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Atrophic Pap Smears, Differential Diagnosis and Pitfalls: A Review
Atrophic Pap Smears, Differential Diagnosis and Pitfalls: A Review
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http://www.ijwhr.net doi 10.15296/ijwhr.2015.27
Open Access
Open Access Review
ReviewArticle
International
International Journal
Journal of Women’s
of Women’s Health
Health and Reproduction
and Reproduction Sciences
Sciences
Vol.Vol.
3, No. 3, July
6, No. 2015, 126–131
1, January 2018, 2–5
ISSN 2330-
ISSN 4456
2330- 4456
Women onPap
Atrophic the Smears,
Other Side of War andDiagnosis
Differential Poverty: Its
andEffect
on the Health
Pitfalls: of Reproduction
A Review
Ayse Cevirme1, Yasemin Hamlaci2*, Kevser Ozdemir2
Ali Dastranj Tabrizi1*
Abstract
War and poverty are ‘extraordinary conditions created by human intervention’ and ‘preventable public health problems.’ War and
Abstract
poverty have many negative effects on human health, especially women’s health. Health problems arising due to war and poverty are
As a unique preventable cancer, invasive cervical carcinoma is the second most common cancer among the women in developing
being observed as sexual abuse and rape, all kinds of violence and subsequent gynecologic and obstetrics problems with physiological
countries. Change in women’s lifestyle, worldwide spread of HPV infection and women’s lack of effective education and screening
and psychological courses, and pregnancies as the result of undesired but forced or obliged marriages and even rapes. Certainly,
programs in less developed countries constitute the most important factors for its high incidence and mortality rate. From a diagnostic
unjust treatment such as being unable to gain footing on the land it is lived (asylum seeker, refugee, etc.) and being deprived of
perspective, atrophic smears may be interpreted as positive malignant smears in postmenopausal and occasionally in premenopausal
social security, citizenship rights and human rights brings about the deprivation of access to health services and of provision of
women. However, rarely a high grade or malignant smear might be rendered as the atrophic smear. For this reason acquaintance with
service intended for gynecology and obstetrics. The purpose of this article is to address effects of war and poverty on the health of
atrophic smears and their diagnostic challenges should be included in pathology and cytotechnology training courses. In this review,
reproduction of women and to offer scientific contribution and solutions.
usual pattern of atrophic smears and differential diagnosis of atrophic smears along with mimics will be presented for decision
Keywords: Poverty, Reproductive health, War
making and particularly avoiding overdiagnosis.
Keywords: Atrophic Pap smear, Invasive cervical cancer, HPV infection
Introduction thought that severe military conflicts in Africa shorten
Throughout the history of the world, the ones who had
Introduction the expected
follows: lifetime
(a) a brief for inspection
more than of 2 years.
usual In general,
pattern of atrophic
confronted the bitterest face of poverty and war had al- WHO had calculated that 269 thousand people had died
Although cervical cancer incidence has been dramatically smears, (b) main differential diagnosis which can mimic
ways been the women. As known poverty and war affects in 1999 due to the effect of wars and that loss of 8.44 mil-
declined
human healthin developed countries
either directly due to thethe
or indirectly, implementation
effects of atrophic
lion healthy smears,
years of life had(c) occurred
pitfalls (2,3).
which may lead to over
of
thissystematic
condition on andhealth
organized screening
and status of women intoinhealth
the so-care Warsinterpretation,
negatively affectand the finally,
provision (d)ofsuggestive strategies for
health services.
systems,
ciety should thisnotpreventable
be ignored. This malignancy
study intends comprises
to cast the Health correct decision
institutions suchmaking
as hospitals, laboratories and
second
light on most common
the effects cancer
of war and povertyin women in developing health centers are direct targets of war. Moreover, the wars
on the reproductive
health of women.
