plas-
ma cell component. Kappa and lambda
light chains are typically not expressed,
but a minority of cases show staining for
monotypic light chains by immunohisto-
chemistry or in situ hybridization, despite
the absence of light chains on immuno-
fixation studies {370,371,4230}.
Genetic profile
IG genes are clonally rearranged and
contain high levels of somatic hypermu- Fig.13.35 Gamma heavy chain disease. Bone marrow biopsy. A Small aggregates composed of plasma cells and
tation. Deletions in the IGHG gene are lymphoid cells are present, constituting approximately 5% of the overall marrow cellularity. B Some plasma cells
appear mature; others are atypical, with open chromatin. C lmmunohistochemical staining shows clgG. Images from
present that result in expression of an Munshi NC et al. (2785).
abnormal ly truncated heavy chain pro-
tein that cannot bin d light chain to form istic of lymphoplasmacytic lymphoma is phop lasmacytic infi ltrates appear to re-
a complete immunog lobulin molecu le. absent in gamma HCD {1526}. spond to non-anthracycline-containing
These deletions involve IGHV and vari- chemotherapy, and responses to rituxi-
able proportions of the CH1 domain, and Prognosis and predictive factors mab and other single agents have also
there may be insertions of large amounts The cl inical course is highly variable, been reported {370,4230}.
of DNA of unknown origin {57,370,1132, rang ing from indolent to rapidly progres-
1243,1249,4230}. sive. One study of 23 cases reported a
Abnormal karyotypes have been found median survival time of 7.4 years, with
in about half of the reported cases, but more than half of the deaths unrelated to
no specific or recurrent genetic abnor- the lymphoproliferative disorder {4231}.
mality has been reported {371,4231 }. The There is no standard ized therapy. Most
MYDBB L265P mutation that is character- patients with low-grade-appearin g lym-
2 2 2
3 3 3
4 4
5 5
6 6 6 6
7 7 7 7
SPE lgG lgA lgM UPE lgG lgA lgM
A B
Fig. 13.36 Gamma heavy chain disease. A A distinct band was identified by serum protein electrophoresis (SPE) in the IG reg ion anodal to the point of origin (arrow). The
M protein (also called M component) typed as lgG (denoted by the band seen in the lgG lane), but without a corresponding light chain (only faint polyclonal patterns were seen in
the kappa and lambda lanes). B Urine protein electrophoresis (UPE) revealed similar resu lts, with a broad monoclonal band correspond ing to lgG without a corresponding light
chain. Reprinted from Munshi NC et al. (2785).
Synonyms
Mediterranean lymphoma; immunoprolif-
erative small intestinal disease
Epidemiology
Alpha HCD is the most common of the
HCDs. Unlike the other HCDs, alpha
HCD involves a young age group, with phoresis, or immunoselection techniques and the CH1 domain, and there may be
a peak incidence rate in the second and {370,4230}. insertions of DNA of unknown origin {48,
third decades; it is rare in young children 4230}. Cytogenetic abnormalities have
and older adults, and there is an equal in- Microscopy been reported in rare single cases. The
cidence in males and females. It is most The lamina propria of the bowel is heav- t(11 ;18)(q21 ;q21) (B!RC3/MALT1) trans-
common in areas bordering the Mediter- ily infiltrated with plasma cells and ad- location associated with gastric and pul-
ranean Sea, including northern Africa, mixed small lymphocytes; marginal zone monary MALT lymphomas has not been
Israel and Saudi Arabi a. It is associated B cells may be present, with formation of described (4421}.
with factors linked to low socioeconomic lymphoepithelial lesions. The lymphop-
status, including poor hygiene, malnu- lasmacytic infiltrate separates the crypts, Prognosis and predictive factors
trition, and frequent intestinal infections and villous atrophy may be present {1781, In the early phase, alpha HCD may com-
(48,3298,3617,4230}. 3239,3298}. Sheets of large plasmacyt- pletely remit with antibiotic therapy. In
oid cells and immunoblasts that form sol- patients with more advanced disease,
Etiology id, destructive aggregates with ulceration multiagent chemotherapy is typically
Chronic intestinal infection, in some cas- characterize progression to diffuse large required. Treatment with anthracycline-
es with Campy/obacter jejuni, is believed B-cell lymphoma {370,4230}. containing regimens has been reported
to result in chronic inflammation, a set- to result in remission and long-term sur-
ting in which neoplastic transformation lmmunophenotype vival in 67% of patients (48, 3295,4230}.
of a clone of abnormal B cells develops The plasma cells and marginal zone cells
(2248,3072} express monoclonal cytoplasmic alpha
chain without light chains. Marginal zone
Localization cells express CD20 and are negative for
Alpha HCD involves the gastrointestinal CDS and CD10; plasma cells are typi-
tract (mainly the small intestine) and mes- cally CD20-negative and CD138-positive
enteric lymph nodes. The gastric and (1 781 }.
colonic mucosa may also be involved .
The bone marrow and other organs are Postulated normal counterpart
usually not involved , although respiratory A post- germinal centre B cell that can
tract and thyroid involvement has been differentiate into a plasma cell, with an
described in rare cases (3617,4040}. abnormal IGHA gene
Plasma cell neoplasms result from ex- Table 13.04 Plasma cell neoplasms
pansion of a clone of immunoglobulin-
Non-lgM (plasma cell) monoclonal gammopathy Clinical variants
secreting, heavy chain class-switched, of undetermined significance (precursor lesion)
terminally differentiated B cells that
typically secrete a single homogeneous Plasma cell myeloma Smouldering (asymptomatic) plasma cell myeloma
monoclonal immunoglobulin called an Non-secretory myeloma
M protein; the presence of such a pro- Plasma cell leukaemia
tein is called monoclonal gammopathy. Plasmacytoma Solitary plasmacytoma of bone
The plasma cell neoplasms discussed Extraosseous (extramedullary) plasmacytoma
in this section include plasma cell my-
eloma, plasmacytoma, disorders defined Monoclonal immunoglobulin Primary amyloidosis
by tissue immunoglobulin deposition deposition diseases Systemic light and heavy chain deposition diseases
(primary amyloidosis and light and heavy Plasma cell neoplasms with associated POEMS syndrome
chain deposition diseases), and clonal paraneoplastic syndrome TEMPI syndrome (provisional)
plasma cell proliferations with an associ-
ated paraneoplastic syndrome (POEMS
syndrome and TEMPI syndrome) (see are detailed in the section on lymphop- Synonym
Table 13.04). Non-lgM monoclonal gam- lasmacytic lymphoma and will not be dis- Monoclonal gammopathy, NOS
mopathy of undetermined significance, cussed further in th is section.
a precursor lesion with the potential to Non-lgM (plasma cel l) MGUS is defined Epidemiology
evolve to a malignant plasma cell neo- as the presence in the serum of an lgG, MGUS is uncommon in patients aged
plasm, is also included. Other immuno- lgA, or (rarely) lgD M protein at a con- < 40 years but is found in approximately
globu lin-secreting disorders that consist centration < 30 g/L; clonal bone marrow 3-4% of individuals aged >50 years and
of both clonal lymphocytes and plasma plasma cells< 10%; and absence of end- in > 5% of individuals aged > 70 years;
cells, including lymphoplasmacytic lym- organ damage such as hypercalcaem ia, 80-85% of cases are non-lgM MGUS
phoma, the heavy chain diseases, and renal insufficiency, anaemia, and bone (2175, 2176). Approximately 60% of pa-
lgM monoclonal gammopathy of unde- lesions (CRAB) and amyloidosis attrib- tients with non-lgM MGUS are men, and
termined significance, are discussed in utable to the plasma cell proliferative it is nearly twice as frequent in Black pop-
other sections. disorder (Table 13.05) (3290). The risk ulations as in White populations (2171,
of progression to plasma cell myeloma, 2210,2211,3685).
light-chain amyloidosis, or a related dis-
Non-lgM monoclonal order is 1% per year. Light-chain MGUS Etiology
gammopathy of undetermined consists only of monoclonal light chains. No cause of MGUS has been identified,
It is defined by an abnormal free light but there is an increased prevalence in
significance
chain ratio and an increase of involved families with members with a lymphoid or
Definition light chain with complete loss of heavy plasma cell proliferative disorder {1441,
There are two major types of monoclo- chain expression. The urinary light chain 2212). Transient oligoclonal and mono-
nal gammopathy of undetermined sig- excretion must be < 0.5 g/24 hour. The clonal gammopathies may occur in solid
nificance (MGUS): plasma cell and lym- plasma cell content is < 10%, and there organ and bone marrow I stem cell trans-
phoid/lymphoplasmacytic, which have is no end-organ damage attributable to plant recipients {2171,2679,3330).
different genetic bases and different the plasma cell disorder (1004,2167).
outcomes in terms of malignant progres- The rate of progression of light-chain Localization
sion. Plasma cel l MGUS and lymphoid/ MGUS is approximately 0.3% per year The clonal plasma cells producing non-
lymphoplasmacytic MGUS can usually (Table 13.06). Although the M protein lgM MGUS are in the bone marrow.
be distinguished by morphology, but this reflects the presence of an expanded
analysis is not always precise. Instead, clone of immunoglobulin-secreting Clinical features
MGUS is classifi ed as lgM MGUS, which plasma cells, non-lgM MGUS is consid- Patients exh ibit no symptoms or physi-
is mostly lymphoid/lymphoplasmacytic, ered a premalignant neoplasm, which in cal findi ngs rel ated to non-lgM MGUS,
or non-lgM MGUS, which is mostly plas- most cases does not progress to overt and the typical laboratory and rad io-
ma cell, although about 1% of plasma malignancy. graphical abnormalities associated with
cell MGUS cases actually produce an plasma cel l myeloma are lacking. The
lgM M protein. Features of lgM MGUS ICD-0 code 9765/1 M protein is often identified in the course
PCM
Prognosis and predictive factors Clonal bone marrow plasma cell percentage ~ 10% or biopsy-proven plasmacytoma and
In most cases, the clinical course of MGUS ~ 1 of the following myeloma-defining events:
is stable, with no increase in M protein or End-organ damage attributable to the plasma cell proliferative disorder:
other evidence of progression, but in a - Hypercalcaemia: serum calcium> 0.25 mmol/L (> 1mg/dL) higher than the upper limit of normal or
substantial minority, there is evolution to >2.75mmol/L (> 11 mg/dL)
an active plasma cell myeloma, solitary - Renal insufficiency:
plasmacytoma, or amyloidosis {1762, creatinine clearance <40 ml/minute or serum creatinine > 177 µmol/L (> 2 mg/dL)
- Anaemia: a haemoglobin value of> 20 g/L below the lower limit of normal or a
2171). The risk of progression is about 1%
haemoglobin value< 100g/L
per year (0.3% for light-chain MGUS) and - Bone lesions: ~ 1osteolytic lesion on skeletal radiography, CT, or PET /CT
indefinite, persisting even after 30 years
~ 1 of thefollowing biomarkers of malignancy:
{2171,2176). The size and type of M pro- - Clonal bone marrow plasma cell percentage ~ 60%
tein and serum free light chain ratio are - An involved-to-uninvolved serum free light chain ratio~ 100
significant prognostic indicators {1762 , - > 1 focal lesion on MRI
2172,2176,3080,4078). The risk of pro- Smouldering (asymptomatic) PCM
gression for patients with an M protein Both criteria must be met:
concentration of 25 g/L is > 4 times that - Serum M protein (lgG or lgA) ~30 g/L or urinary M protein~ 500 mg/24 hours and/or
of patients with a concentration < 5 g/L. clonal bone marrow plasma cell percentage of 10-60%
Patients with lgA MGUS are at greater - Absence of myeloma-defining events or amyloidosis
risk of progression (-1.5% per year) to a
malignant d isorder than are patients with
lgG or light-chain MGUS {2171). Patients based on a comb ination of clin ical, mor- rad iation has been assoc iated with an in-
with lgG or lgA MGUS with an abnormal phological, immunolog ical, and radiologi- creased incidence of PCM {2292,2353).
serum free li ght chain ratio at diagnosis cal features. The diagnostic criteria for An antigenic stimu lus g iving rise to mul-
are at higher risk of progression than are PCM are listed in Table 13.07. tiple benign clones could be followed by
patients with a normal ratio {2171,3292} . a mutagenic event initiating mali gnant
Individuals with marked predominance ICD-0 code 9732/3 transformation {1522). Most patients have
of aberrant plasma cells (> 90%) on f low
cytometry have a significantly higher risk Synonyms
of progression to myeloma {2974,3138}. Multiple myeloma; medullary plasmacy-
DNA aneuploidy and subnormal levels of toma; myelomatosis; Kahler disease (no
polyclonal immunoglobulin appear to be longer used); myeloma, NOS
additional clin ical risk factors {3138). An
evo lving c linical phe notype also predicts Epidemiology
an increased probab ility of progress ion PCM accounts for about 1% of mali g-
to myeloma {3137). Several risk stratifica- nant tumours, 10-15% of haematopoi-
tion models identify subgroups of cases etic neoplasms, and 20% of deaths from
of non- lgM MGUS that progress to mye- haematological malignancies {1851,
loma at rates ranging from approximately 2164,3357). In the USA in 2015, an es-
0.3% to 12% per year {2167,3137,3138, timated 26 000 cases were diagnosed
3292,4496). and > 11 000 patients died of PCM
{3673). PCM is more common in men
than in women, with a male-to-female ra-
Plasma cell myeloma tio of 1.1: 1. It is nearly twice as frequent
in Black pop ul ations as in White popu la-
Definition tio ns {2 164,3357,3673). PCM is almost
Plasma cell myeloma (PCM) is a bone never found in ch ildren and very infre-
marrow-based, mu ltifocal neoplastic pro- quently in adults aged < 30 years {840,
liferation of plasma cells, usually associat- 390}; the incidence increases progres-
ed with an M prote in in serum and/o r urine sively with patient age the reafter, with
and evidence of organ damage re lated to about 90% of cases occurrin g in patients
the plasma ce ll neoplasm. Bone marrow aged > 50 years (median pati ent age at
is the site of orig in of nearly all PCMs, and d iagnosis: -70 years).
in most cases there is d issem inated bone
marrow invo lvement. Other organs may Etiology
be secondarily invo lved. The disease Chron ic antigenic stimulation from in - Fig. 13.38 Plasma cell myeloma. Radiographs of skull
spans a clinical spectrum from asympto- fection or other chronic disease and ex- (A) and femoral head (B) demonstrate multiple lytic
matic to highly aggressive . Diagnosis is posure to specific toxic substances or bone lesions.
Imaging
Bone lesions are found on rad iog raphical
skeletal survey in about 70% of cases of
PCM, and even more frequently by MRI
and PET/CT !988,2164,3348,4455). Lytic
lesions are most common (accounting
for -70% of the bone lesions found), but
abnormalities also include osteoporo-
sis (accounting for 10-15% of bone le-
sions), pathological fractures, and ver-
tebral compression fractures. The most
Fig. 13.39 Plasma cell myeloma. A Gross photograph of the vertebral column, showing multiple lytic lesions filled frequent sites of lesions, in decreasing
with grey, fleshy tumour. B Vertebral column after maceration, showing multiple lytic lesions. order, are the vertebrae, ribs, skull, shoul-
ders, pelvis, and long bones !4455).
Macroscopy
The bone defects apparent on gross ex-
amination are fill ed with soft, gelatinous,
fish-flesh haemorrhagic tissue.
Microscopy
Bone marrow biopsy
Monoclonal plasma cells may be scat-
tered interstitially, in small clusters, in
focal nodules, or in diffuse sheets {281,
480,3330). There is often bone marrow
sparing and preservation of normal hae-
matopoiesis, with interstitial and focal
patterns of involvement. With diffuse in-
volvement, expansive areas of the bone
marrow are replaced and haematopoie-
sis may be markedly decreased. There is
typically prog ression from interstitial and
focal disease in early PCM to diffuse in-
volvement in advanced stages of disease
{281 }. Generally, when 30% of the bone
:..;;;;;;i
Fig. 13.40 Plasma cell myeloma. Low-magnification (A) and high-magnification (B) views of a bone marrow biopsy.
marrow volume is composed of plasma
There is extensive marrow replacement with neoplastic plasma cells. The pattern of involvement is mixed, interstitial, cells, a diagnosis of myeloma is likely,
and focal. The plasma cells exhibit mature features, with abundant cytoplasm and eccentric nuclei with coarse although rare cases of reactive plasma-
chromatin; most lack visible nucleoli. cytosis can reach that level. A tumoural
on blood smears in about 15% of cases, but the CD38 expression signal tends to and stem cell- associated antigens
usually in small numbers. Marked plas- be dimmer and the CD138 signal brighter (found rarely) {73,291,292,2348,2973,
macytosis accompanies plasma cell than in normal plasma cells {291,2926} 3123,3227,3286,3375,3474). Increased
leukaemia. Unlike in normal plasma cells, CD45 expression of MYC may be detected on
is negative or expressed at low levels; immunohistochemistry, and cyclin 01 is
Kidney CD19 is negative in 95% of cases , and expressed in cases with t(11 ;14)(q13;q32)
Bence Jones protein accumulates as CD27 and CD81 are frequently nega- (IGH/CCN01) and some cases with hy-
aggregates of eosinoph ilic material in the tive or underexpressed {291,2348,2557, perdiploidy {795,3744,4384}.
lumina of the renal tubules. Renal tubular 2725, 2926,3033 ,3474, 3937}. Aberrant There is conflicting evidence regarding
reabsorption of Bence Jones protein is expression of antigens not foun d on nor- the value of immunophenotype as an in-
largely responsible for renal damage in mal plasma cells (or present only in small dicator of prognosis in PCM {2724,3124}.
PCM. subsets of normal cells) is identified in Expression of CD19, CD28, and CD200;
nearly 90% of cases {2348}. These anti- lack of expression of CD45 or KIT
lmmunophenotype gens include CD56 (found in 75-80% of (CD117); and underexpression of CD27
Flow cytometry shows that the neoplastic cases), CD200 (60- 75%), CD28 (-40%), have all been associated with more-ag-
plasma cells have monotypic cytoplas- KIT (CD117; 20- 35%), CD20 (10- 20%), gressive disease; however, none of these
mic lg and usually lack surface lg; the CD52 (8-14%), CD10 and myeloid and markers has been proven by multivariate
cells typically express CD38 and CD138, monocytic antigens (found occasionally), analysis to have independent prog nostic
significance {52,2557,2725,2973}.
Genetic profile
Antigen receptor genes
IG heavy and light chain genes are clon-
ally rearranged. There is a high load of
IGHV gene somatic hypermutation with-
out ongoing mutations, consistent with
derivation from a post- germinal centre,
antigen-d riven B cell {237}.
- •~·
Abnormalities are detected by karyotype
..... a."'. in marrow aspirations showing variation from mature (A,B) cytogenetics in about one third of PC Ms,
Fig.13.45 Plasma cell myeloma. Cytological features
to immature (C,D) plasma cells. The more mature cells have clumped nuclear chromatin, abundant cytoplasm, a and by FISH in >90% {200,728,1231,
low N:C ratio, and only rare nucleoli. In contrast, the less mature cells have more-prominent nucleoli, loose reticular 2180,2188,3541). Abnormalities are both
chromatin, and a higher N:C ratio. numerical and structural and include
Non-hyperdiploid 40%
Cyclin D translocation 18%
t(11;14)(q13;q32) 16%
Fig.13.46 Plasma cell myeloma. Morphological variants based on cytoplasmic features. A So-called Mott cell with t(6;14)(p25;q32) 2%
abundant grape-like cytoplasmic inclusions of immunoglobulin. B Numerous Russell bodies. t(12;14)(p13;q32) <1%
NSD2
trisomies and whole or partial chromo- patterns of trans locations and cyc lin D (also called MMSET)
some deletions and translocations; expression (TC groups), non-lgM MGUS trans location 15%
complex cytogenetic abnormalities are and PCM can be class ified into groups t(4;14)(p16;q32) 15%
common. A molecular cytogenetic classi- that are based mostly on early patho-
fication of PCM proposed by the Interna- genic events (Table 13.10). Some or all MAF translocation 8%
tional Myeloma Working Group (IMWG) of these groups may represent distinct t(14;16)(q32;q23) 5%
is shown in Table 13.08 {1232}. The ge- disease entities that require different t(14;20)(q32;q11) 2%
netic categories are major indicators therapeutic strateg ies {2128,3798). Two t(8;14)(q24;q32) 1%
of prognosis and form the basis for risk other molecu lar classifications based on
Unclassified (other) 15%
stratification of PCM (see Prognosis and unsupervised clustering of tumours by
predictive factors). The IMWG consensus gene express ion profi les are simi lar to
recommendations on genetic testing are the TC groups {473,4474). However, they Table 13.09 The International Myeloma Working Group
(IMWG) consensus recommendations on genetic test-
listed in Table 13.09 {1232). are not generally applicable for non-lgM
ing. Adapted from Fonseca R, et al. (1232)
The most frequent chromosome trans- MGUS, because some of the groups are
locations involve IGH on chromo- based on progression events not found in FISH (on cell-sorted samples or cytoplasmic
immunoglobulin FISH)
some 14q32 and are present in 55-70% MGUS (e.g. proliferation) {2128).
of PCMs {202,1231}. Seven recurrent on- Monosomy or partial deletion of chromo- Minimal panel:
cogenes are involved in 14q32 transloca- some 13 (13q14) is found by FISH in near- t(4;14)(p16;q32),
tions: CCND1 on 11q13 (involved in 16% ly half of PCMs. It is sometimes an early t(14;16)(q32;q23),
of cases), MAFon 16q23 (in 5%), FGFR3/ event (present in about 35% of non-lgM del(17p13)
NSD2 (also called FGFR3/MMSET) on MGUSs) but can also be a progression More comprehensive panel:
4p16.3 (in 15%), CCND3 on 6p21 (in event, particularly in PCM with t(11 ;14) t(11 ;14)(q13;q32),
2%), MAFB on 20q11 (in 2%), MAFA on {711,1231). MYC(and rarely MYCN) locus del 13,
8q24 (in < 1%), and CCND2 on 12p13 (in rearrangements are present in nearly half ploidy category,
< 1%) (see Table 13.08 and Table 13.10) of PCM tumours. These reposition MYC chromosome 1 abnormalities
{200,1232,2128}. Together these seven near a promiscuous array of plasma Clinical trials should incorporate gene expression
translocations are found in about 40% of cell-specific super-enhancers (includ- profiling
cases of PCM, most of which are non-hy- ing IGH, IGK, and IGL super-enhancers).
perdiploid (i.e. with < 48 or > 75 chromo- The MYC rearrangements may some-
somes). The remaining PCMs are mostly times contribute to the progression from DIS3 {109,1232,2128,2383). Epigenetic
hyperdiploid (usual ly with gains in three non-lgM MGUS to PCM, but can also changes manifested by DNA methy-
or more of the odd -numbered chromo- occur at later stages of PCM progres- lation are also associated with tumour
somes 3, 5, 7, 9, 11, 15, 19, and 21) and sion {26) Mutually exclusive activatin g progression.
on ly infrequently have one of the seven mutations of KRAS, NRAS, or BRAF are Myeloma tumour cel ls from individual pa-
recurrent IGH translocations listed above present in about 40% of PCMs and are tients often have heterogeneous somatic
{728,729,1231). candidates for mediating the transition of genetic abnormalities reflecting the pres-
IGH translocations and hyperdiploidy ap- non-lgM MGUS to myeloma in some pa- ence of multiple subc lones. Tumour sub-
pear to be early events in the genesis of tients {2383,3312,4496). clones can have activating mutations of
plasma cell neoplasms, unified by asso- Other recurrent genetic changes asso- NRAS, KRAS, or BRAF; although each
ciated upregu lation of one of the cyc li n D ciated with disease progression include subclone can have only one of these mu-
genes (CCND1, CCND2, or CCND3) secondary IGH or IGL translocations; tations. This has important therapeutic
{351,2128}. Gene expression profiling deletion and/or mutation of TP53 (17p13); implications, because a specific thera-
can determine the expression levels of gains of chromosome 1q and loss of 1p; peutic regimen may target one or more
CCND1, CCN02, and CCND3 RNA and mutations of genes that result in activation specific subclones but have little or no
identify tumours that overexpress onco- of the NF-kappaB pathway; mutations of effect on other subclones {1979, 2383).
genes dysregulated by the seven recur- FGFR3 in tumours with t(4;14); and inac- Although genetic events appear to play
rent IGH translocations . On the basis of tivation of CDKN2C, RB1, FAM46C, and the key role in initiation and progression
bl
'ii
Cl!)
~
Q
...
::i~::
·f.iiii .;
.... ..r:: . ·.'
Q
Q
c .:~~:=
myeloma (SPCM) have 10-60% clonal 0
CD
(.) ()
·: :··:..
.e
.g
Table 13.07, p. 243) {2165,2174,3290}. ;::: E
IQ
I'll
"Cl
!J
Approximately 8-14% of patients with ~ .g iij
Q
plasma cell myeloma (PCM) are in itially () j '5
ii
diagnosed with SPCM (2119,2174). The (,)
I'll
.:;i
disorder is similar to monoclonal gam-
mopathy of undetermined sign ificance in
s
its lack of cl inical manifestations, but is CD56 kappa Intracellular Kappa
much more likely to progress to sympto-
matic PCM {992,2165,2174,2176}. Most
Fig.13.47 Plasma ce ll myeloma. Flow cytometry histograms of bone marrow. The neoplastic plasma cells are
patients have 10-20% bone marrow indicated in red and normal B lymphocytes in blue. The myeloma cells express bright CD38 and are negative for
plasma cells, and the median level of CD20, CD19, and CD10. They express CD56 and partial CD45, are negative for surface light chains, and express
serum M protein is nearly 30 g/L. Nor- cytoplasmic kappa.
mal polyclonal immunoglobulins (lgs)
are reduced in > 83% of patients, and
53% of patients have monoclonal light
chains in the urine {2164,2165}. Light
chain SPCM is characterized by 10-60%
bone marrow clonal plasma cells and
urinary light chain M protein excretion of
20.5 mg/24 hours.
Some patients with SPCM have stable
disease for long periods, but the cumu-
lative probability of progress ion to symp-
tomatic PCM or amyloidosis is approxi-
mately 10% per year for the first 5 years,
3% per year for the next 5 years, and 1%
per year thereafter; the median time to
progression is about 5 years {2174}. For
light chain SPCM, the rate of progression
is 5% per year for the first 5 years, 3% per
year for the next 5 years, and then 2%
per year for the fo ll owing 5 years. Risk
factors for earlier progression to sympto-
matic PCM include the presence of both
> 10% bone marrow plasma cells and
> 30 g/L M prote in, detection of bone le-
sions by MRI, a high percentage of bone
marrow plasma cells with an aberrant
immunophenotype, an abnormal serum
free light chain ratio, a high-risk gene ex-
pression profile, a high plasma cell prolif- Fig.13.48 Plasma cell myeloma. lnterphase FISH analyses of recurrent abnormalities. A Fusion signals for t(4;14)
eration rate, and circulating plasma cel ls (p16;q32). Probes for IGH are green and probes for FGFR3/NSD2 (also called FGFR3/MMSET) are red. Two fusion
(969, 1005, 1007, 2174, 2558}. Therapeutic signals (indicated by arrowheads) most likely identify der(4) and der(14), but could represent two copies of der(4). B
Extra copies of three chromosomes in a hyperdiploid tumour. Three copies of chromosome 5 (LSI D5S23/D5S721,
intervention for the highest-risk patients
green) and chromosome 9 (CEP 9, aqua, circled) and four copies of chromosome 15 (CEP 15, red). CTwo copies of
has been shown to delay progression to chromosome 17 (CEP 17, green) and deletion of one copy of TP53 (red). D Loss of one copy of chromosome 13/13q.
symptomatic PCM and to improve overall LSI 13 containing RB1 (green), D13S19 (red). In all four panels, the cytoplasm is blue due to immunostaining of lg-
survival (1007,2558,3293}. kappa or lg-lambda expressed by the tumour plasma cells, and the probes are from Vysis. Courtesy of Dr R. Fonseca.
Clinical features and predisposing Usually in advanced PCM, HIV infection and iatrogenic No known predisposing factors,
factors sometimes pure extraosseous relapse immunosuppression, broad patient age range, rare cases in
after treatment elderly immunocompetent patients post-transplantation setting {3352}
Location Any site, Predominantly extranodal, 80% in head and neck region,
with or without leukaemic peripheral oral cavity, gastrointestinal tract, mostly extra nodal
blood involvement skin, and lymph nodes;
50% in immunocompetent patients
Disease stage Usually in advanced-stage PCM >90% either stage I or IV Mostly stage IE-llE
Molecular alterations PCM cytogenetics, with PCM-type translocations absent t(11;14) translocation and
50-70% IG translocations 50% MYC rearrangement MYC rearrangement absent
MYC rearrangement frequent with
PB morphology
Fig.13.50 Plasmacytoma. lmmunoglobulin expression. A Typical plasma cell morphology. B Cytoplasmic kappa light chain positivity. C Absence of lambda light chain expres-
sion. D Expression of cytoplasmic gamma heavy chain. E,F Absence of mu and alpha heavy chains.
Microscopy infiltrates of PCM is impossible by mor- ytypic reactive plasma cell infiltrates. Ex-
The morphological features are similar to phology, although extraosseous PCM pression of CD20 by lymphocytes within
those of SPB. However, in extraosseous more frequently shows ce llular atypia or the lesion or by the plasmacytoid cel ls,
sites, the distinction between lymphomas blastic features {2107} The differential or expression of mu rather than alpha or
that exhibit extreme plasma cell differen- diagnosis of extraosseous tumours with gamma heavy chain, favours a diagno-
tiation and plasmacytoma can be difficu lt plasmacytic or plasmablastic features is sis of lymphoma over plasmacytoma. On
{990}. MZL of the mucosa-associated detailed in Table 13.14. Rarely, extraosse- flow cytometry, the clonal plasma cells of
lymphoid tissue type, lymphoplasmacytic ous plasmacytoma is accompanied by a lymphomas are more likely than those of
lymphoma, and (poss ibly) plasmab lastic local, occas ionally tumour-forming amy- PCM or plasmacytoma to express CD19
lymphoma may be misdiagnosed as plas- loid deposit. (positive in 95% vs 10%) and CD45 (in
macytoma {990,1742). Distinction from an 91% vs 41%) and to lack CD56 (positive
MZL with marked plasma cell differentia- lmmunophenotype in 33% vs 71%) {3609}. In some cases,
tion is especially problematic, particularly The immunophenotype appears to be extraosseous plasmacytoma and lym-
in the skin, upper airway, and gastroin- similar to that of PCM, although certain phoma with extreme plasma cell differen -
testinal tract, and may not be possib le by differences may be helpful for diagno- tiation cannot be immunophenotypically
morphological assessment. A search for sis. Extraosseous plasmacytoma usually distinguished with certainty.
areas of a biopsy with lymphocyte prolif- lacks cyc li n D1 express ion and shows
eration typical of MZL is fruitful in some less-frequent and weaker positivity for Genetic profile
cases . In others, a clonally related lym- CD56 {2107}. lmmunohistochemistry or The genetic features have not been ex-
phocyte population may be identified by in situ hybrid ization for immunoglobulin tens ively studied, but appear to be simi-
flow cytometry {1742,3609}. Distinguish - light chains can be useful in distinguish- lar to those of PCM, with the exception of
ing plasmacytoma from extraosseous ing a monotypic plasmacytoma from pol- a lack of t(11;14)(q13;q32) (IGH/CCN01)
translocations and aberrations of MYC
{379,384,41 O}.
Fig.13.52 Extramedullary plasmacytoma of the skin with abundant Russel l body formation, wh ich can show
non-specific staining by immunohistochemistry (A,B). Monoclonality is demonstrated by non-radioactive in situ
hybridization showing absence of kappa (C) and presence of lambda (D) mRNA transcripts.
Monoclonal immunoglobulin cell myeloma (PCM) are lacking, but Clinical fin dings are usually related to
deposition diseases there is a moderate increase in monoclo- deposition of amyloid in organs and tis-
nal plasma cells in the bone marrow. sues. Early signs of disease include pe-
Definition ripheral neuropathy (present in 17% of
The monoclonal immunoglobulin (lg) dep- ICD-0 code 9769/1 cases), carpal tunnel syndrome (in 21%),
osition diseases are closely related dis- and bone pain (in 5%). Symptoms refer-
orders characterized by visceral and soft Synonyms able to congestive heart failure (present
tissue deposition of aberrant lg, resulting lmmunoglobulin deposition disease; in 17% of cases), nephrotic syndrome
in compromised organ function {190,509, systemic light chain disease (in 28%), or malabsorption (in 5%) are
9 13, 1627, 1906, 2163,3234,3300, 3626). relatively common {2163). Physical find-
The underlying disorder is typically a plas- Epidemiology ings include hepatomegaly in 25- 30%
ma cell neoplasm, or rarely a lymphoplas- The reported annual incidence of primary of patients, macroglossia in about 10%,
macytic neoplasm; however, the lg mole- amyloidosis is approximately 1 case per and purpura (most commonly periorbital
cule usually accumulates in tissue before 100 000 population, and appears to have or facial) in about 15% {2163). Haemor-
the development of a large tumour burden been stable {2163,2168) The median rhagic manifestations can result from fac-
{1346,1347). Therefore, patients typically patient age at diagnosis is 64 years, and tor X binding to amyloid, fibrinolysis, dis-
do not have overt myeloma or lymphoma > 95% of patients are aged > 40 years; seminated intravascular coag ulation, and
at the time of the diagnosis. There are 65-70% are male {2163,2166, 2168). Ap- loss of vascular integrity due to amyloid
two major categories of monoclonal lg proximately 20% of patients with primary deposition. Oedema is often present in
deposition diseases: primary amyloidosis amyloidosis have PCM {1762,2163,2164, patients with congestive heart failure or
and light chain and heavy chain deposi- 2168,3626). nephrotic syndrome {21 63). Splenomeg-
tion diseases. These disorders appear to aly and lymphadenopathy are uncom-
be chemically different manifestations of Localization mon. Rad iographical lesions of bone are
similar pathological processes, resulting Amyloid light chain accumulates in many restricted to patients with myeloma and
in clinically similar conditions. tissues and organs, including the sub- amyloidosis.
cutaneous fat, kidneys, heart, liver, gas-
Primary amyloidosis trointestinal tract, peripheral nerves, and Clinical features
bone marrow. The diagnostic biopsy site An M protein is detected in the serum or
Definition is typically the abdominal subcutaneous urine by the combination of immunofixa-
Primary amyloidosis is caused by a fat pad or bone marrow {2163,3626). In tion and serum free light chain ratio in 99%
plasma cell or (rarely) a lymphoplasma- most cases, the monoclonal plasma cell of patients {1487,1968,2163}. The median
cytic neoplasm in which the monoclonal proliferation is in the bone marrow. concentration of the serum M protein is
plasma cells secrete intact or fragments
of abnormal immunoglobulin light chains
that deposit in various tissues and form
a beta-pleated sheet structure (amyloid
light chain). The abnormal light chains
include the N-terminal (variable) region
and part of the constant region of the
light chain {509). Most light chain vari-
able (V) reg ion subgroups are potentially
amyloidogenic, but V lambda VI is always
associated with amyloidosis {509). The
amyloid tissue deposits accumulate and
·-
lead to organ dysfunction {1487). In most Fig.13.54 Primary amyloidosis. Pulmonary blood vessel with amyloid deposition, showing Congo red staining (A)
cases, the diagnostic criteria for plasma and apple-green birefringence in polarized light (B).
,, • • •.,. •
• • •• ~ ..' .. ~
".
{) t> . •
• "" •
..
f1 0-
• l
~
..
•.. •
..
,q ••
"l>
•
:
lmmunophenotype
LCDD has a high prevalence of kappa
light chains (80%), with overrepresen-
tation of the V kappa IV variable region
{510,3230} lmmunohistochem istry on
bone marrow sections may reveal an ab-
errant kappa/lambda ratio {4349}.
Fig.13.56 Light chain deposition disease in kidney showing (A) pale amorphous patches within glomeruli (nodular
glomerulosclerosis and (B) immunoftuorescence stain showing renal tubular and extratubular deposition of kappa Genetic profile and pathophysiology
light chain in a smooth linear pattern. The genetic profile of cases associated
with PCM is similar to that of other PCMs.
of cases), liver (in 19%), and peripheral The M protei n in non-amyloid lg deposi-
ICD-0 code 9769/1 nervous system (in 8%) {366,2641,3230}. tion diseases has undergone structural
HCDD of the lgG3 or lgG1 isotype results change due to deletion and mutation
Synonym in hypocomplementaemia, because the events {509,510,1906,3234}. In LCDD,
Randall disease lgG3 and lgG1 subclasses most readily the primary defect involves multiple muta-
fix complement {1627,1906,2340}. There tions of the IG light chain variable region,
Epidemiology is a detectable M protein in about 85% with kappa light chain of V kappa IV type
These are rare diseases occurring at a of cases. Kappa deposition is found in at notably overrepresented {509,510,3234}.
median patient age of 58 years (range: least two thirds of cases of LCDD. Gam- In HCDD, the critical event is deletion of
33-79 years); 60-65% of patients are ma deposits are most common in HCDD, the CHI constant domain, which causes
men {509,1906,3230,3234,3542}. There but alpha deposition has also been re- failure to associate with heavy chain-
is no evidence of an ethnicity effect. ported {2340}. binding protein, resulting in premature
LCDD is the most common, and fre- secretion {190,1627,1906,2340,3234}. In
quently occurs in association with plas- Microscopy HCDD, the variable regions also contain
ma cell myeloma (PCM; in 40- 65% of In most cases , bone marrow is involved amino acid substitutions that cause an in-
cases) or in patients with M protein and with a plasma cell proliferative disorder, creased propensity for tissue deposition
marrow plasma cells at monoclonal gam- most frequently PCM {3230}. Rarely, and for binding blood elements {190,509,
mopathy of undetermined significance lymphoplasmacytic lymphoma, mar- 1906}.
levels. Some cases are idiopathic or oc- ginal zone lymphoma, or chron ic lym-
cur with a lymphoproliferative disorder phocytic leukaemia is the associated Prognosis and predictive factors
{510,3230}. neoplasm {4299}. Deposition of the light Older patient age, associated PCM, and
or heavy chains is most frequently found extrarenal light chain deposition are pre-
Localization in renal biopsies but can be observed in dictors of higher risk and unfavourable
The plasma cell proliferative disorder is bone marrow and other tissues in some survival {2641,3230}. The median over-
in the bone marrow. Deposition of aber- cases . all survival of patients with LCDD varies
rant immunoglobulin (lg) may involve The aberrant lg deposits consist of amor- from 4 years to 14 years in one recent
many organs, most commonly the kid- phous eosinophil ic material that is non- series {3230,3542}.
neys {3230}. The liver, heart, peripheral amyloid and non-fibrillary, and does not
nerves, blood vessels, and occasionally stain with Congo red. In LCDD, renal bi-
joints may also be involved {366,2641, opsies typically show nodular sclerosing Plasma cell neoplasms with
3230}. Diffuse or nodular pulmonary in- glomerulonephritis. The deposits consist associated paraneoplastic
volvement has also been reported {366, of retractile eosinophilic material in the
syndrome
3420} There is prominent deposition of glomerular and tubular basement mem-
the aberrant lg on basement membranes, branes. lmmunofluorescence microscopy
elastic fibres, and collagen fibres. most often identifies kappa chains. A POEMS syndrome
hallmark of LCDD is prominent, smooth,
Clinical features ribbon-like linear peritubular deposits of Definition
Patients have symptoms of organ dys- monotypic lg along the outer edge of the POEMS synd rome is a paraneoplastic
function as a result of diffuse, systemic tubular basement membrane. By electron syndrome associated with a plasma cell
lg deposits. As many as 96% of patients microscopy, these deposits are typically neoplasm, usually characterized by fibro-
with LCDD present with renal mani- non-fibrillary, powdery, and electron- sis and osteosclerotic changes in bone
festations {3230}. Nephrotic syndrome dense, with an absence of the beta-pleat- trabeculae, and often with lymph node
and renal failure are the most common ed sheet structure by X-ray diffraction changes resembling the plasma cell vari-
features {968,3230,3542}. Symptomatic {2340,2537,3230}. In some cases, plasma ant of Castleman disease. The POEMS
extrarenal deposition, which is uncom- cells are found in the vicinity of lg depos- acronym stands for polyneuropathy, or-
mon in LCDD, involves the heart (in 21% ganomegaly, endocrinopathy, mono-
Definition Epidemiology
Extranodal marginal zone lymphoma MALT lymphoma accounts for 7-8% of
of mucosa-associated lymphoid tissue all B-cell lymphomas {1} and for as many
(MALT lymphoma) is an extranodal lym- as 50% of primary gastric lymphomas
phoma composed of morphologically {1016,3275). Most cases occur in adults,
heterogeneous small B cells includ in g with a median patient age in the sev-
marginal zone (centrocyte- like) cells, enth decade of life. Men and women are
cells resembling monocytoid cells, small about equally affected, although there
lymphocytes, and scattered immuno- are site-specific sex differences, with a
blasts and centroblast-like cells . There female predominance reported for cas-
is plasmacytic differentiation in some es in the thyroid and salivary glands {1,
cases. The neoplastic cells res ide in 1999}. There is geographical variability,
the marginal zones of reactive B-cell fol- with a higher incidence of gastric MALT
licles and extend into the interfollicular lymphoma reported in north-eastern Italy
region as well as into the follicles (follicu- {1016}, and a special subtype called al-
lar colon ization). In epithelial tissues, the pha heavy chain disease (also known
neoplastic ce lls typical ly infiltrate the ep i- as immunopro liferative small intesti-
thelium, forming lymphoepithelial lesions nal disease) occurs in the Middle East
{1044,1782). Thus, MALT lymphomas {48,4230}, the Cape region of South Af-
variably recapitulate Peyer's patch- type rica {3239}, and a variety of other tropi-
lymphoid tissue, the prototypical nor- cal and subtropical locations (see Alpha
mal mucosa-associated lymphoid tissue heavy chain disease, p. 240). Fig.13.57 MALT lymphoma. A Resection specimen of
(MALT). MALT lymphomas aris in g at any a gastric MALT lymphoma. B MALT lymphoma of the
anatomical site share many characteris- Etiology conjunctiva.
tics, but there are also site-specific differ- In many MALT lymphoma cases, there is
ences with respect to etiology, morpho- a history of a chronic inflammatory disor- lymphoma {1199,3954). The continued
logical features, molecular cytogenetic der that results in accumulation of extran- proliferation of gastric MALT lymphoma
abnormalities, and clinical course {502, odal lymphoid tissue (called acquired ce ll s from patients infected with H. py-
1044,2140} MALT). The chronic inflammation may be lori depends on the presence of T cel ls
the result of infection, autoimmunity, or specifically activated by H. pylori anti-
ICD-0 code 9699/3 unknown other stimuli. gens and/or direct oncogenic effects of
The link between infection and MALT H.pylori prote ins on B ce ll s {1741,2137).
lymphoma is most c learly established The importance of th is stimulation in vivo
for Helicobacter pylori and gastric MALT has been c learly demonstrated by the
Fig.13.58 Gastric MALT lymphoma. A The tumour cells surround reactive fol licles and infiltrate the mucosa. The follicles have a typical starry-sky appearance. B The marginal
zone cel ls infiltrate the lamina propria in a diffuse pattern and have colonized the germinal centres of reactive B-cell follicles . The colonized follicles do not show a starry-sky
pattern.
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) 259
induction of remissions in gastric MALT ocular adnexal MALT lymphoma and cu- with primary Sjogren syndrome have an
lymphomas with antibiotic therapy to taneous MALT lymphoma, respectively estimated risk of lymphoma 14-19 times
eradicate H. pylori {4366). In the first {611,1199,1201). There is great variation that of the general population {2319,
study in which the association of gastric in the strength of these associations, 4497); most lymphomas in patients with
MALT lymphoma with H. pylori infection which might relate in part to geographi- Sjogren syndrome are MALT lymphomas.
was examined, the organism was present cal diversity {658,2296,3454). A similar In patients with Hashimoto thyroiditis, the
in > 90% of cases {4367). More recent role has been proposed for Campylobac- risk of developing lymphoma is 3 times
studies, in the era of antibiotic eradica- ter infection in patients with alpha heavy that in the general population, and the
tion therapy for H. pylori gastritis, suggest chain disease. risk of thyroid lymphoma 70 times that
that the overall incidence of gastric MALT In other cases, acq uired MALT second- in the general population , for an overall
lymphoma is decreasing, and that a ary to autoimmune disease may serve lymphoma risk of 0.5-1. 5% {1 17,1671 ,
much smaller proportion of cases (32%) as the substrate for lymphoma develop- 1959). Approximately 90% of thyroid lym-
are now associated with H. pylori at dia- ment {1779). Autoimmune-based chronic phomas have evidence of lymphocytic
gnosis {2414, 3621). inflammation in the form of Sjogren syn- thyroiditis {957,4265)
A role for antigenic stimulation by Chla- drome and Hashimoto thyroiditis is known
mydia psittaci and Borrelia burgdorferi to precede salivary gland and thyroid Localization
has been proposed for some cases of MALT lymphomas, respectively. Patients The stomach is the most common site of
MALT lymphoma, affected in 35% of all
cases. Other common sites include the
eyes and ocu lar adnexa (affected in 13%
of cases), skin (9%), lungs (9%), salivary
glands (8%), breasts (3%), and thyroid
(2%) {1999}.
Clinical features
Most patients present with stage I or II
disease, but 23- 40% have involve-
ment of multiple extranodal sites {1905,
2140). Staging in patients with multiple
extranodal lesions may be challenging,
because at least some cases constitute
multiple clonally unrelated proliferations
rather than truly dissem inated disease
{2081). Making this distinction may not
be possible in routine practice. A minori-
ty of patients (2-20%) have bone marrow
involvement {148,3276,3953). The fre-
quency of bone marrow involvement and
involvement of multiple extranodal sites
is higher in non-gastric MALT lymphoma
than in gastric cases. Generalized nodal
involvement is rare (reported in < 10% of
cases) {1905 ,2140,3952}. Plasmacytic
Microscopy
The characteristic marginal zone B cells
have smal l to medium-sized, slightly ir-
regular nuclei with moderately dispersed
chromatin and inconspicuous nucleoli,
resembling those of centrocytes, and
relatively abundant, pale cytoplasm . The
accumulation of even more pale-staining
cytoplasm may lead to a monocytoid ap-
pearance, which is especially common in amples, this can lead to a close resem- should not be applied to a DLBCL even if
salivary gland MALT lymphomas. Alterna- blance to follicular lymphoma. Lymphoe- it has arisen in a MALT site or is assoc i-
tively, the marginal zone cells may more pithelial lesions, defined as aggregates ated with lymphoepithelial lesions.
closely resemble small lymphocytes. of 23 marginal zone cells with distortion
Plasmacytic differentiation is present in or destruction of the epithelium, may be lmmunophenotype
approximately one third of gastric MALT seen in glandular tissues, often together The neoplastic cells of MALT lymphoma
lymphomas, is frequently found in cutane- with eosinophilic degeneration (oxyphilic are CD20+, CD79a+, CD5-, CD10-,
ous MALT lymphomas, and is a constant change) of epithelial cells. CD23-, CD43+/-, and CD11c+/- (weak).
and often striking feature in thyroid MALT In lymph nodes, MALT lymphoma in- Infrequent cases are CD5+, and very rare
lymphomas. In some MALT lymphomas, vades the marginal zone, with subse- cases are CD1 O+ but BCL6- {2140,3954}.
there is a marked predominance of plas- quent interfolli cular expansion. Discrete Staining for CD21, CD23, and CD35 typi-
ma cells, resulting in resemblance to an aggregates of monocytoid-like B cells cally reveals expanded meshworks of
extramedu ll ary plasmacytoma. Cutane- may be present in a parafol li cular and fo lli cular dendritic ce ll s, corresponding
ous plasmacytomas are diagnosed as perisinusoidal distribution . Cytological to colonized foll icles. The demonstration
MALT lymphoma. Amyloid deposition is heterogeneity is still present, and both of light chain restriction is helpful in the
seen in some cases. Large cells resem- plasmacytic differentiation and follicu lar differential diagnosis with reactive hyper-
bling centroblasts or immunoblasts are colonization may be seen. plasia. Recent reports have highlighted
usually present, but are in the minority. MALT lymphoma, by definition, is a lym- IRTA1 as a poss ible specif ic marker for
The lymphoma cells infiltrate around re- phoma composed predominantly of smal l marginal zone lymphomas, including
active B-cell follicles external to a pre- cells . Transformed centroblast-like or MALT lymphoma, although IRTA1 anti -
served mantle in a marginal zone dis- immunoblast-like ce lls may be present bodies are not yet wide ly available {1137,
tribution, and spread out to form larger in variable numbers, but when solid or 1154). MNDA stain in g may facil itate the
confluent areas that eventually replace sheet-like proliferations of transformed differential diagnosis of MALT lymphoma
some or most of the follicles, often leav- cells are present, the tumour shou ld be versus follicular lymphoma, because this
ing small remnants of germinal centres, diagnosed as diffuse large B-cell lympho- nuclear antigen is expressed in 61-75%
which can be highlighted by negativ- ma (DLBCL) and the presence of accom- of MALT lymphomas but< 10% of follicu-
ity for BCL2 {1784,1785). The lymphoma panying MALT lymphoma noted . The term lar lymphomas {1922,2645).
ce ll s sometimes specifically colon ize 'high -grade MALT lymphoma' should not The tumour cells of MALT lymphoma typi-
reactive germinal centres; in extreme ex- be used, and the term 'MALT lymphoma' cal ly express lgM heavy chains, and less
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) 261
Table 13.16 Anatomical site distribution and frequency of chromosomal translocations and trisomies 3 and 18 in MALT lymphomas.
Data summarized according to Streubel B et al. {3812} and Remstein ED et al. {3340}
Frequency(%)
Thyroid 0- 17 0 0-50 0 17 0
Definition and occasionally the peripheral blood nant monocytoid B-cel l population are
Nodal marginal zone lymphoma (NMZL) (106,347,2834,4123). uncommon. Plasma cell differentiation
is a primary nodal B-cell neoplasm that may be prominent, and the differential
morphologically resembles lymph nodes Clinical features diagnosis with lymphoplasmacytic lym-
involved by marginal zone lymphoma Most patients present with asympto- phoma or even nodal plasmacytoma may
(MZL) of the extranodal or splen ic types, matic, localized, or generalized periph- be difficult. The presence of remnants of
but without evidence of extranodal or eral lymphadenopathy (137,347). The follicu lar dendritic cell meshworks sug-
splenic disease. head and neck lymph nodes are more gestive of colonized follicles favours the
frequently involved (4123}. B symptoms diagnosis of NMZL. Prominent eosino-
ICD-0 code 9699/3 are present in 10-20% of patients. Bone philia may be present. Some cases have
marrow infiltration is seen in one third of more-numerous large transformed cells
Synonyms patients {4123}. The presence of a pri- (sometimes > 20%). However, these cells
Monocytoid B-cell lymphoma; mary extranodal MZL should be ruled are usually mixed with small cells and
parafollicular B-cell lymphoma (obsolete) out, because approximately one third of may be more common in the colonized
cases presenting as NMZL in fact con- germinal centres (2834,4046). Some
Epidemiology stitute nodal dissemination of a MALT cases mimic splenic MZL, with the neo-
NMZL accounts for on ly 1.5-1.8% of all lymphoma, wh ich is particularly common plastic cells being small to medium-sized
lymphoid neoplasms, and has an annual in patients with Hashimoto thyroiditis or lymphocytes with pale cytoplasm and
incidence of 0.8 cases per 100 000 adults Sjogren syndrome (542). occasional transformed cells growing in-
(106,347,2834). Most cases occur in side an attenuated mantle zone and often
adults, with a median age of -60 years, Microscopy around a residual germinal centre (542).
and the proportion of males and fema les Lymph nodes demonstrate a smal l-cel l Compos ite NMZL and Hodgkin lympho-
affected is similar (106,4123). This lym- lymphoid proliferation that surrounds re- ma have been reported {4473).
phoma can also occur in children, and is active follicles and expands into the in- Bone marrow involvement is usually inter-
then separately designated as paediatric terfollicular areas. Follicular colonization stitial or nodular, with an intertrabecular
NMZL {3866) . A significantly increased may be present. In cases with a diffuse or paratrabecu lar d istribution. An intrasi-
incidence has been observed among fe- pattern, follicle remnants may be de- nusoidal infiltration may be seen but is
males with autoimmune d isorders (442}. tected with immunohistochemical stains less common (437,1757).
