PATHOLOGY
VULVA, VAGINA, AND CERVIX
Dr. Soccorro Cruz-Yanez
CONGENITAL
 Imperforate Hymen (Hematocolpos)
 Atresia
 Abesence (Agenesis)
 Septate
 Double (Didelphys)
o True separate organs develop
IINFECTIONS OF THE FEMALE LOWER
GENITAL TRACT
Candida
 Common in immunocompromised
 Part of normal vaginal flora
 Candidiasis – Typical result of disturbance in the vaginal’s
microbial ecosystem
 Not considered STD
 Diabetes Mellitus, antibiotics, oral contraceptives and
pregnancy may enhance the development of infection due to
disturbance in cell-mediated immunity
Gross: Small white surface patches with discharge and pruritus.
Manifestation: Vulvovaginal pruritis, erythema, swelling and
curd-like vaginal discharge
Diagnosis: Pseudospores or filamentous fungal hyphae in wet
KOH mounts of the discharge or Pap smear
Trichomonas Vaginalis
 Large, flagellated ovoid protozoan, identified in pap smear or
in wet mounts
 Usually transmitted by sexual contact
 Develops within 4 days to 4 weeks
 Asymptomatic, sometimes a yellow frothy vaginal
discharge, vulvovaginal discomfort, dysuria and dyspareunia
(painful intercourse)
 Vagina is fiery-red appearance (“strawberry cervix”),
marked dilatation of cervical mucosal vessel
Histology: Inflammation is confined to the mucosa and the
lamina propria immediately below
Gardnerella Vaginalis (Bacterial Vaginosis)
 Overgrowth of multiple Gram negative coccobacilli
colonizing bacteria
 Pap smear: Clue cells (squamous cells coated with gram
negative coccobacilli)
Signs & symptoms: Homogenous thin, malodorous discharge,
pH > 4.5, fishy odor
Clinical Complication: In pregnancy it is associated with
premature rupture of membranes (PROM) and chorioamnionitis
Chlamydia Trachomatis
 Takes form of cervicitis but can ascend to the uterus and
fallopian tubes results to endometritis and salpingitis
 One of the causes of PID
 Major cause of infertility in women
Herpes Simplex Virus
 Sexually transmitted , caused by HSV- 2: Genital mucosa and
skin (HSV-1: Oropharyngeal infection)
 10% of unscreened women, 50% of women in STD clinics
and 20% among 40 years age population
 Involves cervix, vagina and vulva (order of frequency)
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January 5, 2012
Signs & symptoms: Leukorrhea (genital discharge), painful
vesicles, ulcers, neuropathy, painful urination and urine
retention, fever, malaise, tender inguinal lymph node (initial)
Complication: Intrauterine fetal infection due to neonatal
transmission, malignant transformation
Gross: Red papule  Vesicles  Painful coalecsent ulcers
Note:
Painful red papules in the vulva would begin to appear 3-7
days after contact. Lesions heal spontaneously after 1-3 weeks
but latent infection of the regional nerve ganglia may persist.
Histology: Multinucleated giant cells, ground glass nuclei, ,
molding (kissing nuclei), eosinophilic intranuclear inclusion
bodies
Fig. 1. Left: Herpes Simplex: multinucleation, molding, margination.
Right: multinucleation, intranuclear inclusion bodies
 Latent infections can occur and 2/3 of patients suffer
recurrences
 Transmission may occur in active or latent phase but less
likely in asymptomatic carriers
 Can also be seen in males: Mucocutaneous Vesicular
Disease (skin and mucus membranes affected)
Diagnosis: Serologic test – PCR, ELISA, IF antibody test (Anti-
HSV antibodies in serum = Recurrent/latent infection)
Treatment: No effective treatment for latent HSV but acyclovir or
famciclovir shorten length of initial and recurrent symptomatic
phase
Human Papilloma Virus
 Sexually transmitted agent in cervical cancer pathogenesis
 Involved in pathogenesis of vulvar, vaginal and cervical
neoplasia and other squamous tumor of skin and mucous
membranes
 Cause of vulvar condyloma acuminatum, “venereal wart”
(benign raised or wartlike/verrucous lesion)
 HPV DNA detected by hybridization techniques in 85% of
cervical cancers and 90% of condylomas and precursor
lesions
 Low risk HPV types 6, 11, 42, 44 – Associated with
mucocutaneous lesions
 High risk types 16, 18, 31, 33 – Associated with cervical CA
Condyloma Acuminatum
 Papilloma virus HPV 6 (high risk)
Gross: Verrucous, papillary growths, “cauliflower-like” or may
be sessile, may be solitary but they are more frequently multiple
and often coalesce. Involves the anogenital area
Histology: Acanthosis (lining epithelium grows downward),
hyperkeratosis (thickening of keratin layer), parakeratosis
(nuclei persists on uppermost level of epithelium showing
induced cell division), papillomatosis, koilocytosis (perinuclear
halo, wrinkling of nuclear membrane producing prune-like effect.,
viral cytopathic change), branching tree-like cores of stroma
covered by squamous
Pathology 1 | 8
 Fig. 2. Left: Condyloma acuminata: Acanthosis (red), hyperkeratosis (blue), Fig. 4. Left: Syphilitic chancre, Granuloma Inguinale. Right: Donovan bodies,
parakeratosis (green) Right: Koilocytes granulomatous reaction without caseation
Note:
 Diagnostic cell for HPV: koilocyte IINFECTIONS OF THE FEMALE UPPER
 Remember: GENITAL TRACT
 HPV: Koiliocyte
 HSV: Intranuclear inclusion bod
Pelvic Inflammatory Disease
 Molluscum contangiosum: Intracytoplasmic  Etiologic agent: Gonococcus (most common), Chlamydia,
enteric bacteria, polymicrobial (also common) in puerperal
molluscum bodies
infections such as Staph, Strep and C. Perfringens
 Sometimes, there is appearance of koilocytic atypia where
 Associated conditions: Abortions, puerperal infections
infected cells have nuclear enlargement showing atypia and
perinuclear halo.  Common site: Tubes (Condition: Acute suppurative
salpingitis), ovaries
Molluscum Contangiosum  Ascending infection that begins in the vulva or vagina;
 Common self-limiting viral disease of skin spread by direct involve most of the structures in the female genital system.
contact  Endocervical mucosa- most common site of initial
 DNA Poxvirus infection of the skin and mucous membrane involvement (gonococcus)
Gross: Multiple umbilicated, pruritic, pink, papules measuring Signs & symptoms: Pelvic pain, adnexal tenderness, fever,
2- 4 mm on trunk and anogenital (vulva) areas vaginal discharge

