CIN represents a spectrum of intraepithelial changes (dysplasia) with indistinct
boundaries that begins with mild atypia and progresses through stages of more
marked intraepithelial abnormalities to carcinoma in situ. The various categories
form points on a disease spectrum rather than separate disease entities. They
are precursor lesions to invasive squamous cell carcinoma.
Dysplasia is a potentially reversible change characterized by an increase
in mitotic rate, atypical cytologic features (size, shape, nuclear features)
and abnormal organization (cellularity, differentiation, polarity) that fall
short of invasive carcinoma (premalignant change).
Dysplasia may progress to cancer and dysplastic changes may be found adjacent
to foci of cancer.
Population distribution of cervical intraepithelial neoplasia/dysplasia resembles
the epidemiology of an infectious disease that is sexually transmitted. Multiple
male sexual partners, early age at first sexual intercourse and male partner
with multiple previous female sexual partners are very important risk factors.
CIN lesions are characterized by the appearance of white patches on the cervix
following application of acetic acid. Distinct vascular patterns can be seen
on colposcopic examination of the cervix in high grade CIN. Lesions occur
on the anterior lip twice as commonly as the posterior lip. They are found
in the transformation zone and areas of squamous metaplasia in the endocervix
and stop abruptly at the junction with the native portio squamous epithelium
but can extend along the entire endocervical canal. In general, the portion
of CIN on the portio surface is low grade (CIN 1) whereas the portion that
extends into the endocervical canal is high grade (CIN 2 and 3).
Abnormal cellular proliferation, maturation and atypia characterize CIN.
Nuclear abnormality is the hallmark of CIN and includes hyperchromasia, pleomorphism,
irregular borders, and abnormal chromatin distribution. These nuclear abnormalities
persist throughout the epithelium irrespective of cytoplasmic maturation towards
the surface. Mitotic rate is increased and abnormal mitotic figures may be
Histologic grading of CIN is based on the proportion of the epithelium occupied
by dysplastic cells. The epithelium is divided into thirds.
CIN 1 (mild dysplasia): Dysplastic cells occupy the lower third of
CIN 2 (moderate dysplasia): Dysplastic cells occupy up to the middle
third of the epithelium.
CIN 2. Note superficial koilocytosis.
CIN 3 (severe dysplasia, carcinoma in situ): Dysplastic cells extend
into the upper third and may occupy the full thickness of the epithelium.
CIN3. Note adjacent koilocytes (bottom right)
Cytologic grading of CIN also uses a three-tier system. However, the new
Bethesda System for cytological diagnosis divides precursors of cervical squamous
cell carcinoma into low-grade squamous intraepithelial lesion
and high-grade intra-epithelial lesion.
Pap smear of CIN 1. Note large, dark nuclei, but also large amount of surrounding
Pap smear of CIN 3. Note large, dark nuclei with a lesser amount of surrounding
cytoplasm. Compare to superficial cell (lower right hand corner).
Question: What is the correlation between the CIN terminology and
the Bethesda System?
CIN may regress spontaneously, especially CIN1, persist or progress. If untreated,
up to 16% of CIN1 will progress to CIN3 and up to 70% of CIN3 will progress
to invasive squamous cell carcinoma in 1 to 20 years. It is not presently
possible to predict which lesions will progress. However, the risk of progression
to invasive cancer increases and the time required is shorter with increasing
severity of the lesion.
Invasive squamous cell carcinoma
Invasive squamous cell carcinoma of the cervix is the most common malignant
tumor of the female genital tract worldwide. However, there are marked differences
in the relative frequency of the tumor in developed and developing countries.
This is due to differences in the availability of screening (Pap smear) programs.
While there is decreased relative frequency in developed countries due to
screening, cervical cancer continues to be the most frequent malignancy in
women in developing countries.
Patients with invasive squamous cell carcinoma have the same epidemiologic
features as those with CIN. Most cancers probably begin as CIN with gradual
progression over a period of years to carcinoma in situ and then invasive
carcinoma. As with CIN, there is a strong association with HPV infection especially
high-risk types 16 and 18.
The disease is most common in older women, but there is increasing frequency
in younger women.
Question: What is the average age of women with invasive squamous
cell carcinoma compared to CIN?
The presenting symptoms depend on size and stage of the tumor. Patients with
tumors confined to cervix are usually asymptomatic and detected because of
abnormal Pap smear result. Those with clinically visible tumors present with
various degrees of abnormal bleeding.