A relationship to hepatitis C virus infec- for follicu lar dendritic cells and germinal
tion has been detected in some studies centre markers. The neoplastic cells are lmmunophenotype
(137,4503), but not in others {442,4046). composed of variable numbers of mar- Most NMZLs express pan-B-cell mark-
ginal zone (centrocyte- li ke and monocy- ers, with CD43 coexpression in 20-75%
Localization toid) B ce lls, plasma cells in some cases, of cases (3486}. CD23 is usually nega-
NMZL involves peripheral lymph nodes, and scattered transformed B cells {533, tive, but may be expressed in as many
but can also involve the bone marrow 2834,2884,4046). Cases with a predom i- as 29% of cases (4123). CD5 expression
• "'"'~~.,,:~
A I . } .... .......,.. ....-.
Fig. 13.65 Nodal marginal zone lymphoma. A Reactive fol licles are separated by an interfollicular infiltrate of paler-staining cells. B The neoplastic cells have irregularly shaped
nuclei and moderately abundant pale cytoplasm. Occasional plasma cells and transformed blasts are present.
lar areas by CD20+ B ce ll s that common- Clonal rearrangements of the IGHV re- reported in extranodal sites, some cau-
ly coexpress CD43 {3866}. Light chain gion are detected in almost all cases tion is advised because a similar process
restriction can often be demonstrated by {3366). Trisomy 18 may be present in might also occur in the lymph nodes . Par-
immunohistochemistry or flow cytometry approximately one fifth of cases, and oc- ticularly for these reasons, genetic stud-
{3366}. lgD staining may help to delineate casionally trisomy 3 {3366}. The progno- ies in paediatric marginal zone lympho-
an irregular and expanded mantle zone. sis of paed iatric NMZL is exce ll ent, with mas are strongly recommended {3866).
BCL2 is pos itive in half of the cases . a very low relapse rate and long survival A marginal zone hyperplasia mimicking
corn is usually negative {3272). Staining following conservative treatment {3272, NMZL in head and neck lymph nodes of
for CD279/PD1 shows numerous positive 3866). children has been associated with Hae-
cells in the reactive germinal centres, a The differential diagnosis with atypical mophilus inf!uenzae. The marginal zone
feature that may help in the differential marginal zone hyperplasia with mono- ce lls in these cases are lgD-positive
diagnosis with paed iatric-type follicular typic immunog lobulin expression may be {2046).
lymphoma, in which these cells are less difficult, because the large cells in this
numerous and pushed to the periphery of condition also express CD43 {183}; al- ICD-0 code 9699/3
the germinal centre {2369,3272). though this type of hyperplasia has been
Definition Etiology
Follicular lymphoma (FL) is a neoplasm Individuals with a high environmental
composed of follicle centre (germinal cen- exposure to pesticides and herbicides
tre) B cel ls (typically both centrocytes and have increased numbers of cells carrying
centroblasts/large transformed cells), t(14;18)(q32;q21) (IGH/BCL2) in the pe-
which usually has at least a partially fol- ripheral blood {33}. This may help explain
licular pattern. Lymphomas composed of the reported increased risk of FL among
centrocytes and centroblasts with an en- such individuals.
tirely diffuse pattern in the sampled tissue
may be included in this category, but are Localization
relatively rare at presentation. Progression FL predominantly involves the lymph
Fig. 13.68 Follicular lymphoma, lymph node. Vague
in cytological grade is common during the nodes, but also involves the spleen, bone nodules bulge from the cut surface.
natural history of the disease. A diffuse marrow, peripheral blood, and less com-
lymphoma composed of centroblasts is monly Waldeyer ring. Any nodal group
considered evidence of progression to can be involved, but most patients pre-
diffuse large B-cell lymphoma (DLBCL). sent with peripheral lymphadenopathy.
Four variants of FL are recognized: (1) in Pure extranodal presentations are un-
situ follicular neoplasia, formerly called FL common . The most commonly affected
in situ; (2) duodenal-type FL; (3) testicular extranodal sites include the gastrointes-
FL; and (4) the diffuse variant of FL. tinal tract (often in association with mes-
Primary cutaneous follicle centre lym- enteric lymph node involvement), soft
phomas are separately classified {2242, tissue, breast, and ocular adnexa. FL
3848). FL is nearly exclusively a disease arising in the small intestine, in particular
of adults, and very rarely occurs in pa- the duodenum, has distinctive featu res
Fig.13.69 Follicular lymphoma, spleen. The white pulp
tients aged < 18 years. Paediatric-type (duodenal-type FL). is expanded, with multiple pale nodules throughout the
FL, which is a nodal lymphoma that oc- FLs can occur in almost any extranodal spleen. The red pulp is unremarkable.
curs in children and you ng adults, is con- site {1203}. In some cases, the morphol-
sidered a separate entity. ogy, phenotype, and genetics are similar gree of lymphadenopathy and extent of
to those of nodal FL. However, many FLs disease. FOG-PET is less useful in as-
ICD-0 codes in extranodal sites tend to be of higher sessing disease than in more aggressive
Follicular lymphoma 9690/3 grade (grade 3), and may lack BCL2 pro- lymphomas . However, the detection of
Grade 1 9695/3 tein and the BCL2 translocation {302 1, PET-avid disease may be useful in iden-
Grade 2 9691 /3 4148}. tifying patients with higher risk for pro-
Grade 3A 9698/3 gression {112}.
Grade 3B 9698/3 Clinical features
Most patients have widespread disease at Staging
Epidemiology diagnosis, including peripheral and cen- The stage of the disease is now deter-
FL accounts for about 20% of all lympho- tral (abdominal and thoracic) lymphad- mined using the Lugano classification,
mas. The highest incidence rates are re- enopathy and splenomegaly. The bone a modification of the Ann Arbor staging
ported in the USA and western Europe. marrow is involved in 40-70% of cases. system {691 ). Assessment of bone mar-
In eastern Europe, Asia, and developing Only 15-25% of cases are stage I or II row involvement should be accompl ished
countries , the incidence is much lower at the time of diag nosis {1632). Despite with bone marrow biopsy. Bone marrow
{95}. It affects predominantly adults, with widespread disease, patients are usually aspiration has a lower yield, due to the
a median age in the sixth decade of life otherwise asymptomatic. B symptoms diffic ulty is aspirating cells from the para-
and a male-to-female ratio of 1:1.7 {1}. FL such as fever and weight loss are uncom- trabecular lymphoid aggregates. The
is 2-3 times as common in White popula- mon. Waxing and waning of the disease designation of a case as A or B (asymp-
tions as in Black populations {1477}. Un- without therapy is common. The disease tomatic or symptomatic) is no longer re-
like paediatric-type FL, usual FL rarely follows a chronic relapsing clinical course. quired for non-Hodgkin lymphoma sub-
occurs in individuals aged < 18 years. types, accord ing to the Lugano system.
Agric ultural exposure to pesticides and Imaging
herbicides has been associated with an Conventional imaging tools such as CT Macroscopy
increased risk {33,1257,3678). and MRI are useful in assessing the de- The cut surface of lymph nodes involved
Microscopy
Pattern
Most cases of FL have a predominantly
fol li cular pattern, with closely packed
follicles that efface the nodal architec-
ture. Neoplastic follicles are often poorly
defined and usually have attenuated or
absent mantle zones. Unlike in reactive
germinal centres, where the proportion
of centroblasts and centrocytes var-
ies in different zones (polarization), in
FL the two types of cells are randomly
distributed. Similarly, tingible body mac-
rophages, characteristic of reactive ger-
minal centres, are usually absent in FL.
In some cases, follicles may be irregular
and serpiginous, but this growth pattern
does not constitute progression to a dif-
fuse growth pattern . Staining for foll icular
dendritic ce ll (FDC) markers (CD21 and/
or CD23) can be helpful in highlighting
the foll icular pattern. lnterfollicular in-
filtration by neoplastic cells is common
and does not constitute a diffuse pat-
tern. The interfollicular neoplastic ce ll s
are often centrocytes that are smaller
than those in the germin al centres, with
a less irregular nuclear contour, and
they may show immunophenotypic dif-
ferences from the ce ll s in the germinal
centres {1015}. Infrequent cases have a
so-called floral growth pattern that re -
sembles progressive ly transformed ger-
minal centres {4004}.
Spread beyond the lymph node cap-
su le is often associated with sc lerosis,
particul arly in mesenteric and retroperi-
toneal locations. With limited samp li ng
in small biops ies, it may be difficult to
appreciate a follicular pattern. A diffuse
area is defined as an area of the tissue of fo lli cular and diffuse areas be noted in diagnosis of DLBCL should be made
completely lacking follicles as evidenced the patho logy report as follicular (> 75% {1556} (see Grading).
by the absence of CD21+/CD23+ FDCs. follicular), fo llicu lar and diffuse (25-75% Some cases have the morphology and
The distin ction between an extensive follicu lar), or focal ly follicular I predomi - immunophenotype of FL but with no evi-
interfollicular component and a diffuse nantly diffuse (< 25% follicular) {1556}. dence of a follicular growth pattern. This
component is sometimes arbitrary. Dif- However, the presence of diffuse areas phenomenon is usually seen in small bi-
fuse areas composed predominantly of composed entire ly or predom inantly of opsy spec imens, and likely constitutes
centrocytes are not thought to be c li ni- large centroblasts (that would fu lfil the a diffuse area in an FL that was not ad-
cally signif icant. Nevertheless, it is rec- criteria for grade 3 FL) in FL of any grade equately sampled . A repeat biopsy in the
ommended that the relative proportions is equivalent to DLBCL, and a separate same or another site may reveal a fol li cu-
•
Fig.13.72 Follicular lymphoma, illustrating follicular
dendritic cells (FDCs). Two binucleate FDCs are present
location. Such t(14;18)-negative cases
might constitute an unusual variant of
marginal zone lymphoma with foll icular
higher frequency in child ren, but are
also seen rarely in adults {214). They dif-
fer biologically from nodal FL in that they
in the centre of the field. The nuclei are round (but with colonization. lack evidence of the BCL2 translocation.
fiattening of adjacent nuclear membranes) and have Cytologically they are of high cytologi-
bland, dispersed chromatin with one small, centrally Bone marrow and blood cal grade, usually grade 3A, but have a
located nucleolus. The cytoplasm is not seen in H&E-
In bone marrow, FL characteristically lo- good prognosis, even without add itional
stained or Giemsa-stained sections. Centroblasts,
unlike FDCs, have vesicular chromatin and multiple calizes to the paratrabecular region and therapy beyond surgical excision {1608,
distinct nucleoli that are usually located adjacent to the may spread into the interstitial areas. A 2369,2386}.
nuclear membranes. follicular growth pattern with a meshwork
Fig. 13.74 Bone marrow involvement by follicular lymphoma. A At low magnification, paratrabecular lymphoid aggregates are visible. B The cells are small centrocytes.
immunostaining in germinal centre cells cases have a proliferation index > 20%, Grading
requires caution, because T cells, pri- although there is considerable variation FL is graded by counting or estimat-
mary follicles, and mantle zones normally among studies, probably due to techni- ing the absolute number of centroblasts
express this protein. cal differences in immunostaining (2088, (large or small) in 10 neoplastic follicles,
In addition to FDCs, neoplastic follicles 2520,3008,4250). A subgroup of mor- expressed per high-power (40x mag-
contain numerous other non-neoplastic phologically low-grade FLs with a high nification, 0.159 mm 2 ) microscopic
cells normally found in germinal centres, proliferation index has been described field (HPF) {1820,2485, 2835). At least
including follicular T cells (CD3+, CD4+, {2088,4250); these cases behaved 10 HPFs with in different folli cles must be
CD57+, PD1/CD279+, CXCL13+) and more aggressively than did those with evaluated; these should be representa-
varying numbers of histiocytes. Consist- a low proliferation index, and similarly to tive follicles, not those with the most nu-
ent with the germinal centre phenotype of grade 3 FL {4250). Therefore, Ki-67 stain- merous large cells.
the neoplastic cells, most cases are neg- ing should be considered as an adjunct Grade 1-2 cases have a marked pre-
ative for IRF4/MUM1. However, a subset to histological grad ing, and its use is dominance of centrocytes , with few
of FLs negative for CD10 are positive clinically justified, although not formally centroblasts (grade 1: 0-5 centroblasts
for IRF4/MUM1 {1944} Such tumours requ ired at this time. per HPF; grade 2: 6-15 centroblasts
typically lack the BCL2 translocation but per HPF). As recommended in the 2008
show amplification of BCL6 {1950). They Postulated normal counterpart WHO classification, the combined des-
tend to occur in elderly patients and cy- The postulated normal counterpart is ignation of grade 1-2 is preferred, due
tologically are of higher grade (3A or 38). a germinal centre 8 cell. In cases with to the lack of clinically significant differ-
These cases must be distinguished t(14;18)(q32;q21), the IGH/BCL2 trans- ences between grades 1 and 2, the con-
from large 8 -cell lymphoma with IRF4 location occurs in bone marrow pre- siderable interobserver variation in grad-
rearrangement, which often has at least 8 cells; fully malignant transformation of ing, and variations in grade within a given
a partially follicular growth pattern {2369, these t(14;18)-positive primed cells oc- biopsy.
3491). curs during (re)entry into the germinal Grade 3 cases have > 15 centroblasts
The Ki-67 proliferation index in FL gen- centres in secondary lymphoid organs per HPF. Grade 3 is further subdivided
erally correlates with histolog ical grade; {3425,3426). on the basis of the presence or absence
most grade 1-2 cases have a prolifera- of centrocytes. In grade 3A, centrocytes
tion index < 20%, whereas most grade 3 are still present, whereas grade 38
progression in FL, in which transforma- neutral LOH , and mutations in TNFRSF14 KMT20 (MLL2) play a key role {1435,
tion develops in an earlier common pro- are among the most common findings in 2966). EZH2, KMT20, and CREBBP
genitor rather than one of the later sub- all forms of FL, including the diffuse vari - have all been proposed as possible ther-
clones {1432). ant of FL and paed iatric-type FL {2228). apeutic targets. More recently, activating
TNFRSF14 mutations were initially sug- somatic mutations in RRAGC have been
Cytogenetic abnormalities and gested to be associated with an adverse found in approximately 17% of cases
oncogenes prognosis {702}, but other studies have {2967).
FL is genetically characterized by the not confirmed this association {2228}. Gene expression studies have shown the
t(14;18)(q32;q21) translocation between The number of add itional alterations importance of the microenvironment in
the IGH and BCL2 genes. Alternative increases with histological grade and the pathogenesis, evolution, and prog-
BCL2 translocations to IG light chain transformation {3508). Rare cases of FL nosis of FL {878 ,1382). Transformation
genes have been reported . The t(14;18) carry t(8;14)(q24;q32) or variants togeth- to DLBCL may occur via various genetic
translocation is present in as many as er with t(14;18) {185,4214}, and prog res- pathways, including inactivation of TP53
90% of grade 1- 2 FLs {1700, 3434). Due sion to a high-grade so-called double-hit and CDKN2A and activation of MYC
to the variation in breakpoint region s, lymphoma may occur, with translocations {884,1089,2395,3195,3508).
FI SH is more sensitive than PCR-based affecting both BCL2 and MYC {3082).
approaches for detecting the transloca- Gain-of-function mutations in the H3K27 Genetic susceptibility
tion {4094). Caution is advised because methyltransferase EZH2 are relatively Genome-wide association stud ies have
classic cytogenetics cannot be used to common in FL, and appear to be an identified five susceptibility loci for FL
distinguish IGH/BCL2 from IGH/MALT1 early event in the evolution of the disease outside the HLA region {3690). Consist-
translocations. FLs negative for BCL2 {513). Additionally, driver mutations in the ent with these data, FL has an increased
rearrangement are more likely to have chromatin reg ulator genes CREBBP and incidence in patients with a history of
a late germinal centre gene expression lymphoma in first-degree fami ly mem-
profile {2259}, but the absence of the bers {2354).
translocation has no apparent impact
on prog nosis {2258}. However, BCL2 re- Prognosis and predictive factors
arrangements are much less frequent in The prognosis of FL is closely related to
grade 38 FL {3008). Similarly, testicular the extent of the disease at diagnosis.
FL, seen mainly in young boys, is nega- The FLI PI, a modification of the Interna-
tive for the BCL2 rearrangement. Abnor- tional Prognostic Index (I Pl ), is useful in
malities of 3q27 and/or BCL6 rearrang e- predicting outcome {1,2,3720). The FLIPI
ment are found in 5-15% of FLs, and uses five independent predictors of infe-
have also been reported in testicular FL rior survival: age > 60 years, haemoglo-
{1 219). bin concentration < 12 g/dL, elevated
In addition to t(14;18), other genetic al- serum lactate dehydrogenase, Ann Ar-
terations are found in 90% of FLs: most bor stage 11 1/IV (disseminated disease
commonly, loss of 1p, 6q, 10q, and 17p in the Lugano system), and > 4 involved
and gains of chromosomes 1, 6p, 7, 8, nodal areas. The presence of 0- 1, 2, 3-5
12q, X, and 18q {1750,2931,4005). One of these adverse factors, respectively,
of the most commonly affected regions is defines low-risk, intermediate-risk, and
1p36, which contains TNFRSF14 {1434). high-risk disease. Genetic profiling may
Copy-number alterations, acquired copy- provide additional information {3094).
Microscopy
ISFN is generally not apparent in rou-
tine H&E-stained sections {789}. Lymph
nodes contain reactive follicles with well-
formed germinal centres. The affected
follicles are similar in size and shape to
adjacent uninvolved follicles, although
on close inspection closely packed cen-
trocytes may be appreciated. The lesion
can also be seen in reactive follicles in
Fig.13.79 In situ follicular neoplasia. A The lymph node is unremarkable, with preserved nodal architecture. extranodal sites, i.e. any location where
B CD20 staining shows a normal distribution of follicles. C BCL2 staining highlights strongly positive centrocytes reactive follicles are identified. ISFN is
within the affected germinal centre. D The atypical cells show strong staining for CD10. distinct from partial involvement by FL,
:··/~·~ct
:·.~""
Fig.13.80 In situ fol licular neoplasia. A The lymph node architecture is preserved, with CD20-positive cells present in fol licles. B Several germinal centres contain strongly
BCL2-positive ce lls. C The BCL2-positive follicles are strongly CD10-positive.
in which only selected foll icles within common molecular mechan isms {1457}. very early step in lymphomagenesis. In
a lymph node may be involved {i848}. addition to the BCL2translocation, muta-
Partial involvement can usually be sus- lmmunophenotype tions in EZH2 (Y64i) were also reported
pected based on H&E-stained sections, ISFN can only be detected by immuno- {3568}. Deletions at i p36 encompass-
whereas ISFN can only be observed histochemistry for BCL2, and is gener- ing the TNFRSF14 gene have also been
with subsequent immunohistochemical ally not suspected on H&E staining . The seen {2480}. This aberration is com-
stains. Partial involvement is associated BCL2-pos itive cells are exclusive ly cen - mon to many B-ce ll lymphomas. Lymph
with lower-stage disease {2i}, but pro- trocytes, and BCL2 is very strongly ex- nodes showing partial involvement by FL
gression can occur. pressed, with a higher intensity than in have also been found to have a relatively
ISFN may be detected in lymph nodes adjacent T cells or mantle zone cells. The low level of genomic alterations {2480,
involved by other forms of lymphoma, BCL2-pos itive centrocytes also show 3568}. In cases in wh ich ISFN and overt
most often other lymphomas of B-ce ll increased exp ression of CDiO. Flow cy- FL are see n in the same patient, there
lineage, which include chron ic lympho- tometry may demonstrate CDiO-positive, are additional genetic alterations in the
cytic leukaemia, mantle cell lymphoma, BCL2-positive, light chain restricted FL that are not present in the ISFN {414,
marginal zone lymphoma, diffuse large B cells, often in the presence of more 3568}. Some of these secondary events
B-cell lymphoma, and class ic Hodgkin numerous other CDiO-positive or CDiO- lead to mutations in BCL2, resu lting in
lymphoma {i848,2698 ,3i84}. ISFN has negative B cells {3 i 84}. negative staining of the FL with the com -
also been reported to coexist in the monly used clone 124 anti body to BCL2
same anatom ical site with in situ man- Genetic profile {414,1848).
tle cell neoplasia {3428}. Activation- ISFN cells are positive for t(14;18), but
induced cytidine deaminase is involved are found to have very few other ge- Prognosis and predictive factors
in initiating chromosomal breaks that netic aberrations when exam ined by ar- For patients with incidentally diagnosed
lead to both the t(14;i8) and the t(i1;i4) ray comparative genomi c hybridization ISFN and no other evidence of FL on
translocations, wh ich is suggestive of {2480 ,3568}, suggesting that this is a clinical evaluation, the risk of subse-
quent FL is very low (s 5%) {353,1848}.
Table 13.19 Histological features distinguishing in situ follicular neoplasia (ISFN) from partial involvement by follicu lar Most studies have not found that the
lymphoma (FL). Modified from Jegalian AG et al. {1848) number of follic les involved within a sin-
In situ follicular neoplasia Partial involvement by FL
gle lymph node showing ISFN predicts
the subseq uent ri sk of lymp homa {i848,
Nodal architecture intact Altered architecture evident on H&E staining 3i84}. High levels of FL-like B ce ll s in the
Follicle size normal Follicle size often expanded peri pheral blood are associated with an
increased risk of subsequent FL {3425},
Involved foll icles widely scattered Involved follicles grouped together but levels so low that the ce lls can only
Mantle cuff intact, with sharp border to germinal Mantle cuff often attenuated or with be identified with multiple rounds of PCR
centre blurred border to germinal centre amplification carry no increased risk. For
patients with other sites of lymphadenop-
BCL2 and CD10 immunostaining very strongly positive BCL2 and CD10 immunostaining more variable athy at presentation with ISFN, additional
in intensity
biopsy is recommended, because other
Composed almost exclusively of centrocytes Composed of centrocytes and few centroblasts forms of lymphoma (usual ly B-ce ll lym-
phomas) may exist with ISFN {353,1288,
Atypical ce lls confined to the germinal centre Atypical cells (CD10+, BCL2+) may be found i848,3i 84}.
outside the germinal centre
"
moderate to high proliferation rate (> 30% Postulated normal counterpart 3567A}. MAP2K1 mutations are identi-
of follicular cells), usually without evi- A germinal centre B cell fied in approximately 40- 50% of cases
dence of polarization in the foll icles. The {2400A,3567B}.
follicular dendritic cell markers (CD21 Grading
and CD23) outline meshworks within the Although most cases would meet the cri- Prognosis and predictive factors
follicles. lgD is negative and shows ei- teria for grade 3 FL, grading is not used if The prognosis is excellent. Most data
ther absent or attenuated mantle cuffs. the criteria for the diagnosis of PTFL are indicate that patients with localized dis-
IRF4/MUM1 is negative; strong positivity met. ease amenable to surgical excision do
should raise the possibility of large B-cell not require radiation or chemotherapy
lymphoma with IRF4 rearrangement. Genetic profile {176,2400}. In one study, there was no
Plasma cells are sparse; an abundance PCR techniques for the detection of difference in clinical outcome between
of plasma cells raises the possibility of re- JG gene rearrangements are positive, patients with and without genetic aber-
active hyperplasia. Flow cytometry iden- which is helpful in ruling out many, but rations {2524}; however, most of the pa-
tifies a monotypic popu lation of B cells not all, cases of florid follicular hyper- tients received multiagent chemotherapy.
positive for CD10 and negative for CD5. plasia {2145}. Aberrations affecting the Areas of DLBCL exclude the diagnosis
However, rare cases of florid follicular BCL2, BCL6, or IRF4 loci are absent. PT- of PTFL as it is currently defined {2997).
hyperplasia, most commonly in young FLs generally lack mutations in KMT20 The diagnosis should be made with cau-
boys, can have clonal popu lations of (MLL2), CREBBP, and EZH2, genes fre- tion in patients aged > 25 years, because
CD10+ B cells detected by flow cytom- quently mutated in usual FL {1435,2966}, the differential diagnosis with usual FL of
etry that are usually small, with monoclo- including cases negative for BCL2 grade 3A or 38 can be challenging . Cor-
nality in JG rearrangement studies {2145}. rearrangements {2400A,3567A} The relation with clinical features is essential
Architectural effacement is a key feature most common genetic aberrations are in older patients.
that distinguishes PTFL from reactive fol- deletion at 1p36 and deletions or muta-
licular hyperplasia with clonal B cells. tions affecting TNFRSF14 {2400A,2524,
Definition
Large B-cell lymphoma (LBCL) with IRF4
rearrangement is an uncommon subtype
of LBCL that can be entirely diffuse, fol-
licular and diffuse, or entirely follicular.
It is characterized by strong expression
of IRF4/MUM1 , usually with IRF4 re-
arrangement. It occurs primarily in ch il-
dren and young adults, with predomi-
nantly Waldeyer ring or head and neck
lymph node involvement (2369,3491}.
Despite its common occurrence in the
paediatric age group, it is distinct from
paediatric-type follicular lymphomas,
even when purely follicular {2369,2400).
Epidemiology Fig.13.85 Large 8-cell lymphoma with IRF4 rearrangement. Low-magnification view of tonsil shows large abnormal
LBCL with IRF4 rearrangement is rare, follicles. Residual reactive germinal centres are visible at lower left.
accounting for just 0.05% of diffuse
LBCLs. The patient age range at presen-
tation is 4- 79 years, with a median age
of 12 years and an equal sex distribution.
Th is entity is significantly more frequent
in children (individuals aged < 18 years)
than in adults (P<0.001) (3491).
Localization
Most patients present with enlarged
lymph nodes of the head and neck re-
gion. The Waldeyer ring is also a frequent
site of disease. Another reported site of
involvement is the gastrointestinal tract
(898,2369,3491).
Fig.13.86 Large 8-cell lymphoma with IRF4 rearrangement. Monotonous proliferation of medium-sized to large
Clinical features cells which appear distinct from both typical centrocytes and centroblasts and that lacks a starry-sky pattern.
Most patients present with isolated lymph
node or tonsillar enlargement (stage 1-11) pattern. Unlike in paed iatric-type foll icu- rate is usually high, with no evidence of
(3491}. lar lymphoma, the follicles generally lack polarization in the neoplastic fol licles. In
a serpiginous configuration and starry- the appropriate clinical context, cases
Microscopy sky pattern. with coexpression of CD10, BCL6, and
The neoplastic cells are medium-sized to IRF4/MUM1 should be screened for IRF4
large, with chromatin which is more open lmmunophenotype rearrangements.
than typically seen in centrocytes and The atypical cells have a mature B-cell
small, basoph ilic nucleoli. Mitotic figures phenotype and are positive for CD20, Postulated normal counterpart
are infrequent, and a starry-sky pattern is CD79a, and PAX5. IRF4/MUM1 is typi- Germinal centre B cell with IRF4
absent. When a follicular pattern is pres- cally strongly expressed, and BCL6 is rearrangement resulting in IRF4/MUM1
ent, the neoplastic foll icles are large, with positive, whereas PRDM1 (also known expression
a back-to-back growth pattern and ab- as BLIMP1) is usually negative. CD10
sent or attenuated mantle zones. Many and BCL2 expression is observed in Genetic profile
cases have an entirely diffuse growth 66% of cases (3491}. The proliferation lmmunoglobulin genes are clonally re-
Definition Synonyms the legs, and 15% with multifocal skin le-
Primary cutaneous follicle centre lym- Reticulohistiocytoma of the dorsum; sions {2062,3623.4499).
phoma (PCFCL) is a tumour of neoplastic Crosti lymphoma
follicle centre cells, includ ing centrocytes Clinical features
and variable numbers of centroblasts, Epidemiology The clinical presentation consists of firm
with a follicular, follicular and diffuse, or PCFCL accounts for approximately 50% erythematous to violaceous plaques,
diffuse growth pattern . It generally pre- of primary cutaneous B-cell lymphomas. nodules, or tumours of variable size.
sents on the head or tru nk {4320). Lym- It mainly affects middle-aged adu lts, with Particularly on the trunk, tumours may
phomas with a diffuse growth pattern a male-to-female ratio of approximately be surrounded by erythematous pap-
and a monotonous proliferation of centro- 1.5:1 {1530,3623.4499}. ules and slightly infiltrated, sometimes
blasts and immunoblasts are classified, figurate plaques, which may precede
irrespective of site, as primary cutaneous Localization the development of tumorous lesions by
diffuse large B-cell lymphoma, leg type PCFCL characteristically presents with months or years {358,3517.4322). PCFCL
{4320}. solitary or localized skin lesions on the with this typical presentation on the back
scalp, forehead, or trunk. Approximately was formerly referred to as reticulohis-
ICD-0 code 9597/3 5% of cases present with skin lesions on tiocytoma of the dorsum or Crosti lym-
•
1 ~ ~
• H '
Fig.13.89 Primary cutaneous follicle centre lymphoma. Fig.13.90 Primary cutaneous follicle centre lymphoma with a follicular growth pattern. A Note the distinct
A Characteristic clinical presentation on the scalp. follicular structures. B Detail of neoplastic follicle showing a monotonous proliferation of follicle centre cells with no
B Characteristic clinical presentation with localized skin polarization, attenuated mantle zone and absence of tingible body macrophages. C Monotonous neoplastic follicle
lesions on the chest. centre cells are seen at higher magnification. D Unlike in reactive germinal centres, the Ki-67 stain shows only
scattered positive cells in the neoplastic follicle.
Microscopy
PCFCL shows perivascular and periad-
nexal to diffuse infiltrates, with almost
invariable sparing of the epidermis. The
infiltrates show a spectrum of growth pat-
terns, with a morphological continuum
from follicular to follicular and diffuse to
diffuse {3517,4320,4322}. Cases with a
follicular growth pattern show nodular in-
filtrates throughout the entire dermis, often
extend ing into the subcutis. Unlike in cuta-
neous follicular hyperp lasias, the follicles
in PCFCL may be poorly defined, show a
monotonous proliferation of BCL6+ follicle
centre cells enmeshed in a meshwork of
CD21+/CD35+ follicular dendritic cells,
lack tin gible body macrophages, gener-
ally have an attenuated or absent mantle Fig.13.91 Primary cutaneous follicle centre lymphoma with a diffuse growth pattern. A Diffuse non-epidermotropic
infiltrate. B The tumour cells express CD20. C Higher magnification shows that the cellular infiltrate contains many
zone, and show a low proliferation rate
multilobated cells.
{606,1408}. Reactive T cells may be nu-
merous, and a prom inent stromal compo-
nent is usually present. with a diffuse growth pattern {903,1409, matic hypermutation are present, but
Cases with a diffuse growth pattern usu- 1654,2016,2062,2674,3623}. Most cases may not be detectable by PCR {6,1325}.
ally show a monotonous population of either do not express BCL2 or only show
large centrocytes, some of wh ich may faint BCL2 staining (weaker than in ad- Cytogenetic abnormalities and
have a multilobated appearance, and mixed T cells) in a minority of neoplastic oncogenes
variable numbers of adm ixed centro- B ce ll s {606,610,715,1318,1654,2062, In many stud ies, PCFCLs, including
blasts {358,1421,3517,4322}. In rare cas- 3623} However, several studies have re- cases with a follicular growth pattern,
es, the large centrocytes may be spindle- ported BCL2 expression in a substantial do not show (or rarely show) BCL2
shaped {607,1406}. In some cases, foci proportion of PCFCLs with at least a par- rearrangements {10,610,715,1318,1408,
of CD21+/CD35+ follicular dendritic cells tially follicular growth pattern {37,1409, 1409,1494,1524,1525,3164,4183}. How-
may still be present; in other cases, they 2016,2674,3164} Strong expression of ever, other studies using PCR and/or
may be totally absent {1494}. The pro lif- both BCL2 and CD10 by the neoplastic FISH report BCL2 rearrangements in
erative fraction in these diffuse PCFCLs B ce ll s should always raise suspicion of about 10- 40% of PCFCLs with a follicu-
is generally high. a nodal follicular lymphoma involving the lar growth pattern, as well as in some to-
skin secondarily. Staining for IRF4/MUM1 tally diffuse cases {37,2016,2674,3859}.
lmmunophenotype and FOXP1 is negative in most cases; PCFCLs have the same gene expression
The neoplastic ce lls express CD20 and staining for CDS and CD43 is always profile as germinal centre B-cell-sub-
CD79a, but are usually immunoglobulin- negative {2062,3623}. type diffuse large B-cell lymphomas,
negative by immunohistochemistry. Flow and often show amplification of REL {6,
cytometric studies are reported to dem- Postulated normal counterpart 986,1653}. Deletion of chromosome
onstrate restricted light chain expression A mature germinal centre B cell 14q32.33 has been reported {986}. Un-
in almost 3/4 of cases {3549A}. PCFCLs like in primary cutaneous diffuse large
cons istently express BCL6 . CD10 may be Genetic profile B-cel l lymphoma, leg type, inactivation
positive in cases with a follicular growth Antigen receptor genes of CDKN2A and CDKN2B gene loci on
pattern, but is generally negative in cases Clonal ly rearranged IG genes with so- chromosome 9p21 .3 by deletion or pro-
A ·I
t •I '.
1~.
Fig.13.92 Primary cutaneous follicle centre lymphoma, spindle-shaped morphology. A Diffuse proliferation of
centrocytes with a spindled morphology. B Detail of spindle-shaped cells. C Ki-67 stain shows high proliferation
rate. D The cells are strongly positive for CD79a but (E) negative for BCL2.
ICD-0 codes
Mantle cell lymphoma 9673/3
In situ mantle cel l neoplasia 9673/1
Synonyms
Mantle zone lymphoma (obso lete); malig-
nant lymphoma, lymphocytic, intermedi-
ate differentiation, diffuse (obsolete); ma-
lignant lymphoma, centrocytic (obsolete);
mali gnant lymphomatous polyposis; in
A B
situ mantle cel l lymphoma (for in situ
Fig.13.93 Mantle cell lymphoma involving the co lon (multiple lymphomatous polyposis). Gross photographs.
mantle cell neoplasia) A Overview showing one large and multiple small polypoid mucosal lesions. B Closer view showing tiny polypoid
mucosal lesions.
Epidemiology
Mantle cell lymphoma accounts for to-female ratio of ::::2:1 {139,423,543, ment, are also important sites of disease
approximately 3-10% of non-Hodgkin 22 19,3849,3854). {139,423,2896,3849). Other extranodal
lymphomas {1}. It occurs in midd le-aged sites are also frequently involved , includ-
to older individuals, with a median age Localization ing the gastrointestinal tract (where in-
of about 60 years. There is a variably Lymph nodes are the most commonly in- filtration may be subc linical), Waldeyer
marked male predom in ance, with a male- volved site. The spleen and bone marrow, ring, lungs, and pleura {1324,3487). An
with or without peripheral blood involve- uncommon but distinctive presentation is
Fig. 13.94 Mantle cel l lymphoma, peripheral blood, cytological variation. A This typical mantle cell lymphoma demonstrates relatively small lymphoid cells with clumped
chromatin and prominent nuclear clefts. B In contrast, the cells in this blastoid mantle cell lymphoma are larger and have prominent nucleoli. C This mantle cell lymphoma could
easily be confused morphologica lly with chronic lymphocytic leukaemia.
Clinical features
Most patients present with stage 111 or,
usually, stage IV disease with lymphade-
nopathy, hepatosplenomegaly, and bone
marrow involvement {423,543,2896,
3854). Extranodal involvement, usually
in the presence of extensive lymphad-
enopathy, is common. Peripheral blood
involvement is also common, and can
be identified by flow cytometry in almost
all patients {1192}. Some patients have a
marked lymphocytosis, wh ich can close-
ly mimic prolymphocytic leukaemia {139,
423,2896}, an acute leukaemia {4204),
or chronic lymphocytic leukaemia. Some
patients present with leukaemic non-nod-
al disease, sometimes with splenomega-
ly. These cases constitute a different vari-
ant of the disease (see below).
Macroscopy
Most cases of multiple lymphoma-
tous polyposis constitute mantle cell
lymphoma.
Microscopy
Classic mantle cell lymphoma is a mono-
morphic lymphoid proliferation with a
vaguely nodular, diffuse, mantle zone, or
rarely follicular growth pattern {245,2219,
2269,3849,4018). Mantle cell lymphoma
with a mantle zone growth pattern should
be distinguished from in situ mantle cell
neoplasia (see discussion below). Most
cases are composed of small to medium-
sized lymphoid cells with slightly to mark- f .
edly irregular nuclear contours, most Fig. 13.95 Mantle cell lymphoma, lymph nodes. A There is diffuse architectural effacement and typical pale
closely resembling centrocytes. The nu- hyalinized vessels. B In addition to diffuse areas, note the prominent vague neoplastic nodules. C A mantle zone
clei have at least somewhat dispersed growth pattern is seen in this lymph node with an intact architecture.
chromatin but inconspicuous nucleoli.
Neoplastic transformed cells resembling {1187), and the marginal zone-like vari- positive nuclei) is critical because of its
centroblasts, immunoblasts, or paraim- ant is of greatest interest because of its prognostic impact.
munoblasts and proliferation centres are potential confusion with marginal zone Hyalinized small vessels are commonly
absent; however, foci mimicking prolifera- lymphomas. Mantle cell lymphoma in seen. Many cases have scattered single
tion centres may be present {3855A}, and the peripheral blood or in bone marrow epithelioid histiocytes, which in occasion-
a spectrum of morphological variants is aspirates shows the same cytolog ical al blastoid or pleomorphic cases can cre-
recogn ized, which can also cause dia- spectrum that is seen in tissue sections; ate a so-called starry-sky appearance.
gnostic confusion (Table 13.21, p.285). however, nucleoli are sometimes more Non-neoplastic plasma cells may be
The blastoid and pleomorphic variants prominent, even in cases of classic type. present, but true plasmacytic differentia-
are considered to be of important clini- Although mantle cell lymphoma is not tion, which can be very marked, is seen
cal significance. The small-cell variant graded, evaluation of the proliferative only rarely {2645,3347,3851,4444,4445).
is overrepresented among cases of leu- fraction (either by counting mitotic fi gures Splenic involvement, characterized by
kaemic, non-nodal mantle cell lymphoma or estimating the proportion of Ki-67- white pulp and variable red pulp infiltra-
CDK4/6
Cyclin 01
~ l.____
RBI®+ E2F
•liiiC
iD
Cyclin E
i iK
!ii2i!!!!I•
also been suggested {207S}. Most cases
are of pre-germinal centre origin, but
some are of post-germinal centre origin.
-
1- I MDM2 1 1- ~ tated in most cases, but in 1S-40% of
. °" IATM I
cases, IG genes show somatic hyper-
mutation, although the load of mutations
is usually lower than in mutated chronic
Fig. 13.96 Mantle cell lymphoma (MCL). Cell-cycle and DNA damage repair pathways altered in MCL. The cyclin D1 I
CDK4/6 complex promotes phosphorylation of RB (also called RB1). This leads to release of the E2F transcription
lymphocytic leukaemia {S34,2008,2992,
factors, which then lead to progression of the cell cycle into the S phase. The cyclin D1 I CDK4/6 complex is inhibited 39SO}. A biased use of the IGHV genes
by p16 (also called CDKN2A). BMl1 is a transcriptional repressor of the CDKN2A!ARF locus. Abnormalities in MCL has been reported, suggesting that man-
that lead to progression of cells from G1 to S phase include increased cyclin D1 in almost all cases, as wel l as loss tle cell lymphoma may originate from
of p16, RB1 deletions, increased CDK4, and increased BMl1 in a minority of cases, especially those that are more specific subsets of B cells {S34,2008,
aggressive. Deregulated E2F also induces ARF transcription. ARF leads to stabilization of p53 by inhibiting the 2992,39SO}. Together with other obser-
activity of MDM2, which leads to the degradation of p53. The tumour suppressor p53 leads to increased expression
vations, this finding suggests that at least
of p21 (also called CDKN1A) and to cell-cycle arrest or apoptosis. ATM is required for activation of p53 after DNA
damage. Many MC Ls have ATM abnormalities, and some patients have germ line mutations of this gene. Some MC Ls
a substantial proportion of mantle cell
have loss or transcriptional repression of the CDKN2A/ARF locus (lacking p16/ARF), loss or mutation of TP53, or lymphomas show evidence of antigenic
high levels of MDM2. Finally, cyclin EI CDK2 complexes also lead to cell-cycle progression, and are inhibited by drive {1S09,4391}.
p21 and p27 (also called CDKN1 B). In MCL, increased levels of cyclin D1 lead to sequestration of these cell-cycle
inhibitors, and they may also increase p27 degradation {1843). Cytogenetic abnormalities and
oncogenes
tion, can mimic a splenic marginal zone CD23 is negative or weakly positive. Nu- The t(11;14)(q13;q32) translocation be-
lymphoma, with smaller cells with lit- clear cyclin 01 is expressed by > 9S% tween an IGH gene and CCND1 (encod-
tle cytoplasm centrally in the white pulp of mantle cell lymphomas, includ ing the ing cyclin D1) is present in> 9S% of cases
nodules and a peripheral zone where minority of cases that are CDS-nega- and is considered to be the primary ge-
the neoplastic cells more closely resem- tive {700,38SS,4026} SOX11 is positive netic event {2301,3408,409S,4146,4323,
ble marginal zone cells, being some- with the most sensitive monoclonal an- 4324} Variant CCND1 translocations with
what larger and with more abundant tibody in > 90% of mantle cell lympho- the IG light chains have also been report-
cytoplasm. mas, including cyclin D1-negative and ed but are very uncommon. The translo-
Histological transformation to a typical blasto id cases {2769,2816,3721}. Cau- cation results in deregulated overexpres-
diffuse large B-cell lymphoma does not tion is advised, because the specificity sion of CCND1 mRNA and protein (422,
occur; however, loss of a mantle zone and sensitivity of SOX11 antibodies vary 889,3627). Some mantle cell lymphomas
growth pattern, increase in nuclear size, widely. Aberrant phenotypes have been express aberrant transcripts, resulting
pleomorphism and chromatin dispersal, described (sometimes in association in an increased half-life of cyclin D1. Tu-
and increase in mitotic activity and Ki-67 with blastoid or pleomorphic variants), mours with these truncated transcripts
proliferation index can be seen in some including absence of CDS and expres- have very high levels of cyclin 01 expres-
cases at relapse (139,2219,2896,3849, sion of CD10 and BCL6 {41,S3S,1294, sion (422,889,3627}, high proliferation
4208). Some such cases fu lfil the criteria 2737,442S}. Rare cases express other rates, and more-aggressive clinical be-
for a blastoid or pleomorphic mantle cell antigens more typically associated with haviour (3413}. Deregulated expression
lymphoma (see below). Cases that are chronic lymphocytic leukaemia, such of cyclin D1 is assumed to overcome the
blastoid at diagnosis may relapse with as LEF1 or CD200, with LEF1 more like- cel l cycle suppressive effect of RB and
classic morphology (4208}. ly to be seen in blastoid or pleomorphic p27 in addition to other effects, leading to
mantle cell lymphoma and CD200 in the the development of mantle cell lymphoma
lmmunophenotype leukaemic non-nodal variant {636,111S, (1841,3264} Nevertheless, it is not suffi-
The cells express relatively intense sur- 11 S7,2633,3SOS}. lmmunohistochemical cient by itself to lead to mantle cell lym-
face lgM/lgD, more frequently with lamb- staining often reveals loose meshworks phoma, as demonstrated both with animal
da than kappa restriction {S43,3849, of follicular dendritic cells. models and by observations related to
4018}. They are uniformly BCL2-positive CCN01-rearranged clonal populations in
{38S3}; usually positive for CDS, FMC?, Postulated normal counterpart the peripheral blood of healthy individuals
and CD43; sometimes positive for IRF4/ The postulated normal counterpart is a {2247) In addition to the molecular cy-
MUM1; and negative for CD10 and BCL6 . peripheral B cell of the inner mantle zone; togenetic abnormalities described below,
In recent years, overall survival appears but with > 30% as a currently accepted blood involvement (at least in patients
to have improved among at least some cut-off point) are associated with an ad- with adenopathy) {302,423,543,847,939,
subsets of patients. A subset of asympto- verse prognosis {962,1038,1416,1964, 1453,2399,2892,3200,3494,3522,3849).
matic patients with indolent disease who 4001). Cases with < 10% Ki-67-positive Lack of SOX11 expression has been as-
can be followed, at least initially, without cells have a more indolent course. Ki-67 sociated with more-indolent mantle cell
any therapy has also been increasingly expression has also been incorporated lymphoma in some studies; however,
recognized and includes many of the pa- into the biological, prognostically impor- other studies have found these cases to
tients with one of the clinicopathological tant Mantle Cell Lymphoma International be more aggressive, perhaps related to
mantle cell lymphoma variants described Prognostic Index (MIPI) score, which also acquis ition of TP53 abnormalities, which
below {571,1037,1118,1187,2522,2992}. includes patient age, Eastern Cooperative are present in a substantial subset of the
Assessment of proliferation rate is criti- Oncology Group (ECOG) performance cases {1187,2841,2892,2908}. The small-
cal; high mitotic rate (> 10- 37.5 mitoses score, lactate dehydrogenase leve l, and cell variant also appears to have a more
per 15 high-power fields or > 50 mitoses/ white blood ce ll count {1319,1704). In a indolent course; the impact of a mantle
mm 2) {139,423,3849,4001} and high Ki- major gene expression profiling study, zone or nodular pattern is less certain, but
67 proliferation index (variably defined, the most significant prognostic ind ica- at least some nodular cases are probably
tor in mantle cell lymphoma was also the associated with a more indolent course
proliferation signature score, which fur- {423,571, 2219, 2449, 2896,3413,3849,
ther high li ghts the cl inical importance of 4001). The literature is not uniform with
proliferation rate in this entity {3413}. The regard to the impact of individual chromo-
following features have been reported somal gains or deletions, limiting their util-
in at least some studies to be adverse ity. The prognostic value of 9p (CDKN2A)
prognostic factors (although they are not and 17p (TP53) deletions has been con-
necessarily all independent of the prol if- firmed in cl inical trials with new therap ies,
erative fraction): blastoid or pleomorphic and seems to be independent of prolif-
morphology, karyotypic complexity, TP53 eration {939}. Other chromosomal altera-
mutation/overexpression/loss, CDKN2A tions have been associated with a poor
deletion, and a variety of individual clini- prognosis independent of the proliferative
cal parameters including overt peripheral fraction, but these associations need to
be confirmed in patients treated with cur- survival. Expression profiling and experi- defined as the presence of cyclin D1-
rent therapeutic approaches {3494,3S22}. mental studies suggest that these cases positive lymphoid cells with CCND1 re-
have a lack of tumour invasion properties arrangements restricted to the mantle
Leukaemia non-nodal mantle and angiogenic potential, perhaps ac- zones of otherwise hyperplastic-appear-
cell lymphoma counting for the absence of significant ing lymphoid tissue {S71,288S}. Periph-
adenopathy {928 ,3039). Patients with eral blood involvement or involvement
Leukaemic non-nodal mantle cell lym- this variant have been reported to have a at more than one site does not exclude
phoma is defined as mantle cell lym- better prognosis than those with classic the diagnosis, with some cases probably
phoma in which the patient presents mantle cell lymphoma (median survival: constituting the leukaemic non-nodal
with peripheral blood, bone marrow, 79 months) and are overrepresented in type of mantle cell lymphoma but with in-
and sometimes splenic involvement but studies of patients with mantle cell lym- volvement of the mantle zone (i.e. in situ)
without significant adenopathy (typi- phomas that have followed an indolent in lymph nodes enlarged for some other
cally defined as peripheral lymph nodes course, often not requiring therapy for reason. Extranodal involvement may also
< 1-2 cm and without adenopathy on long periods {111S,1187,2992}. How- be present. The cyclin 01-positive cells
CT, if performed) {111S,1 187,2992}. Like ever, some cases of this subtype may are typically in the inner mantle zone, but
in chron ic lymphocytic leukaemia, it ap- progress to an agg ressive disease, with may rarely be scattered throughout the
pears that these circulating cells may or without the development of lymphad- mantle zone, in the outer mantle zone, or
reversibly infiltrate extranodal inflamma- enopathy, sometimes with rapidly pro- very rarely intrafollicular. When the man-
tory sites (e.g. with He/icobacter py/ori- gressive splenomegaly and sometimes tle zones are expanded and completely
associated gastritis) and may remain lo- with transformation to a blastoid or ple- replaced by cyclin D1-positive lymphoid
calized to the mantle zone, overlapping omorphic variant. Acquisition of TP53 cells, the diag nosis of overt mantle cell
with in situ mantle cell neoplasia. The mutations or other oncogenic alterations lymphoma with a mantle zone growth
neoplastic cells in leukaemic non-nodal may be associated with this aggressive pattern is more appropriate. Compared
mantle cell lymphoma are more likely to evolution {3439). Although monoclonal with classic mantle cell lymphoma, these
be small, resembling chronic lymphocyt- B-cell lymphocytosis of mantle cell lym- cases are more likely to be CDS-nega-
ic leukaemia- type cells, SOX1 1-negative, phoma type is not recognized, there is a tive, and they include both SOX11-posi-
and to have somatic IG hypermutation small proportion of healthy individuals (at tive and a moderate number of SOX11-
{928,111S,1187,2992}. CDS expression least 7%) with circulating cells that have negative cases. These cases are very
may be less common than in other man- IG H/CCND 1 translocations detected rare (none were found in two series of
tle cell lymphomas. Leukaemic non- with highly sensitive techniques, which at least 100 hyperplastic lymph nodes)
nodal mantle cell lymphomas are more can persist for years and may increase and are usually identified as an inciden-
likely than classic mantle cell lymphomas in number over time {2247). A report of tal find ing, sometimes associated with
to have < 30- 40% CD38 positivity, and simultaneous development of mantle other malignant lymphomas, when cyclin
at least a subset is more likely to have cel l lymphoma in a recipient and donor D1 immunohistochemical staining is per-
;:::2% CD200 positivity, a phenotype that 12 years after allogeneic bone marrow formed {S71,22A}. In situ mantle cell neo-
may overlap with that of chronic lympho- transplantation is also consistent with plasia often has an indolent course with
cytic leukaemia {111 S,2992}. Cytogenetic a very long latent period for mantle cell long-term survival, frequently with stable
studies show few abnormalities other lymphoma after an initial event {7SO}. disease even without therapy. However,
than the CCND1 translocation, whereas caution is advised, because rare cases
classic mantle cell lymphoma typically In situ mantle cell neoplasia may progress to overt mantle cel l lym-
has greater genomic instability and a phoma and occasional patients have
more complex karyotype {1187,3439}. In situ mantle cell neoplasia, formerly re- been reported who have not done well
Although not considered a prognostic ferred to as in situ mantle cell lymphoma {S71,1949,33S1}. The proportion of overt
indicator, mutated IG genes have been or mantle cell lymphoma-like B cells of mantle cell lymphoma preceded by in
identified in patients with longer-term uncertain/undetermined significance, is situ mantle cell neoplasia is controversial.
Definition Table 13.22 Large B-cell lymphomas; italics indicate that an entity is provisional
Diffuse large B-cell lymphoma (DLBCL) Diffuse large B-cell lymphoma, NOS
is a neoplasm of medium or large B lym- Morphological variants
phoid cells whose nucle i are the same Centroblastic
size as, or larger than, those of normal lmmunoblastic
macrophages, or more than twice the Anaplastic
size of those of normal lymphocytes, with Other rare variants
Molecular subtypes
a diffuse growth pattern.
Germinal centre B-cell subtype
Morphological, biolog ical, and clinical Activated B-cell subtype
studies have subd ivided DLBCLs into
morphological variants, molecular sub - Other lymphomas of large B cells
types, and distinct disease entities (Ta- T-cell/histiocyte-rich large B-cell lymphoma
ble 13.22). However, there remain many Primary diffuse large B-cell lymphoma of the CNS
cases that may be biologically heteroge- Primary cutaneous diffuse large B-cell lymphoma, leg type
EBV-positive diffuse large B-cell lymphoma, NOS
neous, but for which there are no clear
Diffuse large B-cell lymphoma associated with chronic inflammation
and accepted criteria for subdivision . Lymphomatoid granulomatosis
These cases are c lassified as DLBCL, Large B-cell lymphoma with IRF4 rearrangement
NOS, which encompasses all cases that Primary mediastinal (thymic) large B-cell lymphoma
do not belong to a specific diagnostic lntravascular large B-cell lymphoma
category listed in Table 13.22. DLBCL, ALK-positive large B-cell lymphoma
NOS can be subd ivided into germ i- Plasmablastic lymphoma
HHVB-positive diffuse large B-cell lymphoma
nal centre B-cell (GCB) subtype and
Primary effusion lymphoma
activated B-cell (ABC) subtype. Focal
involvement of follicular structures in High-grade B-cell lymphoma
DLBCL, which can be highlighted by im- High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements
munohistochemical stainin g for follicu lar High-grade B-cell lymphoma, NOS
dendriti c cells, does not require the ad- B-cell lymphoma, unclassifiable
ditional diagnosis of a grade 3B foll icular B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and
lymphoma. classic Hodgkin lymphoma
ICD-0 codes
Diffuse large B-ce ll lymphoma, NOS aggressive lymphoma (referred to as DLBCL associated with chron ic inflam -
9680/3 secondary), such as c hronic lympho- mation or lymphomato id granulomatosis).
