Subject: PATHOLOGY

Topic: 5.4. Cervix

Lecturer: Dr. Janet Lim-Dy
Date: January 13, 2015

OUTLINE layer
I. Cervix During reproductive years, the more prominent are the
A. Introduction superficial and intermediate cells
B. Anatomy Review The underlying stroma is made up of loose fibrous CT rich with
C. Inflammatory Conditions small small blood vessels.
II. Squamous Metaplasia of the Cervix
III. Nabothnian Cyst
IV. Endocervical Polyp
V. Premalignant and Malignant Lesions
A. Cervical Intraepithelial Neoplasia
VI. Cervical Squamous Cell Carcinoma
A. Description
B. Large Cell Keratinizing
C. Large Cell Non Kertanizing
D. Small Cell
VII. Adenocarcinoma of the Cervix
A. Description
B. Cervical CA Screening and Prevention

I. CERVIX
A. Introduction Figure 2. Normal squamo-columnar junction/transformation zone (green
arrow).
Cervix is often the seat of diseases, fortunately most cervical
lesions are benign. But, it is also the site of the most common
cancer in women
Diseases of the cervix:
o Inflammations
Acute and chronic cervicitis
Endo-cervical polyps
o Cervical Intraepithelial Neoplasia (CIN)
o Squamous cell carcinoma (SCCA)

Figure 3. Normal squamo-columnar junction/transformation zone: where

endocervix and ectocervix meet. Importance: almost all the lesions in the
cervix arise from this area because this area is unstable and susceptible to
atypical changes, metaplastic changes, and HPV infections.

Figure 1. Left: Gross Normal Ectocervix: smooth, shiny and glistening, tan
brown. Right: Normal ectocervix lined by stratified squamous epithelium

B. Anatomy Review
Cervix is the lower part of the uterus that connects this organ into
the vagina.
It has 2 parts: ectocervix and endocervix
Endocervix opens into the Ectocervix through the external os. the
size and appearance of this opening will depend on the parity of
the patient. Usually it is small and round.In a multigravida, the
external os will have a fish mouth appearance/ smiling cervix.
The lining epithelium of the ectocervix is similar to the vaginal Figure 4. Diagram of squamo-columnar junction/ transformation zone.
Endocervix (left most) - columnar + reserve cell (2 layers). The squamous
mucosa: stratified squamous epithelium, non keratinizing
epithelium of the cervix is divide into inner layer basal cell; the mid zone w/
Divisions: basal, mid zone and superficial para basal and intermediate cells; and superficial layer (3 layers). It is in the
The younger the patient, the more prominent layer is the basal squamo-coloumnar junction were metaplasia would occur would occur

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 Can be acute or chronic (more commonly seen) C. Inflammatory Conditions: Acute and Chronic Cervicitis
Acute cervicitis are associated with some sexually transmitted
diseases
S/sx: discharge, itching, discomfort
Dx: Clinical evaluation, culture, and Papanicolaou smear
examination
Common in multiparous and nulliparous women

PATHOGENESIS
o Squamous cells above the midzone have a clear cytoplasm w/c is
due to presence of glycogen. To confirm that it is glycogen, use
PAS stain. This glycogen maintains an acidic pH in the cervix.
o This glycogenated squamous cells provide a substrate for
endogenous bacteria (lactobacilli) causing an acidic pH
o Lactobacilli: produces
lactic acid (vaginal pH below 4.5)
H2O2 (bacteriotoxic) Figure 6. Histologic Biopsy of Acute cervicitis. Edema, acute inflammatory cells
(neutrophils),erosions (not depicted here, but acantholysis can be seen), and
o H2O2 production and low pH allow overgrowth of other
reactive epithelial change. Note: Acute cervicitis may be caused by non-
organisms + traumaresults in inflammation and a specific bacterial infection or may arise secondary to specific sexually
spectrum of changes: transmitted diseases e.g. gonorrhoea, herpes etc. The pathological
Squamous metaplasia appearances are those of the standard acute inflammatory process as seen
Nabothian cysts elsewhere in the body.
formed secondary to extensive squamous
metaplastic
o change in the transformation zoneobstruct endocervical
glandsdilation of endocervical glandaccumulation of
secretions within the lumen
Cervicitis
Repair and ulcerations
o Menstruation alters (raises) vaginal PH, making the woman
more prone to infection

Figure 7. PAP smear: a diagnostic procedure to determine cervicitis

Figure 5. Left: Gross Normal cervix Right: Cervicitis

Figure 8. Pap smear: Right: Acute cervicitis. Lots of neutrophils present.