Early lesions may be indurated or ulcerated while more advanced tumors form
exophytic fungating masses or endophytic ulcerated or infiltrative masses
that produce an enlarged, hard, barrel-shaped cervix.
Ulcerated fungating carcinoma of the cervix.
The histologic appearances vary considerably with different degrees of differentiation.
Keratinizing types show various sizes and shapes of well-differentiated nests
or cords of squamous epithelium with keratin pearls. The nonkeratinizing types
contain sheets of tumor cells, some of which show single cell keratinization,
or basaloid cells with no evidence of keratinization.
Keratinizing squamous cell carcinoma. Note keratin pearls in nests of squamous
Nonkeratinizing squamous cell carcinoma.Basaloid cells with no evidence of
Invasive squamous cell carcinoma of the cervix spreads mainly by direct extension
and through lymphatics and rarely by hematogenous route. The more extensive
the local disease, the more the likelihood of lymph node involvement. The
more advanced the disease, the greater the likelihood of distant organ metastases.
Liver is the commonest site for distant metastases.
Question: What is the most important prognostic factor in cervical
Question: What is the commonest cause of death in patients with cervical
Microinvasive squamous cell carcinoma (MICA)
Definition: The term microinvasive carcinoma is used to describe the
earliest form of invasive squamous cell carcinoma detectable in patients with
CIN. In MICA, one or more tongues of carcinoma extend down from the dysplastic
epithelium and break through the basement membrane to invade the underlying
stroma. There is no general agreement as to what exactly constitutes MICA.
The International Federation of Gynecologists and Obstetricians (FIGO) defines
MICA as: invasive carcinomas identified only microscopically i.e. Stage 1a.
Divided into Ia1 cancers with stromal invasion up to 3mm in depth and no greater
than 7mm wide; Ia2 when invasion is at 3-5mm depth and no greater than 7mm
wide. Lymphatic vascular involvement would not exclude a patient from this
definition. All grossly visible lesions even with superficial invasion are
Most gynecologic oncologists in U.S. use the Society of Gynecologic Oncologists
(SGO) definition: cancer in which a neoplastic epithelium invades the stroma
in one or more places to a depth of 3mm or less below the base of the epithelium
and in which lymphatic or vascular involvement is not demonstrated.
The concept of MICA should be applied only to squamous cell carcinomas.
All invasive adenocarcinomas should be regarded as frankly invasive and treated
as the same.
MICA cannot be clinically differentiated from CIN with certainty although
the presence of abnormal vascular pattern may suggest the diagnosis. The diagnosis
is made by histologic examination of a cone biopsy, which allows multiple
step sections at 2mm interval.
Usually, the intraepithelial lesion is high grade, but in a few cases may
be more differentiated. Typically the tumor cells forming the invading tongues
of MICA look better differentiated than the dysplastic cells forming the CIN
in the adjacent epithelium.
Microinvasive carcinoma showing tongue of tumor invading the stroma.
High power view. Note the well-differentiated appearance of the MICA.
MICA extends more deeply to become clinically invasive squamous cell carcinoma
if not removed. Likelihood of lymph node metastases depends on the depth of
invasion and, probably, on lymphatic vascular involvement. The incidence of
lymph node involvement is rare for cancers invading up to 3mm while it is
about 3% for those invading between 3mm and 5mm.
This is a heterogeneous group of malignant glandular neoplasms of the cervix
with different histological features. The commonest is the mucinous type.
There is no significant difference in age distribution with cervical squamous
cell carcinoma. Epidemiologic risk factors are also similar.
Question: What are the epidemiologic risk factors for invasive carcinoma
of the cervix?
The majority of patients present with abnormal vaginal bleeding, some with
vaginal discharge or pelvic pain. Most of the tumors arise in the transformation
zone. Most form exophytic, fungating, papillary or polypoid masses, while
others are endophytic with either diffuse or nodular enlargement or produce
no grossly visible lesion on examination. Some of those with inapparent gross
lesions have early invasive carcinoma, but others are frankly invasive carcinoma
arising deep, and hiding, in the canal beyond vision.
Well-differentiated exophytic tumors often have papillary pattern, while
the endophytic ones show a tubular, glandular pattern. Poorly differentiated
tumors are largely composed of solid sheets of tumor cells with only occasional
evidence of gland formation.
Invasive adenocarcinoma of the cervix spreads by direct extension and lymph
node metastasis similar to squamous cell carcinoma. However, lymph node metastases
tend to occur earlier and overall survival rate is poorer than in squamous
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