Germ inal centre B-cell subtype 9680/3 cytic leukaemia/small lymphocytic lym-
Activated B-cell subtype 9680/3 phoma, follicular lymphoma, marginal Localization
zone lymphoma, or nodular lymphocyte Patients may present with nodal or ex-
Epidemiology predominant Hodgkin lymphoma . Un- tranodal disease; as many as 40% of
DLBCL, NOS, constitutes 25-35% of derlying immunodeficiency is a signif i- cases are conf ined to extranodal sites
ad ult non-Hodgkin lymphomas in devel- cant risk factor. DLBCLs, NOS, occ urring at least initially {1,95). The most common
oped countries, and a higher percentage in the setting of immunodeficiency are
in developing countries. It is more com - more often EBV-positive than sporad ic
mon in elderly individuals. The median cases. In DLBCL cases without an overt
patient age is in the seventh decade of immunodeficiency, the EBV infection rate
life, but it can also occur in children and varies from 3% in western populations
young adu lts. It is sl ightly more common to approximately 10% in Asian and Latin
in males than in females {1,95). American populations, and the lympho-
ma is typically of the ABC subtype {325,
Etiology 1017,1367,1655,2701,2956,3696). Impor-
The etiology of DLBCL, NOS, remains tantly, EBV pos itivity in most tumour cells
unknown . These tumours usually arise shou ld lead to a diagnosis of either EBV-
de novo (referred to as primary) but can positive DLBCL, NOS, or another spe- Fig.13.101 Diffuse large B-cell lymphoma, NOS.
also represent transformation of a less cific type of EBV-positive lymphoma (e.g. Involved spleen contains large tumour nodules.
:5'"'
::J
~~nth
- GCB
-+-
•--
~
- PFS. 73%; 95% CJ, 62%to a..<.s".+' 12-month PFS, 64%; 95% Cl, 49% to 84%
translocation tend to have a higher Ki-67 20 24-month PFS, 64%; 95% Cl. 53% to 78%
Non-GCB
24-month PFS, 59%; 95% Cl, 44% to 80%
Non-GCB
proliferation index, although it is highly 12-monlh PFS, 39%; 95% Cl, 25% to 62%
24-month PFS, 28%; 95% Cl, 15% to 51%
12-month PFS, 72%; 95% Cl, 55% to 94%
24-month PFS, 60%; 95% Cl. 4 1% to 87%
ings in European studies have been rep- Fig. 13.107 Diffuse large B-cell lymphoma (DLBCL). Outcomes of historical control patients treated with the
licated in eastern Asian populations, sug- CHOP chemotherapy regimen plus rituximab (R-CHOP) and study patients treated with lenalidomide added to
gesting a common risk {286,3888} The R-CHOP (R2CHOP), in the germinal centre B-cell (GCB) versus the activated B-cell (ABC; non-GCB) subtypes
identities of the candidate genes in these of DLBCL. A Progression-free survival (PFS) of patients treated with R-CHOP. B PFS of patients treated with
R2CHOP. C Overall survival (OS) of patients treated with R-CHOP. DOS of patients treated with R2CHOP (2903}.
loci suggest that immune recognition and
Lenalidomide is effective in patients with ABC lymphomas, mitigating the negative impact of the ABC phenotype on
immune function may underlie the patho- patient outcome.
genesis of DLBCL {602}. From: Nowakowski GS, et al. (2015) Lenalidomide combined with R-CHOP overcomes negative prognostic impact
of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. (2903}
Prognosis and predictive factors Reprinted with permission. © 2015 American Society of Clinical Oncology. All rights reserved.
Clinical features
In the R-CHOP era, the 5-year progres- Morphology and BCL6 are examples of biomarkers
sion-free and overall survival rates are There are many conflicting reports on of which the reported prognostic effect
approximately 60% and 65%, respec- the prognostic impact of immunoblastic was altered by the add ition of rituximab
tively {3611 }. Disease stage and patient features {1105,3009}. Some studies have to the CHOP chemotherapy regimen
age are significant factors affecting sur- found an adverse prognostic impact of {2766,4337}. Many of these immunohis-
vival. The International Prognostic Index immunoblastic morphology, whereas oth- tochemistry-based biomarkers reflect bi-
(IPI), wh ich incorporates five clinical ers have not. Reproducibility and varia- ology, but are not predictive. Moreover,
variables, remains a valuable prognos- ble criteria remain significant obstacles in the resu lts obtained in these studies are
tic tool , although newer variations have these studies. The immunoblastic variant often conflicting, and their interpretation
been described that are better able to is associated with MYC translocations, is therefore controversial. The current
identify patients with the highest-risk clin- typically involving IG loci. These cases emphasis is on developing predictive
ical features {3610,4491}. Other clinical frequently express CD10 {1685}. biomarkers in DLBCLs where knowledge
prognostic factors associated with inferi- of a biomarker impacts an initial or sub-
or outcome include tumour bulk (masses lmmunophenotype sequent therapeutic decision. Predictive
~ 10 cm), male sex, vitamin D deficiency, Many immunohistochemical markers markers cu rrently include markers for the
low body mass index, elevated serum have been reported to have prognostic determination of cell of origi n (i.e. GCB
free light chains, monoclonal serum lgM impact, but most have not been vali- subtype vs ABC subtype) being tested
proteins, low absolute lymphocyte/mono- dated and are therefore not accepted as now in the context of phase Ill cl inical tri-
cyte count, and concordant (but not dis- robust or routine biomarkers {212,2397, als and markers of the presence of rel -
cordant) bone marrow involvement {568, 2917}. All biomarkers require reassess- evant oncogene translocations (see be-
831,1035 ,1673, 2586, 2797,31 61, 3220, ment using standard of care therapy. De low), in particular involving the MYC gene
3612,4314}. Concordant bone marrow novo CD5+ DLBCL is variably reported {3601}. A recent meta-analysis clearly es-
involvement also pred icts an increased to have prog nostic importance {754, tablished the prognostic significance of
risk of CNS relapse and in some centres 2681, 2879 ,4399). It is often associated cell of origin as determined by gene ex-
dictates CNS prophylaxis. with high-risk clinical features, espe- pression profiling, but not based on most
cially in Asian countries, and is usually immunohistochemical algorithms {3325}.
of ABC subtype {1110, 2681,4406}. BCL2 More controversial is the assessment of
Definition
T-cell/histiocyte-rich large B-cell lym-
phoma (THRLBCL) is characterized by a
limited number of scattered, large B cells
embedded in a background of abundant
T cells and histiocytes. THRLBCL may
arise de nova; however, more recent data
suggest the possibility of a closer rela-
tionship with progression forms of nodular
lymphocyte predominant Hodgkin lym-
phoma (NLPHL) than previously thought,
indicating that NLPHL may proceed to or
contain areas indistinguishable from THR-
LBCL. In small biopsies in particular, dif-
ferentiating between a progression form
of NLPHL (i.e. NLPHL with THRLBCL-like
transformation) and de nova THRLBCL
may be difficult, if not impossible.
Synonyms
T-cell- rich B-cell lymphoma; B-cell lym-
phoma rich in T cells and simulating Hodg-
kin disease; histiocyte-rich/T-cell-rich
large B-cell lymphoma; T-cell-rich large
B-cell lymphoma; T-cell-rich/histiocyte-
rich large B-cell lymphoma; histiocyte-
rich large B-cell lymphoma
Epidemiology
THRLBCL mainly affects middle-aged diagnosis with NLPHL, clinical staging (LP) cel ls of NLPHL, but usually show
men. It accounts for< 10% of all DLBCLs. procedures (including imaging analyses) greater variation in size and , in some cas-
are important. NLPHL usually affects one es, may resemble centroblasts or more
Localization or two regions, whereas THRLBCL fre- pleomorphic cells, mimicking Reed-
THRLBCL mainly affects the lymph quently manifests as systemic disease. Sternberg or Hodgkin cells (19,3299).
nodes, but bone marrow, liver, and Because THRLBCL is more PET-avid They are typically found within clusters of
spleen involvement is frequently found at than is NLPHL, stag ing procedures such bland-looking non-epithelioid histiocytes
diagnosis. as FOG-PET and CT may facilitate the that may not be obvious on conventional
differential diagnosis {246). examination. These histiocytes are a main
Clinical features and distinctive component of THRLBCL
Patients present with fever, malaise, Microscopy and are useful for the diagnosis {1448).
splenomegaly, and/or hepatomegaly. THRLBCL has a diffuse or less common- Nearly all of the background lymphocytes
At diagnosis, almost half of cases are at ly vaguely nodular growth pattern replac- are of T-cell lineage, with typically only
an advanced Ann Arbor stage, with an ing most of the normal lymph node pa- very few scattered B cel ls. Meshworks of
intermediate-risk to high-risk International renchyma. It is composed of scattered, follicular dendritic cells are absent. Eo-
Prognostic Index (IPI) score (Table 13.24). single large B cells embedded in a back- sinophils and plasma cells are not found.
The disease is often refractory to the ground of small T cells and variable num- De novo TH RLBCLs are usually diffuse
chemotherapy regimens currently in use. bers of histiocytes. The tumour cells are and do not show the typical small B-cell
always dispersed and do not form aggre- background of NLPHL. However, there
Imaging gates or sheets. These cells may mimic are cases of NLPHL in which the small
Because of the important differential the neoplastic lymphocyte predomi nant B cells are diminished in number, and in
Definition
Primary diffuse large 8 -cell lymphoma
(OLBCL) of the CNS is defined as DLBCL
arising within the brain, spinal cord, lep-
tomeninges or eye. Excluded are lym-
phomas of the dura, intravascular large
8-cell lymphomas, lymphomas with evi-
dence of systemic disease or secondary
lymphomas, and all immunodeficiency-
associated lymphomas.
Synonyms
Primary CNS lymphoma; primary intraoc-
ular lymphoma; lymphomatosis cerebri
(no longer recommended)
Epidemiology
CNS DLBCL accounts for < 1% of all Fig.13.110 Primary diffuse large B-cell lymphoma of the CNS. Nuclear MRI. T1-weighted image after gadolinium
non-Hodgkin lymphomas and 2.4-3% injection (A) and FLAIR sequences (B). There are two enhancing mass lesions in the basal ganglia.
of all brain tumours {3556). The overall
annual incidence rate of CNS DLBCL cells may also contribute to organ restric- supratentorial space, including the frontal
is 0.47 cases per 100 000 population tion {2710). Upon relapse, CNS DLBCLs lobe (affected in 15% of cases), temporal
{4196). This lymphoma can affect pa- show a restricted homing to the main im- lobe (in 8%), parietal lobe (in 7%), occipi-
tients of any age, with a peak incidence mune sanctuaries (i.e. the brain, eyes, tal lobe (in 3%), basal ganglia and perive-
in the fifth to seventh decade of life, a and testes) {416,1552,1828,3289), and ntricular brain parenchyma (in 10%), and
median patient age of 56 years, and a primary testicular and intraocu lar lym- corpus callosum (in 5%). Less frequently
male-to-female ratio of 3:2. In the past phomas frequently spread to the CNS affected sites include the posterior fossa
two decades, an increased incidence {4205}, suggesting that the tumou r cells (affected in 13% of cases) and spinal cord
has been reported among patients aged need to hide in an immune sanctuary. (in 1%) {919). A single tumour is present
>60 years {821,4196). Many DLBCLs of the CNS and testis in 60-70% of cases, with the remainder
show decreased or absent expression of presenting as multifocal disease {919).
Etiology HLA class I and II proteins, allowing the The leptomeninges may be involved, but
In immunocompetent individuals, the eti- tumour cells to further escape from im- exclusive meningeal manifestation is unu-
olog ical factors are unknown. Viruses, in- mune attack {415,3355). sual. Approximately 20% of patients pre-
cluding EBV, HHV6 {3114), HHV8 {2708), sent with or develop intraocular lesions,
and the polyomaviruses SV40 and Localization and 80 - 90% of patients with intraocular
BK virus {2705,2795), do not play a role. About 60% of CNS DLBCLs involve the DLBCL develop contralateral tumours
Pathogenically, expression or absence of
' . . .. ·. ~ • . . . - ·+l! -
chemokines and chemokine receptors or , ... ; ...... ... • ....... ..,. : •• -~.. 'CW ;··. ·•••• .. • . •
cytokines may contribute to the specific
localization {3706). Tumour cells and en-
t • • "~
•: •.
,/
.. it': ! :
• • ~. ••
:- . .• .. .:. . .
.. •·
·\·
. ;._ :. ' ....--. ....!' ·: •
~·
...
'l • J
... . . .
• ~~ .,
.
....
, ""•JI' • • • • • . .. • .. . .... :.
dothelial cells may interact via activation • •, •• • .,, • > , !.~ . ~,. •.~. . . • ~, .
of IL4 to create a favourable microenvi- .; .. . : .. • •.or .. . • . • . . ~ • ..~.
~
·.•• ......'111.. . ·~•..~ • "'~• ·"*• '\·. •. ~• •.··.!. ..: ~ (...... ..'
• • • J. • •• .. ..;. •
·B - ·..
..
• ... ....
....,•-• .. •• • ...·r.:··
•
~ • ·: •
~·
. • -:; •
·...•. . :·
l
• : .•>
•. ·t·. • ~ '
,, .
,. 4'
•
... . .
• '111._
. •
• .:-..
• ' • • • •
• • ,;t.
.. •
i
receptor signalling. This interaction be- Fig.13.111 Primary diffuse large B-cell lymphoma of the CNS. A Histology of a case with very scarce lymphoma
tween CNS antigens and the lymphoma cells (arrows). B CD20 immunohistochemistry highlights the neoplastic cells.
and parenchymal CNS lesions. Dissemi- mours may diffusely infiltrate large areas tant to withhold corticosteroids before bi-
nation to extraneural sites, in clu ding the of the hem ispheres without forming a dis- opsy, because they in duce rapid tumour
bone marrow, is very rare; in these cases, tinct mass. Meningeal involvement may shrinkage. Corticosteroids have been
preferential spread to the testis has been resemble meningitis or meningioma, but shown to prevent diagnosis in as many
noted {416,1552,1828,3289). can also be grossly in conspicuous. as 50% of patients {485).
BLNK
CARD11 ..
activation
NF·KB
activation
mour cells is in part due to miscarried HSP90a .. NF·teB
MyD88
IG class-switch rearrangements during /GH, IGL, ... activation
which the S-mu region is deleted {2713). PRDM1 . .Block of B cell
PRDM1 mutations also contribute to im- differentiation
paired IG class-switch recombination
{825). Fig.13.113 Pathogenesis of primary diffuse large B-cell lymphoma of the CNS (PCNSL). ASHM, aberrant somatic
Translocations recurrently affect the IG hypermutation; BCR, B-cell receptor; CSR, class-switch recombination; SHM, somatic hypermutation.
genes (in 38% of cases) and BCL6 (in
17-47%), whereas MYC translocations es), INPP50 (also called SHIP; in 25%), suiting in severe cognitive, motor, and
are rare and BCL2 translocations are CBL (in 4%), BLNK (in 4%), CARD11 (in autonomic dysfunction, particularly in el-
absent {478,519,2716). FISH and ge- 16%), MALT1 (in 43%), and BCL2 (in derly patients {14). Most protocols report
nome-wide SNP analyses have revealed 43%), which may foster proliferation and a median progression-free survival of
recurrent gains of genetic material most prevent apoptosis {665,1403,2097,2707, about 12 months and an overall survival
freq uently affecting 18q21.33-23 (in 43% 2712,2714,3595). of approximately 3 years . In a subgroup
of cases), including the BCL2 and MALT1 Epigenetic changes may also contribute of elderly patients with methylated MGM T
genes; chromosome 12 (in 26%); and to CNS DLBCL pathogenesis, including within the lymphoma cells, temozolomide
10q23.21 (in 21%) {3595). gene silencing by DNA methylation. Hy- monotherapy appeared to be therapeuti-
Loss of genetic material most frequently permethylation of DAPK1 (seen in 84% cally effective {2144).
involves 6q21 (in 52% of cases), 6p21 (in of cases), CDKN2A (in 75%), MGMT (in On biopsy, the presence of reactive
37%), 8q1 2.1-1 2.2 (in 32%), and 10q23. 21 52%), and RFC (in 30%) may be of poten- perivascular CD3+ T-cell infi ltrates has
{3595). Heterozygous deletions, homozy- tial therapeutic relevance {753,774, 11 94, been associated with improved survival
gous loss, or copy-neutral LOH of chro- 3595). (3213}. LM02 protein expression by the
mosomal region 6p21 .32 affects 73% of tumour cells has been associated with
CNS DLBCLs; the 6p21 reg ion harbours Prognosis and predictive factors prolonged overall survival {2394). BCL6
the MHC class II encod ing genes HLA- Patients with CNS DLBCL have a remark- expression has been suggested as a
DRB, HLA-DOA, and HLA-008 {1883, ably worse outcome than do patients prognostic marker, although conflicting
3355,3595). Approximately 50% of CNS with systemic DLBCL. Older patient age favourable versus unfavourable conclu-
DLBCLs have lost expression of HLA (> 65 years) is a major negative prognos- sions have been reported {2694, 3237,
class I and II gene products {415,3356). tic factor and is associated with reduced 3308,3727} Del(6)(q22) has been asso-
The MYOBB L265P mutation is highly re- survival as well as an increased risk of ciated with inferior overall survival {519,
current: present in more of half of the cas- neurotoxicity related to therapy {14,2084). 1403}.
es {2707). Other pathways involving the High-dose methotrexate-based poly- With improvement of outcome, some
B-cell receptor, the toll-like receptor, and chemotherapy is currently the treatment sporadic systemic relapses have been
the NF-kappaB pathway are frequently of choice {2084}. The inclusion of whole- observed; these can involve any organ,
activated due to genetic alterations af- brain irradiation may improve outcome, but relatively frequently involve the testis
fecting the genes CD79B (in 20% of cas- but carries the risk of neurotoxicity re- and breast {1 828).
Fig.13.115 Primary cutaneous diffuse large B-cell lymphoma, leg type. A Note the large transformed cells with prominent nucleoli. B Strong cytoplasmic staining for lgM.
Fig.13.116 Primary cutaneous diffuse large B-cell lymphoma, leg type. A Strong cytoplasmic staining for BCL2. B Neoplastic cells show nuclear staining for BCL6. C Neoplastic
cells show nuclear staining for IRF4/MUM1.
cases), C0798 (in 20%), and TNFAIP3 type, may be considered a cutaneous come for patients when rituximab is add-
(encoding TNFAIP3, also called A20; counterpart of activated B-cell subtype ed to a multiagent chemotherapy (CHOP
in 40%), strongly suggest constitutive diffuse large B-cell lymphoma {3165}. or CHOP-like) regimen {1 423,1530} Multi-
NF-kappaB activation in PCLBCL, leg ple skin lesions at diagnosis, inactivation
type {2067,3163,3165}. The similarities Prognosis and predictive factors of CDKN2A , and MYDBB L265P mutation
in gene expression profi le and cytoge- Earlier studies reported a 5-year survival have been reported to be associated
netic alterations, including transloca- rate of approximately 50% {1 421 ,1422, with an inferior prognosis {986,1421 ,1422,
tions and NF-kappaB activating muta- 4189}. However, recent studies have re- 3162,3623,3625}.
tions, underscore that PCLBCL, leg ported a significantly better clinical out-
Definition exclusion of the more specific types of {325, 1017,1367,1674, 2405 , 2701, 2956,
EBV-positive diffuse large B-cell lympho- EBV-positive lymphoma. Although many 2957,3018,3019,3063}. Most cases oc-
ma (DLBCL), NOS, is an EBV-positive cases have a distinctive histological ap- cur in patients over age 50, with a peak
clonal B-cell lymphoid proliferation {780, pearance, routine EBV testing is required in the eighth decade {3661 }. However,
1017, 2701,2867,2957,3018,3019,3063, for all cases to be identified. The clinical cases also occur in younger patients
3661}. Excluded from this category are outcome is variable {1 65,1017,1018,2867, sporadically, with a second smaller peak
cases of lymphomatoid granulomatosis, 3018,3019}. in the third decade {2867}. EBV-positive
cases with evidence of acute or recent DLBCL is more common in males, with
EBV infection, other well-defined lympho- ICD-0 code 9680/3 a male-to-female ratio of 1.2-3.6:1 {1017,
mas that may be EBV-positive (such as 1675,2867,3018,3019,3661}.
plasmablastic lymphoma and DLBCL as- Synonyms
sociated with chronic inflammation), and EBV-positive diffuse large B-cell lympho- Etiology
EBV-positive mucocutaneous ulcer (lo- ma of the elderly; senile EBV-associated The increased incidence of EBV-positive
calized EBV-driven proliferations affect- B-cell lymphoproliferative disorder; age- DLBCL in older patients is believed to
ing cutaneous or mucosal sites). related EBV-positive lymphoproliferative be related to immunosenescence {1017,
This disease was formerly designated as disorder 2746,3018,3019} Alterations in the im-
EBV-positive DLBCL of the elderly, but mune microenvironment may play a role
the restriction to elderly patients has been Epidemiology at any patient age {668,2867).
removed; although the disease usually EBV-positive DLBCL accounts for
occurs in individuals aged > 50 years, it <5 -15% of DLBCLs among Asian Localization
can present over a wide age range {326, and Latin American patients and < 5% Nodal or extranodal sites can be involved.
781,1675,2867,3661 }. The NOS designa- among western patients, with no docu- The most common extranodal sites are
tion has been added to emphasize the mented predisposing immunodeficiency the lungs and gastrointestinal tract {1017,
Clinical features
The clinical features at presentation are
variable {1017,1663,2867,3018,3019).
More than half of the patients have a high
or high-intermediate International Prog-
nostic Index (IPI) score. Most patients
have detectable EBV DNA in serum or
whole blood, but this can also be seen
in patients with EBV-negative DLBCL
{2316,2961}.
Microscopy
The histological features overlap w ith
those of other EBV-related lymphoid pro-
liferations, including EBV-positive c lass ic
Hodgkin lymphoma. The neoplastic com-
ponent most often consists of a variable
number of large transformed cells/immu-
noblasts and Hodgkin/Reed-Sternberg- . ,,,.
~ ()
like cells. There is a variable component Fig.13.117 EBV-positive diffuse large B-cell lymphoma. A This polymorphic lesion shows geographical
of reactive elements, including small necrosis. BThere is a mixed proliferation of immunoblasts and medium-sized lymphoid cells, as well as small reactive
lymphocytes, plasma cells, histiocytes, lymphocytes. C Monotonous proliferation of immunoblast-like or Hodgkin/Reed-Sternberg-like cells with prominent
and epithelioid cells. The rich back- central nucleoli.
ground of small lymphocytes and histio-
cytes may resemble T-cell/histiocyte-rich for the pan-B-cell antigens CD19, CD20, tumour cells often express POL1 and
large B-cell lymphoma, also referred to CD22, CD79a, and PAX5, and have an PDL2, providing a mechanism for im-
as the polymorphic pattern in some stud- activated-B-cell immunophenotype, be- mune escape {668,2867,4431).
ies {2867,4087). This is the most common ing positive for IRF4/MUM1 and nega- In situ hybridization for EBV-encoded
pattern in young patients. Other cases tive for CD10 and commonly BCL6 {1017, small RNA (EBER) is mandatory for the
are more monomorphic, and may be dif- 2867,3018,3019}. CD30 is frequently diagnosis of EBV-positive DLBCL, NOS.
ficult to distinguish from EBV-negative positive and CD15 is sometimes coex- With EBER in situ hybridization, more
DLBCL without ancillary studies {165, pressed, but other phenotypic features than 80% of the atypical cells are posi-
780,1017,1018,2701,3018,3019). Large typical of classic Hodgkin lymphoma tive. Small numbers of EBER -positive
areas of geographical necrosis and an- are usually lacking {668,1017,2867). cells may be present as bystander B-
gioinvasion are other characteristic find- Light chain restriction may be difficult to cells in EBV-negative B-cell or T-cell lym -
ings, but they are not always present demonstrate. EBNA2 and LMP1 are ex- phomas {2867,2960,3821}.
pressed in 7-36% and > 90% of cases,
lmmunophenotype respectively, indicating type Ill and (more Postulated normal counterpart
The neoplastic cells are usually positive often) type II EBV latency {2867). The A mature B cell, transformed by EBV
...
Fig.13.118 EBV-positive diffuse large B-cell lymphoma with a T-cell/histiocyte-rich large B-cell lymphoma-like pattern. A Scattered large tumour cells are observed in a
lymphohistiocytic microenvironment. B Scattered large tumour cells are positive for CD20. C In situ hybridization for EBV-encoded small RNA (EBER) highlights scattered
tumour cells.
EBV-positive diffuse large B-cell lymphoma, not otherwise specified (NOS) 305
Fig.13.121 EBV-positive mucocutaneous ulcer in the palate. A The squamous epithelium is ulcerated, with an underlying atypical lymphoid infiltrate. The lesion is circumscribed
at the base, with underlying reactive lymphocytes. B In situ hybridization for EBV-encoded small RNA (EBER) reveals scattered EBV-positive cells superficially, with reactive
lymphocytes at the base. C The atypical lymphoid cells are large, with prominent basophilic nucleoli. Admixed lymphocytes and histiocytes are abundant.
lmmunophenotype
The large transformed immunoblasts and
Hodgkin/Reed- Sternberg-like cells are
B cells that in most cases have CD20
expression ranging from strong to weak
and heterogeneous. These cells are
positive for PAX5 and OCT2, with vari-
able expression of BOB 1. They have an Fig. 13.122 EBV-positive mucocutaneous ulcer in the intestine, post-transplant. A This case is associated with iatro-
activated-B-cell phenotype, being nega- genic immunosuppression. Note the sharply circumscribed base. B The EBV-positive cells are strongly positive for
CD30. C Numerous CD3+ T cells are admixed with the EBV-positive cells. D The atypical cells are strongly positive
tive for CD10 and BCL6 and positive for
for CD20.
IRF4/MUM1, and are CD30-positive.
CD15 is expressed in about half of the
cases. CD79a is often positive. EBV is Postulated normal counterpart immunosuppressive therapy. In patients
consistently positive, with transformed An EBV-transformed post-germinal cen- in whom immunosuppression cannot
cells commonly positive for LMP1. Posi- tre B cell be reversed, responses to rituximab, lo-
tivity for EBV-encoded small RNA (EBER) cal radiation , and chemotherapy have
parallels expression of most B-cell anti- Genetic profile been observed. Spread to distant sites is
gens, and is found in a rang e of cell sizes, Fewer than half of all EBVMCUs show rare, but local progression may be seen.
from small lymphocytes to immunoblasts clonal IG gene rearrangements. Studies The outcome is superior to that to other
and cells with Hodgkin/Reed-Sternberg of TR gene rearrangement often reveal immunodeficiency-associated EBV-driv-
cell morphology. The background con- an oligoclonal or restricted pattern by en lymphoproliferative disorders (1017,
sists mainly of T cells, with numerous PCR (971 ,1017,1018}. 1565,2597,3852,4408}. However, rare
CDS+ T cells. A dense rim of CD3+ lym- cases of relapses or progression to more
phocytes is present between the lesion Prognosis and predictive factors widespread disease (2721} have been
and adjacent soft tissue. Case reports and series suggest a be- reported.
nign natural history, with nearly al l re-
ported cases respond ing to reduction of
Definition
Diffuse large B-cell lymphoma (DLBCL)
associated with chronic inflammation is a
lymphoid neoplasm occurring in the set-
ting of longstanding chronic infl ammation
and showing association with EBV. Most
cases involve body cavities or narrow
spaces. Pyothorax-associated lympho-
ma (PAL) is the prototypical form, devel-
oping in the pleural cavity of patients with
longstanding pyothorax.
Chronic Development
pyothorax of lymphoma
ICD-0 code 9680/3 (latent)
Etiology
Artifi cial pneumothorax, used in the past
as a form of surgical therapy for pulmo-
nary tuberculosis, is the only significant
risk factor for development of PAL among
patients with chronic pyothorax {120,
1679). PAL is strongly assoc iated with
EBV, with expression of EBNA2 and/or A
LMP1 together with EBNA1 (i.e. usually Fig.13.124 Pyothorax-associated lymphoma. A,B Massive tumour proliferation surrounding the entire lung.
D L711
Microscopy DL817
DL617
present.
lmmunophenotype
Fig.13.125 The patterns of gene expression in pyothorax-associated lymphoma (PAL) and nodal diffuse large B-cell
Most cases express CD20 and CD79a.
lymphoma (DL) are significantly different. Modified from Nishiu M et al. (2882).
However, a proportion of cases may show
plasmacytic differentiation, with loss of
CD20 and/or CD79a, and expression of Genetic profile differentially expressed genes is IF/27,
IRF4/MUM1 and CD138. The lymphoma IG genes are clonally rearranged and hy- which is known to be induced in B lym-
has an activated B-cell phenotype. CD30 permutated, but lack ongoing mutations phocytes by stimulation of interferon al-
can be expressed. Occasional cases {2680,3875). TP53 mutations are found pha, consistent with the role of chronic
also express one or more T-cell markers in about 70% of cases, usually involving inflammation in this condition. Downreg-
(CD2, CD3, CD4, and/or CD?), causing dipyrimidine sites, which are known to ulation of HLA class I expression, which
problems in lineage assignment {2734, be susceptible to mutagenesis induced is essential for efficient induction of host
2818,3150,4022}. by ionizing rad iation {1 679). MYC gene cytotoxic T lymphocytes, and mutations
In situ hybridization for EBV-encoded amplification is common {4412}, and of cytotoxic T-lymphocyte epitopes in
small RNA (EBER) shows positive la- TNFAIP3 (also called A20) is deleted in EBNA3B, an immunodominant antigen
belling of the lymphoma cells. Type Ill a proportion of cases {100}. Cytogenetic for cytotoxic T-lymphocyte responses,
EBV latency (i.e. positivity for LMP1 and studies show complex karyotypes with might also contribute to escape of PAL
EBNA2) is characteristic {1 263,3150). numerous numerical and structural ab- cells from host cytotoxic T lymphocytes
normalities {3874). The gene expression {1926,1927).
Postulated normal counterpart profile of PAL is distinct from that of nodal
An EBV-transformed post-germinal DLBCL, which may be attributable to the
centre B cell presence of EBV {2882). One of the most
\l
Fig.13.126 Pyothorax-associated lymphoma. A Diffuse infiltrate of large lymphoid cells with distinct nucleoli and ample cytoplasm. B Tumour cells uniformly express CD20.
C In situ hybridization for EBV-encoded small RNA (EBER) reveals positive signals for EBV in the nucleus of tumour cells.
Epidemiology Macroscopy
LYG is a rare condition . It usually presents LYG most commonly presents as pu lmo-
in adulthood, but may be seen in chil- nary nodules that vary in size. The lesions
dren with immunodeficiency disorders. are most often bilateral in distribution, in-
It affects males more often than females, volving the mid- and lower lung fields.
with a male-to-female ratio of ;::>:2:1 {1965, Larger nodules frequently exhibit central
3726). It appears to be more common in necrosis and may cavitate. Nodular le-
western countries than in Asia. sions are found in the kidneys and brain,
usually associated with central necrosis A
Etiology {1966,3726). Skin lesions are extremely
LYG is an EBV-driven lymphoprolifera- diverse in appearance. Nodular lesions
tive disorder. Individuals with underlying are found in the subcutaneous tissue.
immunodeficiency are at increased risk Dermal involvement may also be seen,
{1490,1544). Predisposing cond itions in- sometimes with necrosis and ulceration.
clude allogeneic organ transplantation, Cutaneous plaques or a maculopapular
Wiskott- Aldrich syndrome (eczema- rash are less common cutaneous mani-
thrombocytopenia- immunodefic iency festations {309,1823,1 965,2604).
syndrome), HIV infection, and X-linked
lymphoproliferative syndrome. Patients Microscopy
presenting without evidence of under- LYG is characterized by an angiocen-
Fig.13.129 Lymphomatoid granulomatosis.
lying immunodeficiency usually manifest tric and angiodestructive polymorphous
A Involved lung. Large nodules show central cavita-
reduced immune function on careful clini- lymphoid infiltrate {1965 ,1966,2087, tion. B Large necrotic nodules are also found in the
cal or laboratory analysis {3733,4332}. 3726). Lymphocytes predominate and kidney.
are admixed with plasma cells, immu-
Localization noblasts, and histiocytes. Neutrophils background {1490,1966,1967). The EBV-
Pulmonary involvement occurs in > 90% and eosinophils are usually inconspicu- positive cells usually show some atypia.
of patients and is usually present at ini- ous. The background small lymphocytes They may resemble immunoblasts or less
tial diagnosis. Other common sites of may show some atypia or irregularity, but commonly have a more pleomorph ic ap-
involvement include the brain, kidneys, do not appear overtly neoplastic. LYG pearance reminiscent of Hodgkin cells.
liver, and skin. Involvement of the upper is composed of a variable but usual- Multinucleated forms may be seen. Clas-
respiratory tract or gastrointestinal tract ly small number of EBV-positive B cel ls sic Reed- Sternberg cells are generally
is relatively uncommon {841,1966,3726}. admixed with a prominent inflammatory not present; if seen, they shou ld raise the
Grading
The grading of LYG relates to the propor-
tion of EBV-positive B cells relative to th e
reactive lymphocyte background (1491,
1966,2357,3726}. It is most important to
distinguish grade 3 from grade 1 or 2. A
uniform population of larg e atypical EBV-
positive B cells without a polymorphous
background should be classified as EBV-
positive, diffuse large B-ce ll lymphoma,
NOS and is beyond the spectrum of LYG
as currently defined .
Grade 1 lesions contain a polymorphous
lymphoid infiltrate without cytological
atypia. Large transformed lymphoid
Fig.13.131 Lymphomatoid granulomatosis. A Grade 1 lesion of the lung shows a polymorphous infiltrate in the
cells are absent or rare, and are better vascular wall. B Grade 3 lesion of the brain contains numerous large transformed lymphoid cells. C Grade 3 lesion.
appreciated by immunohistochemistry. The cells are positive for EBV by in situ hybridization for EBV-encoded small RNA (EBER). D Large pleomorphic cells
When present, necrosis is usually focal. may be seen, most commonly in grade 3 lesions and rarely in grade 2 lesions.
Genetic profile
Antigen receptor genes
lmmunoglobulin genes are rearranged
and may be class switched, with a high
load of somatic hypermutations without
ongoing mutation activity {2262).
lmmunophenotype
PMBL expresses B-cell-lineage antigens
such as CD19, CD20, CD22, and CD79a,
but commonly lacks immunog lobu lin de-
spite a functional IG gene rearrangement
and expression of the transcription fac-
tors PAX5, BOB1, OCT2, and PU1 {1915,
2379,3179,4274}. Flow cytometric stud ies
may demonstrate surface IG in a sub-
set of cases {4274). CD30 is present in
> 80% of cases; however, staining is usu-
ally weak and heterogeneous compared
to that in CHL {1633,3179). CD15 may be
expressed in a minority of cases {2800}.
EBV is almost always absent {589}. The
neoplastic cells are frequently positive
for IRF4/MUM1; present in 75% of cases,
Cytogenetic abnormalities and The genomic profile also typically con- mechanism {2763}, with BCL6 mutations
oncogenes tains gains in chromosome 2p16.1 (seen detected in about half of the cases {2477).
Rearrangements of BCL2, BCL6, and in -50% of cases), where candidate The landscape also includes truncating
MYC are absent or rare {3548,4067). Re- genes REL and BCL11A are amplified in a immunity pathway, ITPKB, MFHAS1, and
arrangements or mutations in the class II proportion of cases, leading to a frequent, XP01 mutations {1049).
major histocompatibility complex (MHC) albeit inconsistent, nuclear accumula-
transactivator Cl/TA at 16p13.13 have been tion of their proteins {3384,4296,4297). Genetic susceptibility
reported in as many as 53% of PMBLs, Gains involving chromosomes Xp11 .4-21, Exome sequencing of a family with three
resulting in downregulated MHC class II Xq24-26, 7q22, 12q31, and 9q34 {344) siblings with PMBL suggested KMT2A
molecules, creating an immune-privileged are also seen in approximately one third (previously called MLL) as a cand idate
phenotype in PMBL. Translocations involv- of PMBLs. PMBL has a constitutively predisposition gene, but these findings
ing Cl/TA occur with CD274 (also called activated NF-kappaB pathway {1208}, warrant replication {3465).
POC01LG1 or POU) and POC01LG2(also which might be due to deleterious muta-
called POL2); CD274 and PDCD1LG2 are tions in the TNFA IP3 gene, present in as Prognosis and predictive factors
also reported to fuse with partners other many as 60% of PMBLs {1049,3572A}. Variations in microscopic appearance do
than Cl/TA in some cases {2763,3779, These tumours also have a constitutively not predict differences in survival {31 12).
4081). Together with gains and amplifica- activated JAK/STAT signalling pathway, PMBL should be distinguished from B-
tions at chromosome 9p24.1 , including the also found in CH L, that seems to be fre- cell lymphoma, unclassifiable, with fea-
JAK2/POCD1LG2/POCD1LG1 locus (in as quently related to inactivating mutations tures intermediate between DLBCL and
many as 75% of cases) {344,1881,2624, of SOCS1 {2624,3777,4073,4297). Muta- CH L, which is more aggressive {4047).
4300}, these aberrations in the POL locus tions affecting the STAT6 DNA-bind ing Response to intensive chemotherapy,
likely explain the common overexpression domain and in PTPN1, a negative regula- with or without radiotherapy, is usually
of PDL1 and PDL2 in PMBL {668,3645). tor of JAK/STAT signalling, are also com- good. PMBL is associated with a more
This profile, with Cl/TA alterations and also mon, found in in as many as 72% and favourable survival than are the germinal
copy-number gains and high-level amplifi- 25% of PMBLs, respectively, but are al- centre B-cell and activated B-cell sub-
cation of the POL locus (in 29-70% of cas- most absent in DLBCL {1 049,1495,2280, types of DLBCL, and recently developed
es), occurs almost exclusively in PMBL; it 2504,3363). The genetic landscape of chemotherapy protocols have shown
is unique among the LBCLs but shows PMBL suggests activation-induced cy- high cure rates in adults and children
similarities to what is found in CH L {1436, tid ine deaminase- med iated aberrant {1058,2667,3412,4346). Extension into
3779,4081). somatic hypermutation as the mutational adjacent thoracic viscera, pleural or peri-
cardia! effusion, and poor performance
status are associated with inferior out-
come {115,589,2233,2234,3535,3538}.
FOG-PET predicts survival after chemo-
immunotherapy {605,2514)
Definition
lntravascular large B-cell lymphoma is a
rare type of extranodal large B-cell lym-
phoma characterized by the selective
growth of lymphoma cells with in the lu-
mina of vessels, in particu lar capil laries,
and with the exception of larger arteries
and veins.
Synonyms
Malignant angioendotheliomatosis;
angioendotheliomatosis proliferans
syndrome; intravascular lymphomatosis;
angioendotheliotropic lymphoma
(all obsolete) Fig. 13.137 Neurolymphomatosis as the relapse of intravascular large B-cell lymphoma. A FOG-PET/CT studies
demonstrate hyperintense FOG uptake in the left lumbar plexus (white arrows), representing lymphoma invasion
of the sciatic nerve. B A thin-sliced coronal image from gadolinium-enhanced T1-weighted MRI of the lumbosacral
Epidemiology plexus also reveals the enhanced and enlarged left sciatic nerve (yellow arrows). Reprinted with permission from:
This tumour occurs in adults, with a medi- Matsue K, Haya ma BY, lwama K, et al. {2570}
an age of 67 years (range: 13-85 years)
and a male-to-female ratio of 1.1:1. The in western females; it is characterized by Microscopy
frequency and clinical presentation differ restriction of the tumour to the skin and is The neoplastic lymphoid cells are mainly
according to patients' geographical ori- associated with a better prognosis {1193, lodged in the lumina of small or interme-
gin (West vs Far East) {1196,2789,3214, 3214}. Conventional staging procedures diate sized vessels in many organs. Fi-
3215,3655). are generally associated with a high pro- brin thrombi, haemorrhage, and necrosis
portion of false negatives due to the lack may be observed in some cases. The tu-
Localization of detectable tumour masses. A random mour ce ll s are large, with prominent nu-
This lymphoma is usually widely dissemi- skin biopsy of normal-appearing skin and cleo li and frequent mitotic figures . Rare
nated in extranodal sites, including the transbronchial lung biopsy are often help- cases have cells with anaplastic features
bone marrow, and may present in virtual- ful to make the diagnosis. Tumour cells or smaller size {3215}. Minimal extravas-
ly any organ. However, the lymph nodes are often seen in subcutaneous tissue cular location of neoplastic cells may
are usually spared. irrespective of the absence of skin erup- be seen. In the CNS, recurrences may
tion, even in the haemophagocytic syn- be associated with extravascular brain
Clinical features drome- associated form {2569}. masses {1642,3657) Sinusoidal involve-
Two major patterns of clinical presenta- ment occurs in the liver, spleen, and bone
tion have been recognized: a so-called marrow. Malignant cells are occasionally
classic form (mostly present in western detected in peripheral blood {3215).
countries) characterized by symptoms re-
lated to the main organ involved, predom- lmmunophenotype
inantly neurological or cutaneous, and a Tumour ce ll s express mature B-cell-
haemophagocytic syndrome-associated associated antigens. CD5 and CD10
form, originally documented as an Asian coexpression is seen in 38% and 13%
variant, in which patients present with of the cases, respectively. Almost all
multi organ failure, hepatosplenomegaly, CD10-negati ve cases are pos itive for
and pancytopenia {1196,2789,3214,3215, IRF4/MUM1. An increasing number of
3655). Exceptions to these geographical intravascular NK/T-cell lymphomas with
distributions may occur. B symptoms, in EBV-positive tumour cells {1317,4241)
particu lar fever, are very common, occur- and rarely intralymphatic anaplastic large
ring in 55-76% of patients, in both types cell lymphomas, ALK-negative {2644,
of presentation. An isolated cutaneous Fig.13.138 lntravascular large B-cell lymphoma. 3871}, have been reported, but they
variant has also been identified, invariably Skin involvement. should be considered different entities.
The intravascular growth pattern has been studied to demonstrate recurrent rate of 60-81% (1195,1197,3655,3656).
been hypothesized to be secondary to a abnormalities {3655 ,3656). However, CNS relapse, which occurs in
defect in homing receptors on the neo- -25% of cases {3657} and neurolympho-
plastic cells {1204}, such as the lack of Prognosis and predictive factors matosis {2570} are serious complications
CD29 (integrin beta-1) and CD54 (ICAM1) lntravascular large B-cell lymphoma is in the rituximab era. Neither the clinical
adhesion beta-molecules {3212). generally aggressive, except for the cas- type of presentation nor clinical parame-
es with disease limited to the skin {3655}. ters predict CNS relapse.
Postulated normal counterpart The poor prognosis is due in part to the
A transformed peripheral B cell delay of timely and accurate diagnosis
related to the protean presentation of
Genetic profile this lymphoma. Chemotherapeutic regi-
lmmunoglobulin genes are clonally re- mens with rituximab have significantly
arranged . Karyotypic abnormalities have improved the clinical outcomes of these
been described, but too few cases have patients, with a 3-year overall survival
" .'f\"'"'"VO
~ .. ~ ...
- - ' ..
..
,,. ...t.....
7
Definition 1307). Atypical multinucleated neoplastic acteristically strong ly express EMA and
ALK-positive large B-cell lymphoma giant cells may be seen. plasma cell markers such as CD138,
(LBCL) is an aggressive neoplasm of VS38, PRDM1 (also known as BLIMP1),
ALK-positive monomorphic large immu- lmmunophenotype and XBP 1, and are negative or only
noblast-like B ce ll s, wh ich usually have a Lymphoma cells are strongly positive for pos itive in occasional ce ll s for B-cell line-
plasma cell phenotype. the ALK prote in, with most demonstrat- age-assoc iated antigens (CD20, CD79a,
ing a restricted granular cytoplasmic and PAX5). IRF4/MUM1 is also positive
ICD-0 code 9737/3 staining pattern highly indicative of the {951,3763,4111}. CD45 is weak or nega-
express ion of the CLTC-ALK fusion pro- tive {951,1307,2230}. CD30 is negative
Synonyms te in. Few cases show cytoplasmic, nu- {951}, although focal and weak staining
Large B-cell lymphoma expressing the clear, and nucleolar ALK staining associ- has been reported in a few cases {3763}.
ALK kinase and lacking the t(2;5) translo- ated with the NPM1-ALK fusion protein. Most tumours express cytoplasm ic im-
cation; ALK-positive plasmablastic B-cell ALK translocations with other partners munoglobulin (usually lgA, more rarely
lymphoma (both obsolete) may be associated with a cytoplasmic lgG) with light chain restriction {951 }. As
staining pattern. The tumours also char- described in some plasma cell tumours,
Epidemiology
Th is lymphoma is very rare, accountin g
for< 1% of diffuse LBCLs. It seems to oc-
cur more frequently in young men, with a
male-to-female ratio of 5:1, but spans all
age groups, with a patient age range of
9-85 years (median: 43 years). One third
of cases occur in the paed iatric age
group {2230,3333}. There is no associa-
tion with immunosuppression.
Localization
The tumour mainly invo lves lymph nodes
{22,951,1307,1790,3333,3763} or pre-
sents as a mediastinal mass {907,1348}.
Extranodal involvement has also been re-
ported, at sites such as the nasopharynx
{2976}, tongue {907}, stomach {2601},
bone {2976}, soft tissue {713}, liver,
spleen, and skin {2230}.
Clinical features
Most patients present with generalized
lymphadenopathy, and 60% present in
advanced stage Ill/IV. Bone marrow is
infiltrated in 25% of cases {2230}.
Microscopy
The lymph nodes show a marked dif-
fuse infiltrate, frequently with a sinusoidal
growth pattern. The infiltrate is composed
of monomorphic large immunoblast-like
cells with round pale nuclei containing
a large central nucleolus and abundant
amphophilic cytoplasm. Some cases
show plasmab lastic differentiation {951, Fig.13.141 ALK-positive large B-cell lymphoma. A,B Neoplastic cel ls show immunoblastic and plasmablasticfeatures.
Genetic profile Fig.13.142 ALK-positive large B-cell lymphoma. Tumour cells are positive for A EMA with a cytoplasmic membra-
The IG genes are clonally rearranged nous pattern, B for lgA, and (C for ALK with a restricted granular cytoplasmic pattern, highly indicative of the expres-
{713,1307). The key oncogenic factor of sion of the CLTC-ALK fusion protein.
this tumour is ALK overexpression due
to the fusion protein generated by the locations are typically detected in the con- Prognosis and predictive factors
translocation of the ALK locus on chro- text of complex karyotypes {713,907,1307, In one study, the reported median overall
mosome 2. The most frequent abnormal- 1348, 1790,2230, 2601,3333,3763,4111 }. survival of patients with stage Ill/IV dis-
ity is t(2;17)(p23;q23), responsible for a ALK protein oncogen ic mechanisms in- ease was 11 months {3333). Longer sur-
CLTC-ALK fusion protein. Few cases clude activation of the STAT3 pathway; vival(> 156 months) has been reported in
are associated with the t(2;5)(p23;q35) concordantly, ALK-positive LBCLs ex- children {951,2976). These tumours are
translocation, as described in ALK-pos- press high phospho-STAT3 {4111 }. MYC usually negative for CD20 antigen, and
itive anaplastic large cell lymphoma {22, is also expressed in the absence of MYC are thus unlikely to be sensitive to rituxi-
2976). A cryptic insertion of three ALK translocations or amplifications, prob- mab. Patients presenting with localized
gene sequences into chromosome 4q22- ably due to transcriptional activation disease (stage 1-11) have been found to
24 has also been reported. ALK may also downstream of STAT3 {4111}. Oncogenic have significantly longer survival {2230).
be fused to SQSTM1, SEC31A, or other Alk activation in murine B cells gener-
uncommon fusion partners. These trans- ates plasmablastic B-cell tumours {709}.
Definition PBL also occurs in children with immu- (IPI) score. CT and PET show disseminat-
Plasmablastic lymphoma (PBL) is a very nodeficiency, mainly due to HIV infection ed bone invo lvement in 30% of patients
aggressive lymphoma with a diffuse pro- {417,578,785,936,2365). (3942). A paraprotein may be detected
liferation of large neoplastic cells, most in some cases {3865). Tumours with fea-
of which resemble B immunoblasts or Etiology tures of PBL may occur in patients with
plasmab lasts, that have a CD20-nega- Immunodeficiency, due to various caus- prior plasma cell neoplasms, including
tive plasmacytic phenotype. It was origi- es, predisposes individuals to the de- plasma cell myeloma. Such cases should
nal ly described in the oral cavity and velopment of PBL. The tumour cells are be considered plasmab lastic transforma-
frequently occurs in association with HIV EBV-infected in most patients (417,785, tion of myeloma and distinguished from
infection, but it may also occur in other 936,1023} primary PBL.
sites, predominantly extranodal, and in
association with other causes of immu- Localization Microscopy
nodeficiency (785,936}. Some cases, PBL most frequently presents as a mass PBLs show a morphological spectrum
particularly in the oral cavity (i.e. the oral in extranodal regions of the head and varying from a diffuse and cohesive pro-
mucosa type), look most like a diffuse neck, in particular the oral cavity, with the liferation of cells resembling immunob-
large B-cell lymphoma (LBCL); other gastrointestinal tract being the next most lasts to ce lls with more obvious plasma-
cases have morphologically recogn iz- common site. Other extranodal localiza- cytic differentiation, which may resemble
able plasmacytic differentiation. Other tions reported in > 1% of cases include cases of plasmablastic plasma cell
subtypes of LBCLs with a plasmablas- the skin, bone, genitourinary tract, nasal myeloma. Mitotic figures are frequent.
tic immunophenotype (e.g. ALK-positive cavity and paranasal sinuses, CNS, liver, Apoptotic cells and tingible body mac-
LBCL and HHV8-associated lymphopro- lungs, and orbits. Nodal involvement is rophages may be present. Cases with
liferative disorders) are not included in found in < 10% of cases overal l, but in monomorphic plasmablastic cytology
this category. 30% of post-transplant cases (578,785, are most commonly seen in the setting
936,1023} of HIV infection and in the oral, nasal,
ICD-0 code 9735/3 and paranasal sinus areas (i.e the oral
Clinical features mucosa! type). Conversely, cases with
Epidemiology Disseminated stage Ill/IV disease, includ- plasmacytic differentiation tend to occur
This lymphoma occurs predominantly ing bone marrow involvement, is found more commonly in other extranodal sites,
in adults with immunodeficiency, most at presentation in 75% of HIV-positive as well as in lymph nodes (785,936}.
commonly due to HIV infection but also patients and 50% of post-transplant pa- The differential diagnosis of cases with
in the setting of iatrogenic immunosup- tients, but in on ly 25% of patients without plasmacytic differentiation may include
pression (transplantation and autoim- apparent immunodeficiency (578). Most anaplastic or plasmablastic plasma
mune diseases) and in elderly patients patients have an intermediate-risk or ce ll myeloma. A history of immune de-
with presumptive immunosenescence. high-risk International Prognostic Index fic iency and the presence of EBV by in
lmmunophenotype
The neoplastic cells express a plasma
cell phenotype, inc luding positivity for
CD138, CD38, VS38c, IRF4/ MUM1,
PRDM1 (also called BLIMP1), and XBP1 .
