Benign and premalignant disease of the cervix

Dr. Amal mubarak

Objectives
1.the student be able to understand the histology of cervix and histological changes during
reproductive life
2. the student be able to know the benign disease of the cervix and their managements
3. the student be able to recognize the importance of cervical screening programs
4. The student be able interpret the result of screening test
5. the student be able to manage the premalignant disease of the cervix

ANATOMY OF THE CERVIX

The cervix constitutes the lower third of the uterus
It is in two parts, the endocervix and the ectocervix.
Before puberty, the dividing line between the endo and ectocervix is sharp, and is
determined by the character of
the lining epithelium: the ectocervix is covered with squamous epithelium and the
endocervix is covered with columnar epithelium.
Under the influence of oestrogen (e.g. at puberty, during pregnancy or when the combined
pill is taken), the cervix enlarges, so that the columnar epithelium of the endocervix can be
seen on the ectocervix.
The so-called ‘transformation zone’ (TZ) is defined as the area between the original SCJ and
the current SCJ where the epithelium changes from columnar to squamous epithelium over
time.
The transformation zone is a dynamic area that responds to changes in endogenous or
exogenous oestrogen.
it is susceptible to infection with the human papilloma virus (HPV), which is known to lead
to possible dysplastic change, and this in turn may lead to cervical cancer.

• Terms & definitions

Squamo-columnar junction (SCJ): Where squamous and columnar tissue meet; this is not
fixed, but is affected by metaplasia
Metaplasia: A physiological process whereby columnar epithelium is replaced by squamous
tissue in response to the acid environment of the vagina
Transformation zone: That area on the cervix that has undergone metaplasia; it is bounded
by the original SCJ and the present SCJ
Dysplasia: A histological term describing architectural abnormalities within tissue
Dyskaryosis: A cytological term describing the nuclear abnormalities not synonymous with
dysplasia
Cervical ectropion
This is a benign condition which looks like a ‘raw’ area on the cervix.
This is due to the presence of columnar epithelium found on the vaginal aspect of the
cervix.
A cervical ectropion is commonly and erroneously named ‘cervical erosion’.
An ectropion commonly develops under the influence of the three Ps: Puberty, Pill and
Pregnancy.
The fragile, glandular columnar epithelium of a large cervical ectropion may predispose to
intermenstrual and postcoital bleeding (IMB, PCB).
Some women may present with an excessive, clear, odourless mucus-type discharge.

Treatment
To reduce the ectropion and associated symptoms women should be changed from
oestrogen-based hormonal contraceptives.
The other option is cervical ablation where the visible glandular producing columnar cells
are ablated,
usually with cryocautery, as an outpatient.
Prior to treatment end, cervical and lower genital tract swabs are taken to exclude
chlamydia and other sexually-transmitted infections and normal cervical cytology should be
confirmed to exclude cervical premalignancy and malignancy
Nabothian follicles
Sometimes the columnar glands within the transformation zone become sealed over,
forming small, mucus-filled cysts visible on the ectocervix.
These are termed ‘nabothian follicles’ and are of no pathological significance.
No treatment is usually required although extremely large ones can be drained using a
large-bore needle .
Cervical polyps
Cervical polyps are benign tumours arising from the endocervical epithelium and may be
seen as smooth,reddish protrusions.
They are usually asymptomatic, being identified incidentally during a routine cervical
smear, but as with a cervical ectropion they can cause vaginal discharge, IMB and PCB. They
are easily removed by avulsion with polyp forceps as an outpatient

Cervical stenosis
Cervical stenosis refers to pathological narrowing of the endocervical canal and is usually an
iatrogenic phenomenon caused by a surgical event.
Treatment of premalignant disease of the cervix using a cone biopsy or loop diathermy can
cause cervical stenosis, as can endometrial ablation affecting the os.
The ensuing trapped blood in the uterus (haematometra) causes cyclical dysmenorrhoea
with no associated menstrual bleeding.
Treatment is by surgical dilatation of the cervix under ultrasound or hysteroscopic
guidance.
 premalignant disease of the cervix
Cervical screening has been shown to reduce both the incidence and the number of deaths
from cervical cancer in higher income countries.
It has been estimated that cervical screening prevents around 5,000 deaths every year in
the UK alone.