Histology: Cup-like verrucous epidermal hyperplasia with Complications:

eosinophilic intracytoplasmic molluscum bodies (virions) - Peritonitis (if the fallopian tube is affected, the ampullary
area is patent, and pus is discharged into peritoneal cavity)
 Four types of MC Viruses. MCV 1-4 - Intestinal obstruction secondary to adhesions
o MCV1 – Most prevalent - Infertility – due to impenetrable lumen for oocyte
o MCV2 – Most sexually transmitted - Bacteremia (Sepsis)
 Common in 2-12 year-old children Note:
o Most affected area: Trunks, arms and legs  Recall anatomy: Distal ends of fallopian tube are open
 In adult, common area: Genitals, lower abdomen, buttocks
allowing access of bacterial infection to pelvic peritoneal
and inner thigh
space
 Diagnosis based on appearance of pearly, dome-shpaed
 Other causes: Abortions and normal/abnormal deliveries
papules w/ dimpled center
(puerperal infections), infections related to pregnancy
Histology:
- Tubal mucosa – Congested and diffusely infiltrated by
neutrophils, plasma cells and lymphocytes
- Tubal lumen – Purulent exudate leaks out of fimbriated end
 Salpingo-oophiritis – Infection spill over to ovary
Fig. 3 Left: cup-shaped lesion with eosinophilic intracytoplasmic inclusions. Right:  Also tubo-ovarian abscesses and pyosalpinx (collection of
Eosinophilic Intracytoplasmic Inclusions (pink bodies) pus in tubal lumen)may occur
Syphilis VULVA
 Chancre – Ulceration, chronic inflammation including plasma Benign Cystic Lesion
cells and vasculitis
 Condyloma Lata – Like chancre with epithelial hyperplasia Epidermoid Cyst of the Vulva
 Diagnosis- Dark field microscope, flourescence, silver stain,  Also known as Keratinous cyst or Epithelial Inclusion Cyst
serology  Fibrous outer cyst wall
 Syphilitic chancre  Inner cyst wall shows flattened stratified squamous epithelium
o Treponema pallidum  Keratosis in epithelium
o Gross: Painless shallow ulcer  Keratin material inside lumen or amorphous material
o Histology: Ulceration, chronic inflam, predominance of Bartholin Cyst
plasma cells, vasculitis  Lesions arise from inflammatory scarring and obstruction
 Granuloma inguinale of the duct with accumulation of secretions and cystic
o Calymmatobacterium granulomatis dilatation
o Gross: Painless ulcers w/ rolled borders & a friable base +  Cyst wall epithelium usually transitional, but may be
lymphadenopathy squamous, cuboidal to low-columnar mucinous
o Histology: Donovan bodies, granulomatous reaction  Secondary to inflammation, obstruction of the Bartholin
without caseation glands
 3 stages:  Acute inflammation within the gland (adenitis) and may result
1. Primary – Initial infection, STD, ulceration, clean shiny in an abscess
ulcer base  May recur when inadequate surgical removal
2. Secondary – Flat condyloma  Relatively common, occur at all ages
3. Tertiary – Deposition, inflammation of the CVS, aortitis,  Up to 3-5 cm in diameter, produce pain and local discomfort
nerve tabes dorsales, hepar lobatum