CD45, CD20, and PAX5 are either nega-
tive or sometimes weakly positive in a
minority of cells. CD79a is positive in
approximately 40% of cases {578,2699, In situ hybridization for EBER is posi- has been identified in approximately 50%
4111} Cytoplasmic immunoglobulin is tive in 60-75% of cases, but LM P1 is of cases, more frequently in EBV-positive
common ly expressed, most frequently rarely expressed. PBL is more frequently tumours (74%) than in EBV-negative tu-
lgG and either kappa or lambda light EBV-positive in HIV-positive and post- mours (43%), and it is associated with
chain. CD56 is detected in 25% of cas- transplant patients than in HIV-negative MYC protein expression {400,3865,4110,
es. It is usually negative in the oral mu- patients {578,2755). HHV8 is consistently 4111 }. The rearrangement usually occurs
cosa/ type, but may be seen in cases absent. with IG genes {4110}.
with plasmacytic differentiation. EMA
and CD30 are frequently expressed. The Postulated normal counterpart Prognosis and predictive factors
Ki-67 proliferation index is usually very A plasmablast (i.e. a blastic proliferat- The prognosis is generally poor; more
high (> 90%). BCL2 and BCL6 expres- ing B cell that has switched its pheno- than three quarters of patients die of
sion is usually absent, whereas CD10 is type to the plasma cell gene expression the disease, with a median survival of
expressed in 20% of cases. Cyclin 01 programme) 6-11 months {578,2755). Newer thera-
is negative. Some cases express the pies and better treatment of HIV infection
T-cell associated markers CD43 and Genetic profile may be associated with a better prog-
CD45RO {578,785,936,1023,4164). Re- Clonal IGH rearrangement is demon- nosis, but the results are not consistent
active infiltrating T cells are usually very strable, even when immunoglobulin ex- across studies {578). Evaluation of prog-
scarce. Some LBCLs may have marked pression is not detectable, and IGHV nostic parameters has not yielded con-
morphological plasmablastic features may have somatic hypermutation or be sistent resu lts. However, MYC transloca-
but strong ly express CD20, CD79a, and unmutated with a germline configuration tion has been associated with a worse
PAX5 {3682}. These cases should not be {1273). outcome in two studies {578, 2755).
considered PBL and are better classified Genetic studies have revealed freq uent
as diffuse LBCL, NOS. complex karyotypes. MYC translocation
Definition
Primary effusion lymphoma (PEL) is a
binding IKBKGG/NEMO and prevents
death-receptor induced apoptosis. PELs
--
large B-cell neoplasm usually presenting also express vlRF3, which inhibits HLA
as serous effusions without detectable transactivators, resulting in inefficient
tumour masses. It is universally associat- recognition and killin g by T cells {3468}.
ed with the human herpesvirus 8 (HHV8), Secretome analys is has revealed pro-
...
also called Kaposi sarcoma-associated teins involved in inflammation, immune
herpesvirus. It most often occurs in the response, and cell cycle and growth;
setting of immunodeficiency. Some pa- structural proteins; and other proteins
tients with PEL secondarily develop solid {1385}.
tumours in adjacent structures such as
Fig.13.146 Primary effusion lymphoma. Pleural fiuid
the pleura. Rare HHV8-positive lympho- Localization cytology. There is marked pleomorphism, with promi-
mas indistinguishable from PEL present The most common sites are the pleural, nent nucleoli and a plasmacytoid appearance in the
as solid tumour masses, and have been pericardia!, and peritoneal cavities. Typi- cytoplasm (Wright stain).
termed extracavitary PEL. cally only a single body cavity is involved
{308,955,3006}. PEL has also been re- factor, followed by injection drug use.
ICD-0 code 9678/3 ported in unusual cavities, such as an PELs also occur in HIV-seronegative men
artifi cial cavity related to the capsu le of and women who have been exposed to
Synonym a breast implant {3478}. Most cases of HHV8. Patients typically present with ef-
Body cavity-based lymphoma (obsolete) PEL remain restricted to the body cavity fusions in the absence of lymphadenop -
of origin, but subsequent dissemination athy or organomegaly. Approximately
Epidemiology can occur. Extracavitary tumours with one third to half of the patients have
Most cases arise in young or midd le- morphological and phenotypic charac- pre-existin g or develop Kapos i sarcoma
aged men who have sex with men and teristics similar to those of PEL can occur {110), and the CD4+ cell count is gener-
who have HIV infection and severe im- in extranodal sites including the gastro- ally low. Occasional cases are associ-
munodeficiency {2803,3479). There is intestinal tract, skin, lungs, and CNS, or ated with multicentric Castleman disease
frequent co infection with monoclonal can involve the lymph nodes {631,824, {3946}. PEL should be distinguished from
EBV {623,2803,3479}. PEL has also 955}. the rare HHV8-negative effus ion-based
been reported in recipients of so li d or- lymphoma morphologically similar to
gan transplants {1030,1875,2417). The Clinical features PEL that has been described in patients
disease also occurs in the absence of PELs occur mainly in males. The median with fluid overload states {59,1753,2891,
immunodeficiency, usually in elderly pa- patient age at presentation is 42 years 3386,4378), as we ll as from the EBV-
tients, both men and women {3946). In in HIV-infected in dividuals and 73 years associated HHV8-negative large B-ce ll
these patients, the lymphoma cel ls con- in the general population. Male homo- lymphomas also occurring with chron ic
tain HHV8 and may lack EBV (775,3478}. sexual contact is the most common risk suppurative infl ammation (diffuse large
B-cell lymphoma associated with chronic
Etiology inflammation), such as pyothorax-asso-
The neoplastic cel ls are positive for HHV8 ciated lymphoma {121,804). Cases of
(Kaposi sarcoma-associated herpesvirus extracavitary PEL occu r in lymph nodes
or KSHV) in all cases . Most cases are co- or extranodal sites without lymphoma-
infected with EBV {110,157,1683,3479), tous effusions during the course of the
but EBV has restricted gene expression disease. These cases are similar to PEL
and is not required for the pathogenesis. in the ir clinical presentation occurrin g
HHV8 encodes> 10 homologues of cel- in HIV-positive men and morphology
lul ar genes that provide proliferative and {3044). Other lymphomas, inc lu ding Bur-
anti-apoptotic signals {116,156,172,1895). kitt lymphoma, can present with a malig -
HHV8-encoded proteins and microR- nant effusion and are unrelated to PEL.
NAs include LANA1, vi RF3, vFLI P, and Fig. 13.145 Primary effusion lymphoma (PEL). Solid
tissue mass from the mediastinum of an HIV-positive
miR-K1 {116,156,172,1895,4090}. HHV8
patient with PEL presenting with pleural effusions.
Microscopy
IL6 prevents apoptos is by suppressing The cells are large and pleomorphic, with eosinophilic In cytocentrifuge preparations, the cells
proapoptotic catheps in D {670). HHV8- macronucleoli and abundant cytoplasm. Many cells exh ibit a variety of appearances, rang-
encoded vFLIP activates NF-kappaB by have an anaplastic or plasmacytoid appearance. ing from large immunoblastic or plasma-
blastic cells to cells with more-anaplastic low. The cells usually lack T/NK-cell an- diagnosed as PEL. Nearly all cases of
morphology. Nuclei are large and round tigens, although aberrant expression of PEL contain clonal EBV; the exceptions
to more irregular in shape, with prominent T-cell markers may occur, and may be are in the non-HIV infected population,
nucleoli. The cytoplasm can be abundant more frequent in cases of extracavitary which may be EBV-negative. No recur-
and is deeply basophi lic, with vacuoles PEL {308,431,826,3044,3477). The nu- rent chromosomal abnormalities have
in occasional cells. A perinuclear hof clei of the neoplastic cells are positive been identified . HHV8 viral genomes are
consistent with plasmacytoid differentia- for the HHV8-associated latent protein present in all cases. Gene expression
tion may be seen. Some cells resemble LANA1 (also called ORF73) {1065). This profiling of AIDS-related PEL shows a dis-
Hodgkin or Reed-Sternberg cells. Mitotic is very useful in establishing a diagno- tinct profile, with features of both plasma
figures are numerous . The cells often ap- sis. Despite the usual positivity for EBV cells and EBV-transformed lymphoblas-
pear more uniform in histological sec- by in situ hybridization for EBV-encoded toid cell lines {2040). PELs lack struc-
tions than in cytospin preparations {1 10, small RNA (EBER), EBV LMP1 is absent tural alterations in the MYC gene but
955,2803). {110,775,1683,3946) EBV-negative PELs have deregulated MYC protein due to the
The histological features of extracavi- usually occur in elderly HIV-negative pa- activity of HHV8 encoded latent proteins
tary PELs include an immunoblastic to tients from HHV8-endemic areas such as {4017} They also lack mutations in the
anaplastic morphology similar to that the Mediterranean {3725). Solid tumours RAS fami ly of genes and TP53, as well
seen in effu sions. There may be lymph constituting the extracavitary variant of as rearrangements of CCND1, BCL2,
node sinus involvement, and staining for PEL have a phenotype similar to that of and BCL6. A subset have mutations in-
HHV8 may be helpful in differentiating PEL but express B-cell associated anti- volving BCL6 {1271). They have complex
these cases from anaplastic large cel l gens and immunoglobu lins slightly more karyotypes with numerous abnormalities,
lymphoma {826}. Pleomorphic large cells frequently {631). They may have lower ex- including trisomy 12, trisomy 7, and ab-
may have a Hodgkin-li ke appearance, pression of CD45 but higher expression normalities of 1q21-25 {1271). Compara-
necessitating differentiation from classic of CD20 and CD79a, as well as aberrant tive genomic analysis has revealed gains
Hodgkin lymphoma. There may be in- expression of T-cell markers {3044). in chromosomes 12 and X {2780}.
volvement of endothelial-lined lymphatic
or vascular channels, and cases resem- Postulated normal counterpart Prognosis and predictive factors
bling intravascular lymphoma have been Post-germinal centre B cell with plasma- The clinical outlook is extremely un-
reported {826). blastic differentiation favourable, and median survival is
< 6 months. Rare cases have responded
lmmunophenotype Genetic profile to chemotherapy and/or immune modu-
The lymphoma cells usually express lmmunoglobulin genes are clonally re- lation {1357).
CD45 but lack pan- B-cell markers such arranged and hypermutated, indicating a
as CD19, CD20, and CD79a {2054,2803}. B-cell derivation {2565,4234) Some cas-
Surface and cytoplasmic immunoglobu- es also have rearrangement of TR genes
lin is absent. BCL6 is usually absent. Ac- in addition to IG genes (so-called geno-
tivation and plasma cell-related markers typic infidelity) {1667,3477). Rare cases
and a variety of non-lineage associated diagnosed as T-cell PEL have been re-
antigens such as HLA-DR, CD30, CD38, ported, as well as a case with monoclo-
VS38c, CD138, and EMA are often de- nal TR and IG H pseudomonoclonality
monstrable. Levels of immunoglobulin due to extremely low numbers of B cells
expression are usually undetectable or {824,2245). Such cases should not be
Definition most cases of PEL are EBV-positive, lack Multicentric Castleman disease
In addition to causing Kaposi sarcoma, cytoplasmic immunoglobulins, express
which may involve the lymph nodes, the activation and plasma cell-associated Definition
human herpesvirus HHV8 (also call ed Ka- antigens, including CD30, CD38, CD138, Multicentric Castleman disease (MCD) is
pos i sarcoma-assoc iated herpesvirus) is and EMA, and arise from a terminally dif- a clinicopathological entity that encom -
respo nsible for a spectrum of lymphopro- ferentiated rather than a na·rve B cell. passes a group of system ic polyclonal
liferative disorders. These include HHV8- Rare cases of other HHV8-positive lym- lymphoproliferative disorders in wh ich
positive mu lticentric Castleman disease phomas have been described, including there is a proliferation of morphologi-
(MCD); HHV8-positive diffuse large B- a case with a Hodgkin-like appearance cally ben ign lymphocytes , plasma cells,
ce ll lymphoma (D LBC L), NOS, wh ich fre - in an immunocompetent patient and cas- and vesse ls, due to excess ive produc-
quently arises in the backgro und of MCD; es resembling intravascular large B-cell tion of cytoki nes, in partic ul ar IL6 {556,
and germinotropic lymphoproliferati ve lymphoma {834,1206). Node-based 1133}. Acti vation of the IL6R signalling
disorder (GLPD). Except for GLPD, these HHV8-positive B-cell lymphomas with pathway by the virus plays a key role in
disorders are most commonly seen in anaplastic large cell morphology have the development of HHV8-infected B-
the setting of HIV infection and in HHV8- also been reported, and may constitute cell lymphoproliferative lesions, including
endem ic areas, but they can also occur an anaplastic variant of HHV8-positive MCD {1048). In patients with HIV, MCD
in other immunosuppressed states, in- DLBCL, NOS {558,1721). is almost always HHV8-related. In the
cluding following transp lantation {2238}. absence of HIV, MCD is HHV8-related in
GLPD is most commonly seen in immu- as many as 50% of cases , and usually
nocompetent ind ividuals. Primary effu - occurs in HHV8-endemic areas {1029).
sion lymphoma (PE L) and extracavitary
PEL are also caused by HHV8, but are Table 13.25 Key features of HHV8-positive multicentric Castleman disease (MCD); diffuse large 8-cell lymphoma
discussed elsewhere (see Primary effu- (DL8CL), NOS; and germinotropic lymphoproliferative disorder (GLPD)
sion lymphoma, p. 323). HHW-posltlve
Feature HHVB·posltlve MCD DLBCL,NOS HHYB·posltlve GLPD
Associated conditions Clinical Generalized Large lymph node Localized or sometimes
Kaposi sarcoma is frequently present in presentation lymphadenopathy Splenic mass multifocal lymph node
patients with MCD and HHV8-positive Splenomegaly involvement
Extranodal sites
DLBCL, NOS, arising in MCD. PEL and Constitutional symptoms Peripheral blood
its extracavitary counterpart may compli -
cate HHV8-positive MCD. Microscopy Abnormal follicles Sheets of large Retention of architecture
Plasmablasts predominantly plasmablastic cells with germinal centres
Other HHVB-positive lymphoproliferative in mantle zones containing variable numbers
of plasmablasts sometimes
disorders lnterfollicular plasma cell
replacing follicles
Although most cases of HHV8-positive hyperplasia
lymphoproliferative disorders fa ll within Phenotype 8-cell antigens +/- 8-cell antigens +/- 8-cell antigens -
the spectrum defi ned above, individual clgM lambda + clgM lambda + Monotypic kappa or lambda
cases have been repo rted in which there
IRF4a + IRF4a + Any heavy chain
are overlapping featu res . For example,
CD138- CD138- CD138-
cases arising in the background of MCD
intermediate between HHV8-positive CD30 +/-
DLBCL and GLPD have been reported Clonality Polyclonal Monoclonal Polyclonal or oligoclonal
in HIV-positive and HIV-negati ve patients HHVB LANA1 + + +
{1404A}. They may resemble HHV8-
pos itive DLBCL, NOS, but are also posi- EBER +
tive for EBV-encoded small RNA (EBER) HIV status +/- +/-
{3052,3616). Although GLPD tends not to Poor but improved with
progress, one reported case evo lved to a Prognosis Poor Usually responds to treatment
new therapies
high-grade HHV8-positive, EBV-positive
EBER, EBV-encoded small RNA.
lymphoma {826). The differential between
HHV8-positive DLBCL, NOS, and extra- a Also known as MUM1.
cavitary PEL may be problematic, but
Epidemiology
HHV8-positive MCD occurs worldwide
in immunosuppressed patients, particu-
larly in association with HIV/AIDS. It may
also affect immunocompetent individuals
in HHV8-endemic areas (e.g. sub-Saha-
ran Africa and Mediterranean countries)
{425}. In HIV-infected patients, there is
a strong association with sexual trans-
mission, and men are predominantly
affected.
Etiology
MCD is a heterogeneous group of dis-
orders thought to arise from excessive
hypercytokinaemia, most notably of IL6
{1133). In HHV8-positive MCD, the plas-
mablastic cells are infected with HHV8,
which produces viral IL6. In addition,
HHV8-encoded proteins and microRNAs
provide proliferative and anti-apoptotic
signals contributing to the pathogenesis.
These include LANA1, LANA2, IL10,
vFLI P, and miR-K1 {116,156,172,1895,
4090). HHV8-encoded vG PCR induces
expression of proinflammatory and an-
giogenic factors contributing to the in-
flammatory and hyperproliferative nature
of the lesions, and also constitutively
activates the nuclear factor of activated
T cells {3097).
Localization
HHV8-positive MCD usually presents
with generalized lymphadenopathy and
splenomegaly.
Clinical features
Patients with HHV8-positive MCD pre-
sent with constitutional symptoms, en-
larging lymph nodes, and splenomegaly.
;~ Constitutional symptoms include fever,
night sweats, fatigue, weight loss, and
Fig.13.149
• -- '°"'
HHV8-positive multicentric Castleman disease. A lmmunostaining for HHV8 LANA1 shows localization respiratory symptoms {440). Kaposi sar-
in the plasmablasts present in the mantle zones. B Staining for lgM shows localization within the cytoplasm of the coma is commonly also present {1064,
plasmablastic cells C Plasmablasts are negative for kappa light chains. The interfollicular reactive plasma cells stain 2968}. In addition to lymphadenopathy,
positively. D Plasmablasts stained for lambda light chains show lambda light chain restriction. patients may have hepatosplenomegaly
and a skin rash {556). Laboratory find-
MCD is idiopathic in HHV8-negative germinal centres {1132A,3475A,4450A}. ings include anaemia, thrombocytope-
and HIV-negative patients. Idiopathic The diagnosis requires exclusion of in- nia, hypoalbuminaemia, hypergamma-
HIV- and HHV8-negative multicentric fectious, neoplastic, and autoimmune globulinaem ia, and elevated C-reactive
Castleman disease (iMCD) is a systemic diseases that may have similar clin ical protein {556).
disease with constitutional symptoms, presentations. In this syndrome, the
laboratory abnormalities, and multicen- hypercytokinaemia may be driven by Microscopy
tric lymphadenopathy characterized by inflammatory disease or inflammatory The B-cell follicles of lymph nodes and
polytypic plasmacytosis and variably gene mutations, autoantibodies, ectopic spleen show varied degrees of involution
prominent hypervascu lar or regressed cytokine secretion, as seen in paraneo- and hyalinization of their germinal cen-
Genetic profile
Despite the constant expression of mono-
typic lgM lambda by the plasmablasts in
HHV8-positive MCD, carefu l molecu lar
studies have shown that they constitute
a polyc lonal population {1048). The plas-
mablastic aggregates that can develop
during the progression of MCD may be
monoclonal or oligoclonal.
Fig.13.151 HHVB-positive diffuse large B-cell lymphoma, NOS, arising in multicentric Castleman disease. A
Prognosis and predictive factors Sheets of plasmablasts efface normal lymph node architecture. B High magnification showing sheets of neoplastic
Prognosis has been poor, related to the plasmablasts. C Tumour ce lls are negative for immunoglobulin kappa light chain. D Tumour cells are positive for
lymphoid proliferation and underlying lambda light chain indicating lambda light chain restriction.
..
.... ..~·· .
Fig.13.152 HHV8-positive germinotropic lymphoproliferative disorder. A Germinal centre replaced by confiuent sheets of plasmablasts. B Germinal centre largely replaced by
plasmablasts. C Plasmablasts are seen within a hyperplastic germinal centre. D Clusters of plasmablasts within hyperplastic germinal centres.
Definition
Burkitt lymphoma (BL) is a highly aggres-
sive but curable lymphoma that often pre-
sents in extranodal sites or as an acute
leukaemia. It is composed of monomor-
phic medium-sized B cells with baso-
philic cytoplasm and numerous mitotic
figures, usually with a demonstrable MYC
gene translocation to an IG locus. The
frequency of EBV infection varies accord-
ing to the epidemiological subtype of BL.
No single parameter, such as morphol-
ogy, genetic analysis, or immunopheno-
typing, can be used as the gold standard
for diagnosis of BL; a combination of sev-
eral diagnostic techniques is necessary.
,.,...,
Fig.13.158 Burkitt lymphoma. In one case, Giemsa (A) and H&E (B) staining highlights uniform tumour cel ls with multiple small nucleoli and finely dispersed chromatin. In another
case, Giemsa (C) and H&E (D) staining highlights greater nuclear irregularity.
is the most frequent site of involvement. as leukaemia with peripheral blood and many mitotic figures, as wel l as a high
Like in endemic BL, the ovaries, kidneys, bone marrow involvement {2443,2444, rate of spontaneous cell death (apopto-
and breasts may also be involved {4369\. 3741\. Burkitt leukaemia tends to involve sis). A so-called starry sky pattern is usu-
Breast involvement, often bilateral and the CNS at diagnosis or early in the dis- ally present, wh ich is due to the presence
massive, has been associated with onset ease course. Its high and immediate che- of numerous tingible body macrophages.
during puberty, pregnancy, or lactation. mosensitivity easily leads to an acute tu- Some cases have a florid granulomatous
Retroperitoneal masses may result in spi- mour lysis syndrome. Involvement of the reaction that may cause difficulties in the
nal cord compression with paraplegia. bone marrow or presentation as acute recognition of the tumour. These cases
Lymph node presentation is unusual, but leukaemia is uncommon in endemic BL typically present with limited stage dis-
more common in adults than in children. {2442\. ease and have an especially good prog-
Waldeyer ring or mediastinal involvement nosis {1549,1666).
is rare. In immunodeficiency-associated Macroscopy Some cases of BL may show greater nu-
BL, nodal localization and bone marrow Involved organs are replaced by masses clear pleomorphism despite clinical, im-
involvement are frequent {3396\. with a fish-flesh appearance, often associ- munophenotypic, and molecular features
ated with haemorrhage and necrosis. Ad- characteristics of typical BL. In such cas-
Clinical features jacent organs or tissues are compressed es, the nucleol i may be more prominent
Patients often present with bulky disease and/or infiltrated. Nodal involvement is and fewer in number. In other cases, par-
and high tumour burden due to the short rare in endemic and sporadic BL, but ticularly in adults with immunodefi ciency,
doubling time of the tumour. In the typical more frequent in immunodeficiency-asso- the tumou r cells exhibit plasmacytoid
paediatric cases, the parents of affected ciated BL. Even when nodal involvement differentiation, with eccentric basophilic
children usually report symptoms of only is not present, uninvolved lymph nodes cytoplasm and often a single central
a few weeks' duration. Specific clinical may be surrounded by tumour. nucleolus {3396}. These morphological
manifestations at presentation may vary features are consistent with gene expres-
according to the epidemiolog ical sub- Microscopy sion profile studies suggesting that the
type and the site of involvement. The prototype of BL is observed in en- morphological spectrum of BL is broader
Paediatric BL cases are staged accord- demic BL, in a high proportion of spo- than previously thought {1732).
ing to the system proposed by Murphy rad ic BL cases, in particular in children,
and Hustu {2793). A revised international and in many cases of immunodeficiency- lmmunophenotype
paediatric non-Hodgkin lymphoma stag- related BL. The tumour cells are medium- The tumour cells typically express mod-
ing system has been recently proposed sized and show a diffuse monotonous erate to strong membrane lgM with light
{3417\. Localized-stage (I or II) disease pattern of growth. The cells appear to be chain restriction , B-cell antigens (CD19,
and advanced-stage (I ll or IV) disease cohesive but often exhibit squared-off CD20, CD22, CD79a, and PAX5), and
are found in approximately 30% and 70% borders of retracted cytoplasm in forma- germinal centre markers (CD10 and
of patients, respectively, at presentation. lin-fixed material. The nuclei are round, BCL6). CD38, CD77, and CD43 are also
Upon initiation of therapy, a tumour lysis with finely clumped chromatin, and con- frequently positive {280,2190,2826). Al-
syndrome can occur due to rapid tumour tain multiple basophilic medium-sized, most all BLs have strong expression of
cell death. paracentrally located nucleoli. The cyto- MYC protein in most cells {3902). The
plasm is deeply basoph ilic and usually proliferation rate is very high, with nearly
Burkitt leukaemia variant contains lipid vacuoles, which are better 100% of the cells positive for Ki-67. The
A leukaemic phase can be observed in seen in imprint preparations or fine-nee- characteristic cytoplasmic lipid vesicles
patients with bulky disease, but only rare dle aspiration cytology. The tumour has can also be demonstrated by immunohis-
cases, typically in males, present purely an extremely high proliferation rate, with tochemistry on paraffin-embedded tissue
Definition
Burkitt-like lymphoma with 11 q aberra-
tion is a subset of lymphomas identified
by several recent studies that resem-
ble Burkitt lymphoma (BL) morphologi-
cally, to a large extent phenotypically,
and in terms of microRNAs and gene
expression profile, but that lack MYC
rearrangements. Instead, they have a
chromosome 11q alteration character-
ized by proximal gains and telomeric
losses: specifically, interstitial gains
including a minimal region of gain in
11 q23. 2-23.3 and losses of 11 q24.1-ter
(195,3175,34901. These lymphomas lack
the 1q gain frequently seen in BL and ...
have more-complex karyotypes than BL. Fig.13.161 Burkitt-like lymphoma with 11q aberration. The tumour cells are medium-sized to large, with a high mitotic
index. A starry-sky pattern is usually seen.
They also have a certain degree of cy-
tolog ical pleomorphism, occasionally a
follicular pattern, and frequentl y a nodal
presentation {3490,4454). The clinical
chrll +11q21-q23.3
course seems to be similar to that of BL, I.I
-11q23.3-q25
Fig. 13.162 Burkitt-like lymphoma with 11q aberration. Chromosomal view of chromosome 11 analysed by OncoScan
array, depicting gains of 11q21 -23.3 in blue and terminal losses of 11q23.3-25 in red.
Definition some rare follicular lymphomas and B- classifiab le, with features intermediate
High-grade B-cell lymphoma (HGBL) lymphoblastic leukaemia/lymphomas) between DLBCL and BL). Less com-
is a group of aggressive, mature B-cell that have a MYC (8q24) rearrangement monly, they have a blastoid appearance,
lymphomas that for biological and clini- in comb ination with a BCL2 (18q21) and/ morphologically mimicking lymphoblas-
cal reasons should not be classified as or a BCL6 (3q27) rearrangement, i.e. the tic lymphoma or the blasto id variant of
diffuse large B-ce ll lymphoma (DLBCL), so-called double-hit and triple-hit lym- mantle ce ll lymphoma.
NOS, or as Burkitt lymphoma (BL). There phomas. Morphologically, these cases The second category, HGBL, NOS, en-
are two categories of HGBL {1547,3846). typically either resemble DLBCL, NOS, compasses cases that either have fea-
The first category, HGBL with MYC and or can have features of both BL and tures intermediate between DLBCL and
BCL2 and/or BCL6 rearrangements, en- DLBCL (referred to in the 2008 WHO BL or appear blastoid, but by definition
compasses all B-cell lymphomas (except classification as B-cell lymphoma, un- do not harbour a genetic double hit as
defined above. This category excludes
cases with the morphology of DLBCL,
Morphology Blastoid DLBCL DLBCL/BL BL wh ich should be diagnosed as such,
even if they have a high proliferative
fraction.
Synonym
B-cell lymphoma, unclassifiable, with
/HC TdT+, CDlO+, CDlO+, BCL6+, BCL2-/w, features intermediate between diffuse
BCL6-, CCNDl- Ki67 -100%
large B-cell lymphoma and Burkitt lym-
phoma (no longer recommended)
cations, the morphological appearance Fig.13.164 Double-hit high-grade B-cell lymphoma with MYC and BCL2 rearrangements. A At low magnification,
many cases show a prominent starry-sky appearance. B In the same case, at higher magnification, note the
of the HGBL with MYC and BCL2 and/or
intermediate size of the tumour cells, with slightly irregular contours and relatively large nucleoli, which are all
BCL6 rearrangements shou ld be noted in features somewhat atypical for a Burkitt lymphoma. C BCL2 staining of the same case. In most cases with a BCL2
a diagnostic comment. breakpoint, BCL2 expression is very high, which is in contrast to cases with a BCL6 breakpoint.
Rare cases of B-lymphoblastic leukae-
mia/lymphoma with MYC and BCL2
translocations, sometimes transformed most double-expressers are not double- Epidemiology
from an antecedent or synchronous fol - hit lymphomas; the majority are the ac- These lymphomas mostly present in
licular lymphoma, are not included in this tivated B-cell subtype of DLBCL, and elderly patients, with a median age at di-
category, and should be classified as B- do not harbour translocations {3846). agnosis in the sixth to seventh decade;
lymphoblastic leukaem ia/lymphoma with Specifi cally, it is important to distinguish with the youngest reported patients aged
the translocations specified in a com- DLBCL with MYC and BCL2 co-expres- approximately 30 years. Both men and
ment. Patients with such cases are usual- sion, which is not a diagnostic catego- women are affected, with a slight male
ly treated like patients with lymphoblastic ry, from high grade B-cell lymphomas predominance {194,2350,31 43,3183,
leukaemia {896,1349,2061, 2121,4446). with MYC and BCL2 and/or BCL6 re - 3846). In one study of triple-hit lympho-
Rearrangements of MYC, BCL2, and arrangements that also often show this mas (i.e. with involvement of MYC, BCL2,
BCL6 should be detected by a cytoge- double-expression and BCL6), all patients were men {4254).
netic/molecular method such as FISH . This classification is primarily applica-
The presence of only copy-number in- ble to de novo cases; lymphomas with Etiology
crease/amplification or somatic muta- a proven history of a pre-existing or co- By definition, these mature B-cell lym-
tions, without an underlying rearrang e- existent indolent lymphoma (of follicular phomas harbour two or more recur-
ment, is insufficient to qualify a case for or other type) should be diagnosed as rent cytogenetic events, and in almost
this category. There are indications that such (e.g. HGBL with MYC and BCL2 all cases, classic cytogenetic analysis
such cases are also agg ressive, similar rearrangements, transformed from folli- also shows many additional abnormali-
to the double-hit lymphomas, but there cular lymphoma). ties (complex karyotype). It is likely that
are insufficient data to justify the inclu- the rearrangement of MYC is a second-
sion of such cases in this category. ICD-0 code 9680/3 ary event, but this has only been proven
Although so-called double-expresser for the combination of BCL2 and MYC
DLBCLs that show immunohistochemi- Synonyms rearrangements in patients who first had
cal overexpression of MYC and BCL2 (Subset of) B-cell lymphoma, unclassifi- a follicular lymphoma and later devel-
protein also have a relatively poor prog- able, with features intermediate between oped a MYC rearrangement, and in pa-
nosis, overexpression cannot be used diffuse large B-cell lymphoma and Bur- tients with de novo disease in which two
as a surrogate marker for double-hit kitt lymphoma (no longer recommend- subclones with and without the MYC rear-
cytogenetic status. Most double-hit lym- ed); (subset of) diffuse large B-cell lym- rangement are present. Although it might
phomas are also double-expressers, but phoma; double or triple-hit lymphoma be envisaged that all lymphomas with
Localization
More than half of all patients present w ith
widespread disease, includ in g involve-
ment of the lymph nodes. There can also
be involvement of more than one extra-
nodal site (occurring in 30- 88% of cas-
es), the bone marrow (in 59-94%), and
even the CNS (in as many as 45%) {2350,
3158,3523).
Fig.13.165 Triple-hit high-grade B-cell lymphoma with MYC, BCL2, and BCL6 rearrangements. This case shows the
Clinical features morphology of a diffuse large B-cell lymphoma, NOS, with large tumour cells with abundant cytoplasm, large nuclei,
Most patients (70-100%) present w ith and prominent nucleoli.
advanced disease (stage IV according
to the Ann Arbor classification), more
than one extranodal localization , a high
International Prognostic Index (IPI), and
elevated lactate dehydrogenase levels
{2350,3158,3523,3846). Extranodal lo-
calizations include the bone marrow and
CNS. Double-hit HGBLs are particu -
larly enriched in patients diagnosed with
DLBCL who do not respond we ll to induc-
tion therapy with the CHOP chemothera-
py regimen plus rituximab (R-CHOP) or
who have early relapses after complete
remission {843).
Microscopy
Double-hit HGBLs have variable morphol-
Fig.13.166 Double-hit high-grade B-cell lymphoma with MYC and BCL6 rearrangements. This case shows monomor-
ogy. The specific morphological appear- phic tumour cells with indistinct cell borders, relatively large nuclei (somewhat larger than those of macrophages) and
ance shou ld be stated in a diagnostic prominent, often single nucleoli.
comment. Although the incidence differs
between studies, most authors conclude liferation index (see below). Therefore, a Because these lymphomas can be indis-
that approximately half of the cases have low proliferation rate does not exclude this tinguishable from other DLBCL, a double-
the morphology of a DLBCL, NOS {193, type of lymphoma. The nuclei have a vari- hit statu s should be investigated in all
194, 1820, 1865, 2304, 3158,3523,3712}. able size and contour, with some cases DLBCLs, NOS, using cytogenetic or mo-
This is due to the fact that DLBCL is by showing nuclei that are 3- 4 times the size lecular cytogenetic studies . Some pathol-
far the most frequent lymphoma subtype, of normal lymphocytes (much larger than ogists may prefer to look for evidence of
and approximately 4- 8% of all DLBCLs BL cells). The cytoplasm is usually more a double-hit only after immunohistochemi-
are double-hit lymphomas. In a recent abundant and less basophilic than in BL. cal or other pre-selection (see below).
study, 69% of the MYC and BCL2 double-
hit lymphomas and 85% of the MYC and
BCL6 double-hit lymphomas had DLBCL
morphology {2304). The differences be-
tween individual studies may be due to re-
ferral bias, inclusion bias, and the variable
morpholog ical criteria {2720A,3712}. The
growth pattern is completely diffuse, of-
ten with relatively few small lymphocytes.
Some fibrosis may be present. Starry-sky
macrophages may be present, sometimes
only focally. The numbers of mitotic figures
Fig.13.167 Double-hit high-grade B-cell lymphoma Fig.13.168 Double-hit high-grade B-cell lymphoma
-
and apoptotic figures are high ly variab le, with MYC and BCL6 rearrangements. The intensity of with MYC and BCL2 rearrangements. The Ki-67 prolif-
with some cases having a low number of BCL2 staining is variable in such cases, and can be eration index is -90%.
mitotic figures and also a low Ki-67 pro- negative.
..
~ ...- ..
a z. ~ ~. .....:, • -
_ ,,..._ _. _ ~:;
_• •'mt!t4..tw• . ·
-~DINlL.,.-.0:
Fig.13.171 Triple-hit high-grade 8-cell lymphoma, with MYC, BCL2, and BCL6 rearrangements. A Note the low and heterogeneous Ki-67 proliferation index of -40%. This case
illustrates that Ki-67 staining cannot be used for selecting diffuse large 8-cell lymphoma cases for FISH analysis. B In the same case, homogeneous and strong p53 staining is
highly suggestive of a TP53 mutation.
4077} and therefore could be missed by 1439,1440,1866,3143,4085). Neverthe- of the IG genes (usually IGH, less fre-
such a se lection procedure. less, some authors suggest performing quently IGK or IGL); in the other cases,
Ki-67 immunohistochem istry shows FISH stud ies on ly in cases with > 30% or MYC has a non-IG partner, such as at
variable resu lts. In cases that mimic BL, > 40% MYC-positive tumour cells. 9p13 (gene unknown), 3q27 (BCL6),
the Ki-67 proliferation index is 80- 95%. or other loci {193,3118). Some reports
However, in cases with DLBCL morphol- Postulated normal counterpart suggest that an IG/MYC translocation
ogy, the index may be deceptively low The li mited gene expression data avail- confers a poor outcome compared with
(<30%). Therefore, the Ki-67 proliferation able and the applied immunoh istochemi- cases in whi ch MYC has a non-IG part-
index cannot be used to se lect cases for cal algorithms suggest that almost all ner {193,802,1865,3118}, but the clinical
MYC FISH {2564,4113}. cases with MYC and BCL2 rearrange- impact of the individual non-IG partners
Similarly, MYC protein expression cannot ments originate from mature germinal is not fully established. Identification of
be used to select cases for FISH either. centre B cells, whereas the cell of origin an IGK-MYC or IGL fusion requires the
Although there is consensus that high ex- for cases with MYC and BCL6 rearrange- use of dual fusion probes, because the
press ion (in > 80% of nuclei) is present in ments is more variab le {802,3601}. identification of MYC and IGK or IGL
most cases of BL with an IG/MYC trans- rearrangements using only break-apart
location, there is much more variability in Genetic profile probes does not exclude the possibility
the double-hit lymphomas; most authors By definition, these lymphomas have a of two separate unrelated translocations
have concluded that MYC staining is not MYC (8q24) rearrangement as detected {802).
reliable enough to be used for the se lec- by classic cytogenetics, FISH, or other In add ition to MYC rearrangement, all
tion of cases that should have cytogenet- molecular genetic tests. In approximately cases contain a BCL2 rearrangement at
ic or molecular/cytogenetic testing {722, 65% of cases, MYC is juxtaposed to one 18q21 and/or a BCL6 rearrangement at
Definition ported rarely in children {2995l. Medias- and shows less of a male predominance
B-cell lymphoma, unclassifiable, with tinal presentations are infrequent among {1077,1121}. Cases of composite CHL
features intermediate between diffuse elderly patients {1077,1121). Most cases and PMBL and cases of sequential de-
large B-cell lymphoma (D LBCL) and have been reported from western coun- velopment of CH L and PMBL in the same
classic Hodgkin lymphoma (CHL) is a tries. Like CHL, these tumours are less patient are not strictly accepted as ex-
B-cell-lineage lymphoma that demon- common in Black and Asian popu lations. amples of MGZL, but are thought to be
strates overlapping clinical, morphologi- biologically related phenomena {1402,
cal, and/or immunophenotypic features Etiology 3140). When seen sequentially, CHL is
between CHL and DLBCL, especially The etiology is unknown, but gene ex- more often the initial presentation, fol-
primary mediastinal (thymic) large B-cell pression profiling stud ies and genetic lowed by PMBL {4463).
lymphoma (PMBL). These lymphomas stud ies have revealed close links to
are most commonly associated with me- PMBL and CHL {1059). Microscopy
diastinal disease, but similar cases have A characteristic feature is the broad
been reported in peripheral lymph node Localization spectrum of cytological appearances
groups as the primary site. Mediastinal The most common presentation is with within a given tumour; some areas more
cases are often referred to as medias- a large anterior mediastinal mass, with closely resemble CHL and others resem-
tinal grey-zone lymphoma (MGZL) and or without involvement of supraclavicu- ble PMBL. There is also variation across
non-mediastinal cases as grey-zone lym- lar lymph nodes {1297,4047). Peripheral different cases, with some examples be-
phoma (GZL), avoiding the cumbersome and intra-abdominal lymph nodes are ing more Hodgkin-like and others more
nomenclature of the official diagnosis. less commonly involved. There may be closely resembling either PMBL or dif-
spread to lung by direct extension, as fuse large cell lymphoma. As discussed
ICD-0 code 9596/3 well as spread to liver, spleen, and bone below (see lmmunophenotype), discord-
marrow. Non-lymphoid organs are rarely ance between the cytological appear-
Synonyms involved, unlike in PMBL. ance and the immunophenotype is com-
Mediastinal grey-zone lymphoma; Hodg- mon. Tumour cell density is high, often
kin-like anaplastic large cell lymphoma Clinical features with sheet-like growth of pleomorphic
(obsolete) Most patients have bulky mediastinal tumour cells in a diffusely fibrotic stroma
masses, sometimes leading to supe- {1297,4047). Focal fibrous bands may be
Epidemiology rior vena cava syndrome or respiratory seen in some cases. The cells are larger
MGZL is most common in young men, distress. Supraclavicu lar lymph nodes and more pleomorphic than is typical in
usually presenting in patients aged may be involved. Non-mediastinal GZL PMBL, although some centroblast-like
20-40 years {1297,4047). It has been re- more often presents in older patients, cells may be present. There is usually a
sparse inflammatory infiltrate, although for CD20, usually with variable intensity. CHL and PMBL. In one series, p53 was
eosinophils, lymphocytes, and histio- Additionally, CD30 may be expressed in expressed in most cases {1300}. Expres-
cytes may be present focally. Necrosis a subset of DLBCLs, and should not lead sion of cyclin E and p63 in most cases
is frequent, but unlike in CHL, the ne- to a diagnosis of MGZL by itself. Nota- has also been reported {1077) Most cas-
crotic areas do not contain neutrophilic bly, PMBL is frequently positive for CD30 es of MGZL are negative for EBV; positiv-
infi ltrates. Due to the variations in histo- {1633). ity for EBV-encoded small RNA (EBER)
logical pattern in different portions of the MAL, a marker associated with PMBL, is or LMP1 should prompt suspicion for
tumour, diagnosing these lymphomas on expressed in at least a subset of the cas- EBV-positive DLBCL, especially in elder-
a core needle biopsy is challenging and es presenting with mediastinal disease ly patients. However, rare cases of MGZL
not recommended. {805,4047). Supporting a relationship to have been EBV-positive {2867).
PMBL, nuclear c-REL/p65 protein has In instances of composite or metachro-
lmmunophenotype been identified in the cases tested {1300, nous lymphomas, the various compo-
The lymphoma cells exhibit an aberrant 3384). IRF4/MUM1 is usually positive, nents exhibit a phenotype characteristic
immunophenotype, making the distinc- but is not useful in differential diagnosis, of that entity, either CHL or PMBL.
tion between CHL and PMBL difficult because it is positive in most cases of
{1297,4047). Neoplastic cells typically ex-
press CD45. Cases in which the cytolog i-
cal appearance might suggest CHL show
preservation of the B-cell programme,
with strong and uniform positivity for
CD20 and CD79a. CD30 is usually posi-
tive, and CD15 may be expressed. Cases
in wh ich the histolog ical appearance on
H&E staining might suggest PMBL show
loss of B-cell antigens but positivity for
CD30 and CD15. Surface or cytoplasmic
immunoglobulin is absent. The transcrip-
tion factors PAX5, OCT2 , and BOB1 are
usually expressed . BCL6 is variably posi-
tive but CD10 is generally negative. ALK
is cons istently negative. The background
lymphocytes are predominantly positive
for CD3 and CD4, as seen in CHL.
Weak or variable pos itivity for CD20 in a
tumour otherwise compatib le with a di-
agnosis of nodular sclerosis CHL should
not lead to a diagnosis of B-cell lympho-
ma, unclassifiable, with features interme-
Fig.13.178 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and CHL. There is a sheet-
diate between DLBCL and CHL. Particu- like growth of pleomorphic lymphoid cel ls. Some binucleated cells are present, but there is marked variation in cell
larly with antigen-retrieval techn iques, size and shape. The biopsy was taken from a 28-year-old man with a mediastinal mass and supraclavicular lymph
nodular sclerosis CHL may be positive node involvement.
Genetic profile
Clonal rearrangement of the IG genes is
positive by PCR in most cases, presum-
ably due to the high content of tumour
cells in comparison with CHL. Many of
the genetic aberrations identified by
FISH are similar to those observed in
PMBL {1077). Gains and amplification
of the JAK2 and PDCD1LG2 (also called
PDL2) loci at 9p24.1 are common, seen
in > 50% of cases. Increased expression
of CD274 (PD-L1) may occur as a result.
Also frequent are gains/amplification at
2p16.1 involving REL. Breaks in the Cl/TA . .
locus at 16p13.13 have been reported in Fig.13.179 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic HL. A Sheets
approximately one third of cases {1077}. of tumour cells resembling lacunar cells are present, with a minimal infiammatory background. B In the same case,
Gains in MYC have been observed the tumour cells are strongly positive for CD20. C CD79a is uniformly positive. D CD15 is positive, but the sheet-like
growth and strong staining for CD20 and CD79a favour mediastinal grey-zone lymphoma.
in 20-30% of cases. The aberrations
above are seen in both mediastinal and
non-mediastinal cases, although gains/
amplification at 9p24.1 are more com-
mon in patients with mediastinal than
non-mediastinal presentations, occurring
in 61% and 38% of such cases, respec-
tively {1077}.
Etiology
The underlying pathophysiological mech-
anisms of T-LGLL are not well under-
stood, and this disorder is fairly unique
in that the clonal T-cell LGLs (T-LGLs)
retain many phenotypic and functional
properties of normal cytotoxic T lympho-
cyte effector memory cells {377). One
theory is that T-LGLL arises in a setting
of sustained immune stimulation. The fre-
quent association of T-LGLL with autoim-
mune disorders supports this hypothesis
{377,4343). The absence of homeostatic
apoptosis is also a feature of the T-LGLs;
these cells express high levels of FAS
and FASL, leading investigators to pro-
pose activation of prosurvival pathways
in T-LGLs, which prevents activation-
induced cell death {1112,3549). FASL
levels are elevated in the sera of many
patients, and this elevation is postulat-
ed to be important in the pathogenesis
........
Fig. 14.05 T-cell large granular lymphocytic leukaemia. The various morphological variants of large granular lympho-
of neutropenia {2368}. Other pathways cyte in the peripheral blood (Wright stain).
o eo..d~~~-=~::::::;;~;;;;~~~~~~~~~~
D o... .._.....,,
0 $«.........,.,_
affect codon Y640 or 0661 {18S4,2086}.
Very rarely, STAT58 SH2 domain muta-
O n~iw;U;oi~n tions have been documented , and the
e MlOIOnlnTLGl
e ""-UtlOt!S'INKlGL
N642H mutation may be associated with
more-aggressive disease {3288).
There is no recurrent karyotypic ab-
normality, but numeric and structural
chromosomal abnormalities have been
described in a small number of cases
c Y&40F
• Q661Y
{2203).
a S61'R
CJ 06elV
Prognosis and predictive factors
........
Q N&471
• Gtt&R
The lymphoproliferation is typically in-
• 06611 dolent and non-progressive, and some
• kl~....,
investigators feel that this entity is better
regarded as a clonal disorder of uncer-
Fig.14.08 STAT3 mutations in large granular lymphocytic leukaemia (LGL). From: Jerez A et al. (1854) tain significance than as a leukaemia.
Morbidity is associated with the cytope-
Variant similar to the restricted expression of TCR- nias (especially neutropenia), but mortal-
Cases that morphologically resemble beta family members {2416, 2740). T-LGLs ity due to this cause is uncommon. In a
T-LGLL but have an NK-cell immunophe- express the cytotoxic effector proteins series of 6B cases, the actuarial median
notype, i.e. that are negative for surface TIA1, granzyme B, and granzyme M. Bone survival was 161 months {967). There
CD3 (sCD3) and T-cell receptor (TCR) marrow core biopsy immunohistochem- appears to be no difference in survival
expression, are classified with the NK- istry can confirm the diagnosis by high- between cases with and without STAT3
cell disorders. lighting the interstitial and intrasinusoidal mutation , although mutation seems to
T-LGL infiltrates and revealing the non-ne- be associated with more-symptomatic
Cytochemistry oplastic nature of the nodular aggregates disease and shorter time to treatment
The granules are positive for acid phos- {2738,2741,3003}. failure l18S4,2086} The rare finding of
phatase and beta-glucuronidase. En- STAT58 mutations appears to be as-
zyme cytochemical studies are rarely Cell of origin sociated with more aggressive disease
performed for routine diagnosis. A subset of COB+ alpha beta T cells for {32BB,1327,402S}. Rare cases have un-
the common type and a subset of gam- dergone transformation to a peripheral
lmmunophenotype ma delta T cells for the rare type express- T-cell lymphoma composed of large cells
T-LGLL is typically a disorder of mature ing the gamma delta TCR {2SBS}. Some of the aggressive cases
CD2+, CD3+, CD8+, CDS?+, and al- may represent peripheralization of a pe-
pha beta TCR- positive cytotoxic T cells Genetic profile ripheral T-cell lymphoma. Conversely,
(6S0,3046}. Uncommon variants include Antigen receptor genes rare cases with spontaneous remission
CD4+ I alpha beta TCR- positive cases As a rule, cases classified as T-LG LL have also been reported {4338). Patients
and gamma delta TCR- positive cases; ap- are clonal as documented by TR gene who require treatment may benefit from
proximately 60% of the latter express COB, rearrangement studies {2203). The TRG cyclosporine, cyclophosphamide, and
and the remainder are CD4/CDB-negative gene is rearranged in al l cases, regard - corticosteroids or low-dose methotrex-
(6S0,233S,3046,3S04,3620}. Abnormally less of the type of TCR expressed. TRB ate, which has been reported to induce
diminished or lost expression of CDS is rearranged in cases expressing the al- clinical remission in as many as SO% of
and/or CD? is common in T-LGLL {2416, pha beta TCR, but the TRB gene may be patients {6S0,2203,300S}. Some patients
2740). CDS? and CD1 6 are expressed in in germline configuration in gamma delta have benefited from pentostatin {300S}.
>BO% of cases {2203 ,2740). Expression TCR cases {4194). Deep sequencing of Splenectomy has been performed in
of CD94/NKG2 family and killer-cell immu- the TRB CDR3 has demonstrated that the patients with a large spleen, but does
noglobulin-like receptor (KIR) family mem- dominant clonotypes in the CD8+ LG Ls not correct the cytopenia. In light of the
bers, which are major histocompatibility tend to be private and not commonly discovery of activation of the STAT3 or
complex (MHC) class I receptors, can be shared in the CDR3 repertoire seen in STATSB pathway in patients with (and
detected in ;;:SO% of T-LGLLs, but expres- normal individuals {76B}. possibly also patients without) activating
sion of CDS6 is infrequent. KIA-positive mutations {18S4}, inhibiting th is pathway
cases usually show uniform expression of Cytogenetic abnormalities and could be an option for the treatment of
a KIA- family member, and this finding can oncogenes T-cell and NK-cell LGL proliferations.
serve as a surrogate indicator of clonality STAT3 mutations have been found in
Etiology
A transient increase in circulating NK cells
can be encountered in many conditions,
such as autoimmune disorders and viral
infections {2204,3274). NK-cell activation
due to an unknown stimu lus, presum-
ably viral, is postulated to play a role in
the early pathogenesis of CLPD-NKs by
selecting and expanding NK-cell clones,
although no evidence of direct NK-cell
infection has been observed {1113,2336, ~ '"lr-ir-r-T"T"TTl'inr-n,.,_...,..,.,..,....T
2398,3274,3605,4456,4457). The tyros- 10° 10' 10$ 10° 10' 10s
ine kinase inhibitor dasatinib produces a 158aAPC·A 158e PE-A
sustained increase in NK cells that can
be monoclonal {2113,2796). One third of Fig.14.09 Chronic lymphoproliferative disorder of NK cells (CLPD-NK). Peripheral-blood fiow-cytometric immuno-
phenotyping reveals an increase in CD16+/CD3- NK cells (upper panel, red arrow). Selective gating on these cells
cases have activating mutations in the
reveals that they uniformly express the killer-cell immunoglobulin-like receptor isoform CD158a (lower-left panel,
STAT3 SH2 domain {1163,1854). orange arrow) and lack expression of the isoforms CD158b and CD158e (lower-right panel, orange arrow). This
restricted pattern of killer-cell immunoglobulin-like receptor expression by NK cells is abnormal and supports the
diagnosis of CLPD-NK.
Genetic susceptibility
A genetic susceptibility may be linked to
haplotypes containing higher numbers of
activating KIR genes {1113,3605,4456).
Definition
Aggressive NK-cell leukaemia is a sys-
temic neoplastic proliferation of NK cells
frequently associated with EBV and an
aggressive clinical course.
Synonym
Aggressive NK-cell leukaemia/lymphoma
Epidemiology
This rare form of leukaemia is much more
prevalent among Asians than in other
ethnic populations {3460}. Patients are
most commonly young to middle-aged
adults, with a median age of 40 years
and two incidence peaks, in the third and
fifth decades of life {1786,2297,3062,
3728,3840}. There is no definite sex pre-
dilection {640,647,1756,2155,2157,2297,
2999, 3460 ,3462 ,3728, 3840}. Fig.14.11 Aggressive NK-cell leukaemia. A In this blood smear, the neoplastic cel ls are very similar to normal large
granular lymphocytes. B In the peripheral blood, the neoplastic cells in this case have basophilic cytoplasm and
nuclei with more open chromatin and distinct nucleoli. Azurophilic granules can be seen in the cytoplasm. C The
Etiology
neoplastic cells are negative for surface CD3, whereas the normal T lymphocytes are stained. D Neoplastic ce lls
Little is known about the etiology of ag- show strong immunoreactivity for CD56.
gressive NK-cell leukaemia, but the
strong association with EBV suggests a
pathogenetic role of the virus . In younger There can be overlap with extranodal stitutional symptoms, and a leukaemic
patients, the leukaemia may evolve from NK/T-cell lymphoma showing multiorgan blood picture. The number of circulating
chron ic active EBV infection {1788,1789, involvement; it is unclear whether aggres- leukaemic cells may be low or high (a
3062}. sive NK-cell leukaemia is the leukaemic few per cent to > 80% of all leukocytes);
counterpart of extranodal NK/T-cell lym- anaemia, neutropenia, and thrombocyto-
Localization phoma {640}. penia are common. Serum lactate dehy-
The most commonly involved sites are the drogenase levels are often markedly ele-
peripheral blood, bone marrow, liver, and Clinical features vated. Hepatosplenomegaly is common,
sp leen , but any organ can be invo lved. Patients usually present with fever, con - sometimes accompan ied by lymp hade-
Fig.14.12 Aggressive NK-cell leukaemia. In situ hybrid- Fig.14.13 Aggressive NK-cell leukaemia complicated Fig. 14.14 Aggressive NK-cell leukaemia. The neoplas-
ization for EBV-encoded small RNA (EBER) highlights by haemophagocytic syndrome. The marrow biopsy tic cells in this marrow aspirate smear show substantial
the neoplastic cells in the bone marrow biopsy. The nu- shows neoplastic cells with substantial nuclear pleo- nuclear pleomorphism. Histiocytes with phagocytosed
clear atypia in this example is striking. morphism and irregular nuclear foldings. There are red blood cells are apparent.
admixed histiocytes with phagocytosed red blood cells.
..•.·l.J..~-·oo..
Fig.14.16 Aggressive NK-cell leukaemia. Bone marrow biopsy. A Patchy involvement by neoplastic cells with sub-
stantial nuclear pleomorphism. B lmmunostaining for CD3 highlights the neoplastic population and accentuates
the nuclear irregularities. C Extensive bone marrow involvement by a monotonous population of uniform-looking
cells. D The neoplastic cells stain positively for CD56.