Epidemiology and aetiology

Cervical cancer is caused by persistent high-risk HPV infection.
HPV is a small, double-stranded(DNA) virus of which there are more than 100 different
types.
These are classified as low-risk or high-risk types, depending on their ability to cause
cancer.
Low-risk types HPV 6 and 11 cause benign warts, while high-risk types HPV 16, 18, 31, 33
and 45 cause cervical cancer.
HPV infection is spread during sexual intercourse.
Infection is very common following the onset of sexual activity and up to 80% of adults
show serological evidence of previous infection.
Infection is usually transient and of no clinical consequence, but a minority of individuals
develop a persistent genital infection that predisposes them to premalignant and malignant
change.
Smoking increases the risk of persistent infection.
Women who are immunocompromised, for example those (HIV) and
transplant recipients on long-term immunosuppressive therapy, are
particularly at risk of premalignant and malignant disease of the cervix.
When HPV infection persists in certain individuals, it triggers an oncogenic process in the
region of the TZ where metaplasia occurs. Integration of HPV DNA into the basal epithelial
cells leads to
immortalization and rapid cellular turnover.
This disordered immaturity within the epithelium is called ‘cervical intraepithelial neoplasia’
(CIN) and is truly an intraepithelial condition (cancer is diagnosed when this process breaks
the basement membrane).
Immature cells are hyperchromatic with large nuclei, minimal cytoplasm and abnormal
mitotic figures.
CIN is classified as either low-grade (CIN 1) or highgrade disease (CIN 2 and 3), depending
on whether the abnormal cells are seen in the bottom third or top
two-thirds of the cervical epithelium, respectively.
Classification of CIN

Diagnosis and investigations

Cervical cytology
Cells exfoliated from the cervix can be examined under the microscope and this acts as a
good screening test.
Originally the ‘Pap smear’ was introduced by Papanicolou, where cells were removed from
the cervix using a wooden spatula and placed on a glass slide and fixed.
The Pap smear has now been
superseded by liquid-based cytology (LBC), whereby a small brush is used to sample cells
from the TZ and the brush head placed in fixative.
• Spread on glass slides
• As thin as possible
• Properly labeled
• Fixation of samples immediately with alcohol
Abnormal cervical cytology shows squamous cells at different stages of maturity
(dyskaryosis).
Like CIN, cervical cytology is classified as low grade (minor cytological abnormalities
showing mild dyskaryosis or borderline change) or high grade (moderate and severe
dyskaryosis) .
There is some correlation between the grade of cytological abnormality and the extent of
CIN found on the cervix, but this is not totally reliable.
Cervical cytology triages patients to the colposcopy clinic for further assessment.
The sensitivity of a single cervical smear for high-grade CIN detection is between 40% and
70%; however, as there is slow progression for most women with CIN to cancer, if a lesion
is missed then this should be picked up on a subsequent test.
Women who attend regularly for cervical cytology have a very low risk of developing
cervical cancer.

The role of HPV testing in cervical screening

High-risk HPV testing improves the sensitivity of cervical screening. Its value lies in its
extremely high negative predictive power, which means that if a woman tests high-risk HPV
negative, her risk of developing cervical cancer over the next 5–10 years is exceptionally
low.

Pap smear

Many countries, including the UK, are now moving towards primary HPV screening; that is,
testing all cervical cytology specimens for high-risk HPV first, and carrying out reflex
cytological assessment on those that test positive. This will reduce the costs of the
screening programme, since HPV testing is automated and achieves a high throughput,
while cytological assessment is manual and requires a skilled workforce
The National Cervical Screening Programme
Since 1988, the UK has offered population-based cervical screening. Women aged 25–64
are invited every 3–5 years to take part in the screening programme.
25 to 49 every 3yr ,50-64 every 5yr.
Colposcopy
Colposcopy is the examination of the magnified cervix using a light source . It is used for
both diagnosis and treatment.
The woman undresses and places her legs in the semi-lithotomy position.
A speculum is placed in the vagina and the cervix examined with a light source, under
magnification (5–20-fold)