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Note: Note:
Bartholin glands in women are analogous to Cowper’s  Clinical Importance: Screen for dystrophies in post
(bulbourethral) glands in men. They are also called greater menopausal patients/elderly patients. Some types of
vestibular glands. Inflammation or obstruction to the ducts of dystrophies are associated with malignancy
these glands can cause cyst formation.  Some of these, when extensive, produce obstruction and
narrowing of introitus
Squamous Cell Hyperplasia
 Also known as Hyperplastic Dystrophy, Lichen Simplex
Chronicus
 May be associated with CA esp if atypia is present
 Nonspecific condition resulting from rubbing or scratching
of the skin to relieve pruritis
Fig. 5. Gross and Histo of Bartholin’s Duct Cyst  Appear clinicially as an area of leukoplakia
Histology:
Epithelial Tumors of the Vulva - Hyperplasia of vulvar epithelium
Fibro-epithelial Polyp - Thick epidermis
 Also known as Achrocordon or skin tags - Hyperkeratosis
 No clinical significance, except that it may produce discomfort - Dermal inflammation
during intercourse and may cause bleeding/mechanical
trauma of polyp Lichen Sclerosus
 Also known as Chronic atrophic vulvulitis
Gross: Papillomatous pedunculated growths of the vaginal wall,
 1-4% risk of development of Ca, but not considered a pre-
usually solitary and small,
malignant lesion
Histology: Central connective tissue stalk lined by squamous  Pathogenesis: Auto-immune – Due to presence of activated
epithelium T-cells in subepithelial inflammatory infiltrate
 Most commonly seen in post menopausal women
 Lichen Sclerosus et Atrophicus – Smooth white plaques or
papules
o Pale, dry, scaly, gray parchment-like skin with atrophy of
labia and narrowed introitus, complains of dyspareunia
Histology:
- Thin epidermis
- Hyperkeratosis
Fig. 6. Gross: Papillomatous pedunculated growths. Histology: Central connective - Loss of rete pegs
tissue stalk lined by squamous epithelium - Dermal fibrosis with no appendages
- Dermal mononuclear inflammation
Papillary/ Nodular Hidradenoma
 Hidradenoma: Benign sweat gland tumor of the vulva/vagina Note:
 Lined by squamous epithelium This type of “lichenoid” disorder has HYPER-plastic
 Located in the L. majora or minora epidermis, NOT atrophic. The “hyperplasia” is felt to be related to
“itching” or mechanical epidermal irritation
Gross: Small, sharply circumscribed ovoid, painless, discrete
nodules
Histology:
- Papillary structures, tubules, & acini lined by cuboidal cells
- Identical in appearance to intraductal papillomas of the
breast
- Consists of papillary projections with 2 layers of cells:
 Top columnar, secretory cells and underlying layer of Fig 8. Gross and histology of Lichen sclerosis
flattened “myoepithelial cells” – Characteristic of
sweat glands and sweat gland tumors Vulvar Intraepithelial Neoplasia (VIN)
 Premalignant vulvar lesion, high risk
 Biologic and morphologic continuum of cellular atypia
 Divided into: VIN I. VIN II. VIN III
 May be multicentric
 HPV related in 90% of cases HPV type 16, 18
 10 – 30% may have associated vaginal cervical HPV
 5% of VIN III (severe dysplasia) progress to carcinoma
elderly and immunosuppressed
Fig. 7. Gross: small nodules. Histology: Papillary structures, tubules, and acini  30% associated with vaginal or cervical carcinoma
lined by cuboidal cells  Classic VIN
Non-neoplastic Epithelial Disorders o Nuclear atypia of the squamous cells, increased mitoses
and lack of cellular maturation
 Characterized by opaque, white, plaquelike mucosal
o Analogous to cervical squamous intraepithelial lesions
thickening with vulvar discomfort and itching.
 Precursor lesions of vulvar carcinomas Gross: Discrete white (hyperkeratotic), flesh colored or
 Types pigmented slightly raised lesions
1. Lichen sclerosus
2. Squamous hyperplasia