EBV-associated T-cell and NK-cell lym- Table 14.01 Classification of EBV-positive T-cell and NK-cell proliferations
phoproliferative disorders in the paediat- Diagnosis Usual patient age group(s)
ric age group can be categorized into two
major groups: systemic EBV-positive T- EBV-positive haemophagocytic lymphohistiocytosis Paediatric, adolescent
cell lymphoma of childhood and chronic (benign, may be self-limited)
active EBV infection. Both occur with in- Systemic CAEBV Paediatric, adolescent
creased frequency in As ians and in Native
Americans from Central and South Amer- Cutaneous CAEBV, hydroa vacciniforme-like lymphoproliferative disorder Paediatric, adolescent
ica and Mexico. Systemic EBV-positive
Cutaneous CAEBV, severe mosquito bite allergy Paediatric, adolescent
T-cell lymphoma of childhood has a very
fulminant clin ical course, usually associ- Systemic EBV-positive T-cell lymphoma Paediatric, adolescent
ated with a haemophagocytic syndrome.
Chronic active EBV infection of T- and NK- Aggressive NK-cell leukaemia Adult
cell type shows a broad range of clinical
Extranodal NK/T-cell lymphoma, nasal type Adult
manifestations, from indolent, localized
forms such as hydroa vacciniforme-like Nodal peripheral T-cell lymphoma, EBV-positive' Adult
lymphoprol iferative disorder and severe
mosquito bite allergy to more systemic CAEBV, chronic active EBV infection.
disease characterized by fever, hepatos- • Included within the category of peripheral T-cell lymphoma, NOS.
plenomegaly, and lymphadenopathy, with
or without cutaneous manifestations dis-
eases. Additionally, sign ificant overlap in scribed using a variety of terms, includ ing order, and is therefore now cons idered
the morphological features of the follow- fulm inant EBV-positive T-cell lymphopro- equivalent to systemic EBV-positive T-ce ll
ing conditions is present Therefore, cor- liferative disorder of childhood {3269}, lymphoma of childhood {3269}. The term
relation with clinical features is critical for sporadic fatal infectious mononucleosis, CAEBV was coined to describe an in -
accurate diagnosis. fulminant haemophagocytic syndrome fectious mononucleosis- like syndrome
in ch il dren (in Taiwan, Ch ina) {3822); fa- persisting for at least 6 months and as-
tal EBV-associated haemophagocytic sociated with high titres of lgG antibod-
Systemic EBV-positive T-cell syndrome (in Japan) {2011}; and severe ies against EBV viral capsid antigen and
lymphoma of childhood CAEBV {2025,2963,3838}. The term ful- early antigen, with no association with
minant or fatal haemophagocytic syn- malignancy, autoimmune diseases, or
Definition drome was used to describe a systemic immunodeficiency {3809}. Because the
Systemic EBV-positive T-cell lymphoma disease secondary to acute primary EBV earl iest described cases, wh ich were
of childhood is a life -threatening ill ness of infection affecting previously healthy chi l- found in western populations, showed
chi ldren and young adults, characterized dren, but the disease has since been EBV predom inantly in B cells {779,3809},
by a clonal proliferation of EBV-infected shown to be a monoclonal CDS+ T-cell CAEBV was originally thought to be a
T cells with an activated cytotoxic phe- EBV-associated lymphoproliferative dis- disorder affecting B ce lls, but has since
notype. It can occur shortly after primary been shown to affect primarily T cells and
acute EBV infection or in the setting of NK cells {780,2025,2026). Progress ion
chronic active EBV infection (CAEBV). to EBV-positive T-cel l lymphoma is not
It has rapid progression, with multior- unusual {1877,1918,2026,3269). A more
gan failure, seps is, and death, usually severe form of CAEBV, characterized by
within a timeframe of days to weeks. A high fever, hepatosplenomegaly, exten-
haemophagocytic syndrome is nearly al - sive lymphadenopathy, haemophago-
ways present This entity has some clin- 72 bp- cytic syndrome, and pancytopenia, has
icopathological features overlapping with been described in patients in Japan
those of aggressive NK-cell leukaemia. {2025,2028,3838}. These patients had
TCRG higher viral copy numbers in peripheral
ICD-0 code 9724/3
Fig. 14.17 Systemic EBV-positive T-cell lymphoma of
blood, as well as monoclonal expan-
ch ildhood. PCR for TR gamma rearrangement dem- sion of EBV-infected T cel ls or NK cells.
Synonyms and historical terminology onstrates an identical T-cell clone in liver, spleen, and Severe CAEBV with monoclonal EBV-
Historically, this process has been de- lymph nodes. positive T-cell proliferation is part of the
........""""-.....
Fig.14.19 Systemic EBV-positive T-cell lymphoma of childhood. Lymph node. A The lymph node shows partial preservation of the architecture with residual regres-
sive follicles and expanded interfollicular area. Inset: The interfollicular infiltrate is polymorphic with some relatively large cells with irregular nuclei and prominent nucleoli.
B The infiltrating lymphocytes are CDS-positive. Inset: The atypical cells are CDS-positive C Many cells are positive for EBV-encoded small RNA (EBER). Inset: Double staining
demonstrates that the EBER positive cells (black) are positive for CDS (brown).
Fig. 14.21 Systemic EBV-positive T-cell lymphoma of childhood. A The spleen shows depletion of the wh ite pulp and prominent sinusoidal and nodular lymphoid infiltrates.
The nodules are composed predominantly of CD4+ cells. B In situ hybridization for EBV-encoded small RNA (EBER) shows that the CD4+ cel ls are also positive for EBV RNA.
Chronic active EBV infection Synonym genes related to the EBV immune response
of T- and NK-cell type, Systemic chronic active EBV infection of are responsible for the development of this
T-cell and NK-cell type disease {780,2023). EBV-specific cyto-
systemic form
toxic T lymphocyte activity is impaired in
Definition Epidemiology patients with CAEBV {780,3829,4071).
Chronic active EBV infection (CAEBV) of Systemic CAEBV of T- and NK-cell type
T-cell or NK-cell type is a systemic EBV- has a strong racial predisposition, with Localization
positive polyclonal, oligoclonal, or (often) most cases reported from Asia, primar- This is a systemic disease. The most
monoclonal lymphoproliferative disorder ily in Japan {1954, 2025,2026, 2951, commonly involved sites are the liver,
characterized by fever, persistent hepa- 3838}; the Republic of Korea {1676}; and spleen, lymph nodes, bone marrow, and
titis, hepatosplenomegaly, and lymphad- Taiwan, China {4244). It has also been skin. The lungs, kidneys, heart, CNS, and
enopathy, which shows varying degrees reported in Latin America and rarely in gastrointestinal tract can also be involved
of clinical severity depend ing on the host western {3422,3592,3730} and African {2025, 2026, 3062).
immune response and the EBV viral load. populations {3353). It occurs most often
The revised diagnostic criteria for CAEBV in children and adolescents. Adult-onset Clinical features
include infectious mononucleosis- like disease is rare and appears to be rapidly Approximately 50% of patients present
symptoms persisting for > 3 months, in- prog ressive and more aggressive {124, with infectious mononucleosis- like ill-
creased EBV DNA(> 10 25 copies/mg) in 1792). There is no sex predilection. ness, including fever, hepatospleno-
peripheral blood, histological evidence of megaly, and lymphadenopathy. Accom-
organ disease, and demonstration of EBV Etiology panying symptoms include ski n rash
RNA or viral protein in affected tissues in Although the etiology is unknown, the (occurring in 26% of cases), severe mos-
patients without known immunodeficien- strong racial predisposition for the devel- quito bite allergy (in 33%), hydroa vaccini-
cy, malignancy, or autoimmune disorders. opment of CAEBV of T- and NK-cell type forme- like eruptions (in 10%), diarrhoea
in immunocompetent individuals strongly (in 6%), and uveitis (in 5%). Laboratory
suggests that genetic polymorphisms in tests reveal pancytopenia and abnormal
~
•
.... . .
• #
~
•' :
Fig.14.24 Chronic active EBV infection of probable NK-cell type in the intestine of a 4-year-old girl with recurrent bowel perforation and NK-cell lymphocytosis. A Colon resection
with ulceration of the mucosa. B The submucosa shows granulation tissue and a subtle lymphoid infiltrate without atypia. C In situ hybridization for EBV-encoded small RNA
(EBER) shows scattered positive cells. Inset: Double staining shows that the EBER+ cel ls (brown) are CD3-positive (red). CD56 was positive in fewer cells (not shown).
liver function . In most patients, EBV se- include haemophagocytic syndrome lmmunophenotype
rology reveals high titres of lgG antibod- (which occurs in 24% of cases), coronary The immunophenotype of the EBV-infect-
ies against EBV viral capsid antigen and artery aneurism (in 9%), hepatic failure (in ed cells varies; it includes T cells in 59%
early antigen. All patients have increased 15%), interstitial pneumon ia (in 5%), CNS of cases, NK cells in 41%, and both T and
levels of EBV DNA (> 10 25 copies/mg) involvement (in 7%), gastrointestinal per- NK cells in 4% . CAEBV of B-cell pheno-
in the peripheral blood. The clinical foration (in 11%), and myocarditis (in 4%). type is seen in only 2% of cases. Unlike
course varies but is usually protracted, Due to the variety of the clinical pres- the T cells in systemic EBV-positive T-cell
with some patients surviving for many entations, diagnosis is often delayed. lymphoma of childhood, the T cells in
years without disease progression. The Progression to NK/T-cell lymphoma or CAEBV are predominantly CD4-positive,
severity of CAEBV is probably related aggressive NK-cell leukaemia occurs in and less often show a cytotoxic CDS+
to the immunological response of the 16% of cases {1676,2026,202S,2951}. phenotype {7S0,2026}. EBV-encoded
individual and to the EBV viral load. The small RNA (EBER) is positive
clinical course also varies depending on Microscopy
the predom inant infected cel l type in the The infiltrating cells do not show changes Cell of origin
peripheral blood (2024,2025}. Patients suggestive of a neoplastic lymphopro- The postulated cells of origin are CD4+
with T-cell CAEBV have a shorter survival liferation. The liver shows sinusoidal T ce ll s, NK ce lls, cytotoxic CDS+ lympho-
time than patients with NK-cell disease. and portal infiltration suggestive of vi- cytes, and (rare ly) gamma delta T ce lls.
Patients with T-cell CAEBV often present ral hepatitis. The spleen shows atrophy
with prominent systemic symptoms and of the white pulp with congestion of the Genetic profile
high titres of EBV-specific antibodies and red pulp. The lymph nodes exhibit vari- Chromosomal aberrations are detected
have rapid disease progress ion. In con- able morphology, including paracortical in a minority of cases (2026}. One se-
trast, patients with NK-cell disease, in ad - and follic ul ar hyperplasia, focal necrosis, ries reported monoclonally rearranged
dition to mild systemic symptoms, often and small epithe lioid granulomas. Bone TR genes in S4% of cases, oligoclonally
have severe mosquito bite al lergy, rash, marrow biopsies usually appear normal. rearranged TR genes in 11%, and poly-
and high levels of lgE, and do not always In cases complicated by haemophago- clonal TR genes in on ly 5% of cases
have elevated EBV-specific antibody cytic synd rome, sinus histiocytosis with (2026). However, this report includes
titres. Life-threate ni ng complications erythrop hagocytosis is present (2026). cases of 'severe CAEBV', wh ich might be
Fig.14.25 Chronic active EBV infection in lymph node. A The lymph node shows follicular and paracortical hyperplasia. B At high magnification, the interfollicular areas show a
polymorphic infiltrate lacking cytolog ical atypia. C In situ hybridization for EBV-encoded small RNA (EBER) shows scattered positive cells. Inset: Double staining shows that the
EBER+ cel ls (black) are CD4-positive (brown).
, -
B Higher magnification.
'
Postulated normal counterpart (2025). Chromosomal alterations are rare- course, with an increased risk of de-
Mature activated NK cell ly identified (2026). In situ hybridization veloping haemophagocytic syndrome
for EBV-encoded small RNA (EBER) is and aggressive NK-cell leukaemia after
Genetic profile positive in a fraction of the NK ce ll s. LMP1 2-17 years (med ian: 12 years). Pati ents
NK cells are infected with monoclonal is detected by PCR in peripheral blood, with chromosomal abe rrations appear
EBV as demonstrated by term inal repeat ind icating type II EBV latency (1804). to have a higher risk of developing lym-
analysis, indicating clonal expansion of phoma/leukaemia (2026,4015).
NK cells. Rarely, monoclonal TR gene Prognosis and predictive factors
rearrangement has been documented Patients usually have a long clinical
Definition an average patient age of 58 years. The Table 14.02 Clinical spectrum of
Adu lt T-ce ll leukaemia/lymphoma (ATLL) male-to-female ratio is 1.5:1. ATLL is· a HTLV-1 - associated diseases "
.. · , 1r_.;hi w~f· , ·
is a mature T-cell neoplasm most often system ic disease, and the prog nos is is Neoplastic disorders
composed of highly pleomorphic lym- poor (Fig . 14.45, p. 367). Adu lt T-cell leukaemia/lymphoma
phoid cell s. The disease is usually widely Smoulderi ng
dissem inated and is caused by the hu- ICD-0 code 9827/3 Chron ic
man retrovirus HTLV-1. Most ATLL pa- ·r Acute
Lymphomatous
tients present with widespread lymph Synonyms 1
Clinical features
Several clinical variants have been identi-
fied: acute, lymphomatous, chronic, and
smouldering (see Table 14.03) {3660}.
Fig.14.32 Adult T-cell leukaemia/lymphoma. Macroscopic findings of cutaneous lesions have been classified as The acute variant is most common and
A erythema, B papules, and C nodules. is characterized by a leukaemic phase,
often with a markedly elevated white
but the affected patients often derive from factor (HBZ) is thoug ht to be important blood cell (WBC) count, skin rash, and
an endemic region of the world. ATLL oc- for T-cell proliferation and oncogenesis generalized lymphadenopathy. Hyper-
curs only in adults, and the patient age {3532}. However, add itional genetic alter- calcaemia, with or without lytic bone
at onset ranges from the third to the ninth nations acquired over time may result in lesions, is a common feature. Patients
decade of life, with an average patient the development of a malignancy. Hyper- with acute ATLL have systemic disease
age of 58 years. The male-to-female ratio methylation is associated with disease accompanied by hepatosplenomegaly,
is 1.5:1 {4405}. progression {3528}. HTLV-1 can also indi- constitutional symptoms, and elevated
rectly cause other diseases (Table 14.02), lactate dehydrogenase. Leukocytosis
Etiology such as HTLV-1-associated myelopathy I and eosinophilia are common . Many pa-
HTLV-1 is causally linked to ATLL, but tropical spastic paraparesis {3880}. tients have an associated T-cell immuno-
HTLV-1 infection alone is not sufficient to deficiency, with frequent opportunistic
result in neoplastic transformation of in- Localization infections such as Pneumocystis jirovecii
fected cells. HTLV-1 enters cells mainly Most patients present with widespread pneumonia and strongyloidiasis.
through cell-to-cell contact via three lymph node involvement and involvement The lymphomatous variant is character-
cellular molecules: heparan su lfate pro- of the peripheral blood. The number of ized by prom inent lymphadenopathy but
teoglycan, neuropilin 1, and the glucose circulating neoplastic cells does not cor- without peripheral blood involvement.
transporter GLUT1 {1352}. Neuropilin 1 relate with the degree of bone marrow Most patients present with advanced-
appears to function as the viral receptor. involvement. This suggests that circu lat- stage disease similar to the acute form,
The p40 tax viral protein leads to tran- ing cells are recruited from other organs, although hypercalcaemia is seen less
scriptional activation of many genes in such as the skin, which is the most com- often.
HTLV-1- infected lymphocytes {1241l. In mon extralymphatic site of involvement Cutaneous lesions are common in both
addition, the HTLV-1 basic leucine zipper (involved in > 50% of cases). the acute and the lymphomatous forms
1 2 3 4
9kb-
Fig.14.38 Adult T-cell leukaemia/lymphoma (ATLL). A The pleomorphic (medium-sized and large cell) type shows a diffuse proliferation of atypical medium-sized to large lym-
phoid cells with irregular nuclei, intermingled with cerebriform giant cells (centre). B The lymph nodes in the pleomorphic small-cell type show a diffuse proliferation of atypical
medium-sized to small lymphoid cells. C The presence of pleomorphic tumour cells and background eosinophilia may simulate classic Hodgkin lymphoma.
lmmunophenotype
Tumour cells express T-cell- associated
antigens (CD2, CD3, CD5), but usually
lack CD?. Most cases are CD4-positive
and CDS-negative, but a few are CD4-
"
Fig.14.39 Adult T-cell leukaemia/lymphoma (ATLL). A The lymph nodes in Hodgkin-like ATLL show Reed-Stern-
berg-like giant cells of B-cell (not T-cell) lineage, which (B) react with CD30 antibody and are EBV-positive (not
negative and CDS-positive or double-
positive for CD4 and CDS. CD25 is
shown). strong ly expressed in nearly all cases.
The large transformed cel ls may be posi-
tive for CD30, but are negative for ALK
{3SS2} and cytotoxic molecules. Tumour
cells frequently express the chemokine
receptor CCR4. FOXP3, a feature of
T regulatory (Treg) cells, is expressed in
a subset of cases {194S,339S}, but often
only in a subset of the neoplastic cells.
Grading
Monoclonal There is no formal grading system for
(malignant transformation) ATLL. However, the four clinical vari-
ATLL ants - acute (leukaemic), lymphomatous,
chronic , and smouldering - vary in their
Monoclonal
clinical course and cytological atypia
{3660). In the chronic and smoulder-
Polyclonal intermediate ing forms the neoplastic cells are small,
Not and can have minimal cytological atypia.
Pronounced cytolog ical atypia is seen in
the acute and lymphomatous forms.
Oncogenes and other molecular of which are involved in T-ce ll receptor Prognosis and predictive factors
changes signal ling. This study also confirmed a Clin ical subtype, patient age, perfor-
Neoplastic cells show monoclonal inte- high incidence of CCR4 mutations and mance status, and serum calcium and
gration of HTLV-1. No clonal integration identified mutations in CCR7 in some lactate dehydrogenase levels are major
is present in healthy carriers {4075). Tax, other cases. The additi onal mutations prognostic factors (4410). The survival
encoded by the HTLV-1 pX reg ion, is a identified affect the NF-kappaB pathway time for the acute and lymphomatous
critical non-structural protein that plays and genes involved in T-cell signalling. variants ranges from 2 weeks to > 1 year.
a key role in leukaemogenesis and acti- Whole-genome sequencing identified in- Death is often caused by infectious com-
vates a variety of cellular genes {3126}. tragenic deletions involving TP73, a hom- pl ications, including P. jirovecii pneumo-
Enhancement of cAMP response ele- ologue of TP53. These deletions resulted nia, cryptococcal mening itis, disseminat-
ment-bind ing transcription factor (CREB) in mutant p73, lacking the transactiva- ed herpes zoster, and hypercalcaemia
phosphorylation by Tax appears to play tion domain (TAD). Recurrent splice-s ite (3660}. The chronic and smouldering
a role in leukaemogenesis {2022). CREB mutations were found in GATA3, HNRN- forms have a more protracted clinical
is high ly phosphorylated in a panel of PA281, and FAS. course and better survival , but can pro-
HTLV-1 - infected human T-cell li nes, and ATLL genomes demonstrated prom inent gress to an acute phase with an aggres-
Tax is respons ible for promotin g elevated CpG island DNA hypermethyiation, lead - sive cou rse in approxi mate ly 25% of
leve ls of CREB phosphorylation . Howev- ing to transcriptome silencing of many patients {1961 ,2954).
er, Tax is not critical to sustained tumour genes, including genes encoding major
cell growth and is inactivated in a high histocompatibi lity complex (MHC) class I,
proportion of cases of ATLL {1957). HBZ death receptors, and immune check-
also appears to play a critical role in tu- po ints, providin g a mechanism for im-
morigenesis {4487). HBZis the only gene mune escape of the tumour ce lls {1957).
that is cons istently expressed in all ATLL
cases; it modulates a variety of ce llu lar
OS according to the clinical subtypes.
signalling pathways that are related to
ce ll growth, immune response, and T-cell
1.0
differentiation . In who le-transcriptome ~ST(-.) 95•;c1
Definition
Extranodal NK/T-cell lymphoma, nasal
type, is a predominantly extranodal lym-
phoma of NK-cell or T-cell lineage, char-
acterized by vascular damage and de-
struction, prominent necrosis, cytotoxic
phenotype, and association with EBV.
It is designated an NK/T-cell lymphoma
because although most cases appear
to be genuine NK-cell neoplasms, some
cases are of cytotoxic T-cell lineage.
Synonyms
Ang iocentric T-cell lymphoma (obsolete);
malignant reticulosis, NOS (obsolete);
malignant midline reticulosis (obsolete);
polymorphic reticulosis (obsolete); lethal
midline granuloma (obsolete); 'Jll.....~VJ~ r
w~
. ·• ....::'J\ls.Jiira!:Wii
T/NK-cell lymphoma Fig.14.47 Extranodal NK/T-cell lymphoma of the skin. Fig.14.48 Extranodal NK/T-cell lymphoma of the skin,
The lymphomatous infiltrate involves the epidermis, intravascular variant. Neoplastic cells are confined to
Epidemiology dermis, and subcutaneous tissue. Necrosis is prominent vascular spaces. Note the uninvolved hair follicle and
Extranodal NK/T-cell lymphoma is more in the dermal component. glandular structures.
prevalent in Asians and the indigenous
populations of Mexico, Central and South mal form {133,649,1091,1646,191 6,2607, sion, including following transplantation
America {187,640,2232,3266,3949l. It 3266,3842,4133} with type II latency (1 702,2156).
occurs most often in adults, with a report- (EBNA1+, EBNA2-, LMP1 +), and com-
ed median patient age of 44-54 years monly shows a 30 bp deletion in the LMP1 Localization
(189, 647, 704, 1484, 1858, 23 05, 3 062, gene (708,1000,1091,2139,3868}. Most Extranodal NK/T-cell lymphoma almost
3210). It is more common in males than stud ies show that the EBV is almost al- always has an extranodal presentation.
in females. ways of subtype A (275,1091,1484,3120, The upper aerod igestive tract (nasal cav-
3842,4023) The disease activity can be ity, nasopharynx, paranasal sinuses, and
Etiology monitored by measuring circulating EBV palate) is most commonly involved, with
The very strong association with EBV, DNA; a high titre is correlated with ex- the nasal cavity being the prototypical site
irrespective of the ethn ic ori gin of the tensive disease, unfavourable response of involvement. Preferential sites of extra-
patients, suggests a pathogenic role of to therapy, and poor survival {188,4257). nasal involvement include the skin, soft
the virus (133,647,649,1091 ,1916,3266, Extranodal NK/T-cell lymphomas can tissue, gastrointestinal tract, and testes.
41 33). EBV is present in a clonal episo- occur in the setting of immunosuppres- Some cases may be accompanied by
secondary lymph node involvement {640,
647,1996,2154,3154,4023}. Rare cases
with features of intravascular lymphoma
have been reported, involving sites such
as the skin and CNS {2138,2372,2810,
4385).
Primary EBV-positive nodal T-cell or NK-
cell lymphomas have been reported {178,
718, 1901}. These usually have a mono-
morphic pattern of infiltration and lack
the angiodestruction and necrosis seen
Fig. 14.46 Extranodal NK/T-cell lymphoma, nasal type. A Expansion of the nasal bridge. B CT. The tumour in the in extranodal NK/T-cell lymphoma. They
nasal cavity extends upwards into the orbit, resulting in proptosis. are more common in elderly patients, or
in the setting of immune deficiency. They tract (often referred to as extranasal NK/ nodes can be involved as part of dissem-
are considered a variant of peripheral T-cell lymphomas) have variable presen- inated disease. Marrow and peripheral
T-cel l lymphoma, NOS, and seem dis- tations, depending on the major site of blood involvement can occur, and such
tinct from cases with primary extranodal involvement. Skin les ions are common ly cases may overlap with aggressive NK-
presentations. nodular, often with ulceration. Intestinal cell leukaemia.
lesions often manifest as perforation or
Clinical features gastrointestinal bleeding. Other involved Microscopy
Patients with nasal involvement present sites present as mass lesions. The pa- The histological features of extranodal
with symptoms of nasal obstruction or tients common ly have high stage disease NK/T-cell lymphoma are similar irrespec-
epistaxis due to the presence of a mass at presentation, with involvement of multi- tive of the site of involvement. Mucosal
lesion, or with extensive destructive mid- ple extranodal sites. Systemic symptoms sites often show extensive ulceration.
facial lesions (lethal midline granuloma). such as fever, malaise, and we ight loss The lymphomatous infiltrate is diffuse
The lymphoma can extend to adjacent can be present (647,1996,4357). Lymph and permeative. Mucosal glands often
tissues, such as the nasopharynx, para-
nasal sinuses, orbits, oral cavity, palate,
and oropharynx. The disease is often lo-
calized to the upper aerodigestive tract at
presentation, and bone marrow involve-
ment is uncommon (4356). The disease
may disseminate to various sites (e.g. the
skin, gastrointestinal tract, testes, and
cervical lymph nodes) during the clinical
course. Some cases may be complicat-
ed by haemophagocytic syndrome (704,
... • .. .I
2154) Fig.14.50 Extranodal NK/T-cell lymphoma, nasal type. A The lymphomatous infiltrate shows infiltration and destruc-
Extranodal NK/T-cell lymphomas occur- tion of an artery. B In th is case involving the skin, the lymphomatous infiltrate has an angiocentric angiodestructive
ring outside of the upper aerodigestive quality.
become widely spaced or are lost. An an- phocytes, plasma cells, histiocytes, and variably expressed. Other T-cell-associ-
giocentric and angiodestructive growth eosinophils), may mimic an inflammatory ated and NK-cell-associated antigens,
pattern is frequently present, and fibri- process {640,1591). The lymphoma can including CD4, COB, CD16, and CD57,
noid changes can be seen in the blood sometimes be accompanied by florid are usually negative. The su bset of cases
vessels even in the absence of angioinva- pseudoepithel iomatous hyperplasia of of cytotoxic T-cell lineage may express
sion. Coagulative necrosis and admixed the overlying epithelium (2355) CDS, COB, and T-cell receptor (gamma
apoptotic bodies are common findings. delta or alpha beta) (1B58,3210,4407}.
These have been attributed to vascular lmmunophenotype Cytotoxic molecules (e.g. granzyme B,
occlusion by lymphoma cells, but other The most typical immunophenotype TIA1, and perforin) are positive {1091}.
factors (e.g. chemokines and cytokines) of extranodal NK/T-cell lymphoma is: HLA-DR, CD25, FAS (also known as
have also been implicated {3943). CD2+, CD5-, CD56+, surface CD3- (as CD95), and FASL are commonly ex-
The cytological spectrum is very broad. demonstrated on fresh or frozen tissue), pressed {2B5B,2955}. CD30 is positive
Cells may be small, medium-sized, large, and cCD3-epsilon+ (as demonstrated on in about 30% of cases {1 B9,14B4, 2021,
or anaplastic. In most cases, the lympho- fresh, frozen, or fixed tissues) {640,64B, 2139,2305). Nuclear expression of mega-
ma is composed of medium-sized cells 1B14,1819,3266,4069}. CD56, althoug h a karyocyte-associated tyrosine kinase
or a mixture of small and large cells. The highly useful marker for NK cells, is not (MATK) is common {3210,3B90}.
cells often have irregu larly folded nuclei, specific for extranodal NK/T-cell lym- Lymphomas that demonstrate a CD3-
which can be elongated. The chromatin phoma, and can be expressed in some epsilon+, CD56 - immunophenotype are
is granular, except in the very large cells, peripheral T-cell lymphomas. CD43 and also classified as extranodal NK/T-cell
wh ich may have vesicular nuclei. Nucle- CD45RO are often positive, and CD? is lymphomas if both cytotoxic molecules
oli are generally inconspicuous or small.
The cytoplasm is moderate in amount
and often pale to clear. Mitotic figures
are easily found, even in small cell- pre-
dominant lesions. On Giemsa-stained
touch preparations, azurophilic granules
are commonly detected. Ultrastructurally,
electron-dense membrane-bound gran-
ules are present.
Extranodal NK/T-cell lymphomas, par-
ticularly those in wh ich small-cell or
-<l"
mixed-cell populations predominate, Fig.14.53 Extranodal NK/T-cell lymphoma, nasal type. A This example is difficult to diagnose because the neo-
and those accompanied by a heavy ad- plastic cells are practically indistinguishable from normal small lymphocytes. There are many admixed plasma
mixture of inflammatory cells (small lym- cells. B The presence of large numbers of cells staining for CD56 supports a diagnosis of lymphoma.
Introduction Table 14.04 Comparison of enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic
intestinal T-cell lymphoma (MEITL)
Jaffe E.S. Bhagat G. Feature EATL MEITL
Chott A Tan S.Y.
Ott G. Stein H. Ethnicity (excess incidence) Northern European Asian, Hispanic
Chan J.K.C. Isaacson P.G. Risk factors Coeliac disease, HLA-DQ2/DQ8 None recognized
Staging mesenteric lymph nodes are commonly many as 40% of cases exhibit predomi-
The Ann Arbor staging system, with or involved. Occasionally, lymph node in- nant large cell or anaplastic cytomor-
without the modification proposed by Ro- filtration by EATL occurs in the absence phology {2456). Angiocentricity and an-
hatiner et al. {3394}, is frequently used for of macroscopic evidence of intestinal gioinvasion, as well as extensive areas of
staging EATL. High stage disease is de- disease. necrosis, are frequently observed. Most
tected in 43-90% of patients at diagnosis tumours have an admixture of inflam-
{932,1276,2456,3675). Microscopy matory cells, including large numbers of
The neoplastic lymphocytes exhibit a histiocytes and eosinophils, which may
Macroscopy wide range of cytological appearances obscure the relatively small number of
The tumour may form ulcerating nodules, {2456,4370). Most lymphomas show neoplastic cells in some cases. Intra-
plaques, strictures, or (less commonly) pleomorphic medium-sized to large cells epithelial spread of tumour cells may be
a large exophytic mass. The uninvolved with round or angulated vesicular nu- striking, but sometimes only si ngle scat-
mucosa can be thin and can show loss clei, prominent nucleoli, and moderate tered atypical lymphocytes are observed
of mucosal folds. The mesentery and to abundant pale-staining cytoplasm. As in the epithelium. The intestinal mucosa
~... . -
Fig. 14.59 Adjacent uninvolved mucosa in enteropathy-associated T-cell lymphoma. Increased numbers of intraepithelial lymphocytes (A) are CD3-positive (B), COB-negative
(C), and CD56-negative (D).
A Genetic profile
TRB or TRG genes are clonally re-
arranged in virtually all cases {169,2456,
2794). Unlike primary nodal peripheral
T-cell lymphoma, most EATLs (-80%)
either display gains of the 9q34 region,
which harbours known proto-oncogenes
(e.g. NOTCH1, ABL1, and VAV2) or, alter-
natively, show deletions of 16q12.1 (297,
596,937,4471) Similar changes are also
observed in monomorphic epitheliotrop-
B ic intestinal T-cell lymphoma. However,
Fig.14.61 Enteropathy-associated T-cell lymphoma (EATL). A Capillary gel electrophoresis showing a clonal TRB EATLs frequ ently display chromosomal
gene rearrangement product (dominant peak on the right) in a duodenal biopsy sample from an individual with type 2 gains of chromosomes 1q and 5q, which
refractory coeliac disease. B Capillary gel electrophoresis showing a similar clonal TRB gene rearrangement in an are less common in monomorphic epi-
EATL that arose in the stomach a couple of years later. theliotropic intestinal T-cell lymphoma
(937,4471 }.
villous atrophy is usually severe (subtotal EATL (3571,3864) Disruption of intestinal Losses at 9p are detected in 18% of
or total). The intraepithelial lymphocytes immune homeostasis by deregulated ex- EATLs; however, LOH at 9p21, targeting
lack significant cytological atypia, but pression of IL15 contributes to disease the cell-cycle inhibitor CDKN2A/B is ob-
they can be widely distributed through- pathogenesis {7,1747,2635,2639}. IL15 served in 56% of cases, accompanied
out the gastrointestinal tract {599,2454, also increases su rvival of the aberrant by loss of p16 protein expression (2923,
4186). Small aggregates of lymphocytes intraepithelial lymphocytes (2457), which 4471). Loss of the 17p12-13.2 region,
are seen in the lamina propria in approxi- can facilitate genomic instability and ac- containing the TP53 tumour suppressor
mately half of the cases (4178). Some quisition of genetic abnormalities. gene, is noted in 23% of EATLs, but aber-
cases exhibit ulcerated mucosa associ- Recurrent gains of chromosome 1q22-44 rant nuclear p53 expression can be seen
ated with variable degrees of chronic are detected in type 2 refractory coeliac in 75% of cases (937,2923}. Recent stud-
inflammation and a relative paucity of disease in common with EATL (297,937, ies have reported recurrent mutations in
intraepithelial lymphocytes (ulcerative je- 2454,4187,4471). This finding suggests constituents of the JAK-STAT signalling
junitis) (169,223,599). early acquisition of chromosome 1q ab- pathway in EATL {2869A} Add itionally,
The identification of TCR gene rearrange- normalities in the evolution of EATL. Loss the detection of JAK1 and STAT3 muta-
ments of similar size in biopsies exhibit- of p16 protein, in the absence of LOH at tions in type 2 refractory coeliac disease
ing features of type 2 refractory coeliac chromosome 9p21, is observed in 40% implicates deregulation of JAK-STAT sig-
disease and concurrent or subsequent of type 2 refractory coeliac disease cas- nalling to be an early event in disease
EATL helped establish that the aberrant es exhibiting features of ulcerative jejuni- pathogenesis {1116A}.
intraepithelial lymphocytes are precur- tis, and aberrant nuclear p53 expression
sors of EATL in a proportion of cases and can be detected in 57% of cases in the Genetic susceptibility
that they constitute a neoplastic popula- absence of molecular lesions of TP53 Coeliac disease, or gluten-sensitive
tion (low-grade lymphoma of intraepithe- (2923). enteropathy, predisposes to EATL. Coe-
lial T lymphocytes, EATL in situ, or cryptic Most patients have severe symptoms liac disease is a polygenic disorder with
EATL) {169, 223,562,599,4371 }. and they usually have profound malnour- various ri sk loci associated, including the
In most cases, the aberrant intraepithe- ishment (body mass index < 18) due to HLA locus. EATL is associated with the
lial lymphocytes are considered to be of protein-losing enteropathy {1755,2454, HLA-DOA 1*0501 and HLA-0081*0201
alpha beta TCR lineage. However, recent 3445). Large ulcers or stenotic areas genotypes {49). More than 90% of EATL
studies have suggested that some cas- are frequently observed on endoscopy patients carry HLA-002.5 heterodimers
es might derive from gamma delta TCR (2454). As systemic dissemination of ab- encoded by HLA-OQA 1*05 and HLA-
T cells or possibly immature T/NK-cell errant intraepithelial lymphocytes occurs 0081 *02 alleles, either in cis or trans
precursors (innate immune cells), and in a high proportion of cases (44- 60%), configu ration (1708}.
that the maturational state of the cell of patients may present with extraintestinal
orig in could impact the risk of extraintes- symptoms or disorders (e.g. skin lesions)
tinal dissemination and transformation to (2454,4178,4186). The 5-year survival
Indolent T-cell Fig. 14.68 Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, duodenum. Infiltrate fills the lami-
lymphoproliferative disorder of na propria and focally extends beyond the muscularis mucosae. However, glands are largely intact.
the gastrointestinal tract
Jaffe E.S. Bhagat G. Clinical features c lini cal course. A subset of patients are
Chott A. Tan SY Presenting symptoms include abdominal at risk for disease progression and more
Ott G. Stein H. pain, diarrhoea, vomiting, dyspepsia, and widespread disease, usually after many
Chan J.K.C. Isaacson P.G. weight loss {561,3145). The clinical course years {561,2506).
is chronic, but progression to d issem inat-
ed disease has been reported infrequent- Macroscopy
Definition ly. Peripheral lymphadenopathy is not The mucosa of affected sites in the gas-
Indolent T-cell lymphoproliferative disor- present, but a subset of patients exhibit trointestinal tract is thickened, with promi-
der of the gastrointestinal tract is a clonal mesenteric lymphadenopathy {2506). nent folds or nodularity. In some cases,
T-cell lymphoproliferative disorder that the infiltrate produces intestinal polyps
can involve the mucosa in all sites of the Spread resembling lymphomatous po lyposis
gastrointestinal tract, but is most com- Mu ltiple sites in the gastrointestinal tract {1640,1794}. The mucosal surface can
mon in the small intestine and colon. The are involved, with a chron ic relapsing be hyperaemic, with superficial erosions .
lymphoid cells infiltrate the lamina pro-
pria but usually do not show invasion of Microscopy
the epithelium. The c linical course is in - The lamina propria is expanded by a
dolent, but most patients do not respond dense, non-destructive lymphoid infil-
to conventional chemotherapy. A sub - trate {3145). Infiltration of the muscularis
set of cases progress to a higher-grade mucosae and submucosa may be seen
T-cell lymphoma with spread beyond the focally. The mucosal glands are dis-
gastro intestinal tract. placed by the inf iltrate but not destroyed.
However, epitheliotropism is occas ionally
ICD-0 code 9702/1 seen. The infiltrate is monotonous, com -
posed of small, round, mature-appearing
Epidemiology lymphocytes. Admixed inflammatory
Fig. 14.69 Indolent T-cell lymphoproliferative disorder
The disease presents in adulthood, more of the gastrointestinal tract. Small polypo id lesions are cells are rare, but epithelioid granulo-
frequent ly in men than in women. Rare hyperaemic. Reprinted from Perry AM et al. {3145). mas may be foca lly present {563,2506).
cases have been reported in chi ldren. No Some of the histolog ical changes may re-
ethnic or genetic factors have been iden- semb le those of Crohn d isease; whethe r
tified for increased risk. However, some some of these patients truly have preced-
patients have a history of Crohn disease ing inflammatory bowel disease remains
{3145). uncertain.
Localization lmmunophenotype
Most patients present with d isease af- The ce ll s have a mature T-cell pheno-
fecting the small bowel or colon {3145, type, positive for CD3 . Most reported
3305). However, all sites in the gastroin- cases have been positive for CDS {3145},
testinal tract can be invo lved, inc luding but CD4 has been expressed in a sig-
the oral cavity and oesophagus {1082). Fig.14.70 Indolent T-cell lymphoproliferative disorder nificant number {561,2506,3305}. The
The bone marrow and peripheral blood of the gastrointestinal tract. The mucosa displays mul- CDS+ cases express TIA1, but gran-
are usually not involved. tiple small polyps (arrows). From Perry AM et al. {3145). zyme B is generally negative. Other
Cell of origin
The postulated cell of origin is a mature
peripheral T cell
Genetic profile
All reported cases have had clonal re-
arrangements of TR genes, either TRG or
TRB {2506,3145). Recurrent mutations or
translocations have not been identified.
In limited studies, activating mutations of
STAT3 were absent. In situ hybridization
for EBV-encoded small RN A (EBER) was
negative in all cases stud ied.
:..
Fig.14.73 Indolent T-cell lymphoproliferative disorder Fig.14.74 Indolent T-cell lymphoproliferative disorder
of the gastrointestinal tract. The Ki-67 proliferation in- of the gastrointestinal tract. CDS, duodenal biopsy.
dex is extremely low. Glands are largely intact, but some epitheliotropism is
seen.
Definition T-cell lymphomas {904,4217}. Peak inci- 3414}. Rare cases have been reported
Hepatosplenic T-cell lymphoma (HSTL) dence occurs in adolescents and young in patients with psoriasis or rheumatoid
is an aggressive subtype of extranodal adults (median patient age at diagnosis: arthritis receiving tumour necrosis factor
lymphoma characterized by a hepato- -35 years), with a male predominance inhibitors and immunomodulators {3825}.
splen ic presentation without lymphad- {178,319,797}.
enopathy and a poor outcome. The Localization
neoplasm results from a proliferation of Etiology Patients present with marked spleno-
cytotoxic T cells, usually of gamma delta As many as 20% of HSTLs arise in the megaly and usually hepatomegaly, but
T-cell receptor type. It is usually com- setting of chronic immune suppression, without lymphadenopathy. The bone
posed of medium-sized lymphoid ce ll s, most common ly during long-term immu - marrow is almost always involved {178,
demonstrating marked sinusoidal infiltra- nosuppressive therapy for so li d organ 319,797,4166}.
tion of sp leen, liver, and bone marrow. transp lantation or prolonged antigenic
stimulation {319,4168,4375} In this set- Clinical features
ICD-0 code 9716/3 ting, HSTL is regarded as a late-onset HSTL typically presents with hepatos-
post-transplant lymphoproliferative disor- plenomegaly and systemic symptoms .
Epidemiology der of host origin. A number of HSTL cas- Patients usually man ifest marked throm-
HSTL is a rare form of lymp homa, report- es have been reported in patients (espe- bocytopenia, often with anaemia and
ed in both western and As ian countries. cially children) treated with azathioprine leukopenia. Peripheral blood involvement
It accounts for 1-2% of all peripheral and infliximab for Crohn disease {922, is uncommon at presentation but may
Fig. 14.75 Hepatosplenic T-cell lymphoma. A Cords and sinusoids of the spleen are infiltrated by a monotonous population of neoplastic lymp hoid cel ls with medium-sized nuclei
and a moderate rim of pale cytoplasm. B The neoplastic cel ls diffusely infiltrate the hepatic sinusoids. C The bone marrow is usually hypercellular, with neoplastic cel ls infiltrating
sinusoids. D Neoplastic cells in the bone marrow are highlighted with immunohistochemistry for CD3. ·
Fig.14.77 Subcutaneous panniculitis-like T-cell lymphoma. A Tumour cel ls are associated with abundant histiocytes
Clinical features
conta ining apoptotic debris. B Neoplastic cells have round to oval hyperchromatic nuclei with inconspicuous nucleoli
and abundant pale cytoplasm. Cl ini cal symptoms are primarily related
to the subcutaneous nodul es. Systemic
symptoms may be see n in as many as
50% of patients. Laboratory abnormali-
ties, inc lu din g cytopen ias and elevated
liver function tests are common, and
a frank haemophagocytic syndrome
is seen in 15-20% of cases {1401}. In
such cases, hepatosplenomegaly may
be present. Lymph node involvement
is usually absent. Bone marrow invo lve-
ment has been reported rarely, with in-
Fig.14.79 Subcutaneous panniculitis-like T-cell
vo lvement of fat cells w ithin the marrow
Fig.14.78 Subcutaneous panniculitis-like T-cell
lymphoma. Neoplastic cells rim fat spaces. They are lymphoma. CDS staining highlights the atypical cel ls space {2133) .
usually medium-sized, with coarse chromatin. Mitotic rimming fat spaces.
figures are evident.
C-ALCL, cutaneous anaplastic large cell lymphoma; G, in germline configuration; PCGD-TCL, primary cutaneous gamma delta T-cell lymphoma; PDC, plasmacytoid
dendritic cell; R, rearranged; SPTCL, subcutaneous panniculitis-like T-cell lymphoma; TCL, T-cell lymphoma; TR, T-cell receptor.
1 •" ._ ...... :
..__,....,~· . --<\. 4'o.- k
Fig. 14.80 Subcutaneous panniculitis-like T-cell lym- Fig. 14.81 Subcutaneous panniculitis-like T-cell lym- Fig. 14.82 Subcutaneous panniculitis-like T-cell lym-
phoma. CD4 is negative in tumour cells but positive in phoma. The neoplastic cells stain for beta F1 , indicative phoma. Tumour cells have a cytotoxic phenotype and ex-
macrophages, which may be abundant. of origin from alpha beta T cells. press granzyme B as well as other cytotoxic molecules.
Definition lifestyle factors have also been associ - tracted period. Extracutaneous dissemi -
Mycosis fungoides is an epidermotro- ated with increased risk: obesity and nation may occur in advanced stages,
pic, primary cutaneous T-cell lymphoma a smoking history of 2:40 years {167). It mainly to the lymph nodes, liver, spleen,
characterized by infiltrates of small to me- has been speculated that mycosis fun- lungs, and blood {892). Involvement of
dium-sized T lymphocytes with cerebri- goides might be assoc iated with certain the bone marrow is rare {4320}.
form nuclei. The term mycosis fungo ides retroviruses, but no such association has
should be used only for classic cases, been identified through high-throughput Clinical features
characterized by the evolution of patch- sequencing {956). Mycosis fungoides has an indolent
es, plaques, and tumours, or for variants clinical course, with slow progression
with a sim il ar clinical course. Localization over years or sometimes decades from
The disease is generally limited to the patches to more-infiltrated plaques and
ICD-0 code 9700/3 skin, with variable distribution, for a pro- eventually tumours. In early stages, the
Epidemiology
Mycosis fungoides is the most common
type of cutaneous T-ce ll lymphoma and
accounts for almost 50% of all primary
cutaneous lymphomas {4320). Most pa-
tients are adults/elderly, but the disease
can also be observed in children and
adolescents {395,1218). The male-to-
female ratio is 2:1 {4320). Worldwide, the
incidence is about 10 cases per one mil-
lion population, with marked regional
variation {2085) and a higher incidence
in Black populations {1636}. An elevated •
risk of mycosis fungoides has been as-
sociated with several profess ions, includ-
ing crop and vegetable farming, painting,
woodworking, and carpentry. These find-
ings suggest possible environmental co-
factors in the pathogenesis of the disease
{167). Studies have shown increased risk Fig. 14.84 Early mycosis fungoides. Fig. 14.85 Early mycosis fungoides. A localized
for individuals in the petrochemical, tex- Generalized patches and thin plaques (stage IB). patch/thin plaque covering< 10% of the body surface
tile, and metal industries {776). Certain (stage IA).
"'
Fig. 14.90 Early mycosis fungoides. Neoplastic cells can be seen lining up in the basal
layer, referred to as a string-of-pearls pattern (CD3 stain).
T2 Patches, papules, or plaques covering > 10% of the skin surface. May further stratify into T2a (patch only) vs T2b (plaque ± patch)
T3 ~ 1 tumour"(~ 1 cm in diameter)
Lymph nodes
NO No clinically abnormal peripheral lymph nodesd; biopsy not required
N1 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 1 or NCI LN 0-2
N1a: Clone-negative•
N1 b: Clone-positive•
N2 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 2 or NCI LN3
N2a: Clone-negative•
N2b: Clone-positive•
N3 Clinically abnormal peripheral lymph nodes; histopathology Dutch grade 3-4 or NCI LN4; clone-positive or clone-negative
Viscera
MO ~vi sceral organ involvement
M1 J Visceral organ involvement (must have pathology confirmation1; organ involved should be specified)
Blodi
B0 Absence of significant blood involvement:
$ 5% of peripheral blood lymphocytes are atypical (Sezary) cells 9
BOa: Clone-negative•
BOb: Clone-positive•
B1 Low blood tumour burden: > 5% of peripheral blood lymphocytes are atypical (Sezary) cells, but criteria for B2 are not met
B1a: Clone-negative•
B1b: Clone-positive•
Stage
IA T1, NO, MO, B0-1 IB T2, NO, MO, B0-1
Ill T4, N0- 2, MO, B0-1 lllA T4, N0-2, MO, BO lllB T4, N0-2, MO, B1
{2972). Recognition of the early infiltrates localization of the neoplastic infiltrate, cal cells have medium-sized or large
can be difficult and can be facilitated by folliculotropic mycosis fungoides is less cerebriform nuclei and either a CD4-/
PCR for clonal TR rearrangement analy- accessible to skin-targeted therapies. CD8+ phenotype or (less commonly) a
sis {2972). N3 lymph nodes may simulate The 5-year disease-specific survival rate CD4+/CD8- phenotype. CD30 is often
peripheral T-cell lymphoma, NOS, or is approximately 70- 80%, which is sig- expressed. Unlike with classic mycosis
Hodgkin lymphoma. nificantly worse than that seen in classic fungoides, neither extracutaneous dis-
plaque-stage mycosis fungoides {4131). semination nor disease-related deaths
Variants have ever been reported {4320).
Folliculotropic mycosis fungoides Pagetoid reticulosis
Folliculotropic mycosis fungoides is char- Pagetoid reticulosis is characterized by Granulomatous slack skin
acterized by infiltrates of atypical (cere- patches or plaq ues with an intraepider- Granulomatous slack skin is an extreme-
briform) CD4+ T lymphocytes involving mal proliferation of neoplastic T cells ly rare subtype of cutaneous T-cell lym-
hair follicles, often with sparing of the {1516}. The term shou ld only be used phoma characterized clinical ly by the
epidermis {608}. Many cases show muci- for the localized type (Woringer-Kolopp development of bulky, pendu lous skin
nous degeneration of the hair follicles (fol- type) and not for the disseminated type folds in the flexural areas (axillae, groin),
licular mucinosis), but mucin deposition (Ketron- Goodman type), because most and histolog ically by a granulomatous
can be absent {1222,4131). The lesions cases corresponding to the latter cat- infiltrate within the dermis and subcuta-
preferentially involve the head and neck egory would instead be classified as ag- neous tissues, with clonal CD4+ T cells,
area and often present with grouped fol- gressive epidermotropic CD8+ cytotoxic abundant macrophages with many multi-
licular papu les and plaques associated T-cell lymphoma or cutaneous gamma nucleated giant cells, and loss of elastic
with alopecia {4131}. Due to the deep delta T-cell lymphoma {4320). The atypi- fibres {1989,2241}. Most reported cases
lmmunophenotype
The typical phenotype is C02+, CD3+,
TCR beta+, C05+, C04+, COB-, TCR
gamma-. Cases with a cytotoxic phe-
notype (COB+ and/or TCR gamma+) are
well recognized {2547,3390}. Such cases
have the same clinical behaviour and
prognosis as C04+ cases, and should
not be considered a separate entity
{2547). A COB+ phenotype has been re-
ported more commonly in paediatric my-
cos is fungoides. Expression of CD56 has
been observed in otherwise conventional
mycosis fungoides . A lack of CD7 is fre-
quent in all stages of the disease. Cu-
taneous lymphocyte antigen (CLA), as-
sociated with lymphocyte homing to the Fig.14.97 Granulomatous slack skin.
skin, is expressed in most cases. Other Diffuse lymphoid infiltrates admixed with histiocytes and
alterations in the expression of T-cell an- with several large, multinucleated giant cells.
tigens may be seen, but main ly occur in
the advanced (tumour) stages. Partial variants constitute the vast majority of cutaneous and extracutaneous disease,
expression of C030 by neoplastic cells all driver mutations, including mutations as reflected by the clinical stage. Patients
may be found in all stages, in particular in multiple components of the TCR and with limited disease generally have an ex-
in plaques and tumours of the disease. IL2 signalling pathways, in genes that cellent prognosis, with a similar survival
Cytotoxic granule-associated proteins drive T helper 2 (Th2) cell differentiation, as the general population {27,95B,3256,
are uncommonly expressed in the early in genes that facilitate escape from TGF- 4132}. Large Pautrier microabscesses
patch/plaque lesions, but may be posi- beta-mediated growth suppression, and dermal atypical lymphocytes in early
tive in neoplastic cells in more-advanced and in genes that confer resistance to lesions have been associated with pro-
lesions {41BB}. tumour necrosis factor receptor super- gression to advanced stage {4212). In
family (TNFRSF)-mediated apoptosis advanced stages, the prognosis is poor,
Cell of origin {736,259B,4039,4091,4134} Constitutive in particular in patients with skin tumours
A mature skin-homing C04+ T cell activation of STAT3 and inactivation of and/or extracutaneous dissemination
CDKN2A (also called p16/NK4a) and {337,4132). Failure to achieve complete
Genetic profile PTEN have been identified and may be rem ission after the first treatment, pa-
TR genes are found to be clonally re- assoc iated with disease progression tient age > 60 years, and elevated lactate
arranged in most cases when sensitive {3547). dehydrogenase are adverse prognostic
techniques (e.g. BIOME0-2) are used parameters {27,973), as is histological
{3211 }. Complex karyotypes are present Prognosis and predictive factors transformation with increase in blast cells
in many patients, in particu lar in the ad- The sin gle most important prognostic fac- (>25%) {155,609}.
vanced stages. Somatic copy-number tor in mycosis fungoides is the extent of
Definition Table 14.07 Histopathological staging for clinically abnormal lymph nodes (> 1.5 cm) in mycosis fungoides and
Sezary syndrome (SS) is defined by Sezary syndrome
the triad of erythroderma, generalized ISCL/EORTC
lymphadenopathy, and the presence of {2972} Dutch system {3552A} NCI classification {3532A}
clonally related neoplastic T cells with
N1 Category 1: LN O:
cerebriform nuclei (Sezary cel ls) in skin , DL, no atypical CMCs No atypical lymphocytes
lymph nodes, and peripheral blood . In
addition, one or more of the following LN 1:
criteria are required: an absolute Sezary Occasional, isolated atypical lymphocytes
cell count 21000/µL, an expanded CD4+ LN2:
T-cell population resu lting in a CD4:CD8 Clusters (3- 6 cells) of atypical lymphocytes
ratio of 210, and loss of one or more N2a Category 2: LN3:
T-cell antigens. SS and mycosis fungoi - DL with early involvement and Aggregates of atypical lymphocytes, but
des are c losely related neoplasms, but scattered atypical CMCs architecture preserved
are considered separate entities on the
N3 Category 3: LN4:
basis of differences in c linical behaviour Partial effacement of architecture, Partial or complete effacement of architecture,
and cell of origin {4211}. with many CMCs with many atypical lymphocytes
Category 4:
ICD-0 code 9701/3
Complete effacement of architecture
Synonym CMC, cerebriform mononuclear cell with nuclei >7.5 µm; DL, dermatopathic lymphadenopathy;
Sezary disease EORTC, European Organisation for Research and Treatment of Cancer;
ISCL, International Society for Cutaneous Lymphomas; NCI, United States National Cancer Institute.