The application of acetic acid and iodine solutions highlights abnormal areas of the cervix
that can be biopsied.
Acetic acid causes nucleoproteins within cells to coagulate temporarily; therefore, areas of
increased cell turnover, including CIN, appear white

Areas of CIN lack intracytoplasmic glycogen and fail to stain brown when iodine is applied
CIN is a preneoplastic process and the process of angiogenesis (new blood vessel
formation) is apparent in CIN when viewed through the colposcope If CIN is present, the
colposcopist determines whether the appearances are low or high grade.
The latter can be treated in the clinic on the same visit (known as ‘see and treat’); the
former can be monitored with a subsequent colposcopy and cytology 6 months later.
A biopsy usually helps make the decision if unsure (‘select and treat’)

Outcome of CIN
 Spontaneous regression.
 Progression to invasive cancer.
Progression from one stage to another takes years.
Detection and treatment of CIN prevents cancer cervix.

Treatment of premalignant disease of the cervix

The aims of treatment are to effectively eradicate CIN, ensuring that post-treatment
cytology is negative, while minimizing harm to the patient from the treatment.
High-grade CIN requires treatment, usually with excision or ablation.
Low-grade CIN regresses spontaneously in up to 60% of cases; therefore, close follow-up
with colposcopy and cytology 6 months after initial diagnosis is favored as this avoids over
treating lesions that might have regressed
the favored method of treatment for highergrade CIN is loop diathermy (large loop excision
of transformation zone, LLETZ).
Under local anaesthetic, a diathermy wire loop is used to remove a portion of the cervix
that includes the TZ with the area of CIN .
CIN can develop within the crypts of the epithelium and therefore excisional techniques
need to be at least 7 mm deep.
The advantages of this excisional technique are:
that it is clinically effective (95% of patients have negative cytology at 6 months),
cost-efficient (patients can be treated at the first hospital visit
it provides a specimen for pathological assessment (1% of loop biopsies have an
unsuspected microscopic cancer).
The disadvantage : potential impact on obstetric outcome.
a large excision or repeat excisions remove a substantial proportion of the cervix, there is
an increased risk of midtrimester miscarriage and preterm delivery in subsequent
pregnancies.
This concern relates to young women who have not completed their family.
Recognizing the potential for overtreatment has been the main reason why women under
25 are not screened, as many lesions in this group of women are associated with HPV
infection and simply regress with observational follow-up
Other options have been suggested for the treatment of CIN including cold coagulation and
cone biopsy.
The term ‘cold coagulation’ is a misnomer as the treatment involves placing a hot probe on
the cervix in outpatients under local anaesthetic.
It is a destructive treatment, is effective for both high- and low-grade CIN but does not
provide a specimen.
Cone biopsy involves cutting away a portion of the cervix under general anaesthetic and
produces a specimen, like a LLETZ.
Its disadvantage relates to the need for a general anaesthetic and 5% of patients may
develop cervical stenosis or incompetence, which has obstetric implications.
It has been largely superseded by loop diathermy.

Patients who have received treatment for CIN undergo a ‘test of cure’ 6 months later.
This includes a high-risk HPV test and cytological assessment.
If negative, the woman is returned to routine recall; that is, cervical screening in 3 years
time .
If positive, repeat colposcopy is indicated to identify any residual, untreated CIN.
A woman with a history of CIN has an increased life-time risk of recurrent CIN and cervical
cancer.
HPV vaccination
HPV vaccines have been shown to be safe and effective at preventing persistent high-risk
HPV infection CIN.
School-based immunization in the UK is aimed at 12–13-year-old girls so it will take many
years to know if HPV vaccination can reduce deaths from cervical cancer.
The bivalent vaccine prevents persistent infection with HPV types 16 and 18, which
together are responsible for more than 70% of cases of cervical cancer.
In 2011, the bivalent vaccine was replaced by the quadrivalent vaccine, which additionally
protects against HPV types 6 and 11, the main perpetrators of genital warts.
Current vaccination strategies are unlikely to result in the eradication of cervical cancer
because other high-risk HPV types are not included and uptake is not universal.
Future strategies will increase efficacy by vaccinating adolescent boys and the development
of new polyvalent vaccines that provide protection against more high-risk HPV types.