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Note:
 Very LOW grade VIN looks almost like normal skin, very
HIGH grade VIN is regarded as carcinoma-in-situ.
 Factors such as loss of maturation pattern, nuclear
aberrations such as enlargement, hyperchromasia,
pleomorphism, mitoses differentiate LOW from HIGH.
1. VIN I
- Mild dysplasia
- Atypical proliferation does not exceed 1/3 the epithelial
thickness
2. VIN II
- Moderate dysplasia
- Atypical proliferation exceeds 1/3 but does not exceed 2/3
of the epithelial thickness
3. VIN III
- Severe dysplasia
- Atypical proliferation exceeds 2/3 the epithelial thickness
Fig. 9. Top: Left – VIN I, Right – VIN II. Bottom: VIN III
Note:
If there is full thickness proliferation – In-situ carcinoma
Vulvar Cancer
 3% of all genital cancers in the female, 2/3 occur in women
older than 60yrs
 85% are squamous cell carcinoma – Most common
histologic type of vulvar Ca
 15%: Basal cell carcinoma, adenocarcinoma, melanoma
 65%: Metastasized to regional nodes (inguinal, pelvic) at time
of diagnosis (very aggressive due to rich lymph nodes in the
vulvar area)
 Lesions less than 2 cm – 80% five-year survival rate
 Larger lesions with positive nodes have less than 10% five
year survival rate
 2 groups
1. Associated with HPV
- Multicentric
- Preceded by VIN
- Also known as Carcinoma in situ or Bowen
disease
- Basaloid and wart carcinomas: Develop from
precancerous in situ lesion called classic VIN
- Histology (Basaloid Ca) – Infiltrating tumor charac.
By nests and cords of small,tightly packed malignant
squamous cells lacking maturation
- Warty Carcinoma – Exophytic papillary architecture
and prominent koilocytic atypia
2. Associated with Squamous cell hyperplasia and
lichen sclerosus
- Infrequently assoc with HPV
- Associated with mutations of p53
- Worse prognosis
- Keratinizing squamous cell carcinomas
- Differentiated VIN (immediate premalignant lesion ):
marked atypia of basal layer w/ apparently normal
epithelial maturation and differentiation in superficial
layers
- Gross: Nodules in background of vulvar inflammation
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- Clinical manifestation: Local discomfort, itching and
exudation
- Histology: Infiltrating tumor charac. By nests and
tongues of malignant squamous epithelium With
prominent central keratin pearls
Invasive Squamous Cancer
 Exophytic fungating mass or endophytic ulcerating lesion
 Histology: Keratinization (keratin pearls) and intercellular
bridges
 Look for evidence of frank stromal invasion
Fig. 10. Ulcerative type of vulvar squamous CA: Hemmorhagic, friable, necrotic
base of lesion vs syphilis with clean base
Paget’s Disease of Vulva
 Large tumor cells lying singly or in small clusters within
epidermis, as well as in appendages
 Cells have abundant clear vacuolated cytoplasms
 Usually no underlying vulvar cancer
 Glandular, of probable sweat gland origin
 Presents as Pruritic, red, crusted, sharply demarcated, map
like area, usually in the labia majora.
 Diagnositic micro feature: Presence of large tumor cells
lying singly or in small clusters w/in epidermis, distinguished
by a “halo” and a finely granular cytoplasm (PAS +)
 Treated with local excision but high recurrence rate due to
paget cells spreading beyond confines of lesion
Fig. 11. Mucosa is weeping, excoriating, ulcerating mucosa with beefy red raw skin
of the vulva
Malignant Melanoma
 Markedly atypical melanocytes within epidermis and
dermis
 Cells round, ovoid to spindly, with large nuclei and prominent
nucleoli
 Brown to black cytoplasmic pigment within cytoplasm and
within melanophages
 Represents less than 5% of all vulvar cancers; peak
incidence: 6th or 7th decade
 Prognosis: Linked to depth of invasion, greater than 60%
mortality- lesions deeper than 1 mm
 May resemble Paget disease grossly and histology
 Differentiated by uniform reactivity with antibodies to S100
protein, absence of antibody reactivity to cytokeratin and lack
of mucopolysaccharides (both present in Paget disease)
Fig. 12. Atypical tumor cells produce melanin pigments
Pathology 4 | 8
 VAGINA Histology:
- Keratinizing or non-keratinizing irreg-shaped nests or
Mesonephric Cyst (Gartner’s Duct Cyst) clusters of squamous cells invading stroma, often with
 Location: Anterolateral wall of the vagina, following the route
eosinophilic cytoplasm, atypical nuclei with coarse
of the mesonephric duct
chromatin, prominent nucleoli, abnormal mitotic figures
 Derived from the Wolffian/mesonephric duct
 Histology: Lined by low cuboidal, non-mucin-secreting cells
devoid of cytoplasmic mucicarmine or PAS (+) material
 Common cyst