Epidemiology a N2 is divided into two categories:
This is a rare disease, accounting for< 5% N2a (without clonally rearranged T cells) and N2b (with clonally rearranged T cells).
of all cutaneous T-cell lymphomas {4320).
It occurs in adults, characteristically pre-
sents in patients aged > 60 years, and Staging in combination with (1) a total Sezary cell
has a male predominance. Staging of mycosis fungoides and SS count 21000/µ L, (2) an expanded CD4+
is performed according to the Interna- T-cell population with a CD4:CD8 ratio
Localization tional Society for Cutaneous Lympho- of 2 10, or (3) an expanded CD4+ T-cell
As a leukaemia, SS is by definition a gen- mas (ISCL) I European Organisation for popu lation with abnormal immunophe-
eralized disease. Any visceral organ can Research and Treatment of Cancer (EO- notype including loss of CD? or CD26
be involved in advanced stages, but the RTC) system (Table 14.06, p. 387) {2972}. {2972). For determination of the Sezary
most common sites are the oropharynx, SS patients are erythrodermic (T4) and cell count, Sezary cells are defined as
lungs, and CNS. Bone marrow involve- have peripheral blood involvement, lymphocytes with hyperconvoluted cer-
ment is variable. which requires demonstration of clonal ebriform nuclei. SS cases are stage IVA1,
TR gene rearrangement (preferably the IVA2, or IVB according to the ISCL/
Clinical features same c lone in skin and peripheral blood) EORTC system.
Patients present with erythroderma and
generalized lymphadenopathy. Other Microscopy
features are pruritus, alopecia, ectropion, The histological features in SS may be
palmar or plantar hyperkeratosis, and similar to those in mycosis fungoides.
onychodystrophy. An inc reased preva- However, the cellular infiltrates in SS are
lence of secondary cutaneous and sys- more often monotonous, and epidermo-
temic malignancies has been reported in tropism may sometimes be absent. In
SS and attributed to the immunoparesis as many as one third of b iopsies from
associated with skewing of the normal patients with otherwise classic SS, the
T-cell repertoire and loss of normal circu- histological picture may be non-specific
lating CD4+ cells {1720). {4062). Involved lymph nodes charac-
Fig.14.98 Sezary syndrome. Generalized skin disease teristically show a dense, monotonous
with erythroderma. infiltrate of Sezary cells with effacement
lmmunophenotype
The neoplastic T cells have a CD3+,
CD4+, CDS- phenotype; characteristi-
cally lack CD? and CD26; and express
PD1 (also known as CD279) in almost all
cases {625). Sezary cells express cuta-
neous lymphocyte antigen (CLA) and
the skin-hom ing receptor CCR4 {1213},
as well as CCR? {2S25}. Flow cytometry
analysis of peripheral blood lymphocytes
shows a CD4+/CD7- (>30%) or CD4+/
Fig. 14.99 Sezary syndrome. Skin infiltrates with epidermotropic infiltrates of atypical, cerebriform lymphocytes.
CD26 - (> 40%) T-cell popu lation {356,
3718}.
Fig.14.100 Sezary syndrome. Morphology of Sezary cel ls in Giemsa-stained blood films (A) and by ultrastructural
Genetic profile
examination (B).
TR genes are clonally rearranged {3211,
430S,4309}. A characteristic gene ex-
pression signature consists of overex- CD28, and TNFRSF1B, may explain the 3546}. Hypermethylation and inactivation
pression of PLS3, ONM3, TWIST1, and constitutive activation of NF-kappaB in of genes involved in the FAS-dependent
EPHA4 and underexpression of STAT4 SS. RHOA mutations described in other apoptotic pathway is common {1S73}.
{1519,1941,4130). mature T-cell lymphomas are also present
Recurrent balanced chromosomal trans- in SS. Recurrent loss-of-function aberra- Prognosis and predictive factors
locations have not been detected in SS, tions also target epigenetic modifiers, in- SS is an aggressive disease, with a me-
but complex numerical and structural al- cluding AR/01A, in wh ich functional loss dian survival of 32 months and a 5-year
terations are common and similar to those from nonsense and frameshift mutations overall survival rate of 10-30%, depend-
in mycosis fungoides {294,552,2491}, and/or targeted deletions is observed in ing on stage {4320). Most patients die
including losses of 1p, 6q, and 10q and around 40% of SS cases {2005). Both of opportunistic infections. Lymph node
gain s of Sq, with isochromosome 17q as single nucleotide mutations and copy- involvement (stage IVA2) and visceral
a recurrent feature of SS {4190}. High- number variants affecting genes encod- involvement (stage IVB) indicate a worse
throughput sequencing techniques have ing members of the JAK/STAT pathway prognosis {343). The degree of peripheral
revealed a markedly heterogeneous pat- may also exp lain the constitutive activa- blood involvement at diagnosis may have
tern of novel gene mutations and focal tion of STAT3 in tumour cells. Mutations an impact on prognos is {2041,42 13}, but
copy-number variants, in dicatin g a high affecti ng chromatin-modifying genes the prognostic relevance of bone marrow
rate of genomic instability {736,2005, such as ONMT3A are also present in involvement is unknown.
4091,4150). Recurrent gain-of-function SS, as are frequent inactivating muta-
mutations affecting genes involved in T- tions of TP53 {736} and deletions of
ce ll receptor signalling, including PLCG1, CDKN2A (also called p16/NK4a) {2S43,
li~~ti.<i~~~~j.~·: •!i,WS~~tlilllr"
>i. <t I
Fig.14.102 Lymphomatoid papulosis type A. A Mixed inflammatory infiltrate with scattered large atypical cells. B Staining for CD30 shows scattered large atypical cells.
C Scattered large anaplastic cells expressing CD30.
lesions disappear within 3- 12 weeks and sheets of large CD30+ T cells with rela- times pageto id infiltrate of atypical small
may leave behind superficial scars. The tively few adm ixed inflammatory cells, to med ium-sized COB+, CD30+ pleo-
du ration of the disease may vary from very similar to cutaneous anaplastic morphic T cells, mimicking primary cuta-
several months to > 40 years. In as many large cell lymphoma (314). neous aggressive epidermotrop ic CDS+
as 20% of patients, LyP may be pre- LyP, Type D lesions (<5%) are character- cytotoxic T-cell lymphoma (3473}
ceded by, associated with, or followed ized by a strongly epidermotropic, some -
by another type of mal ignant lymphoma,
generally mycosis fungoides, cutaneous
anap lasti c large ce ll lymphoma, or Hodg-
kin lymphoma (314,910).
Microscopy
The histolog ical picture of LyP is ex-
tre mely variable, and in part correlates
with the age of the biopsied skin les ion.
Several histological subtypes of LyP have
been described .
Type A LyP is the most common type
(> 80%) and is characterized by scat-
te red or small clu sters of large atypical
(someti mes multinucleated or Reed-
Sternberg- like) CD30+ ce ll s intermingled
with numerous inflammatory ce ll s, includ-
ing small lymphocytes, neutrophils, and/
or eosinoph il s {314}.
LyP, Type B is uncommon (<5%) and is
characterized by a predom inantly ep i-
dermotropic infiltrate of small atypical
CD30+ or CD30- cel ls with cerebriform
nuclei, histolog ically simulating early-
stage mycosis fungoides (314). Fig.14.105 Lymphomatoid papulosis type D. A Marked epidermotropism of COB+ pleomorphic T cells mimicking
LyP, Type C lesions HO%) demonstrate cutaneous aggressive epidermotropic COB+ cytotoxic T-cell lymphoma. B Extensive epidermotropism of small to
a monotonous population or cohesive medium-sized pleomorphic T cells.
Some of these cases may have a gamma locus on 6p25.3 {1938). Patients are sions, and a single LyP lesion may show
delta T-cell phenotype (3390). older adults and often present with local- histological features of multiple subtypes.
Type E LyP (<5%) is characterized by angi- ized skin lesions. Histologically, skin le- Recognition of these different subtypes
ocentric and angiodestructive infiltrates of sions show extensive epidermotropism of LyP is important, to avoid misdiag-
small to medium-sized CDS+, CD30+ ple- by weakly CD30+ small to medium- nosis of other, often more aggressive,
omorphic T cells (1988). Vascular occlu- sized T cells with cerebriform nuclei and types of cutaneous T-cell lymphoma (see
sion, haemorrhages, extensive necrosis, strongly CD30+ medium-sized to large Table 14.08). However, the subtypes have
and ulceration may be present. Clinically, blast cells in the dermis, simulating trans- no therapeutic or prognostic implications.
patients present with a few papulonodular formed mycosis fungoides.
lesions that rapidly ulcerate and evolve into Other rare histological variants have also lmmunophenotype
large necrotic eschar-like lesions. been described, including folliculotropic, The large atypical cells in the lesions of
LyP with 6p25.3 rearrangement (<5%) syringotropic, and granulomatous LyP type A and type C LyP have the same
is characterized by chromosomal re- {1986,1987). Different subtypes of LyP phenotype as the tumour cells in cutane-
arrangements involving the DUSP22-IRF4 may occur in separate but concu rrent le- ous anaplastic large cell lymphoma.
.. ' ,.,
Fig.14.112 Primary cutaneous anaplastic large cell
lymphoma with confluent sheets of large cells with
- Fig.14.113 Primary cutaneous anaplastic large cell
lymphoma with cohesive sheets of CD30+ anaplastic
anaplastic morphology. cells.
Definition
Primary cutaneous gamma delta T-cell
lymphoma (PCGD-TCL) is a lymphoma,
involving primarily the skin, composed of
a clonal prol iferation of mature, activated
gamma delta T cells with a cytotoxic phe-
notype. This group includes cases previ-
ously called subcutaneous pann iculitis-
like T-cell lymphoma with a gamma delta Fig.14.116 Primary cutaneous gamma delta T-cell lymphoma . Lesions are clinical ly diverse, and consist of plaques,
phenotype. Gamma delta T-cell lympho- without ulceration (A) or with ulceration (B), or tumours (C). The lesion may consist of an indurated plaque with
mas presenting primarily in mucosal sites subcutaneous infiltration (D).
Imaging
Abnormal PET and/or CT findings are
common in sites of active disease (1493}.
Microscopy
Three major histological patterns of
involvement can be present in the skin:
epidermotropic, dermal, and subcuta-
neous. Often more than one histological
pattern is present in the same patient in
different biopsy specimens or within a
single biopsy specimen (359,4031,4321).
Epidermal infiltration may occur as mild
epidermotropism to marked pagetoid re-
ticulosis-like infiltrates {359). Subcutane-
ous cases may show rimming of fat cells,
similar to subcutaneous panniculitis-like
T-cell lymphoma of alpha beta origin, but
usually show dermal and/or epidermal
involvement in addition {4031,4321 ). The
neoplastic cells are generally medium-
sized to large, with coarsely clumped
chromatin {4031}. Large b lastic cells with
vesicular nuclei and prominent nucleoli
are infrequent. Apoptosis and necrosis
are common, often with angioinvasion
(4031,4321 }.
lmmunophenotype
The tumour cells characteristically have
a gamma delta TCR- positive, beta F1-
negative, CD3+, CD2+, CD5-, CD?+/-,
CD56+ phenotype with strong expres-
sion of cytotoxic proteins, including
granzyme B, perforin, and TIA1 {1S21,
3495,4031,4321 }. Most cases lack both
~
Fig.14.118 Primary cutaneous gamma delta T-cell lymphoma. Histological patterns are diverse. A Dermal CD4 and CDS, although CDS may be
infiltration is usually present, and, as seen in B, the infiltrate may extend from the epidermis to the subcutis. expressed in some cases {4031,4321}.
C,D Panniculitis-like pattern may be seen. The gamma delta T-cell phenotype (TCR
Definition
Primary cutaneous acral COB+ T-cell
lymphoma is a rare cutaneous tumour
characterized by skin infiltration of clonal
atypical medium-sized cytotoxic lym-
phocytes {3156}. The tumour is clinically
characterized by preferential involvement
of acral sites (in particular the ears) and Fig.14.124 Primary cutaneous acral CDS+ T-cell lymphoma. A Nodule of the right helix. B Nodule of the nose. C
by a good prognosis. Nodule/plaque of the left foot.
••
Fig.14.128 Primary cutaneous acral CD8+ T-cell Fig.14.129 Primary cutaneous acral CD8+ T-cell lym- Fig.14.130 Primary cutaneous acral CD8+ T-cell
lymphoma. Fewer than 10% of the tumour cells are phoma. Several atypical cells show Golgi dot-like stain- lymphoma. Infiltration of cutaneous fat tissue and nasal
positive for Ki-67. ing for CD68 (PGM1), besides normally stained reactive ala muscle.
histiocytes.
phils, and eosinophils are absent or very CDS+ cutaneous lymphomas should to other organs or lymphoid tissue. No
rare. The epidermis is most often spared, be carefully considered {3377). Stain ing chemotherapy is needed. It is impor-
with a grenz zone . Occasionally, minimal for B-cel l markers (CD20 , CD79a) might tant to recognize this disease to avoid
insignificant epidermotropism may be reveal reactive B-cell aggregates or folli- overtreatment.
seen {1446,1515) . Skin appendages are cles. LMP1 and EBV-encoded small RNA
always spared, and angiotropism , an- (EB ER) are negative.
giodestruction, and necrosis are never Primary cutaneous CD4+
seen . The proliferation frequently involves Postulated normal counterpart sma/Vmedium T-cell
the underlying fat tissue . The postulated normal counterpart is
lymphoproliferative disorder
a skin-homing CDS+ T cell . However,
lmmunophenotype cases that are very similar in terms of Gau lard P.
The tumoural infiltrate is composed of morphology, phenotype, and clinical out- Berti E.
T cells that express CD3, CDS, TIA1, come have also been recently described W ill emze R.
and beta F1. TIA1 displays Golgi dot-like in the gastrointestinal tract {3145) and Petrella T.
stain ing. CD4 is always negative. CD2, genital tract {3S63}, suggesting a new Jaffe E.S.
CD5, and CD7 are regu larly positive but lymphoma entity arising from tissue-resi-
one or more of them can be lost o r weak. dent CDS+ memory T cells.
Granzyme B and perforin are generally Definition
negative but may occas ionally be posi- Genetic profile Primary cutaneous CD4+ small/medium
tive. CD56, CD57, CD30, and TdT are Th e neoplastic T cells show c lonal TRG T-cell lymphoproliferative d isorder is char-
always negative, as are the T follicular gene rearrangements. Specific genetic acterized by a predominance of small to
helper (TFH) cell markers (CD10, BCL6, abnormal ities have not yet been de- medium-sized CD4+ pleomorphic T cel ls,
PD1, and CXCL13) {1446). CD6S is fre- scribed . EBV is negative. and by presentation w ith a solitary skin le-
quently positive, displaying as does TIA1, sion in almost all cases, without evidence
Golgi dot-like staining {4345). In the vast Prognosis and predictive factors of the patches and plaques typical of my-
majority of cases, the K i-67 proliferation The tumour has a very good prognosis. cosis fungoides. Because these cases
index is very low (< 10%). A few typical Complete remission after surg ical exci- have the same clinicopathological features
cases with a high pro liferat ion index have sion or rad iotherapy is the rule. Local and benign c lin ical course as cutaneous
been reported {446S}; however, when or extra-site skin recurrence may occur. pseudo-T-cell lymphomas with a nodular
the proliferation index is > 50%, other There is no evidence of dissemination growth pattern {323,626,3267), the term
Clinical features
Patients are asymptomatic; a single slow-
growing skin lesion is the sole manifes-
tation of disease. In rare cases, multiple
lesions are present {323,626). By defini-
tion, there should be no patches typical
of mycosis fungoides.
Fig.14.131 Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder. A Typical presentation as a
solitary lesion on the scalp. B The lesion is usually a single raised erythematous nodule. Microscopy
These lymphomas show dense, diffuse,
or nodular infiltrates with in the dermis,
with a tendency to infiltrate the subcutis.
Epidermotropism may be present focal -
ly, but if epidermotropism is conspicu-
ous, the diagnosis of mycosis fun goides
should be considered. There is a pre-
dominance of small/medium-sized pleo-
morphic T cells {317,323,626,129S,1471,
1S32,3267,3391). A smal l proportion
(<30%) of large pleomorph ic cells may
be present {320). In almost all cases, the
atypical CD4+ T cells are adm ixed with
small reactive CDS+ T cells, B cells, plas-
ma cells, and histiocytes (i ncluding multi-
nucleated giant cells) {323 ,626,3391).
lmmunophenotype
By definition, these proliferations have a
CD3+, CD4+, CDS- , CD30- phenotype.
Loss of pan- T-cell antigens (except for
CD?) is uncommon, and cytotoxic pro-
teins are not expressed {323,626,1471 ,
3391). Atypical CD4+ T cells express
PD1, BCL6 (variable), and CXCL13, sug-
gesting T follicular helper (TFH) cell deri-
vation {626,3391). CD10 is usually nega-
tive. The Ki-67 proliferation index is low
(typically 5%, and at most 20%).
Genetic profile
'primary cutaneous CD4+ small/medium ICD-0 code 9709/1 TR genes are clonally rearranged in most
T-cell lymphoproliferative disorder' is pre- cases {626,3391 ). Specific genetic ab-
ferred, rather than 'primary cutaneous Synonym normalities have not been described.
CD4+ small/medium T-cel l lymphoma'. Primary cutaneous CD4+ small/medium EBV is negative.
Rare cases presenting with widespread T-cell lymphoma (no longer used)
skin lesions, large rapidly growing tu- Prognosis and predictive factors
mours, > 30% large pleomorphic T cells, Epidemiology Patients have an excellent prognosis. ln-
and/or a high proliferative fraction do not This is a rare disease, accounting for 2% tralesional steroids, surgical excision, and
belong to this group {129S,1471). Such of all cutaneous T-cell lymphomas {4320). radiotherapy are preferred modes of treat-
cases usually have a more aggressive ment {323,626,1471). Spontaneous remis-
clinical behaviour and are better classified Localization sion after biopsy has been reported {626,
as peripheral T-cell lymphoma, NOS. These lesions usually present as a soli- 1471,1S32}. Local recurrences are rare.
tary plaque or nodu le, most commonly
Definition Table 14.09 Differentia l diagnosis of nodal peripheral T-cell lymphoma, NOS
Peripheral T-cell lymphoma (PTCL), Disease lmmunophenotypic features
NOS, is a heterogeneous category of
nodal and extranodal mature T-ce ll lym- Peripheral T-cell lymphoma, NOS CD4 >CDS; antigen loss frequent (CD?, CD5, CD4/CD8, CD52);
GATA3-/+; TBX21-/+; cytotoxic granules-/+; CD30-/+; CD56-/+;
phomas that do not correspond to any of
rare cases EBV+
the spec ifically defined entities of mature
T-cel l lymphoma in the current classifi- Angioimmunoblastic T-cell CD4+; expression of at least two (preferably three) of the following
cation (Tab le 14.09). Excluded from th is lymphoma TFH-cell markers: CD10, BCL6, PD1, CXCL 13, CXCR5, ICOS, SAP;
category are tumours with a T fol licular hyperplasia of FDCs (CD21 +)and HEVs (MECA79+);
EBV+ CD20+ B blasts
helper (TFH) cell phenotype, as defined
by the expression of at least two (ideal ly Nodal peripheral T-cell lymphoma Expression of at least two (preferably three) of the following
three) of the fo llowing markers: CD10 , with TFH phenotype TFH-cell markers: CD10, BCL6, PD1, CXCL13, CXCR5, ICOS, SAP;
BCL6, PD1, CXCL13, CXCR5, ICOS, and no hyperplasia of FD Cs or HEVs
SAP {34,2231,2496). PTCL, NOS, nearly Adult T-cell leukaemia/lymphoma CD4+; CD25+; CD?-; CD30-/+; CD15-/+; FOXP3-/+
always presents in adults, and has an
ALK+ anaplastic large cell lymphoma CD30+; ALK+; EMA+; CD25+; cytotoxic granules+/-, CD4+/-;
aggress ive cli nical course. CD3-/+; CD43+
ICD-0 code 9702/3 ALK- anaplastic large cell lymphoma CD30+; EMA+; CD25+; cytotoxic granules+/-; CD4+/-; CD3-/+;
CD43+;PAX5/BSAP-
Synonyms T-cell/histiocyte-rich large B-cell Large CD20+ blasts in background of reactive T cel ls with
T-ce ll lymphoma, NOS; peripheral T-cell lymphoma complete phenotypic profile
lymphoma, pleomorph ic small ce ll; peri- T-zone hyperplasia Expansion of T cells with complete phenotypic profile and
pheral T-cell lymphoma , pleomorphic mixed CD4/CD8, variable CD25 and CD30; scattered CD20+ B cells
medium and large cell; peripheral T-ce ll
lymphoma, large cell; lymphoepithel ioid +, nearly always positive;+/-, majority positive; -/+,minority positive; -, negative
lymphoma; Lennert lymphoma FDC, follicular dendritic cell; HEV: high endothelial venule; TFH, T follicular helper
Epidemiology
These tumours account for approxima- EBV may be found in background B cells. Extranodal presentations can occur, most
tely 30% of PTCLs in western countries commonly in the skin and gastrointestinal
{3365). Most patients are adu lts. These Localization tract {3365). In this settin g, the diagnosis
lymphomas are very rare in ch il dren. The Most patients present with peripheral of PTC L, NOS, shou ld be made only after
male-to-female ratio is 2:1. lymph node involvement, but any site can more specif ic entities have bee n excl ud-
be affected. Advanced -stage disease is ed. Other less freq uently involved sites
Etiology common, with secondary involvement of include the lungs and CNS {2632).
The infection of neoplastic ce ll s by EBV the bone marrow, liver, sp leen, and ex-
is repo rted in a small number of cases, in tranodal tissues {3365). The periphe ral Clinical features
which the virus plays a pathogenetic ro le blood is someti mes invo lved , but leukae- Pati ents most often present with lymph
{178 ,1068,1505,4298). More commonly, mic prese ntation is uncommon {3365). node enlargement, and most have
Fig.14.133 Peripheral T-cell lymphoma, NOS, with prominent clear-cell features (A,B) or large lymphoid cells with vesicular, immunoblast-like nuclei (C).
Variants
Lymphoepithelioid lymphoma
This variant, also known as Lennert lym-
phoma, shows diffuse or (less common-
ly) interfollicular growth . Cytologically,
it consists predominantly of small cells
with slight nuclear irregularities; numer-
ous and sometimes confluent clusters of
epithelioid histiocytes; and some larger,
more atypical, proliferating blasts. There
can be ad mixed inflammatory cells and
Fig.14.134 Peripheral T-cell lymphoma, NOS. A Diffuse infiltrates of large lymphoid cells with pleomorphic, irregular scattered Reed-Sternberg-l ike B cells
nuclei and prominent nucleoli. B Between the neoplastic cells, there are scattered eosinophils and numerous (usually EBV-positive). High endothelial
vessels. C Nuclei are markedly pleomorphic and multilobed. D In some cases, nuclei are round and monomorphic venules are not prominent. In most cases,
in appearance.
the neoplastic cells are CDS-positive and
have a cytotoxic profile {34,1321,1569,
advanced disease with B symptoms dominance of small lymphoid cells with 4411). Th is variant may have a somewhat
{3365). Paraneoplastic features such atypical, irregular nuclei. Hyperplasia of better prognosis than do other forms of
as eosinoph ilia, pruritus, or (rarely) hae- high endothelial venules and/or follicu- PTCL, NOS.
mophagocytic syndrome may be seen lar dendritic cells and the open marginal
{3365). sinuses characteri stic of angioimmu no- Other variants
blastic T-cell lymphoma (AITL) are not The foll icular variant included within the
Microscopy usually seen {1557,1816). An inflammato- PTCL, NOS, category in the 2008 edi-
In the lymph node, these lymphomas ry background is often present, including tion of the WHO classification has been
show paracortical or diffuse infiltrates with smal l lymphocytes, eosinophils, plasma moved to the category of AITL and other
effacement of the normal architecture. cells, large B cells (which may be clonal nodal lymphomas of T follicular helper
The cytological spectrum is extremely irrespective of EBV infection) {4258), and cell origin in this update.
broad, from polymorphous to monomor- clusters of epithelioid histiocytes. Epithe- The same is true for a proportion of cases
phic. Most cases consist of numerous lioid histiocytes are particularly numerous previously designated as the T-zone vari-
medium-sized and/or large cells with ir- in the lymphoepithelioid variant. Extran- ant, because they usually have a TFH-
regular, pleomorphic, hyperchromatic, or odal involvement takes the form of dif- cell phenotype {34). Thus , the growth of
vesicular nuclei; prominent nucleoli; and fuse infiltrates composed of similar cel ls. atypical small T lymphocytes around flor-
many mitotic figures {1557,1816). Clear In the skin, the lymphomatous population id reactive germinal centres {3463,4258)
cells and Reed-Sternberg-like cells can tends to infiltrate the dermis and subcu- is no longer considered to be a variant
also be seen. Rare cases have a pre- tis, often producing nodules, which may of PTCL, NOS, but rather a non-specific
lmmunophenotype
PTCL, NOS, is usually characterized by
an aberrant T-cell phenotype with fre-
quent downregulation of CD5 and CD7
{4298} (see Table 14.09, p. 403). A CD4+/
CD8- phenotype predominates in nodal
cases . CD4/CD8 double-positivity or
double-negativity is sometimes seen, Fig. 14.140 Peripheral T-cell lymphoma, NOS. Neo-
as is CD8, CD56, and cytotoxic granu le plastic cells show partial and variable expression of
expression (e.g . TIA1, granzyme B, and CD30.
perforin) {4298). T-cell receptor beta
(beta F1) is usually expressed, facilitat-
ing the distinction from gamma delta T-
eel! lymphomas and NK-cell lymphomas.
CD15 may be positive, and may be coex-
pressed with CD30 in rare cases {277).
Such cases may show features overlap-
ping with those of ALK-negative (ALK-)
anap lastic large ce ll lymphoma (ALCL),
but are classif ied as PTCL, NOS, under
the current guidelines. CD15 expression
is associated with an adverse prognosis Fig.14.141 Peripheral T-cell lymphoma, NOS. Most
{4298}. neoplastic cells express TBX21.
-
..,..,_ ........
""'"
-Of
,.,..,
10Ul
tt ut
1111•1111taeuu
_.....,.
Fig.14.143 Peripheral T-cell lymphoma (PTCL), NOS. Gene expression profiling identifies two main subgroups of PTCL, NOS, characterized by overexpression of TBX21 and
GATA3, respectively. The former is associated with a more favourable clinical course, with longer overall survival (OS).
Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of TFH-cell origin 407
Epidemiology
AITL occurs in middle-aged and elderly
individuals, with a higher incidence in
males than in females {901}. It is one of
the most common specific subtypes of
PTCL, accounting for 15-30% of non- Fig.14.147 Histological patterns of angioimmunoblastic T-cell lymphoma (AITL). A Early involvement by AITL
characterized by bare, hyperplastic follicles with paracortical expansion and marked vascular proliferation
cutaneous T-cell lymphomas and 1-2% associated with perifollicular or atypical lymphoid cells (pattern 1). B Case with depleted/atrophic follicles reminiscent
of all non-Hodgkin lymphomas {904, of Castleman disease and marked perifollicular expansion of clear cells (pattern 2). C Classic morphology with
3464,4217). effacement of normal architecture and marked vascular proliferation associated with aggregates of atypical lymphoid
cells (pattern 3).
some cases there is amorphous intersti- Variable numbers of B immunoblasts are linked to the functional properties of the
tial precipitate, produc ing a hypocellular usually present in the paracortex, wh ich neoplastic TFH ce ll s {1061}.
appearance. may be positive or negative for EBV by in
Three overlapping patterns are recog- situ hybridization for EBV-encoded small lmmunophenotype
nized {177). In pattern 1, the neoplastic RNA (EBER). EBV-positive B cells are The neoplastic T cells express most
cells surround hyperplastic follicles with present in 80-95% of cases . They range pan-T-cell antigens (e.g. CD3, CD2, and
we ll-formed germinal centres, but often in size, and expans ion of B immunob- CDS) and in the vast majority of cases
lacking well -defined mantle cuffs {3328}. lasts may be prominent {4288,4470) The are positive for CD4. Surface CD3 may
Pattern 1 is difficult to distinguish from EBV-positive B immunoblastic prolifera- be reduced or absent by flow cytometry
reactive follicular hyperplasia, and immu- tion may progress, either composite with {679,3684) Variable numbers of reactive
nohistochemical stains are necessary to AITL or at relapse, to EBV-positive dif- CDS+ T cells are present. Characteristi -
highl ight the neoplastic T cells with their fuse large 8-cell lymphoma {182,4470). cally, the tumour cells show the immuno-
characteristic TFH-ce ll phenotype. In EBV-positive Reed-Sternberg-li ke ce ll s phenotype of normal TFH cel ls, express-
pattern 2, remnants of follicles remain but of 8-ce ll lineage may be present and ing CD10, CXCL13, ICOS, BCL6, and
show regressive changes. The neoplastic may simulate classic Hodgkin lymphoma PD1 (CD279) in 60-100% of cases {177,
cells are more readily identified in the ex- {178,3265). In rare cases, EBV-negative 905,1026,1470,3399). This phenotype is
panded paracortex. In pattern 3, the ar- Reed-Sternberg-like cells of 8-cell line- helpful in distinguishing AITL from atypi-
ch itecture is totally or subtotally effaced; age may be present {2868}. Plasma cells cal paracortical hyperplasia and other
remnants of regressed fo lli cles may be may be very abundant, in rare cases PTCLs {1067,1469), as well as in diag -
seen in the outer cortex, displaced by obscuring the neoplastic T cells {238A, nosing extranodal dissemination {180,
the expanded paracortex. Progression 1736A} The plasma cells are usually pol- 284,2993}. None of these markers is TFH
from pattern 1 to pattern 3 in consecutive yclonal, but may be monoclonal in some cell-specific, and conversely, although
biopsies has been reported {3387). cases. The expansion of normal B cells several TFH-cell markers can usually
In advanced cases, the inflammatory and plasma ce ll s in the les ions has been be detected in the neoplastic cel ls, both
component may be diminished, and the
proportion of clear cells and large ce lls
may increase (so-called tumour cell-rich
AITL), which may simulate a PTCL, NOS.
In such cases, demonstration of a TFH-
cell immunophenotype and the presence
of expanded FDC meshworks are helpful
in diagnosis {178). In some cases, there
may be a prominent infiltrate of reac-
tive epithelioid histiocytes, mimicking a
granu lomatous reaction and resembling :
•I ••,.. '!,,6 .•
lymphoep ithe lioid lymphoma {34,178). ·· ijl"<~f( ••. :-<·
"" ~:, m _,. - C
The polymorphic infiltrate is frequently ·~·.. ·v•~ .
associated with increased extrafollicular 1.~ :~!r~-· ..;~ .. ~;t.\
... ./J • •"
FDC meshworks, which are most promi- -~·· · ·~ .
:,~"';. \
• •.'f.;.?
nent around the HEVs. The neoplastic .•. . _,~
,.~ 0
. "'" "··
::.¥".'\ ,
ce ll s are often arranged in clusters, sur- Fig.14.149 Angioimmunoblastic T-cell lymphoma, Fig. 14.150 Angioimmunoblastic
rounded by dendritic processes and pattern 1. CD10 staining highlights neoplastic T cel ls pattern 3, expressing PD1.
highlighted by CD21. surrounding the hyperplastic germinal centres.
Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of TFH-cell origin 409
Fig.14.154 Follicular T-cell lymphoma, cytological features. The lymph node contains Fig.14.155 Follicula r T-cell lymphoma with a progressive transformation of germinal
an infiltrate of monotonous lymphoid cells with round nuclei and pale, so-called centres (PTGC)-like growth pattern showing nodules with nests of neoplastic cells
*monocytoid+ cytoplasm. reminiscent of follicle centre B cells in PTGCs.
Angioimmunoblastic T-cell lymphoma and other nodal lymphomas of TFH-cell origin 411
In a limited number of cases in which Genetic profile CD4, PD1, CD10, BCL6, CXCL13, and
consecutive biopsies from different time FTCLs show clonal TR gene rearrange- ICOS) and some patholog ical features
points were studied, change of morphol- ments in most cases. About 20% of cas- of angioimmunoblastic T-cell lymphoma
ogy from FTCL to typical AITL or vice es carry a t(5;9)(q33;q22) translocation, (AITL). The minimum criteria for assign-
versa has been observed, suggesting leading to ITK-SYK fusion {1729,3814} ment of TFH-cell phenotype is not very
that these two entities may constitute dif- This translocation appears to be specific well established, but the detection of at
ferent morphological representations of for FTCL; it has not been seen in other least two (ideally three) of the TFH-cell
the same biological process {1729). peripheral T-cell lymphomas, except in markers in addition to C04 is suggest-
a rare case of AITL {181}. Comprehen- ed to assign a TFH-cell phenotype to
lmmunophenotype sive genomic profil ing of FTCL cases a nodal CD4+ T-cell lymphoma. These
The neoplastic T cells express the pan- has not been specifically performed, but neoplasms frequently show a diffuse
T-cell antigens CD2, CD3, and CD5 (with it is likely that some cases of peripheral infiltration pattern without a prominent
frequent loss of CD7) and have a CD4+ T-cell lymphoma with TFH-cell-like im- polymorphic inflammatory background,
T helper (Th) cell phenotype. Consist- munophenotype showing mutations of vascular proliferation, or expansion of fol-
ent with a TFH-cell origin, multiple TFH- TET2, RHOA, and ONMT3A are FTCLs licular dendritic cell meshworks. In some
cell markers (e.g. PD1, CXCL13, BCL6, {2264}. cases, a so-called T-zone pattern may
CD10, and ICOS) are expressed {1729}. be evident {34}. Genetic studies show
Like in AITL, interfollicular CD20+ B im- Prognosis and predictive factors that these cases share some of the ge-
munoblasts, often with EBV reactivity, are The clinical course is not well character- netic alterations seen in AITL, including
present in half of the cases. When Hodg- ized, due to the rarity of the lesion and mutations of TET2, ONMT3A , and RHOA
kin/Reed-Sternberg-like large cells the retrospective nature of most studies. {2264,3485). These phenotypic and ge-
are present, they may show phenotypic The disease appears to have an agg res- netic characteristics suggest that such
features of classic Hodgkin lymphoma, sive course, with half of the patients dying cases may be related to AITL and may
expressing CD30, CD15, PAX5 (weakly), within 24 months of diagnosis {1 729}. constitute a tumour cell-rich variant of
and frequently EBV, but lacking other B- AITL {178}. However, until furth er evi-
cell markers {2868). Such cells should dence showing that they are biologically
not be diagnosed as classic Hodgkin Nodal peripheral T-cell and clinically within the spectrum of AITL,
lymphoma in the absence of a typical lymphoma with T follicular it is recommended that such cases are
classic Hodgkin lymphoma background. classified as peripheral T-cell lymphoma
helper phenotype
CD21, CD23, and CD35 staining often with a TFH-cell phenotype.
reveals a retained follicular dendritic Definition
cel l meshwork structure underlying the It has been recognized that a subset of ICD-0 code 9702/3
follicular lymphoma-like or progressive the peripheral T-cell lymphomas clas-
transformation of germinal centres- like sified as NOS have a T follicular helper
nodular growth pattern. (TFH) cell phenotype (i e. positive for
Definition
ALK-positive (ALK+) anaplastic large 60
cell lymphoma (ALCL) is a T-cell lym-
phoma consisting of lymphoid cells 50
that are usually large and have abun-
dant cytoplasm and pleomorphic, often .,"' 40
Male (n=228)
horseshoe-shaped nuclei, with a chro- "'"' Female (n=158)
'O"
mosomal translocation involving the ALK .,
... 30
gene and expression of ALK protein .Q
E
:I
and CD30. ALCL with comparable mor- z 20 v---
11. llul.Jn~~~~;
10
protein, is considered to be a separate
category: ALK-negative (ALK- ) ALCL. 0 ; - -
ALK+ ALCL must also be distinguished 0-4 5.9 10-1415-19 20-24 25-29 30-34 35-39 40"'4<4 45...9 50-5455-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94
Age
from primary cutaneous ALCL and from
Fig.14.159 Anaplastic large cell lymphoma, ALK-positive. Distribution by patient age and sex (N = 386).
other subtypes of T-cell or B-cell lympho-
ma with anaplastic features and/or CD30
expression. A few cases of indolent ALK+ ALCL re- (75%) have B symptoms, especially
stricted to the skin have been reported high fever {475,1151 }. Rare cases of skin
ICD-0 code 9714/3 {2996}. Clinical history and staging are and satellite lymph node involvement by
requ ired to disti nguish such lesions from ALK+ ALCL following insect bites have
Synonym the aggressive, poor-prog nosis second- been reported {2200}. The significance
Ki-1 lymphoma (obsolete) ary cutaneous involvement by system ic remains unclear. Possibly, ALK+ ALCL
ALK+ ALCL. cells home to these sites of inflammation.
Epidemiology
ALK+ ALCL accounts for approximately Clinical features Microscopy
3% of adult non-Hodgkin lymphomas Most patients (70%) present with ad- ALK+ ALCLs show a broad morphologi-
and 10-20% of childhood lymphomas vanced (stage Ill -IV) disease with pe- cal spectrum {335,643,949,1138,2031,
(3782). ALK+ ALCL is most frequent in ripheral and/or abdominal lymphadeno- 3181). However, all cases contain a vari-
the first three decades of life {335,1151 ) pathy, often associated with extranodal able proportion of cells with eccentric,
and shows a male predominance, with a infiltrates and involvement of the bone horseshoe-shaped, or kidney-shaped
male-to-female ratio of 1.5:1. marrow {475,1151,1543). Most patients nuclei, often with an eosinophilic region
Localization
ALK+ ALC L frequently involves both
lymph nodes and extranodal sites. The
most commonly involved extranodal
sites include the skin, bone, soft tissue,
lungs, and liver {475,1151,1543,3782).
Involvement of the gut or CNS is rare.
Mediastinal disease is less frequent than
in classic Hodgkin lymphoma. The esti-
mated incidence of bone marrow involve-
ment is approximately 10% when inves-
tigated using H&E staining, but higher
(30%) when immunohistochemical stains
are used {1239), because bone marrow
involvement is often subtle. The small-
cell variant of ALK+ ALCL may have a
leukaemic presentation with peripheral Fig.14.160 Anaplastic large cell lymphoma (ALCL), ALK-positive. General features of ALCL, common type. The
blood involvement {301,2031,3752). lymph node architecture is obliterated by malignant cells, and intrasinusoidal cells are observed.
.). ~~- Q • ••
Fig. 14.166 Anaplastic large cell lymphoma, ALK-positive. Different ALK staining patterns. A Nuclear, nucleolar, and cytoplasmic staining associated with the t(2;5) translocation
(expression of the NPM1-ALK fusion protein). B Strong membranous and cytoplasmic staining sparing the nucleus in a case associated with the t(1;2) translocation (expression
of the TPM3-ALK fusion protein). C Finely granular cytoplasmic staining associated with the t(2;17) translocation (expression of the CLTC-ALK fusion protein).
(1138), inflammatory myofibroblastic tu- clonal rearran gement of the TR genes 4059,4339). FISH using an ALK break-
mours {1459), and neural tumours (251 2), irrespective of whether they express apart probe or karyotyping is not manda-
can be positive for ALK but are morpho- T-cell antigens. The remainder show no tory in routine practice if ALK staining is
logically distinguishable from ALCL and rearrangement of TR or IG genes {1237). positive {11 38,3201}. RT-PCR is usually
are negative for CD30. ALK+ ALCL must reserved for detection of minimal residual
also be distinguished from a rare form of Cytogenetic abnormalities and disease in blood or bone marrow {865).
ALK+ systemic histiocytosis occurring in oncogenes All of these translocations result in upreg-
early infancy {646). ALK+ histiocytosis is The genes fused with ALK in various chro- ulation and aberrant expression of ALK,
characterized by a proliferation of large mosomal translocations and the subcel- but the subcellular distribution of ALK
histiocytes that look morphologically lular distribution of NPM1-ALK and ALK staining varies depending on the translo-
different from ALC L cells, are CD30- variant chimeric proteins are shown in Ta- cation partner {11 47).
negative, and express the CD68 antigen ble 14.10. The most frequent genetic al- The ALK gene encodes a tyrosine kinase
(646). teration is a translocation, t(2;5)(p23;q35), receptor belonging to the insulin recep-
between the ALK gene on chromosome 2 tor superfamily, which is normally silent
Postulated normal counterpart and the NPM1 gene on chromosome 5 in lymphoid cells {2753). In the t(2;5)
An activated mature cytotoxic T cell {2199,2541 ,2753). Variant translocations (p23;q35) translocation, NPM 1 (a house-
involving ALK and other partner genes on keeping gene encoding a nucleolar pro-
Genetic profile chromosomes 1, 2, 3, 17, 19, 22, and X tein) fuses with ALK to produce a chimer-
Antigen receptor g enes also occur (801,1152,1177,1623,2195, ic protein in which the N-terminal portion
Approximately 90% of ALK+ ALCLs show 2197, 2542, 2608,3410, 3782,4033,4037, of NPM1 is linked to the intracytoplasmic
~ Q)
60
Gene expression profiling
Supervised analys is by class comparison ~ 40
Differential diagnosis
The principal differential diagnosis of
ALK- ALCL is with PTCL, NOS, and
CHL. Most cases referred to historically
as Hodgkin-like ALCL are now consid-
ered to be tumour cell-rich forms of
Fig. 14.173 Anaplastic large cell lymphoma, ALK-negative, with DUSP22 rearrangement. A Densely packed "' CHL. With complete immunophenotypic
monomorphic large cells. B Strong, uniform staining for CD30. and genetic studies, ALK- ALCL can
be distinguished from CHL in virtually
These markers tend to be absent in cases should raise suspicion for CHL. How- all cases. In contrast, the distinction be-
bearing OUSP22 rearrangements {3069); ever, CD15 may be expressed in some tween PTCL, NOS, and ALK- ALCL is
therefore, although desirable, their ex- cases of PTCL, NOS, and such cases are not always clear-cut, and even experts
pression is not an absolute requirement generally strong ly CD30-positive (277} may disagree on this subject. In gen-
for the diagnosis of ALK- ALCL. About Whether peripheral T-cell neoplasms ex- eral, the WHO classification advocates
43% of cases are positive for EMA, on pressing both CD30 and CD15 should a conservative approach, recommend-
at least a proportion of malignant cells, be classified as ALK- ALCL or PTCL, ing the diagnosis of ALK- ALCL on ly if
a marker that is almost always seen in NOS, remains to be determined. Notably, both the morphology and phenotype
ALK+ ALCL but only occasionally in these cases have a very poor prognosis, are very close to those of ALK+ cases,
PTCL, NOS {3536}. Nuclear phospho- clinically more closely resembling PTCL, with the only distinction being the pres-
STAT3 is expressed in about 43% of NOS. ALK- ALCLs are consistently neg- ence or absence of ALK. ALK- ALCL
cases {836). ative for EBV, i.e. for EBV-encoded small must also be distinguished from primary
In cases that lack all T-cell/cytotoxic RNA (EBER) and LMP1, and the expres- C-ALCL, which can have a similar phe-
markers, CHL rich in neoplastic cells and sion of these markers should strongly notype and morphology. Clinical correla-
other large cell malignancies (e.g. em- suggest the possibility of CHL. tion with stag ing is of paramount impor-
bryonal carcinoma) should be ruled out. ALK- ALCL and ALK+ ALCL lack T-cell tance in this differential. Primary C-ALCL
In th is regard, staining for PAX5 is useful, receptor proteins, and in this respect has a much better prognosis than does
because CHL reveals weak expression of tend to differ from PTCL, NOS {413,1322}. ALK- ALCL.
PAX5 in most cases; however, rare cases Clusterin is also commonly expressed in
of ALCL (ALK- or ALK+) may express both ALK- and ALK+ ALCL, but rarely in Postulated normal counterpart
PAX5 {1175). The demonstration of CD15 PTCL, NOS (2183,2830,3470}; this mark- An activated mature cytotoxic T cell
Genetic profile
Most cases show clonal rearrangement of
the TR genes, whether or not they express
T-cell antigens.
A constellation of genetic find ings, nota-
bly recurrent activating mutations of JAK1
and/or STAT3, has been shown to lead to
constitutive activation of the JAK/STAT3
pathway in ALK- ALCL (836). Translo-
cations involving tyrosine kinase genes
other than ALK also lead to STAT3 activa-
tion in a small subset of systemic and cu-
taneous ALK- ALCLs (836,41 71). These
genetic events in ALK- ALCL partially
explain the biological and pathological
similarities to ALK+ ALCL, in which ALK
fusion proteins lead to constitutive STAT3
activation {710), and may have therapeu-
tic implications.
DUSP22 rearrangements, i.e. chromo-
somal rearrangements in or near the
D USP22-IRF4 locus on 6p25.3, occur in
Fig. 14.174 Anaplastic large cell lymphoma, ALK-negative. A Some of the features raise a differential diagnosis
with PTCL, NOS, expressing CD30, such as absence of hallmark cells. B CD30 is strongly expressed in all tumour about 30% of cases {3069). These are
cells. C Lymphoma cells express CD3. Note a vessel surrounded by normal, small CD3+ T cells. D Tumour cells associated with decreased expression of
express CD4. the DUSP22 dual-specificity phosphatase
Definition studies have not identified an in creased lymphoma diagnosis is 10.9 years, but
This provisional entity is a T-cell lympho- risk of lymphoma in women with breast the interval varies greatly. No association
ma with morphological and immunophe- implants {895,2220,2358,2672). with the type of implant (si li cone vs saline,
notypic features indistin guishable from textured vs smooth) or with breast cancer
those of ALK-negative anaplastic large Localization history has been established.
ce ll lymphoma (ALCL), arising primarily The tumour cells may be localized to the
in association with a breast implant. seroma cavity or may invo lve the peri - Microscopy
capsular fibrous ti ss ue, someti mes form- The tumour cells may be identifi ed initial-
ICD-0 code 9715/3 ing a mass. Locoregional lymph nodes ly in cytology specimens from aspirated
may be involved. effusion fluid. At capsulectomy, the tu-
Synonym mour cells often line the capsule and may
Seroma-associated anaplastic large cel l Clinical features show varying degrees of capsular infiltra-
lymphoma The mean patient age is 50 years (2235, tion. In some cases, they extend beyond
2672,3382}. Most patients present with the capsule to form a mass, which may
Epidemiology stage I disease, usually with a peri-implant be palpable in the specimen at the time
Breast implant-associated ALCL is very effusion and less frequently with a mass. of gross evaluation (51}. The tumour cells
rare, with an estimated incidence of As many as 29% of patients have axillary are typically large and pleomorphic, and
1 case per 500 000 to 3 million women lymphadenopathy, but not all biopsied the so-called hallmark cells seen in other
with implants (461}. Although a possib le nodes are positive for tumour. Rare cases forms of ALCL can usually be identified.
etiolog ical relationship between implants present with disseminated disease. The
and ALCL has been suggested, large mean interval from implant placement to
Fig.14.176 Breast implant-associated anaplastic large cell lymphoma. A The tumour cells have pleomorphic nuclear features. This case had invasion of the capsule and
underlying breast, shown in B and C. B Some tumours may show invasion of the breast, which is associated with a more aggressive clinical course. C Neoplastic cells with
strong staining for CD30 surround a duct in the breast.
Hodgkin lymphomas
Nodular lymphocyte predominant Hodgkin lymphoma
Classic Hodgkin lymphoma
EBV-positive {125, 276, 1190, 2276,4277, have localized disease (stage I or II). Mediastinal involvement is most frequent-
4278). However, there are differences Approximately 60% of patients, most with ly seen in the nodular sclerosis subtype,
between urban and rural areas. For ex- NSCHL, have mediastinal involvement. whereas abdominal involvement and
ample, NSCHL is more common in urban Splenic involvement is common (20%) splenic involvement are more common in
areas, whereas EBV-positive MCCHL is and is associated with an increased risk mixed cellularity cases. B symptoms con-
more common in rural regions {1092) . of extranodal dissemination. Bone mar- sisting of fever, drenching night sweats,
Delayed exposure to childhood infec- row involvement is much less common and significant body weight loss are
tions has been postulated to play a role (5%). Because the bone marrow lacks present in as many as 40% of patients.
{1383} It is possible that EBV infection of lymphatics, bone marrow infiltration in- Most patients with NLPHL are asympto-
a B cell replaces one of the genetic al- dicates vascular dissemination of the matic and present with enlargement of
terations necessary for the development disease (stage IV). The anatomical dis- peripheral lymph nodes; B symptoms are
of CHL. NLPHL is only rarely positive for tribution varies between the histological rare.
EBV (<5% of cases) {1736) . subtypes of CHL {3654). NLPHL tends
to spare axial lymph node groups, and Macroscopy
Localization is more common in peripheral lymph Lymph nodes are enlarged and encap-
CHL most often involves lymph nodes of nodes. The mediastinum is uncommon- sulated, and show a fish-flesh tumour on
the cervical region (75% of cases), fol- ly involved, but mesenteric lymph node cut section. In NSCHL, there is prominent
lowed by the med iastinal, axillary, and involvement may be seen. nodularity, dense fibrotic bands, and a
para-aortic regions. Non-axial lymph thickened capsule. Splenic involvement
node groups, such as mesenteric and Clinical features usually shows scattered nodules within
epitrochlear lymph nodes, are rarely Patients with CHL usually present with the white pulp. Very large masses are
involved. Primary extranodal involve- peripheral lymphadenopathy, localized sometime seen; these can demonstrate
ment is rare. More than 60% of patients to one or two lymph node-bearing areas. fibrous bands in the nodular sc lerosis
Fig.15.04 Age distribution of classic Hodgkin lymphoma (CHL) subtypes. Individua ls with a history of infectious Fig.15.05 Hodgkin lymphoma. This classic Reed-
mononucleosis have a higher risk for the development of CHL. LDCHL, lymphocyte-depleted CHL; LRCHL, Sternberg cell is bi nucleated, with prominent eosinophilic
lymphocyte-rich CHL; MCCHL, mixed cellularity CHL; NSCHL, nodular sclerosis CHL. nucleoli, producing the so-called owl's eye appearance.
From: Mueller NE and Grufferman S (2777).
demonstrable in approximately 95% of ment in the HRS cells, so that the expres- The LP cells are positive for CD20,
cases by their expression of the B-cell- sion of T-cell antigens is either aberrant CD79a, PAX5, OCT2, and BOB1 . EMA
specific activator protein PAX5 (also or artefactual {3614,4176) . Expression of is sometimes positive, but often only in a
cal led BSAP) {1238}. The immunostain- EMA is rare and usually weak if present. fraction of the LP cells. lgD (but not lgM)
ing of HRS ce lls for PAX5 is usually A further characteristic find in g is the ab- is expressed in LP cells in a subset of
weaker than that of reactive B cells, a sence of the transcription factor OCT2 cases, most commonly in young males
feature that makes the PAX5+ HRS cells (also known as POU2F2) in up to 90% of {3231 }. However, stains for immuno-
easily identifiable. The transcription fac- cases in some reports and the absence globulin light chains are generally nega-
tor IRF4/MUM1 is consistently positive in of its coactivator BOB1 (also known as tive. CD30 may be weakly expressed in
HRS cells, usually at high intensity. In one POU2AF1) in the same proportion {2379). some cases, but CD15 is nearly always
study, PRDM1 (also known as BLIMP1), The transcription factor PU1 is consist- negative.
the key regulator of plasma cell differ- ently absent from HRS cells {2379,4027).
entiation, was expressed in only a small Most HRS cells express the proliferation- Cytokines and chemokines
proportion of HRS cells in 25% of CHLs associated nuclear antigen Ki-67 {1332). CHL is associated with overexpression
{492}. The plasma cell-associated ad- CHL cases rich in neoplastic cells may and an abnormal pattern of cytokines
hesion molecule CD138 is cons istently resemble anap lastic large cel l lymphoma and chemokines and/or their receptors
absent {492}. EBV-infected HRS ce ll s ex- (ALCL), a T-cell neoplasm. The ir identi- in HRS cells {1613,1751,1897,1899,1937,
press LMP1 and EBNA1 without EBNA2, fication as CHL is facilitated by demon- 4120), which likely explains the abundant
a pattern characteristic of type 11 EBV strating positivity for PAX5 and absence admixture of inflammatory cells {1876,
latency {950). EBV-encoded LMP1 has of EMA and ALK protein {1238,3782}. The 3944}, the fibrosis {1897}, and the pre-
strong transforming and antiapoptotic detection of EBV-encoded small RNA dominance of T helper 2 (Th2) cells in the
potential. (EBER) or LMP1 favours CHL over ALCL infiltrating T-cell population {4120).