Sometimes offending neutrophils present. Note: In premenopausal elderly
women, we normally see small amounts of neutrophils in pap smear but is not
significant enough to label as cervicitis. In chronic cervicitis, the predominant
cells seen in the pap smear is still the neutrophils.

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 May arise from squamous metaplasia (proliferating squamous
cells obstruct the opening of the nabothian glands).
Size of the cyst should be 1cm or more (1 cm could just be an
irregular cystic dilation)

Figure 9. Chronic Cervicitis: chronic inflammatory cells (lymphocytes,

macrophages), granulation tissue, and fibrosis (fibroblast cells). Squamous
metaplasia of the endocervical epithelium (mucin-secreting columnar) often
Figure 11. Squamous metaplasia with nabothian cyst and chronic cervicitis.
accompanies chronic inflammation. The inflammatory process may lead to
The measurement of the cyst should be 1cm or more to be considered as
occlusion of the endocervical glands with retention of secretions, dilatation
nabothian cyst. The cyst has flattened lining epithelium because of the
and formation of cysts known as nabothian cysts. Chronic cervicitis is
pressure from the accumulated fluid. The fluid is pink and acellular seen in the
ubiquitous in older women and the severity varies considerably.
cavity. The overlying mucosa is acantothotic (thickened).

II. SQUAMOUS METAPLASIA OF THE CERVIX

IV. ENDOCERVICAL POLYP
Replacement of mucus endocervical glands by stratified
Inflammatory, benign, non-neoplastic, exophytic growth within
squamous epithelium (metaplasia) from a columnar mucus
the endocervical canal (up to 5 cm).
secreting cell to stratified squamous epithelium
Inflammatory rather than a true neoplasm
Squamous epithelium may also arise directly from basal reserve
Related to chronic cervicitis and squamous metaplasia of lining of
cells of the endocervical mucosa- reserve cells from the
the cervical gland
endocervix become squamous cell instead of becoming
Most cervical polyps are located in the cervical canal
endocervical/columnar cells
Background of chronic inflammation and irritation (a common
finding in Chronic Cervicitis)

Figure 12. Endocervical polyp. Enlarged cervical opening with

protrudingsmooth, soft, almost mucoid lesion. Not an HPV infection because
condyloma in the cervix is usually flattened.

Figure 10. Squamous Metaplasia of Cervical Glands. Difficult to differentiate

from infiltrating squamous cell carcinoma. Gross: inflammed cervix - reddish,
moist with minimal discharge. Histology: mucosa is covered with squamous
epithelium. You know this is squamous metaplasia of the endocervix because
you can see endocervical glands beneath the mucosa. Note: There are 3
endocervical glands in the slide that shows metaplastic change from columnar
to squamous. You might mistake it for intraepithelial neoplasia (since there is
some atypia) or invasive carcinoma (because it looks like the epithelium is
digging down but these are just actually endocervical glands which undergone
squamous metaplastic change.) background shows chronic inflammation with
minimal fibrosis are seen in chronic cervicitis. Figure 13. Histological appearance of endocervical polyp. Histology:
Benign,non neoplastic ,exophytic growth are really overgrown folds of
III. NABOTHIAN CYST endocervical mucosa of an old cervical polyp. The younger the polyp, the
Cystic dilatation of endocervical glands/ducts with accumulation stroma is more loose, fibromyxoid, and contain numerous dilated endocervical
of secretory material glands. As the polyp becomes older (chronic), the stroma becomes cellular.
Within cervical stroma
Seen in the background of chronic inflammation and fibrosis