Fig. 15. Vaginal Intra-epithelial Neoplasia

Fig. 13. Gartner’s duct cyst.

Squamous Papilloma
 Location: Near the hymenal ring
 Histology: Single papillary frond w/ a central fibrovascular
core, exophytic projections Fig. 16. Squamous cell carcinoma; formation of keratin pearls

Vaginal Intraepithelial Neoplasia (VaIN) FIGO Staging

5-YEAR SALVAGE
System for
 According to Bethesda System: CRITERIA RATES (with
Carcinoma of the
o VaIN 1 or mild dysplasia  LSIL (Low Grade Squamous Vagina STAGE
radiation therapy)
Intraepithelial Lesion), low risk of malignancy 0 Intraepithelial -
 Treatment every 6 months to1year of Pap smear. Limited to vaginal
o VaIN 2/3 or moderate/severe dysplasia or CA-in-situ  I
wall
80%
HSIL (High Grade), high risk of malignant transformation, Extends to
document by biopsy with more frequent surveillance, subvaginal tissue but
II 50%
 Treatment: Surgery not to pelvic wall
side
Gross: Epithelium may appear raised and white or pink Extends to pelvic
III 30%
Histology: Loss of normal maturation, nuclear atypia, increased wall side
mitotic activity, abnormal mitotic figures, acanthosis & Extends beyond true
pelvis or involves
dyskeratosis IV 5%
mucosa of bladder or
Note: rectum
 Presence of koilocytes indicate preexisting HPV infection. IVa Adjacent organs -
IVb Distant organs -

Adenocarcinoma
 Usually seen in young (15 – 20 years old) vs. Squamous cell
Ca (Older women)
 60% of patients have documented exposure in utero to
diethylstilbestrol (DES)
Fig. 14. Left: VaIN I. Right: VaIN II
 Precursor lesion: Vaginal adenosis
Vaginal Carcinoma or Squamous Cell Carcinoma Gross:
 Primary carcinoma of the vagina - Variable size
 Exteremely uncommon (0.6 / 100,000 yearly) - Polypoid & nodular, but some are flat or ulcerated, having a
 1 % of Ca in the female genital tract granular or indurated surface usually located on the upper
 95 % are squamous cell Ca third of the anterior wall of the vagina.
 Risk factors:
o HPV Histology: Vacuolated, glycogen-containing cells
o Cervical Ca Clear Cell Adenoacarcinoma
o Vulvar Ca  Very aggressive
 90% of malignant lesions of the vagina
 Must be located in the vagina, without clinical or histologic Histology: Solid sheets of clear cells, hobnail appearance of
evidence of involvement of the cervix or vulva nucleus, tubulocystic pattern (Most common, clear, glycogen
 Associated with high oncogenic risk HPVs (16, 18, 31) containing cells)
 Vaginal intraepithelial neoplasia
o Premalignant lesion
o Analogous to cevical squamous intraepithelial lesion (SIL)
 Most originates from the proximal 3rd of the vagina
 Metastasis:
o Lesion in lower 2/3 to inguinal nodes
o Lesion in upper 1/3 involve iliac nodes
Gross: Variable – Polypoid, fungating, indurated or ulcerated
lesions. Large exophytic mass in the vaginal vault, like the head Fig. 17. Clear Cell AdenoCA
of a baby