Membranous and less often globular cy- {1731). The most difficult differential di-
toplasmic expression of one or more T- agnosis is with diffuse large B-cell lym- Postulated normal counterpart
cell antigens by a minority of HRS cells phoma displaying anaplastic morphology Classic Hodgkin lymphoma (CHL)
may be encountered in some cases and expressing CD30. There may be The ce ll ular origin of HRS was unknown
{862,4176). However, this is often difficult a true biolog ical overlap between such for many years, because the cells lack
to assess because of the T cells that usu - cases and CHL, especially in cases with the morphology and immunophenotype
ally surround the HRS cells. Most T-cell mediastinal disease. of any normal counterpart. However,
antigen-positive CHL cases have both Unlike CHL, NLPHL generally shows IG gene rearrangement studies have
PAX5 expression and IG gene rearrange- preservation of the B-ce ll programme. provided convinc ing evidence that HRS
cells are clonal and derived from germi- also showed that LP cells are clonal ex- CHL
nal centre B cells despite the frequent ab- pansions of B cells with genotypic fea- HRS cells contain clonal immunoglobulin
sence of B-cell markers other than PAX5. tures of GCBs, indicating that LP cells gene rearrangements in more than 98%
Thus, HRS cells are one of the most ex- constitute a neoplasm of this B-cell type. of cases. The rearranged IGHV genes
treme examples of discordance between harbou r a high load of somatic hyper-
genotype and phenotype {1934,2495}. Genetic profile mutations in the variable (V) reg ion, usu-
The HRS cells of rare CH L cases have Antigen receptor genes ally without signs of ongoing mutations.
been reported to harbour clonally re- Rearrangement studies of antigen recep- However, the B-cell program is down-
arranged TR genes, indicating that ex- tor genes of LP or HRS cells usually pro- regulated in CHL, and HRS cells do not
ceptional cases with morphological fea- vide only reliable results for these cells express immunoglobulin transcripts.
tures of CHL may be derived from T cells when DNA of isolated single LP and HRS Experimental data from several stud ies
{2798 ,3614}. Because the neoplastic cells is investigated and not whole tissue partially explain this defect In approxi-
cells in some cases of peripheral T-cell ONA. mately 25% of cases of CHL nonsense
lymphoma can have an appearance mutations in the V region genes were
similar to that of HRS cells, the differen- NLPHL identified, which were proposed to result
tial diagnosis is challenging. Addition- In all cases LP cells harbour a clonal im- in the failure of lg secretion {1934). A ma-
ally, some peripheral T-cell lymphomas munoglobulin gene rearrangement with a jor contributory factor is the absent or de-
express CD30 and CD15, making their high load of somatic mutations and signs creased expression in most cases of CHL
distinction from CHL even more difficult of ongoing mutations in the variable (V) of the transcription factors (OCT2, BOB1)
{277 }. region . The rearrangements are usually that regu late lg expression {3785}. Final-
functional and IG mRNA transcripts are ly, there is evidence of hypermethylation
Nodular lymphocyte predominant detectable in the LP cells. Consistent of multiple genes and pathways in CHL,
Hodgkin lymphoma (NLPHL) with this finding, the transcription factor which may further contribute to the dam-
Due to their expression of B-cell markers, OCT2 and its coactivator BOB 1, which age to the B-cell programme {2180A}.
LP cells were more readi ly identified as are dominantly involved in the regulation These findings, in conjunction with the
B-cell derived {783,3192,3193}. and this of the expression of IG mRNA, are con- study of composite lymphomas consist-
origin was confirmed by rearrangement sistently expressed {3785}. ing of CHL and follicular non-Hodgkin
studies of the IGH gene. These studies lymphoma, support the assumption that
-• I
Fig.15.09 Classic Hodgkin lymphoma. A EBV-infected Hodgkin/Reed-Sternberg cells strongly express the EBV-encoded latent membrane protein LMP1. B EBV-infected
Hodgkin/Reed-Sternberg cells consistently show a strong expression of EBV-encoded small RNA (EBER) in their nuclei as revealed by non-radioactive in situ hybridization.
Epidemiology
NLPHL accounts for approximate ly 10%
of all Hodgkin lymphoma {2230A}. Pa-
tients are predominantly male and most
are aged 30-50 years.
Localization
NLPHL usually involves cervical, axillary,
or inguinal lymph nodes. Mediastinal
involvement is rare. Mesenteric lymph
node involvement can be seen, unlike in
classic Hodgkin lymphoma (CHL). Pa-
tients with advanced disease may have
involvement of the spleen and bone mar-
row. Rare cases may have destructive le-
sions involving bone.
Fig.15.11 Nodular lymphocyte predominant Hodgkin lymphoma. A The nodules, which are usually larger than those
in fol licular lymphoma and follicular hyperplasia, lack mantle zones. B Three lymphocyte predominant (LP) cells
Clinical features (arrows), also ca lled popcorn cells, with the typically lobed nuclei, are visible in a background of small lymphoid
Most patients present with localized pe- ce lls and a few histiocytes. C CD20 staining reveals that the nodules consist predominantly of B cells. D At higher
ripheral lymphadenopathy (stage I or II). magnification, the strong membrane staining of the LP cells for CD20 is apparent.
cells favour primary THRLBCL. Strongly are similar to the cells of THRLBCL and Pattern A Pattern B
"Classical" Serpiginous/
stained LP cells in association with weak- CHL {477). They show partial loss of their B-cell-rlch nodular Interconnected
ly stained B cells are best identified by B-cell phenotype, and deregulation of
OCT2 or PAX5 immunostaining. many apoptosis regulators and putative
oncogenes. The on ly investigations that
Postulated normal counterpart point to distinct pathogeneses of NLPHL
A germinal centre B cell at the centro- and primary THRLBCL are two com-
blastic stage of differentiation parative genomic hybridization studies
in wh ich more and different genomic ab-
Pattern C Pattern D
Genetic profile errations were identified in NLPHL than Prominent extr.,- T-<elklch nodular
LP cells harbour clonally rearranged IG in THRLBCL (1246,1247). Such different Nodular LltH cells
(IGHV) genes {2493,2947). The clonal genetic patterns were not found in the
rearrangements are usually not detect- gene expression profiling study of micro-
able in whole-tissue DNA but only in the dissected tumour cells of typical cases
DNA of isolated single LP cells. The IGHV of NLPHL and THRLBCL (1570,1571).
genes carry a high load of somatic muta- These studies revealed, in addition to
tions, and also show signs of ongoing mu- a common expression of BCL6, CD75,
tations. The rearrangements are usually EMA, J chain, and PU1, an identical ex- Pattern I! fA1Wn..f
functional , and IG mRNA transcripts are pression of BAG6 (also called BAT3), Diffuse (TCRBCL Diffuse moth-e•ten,
or DLBCL-llke) B-celklch
detectable in the LP cells of most cases HIGD1A, and UBD (also call ed FAT10)
{2493}. EBV infection detected by EBV- in the tumour cells of cases with a nodu-
encoded small RNA (EBER) may be found lar, a nodu lar and diffuse, and a diffuse
in the LP cells in 3-5% of cases in both growth in NLPHL and primary THRLBCL,
children and adults {1736). EBV positivity suggesting the possibility that THRLBCL
might be higher in Asia {653). EBV may may represent a variant or extension of
also be present in bystander lymphocytes NLPHL. This specu lation is supported
{91). BCL6 rearrangements (involving IG by the observation that NLPHL can show Fig.15.17 lmmunoarchitectural patterns in nodular
genes, IKAROS family genes, ABR, and a THRLBCL-like transformation, wh ich lymphocyte predominant Hodgkin lymphoma {1159}.
other partner genes) are present in about is indistinguishable from primary THR- In this schematic illustration, the X's represent lym-
phocyte predominant (LP) cells, the grey background
half of NLPHLs {174,3343,4341}. Aber- LBCL. It is likely that the distinction be-
a B-cell-rich background, and the white background
rant somatic hypermutations were found tween NLPHL and THRLBCL does not a T-cell-rich background. Pattern A So-called clas-
in 80% of NLPHL cases, most frequently lie in different genomic alterations and sic B-cell-rich nodular pattern. Pattern B Serpiginous
in PAX5, but also in PIM1, RHOH (also the immunophenotype of the tumour nodular pattern. Pattern C Nodular pattern with many
called TTF), and MYC {2359). Mutations cells, but rather in the different cellular extranodular LP cells (formerly called L&H cells). Pat-
of SGK1, DUSP2, and JUNB are also re- composition of the microenvironment as tern D T-cell-rich nodular pattern. Pattern E Diffuse,
ported in about half of NLPHLs {1575). described above. T-cell-rich (TCRBCL-like) pattern. Pattern F (Diffuse),
moth-eaten (B-cell-rich) pattern.
DLBCL, diffuse large B-cell lymphoma; TCRBCL,
Relationship between NLPHL and Genetic susceptibility T-cell/histiocyte-rich large B-cell lymphoma.
THRLBCL An increased familial risk of NLPHL has From: Fan Z, Natkunam Y, Bair E, Tibshirani R, Warnke
LP cells by gene expression profiling been noted in some families (3466). RA. Am J Surg Patho/ (2003) {1159}.
However, the specific genetic factors Prognosis and predictive factors tion of the affected lymph node {3125).
have not been identified. NLPHL has also NLPHL in its nodular and its nodular Histopatholog ical variants characterized
been identified in patients with Herman- and diffuse forms develops slowly, with by LP cells outside B-cell nodules, B-cell
sky-Pudlak syndrome type 2 (2391). fairly frequent relapses. It usually re- depletion of the microenvi ronment, or
The affected patients in that study ex- mains responsive to therapy and thus is THRLBCL-like transformation (patterns
hibited NK-cell and T-cell defects. An rarely fatal. The prognosis of patients with C, D, E and Fas described by Fan et al.,
increased risk is also seen in patients stage I or II disease is very good, with a Figure 15.17) are associated more often
with autoimmune lymphoproliferative 10-year overall survival rate > 80% (980, with advanced disease and a higher
syndrome with mutations in FAS (3810), 2888). It is not yet clear whether immedi- relapse rate compared with that of typi-
which may also be linked to defective ate therapy is necessary to achieve this cal NLPHL (1572) Therefore, it is use-
immune surveillance. favourable prognosis; in some countries ful to note these variant features in the
(e.g. France), stage I disease (especially diagnostic report. Clinically recognized
in chi ldren) is not treated after the resec- advanced stages have an unfavourable
prognosis 1980). Progression to diffuse
large B-cell lymphoma has been re-
ported in approximately 3- 5% of cases
1723,1538,2660). The neoplastic cells in
such cases may resemble LP cells or
may have centroblastic or immunoblastic
features. However, they keep their typi-
cal immunophenotype (strong coexpres-
sion of CD20, OCT2, and CD75). In some
... cases, diffuse large B-cell lymphoma
•::"C'ri....~~p•. •• ·~~af.~-~~·~~!i'~ was found to precede NLPHL (1 159).
_.!fr. ~ . -·.t::.~!B~ The large B-cell lymphomas associated
Fig.15.19 Nodular lymphocyte predominant Hodgkin lymphoma. A lmmunostaining for the transcription factor
OCT2, which is involved in the regulation of immunoglobulin expression, produces strong nuclear staining of the with NLPHL, if localized, generally have a
lymphocyte predominant (LP) cells (also called popcorn cells), and weaker labelling of the bystander B cells; thus, good prognosis {1538). A c lonal relation-
OCT2 often highlights the presence and the nuclear atypia of LP cells. B Higher magnification. ship between NLPHL and the associated
diffuse large B-cell lymphoma has been
1.0 1.0 demonstrated 11452,1575,4310). Bone
NS
LP marrow involvement is rare in NLPHL
0.8 0.8 MC and raises the possibil ity of THRLBCL, or
~ 0.6 MC ~0.6 THRLBCL-like transformation, in particu-
:.0 .c lar if the characteristic microenvironment
co co
.c 0.4
e
a.
-ea. 0.4 is absent. Cases of NLPHL with bone
marrow involvement are clinically aggres-
0.2 0.2
p=0.029
sive 12003). Advanced-stage NLPHL
p=0.088
0 0 responds poorly to the chemotherapy
0 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 regimens traditionally used for CHL, but
FFS (years) HD-specific SV (years) HD-specific responds better to the CHOP chemother-
A B
Fig.15.20 Hodgkin lymphoma (HD)- specific survivals associated with the nodular lymphocyte predominant (LP), apy reg imen plus rituximab (Fl-CHOP), or
nodular sclerosis (NS), and mixed cellularity (MC) subtypes of classic Hodgkin lymphoma. A Failure-free survival regimens used for aggressive B-cell lym-
(FFS). B Overall survival (SV). German Hodgkin Study Group (GHSG) phomas 14387).
ICD-0 code
Classic Hodgkin lymphoma 9650/3
Fig.15.21 Nodular sclerosis classic Hodgkin lymphoma. A CT shows a large anterior mediastinal mass. B Chest
X-ray of the same patient shows a mediastinal mass exceeding one third of the chest diameter.
.a .
Fig.15.24 Thymic cyst arising with thymic involvement Fig.15.25 Nodular sclerosis classic Hodgkin Fig.15.26 Nodular sclerosis classic Hodgkin
by Hodgkin lymphoma. Cystic degeneration of the lymphoma, grade 2. Capsular fibrosis is present. Central lymphoma, grade 2. Lacunar Hodgkin/Reed- Sternberg
thymus gland is common with involvement by nodular areas of necrosis are noted in the nodular infiltrate. cells palisade around central necrotic area containing
sclerosis classic Hodgkin lymphoma. numerous neutrophils.
,
....._ - .
Fig.15.27 Nodular sclerosis classic Hodgkin lymphoma
with aberrant CD3. The neoplastic cells are positive for
~f!:ol~...Ji.:t1:.'r.;:rmp-;~b.\._~
Fig. 15.28 Nodular sclerosis classic Hodgkin lymphoma.
This case had aberrant expression of CD2, a finding
A
Fig.15.29 Nodular sclerosis classic Hodgkin
_.,..
Definition
Lymphocyte-rich classic Hodgkin lym-
phoma (LRCHL) is a subtype of classic
Hodgkin lymphoma (CHL) characterized
by scattered Hodgkin/Reed-Sternberg
(HRS) cells and a nodular or (less often)
diffuse cellular background consisting of
small lymphocytes, with an absence of Fig.15.33 Lymphocyte-rich classic Hodgkin lymphoma, nodular variant. CD30 staining highlights the presence of
Hodgkin/Reed-Sternberg cells. They are located within or at the peripheral margin of the follicular mantles, but not
neutrophils and eosinophi ls.
within the germinal centres.
Synonyms
Hodgkin disease, lymphocytic- histio-
cytic predom inance (obsolete); Hodgkin
disease, lymphocyte predominance, dif-
fuse (obsolete); Hodgkin disease, lym-
phocyte predominance, NOS (obsolete)
Epidemiology
LRCHL accounts for approximately 5% of
Fig.15.34 Lymphocyte-rich classic Hodgkin lymphoma, Fig.15.35 Lymphocyte-rich classic Hodgkin
all CH Ls, occurring at a freq uency slightly nodular variant. Cellular nodules are composed of small lymphoma, nodular variant. Classic Reed-Sternberg
less than that of nodular lymphocyte pre- lymphocytes surrounding regressed germinal centres. cells are surrounded by small lymphocytes.
dominant Hodgkin lymphoma (N LPHL).
The median patient age is similar to that
of NLPHL and significantly older than
seen in other subtypes of CHL {980). The
male-to-female ratio is 2:1 {3654).
Localization
Peripheral lymph nodes are typically
involved. Mediastinal involvement and
bulky disease are uncommon {980,3654}.
Microscopy
There are two growth patterns: the com-
mon nodular pattern {91} and the rare
diffuse pattern {91}. The nodules of the
nodular variant encompass most of the in-
volved tissue, so that the T-zone is attenu- Fig.15.38 Lymphocyte-rich classic Hodgkin lymphoma. Fig. 15.39 Lymphocyte-rich classic Hodgkin lymphoma.
ated. The nodules are composed of small CD3- positive T cells form a rosette around an HRS cell. CD15 immunostain of HRS cells.
0.9
NS/MC/LO (12512,442)
0.8
I 0.7
0.6 0.6
A Months B
Fig.15.40 Lymphocyte-rich classic Hodgkin lymphoma. Fig.15.41 Hodgkin lymphoma (HL). Overall survival (A) and overall event-free survival (B) by histological subtype
lmmunostaining for PD1 shows PD1+ T cells forming (3654). LD, lymphocyte-depleted classic HL; LPHL, lymphocyte predominant HL; LRCHL, lymphocyte-rich classic HL;
rosettes around HRS cells MC, mixed cellularity classic HL; NS, nodular sclerosis classic HL. From: Shimabukuro-Vornhagen A, Haverkamp H,
Engert A, et al. (3654). Reprinted with permission. ©2005 American Society of Clinical Oncology. All rights reserved.
lymphocytes and may harbour germinal sc lerosis CHL might be more appropri- bouring cases) as the HRS cells in the oth-
centres, which are usually eccentrically ate. In some cases, sequential biopsies er subtypes of CHL. Thus , the distinction of
located and relatively small or regressed . have shown nodular sclerosis CHL, im- LRCHL from NLPHL is possible by immu-
The HRS cells are predominantly found plying a possible relationsh ip between nophenotyping in nearly all instances {91}.
with in the nodu les, but consistently out- the two subtypes of CHL; this is further The expression of B-cel l transcription fac-
side of the germinal centres. A proportion inferred by the finding of HRS ce lls with in tors such as OCT2, BOB1, and BCL6 has
of the HRS ce lls may resemble lympho- expanded follicular mantle zones in some been found to be more frequent in LRCHL
cyte predominant (LP) cells or mono- cases of nodular sclerosis CHL {1780}. than in the other CHL subtypes {2821).
nuclear lacunar ce lls. This subtype can Coexistence of LRCHL and mixed cel lu- Rosettes with a T follicular helper (TFH)
easily be confused with NLPHL. In the larity CHL occurs but is rare. cell immunophenotype (PD1/CD279+,
past, approximately 30% of cases initially In diffuse LRCHL cases, the small lym - CD57-/+) surrounding the neoplastic cells
diagnosed as NLPHL were later found to phocytes of the cel lular background may are present in as many as 50% of cases
be LRCHL {91}. The demonstration of an be admixed with histiocytes with or with- {2821}. The small lymphocytes in the nod-
immunophenotype typical of classic HRS out epithelioid features. ules have the features of mantle cel ls (i .e.
cells is essential in making th is distinc- positivity for lgM and lgD). Thus, the nod-
tion. Eos inoph il s and/or neutroph ils are lmmunophenotype ules predominantly constitute expanded
absent from the nodules, or if present, The immunophenotype of the neoplastic mantle zones. At least some of them con-
are located in the interfollicular zones and cells and their microenvironment display a tain eccentrical ly located, usual ly small,
are few in number. In rare instances, the mixture of features of NLPHLand CHL. The germinal centres , which are highlighted
LRCH L-typical nodules may be surround- atypical cells in LRCHL show the same im - by a dense meshwork of CD21+ follicu-
ed by fibrous bands associated with ran- munophenotype (CD30+, CD15+/-, IRF4/ lar dendritic cells. Because intact germi-
domly distributed HRS cells in T-cell- rich MUM1+, PAX5+/- , CD20-/+, J chain-, nal centres are infrequent in NLPHL, this
zones . Typing of these cases as nodular CD75-, PU1-, EBV/LMP1+ for EBV-har- feature is helpful in differential diagnosis.
Fig.15.45 Lymphocyte-depleted classic Hodgkin lymphoma. A Many Hodgkin cells with relatively few admixed lymphocytes are visible. B Many bizarre large and small Hodgkin/
Reed- Sternberg cells are present in a cellular background rich in fibrillary matrix. C Scattered Hodgkin/Reed-Sternberg cells in a predominant fibrillary matrix with fibroblastic
proliferation.
Synonyms
Hodgkin lymphoma disease, lympho-
cyte depletion, NOS; classic Hodgkin
lymphoma, lymphocyte depletion, NOS;
Hodgkin lymphoma, lymphocyte deple-
tion, diffuse fibros is (9654/3); Hodgkin J -
Fig.15.46 Lymphocyte-depleted classic Hodgkin Fig. 15.47 Lymphocyte-depleted classic Hodgkin
lymphoma, lymphocyte depletion, reticu- lymphoma. Hodgkin/Reed-Sternberg cel ls are readi ly lymphoma. CD30 immunostaining.
lar (9655/3) seen in a background rich in histiocytes and some small
lymphocytes.
Immunodeficiency-associated
lymphoproliferative disorders
Definition
Lymphoproliferative diseases associated
with primary immune disorders (PIDs) are
lymphoid proliferations that arise in the
setting of immune deficiency due to a pri-
mary immunodeficiency or immunoregu-
latory disorder. Because the pathol-
ogy and pathogenesis of the > 60 Pl Os
are heterogeneous, the manifestations
of these lymphoproliferative diseases
are highly variable. The PIDs most fre-
quently associated with lymphoprolif-
erative disorder are ataxia-telangiectasia
(AT), Wiskott- Aldrich syndrome (WAS),
common variable immunodeficiency
• Ji
(CVID), severe combined immunodefi-
Fig.16.01 Lymphoproliferative disease occurring in X-linked lymphoproliferative disease with features of fatal
ciency (SCID), X-linked lymphoprolifera- infectious mononucleosis. There is a proliferation of B cells with plasmacytoid and immunoblastic features. Note the
tive disease (XLP), Nijmegen breakage prominent apoptosis.
syndrome (NBS), hyper-lgM syndrome
(HlgM), and autoimmune lymphoprolif- T-cel l immune surveillance to EBV is mutations are associated with lympho-
erative syndrome (ALPS). believed to be the primary mechanism mas in the absence of immune abnor-
(1628,3073,3251). The absence of T-cell malities {1483}.
Epidemiology control may be complete (resulting in fa- In AT, an abnormal DNA repai r mecha-
Patients with PIDs have an increased in- tal infectious mononucleosis) or partial nism due to mutations of ATM can contrib-
cidence of lymphomas {1878,3635). Age- (resulting in other lymphoproliferative dis- ute to the development of lymphoma, leu-
specific mortality rates for all neoplasms orders) {1823). kaemia, and other neoplasms {1090). In
in patients with PIDs are 10-200 times WAS is a complex immune disorder, with these cases , non-leukaemic T-cell clones
the expected rates for the general popu- defects in function of T cells, B cells, that have translocations involving the TR
lation. However, given that PIDs are rare, neutrophils, and macrophages. T-cell genes simi lar to those seen in overt leu-
the overall occurrence of PIO-associated dysfunction is sign ificant, and tends to kaemias can be detected in the peripher-
lymphoproliferative disorder is low, ac- increase in severity during the course of al blood. B-cell non-Hodgkin lymphoma,
counting for 2.4% of all paediatric lym- the disease. Hodgkin lymphoma, and lymphoblastic
phoma cases {144). With the exception HlgM results from mutations in the gene leukaemia occur at a high rate and ear-
of CVID, these diseases present primar- for CD40 or CD40 ligand, which affect lier age than do carcinomas in AT. T-cell
ily in the paediatric age group. They are interactions between T cells and B cells prolymphocytic leukaemias are rarer than
more common in males than in females, and impair effective differentiation of initially reported . Prognosis is poor, but
primarily because several of the primary B cel ls into class-switched plasma cells patients may benefit from treatment, with
genetic abnormalities are X-linked, for {1767). an improved survival {3823).
example, XLP, SCIO, and HlgM {1871 ). It In ALPS, mutations in FAS or FASLG (and NBS also results from defects in DNA re-
shou ld be kept in mind that ch ildren can rarely other abnormalities) may contrib- pair due to mutations in the NBN gene
present with a lymphoproliferation with- ute directly to lymphoid proliferations, (also cal led NBS1), resulting in many
out the underlying immunodeficiency be- through the accumulation of lymphoid chromosomal breaks and translocations,
ing known . Especially in polymorphous cells that fail to undergo apoptosis, re- including in antigen receptor genes.
lesions, detection of EBV may indicate an sulting in the accumulation of CD4- and In patients with NBS, lymphoproliferative
underlying immune deficiency. CDS- cells in the peripheral blood and disorder is the most common neoplasm
lymphoid tissues {2331,3711 }. In ALPS, {565,2880,4158). In patients with CVID,
Etiology the severity of the apoptotic defect cor- marked lymphoid hyperplasia may oc-
The cause of the lymphoproliferative dis- relates directly with the risk of develop- cur in the lungs and gastrointestinal tract
order is related to the underlying primary ment of lymphoproliferative disorder {3507}, a setting in which more aggres-
immune defect {2897). EBV is involved {1822) The importance of FAS mutations sive-lymphoproliferative disorder or overt
in most PIO-associated lymphoid prolif- in causing lymphoproliferative disorder is lymphoma may develop {959).
erations {4136}. In these cases, defective supported by the fact that sporadic FAS
Severe combined 1-5% Gamma chain of IL2R, IL4R, IL?R, Recurrent severe bacterial, fungal, EBV-associated lesions, fatal IM
immunodeficiency IL9R, IL15R, IL21R; JAK3 kinase; and viral infections, including (nearly 100%)
IL?R, CD45, CD3-delta or CD3- opportunistic infections; skin rash
epsilon; RAG1/2, Artemis, ADA
CD40 ligand and 1-2% CD40 ligand (CD40L, CD154) Neutropenia, thrombocytopenia, EBV-associated lesions
CD40 deficiencies orCD40 haemolytic anaemia, biliary tract and (DLBCL, Hodgkin lymphoma),
(hyper-lgM syndrome) liver disease, opportunistic infections large granular lymphocytic leukaemia
Wiskott-Aldrich syndrome 1-3% WAS (also called WASP) Thrombocytopenia, small platelets, EBV-associated lesions
eczema, autoimmune disease, (DLBCL, Hodgkin lymphoma,
bacterial infections lymphomatoid granulomatosis)
(3-9%)
Nijmegen breakage syndrome 1- 2% NBN (nibrin, also called NBS1) Microcephaly, progressive mental DLBCL, PTCL, T-ALL/LBL,
retardation, sensitivity to ionizing Hodgkin lymphoma
radiation, predisposition to cancer (28-36%)
Autoimmune <1% FAS (type 1a), Defective lymphocyte apoptosis, NLPHL, CHL, DLBCL, BL, PTCL (rare)
lymphoproliferative syndrome FASLG (type 1b), splenomegaly, adenopathy, (CHL, DLBCL, and BL may be
(Canale- Smith syndrome) CASP10 (caspase 10; type 2a), or autoimmune cytopenias, EBV+ or EBV-)
CASP8 (caspase 8; type 2b) recurrent infections (3-10%)
Localization Clinical features phoid prol iferation is the first sign of the
The presentation depends on the under- Patients often present with symptoms re - underlying immune defect, but in most
lyin g disease. More often, lymphoprolif- sembling those of infecti on or neoplasia patients, the diagnosis of PIO has already
erative disorders present in extranodal (i.e. fever, fatigue, and infectious mono- been estab li shed because of other mani-
sites, most common ly the gastrointestinal nucleosis-li ke syndromes). In some dis- festations (Table 16.01)
tract, lungs, and CNS. eases, such as ALPS and XLP, the lym -
Fig.16.05 Reactive lymph node from a patient with autoimmune lymphoproliferative syndrome. A There is prominent paracortical expansion. B Reactive germinal centres are
present and the paracortex is expanded. C The cells are slightly larger than normal small lymphocytes, with dispersed chromatin.
Genetic profile the TR genes on chromosomes 7 and 14 phoproliferative disorders, the prog nosis
Antigen receptor genes are common. Consequently, these often must be evaluated in each case individu-
Because lymphoproliferative disorder in show breakpoints at 14q1 1, 7q35, 7p13 ally, although clonality testing may be of
PIO is a spectrum from reactive to ag- and chromosomal rearrangements/trans- additional value {4128}. In patients with
gressive lymphoproliferations, the prolif- locations including inv(7)(p13q35), t(7;7) EBV-driven infectious mononucleosis,
erations can be polyclonal, oligoclonal, (p13;q35), and t(7;14)(p13;q11 ), as well a haemophagocytic syndrome may be
or monoclonal. Fatal infectious mono- as t(14;14)(q11 ;q32), which can involve the primary cause of death , usually as-
nucleosis is generally polyclonal; overt the IGH gene locus {3910} Such translo- sociated with marked pancytopenia, liver
lymphomas such as diffuse large B-cell cations may also involve the TCL 1A gene dysfunction, coagulopathy, and further
lymphoma and Burkitt lymphoma have in 14q32.1 and other oncogenes leading infectious complications.
clonal IG heavy and light chain gene re- to T-cell lymphoproliferative diseases, Treatment is determined on the basis of
arrangement {1090,2227,3507}. There is including T-cell prolymphocytic leukae- both the nature of the neoplastic pro-
only limited experience with T-cell clonal- mia and pre-T lymphoblastic leukaemia/ cess and the underlying genetic defect.
ity tests in the setting of PlOs. lymphoma. In general, less-aggressive therapy is
needed than in patients w ithout PIO. Allo-
Cytogenetic abnormalities and Prognosis and predictive factors geneic bone marrow transplantation has
oncogenes The prognosis is related to both the un- been used in patients with WAS, SCIO,
Genetic alterations may be directly re- derlying PIO and the type of lymphopro- and HlgM {1066,1 508}. Because the
lated to the primary immune defect, such liferative disorder. The immunolog ical EBV-driven B-cell expansion in lympho-
as FAS mutation in patients with ALPS, status of the host is an important risk matoid granulomatosis is often not auton-
mutations of the SH201A gene encod- factor {547). The lymphoid proliferations omous, it may respond to immunoregu-
ing for SAP/SLAM in XLP, and many in ALPS are often self-limiting. Lymphoid latory therapy using interferon alfa 2b
chromosomal breaks in NBS {1371, hyperplasias in CVIO may be indolent. {4332}; however, like in post-transplant
3898}. Other abnormalities may occu r Most of the other lymphoproliferative dis- lymphoproliferative disorder, anti-C020
in the course of lymphoproliferative dis- orders in patients with PIO are aggres- directed therapy is more important.
order. In AT, in addition to mutations of sive. However, given the wide variety of
ATM, inversions and translocations of underlying conditions and ensuing lym-
Definition
Lymphomas that develop in HIV-positive
patients are predominantly aggressive B-
cell lymphomas. In a proportion of cases,
they are cons idered AIDS-def ining con-
ditions and are the initial manifestation of
AIDS. These disorders are heterogene-
ous and include lymphomas usually dia-
gnosed in immunocompetent patients,
as well as lymphomas seen much more
often in the setting of HIV infection. The
most common HIV-associated lympho-
mas include Burkitt lymphoma, diffuse
large B-cell lymphoma (DLBCL; often
involving the CNS), primary effusion
lymphoma (PEL), and plasmablastic Fig.16.07 Radiological findings in HIV-associated lymphoma. A Nuclear MRI of the brain showing a large tumour
lymphoma. Classic Hodgkin lymphoma mass in the basal ganglia. B Multiple filling defects are seen in liver.
(CHL) is also increased in the setting of
HIV infection. those with moderate immune defect, pho id proliferations suggests a mu ltistep
the relative ly increased CHL incidence lymphomagenesis. B-cel l stimulation, hy-
Epidemiology could be re lated to improvements in CD4 pergammaglobul inaemia, and persistent
The incidence of all subtypes of non- counts {374,770). Lymphocyte predomi- generalized lymphadenopathy preced-
Hodgkin lymphoma is increased 60- nant Hodgkin lymphoma can occur in ing the development of these lymphomas
200 times in HIV-positi ve patients. Before HIV-infected individuals, but there is no probab ly reflect the role of chronic anti-
comb ination antiretroviral therapy (cART) known association. gen ic stimu lation and impaired immune
was available, primary CNS lymphoma response. Disruption of the cytokine net-
and Burkitt lymphoma were increased Etiology work, leading to high serum levels of IL6
approximately 1000 tim es in compari- Lymphomas in HIV-infected patients and IL10, is a feature of HIV-related lym-
son with the general population {345, are heterogeneous, reflecting several phomas associated with EBV or HHV8.
2285). Since the introduction of cART, pathogenetic mechan isms: chron ic an- EBV is identified in the neoplastic cells
the incidence of non-Hodgkin lymphoma tigen stimulation, genetic abnormalities, of approximate ly 40% of HIV-re lated lym-
has decreased by 50%, mainly due to cytokine deregulation, and the role of phomas, but the detection of EBV varies
decreased CNS lymphoma and the im- EBV and HHV8 {555,557). HIV-related considerab ly with the site of presentation
munoblastic histological subtype {1107). lymphomas are consistently monoclonal and the histological subtype. EBV infec-
Moreover, the decreased incidence of and are characterized by a number of tion is found in 80- 100% of primary CNS
most AIDS-associated non-Hodgkin common genetic abnormaliti es of MYC lymphomas {536} and PELs, in 80% of
lymphomas after cART introduction is and BCL6, as well as tumour suppressor DLBCLs with immunoblastic features,
cons istent with improved CD4 counts genes {1272,4096}. The polyclonal or oli - and in 30- 50% of Burkitt lymphomas
{363,373). cART is also assoc iated with goclonal nature of some HIV-related lym- {1531). Nearly all CH L cases in the set-
in creased su rvival (with a 75% decrease ting of HIV infection are associated with
in mortality), althoug h lymphomas now EBV {191,3754). HHV8 is spec ifically as-
account for a higher proportion of first sociated with PEL, which usually occurs
AIDS-defining illnesses {974,1107). In in the late stages of the disease, in the
contrast, the risk of HIV-associated CHL setting of profound immunosuppression
has remained stable, and burden of dis- {623}.
ease has increased. The incidence of
CHL is about 50 cases per 100 000 per- Prevention
son-years among HIV-infected individu- Despite the therapeutic advances with
als, 5-20 times the incidence in the gen- cART, there is sti ll no effective immun i-
eral population {3649). Because CHL zation or cure for HIV infection. Diversity
incidence is lower among patients with Fig.16.08 HIV-associated diffuse large B-cell lympho- caused by circu lating recomb inant viral
severe immunosuppression than among ma involving the basal ganglia. forms is a major challenge, which has
Fig.16.12 HIV-associated diffuse large 8-cell lymphoma (DL8CL). A Primary CNS DL8CL. B DL8CL, immunoblastic variant. The cells have prominent central nucleoli. C The
cells exhibit marked plasmacytoid differentiation on touch imprint.
lack a starry-sky pattern. lmmunoblastic P!asmab!astic lymphoma cavity type . Other sites of involvement in-
lymphomas consist of larger cells with Plasmablastic lymphoma accounts for clude the gastrointestinal tract, skin, ab-
deeply basophilic or amphophilic cyto- about 2% of all HIV-related lymphomas domen, retroperitoneum, and soft tissue
plasm, and may appear plasmacyto id {554). The blastoid morphology and im- of the extremities {578). Patients do not
with a perinuclear hof. The nuclei contain munophenotype suggest that these usually have a monoclonal gammopathy,
a prom inent central nucleolus. Primary cells retain the blasto id appearance of but may have advanced clinical stage,
CNS lymphomas are usually of the im- immunoblasts or centroblasts, but have with B symptoms and bone marrow in-
munoblastic type {536} They are intrac- acquired the antigen profile of plasma volvement. Histologically, plasmablastic
ranial parenchymal tumours that may be cells . They may occur at all ages but are lymphoma is characterized by sheet-like
deep-seated in the brain or may be mul- rare in paediatric patients. The med ian proliferation of large cells with immuno-
tifocal. In addition to the cerebrum, they patient age at presentation is 38 years blasti c or plasmablastic appearance,
may be located in the basal ganglia and {577). The cell or origin is considered to includ in g central round or oval nuclei
brain stem, and may involve the menin - be an activated B cell after somatic hy- with prominent nucleoli and moderately
ges. Lymphomas tend to follow vascular permutation and class-switch recombi- abundant amphophilic cytoplasm. The
channe ls as perivascular cuffs, and there nation. About 60- 70% of cases are pos i- nuclei may be eccentrically located with
may be adm ixed small lymp hocytes and tive for EBER in the absence of EBNA2 a peri nuclear clearin g or so-called hof. In
glial cells. AIDS-related DLBCLs ex- (compared with about 50% in immuno- the oral cavity, the cel ls may have a more
press B-cel l-l ineage antigens inc luding competent patients with plasmab lastic centroblastic appearance but retain the
CD19 and CD20, and have phenotypes lymphoma) {2755). There is expression plasmablastic phenotype {936). There
similar to those of DLBCLs in the general of MYC in about 50% of cases, which are frequent apoptotic cells, but a starry-
popu lation. Most have IG heavy and light correlates with MYC translocation or sky pattern is rare. The neoplastic cells
chain gene rearrangements, and several sometimes amplification. There are no are negative or weakly pos itive for CD45
proto-oncogenes may be involved in the translocations involving BCL2, BCL6, and usually negative for B-ce ll markers,
pathogenesis, including MYC, BCL2, MALT1, or PAX5. EBV LMP1 is usually including CD19, CD20, and PAX5, but
and BCL6. EBV infection is associated negative (type I EBV latency), although most cases are positive for CD79a, IRF4
with expression of several tumour mark- type Ill latency has been recorded {578). (also called MUM1), PRDM1 (also called
ers that are involved in the NF-kappaB Extranodal presentation is most frequent BLIMP1), CD38, and CD138. lntracyto-
pathway {659). particularly in the oral cavity or jaw. For plasmic lgG may be detected in some
this reason, it is sometimes referred to patients. There may be aberrant expres-
as plasmablastic lymphoma of the oral sion of T-cell markers, including CD2 and
Infectious mononucleosis Absent Admixed small Pel B cells and Pel or very small Simple cytogenetic
lymphocytes, plasma admixed T cells; mcl B-cell population(s); abnormalities
cells, and immunoblasts EBV+ may have clonal/ rarely present
oligoclonal TR genes
Florid follicular hyperplasia Absent Prominent hyperplastic Pel B cells and Pel or very small mcl Non-specific
germinal centres admixed T cells; B-cell population(s) simple cytogenetic
EBV± abnormalities
rarely present
Polymorphic Present Full spectrum of Pel ± mcl B cells and Mel B cells, Some have BCL6
lymphoid maturation admixed T cells; non-clonal T cells somatic hypermutations
seen, not fulfilling criteria most EBV+
for NHL
Monomorphic Usually present Fulfils criteria for an Varies based on Clonal B cells Variably present
NHL (other than one type of neoplasm they and/or T cells (see text)
of the indolent B-cell resemble; (except for rare NK-cell
neoplasmsa) or plasma EBV more variable than cases)
cell neoplasm in other categories
CHL Present Fulfils criteria for CHL Similar to other CHL; IGH not easily Unknown
EBV+ demonstrated
- mcl, monoclonal; pcl, polyclonal.
-CHL, classic Hodgkin lymphoma;.... NHL, non-Hodgkin lymphoma; - I
Monoclonality and polyclonality are only inferred when finding monotypic or polytypic light chain expression.
a EBV-posilive MALT lymphomas at least of skin/subcutaneous tissues should be considered a type of PTLD.
is less sensitive. Most EBV-positive cases ences in the regulation of BCL2 family and frequently involve the allograft {147,
exhibit a type Ill EBV latency pattern, but a proteins between EBV-positive and EBV- 632,2225,3756,4290). In contrast, most
moderate number show a type II pattern, negative PTLD have also been reported PTLDs in stem cell allograft recipients are
and fewer show a type I pattern, although {1354). HHV8-associated PTLDs have of donor origin, as would be expected,
not all of the cells in a given case show been reported, including post-transplant given that successful engraftment results
the same pattern {1405,301 1). Evidence primary effusion lymphoma (1030,1935, in an immune system that is nearly exclu-
of lytic EBV infection can also be docu- 2571); however, the etiology of the vast sively of donor origin {4507)
mented in more than half of the cases and majority of EBV-negative PTLDs is un-
has been associated with plasmacytic known. Some may be due to EBV that is Localization
differentiation {1405). About 20-40% of no longer detectable {3760}, some due to Involvement of lymph node, gastrointes-
PTLDs are EBV-negative, with some se- other unknown viruses, and some due to tinal tract, lungs, and liver is common,
ries reporting an even higher proportion chronic antigenic stimulation, including but disease can occur at almost any site
of cases . Approximately two thirds of the by the transplant itself {385). Two gene in the body {1205,2819,3130,4271). The
T-cell PTLDs are EBV-negative (47,385, expression profiling studies support a CNS is involved uncommonly, either as
1205, 2239, 2756, 2848 ,3845). Further- non-viral etiology for the EBV-negative the only site of disease or in association
more, the proportion of EBV-negative cases, although other studies have failed with multiorgan involvement {575,1119).
PTLDs has increased since PTLDs were to find differences between EBV-positive In solid organ transplant recipients, PTLD
first being reported {2848}. EBV-negative and EBV-negative PTLDs {832,2754, can involve the allograft, which can cause
PTLDs are more common in adults, tend 4100). The EBV-negative cases are still diagnostic confusion because rejection
to occur later after transplantation, and considered to represent PTLD, and some and infection can result in a similar clini-
are more likely to be monomorphic com- may respond to decreased immunosup- cal picture. Allograft involvement appears
pared with EBV-positive cases {1355, pression {2848). more frequently in early-onset, EBV-posi-
2848). Although data are limited, EBV- The majority (> 90%) of PTLDs in solid tive disease and is most common in lung
negative cases appear to have a gene organ recipients are of host orig in, and and intestinal transplant recipients {236,
expression profile similar to that of dif- only a minority of donor origin. Donor- 1355,2980,3296). The non-destructive
fuse large B-cell lymphoma occurring in origin PTLDs appear to be most com- PTLDs often present with tonsil and/or
immunocompetent hosts {2754). Differ- mon in liver and lung allograft recipients, adenoid involvement but can also occur
Clinical features
The clinical features of PTLD are highly
variable and corre late to some extent with
the type of allograft and morphologically
defined categories. PTLD frequently pre-
sents in the first year after transplantation,
especial ly in EBV-seronegative recipients
who acquire early post-transplant EBV
infection, often from the donor. This pat-
tern of presentation is particularly com-
mon in children. However, the median
time to PTLD in some studies, especial-
ly those of adult populations, is several
years, and as many as 15- 25% of cas-
.. .~~~lt~~·~,~
Fig.16.14 Infectious mononucleosis post-transplant lymphoproliferative disorder in the tonsil of an 11-year-old renal
es occur > 10 years after the transplant allograft recipient. A There is preservation of overlying epithelium and crypts, but normal follicles are absent, and
{981,1122,2819,3130}. There is some ev- there is a diffuse lymphoid proliferation. B Polymorphic proliferation of immunoblasts, small lymphoid cells, and
idence for an increase in prevalence of plasma cells. C CD20 staining showing scattered B cells. D In contrast, a stain for CD79a shows more-numerous
positive cells, indicating plasmacytoid differentiation. E In situ hybridization identifies EBV-encoded small RNA
late-onset disease {720), although this
(EBER) expression in most of the cells.
may in part reflect the ever-expanding
population of patients at risk as the num-
ber of long-term survivors of transplanta- es, often at extranodal sites, sometimes However, some infectious mononucleo-
tion increases. EBV-negative PTLD and with organ-specific dysfunction and sis-like PTLDs can be fatal. P-PTLDs
T/NK-ce ll PTLD tend to present later (with occasional ly with widely disseminated and even a significant minority of M-
median times to occurrence of 4-5 years disease. A viral septic shock-like picture PTLDs may also regress with reduction in
and ~6 years, respectively), although is another rare presentation. immune suppression {3346,3769,4271).
T-cell PTLDs following haematopoietic Some factors that have been reported to
stem cell or bone marrow transplanta- Prognosis and predictive factors be associated with a lack of response to
tion occur sign ificantly earlier {851,1625, Although overall mortality rates of decreased immunosuppression include
2239' 2848, 3845,3999}. 25-60% are sti ll quoted {2756), newer elevated lactate dehydrogenase, organ
PTLD presentations vary greatly. Some therapeutic strategies appear to be as- dysfunction, multiorgan involvement, ad-
PTLDs are found incidentally, some sociated with a better overall outcome. vanced stage, bulky disease, and older
present with very vague non-specific The non-destructive PTLDs (previously patient age {3346,4066). Clinical caution
symptoms such as fever and malaise, termed early lesions) tend to regress is required because rebound acute or
and some present with infectious mono- with reduction in immune suppression; if chronic rejection is frequently observed
nucleosis-like fin dings. Others present this can be accomplished without graft during reduction of immunosuppression
with tonsil or adenoid enlargement, rejection, the prognosis is excellent, par- and can lead to graft loss and death
lymphadenopathy or tumorous mass- ticularly in children (2385,2849,4462}. {4271). A proportion of P-PTLDs and
Clinical features
The reported frequency of P-PTLDs var-
ies widely, but they account for a minor-
ity of PTLDs in most stud ies. However, in
ch il dren P-PTLD is generally more com-
mon and frequently follows post-trans-
plantation primary EBV infection {4271).
·- ..,
Fig.16.16 Plasmacytic hyperplasia. A The normal architecture of the lymph node is intact. B Numerous plasma
cells are present.
The clinical presentation of P-PTLDs is
not distingu ishable from that of PTLDs
in general, although they have been
lmmunophenotype
lmmunophenotypic studies demonstrate
B cells and a variable proportion of het-
erogeneous T cells that are usually mod-
erately numerous and sometimes pre-
dominate {1062,2819). Light chain class
restriction does not exclude the diag-
nosis and, when present, may be focal,
or with the presence of d ifferent clonal
populations in the same or different sites
{2819}. The presence of clear-cut light
chain class restriction must be noted in
the diagnostic report, because some of
these cases could also be c lassified as
monomorphic diffuse large B-cell lym-
phoma PTLD with plasmacytic differen-
tiation or as plasma cell neoplasm with
increased transformed cells. Prominent
CD30 expression is common, but unlike
in most cases of classic Hodgkin lym-
phoma, the CD30+ Reed-Sternberg-like
cells are CD20+ and CD1 5- {694,4159).
Most cases of P-PTLD contain numer-
ous cells positive for EBV-encoded small
reported to occur earli er than M-PTLD. which represent the typically prom inent RNA (EBER). Detection of EBV by in situ
Reduction in immunosuppression leads T-cell component. There may be areas hybridization for EBER is a useful tool in
to regression in a variable proportion of of geographical necrosis and scattered the differential diagnosis of PTLD versus
cases; others may progress and require large, bizarre cells that not infrequently rejection in allografts.
treatment for lymphoma {2053,2819, resemble Reed-Sternberg cells (atypi-
3769,4271}. cal immunoblasts). Numerous mitoses Genetic profile
may be present Some cases have areas P-PTLDs are expected to demonstrate
Microscopy that appear more monomorphic in the clonally rearranged IG genes, although
Unlike the three types of non-destructive same or other tissues; thus, there may be the clones are less predominant than
PTLD lesions, P-PTLDs show efface- a continuous spectrum between these in M-PTLD {766,1936,2053,2378). EBV
ment of the underlying tissue architec- lesions and M-PTLD. Other P-PTLDs terminal repeat analysis is the most sen-
ture {1258,1541). However, unlike many have features that more closely resem- sitive method for demonstrating clonal
lym phomas, they show the full range ble those of Hodgkin lymphoma. Some populations in the EBV-positive cases,
of B-cell maturation, from immuno- of these cases were previously referred but is not generally performed. In some
blasts to plasma cells, with small and to as Hodgkin-like. Variably sized, but reported cases, tumours at different sites
medium-sized lymphocytes and cells usually small, lymphoid aggregates with in the same patient may be clonally dis-
with irregular nuclear contours, some of or without plasma cell clusters are seen tinct {628}. About 75% of P-PTLDs are
reported to have mutated IGV genes
without ongoing mutations, and the re-
mainder are unmutated {550). Significant
T-cell clones are not expected. Clonal cy-
togenetic abnormalities may be present
although less commonly detected than in
B-cell M-PTLD {1010,4101}. Comparative
genomic hybridization studies also dem-
onstrate abnormalities in some P-PTLDs,
including some recurrent abnormal ities
also seen in M-PTLD {3207). BCL6 so-
There are (A) numerous variably matic hypermutations are present in a
subset of cases, as is aberrant promoter
...._
Fig.16.22 Classic Hodgkin lymphoma post-transplant lymphoproliferative disorder in a 52-year-old man following renal transplant. The Reed-Sternberg cells were EBV-
positive. A Reed-Sternberg cell surrounded by small lymphocytes and some eosinophils. B,C Reed-Sternberg cells with CD30 expression (B) and Golgi-type CD15 positivity (C).
Localization
Of the cases reported in patients receiv-
ing methotrexate, 40-50% have been
extranodal, occurring at sites such as
the gastrointestinal tract, skin , liver and
spleen, lung, kidney and adrenal gland,
thyroid gland, bone marrow, CNS,
gingiva, and soft tissue {74,1703,1787,
2065,2945,3498}. As is the case for
HSTL in other settings, the spleen, liver,
and bone marrow are the most common Fig.16.24 EBV-positive large B-cell lymphoproliferation in a patient with rheumatoid arthritis treated with
sites of involvement of HSTL in patients methotrexate. This lesion regressed following cessation of therapy.
with Crohn disease receiving immuno-
modulators {2426,3414}. ing the recently recognized EBV-positive Prognosis and predictive factors
mucocutaneous ulcer {1018} and others A significant proportion of patients with
Clinical features more closely resembling a polymorphic methotrexate-associated lymphopro-
The clinical features are the same as PTLD. HSTL in patients who have been liferative disorder have shown at least
those seen in immunocompetent patients treated with infliximab is indisting uish- partial regression in response to drug
with similar-appearing lymphomas . able from HSTL arising in immunocom- withdrawal (Table 16.04). Although most
petent or post-transplant patients. responses have occurred in EBV-positive
Microscopy cases {1703,1752,1764,2387,3498,4403},
The distribution of histological types of lmmunophenotype a proportion of EBV-negative cases also
iatrogenic lymphoproliferations in non- The immunophenotype of the lym- respond {1752,2065}. A variable propor-
transplantation settings appears to differ phoproliferative disorder does not ap- tion of DLBCLs (as many as -40%) have
from that seen in other immunodeficiency pear to differ from that of the lymphomas regressed, while most require cytotoxic
settings, with a probable increase in the in non-immunosuppressed hosts, which therapy. The proportion of polymorphic
frequen cy of Hodgkin lymphoma and they resemble. Among methotrexate- lymphoproliferative disorder patients with
lymphoid proliferations with Hodgkin-like associated DLBCLs, the majority have regression after withdrawal is higher. In
features, such as EBV-positive mucocu- an activated- B-cell immunophenotype, recent studies of methotrexate-asso-
taneous ulcer. Among patients treated especially EBV-positive cases. EBV-pos- ciated lymphoproliferative disorder in
with methotrexate, the reported cases itive methotrexate-associated DLBCLs rheumatoid arthritis patients, the 5-year
are most commonly DLBCL (35- 60%) commonly express CD30 {2065,4403}. overall survival rate was > 70% . Spon-
and CHL (1 2- 25%), with less frequent lmmunophenotype is a useful tool in the taneous regression following methotrex-
cases of follicular lymphoma (3-10%), distinction from lymphoproliferative disor- ate withdrawal has been associated with
Burkitt lymphoma, extranodal marginal ders that may have some Hodgkin lym- EBV positivity and a non-DLBCL type
zone lymphoma of mucosa-associated phoma- like features, but which shou ld of lymphoproliferative disorder, whereas
lymphoid tissue (MALT lymphoma), and not be considered to represent CHL, the patient age > 70 years an d DLBCL type
peripheral T-cell lymphoma {1703,1752, large cells most typically being CD20+/ are predictive of a shorter survival {1752,
1908,2387,2509,3498}. Polymorphic or CD30+/CD15- and CD20-/CD30+/ 4014). Early lymphocyte recovery after
lymphoplasmacytic infiltrates resembling CD15+, respectively. EBV is variably methotrexate withdrawal may be predic-
polymorphic PTLD have been described positive, with type II latency (LMP1 -posi- tive of good response {1 764}. A moderate
in as many as 20% of cases in this setting tive and EBNA2-negative) more common number of patients whose lymphoprolif-
{1752). Peripheral T-cell lymphomas oc- than type Ill (LMP1-positive, EBNA2-pos- erative disorder initially reg resses after
curring in this setting seem to have a com- itive) {1752,4403}. discontinuation of methotrexate later re-
mon extranodal presentation, a cytotoxic lapse and then require chemotherapy
profile, and may include extranodal NK/ Postulated normal counterpart {1703,1752}. Regression after discon-
T-cell lymphomas {2079,3870}. Among The postulated normal counterpart varies tinuation of drug seldom occurs in pa-
CHLs, the mixed-cellularity subtype is depending on the specific type of lym- tients who develop lymphoproliferative
more frequent than nodular sclerosis, phoproliferative disorder. disorder following the administration of
with a significant proportion that cannot TNF blockers. Like in individuals without
be further classified {2387). Lesions con- Genetic profile overt immunodeficiency, cases of HSTL
taining Reed- Sternberg-like cells but The genotype of these immunodeficien- in patients treated with infliximab plus
not fu lfilling the criteria for Hodgkin lym- cy-associated lymphoproliferative disor- thiopurine have a very aggressive clinical
phoma, wh ich in the past were referred ders does not appear to differ from those course, with most survivors treated with
to as Hodgkin-like lesions, have been re- of lymphomas of similar histological types allogeneic bone marrow transplantation
ported {1 911}, with some likely constitut- not associated with immunosuppression. {2426,3414}.