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 V. PREMALIGNANT & MALIGNANT NEOPLASMS intraepithelial lesion (LSIL) and CIN II and CIN III combined into
Worldwide, cervical carcinoma is the third most common cancer one category referred to as high-grade squamous intraepithelial
in women, with an estimated 530,000 new cases in 2008, of lesion (HSIL)
which more than half are fatal.
Pathogenesis: High risk HPVs are by far the most important
factor in the development of cervical cancer.
From Robbins: High risk HPVs are also implicated in squamous
cell carcinomas arising at many other sites, including the vagina,
vulva, penis, anus, tonsil, and other oropharyngeal locations.
The ability of HPV to act as a carcinogen depends on the viral
proteins E6 and E7, which interfere with the activity of tumor
suppressor proteins that regulate cell growth and survival.
Although HPV infects immature squamous cells, viral
replication occurs in maturing squamous cells.
Other risk factors for cervical cancer: Figure 14. Note that the journey from normal epithelium to carcinoma is a
1. Multiple sexual partners GRADUAL one, often taking many years to progress. The basis for classification
is the expansion or the extent of proliferation of immature cell layer from its
2. A male partner with multiple previous or current sexual
normal basal location. Lesions may exhibit HPV cytopathic changes (koilocytic
partners atypia ) CIN I, associated with low risk HPV ( 6, 11, 42, 44 ); Associated with
3. Young age at first intercourse aneuploidy and high risk HPV =CIN II.
4. High parity
5. Persistent HPV infection (predominantly HPV 16; also HPV EPIDEMIOLOGY
18) Risk factors for cervical cancer:
6. Immunosuppression o Persistent HPV infection (16, 18, 31,33)
7. Certain HLA subtypes o HPV 6 and 11 condylomas
8. Use of oral contraceptives o Early age at first intercourse
9. Use of nicotine o Multiple sexual partners
Male partner with multiple previous sexual partners (high-
A. Cervical Intraepithelial Neoplasia risk male sexual partners)
Are pre-malignant change. o Cigarette smoking
Evolution of classification of cervical-lesions o High parity
Peak incidence for CIN is 30 years old
HPV infection is the single most impt. factor in cervical The risk factors for cervical cancer are related to both host and
oncogenesis viral characteristics such as HPV exposure, viral oncogenicity,
HPV infection is usually transient, cleared within 8mos.to 2 yrs. inefficiency of immune response, and presence of co-carcinogens.
But it depends on the type of HPV These include:
Three different classification systems: o Certain HLA subtypes
1. Dysplasia (oldest classification) o Use of oral contraceptives
2. CIN (1, 2 & 3) o Use of nicotine
CIN I: mild dysplasia, involving basal one third of
epithelium LSIL (CIN I) and HSIL (CIN II and III)
CIN II: moderate dysplasia, involving lower and middle
third of epithelium LSIL HSIL
CIN III: severe dysplasia and CIS, involving all layers of Associated with HPV Associated with HPV
epithelium Small percentage progress to Progressive deregulation of cell
3. SIL (Bethesda Classification): LSIL & HSIL HSIL cycle
CIN is now used to characterize precancer of the cervix and Does not progress directly to
describes the aberrant changes occurring in the cervical SCCA
epithelium as it becomes neoplastic and is replaced by abnormal
cells. These abnormal cells show high nuclear cytoplasmic ratio Note
and pleomorphisms. The CIN concept seeks to underscore the fact that
The oldest classification system classified lesions as having mild premalignant disease of the cervix is a continuum and
dysplasia on one end and severe dysplasia/carcinoma in situ on is neoplastic change that starts from one end of a
the other. This was followed by cervical intraepithelial spectrum and may progress to in situ carcinoma.
neoplasia (CIN) classification, with mild dysplasia termed CIN I, Most CIN lesions do NOT progress to invasive cancer,
moderate dysplasia CIN II, and severe dysplasia termed CIN III. but all tend to be treated as potential cancers as it is
Now there is another classification system by Bethesda because not possible to predict clinically or histologically
the decision with regard to patient management is two-tiered which lesion will progress.
(observation for CIN I versus surgical treatment for CIN II and III),
the three-tier classification system has been recently simplified to
a two-tiered system, with CIN I renamed low-grade squamous

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PATHOGENESIS

CIN begins at the squamo-columnar junction in the

transformation zone.
Peak incidence for CIN is 30 years old.
HPV infection is the single most important factor in cervical
oncogenesis
Transient ,cleared within 8mos.to 2 yrs
Immature basal cells / metaplastic squamous cells are susceptible
Epitheial breaks/presence of metaplastic squamous cells HPV
gain access to the host reactivate the mitotic cycle by
inactivating the functions of p53 and RB
DIAGNOSIS: Schiller test, PAP smear and colposcopy
Figure 16. Histologic appearance of High-grade SIL (Carcinoma in situ). There
is nuclear atypia characterized by nuclear enlargement, hyperchromasia (dark
staining), presence of coarse chromatin granules, and variation of nuclear
sizes and shapes. The nuclear changes may be accompanied by cytoplasmic
halos indicating disruption of the cytoskeleton before release of the virus into
the environment. Nuclear alterations and perinuclear halo are
termed koilocytic atypia. The grading of SIL into low or high grade is based on
expansion of the immature cell layer from its normal, basal location. If the
atypical, immature squamous cells are confined to the lower one third of the
epithelium, the lesion is graded as LSIL; if they expand to two thirds of the
epithelial thickness, it is graded as HSIL.