SECTION B UERMMMC Class 2014 Pathology 5 | 8

 Embryonal Rhabdomyosarcoma Botryoides
 Also known as Sarcoma botryoides
 Most common malignant neoplasm of the vagina in infants &
children younger than 5 years old
 Skeletal muscle sarcoma – Tumor consists predominantly of
malignant embryonal rhabdomyoblasts
Gross:
- Gelatinous, soft, gray or tan, nodular, polypoid, rounded,
bulky masses that sometimes fill and project our of the
vagina
- Botryoides = Grapelike
Histology: Rhabdomyoblasts – Spindle-shaped, round, tennis
racket-shaped (due to a small protrusion of cytoplasm from one
end), tadpole-shaped cells with abundant eosinophilic cytoplasm
with a subepithelial dense zone (cambium layer)
 (+) Desmin
 Mistaken for benign inflammatory polyps
 Tend to cause death by penetration into peritoneal cavity or
by obstruction of the urinary tract
Note:
 If there is a malignant tumor in children, in the vaginal canal,
1st thing to think of is tumor of skeletal muscle.
 This is NOT SEEN in ADULTS
Fig. 18. Embryonal Rhabdomyosarcoma botryoides
CERVIX
Cervicitis
 Common in multiparous and nulliparous women.
 The glycogenated squamous cells provide a substrate for
endogenous bacteria causing an acidic pH + trauma 
Results in inflammation and a spectrum of changes
o From squamous metaplasia
o Nabothian cyst
o Repair, erosion or ulceration
 Inflammation of the stroma produces reparative and reactive
changes of the epithelium; may cause nonspecific, abnormal
Pap test result
 Factors that increase alkaline pH which causes overgrowth of
other microbes which may result in cervicitis or vaginitis
o Bleeding
o Sexual intercourse
o Vaginal douching
o Antibiotic treatment
Squamous Metaplasia of the Endocervix
 Replacement of mucus endocervical glands by stratified
squamous epithelium (metaplasia)
 Squamous epithelium may also arise directly from basal
reserve cells of the endocervical mucosa
 Background of chronic inflammation and irritation
Fig. 19. Squamous metaplasia
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Fig. 20. Chronic cervicitis with squamous metaplasia
Nabothian Cyst
 Cystic dilatation of endocervical glands/ducts with
accumulation of secretory material
 Within cervical stroma
 Background of chronic inflammation and fibrosis
Endocervical Polyp
 Benign exophytic growths
 Polypoid lesion with loose fibromyxomatous stromal
containing vessels and dilated mucus-secreting endocervical
glands; may protrude to the cervical os.
 Lined by mucus endocervical glandular epithelium or
metaplastic epithelium
 Produces irregular vagina
o “Spotting” or bleeding
o Ulceration or hemorrhage may be seen
Intraepithelial and Invasive Squamous Neoplasia
Risk factors :
- Early age of first intercourse
- Multiple sexual partners
- Male partner with history of multiple previous or current
sexual partners
- Young age at first intercourse
- Persistent infection of high risk HPV
- Immunosuppression
- Ceratin HLA subtypes
- Oral contraceptives
- Potential risk: Cigarette smoking , high parity , genital
infections, lack of circumcision
 HPV causal relationship :
o High risk HPV remains to be the single most important
factor in cervical oncogenesis
o Virus detected in 85 % of cervical Ca , 90 % in cervical
condyloma and precancerous lesion
o High risk HPV type: 16 (60% of cervical cancer cases), 18
(10% of cervical cancer cases), 31, 33
o Low risk HPV type: 6, 11, 42, 44
o High risk HPV type with ability to link
 Role of HPV in cervical neoplasia
o Infects immature basal cells or immature metaplastic
squamous cells
o Low infectivity in mature superficial squamous cells of
ectocervix, vagina, and vulva
o Viral replication occurs in maturing squamous cells
Fig. 21. Causal relationship of HPV with invasive CA
Pathology 6 | 8