Introduction teristics of terminally differentiated ele- circumstances, they carry the same TR
ments. In line with this, blastic plasma- or IG rearran gements and chromosomal
Pileri S.A. Jones D.M. cytoid dendritic cell (PDC) neoplasm is aberrations as lymphoid neoplasms,
Jaffe R. Jaffe E.S. excluded from this section on histiocytic consistent with transdifferentiation {678,
Facchetti F. and dendritic cell neoplasms, and is dis- 859,860,1172,3313,3633). The histiocytic
cussed after the acute myeloid leukae- and lymphoid neoplasm may share a
mias and related precursor neoplasms, common progenitor (479), but one that
Definition because it stems from a cell that ac- has already undergone IG rearrange-
Histiocytic neoplasms are derived from quires terminal differentiation and den- ment. To date, neither comprehensive
mononuclear phagocytes (macrophages dritic appearance following activation gene expression profiling nor next-gen-
and dendritic cells) or histiocytes. Den- (see Chapter 9, B!astic p!asmacytoid eration sequencing studies have been
dritic cell tumours are related to several dendritic cell neoplasm, p. 173). carried out, with the exception of studies
lineages of accessory antigen-present- Intriguingly, during the past few years, based on canine models {399} and small
ing cells (dendritic cells) that have a role several publications have highlighted the series of follicular dendritic cell (FDC)
in phagocytosis, processing, and pre- fact that, irrespective of their su pposed sarcomas (1460,1569A,2184A, 2383A}.
sentation of antigen to lymphoid cells. normal counterparts (myeloid-derived A next generation sequencing study of
macrophages or myeloid-derived den- 13 FDC sarcomas revealed recurrent
Epidemiology dritic cells), some of these neoplasms loss-of-function alterations in tumour
Tumours of histiocytes are among the are associated with or preceded by a suppressor genes involved in the nega-
rarest tumours affecting lymphoid tis- malignant lymphoma (e.g. follicular lym- tive regu lation of NF-kappaB activation
sues, probably accounting for < 1% of tu- phoma, chronic lymphocytic leukaemia, (38% of cases) and cell-cycle progres-
mours presenting in the lymph nodes or B-lymphoblastic leukaemia/lymphoma or sion (31% of cases) (1 460). The possible
soft tissue (1165,3180). Because several T-lymphoblastic leukaemia/lymphoma, occurrence of BRAF V600E mutation has
of these tumour types were poorly recog- and peripheral T-cell lymphoma) (678, been reported in the setting of histiocytic
nized until recently, their true incidence 859,860,1172,3313,3633). Under these sarcoma, Langerhans cell histiocytosis,
remains to be determined. Historically,
some large cell lymphomas of B-cell or
T-cell type were thought to be histiocyt-
ic or reticulum cell sarcomas on purely
morphological grounds, but only a small
number have proven to be of true mac-
rophage or dendritic cell orig in. Some of p
the regulatory disorders, such as mac- r
rophage activation and haemophagocyt- e
Be
ic syndromes, can have large numbers of I u
o r
histiocytes, but these are non-neoplastic. 0 s
No sex, racial, or geographical predilec- do
tion has been descri bed (Table 17.01). r
s
Histogenesis
The cellu lar counterparts of this group Fiba b
reti um II
Mus in+ T
of neoplasms consist of myeloid-derived Keratins-/+ i
macrophages, myeloid-derived dendritic s
s
cells, and stromal-derived dendritic cells. u
The myeloid-derived macrophages and e
s
dendritic cells constitute divergent lines
of differentiation from bone marrow pre-
cursors, although transdifferentiation or
hybrid differentiation states likely occu r.
Fig. 17.01 Schematic diagram of the origin of histiocytic and dendritic cells. Macrophages and dendritic cells (DCs;
Histiocytic and dendritic cell neoplasms antigen-presenting cells) are derived from a common bone marrow precursor. In contrast, follicular dendritic cells are
tend to reproduce the morphological, thought to be of non-haematopoietic origin.
phenotypic, and ultrastructural charac- +, most (if not all) cells positive;-, all cells negative; - /+, a minority of cells positive; v, variable intensity.
Introduction 467
Localization
Most cases present in extranodal sites
{1688,3180,4216}, most commonly the in-
testinal tract, skin, and soft tissue . Others
present with lymphadenopathy. Rare pa-
tients have a systemic presentation, with I -
multiple sites of involvement, sometimes Fig.17.03 Histiocytic sarcoma. A Histiocytic sarcoma involving the bowel. B Note the abundant cytoplasm, which
referred to as malignant histiocytosis stains strongly for CD68 (C) and lysozyme (D).
{585,3180,4331 }.
cells are usually large and round to oval feature is particularly common in histio-
Clinical features in shape; however, focal areas of spin- cytic sarcoma involving the CNS {699}.
Patients may present with a solitary mass, dling (sarcomatoid areas) may be ob-
but systemic symptoms, such as fever served. The cytoplasm is usually abun- Ultrastructure
and weight loss, are relative ly common dant and eos inophilic, often with some The neoplastic cells show abundant
{1688,3180,4216}. Skin man ifestations fine vacuoles. Haemophagocytosis oc- cytop lasm with numerous lysosomes.
may range from a ben ign-appearing rash curs occas ionally in the neoplastic ce ll s. Birbeck granules and ce ll ular junctions
to solitary lesions to innumerable tumours The nuclei are generally large, round to are not seen.
on the trunk and extremities. Patients with oval or irregularly folded, and often ec-
intestinal lesions often present with intes- centrically placed; large multinucleated lmmunophenotype
tinal obstruction. Hepatosplenomegaly forms are commonly seen. The chroma- By definition , there is express ion of one
and associated pancytopenia may occur. tin pattern is usually vesicu lar, and atyp ia or more histiocytic markers, includ ing
The bone may show lytic lesions {1688, varies from mild to marked. lmmunostain- CD163, CD68 (KP1 and PGM1), and
3180,4216}. ing is essential for distinction from other lysozyme, with typical absence of Langer-
large cell neoplasms, such as large cell hans cell (CD1a, langerin), follicular den-
Microscopy lymphoma, melanoma, and carcinoma. dritic ce ll (CD21, CD35), and myeloid cell
The tumour consists of a diffuse non- A variable number of reactive cells may (CD13, MPO) markers {1688,3180,4216}.
cohesive proliferation of large ce ll s be seen, including small lymphocytes, Both CD68 and lysozyme show granular
(> 20 µm), but a sinusoidal distribution plasma cells, ben ign histiocytes, and cytoplasm ic staining. The lysozyme stain-
may be seen in the lymph nodes, liver, eosinophils. Sometimes the neoplastic ing is accentuated in the Golgi region.
and spleen. The proliferating cells may cells are obscured by a heavy inflamma- CD163 staining is in the cell membrane
be monomorph ic or (more commo nly) tory infiltrate including many neutrophi ls, and/or cytoplasm. Rare ly, weak expres-
pleomo rphic. The in divid ual neoplastic mimicking an inflammatory lesion; thi s sion of CD15 occurs {3180} In addition,
Localization
The disease can be local ized to a single
site, can occur in multiple sites within a
single system (usually bone), or can be
B more disseminated and multisystem
Fig.17.05 Langerhans cell histiocytosis.
{2668,4009). The dominant sites of in-
A Radiograph from a patient with eosinophilic granu- volvement in the solitary form are bone
loma of bone illustrates a discrete punched-out lesion. and adjacent soft tissue (skull, femur,
B Gallium scan shows high uptake in lytic bone lesion. vertebra, pelvic bones, and ribs) and,
less commonly, lymph node, skin, and and T-lymphoblastic leukaem ia, with predominate, along with eos inophils and
lung. Multifocal lesions are largely con- the leukaemia-associated TR gene re- neutrophils. In late lesions, the LCH cells
fined to bone and adjacent soft tissue. In arrangement present in the LCH cells; are decreased in number, with increased
multisystem disease, the skin, bone, liver, th is has been considered a transdifferen- foamy macrophages and fibrosis.
spleen, and bone marrow are the prefer- tiation phenomenon {1173) Involved lymph nodes have a sinus pat-
ential sites of involvement. The gonads tern with secondary infiltration of the
and kidney appear to be spared even in Microscopy paracortex. Spleen shows nodular red
disseminated cases . The key feature is the LCH cells. These pulp involvement. Liver involvement has
are oval; about 10-15 µm; and recog- strong preference for intrahepatic biliary
Clinical features nized by the ir grooved, folded, indented, involvement with progress ive sc lerosing
Patients with un ifocal disease are usu- or lobed nuclei with fine chromatin, in- cho langitis. Bone marrow biopsy is pre-
ally older ch il dren or adults who most consp icuous nucleoli, and thin nuclear ferred to aspiration for documentation of
commonly present with a lytic bone le- membranes. Nuclear atypia is minimal, bone marrow involvement {2670).
sion eroding the cortex. Solitary lesions but mitotic activity is variable and can Large clusters or sheets of LCH cells ac-
at other sites present as mass lesions be high without atypical forms. The cy- companied by eos inophils can be found
or enlarged lymph nodes. Patients with toplasm is moderately abundant and within other lesions (lymphomas and
unisystem multifocal disease are usually slightly eos inoph ilic. Unlike epidermal sarcomas). It remains to be determined
young ch il dren who present with multiple Langerhans cells or dermal perivascular whether these constitute a local reac-
or sequential destructive bone lesions, cells, LCH cells are oval in shape and tive phenomenon or a transdifferentiation
often associated with adjacent soft tissue devoid of dendritic cell processes. The process {752}
masses. Skull and mandibular involve- characteristic milieu includes a variab le
ment is common. Diabetes insipidus fol- number of eosinophils, histiocytes (both Ultrastructure
lows cranial involvement. Patients with mu ltinuc leated LCH forms and osteo- The ultrastructural hall mark is the cyto-
multisystem involvement are infants who clast-type cells, especial ly in bone), neu- plasmic Birbeck granules, whose pres-
present with fever, cytopen ias, skin and troph ils, and small lymphocytes. Plasma ence can be confirmed by langerin
bone lesions, and hepatosplenomegaly cells are usually sparse. Occasionally, expression. The Birbeck granule has a
{142,2669). Pu lmonary disease in ch il d- eosinophil ic abscesses with central ne- tennis-racket shape, and is 200-400 nm
hood is cl inically variable {2927). cros is, rich in Charcot- Leyden crystals, long and 33 nm wide, with a zipper-like
There is an association between LCH may be found . In early lesions, LCH cells appearance.
., 1 •
. t,_
._. . .
Fig .17.08 Langerhans cell histiocytosis, at a later stage of evolution than the case illustrated in Fig 17.07. A This bony lesion shows a greater number of foamy macrophages and
lymphocytes. BA greater number of foamy macrophages and lymphocytes are present, although nuclei with typical grooves are still discernible.
~
....,..... -p,i
_..,~.,.,, -"
. ~
Fig.17.10 Langerhans cell histiocytosis. A Contrast the bland nuclear morphology with that of the sarcoma (see
Figs. 17.11 and 17.12). B Staining is both nuclear and cytoplasmic with 8100. C CD1a uniformly stains the cell
surface, with a perinuclear dot. D Langerin staining is more granular and cytoplasmic.
Epidemiology
LC sarcoma is rare {327,401,3180}, and
almost all reported cases are in adu lts.
The med ian patient age is 41 years
(range: 10-72 years). Rare cases may
be associated with follicular lymphoma
{4302}.
Etiology
Merkel cell polyomavirus sequences .
•i·1o1i
•n~
have been identified in a subset of cases .... ..·.A..:1---~~. I ·
{2786}. Fig.17.11 Langerhans cell (LC) sarcoma. A Nuclear pleomorphism is not a feature of LC histiocytosis (LCH), but
should raise the possibility of malignancy. B 8100 is widely represented, nuclear and cytoplasmic, but variable in
intensity. C Lesional ce lls express surface CD1a more variab le than in LCH. D Langerin is demonstrable, though not
Localization
as much as in LCH in this example.
The skin and underlying soft tissue are
the most common sites of involvement.
Multiorgan involvement can affect the Chromatin is clumped and nucleol i are Postulated normal counterpart
lymph nodes, lung, liver, spleen, and consp icuous. Some cells may have the A mature Langerhans ce ll
bone {401,1202,3180). complex grooves of the LC histiocytosis
ce ll, a key clue to the diagnosis. The mi- Genetic profile
Clinical features totic rate is high, usually> 50 mitoses per At least one case has been found to har-
Most cases are extranodal (involving skin 10 high-power fields. Rare eosinophils bour the BRAFV600E mutation {678).
and bone) and multifocal; high-stage (111- may be admixed.
IV) disease is seen in 44%. On ly 22% of Prognosis and predictive factors
cases are primarily nodal. Hepatospleno- Ultrastructure LC sarcoma is an aggressive, high-grade
megaly is noted in 22% and pancytope- Birbeck granules are present, whereas malignancy, with > 50% mortality from
nia in 11%. desmosomes I junctional specializations progressive disease.
are absent {3180).
Microscopy
The most prominent feature is the overtly lmmunophenotype
malignant cyto logy of a pleomorphic tu- The immunop henotype is identical to that
mour, and on ly the phenotype and/or of LC histiocytosis, although staining for
ultrastructure reveal the LC derivation. individual markers can be focal.
Fig.17.12 Langerhans cell sarcoma. A Tonsillar lesion in a 31-year-old man. The nuclear features and abundant cytoplasm point to a histiocytic lesion. Nuclear pleomorphism
and atypical mitoses indicate high-grade disease. B The Ki-67 proliferation index is high.
Definition
Indeterminate dendritic cell tumour, also
known as indeterminate cell histiocytosis,
is a neoplastic proliferation of spindled to
ovoid cells with phenotypic features sim i-
lar to those of normal indeterminate cells,
the alleged precursor cells of Langer- .~ - ...._,,;
hans cells. These neoplasms are ex- Fig.17.13 Indeterminate dendritic cell tumour. The lesion is positive for CD1a (A) and 8100 protein (B).
traord inarily rare {104,360,412,651,2076,
3407,3672,4160,4174,4363,4374}. There and usually eosinophilic. Multinucleated Cell of origin
may be an association with low-grade giant cells may be present. In some cas- Normal indeterminate cells, the postul-
B-cell lymphoma {4160}. es, there may be spindling of the cells. ated precu rsors of Langerhans cel ls
The mitotic rate varies widely from case
ICD-0 code 9757/3 to case. An accompanying eosinoph ilic Genetic profile
infiltrate is usually not present. One case has been shown to be clonal
Localization by human androgen receptor gene assay
Patients typically present with one or Ultrastructure {4374}. One case has been shown to har-
(more commonly) multiple generalized By definition, these cells lack Birbeck bour BRAF V600E mutation {2916}.
papules, nodules, or plaques on the skin. granules on ultrastructural examination.
Less often, primary lymph node or splen- There can be complex interdigitating cell Prognosis and predictive factors
ic disease has been reported. processes, but desmosomes are lacking. The clinical course has been highly vari-
able, rang ing from spontaneous regres-
Clinical features lmmunophenotype sion to rapid progression. There are no
Systemic symptoms are usually The proliferating cells consistently ex- known prognostic factors. One case
not present. press S100 protein and CD1a. Langerin was associated with the development of
is negative. They are negative for spe- acute myeloid leukaemia {4174}.
Microscopy cific B-cell and T-cell markers, CD30, the
The lesions are usually based in the histiocytic marker CD163, and the folli-
dermis, but may extend into the subcu- cu lar dendritic cell markers CD21 , CD23,
taneous fat. The infiltrate is diffuse, con- and CD35. They are variably positive for
sisting of cells resembl ing Langerhans CD45, CD68, lysozyme, and CD4. The
cells, with irregular nuclear grooves and Ki-67 proliferation index is highly variable.
clefts. Cytoplasm is typically abundant
"" -- ..-iiA. - •
Fig.17.14 Indeterminate dendritic cell tumour. A This is a histiocytic-appearing neoplasm. A multinucleated cell can be seen.
processes, but no Birbeck granules.
Definition
lnterdigitating dendritic cell (IDC) sarco-
ma is a neoplastic proliferation of spindle
to ovoid cells with phenotypic features
similar to those of IDCs.
Fig.17.15 lnterdigitating dendritic cell sarcoma. The tumour is vague ly lobular in lymph node and firm in consistency.
ICD-0 code 9757/3
to ovoid, and may show indentations; lmmunophenotype
Synonym occasional multinucleated cells may be The neoplastic cell s consistently express
lnterd igitating dendritic cell tumour seen. The chromatin is often vesicular, S100 protein and vimentin, with CD1a
with small to large, distin ct nucleoli. Cy- and langerin be in g negative. They are
Epidemiology tological atypia varies from case to case, usually pos itive for fascin and (variab ly)
IDC sarcoma is an extremely rare neo- although the mitotic rate is usually low weakly pos itive for CD68, lysozyme,
plasm, with most stud ies constituting sin- (< 5 mitoses per 10 high-power fields). and CD45 . Strong nuclear staining for
gle case reports or very small series {104, Necrosis is usually not present. There are p53 may be present. They are negative
1179, 2411, 2659, 2812, 2813, 3180,3431, often numerous adm ixed lymphocytes, for markers of fo ll icu lar dendritic ce ll s
4286). The largest series to date have and less commonly, plasma cel ls. The (CD21, CD23, and CD35), MPO, CD34,
consisted of 4 cases (1269,3180,3186}. histological appearance is sometimes specific B-cell-associated and T-cell-
The reported cases have occurred pre- indistinguishable from that of a follicular associated antigens, CD30, EMA, and
dom inantly in adu lts, although one pae - dendritic cell sarcoma, and phenotyping cytokeratins. The Ki -67 proliferation in-
diatric series has been reported (3186). is necessary for prec ise diagnosis. dex is usually 10- 20% (median: 11%)
There is a slight male predominance. {1179). The admixed small lymphocytes
Occasional cases have been associated Ultrastructure are almost always of T-cell lineage, with
with low-grade B-cell lymphoma, and The neoplastic cells show complex inter- near absence of B ce ll s.
rare cases have been associated with digitating cell processes, but well-formed
T-cell lymphoma (1172,1269). desmosomes are not present. Scattered Postulated normal counterpart
lysosomes may be present, but Birbeck lnterdigitating dendritic cell (IDC)
Localization granules are not seen.
The presentation can vary widely. So li -
tary lymph node involvement is most
common, but extranodal presentations,
in particu lar in the skin and soft tissue,
have also been reported.
Clinical features
Patients usually present with an asymp-
tomatic mass, although system ic symp-
toms, such as fatigue, fever, and night
sweats, have been reported. Rare ly,
there may be generalized lymphadeno-
pathy, splenomegaly, or hepatomegaly.
Microscopy
The lesional tissue in lymph nodes is
present in a paracortical distribution w ith
residual follicles. The neoplastic prolifer-
ation usually forms fasc icles, a storiform
pattern, and whorls of spindled to ovoid
cells . Sheets of round cel ls are occasion-
ally found . The cytoplasm of the neoplas-
tic cel ls is usually ab undant and slightly
eos inophilic, and often has an indistinct
border. The nuclei also appear spindled
Synonyms
Dendritic reticulum cell tumour (no longer
recommended); follicular dendritic cell
tumour
Epidemiology
FDC sarcoma is a rare neoplasm {104,
645,2695,3135,3180,4286}. There is a
wide patient age range, with an adult
predominance (median patient age:
50 years) (3180,3543}. The sex distribu-
tion is about equal {3180}.
Etiology
A proportion of cases appear to arise in
the setting of hyaline-vascular Castleman
disease, sometimes with a recog nizable
intermediary phase of FDC proliferation
~
outside the follicles {638 ,645). The Cas-
t.;;,. ··~
Fig. 17.17 lnterdigitating dendritic cell sarcoma. A Note the paracortical pattern of tumour growth in the lymph tleman disease lesion may be found con-
node. B There are scattered small lymphocytes throughout the lesion. C The CD21 stain is negative on the tumour current with the FDC sarcoma, or may
cells, but labels follicular dendritic cells in residual follicles. D In contrast, the stain for 8100 protein is strongly precede the latter by several years.
positive in the tumour cells.
Localization
FDC sarcoma presents w ith lymph node
disease in 31% of cases , extranodal
disease in 58%, and both nodal and ex-
tranodal disease in 10% (3543}. Nodal
disease most often affects the cervical
nodes. A wide variety of extranodal sites
can be affected, most commonly tonsil,
..
-
- ~ . .
Fig.17.18 lnterdigitating dendritic cell sarcoma. A The cells are rounded, and the nuclei are relatively bland, but (B)
have a vesicular chromatin pattern and a single medium-sized nucleolus.
l
gastrointestinal tract, soft tissue, medi-
astinum, retroperitoneum , omentum, and
lung {1670,3543}. Common sites for me-
tastasis include lymph nodes, lung, and
liver (737).
Genetic profile kidney, and lung. Stage may be an im- Clinical features
A subset of cases of IDC sarcoma have portant prognostic factor; however, histo- Patients most often present with a slow-
clonal IG rearrangements, particularly log ical features have not been correlated growing, painless mass lesion, although
when there is an association with low- with clinical outcome. patients with abdominal d isease may
grade B-cell lymphoma, most likely present with abdominal pain. The tu-
constituting examples of transdifferen- mours are often large, w ith a mean size
tiation {680,1172). In cases associated Follicular dendritic cell of 7 cm (3543). Most patients have local-
with t(14;18)-positive follicular lympho- sarcoma ized disease at presentation {3543}. Sys-
ma, identical chromosomal breakpoints temic symptoms are uncommon. Rare
affecting the BCL2 locus are present in Chan J.K.C. patients have paraneoplastic pemphigus
both neoplasms (1172). The TR genes Pileri SA {2250,2536,4240}.
are in a germline configuration {4286}. Fletcher C.DM .
At least one case has been shown to Weiss L.M . Microscopy
harbour somatic BRAF V600E mutation Grogg K.L. The neoplasm consists of spindled to
{2916}. ovoid cells forming fascicles, storiform
arrays, whorls (sometimes reminiscent
Prognosis and predictive factors Definition of the 360° pattern observed in meningi-
The clinical course is generally aggres- Follicu lar dendritic cell (FDC) sarcoma is oma), diffuse sheets, or vague nodules.
sive, with about half of all patients dy- a neoplastic proliferation of spindled to The individual neoplastic cells generally
ing of the disease. Commonly affected ovoid cells showing morphological and show indistinct cel l borders and a moder-
visceral organs include the liver, spleen, immunophenotypic features of FDCs. ate amount of eosinophilic cytoplasm. The
nuclei are oval or elongated, with vesicu- es, often connected by scattered , mature T cells, or mixed B cells and T cells {645 ,
lar or granular finely dispersed chromatin , desmosomes. Birbeck granules and nu - 3180}. Rarely, there are abundant im-
small but distinct nucleoli, and a delicate merous lysosomes are not seen. mature TdT+ T cells {2020,2944}, which
nuclear membrane. The nuclei tend to may be associated with paraneoplastic
be unevenly spaced, with areas showing lmmunophenotype pemphigus.
clustering. Nuclear pseudoinclusions are FDC sarcoma is positive for one or more
common . Binucleated and multinucleated of the FDC markers, such as CD21, Postulated normal counterpart
tumour ce lls are often seen. Although the CD35, and CD23 {2862}. CXCL13 and Fo ll icular dendritic cell (FDC) of the lym-
cytological features are usually relative ly podoplanin (02-40) are common ly posi- phoid follicle
bland , significant cytological atypia may tive, but are not entirely specific {4192,
be found in some cases. The mitotic rate 4450}. Clusterin is often strongly pos itive, Genetic profile
is usually 0-10 mitoses per 10 high-pow- whereas th is marker is usually negative or In one study, 3 of 8 cases of FDC sarco-
er fields, although the more pleomorphic only weakly positive in other dendritic cell ma showed clonal rearrangements of the
cases can show much higher mitotic tumours {1472,1473}. The tumour is usual- IG genes {680}, and thus the presence
rates (> 30 mitoses per 10 high-power ly positive for desmoplakin, vimentin, fas- of antigen receptor gene rearrangements
fields), eas ily found atyp ical mitoses , and cin, EGFR, and HLA-DR {642,3833}, and does not exc lude a diagnosis of FDC
coagulative necrosis. variably positive for EMA, S100 prote in, sarcoma.
The tumour is typically lightly infi ltrated and CD68. Staining for cytokeratin, CD1a, The limited cytogenetic data show com-
by small lymphocytes, which can some- lysozyme, MPO, CD34, CD3, CD79a, plex karyotypes {3144}. A targeted next-
times be aggregated around the blood and HMB45 is negative. The Ki-67 pro- generation sequenc ing study revealed
vessels as well {642}. Less common liferation index is 1-25% (mean: 13%). recurrent loss-of-function alterations in tu-
morphological features include epithe- Positi vity for the FDC secreted protein mour suppressor genes involved in neg-
lioid tumour cells with hyaline cytoplasm, (FDCSP), serglycin (SRGN) and PD-L1 ative regulation of NF-kappaB and cell-
clear cells, oncocytic cells, myxoid has recently been reported in FDC sar- cycle progression {1460}. BRAF V600 E
stroma, flu id-filled cystic spaces, promi- coma {2184A,2383A}. mutation, a common genetic alteration in
nent fibrovascular septa, and admixed The admixed small lymphocytes can be Langerhans cell histiocytos is, is reported
osteoc lastic giant cel ls {642,645,3135, predominantly B ce ll s, predom inantly in 0- 19% of cases {1386,1460}.
3136}. Uncommonly, there is a nodular
growth pattern, with the large neoplastic
ce lls scattered in a background of small
B lymphocytes {2390}. Rare cases may
also show jigsaw puzzle-like lobulation
and perivascular spaces, mimicking thy-
moma or carcinoma showing thymus-like
element {737}.
Ultrastructure
The neoplastic cells have elongated
nuclei, often with cytop lasmic invagina- Fig. 17.22 Follicular dendritic cell sarcoma. This exam- Fig. 17.23 Follicular dendritic cell sarcoma. Positive
tions. There are characteristically numer- ple shows significant nuclear atypia and pleomorphism. cell membrane staining for CD21 with an anastomosing
ous long, slender cytoplasmic process- pattern.
Inflammatory pseudotumour-like
follicular/fibroblastic dendritic
cell sarcoma
Inflammatory pseudotumour-l ike follicu-
lar/fibroblastic dendritic cell (FDC/FRC)
sarcoma occurs predom inantly in young
to middle-aged adults, with a marked
female predilection {697). It typically in-
volves the liver or spleen, but both sites
may be simultaneously involved {134,697,
3619}. Rarely, it selectively involves the
gastrointestinal tract in the form of a poly-
poid lesion {3042). Patients are asympto-
matic or present with abdominal disten-
sion or pain, sometimes accompanied by
systemic symptoms {683,697,733).
Histolog ically, the neoplastic spindled
Fig.17.24 Follicular dendritic cell sarcoma. A Spindle cell proliferation. BA 360° whorl is seen. Note the occasional cells are dispersed within a prominent
multinucleated cells. C In this example, the small lymphocytes are aggregated around the blood vessels. lymphoplasmacytic infiltrate. The nuclei
usually show a vesicular ch romatin pat-
Two studies examining the transcriptional Prognosis and predictive factors tern and small but distinct nucleoli. Nu-
profile of FDC sarcoma have revealed: 1) FDC sarcoma is usually treated by com- clear atypia is highly variable; usually
a peculiar immunological microenviron - plete surgical excision, with or without most cells are bland-looking, but some
ment enriched in TFH and Treg popula- adjuvant radiotherapy or chemotherapy. cells with en larged, irregularly folded or
tions, with special reference to the inhibi- A pooled analysis of the literature showed hyperchromatic nuclei are almost always
tory immune receptor PD1 and its ligands local recurrence and distant metasta- found. Some tumour cells may even re-
PD-L1 and PD-L2, and 2) the highly spe- sis rates of 28% and 27%, respectively semble Reed-Sternberg cells {3619).
cific expression of the genes encoding {3543), but the true figures are likely to Necrosis and haemorrhage are often
for FDCSP and SRGN {1460B,1460C}. be higher, because these adverse events present, and may be associated with a
Conventional FDC sarcomas are nega- are sometimes delayed many years. The histiocytic or granulomatous reaction .
tive for EBV, whereas the inflammatory 2-year survival rates for early, locally ad- The blood vessels frequently show fibri-
pseudotumour-like variant consistently vanced, and distant metastatic diseases noid deposits in the walls. In occasional
shows EBV in the neoplastic cells {697). are 82%, 80%, and 42%, respectively cases, the tumour may be masked by
{3543). Some patients may die from re- massive infiltrates of eosinoph ils or nu-
fractory paraneoplastic pemphigus. merous epithelioid granulomas {2310}.
The neoplastic cells are often positive for
follicular dendritic cell markers , such as
CD21 and CD35, with the staining rang -
ing from extensive to very focal. Howev-
er, in some cases, they may be negative
for follicular dendritic cell markers but
express SMA, raising the possibility of
fibroblastic reticular cell differentiation.
Still other cases are positive for all these
markers or lack these markers {129,697,
733,1399,2293). Both FDC and FRC
share a common mesenchymal origin,
with plasticity in the immunophenotype.
The neoplastic cells are consistently as-
sociated with EBV {134,697), which is
present in a monoclonal episomal form
(3619}.0utcome data are limited, but
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Fig.17.29 Splenic inflammatory pseudotumour-like Fig.17.30 Inflammatory pseudotumour-like follicular Fig.17.31 Inflammatory pseudotumour-like follicular
follicu lar dendritic cell sarcoma. Spindle cells with dendritic cell sarcoma . In situ hybridization for EBV- dendritic cell sarcoma. The atypical spindle cells focally
vesicular nuclei and distinct nucleoli are dispersed in encoded small RNA (EBER) highlights the neoplastic exhibit immunoreactivity for CD21.
a background of chronic inflammatory cells. They show spindle cells. Nuclear atypia in some neoplastic cells
minimal to mild atypia. becomes easier to appreciate.
the tumour appears to be indolent, with Localization digitating dendritic cell sarcoma, but
a tendency to develop repeated intra- This tumour can occur in the lymph lacks the immunophenotypic profil e of
abdominal recurrences over many years nodes, spleen, or soft tissue {104,639, these tumour types. There are often inter-
{683,697}. 1415,1874}. spersed delicate collagen fibres.
Microscopy Ultrastructure
Fibroblastic reticular cell The tumour is histologically simi lar to Ultrastructurally, the spindle cel ls show
tumour follicular dendriti c cell sarcoma or inter- deli cate cytoplasmic extensions and fea-
tures similar to those of myofibroblasts
Weiss L.M. (i.e. filaments with occas ional fusiform
Chan J.K.C. densities, we ll-developed desmosomal
Fletcher C.D.M. attachments, rough endop lasmic reticu-
lum, and basal lam ina-l ike material).
Definition lmmunophenotype
Fibroblastic reticular cel l tumour is very The tumour ce ll s are variably immunore-
rare. Tumours diagnosed as cytokeratin- active for SMA, desmin, cytokeratin (in a
positive interstitial reticulum cell tumours dendritic pattern), and CD68.
probably constitute the same entity {104,
639}. Prognosis and predictive factors
Available data regarding outcome are
ICD-0 code 9759/3 extreme ly limited. The clinical outcome
is variable. Some patients die of the
Fig. 17.32 Fibroblastic reticular cell tumour.
Synonyms disease.
This neoplasm features blunt spindle cells arranged in
Cytokerati n-positive interstitial reticulum poorly formed whorls, with moderate cytological atypia.
ce ll tumour; fibroblastic dendritic cel l Stains for follicular and interdigitating dendritic cells were
tumour negative.
Definition
Disseminated juvenile xanthogranuloma
(JXG) is characterized by a proliferation
of histiocytes similar to those of the der-
mal JXG, commonly having a foamy (xan-
thomatous) component with Touton-type
giant cells. There is evidence for clonal- Fig.17.33 Systemic juvenile xanthogranuloma involving liver. A The infiltrate is portal in nature but spares the bile
ity in some instances. Erdheim-Chester duct. Few Touton cells are present. B There is diffuse factor XII la staining of the portal histiocytes.
disease is distinguished from JXG in the
current classification of histiocytic neo- bone marrow. Retroperitoneal and peri- pattern, and stabilin-1 (MS-1 antigen).
plasms {1101}. aortic involvement is principally noted Factor Xllla staining is common but not
in Erdheim-Chester disease {925,1 256, universal. Fascin stains the cell cyto-
Synonyms 1836). plasm and S100 is positive in < 20% of
Benign cephalic histiocytosis; progres- the cases. However, none of these mark-
sive nodular histiocytosis; generalized Clinical features ers is specific for JXG. CD1a and langerin
(non-lipidaemic) eruptive histiocytosis Skin lesions other than the common pap- are negative {654,2104,3513,4465).
(skin); xanthoma disseminatum (skin ular solitary form are small (1-2 mm) and
plus mucosa lesions); Erdheim-Chester multiple. Soft tissue lesions can be large, Cell of origin
disease (adu lt form with bone and lung and the lesions present as mass effect. The cell of origin is uncertain. Despite
involvement) Optic lesions can cause glaucoma. Like their macrophage phenotype, the cells of
in LCH, CNS and pitu itary lesions can dissem inated JXG have been postu lated
Epidemiology cause diabetes insipidus, seizures, hy- (on the basis of shared factor Xllla and
Solitary dermal JXG is vastly more com- drocephalus, and mental status chang- fascin immunostaining) to originate from
mon than other forms and does not pro- es {925,1256,1836). Unlike in LCH, liver a dermal/interstitial dendritic cell , but
gress to more-disseminated forms {925). involvement does not target the biliary these characteristics have limited spec-
Most deep, visceral, and disseminated system or lead to sclerosing cholangitis ificity {2104).
forms occur by the age of 10 years, half {1826). There is some capacity for le-
within the first year of life {1836}. sions to slowly regress. JXG appears Genetic profile
to be benign, but a concomitant mac- No consistent cytogenetic or molecular
Etiology rophage activation syndrome can lead genetic change has been identified. IG
There is a known association with neu- to cytopenias, liver damage, and (in the and TR rearrangements are germline.
rofibromatosis type 1; patients with both systemic forms) death. There is evidence for clonality in some in-
are at slightly higher risk of juvenile my- stances {1835). Unlike in Erdheim-Ches-
elomonocytic leukaemia {4508). Patients Microscopy ter disease, there are no reported cases
with both Langerhans cell disease (i.e. The JXG cell is small and oval, some- of JXG bearing BRAF mutations {634,
Langerhans cell histiocytosis; LCH) and times slightly spind led with a bland round 1553).
JXG are also encountered. To date, no to oval nucleus without grooves and with
cases of JXG bearing mutations of BRAF pink cytoplasm. Touton cells are less Genetic susceptibility
or other genes involved in the MAPK path- common at non-dermal sites. The cells An association with neurofibromatosis
way have been described {634,1553). become prog ressively lipidized (xan- type 1 is known in some cases.
thomatous). A mixed inflammatory com-
Localization ponent is invariable. Variants include epi- Prognosis and predictive factors
The skin and soft tissues are affected thelioid cells with glassy cytoplasm. The All clinical forms are benign, although
most commonly. Disseminated forms ultrastructural features are histiocytic, multiple lesions in brain, d ura, or pituitary
commonly affect the mucosa! surfaces, without distinguishing features {4465). can cause local consequences and even
in particular within the upper aerodiges- death. Systemic forms that involve liver
tive tract. When skin is involved, there lmmunophenotype and bone marrow have been treated with
seems to be a predilection for the head In common with macrophages, cells LCH-type therapy.
and neck region {925). The CNS, dura, express vimenti n, surface CD1 4, CD68
and pituitary stalk can be affected, as (PGM1) in a coarse granular pattern,
can eye, liver, lung, lymph node, and CD1 63 in a surface and cytoplasmic
Brousse N. Jaffe R.
Pileri S.A. Fletcher C.D.M.
Haroche J. Jaffe E.S.
Dagna L. Harris N.L.
Definition
Erdheim-Chester disease (ECO) is a
clonal systemic proliferation of histio- Fig.17.35 Retroperitoneal Erdheim-Chester disease.
cytes, commonly having a foamy (xan- The infiltrate is made up of foamy histiocytes and Touton
thomatous) component, and contain ing cells admixed with scattered small lymphocytes in a fi-
Touton giant ce ll s (considered to be a brous tissue.
non-Langerhans cell histiocytosis). It
was first described as lipoid granuloma- loventricular groove and diffuse pleural
tosis in 1930 {693}. The name Erdheim- thickening. The clinical consequences
Chester disease was coined in 1972 to are usually not severe, except for reno-
recognize the contribution to the dis- vascular hypertension in a small number
covery of the condition by Erdheim, who of cases, which may requ ire stenting.
was Chester's mentor {693). Diagnosis of Pericardia! involvement can cause peri-
ECO is based on clinical features, imag- carditis, effusion, or even tamponade.
ing, and histology {693,1101}. Orbital infiltration, often bilateral, produc-
es exophthalmos, pain, oculomotor nerve
ICD-0 code 9749/3 palsies, or blin dness. Xanthelasmata of
the eyelids or periorb ital tissue are further
Synonyms ocular manifestations. Pitu itary gland in-
Lipogranulomatosis; lipoid granuloma- filtration causes diabetes insipidus and
tosis; lipid (cholesterol) granulomatosis; (less frequently) hyperprolactinaemia,
polyostotic sclerosing histiocytosis gonadotropin insufficiency, and hypotes-
Fig.17.34 Erdheim- Chester disease (ECO). A Radio-
tosteronism. CNS involvement produces
Epidemiology graph showing a lytic and sclerotic lesion in the distal variable symptoms (cerebellar and py-
ECO is a rare condition. To date, femur and the proximal tibia. There is destruction of the ramidal syndromes, seizures, headache,
< 1000 cases have been reported. The anterior femoral cortex, with an impacted pathological neuropsychiatric symptoms, cogn itive
mean patient age at diagnosis is 55- fracture through the lesion and an anterolateral soft impairment, sensory disturbances, and
60 years, but rare paediatric cases (i.e. in tissue mass extending from the destroyed femur (ar- cranial nerve paralys is). The most seri-
row). Reprinted from Rosier RN and Rosenberg AE
patients aged< 15 years) have also been ous neurolog ical complication is neuro-
{3416A}. B Abdom inal CT from a patient with ECO
reported. The male-to-female ratio is 3:1. showing a soft tissue infiltrate surrounding the aorta degenerative cerebellar disease, which
and kidneys (white arrows). There is a sclerotic lesion is present in 15- 20% of patients with
Localization in the vertebra (black arrow}. Reprinted from Mills JA et ECO. In parti cular, CNS involvement is a
Virtually any organ or tissue can be in- al. {2665A). major prognostic factor in ECO, constitut-
filtrated by ECO. Skeletal involvement ing an independent pred ictor of death at
occurs in > 95% of cases. Card iovas- Clinical features survival analys is.
cular involvement probably occurs in The cl ini cal course of ECO depends on
at least half of all patients, but is likely the extent and distribution of the dis- Imaging
underdiagnosed. One th ird of pati ents ease. Some cases, with les ions limited Characteristic features on imaging stud-
have retroperitoneal involvement. CNS to the bone, are asymptomatic; others, ies are bil ateral and symmetrical corti-
involvement, diabetes insipidus, and/or with multisystemic disease, may fo llow cal osteoscleros is of the diaphyseal and
exophthalmos occur in 20-30% of pa- an aggress ive, rap id clinical course. In metaphyseal parts of the long bones on
tients. CNS involvement may occur due one third of patients, bone involvement X-ray and/or symmetrical and abnormal-
to tissue infiltration by histiocytes or de- may cause mild pain that starts at any ly intense labelling of the distal ends of
generative alterations typically affecting time during the course of the disease the long bones of the legs (and in some
the cerebellum, with involvement due and usually affects the distal limbs. Car- cases, arms) on 99Tc bone scintigraphy.
to degenerative alterations being much diovascular involvement may be asymp- These findings are highly suggestive of
more difficult to treat. Xanthelasma, gen- tomatic and detected incidentally by MRI ECO. Occas ional ly, osteolytic lesions are
erally involving the eyelids or periorb ital or CT. The most common cardiovascular also seen. PET/CT has a high spec ificity
spaces, is the most common cutaneous alteration corresponds to circumferen- for the diagnosis of bone involvement by
manifestation. tial soft ti ssue sheathing of the thoracic ECO. Card iovascular involvement mani-
and abdominal aorta and large arteries, fests as circumferential sheathing of the
infiltration of the right atrium or auricu - thoracic or abdominal aorta (so-called
coated aorta) and large arteries, pericar- S100, CD1a, and langerin, which are all tial diagnosis with juveni le xanthogranu-
dia! effusion (sometimes leading to tam- markers of Langerhans cells. However, loma and some nonspecific inflammatory
ponade), infiltration of the right atrium or cases focally positive for S100 have been lesions challenging {71). Molecular analy-
auriculoventricular groove, and diffuse reported {1101 }. The characteristic immu- sis of such cases may be useful , because
pleural thickening . Retroperitoneal in- nophenotype is shared by all members characteristic genetic aberrations favour
volvement may be prominent around the of the xanthogranuloma family of histio- the diagnosis of ECO {11 01). lmmunohis-
renal capsu le (producing the character- cytoses. As many as 20% of patients with tochemistry may be a useful diagnostic
istic so-called hairy kidney appearance) ECO also have Langerhans cell histiocy- tool for the detection of mutated BRAF, in
and ureters. tosis lesions, and infiltration by ECO and lieu of genetic studies.
Langerhans cell histiocytosis may be
Microscopy present within the same biopsies {1101 }. Prognosis and predictive factors
There is tissue infiltration by histiocytes, Cases of ECO with mutated BRAF are ECO is a chronic disease. The disease
generally with single small nuclei and positive by immunohistochemistry with outcome correlates with sites of in-
foamy (xanthomatous) cytoplasm. Other the VE1 monoclonal antibody to mutated volvement; patients with CNS disease
histiocytes, with compact eosinophi lic BRAF protein {1101}. or multisystemic disease have a worse
cytoplasm, may also be present. A few outcome {149A,974A}. Disease activ-
multinucleated histiocytes with a central Cell of origin ity is assessed by clinical examination,
ring of nuclei (Touton cells) are frequent- The postulated cell of origin is an inter- imaging, and C-reactive protein values,
ly observed. Fibrosis is present in most stitial dendritic cell, but this is the subject but no disease activity score has been
cases and is sometimes abundant. Re- of some debate. established. PET scans are very useful
active small lymphocytes, plasma cells, for assessments of ECO activity {149C}.
and neutrophils are also frequently pres- Genetic profile Histology is not predictive of evolution.
ent. The infiltrate may easily be misdiag- In several cases, clonality has been ECO may respond to therapy with inter-
nosed as a reactive process. identified by classic cytogenetics and feron alpha, but many cases are refrac-
other techniques. Activating mutations tory, especially those with CNS and car-
lmmunophenotype in MAPK pathway genes, most notably diovascular involvement {544A,1552A}.
ECO histiocytes express three mol- BRAF V600E (reported in > 50% of cas- Vemurafenib, an inhibitor of BRAF that
ecules common to macrophages: CD1 4 es), as well as NRAS mutation (recorded is approved for treating patients with
(a monocyte or macrophage receptor in -4% of cases), can be detected in metastatic melanoma and BRAF V600
that binds lipopolysaccharide), CD68 ECO {71,1553). Recurrent mutations in mutations, has recently been used, with
(a largely lysosomal macrosialin), and the Pl3KCA pathway gene have also promising results {544A,1552A,1553A}.
CD163 (a haemoglobin- and hapto- been described (in - 11 % of cases) {71). The reported 5-year overall survival rate
globin-scavenging receptor). In addition, of patients treated with interferon therapy
the cells express factor Xlll a (a tissue Molecular tests and differential is 68% {1498). Older series, perhaps with
transglutaminase) and fascin (an actin- diagnosis less-effective therapy, reported 43% of
bundling protein), both of which are typi- Some cases of ECO may have dominant patients alive after an average follow-up
cal of interstitial and interdigitating den- cutaneous manifestations, without other of 32 months {4192A}.
dritic cells. The abnormal histiocytes lack organ involvement, making the differen-
484 Contributors
Contributors 485
486 Contributors
Contributors 487
488 Contributors
Contributors 489
490 Contributors
Contributors 491
Dr Akin reports receiving personal consulting Dr Feldman reports owning intellectual prop- Dr Kyle reports being on monitoring commit-
fees from Novartis. erty rights in United States patents (held by tees or boards for Celgene, Novartis, Mer-
Mayo Clinic) on reducing IRF4, DUSP22, or ck, Bristol-Myers Squ ibb, Aeterna Zentaris
Dr Arber reports having received personal FLJ43663 polypeptide expression and on de- (Keryx), Onyx Pharmaceuticals (Amgen), and
consulting fees from United States Diagnostic tecting TBL 1XR1 and TP63 translocations. Pharmacyclics. He reports rece iving personal
Standards. consu lting fees from Binding Site.
Dr Fend reports having rece ived travel sup-
Dr Baccarani reports receiving personal con- port from Roche and Janssen Pharmaceuti- Dr List reports rece iving personal consult-
sulting and speaking fees from Ariad, Bristol- cals. ing fees from Cell Therapeutics and Celgene.
Myers Squibb, Novartis, and Pfizer. He reports having rece ived research support
Dr Gascoyne reports rece iving personal from Ce lgene.
Dr Bene reports having received travel and speaking fees and research support from Se-
lodging support from Celgene, Beckman attle Genetics. He reports rece iving personal Dr Macon reports receiving personal consult-
Coulter , Mundipharma, Roche and Chugai. consu lting fees from Celgene, Seattle Genet- ing fees from Seattle Genetics .
She partic ipated in COST EuGESMA, which ics, Genentech, Roche, and Janssen Pharma-
covered travel and lodging expenses . She has ceuticals. Dr Niemeyer reports that the University of
received personal consu lting fees from Beck- Freiburg receives fees from Celgene for her
man Coulter, and as head of the Harmonemia Dr Gatterman reports receiving personal consulting services.
project also received travel and lodging sup- consulting fees and research support from
port from Beckman Coulter. Novartis and Celgene. He reports receiving Dr Orazi reports receiving personal consu lt-
personal speaking fees and travel support ing fees from lncyte and speaking fees from
Dr Bennett reports receiving personal con- from Novartis. lncyte and Novartis. He reports that the De-
sulting fees from Celgene and providing unre- partment of Pathology and Laboratory Medi-
munerated consulting services to GlaxoSmith- Dr Germing reports that the MOS Registry, cine at Weill Cornel l Medical Col lege has a
Kl ine, Onconova Therapeutics, and Amgen. through the University of Dusseldorf, has re- contract with GlaxoSm ithKline to rev iew his-
ceived funding from Novartis, Celgene, Chu- tology sl ides from patients with chronic idi-
Dr BirgegArd reports that the Department of gai , Amgen, and Johnson & Johnson. He re- opath ic thrombocytopenic purpura who have
Med ical Sc iences at Uppsala University has ports receiving personal speaking fees from received long-term recombinant thrombopoi-
rece ived research funding from Shire. He also Celgene and Johnson & Johnson . etin therapy.
reports having received speaking fees from
Sh ire and Renapharma AB , and consulting Dr Ghia reports receiving personal consulting Dr Piris reports rece iving personal speaking
fees from Shire. fees from Gi lead Sciences, Pharmacyclics, fees from Takeda.
Merck, Medlmmune, Roche, and AbbV ie. He
Dr Borowitz reports receiv ing research sup- reports receiving personal speaking fees from Dr Porwit reports receiving meeting travel
port from Bristol-Myers Squ ibb, Amgen, and Gi lead Sciences and research support from support from Beckman Cou lter and personal
Medlmmune, and having received research Roche and GlaxoSmithKl ine. speaking fees from Novartis.
support from Beckman Cou lter. He reports
receiving non-financial research support from Dr Hasserjian repo rts having received per- Dr Radich reports receiving honorari a from
Becton, Dickinson and Company. sonal consulting fees from Sanofi and lncyte. Novartis, Bristol-Myers Squibb, Ar iad, and
Pfizer. He reports that the Fred Hutchinson
Dr Brousse reports having received personal Dr Hellstrom-Lindberg reports receiving un- Cancer Research Center rece ives non-finan-
speaking fees from Roche, Kephren, and Acu itude. restricted research support from Celgene. c ial research support from Novartis.
Dr Chadburn reports receiving personal con- Dr lnghirami reports having received person- Dr Siebert reports rece iving non-financial re-
sulting fees from Clarient. al consu lting fees from Menarini Diagnostics , search support from Abbott.
Celgene, and Seattle Genetics .
Dr Wing Chung Chan reports owning intel- Dr Stein reports rece iving technical research
lectual property rights in a patent (held by the Dr Elaine S. Jaffe reports receiving personal support from HistoGene.
United States National Cancer Institute) on the speaking fees from the French and Australa-
classification of B-cell lymphoma using gene sian Divisions of the International Academy of Dr Swerdlow reports having received person-
expression signatures. Pathology. al consulting fees from Centocor R&D, Travel
Destinations Management Group, and Joh n-
Dr Cook reports having received personal con- Dr Ronald Jaffe reports receiving personal son & Johnson.
sulti ng fees from Med ical Marketing Economics. consu lting fees from GlaxoSm ithKl ine.
Dr Thiele reports having received personal
Dr de Jong reports receiv ing personal con- Dr Jones reports that he is a director and consultin g fees from Sanofi, lncyte and
su lti ng fees from Mi llennium Pharmaceuticals shareholder at Quest Diagnostics. Novartis.
and Ce lg ene.
Dr Kadin reports rece iving personal consu lt- Dr Vardiman reports that his department at
Dr Dogan reports receiving personal consu lt- ing fees from Allergan . the Un iversity of Chicago has received fees
ing fees from Janssen Pharmaceuticals. from Celgene for his consu lti ng services .
Dr Kinney reports that the University of Texas
Dr Escribano reports receiving travel support Health Sc ience Center at San Antonio has re- Dr Whittaker reports that his research unit at
from Thermo Fisher Scientific Brazil. ceived fees from Seattle Genetics for her con- St John's Institute of Dermatology receives
sulting services. fees from Actel ion, Yaupon Therapeutics, and
Dr Falini reports having appl ied for a patent ProStrakan for his consu lting services . He re-
on the clinical use of nucleophosmin protein Dr Kovrigina reports rece iving travel support ports that his unit has also received fees for his
(NPM 1) mutants. and personal consulting fees from Novartis. consulting services from Johnson & Johnson.
A meeting with members of the Clinical Advisory Committees took place at the Gleacher Center, University of Chicago, 31 March to 1 April, 2014.
# Co-chair
# Co-chair
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A note on gene and protein nomenclature: Throughout th is volume, we have used the Human Genome Organisation (HUGO) Gene Nomencla-
ture Comm ittee (HGNC) Gu idel ines (http://www.genenames.org/) for c iting genes and proteins. For immunoglobu lin (IG) and T-ce ll receptor (TR)
al leles, we have used the nomenclature assigned by the lmM unoGeneTics (IMGT) Nomenclature Committee (http://www. imgt.org/) , as recom-
mended by HGNC.