VI. CERVICAL SQUAMOUS CELL CARCINOMA

A. Description
Figure 14. The Squamo-Columnar Junction.
Note
HPVs infect immature basal cells of the squamous
epithelium in areas of epithelial breaks, or immature
metaplastic squamous cells present at the
squamocolumnar junction.
Is an invasive cervical carcinoma.
Most common complaint is bleeding after intercourse ( post-coital
bleed).
Spreads via direct extension or lymphatics
May block cervical os, obstructing menstrual flow and lead to
infection.
May cause ureteral compression, hydronephrosis and renal failure.
Most common histologic subtype of cervical Ca
HSIL is the most immediate precursor

HPVs cannot infect the mature superficial squamous cells that

cover the ectocervix, vagina, or vulva. Establishing HPV
infection in these sites requires damage to the surface
epithelium, which gives the virus access to the immature cells in
the basal layer of the epithelium.
The cervix, with its relatively large areas of immature squamous
metaplastic epithelium, is particularly vulnerable to HPV
infection as compared, for example, with vulvar skin and
mucosa that are covered by mature squamous cells.
This difference in epithelial susceptibility to HPV infection Figure 17. Invasive Cervical Cancer.
accounts for the marked difference in incidence of HPV-related Gross: ectocervix is replaced by mass like lesion. Has a red moist color, firm
cancers arising in different sites, and explains the high and indurated. Histology: Microinvasive cervical ca in a background of HSIL
frequency of cervical cancer.

Figure 15. Gross appearance of High-grade SIL (Carcinoma in situ)

Figure 18. Cervical SCCA. Shows a bulky, fungating mass that arises from the
ectocervix and affecting the endocervix.

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 Histologic grade : in glands. Lined by atypical columnar cells that exhibits cell and nuclear
o Large cell keratinizing most common pleomorphism, stratification/layering of the lining cells, increase cytoplasmic
o Large cell non-keratinizing ratio
o Small cell
Note: In contrast to vulvar carcinoma in which the well differentiated type
has the worse prognosis, the well differentiated type SCCA of cervix has the
better prognosis.

B. Large Cell Keratinizing

Also called Invasive Squamous CA, Large Cell, KERATINIZING
o Better grade as it is similar to mature cells
o Well-differentiated
o Look for keratin pearls and dyskeratosis
B. Cervical CA Screening and Prevention
Cytologic Screening
o Recommendation for the frequency of pap smear: 1st pap
smear should be at age 21 or w/in 3 yrs of onset of sexual
activity.
Histologic Dx
HPV vaccination program

Figure 19. SCCA of the cervix (large cell keratinizing type/well-differentiated):

keratin pearls, stratification of the tumor cells, intercellular bridging, waxy
cytoplasm
C. Large Cell Non-Keratinizing
Also called Invasive Squamous Cell CA, Large Cell, NON-
KERATINIZING
Moderately-differentiated
Best prognosis in terms of response to therapy
D. Small Cell
Morphologically cannot differentiate from undifferentiated small
cell neuroendocrine carcinoma, most aggressive, no keratin
Similar to small cell cancer of the lungs
VII. ADENOCARCINOMA OF THE CERVIX
A. Description
Tall columnar glandular cells with basally oriented nuclei and
apical cytoplasmic mucin
Resembles endocervical mucinous glandular epithelium with
atypia, pleomorphism, mitoses, invasion
Figure 20. Histology: Adenocarcinoma of the cervix. Tumor cells are arranged
Figure 21. Pap smear test which shows the spectrum of cellular changes from
normal to abnormal.
A. Normal superficial cells
B. Koilocytic change: Condyloma accuminatum- CINI/ LSIL.Shows
multinucleation. Although the nuclei are big, there are no coarsening of
chromatin materials. Perinuclear halo-vacuolation
C. CIN II -Large cells with enlarged nuclei and starting to have uneven
distribution of chromatin
D. CIN III/ HSIL -Increase nuclear cytoplasmic ratio, nuclei more irregular, few
cells wherein cytoplasm is almost absent.
Note: 1st paps shoud be at age 21 or w/in 3 yrs of onset of sexual activity
TYPES OF BIOPSY PROCEDURES
o There are three main types of biopsy procedures used to
provide tissue for histology evaluation:
Colposcopic directed biopsy (visible lesion delineated by
colposcopy)
Punch biopsy
Cone biopsy
INDICATIONS FOR CONE BIOPSY
o Lesions which are high in the endocervical canal
o Inconclusive or failed colposcopy, such as positive cytology
and negative biopsy
o Ca in situ on punch or colposcopic biopsy in which there are
large or multifocal lesions on the cervix
o Questionable microinvasion

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