countries (1). ChangeFor thisinpurpose,
women’s thelife
facestyle,
of warworldaffect-wide causeI.the Usualmigration
Patternofofqualified
Atrophic health employees, and
Smears
ing the of
spread women,
HPVthe problem
(human of immigration,
papilloma infection and thus Taking
virus) inequalities the health Pap
servicessmearhitches. inAssessments made indi- women
postmenopausal
in distribution of income based on gender
women’s lack of effective education and screening systems and the effects cate that
occasionally shows a hypocellular backgroundof and may
the effect of destruction in the infrastructure
of all these on the reproductive health of women will be health continues for 5-10 years even after the finalization
in less developed countries constitute the most important display the absence of endocervical or transformation
addressed. of conflicts (3). Due to resource requirements in the re-
factors for the very high incidence and mortality rate in structuring zone investments
componentsafter(6,7) war, the(Figure 1A). Microscopic
share allocated to
less developed societies
War and Women’s Health (2-4). The most common subtypes examination
health has decreased (1). of atrophic smears which is typically seen
of high risk
Famine, HPVs involving
synonymous with warinand cervical
poverty, carcinogenesis
is clearer for are in postmenopausal women usually shows numerous
HPV
women; 16 and
war HPVmeans18deep although other subtypes
disadvantages such as of fullhigh
de- risk Mortalities
parabasal and intermediate cells that may be arranged
and Morbidities
struction,
HPVs mayloss beofdetected
future and asuncertainty
dominant for women. Wars
carcinogenic agent. The ones who are
in small most affected
clusters or as from wars arecells
individual women and 1B and
(Figure
are conflicts that destroy families, societies
On the other hand, low sensitivity and specificity of Pap and cultures children. While deaths depending on
C). A small number of superficial cells may direct violence af- be seen.
that negatively affect the health of community
smear particularly in conventional type impose serious and cause fect the male population, the indirect deaths kill
Presence of a large number of superficial cells along withchildren,
violation of human rights. According to the data of World women and elders more. In Iraq between 1990-1994, in-
consequences including false negative and false positive intermediate cells may indicate the need for hormone
Health Organization (WHO) and World Bank, in 2002 fant deaths had shown this reality in its more bare form
results (5).
wars had been among the first ten reasons which killed with replacement
an increase oftherapy
600% (4).orThe uterine prolapse
war taking treatment. In
five years
From a diagnostic perspective, atrophic
the most and caused disabilities. Civil losses are at the rate smears may these circumstances, parakeratotic
increases the child deaths under age of 5 by 13%. Also 47%cells may also be seen
be misinterpreted as
of 90% within all losses (1). positive smears in postmenopausal of all the refugees in the world and 50% of asylum seekerslow grade
and should not be considered as evidence of
and
War occasionally
has many negative in perimenopausal
effects on humanwomen. health. One However,
of squamouspeople
and displaced intraepithelial
are women lesion (LSIL).
and girls andThe44%parabasal
ref- cells
these is its effect of shortening the average
rarely a high grade or malignant smear might be rendered human life. ugees and asylum seekers are children under
usually show a relatively small amount of cytoplasm and the age of
According
as an atrophic to thesmear.
data of Fortunately,
WHO, the average human lifeofisnew 18 (5).
introduction high nuclear/cytoplasmic ratio. The condensed nuclear
68.1 years forinmales
techniques the and 72.7ofyears
field Papforsmearfemales. It is beingnew As the
including result of leads
chromatin wars and armed hyperchromasia,
to nuclear conflicts, women however,
are no
collection devices and automated machines leads to chromatin clumping and no nucleoli is seen. Absence of
better
Receivedresults.
12 DecemberThis2014,review
Acceptedwill discuss
25 April general
2015, Available cytologic
online 1 July 2015 chromatin clumping, sharp and regular nuclear membrane
features
1
Departmentof atrophic
of Nursing, smears
Sakarya and
University, a number
Sakarya, of common
Turkey. 2Department and absence
of Midwifery, Sakarya of mitotic
University, Sakarya, Turkey. figure are hallmarks of atrophic
*Corresponding author:
morphologic mimics of atrophic
Yasemin smears ofwhich
Hamlaci, Department canSakarya
Midwifery, leadUniversity,
smears
Sakarya,which allow
Turkey. Tel: easy distinction of these cases from
+905556080628,
Email: [email protected]
to overinterpretation. The structure of this review is as high grade intraepithelial or malignant lesions (Figure
Received 8 August 2016, Accepted 19 December 2016, Available online 10 January 2017
1
Women’s Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
*Corresponding Author: Ali Dastranj Tabrizi, MD; Email: [email protected]
www.SID.ir
Dastranj Tabrizi
Archive of SID
1D, 1E). Clusters of endocervical cells usually are seen in lesion. In contrast, in a malignant smear from an invasive
well-taken atrophic smears although their absence should squamous cell carcinoma, the malignant cells dispersed
not be rendered as an insufficient specimen. Usually, haphazardly in the background of some normal appearing
the normal atrophic smears show some debris hanging cells. Although the dirty background of the smear is one
from the cytoplasmic border. These materials should not of the most distinguishing features of malignant smears
be considered as the evidence of malignancy which is due to tumor cell necrosis, some granular material derived
seen widely in squamous cell carcinoma. The absence of from degenerating parabasal cells are usually present in
polymorphonuclear (PMN) debris, clean background of the background of atrophic smears (10,11). Therefore
smears, close adherence of these materials to cytoplasmic close attention should be paid to find marked nuclear
membrane and absence of nuclear atypia are helpful pleomorphism, coarse nuclear chromatin, ragged nuclear
criteria for distinction between atrophic and malignant membranes and relatively easily found mitotic figures for
smears (Figure 1F). the establishment of the diagnosis of invasive squamous
cell carcinoma.
II. Differential Diagnosis
A. Invasive Squamous Cell Carcinoma B. High Grade Squamous Intraepithelial Lesion
Although misdiagnosis of an atrophic smear as a malignant Atrophic smears are prone to be misinterpreted as HSIL.
smear is uncommon even in inexpert hands, extreme In HSIL the smear background is clean. Reactive parabasal
caution should be used to avoid this misinterpretation. cells, especially in atrophic vaginitis, may show some
Sheaths of parabasal cells with high nuclear/cytoplasmic nuclear membrane irregularity and more hyperchromasia.
(N/C) ratio and hyperchromatic nuclei may simulate Awareness of patient’s clinical history and familiarity
malignant cells (8,9). Information about patients’ clinical with reactive changes in an atrophic smear such as
history, pelvic examination and colposcopic findings nucleomegaly, the presence of cytoplasmic vacuoles
along with careful attention to the appearance of nuclear and cytoplasmic polychromasia usually lead to correct
chromatin and nuclear outlines will be useful (Figure diagnosis. Monotonous appearance of smear, evenly
1G). Monotonous appearance of cellular sheaths, uniform distributed chromatin, and smooth nuclear membrane in
nuclear chromatin, absence of mitotic figures, lack of the majority of cells are the main clues to make a correct
tumor diathesis and nonexistence of tad pole cells all diagnosis (Figure 1D, 1F). In doubtful cases, appreciation
are in favor of benign atrophic smear versus malignant of colposcopic appearance of the cervix, patient’s clinical
A B C
D E F
G H
Figure 1. An atrophic smear showing hypocellular background (A). Sheaths of parabasal and intermediate cells that arranged in small
clusters (B) or in individual cells pattern (C). Large nuclear/cytoplasmic ratio, clumped nuclear chromatin in high grade squamous
intraepithelial lesion (D). Coarse chromatin clumping in a high grade lesion (E). Absence of chromatin clumping, sharp and regular nuclear
membrane, absence of nuclear debris and mitotic activity are hallmarks of atrophic smears (F). Typical parabasal cells in an atrophic
smear (G). Typical koilocytes in low grade squamous intraepithelial lesions (H).
International Journal of Women’s Health and Reproduction Sciences, Vol. 6, No. 1, January 2018 3
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Dastranj Tabrizi
Archive of SID
setting and HPV typing usually solve the problem. In features are routinely used in cytology. Shidham et al
some cases, consultation with a clinician and trying a short (18) suggested that P16ink4 immunocytochemistry
course of vaginal estrogen along with repeated smear will may be useful in a precise categorization of Pap smears
be needed (12). with ASCUS or ASC-H diagnosis. In the smears taken
from elderly patients with uterine prolapse, smears may
C. Low Grade Squamous Intraepithelial Lesion contain anucleated superficial and parakeratotic cells due
Occasionally some of the atrophic smears may contain to cervix keratinization. For the most part, the parabasal
epithelial cells with vacuolated cytoplasm and rarely cells are arranged in large flat sheaths which are typical
perinuclear halo. Awareness of patient’s age and her of atrophy. In liquid based smears, more single parabasal
sexual activity, the absence of typical koilocytes with cells can be seen (Figure 1C) and these cells are prone
raisinoid nuclei and also the monotonous appearance of to be misinterpreted as HSIL (19). Attention to evenly
the background assist to avoid overdiagnosis (13) (Figure distributed chromatin, smooth nuclear membrane, and
1H). absence of mitotic figure are relevant cytologic clues
leading to correct diagnosis. Any nuclear abnormalities
D. Atypical squamous cells of undetermined significance including clumped and coarse chromatin, irregular and
Misinterpretation of atrophic smears as Atypical squamous jagged nuclear membrane, mitotic figures and apoptotic
cells of undetermined significance (ASCUS) may be the bodies should be interpreted as evidences of premalignant
most common mistake in inexperienced hands. Although or malignant lesions and should be confirmed by
most of the parabasal cells in atrophic smears show high colposcopy and biopsy. Although atrophic smears may
N/C ratio, the absence of chromatin abnormality would contain anucleated cells due to uterine prolapse, the
be a helpful sign in a differential diagnosis. It should be presence of atypical parakeratotic cells or cells with
mentioned that in the most smears with epithelial cells atypical nuclei and keratinized cytoplasm should be
abnormalities, the abnormal cells show sparse distribution interpreted with extreme caution.
between normal cells. However, most of the atrophic Although the application of the above mentioned
smears show fairly monotonous appearance. It should be cytologic criteria will be useful in most of these difficult
mentioned that ASCUS has low positive predictive value cases, some investigators recommended that utilization of
for a squamous intraepithelial lesion in perimenopausal immunocytologic markers such as Ki67 would be effective
age group and may be overused (14). in some of the problematic cases (20,21). Other studies
proposed that immunocytochemical detection of P16 and
F. Reactive Changes Induced by Radiation Therapy Most ki67 acts as a more accurate route in establishing a correct
of the patients with radiation change in Pap smear have diagnosis (22-24).
atrophic smear due to postmenopausal status, previous A granular background which is commonly seen in
oophorectomy and radiation-induced atrophic changes atrophic smears should not be confused with the tumor
of ovaries. Therefore atrophic smears with radiation- diathesis which is found in the background of malignant
induced atypical changes are at risk of overdiagnosis. In smears due to tumor cell necrosis and ulceration (Figure
these cases, patient’s past medical history and recognition 1C). Clark hypothesized that in ThinPrep slides, blocking
of microscopic appearance of radiation-induced changes of filter coverage by epithelial cells can be mediated by this
are valuable diagnostic criteria for ruling out of tumor debris and inflammatory cells which leads to hypocellular
recurrence. smears (11).
Discussion Conclusion
After menopause, decreased serum estrogen level prevents Although in most cases the diagnosis of atrophic smears is
squamous epithelium maturation beyond the parabasal straightforward, in rare cases particularly in inexperienced
or lower intermediate cell and induces a thin epithelium hands it may be the source of misinterpretation such as
(15,16). These physiologic changes manifested in Pap ASCUS, HSIL or even squamous cell carcinoma. On
smears by hypocellularity and monotonous sheaths of the other hand, some cases of cervical squamous cell
small parabasal cells with rounded or ovoid cytoplasm. carcinoma may be diagnosed as atrophic smears especially
These cells have relatively larger nuclei but overall, the in rapid screening. Therefore, considering patient’s
parabasal cells are much smaller than intermediate cells clinical findings along with the colposcopic appearance of
and their cytoplasm is dense (17) (Figure 1B). In these the cervix would be useful in problematic cases. Moreover,
cells, N/C ratio is relatively high, but the uniform and use of proliferative and oncologic markers such as Ki67
homogenous nuclear chromatin and smooth nuclear and P16 could be valuable in making a correct diagnosis.
membrane are useful characters in differentiation from
high grade squamous intraepithelial lesion or invasive Conflict of Interests
squamous cell carcinoma. However, the above mentioned Author declares that he has no conflict of interests.
4 International Journal of Women’s Health and Reproduction Sciences, Vol. 6, No. 1, January 2018
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Ethical Issues 2009;16(4):765-769. doi:10.1097/gme.0b013e318193e7cd
Not applicable. 13. Jovanovic AS, McLachlin CM, Shen L, Welch WR, Crum
CP. Postmenopausal squamous atypia: a spectrum including
“pseudo-koilocytosis”. Mod Pathol. 1995;8(4):408-412.
Financial Support
14. Keating JT, Wang HH. Significance of a diagnosis of
None to be declared. atypical squamous cells of undetermined significance
for Papanicolaou smears in perimenopausal and
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Copyright © 2018 The Author (s); This is an open-access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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