Fig. 22. Possible etiology of Invasive squamous CA
Cervical Intraepithelial Neoplasia (CIN)
 Pre-cancerous lesions
 Presence of cellular atypia involving part of the cervical
epithelial thickness, with normal cellular maturation towards
the surface
 Atypical changes: dyskeratosis, nuclear pleomorphism,
mitoses, koilocytosis (nuclear atypia an cytoplasmic
perinuclear halo)
 Categories:
1. CIN I (mild dysplasia) - LSIL
2. CIN II (moderate dysplasia) - HSIL
3. CIN III (severe dysplasia / Ca in Situ) -HSIL
 80% of LSILs and 100% of HSILs are associated with high
risk HPVs, 20% of HSILs develop without preexisting LSIL
1. CIN I (Low-grade squamous intraepithelial lesion)
- Also known as Flat Condyloma
- Productive HPV infection but with no significant alteration
of host cell cycle
- Regress spontaneously
- Small percentage progressing to HSIL
- Mild dysplasia, low rate of progression to cancer.
- Atypical proliferation does not exceed 1/3 the epithelial
thickness
- May exhibit HPV cytopathic changes (koilocytic atypia)
- Assoc with low risk HPV ( 6, 11, 42, 44 )
- Raised lesions: Low risk HPV. Flat: high-risk HPV
Fig. 23. Top: Left – CIN I, Right – CIN II. Bottom: CIN III
2. CIN II (High-grade SIL)
- Moderate dysplasia
- Progressive deregulation of cell cycle by HPV
- Increased cellular proliferation and lower rate of viral
replication
- Atypical proliferation exceeds 1/3 but not exceeds 2/3 of
the epithelial thickness
- Toward the prickle and keratinizing cell layer.
- Atypical cells: changes in nucleo-cytoplasmicratio. Varying
nuclear size.
- Associated with aneuploidy and high risk HPV
SECTION B UERMMMC Class 2014
3. CIN III (High-grade SIL)
- Severe dysplasia or Carcinoma-in-situ
- Immature atypical cells, with no surface differentiation.
- Atypical proliferation exceeds 2/3 of the epithelial
thickness or full replacement of the epithelium by atypical
keratinocytes
Diagnosis
- Nuclear atypia
 Nucleae enlargement, hyperchromasia, coarse
granules, variation of nuclear sizes and shapes
- Koilocytic atypia
 Nuclear alteration and perinuclear halo
- LSIL – Atypical immature squamous cells confined to lower
1/3 of epithelium
- HSIL – Atypical immature squamous cells expand to 2/3 of
epithelial thickness
Cervical Carcinoma
Gross: Fungating or exophytic, ulcerating and
infiltrative/endophytic
 2nd most common cancer in women (over half are fatal)
 95 % are squamous cell Ca, 5% adenoCa
 Spread by direct extension to bladder, ureters, rectum,
vagina, peritoneum.
 Distant metastases; ling, liver, bone marrow.
 Local and distal lymphnodes are involved
 Caused by high oncogenic risk HPVs
Squamous Cell Carcinoma of Cervix
 80% of cervical cancer cases
 HSIL is an immediate precursor
 Nests and tongues of malignant squamous epithelium
 3 histologic grades depending on (+) keratin:
1. Invasive Squamous CA, Large Cell, KERATINIZING
- Better grade as it is similar to mature cells
- Well-differentiated
- Look for keratin pearls and dyskeratosis
Fig. 24. Invasive squamous CA, large cell, keratinizing
2. Invasive Squamous Cell CA, Large Cell, NON-
KERATINIZING
- Most common
- Moderately-differentiated
- Best prognosis in terms of response to therapy
Fig. 25. Invasive squamous cell CA, large cell, non-keratinizing
Note:
A general rule: a poorly differentiated carcinoma has a better
response to radiation therapy than that of a well-differentiated
carcinoma
Pathology 7 | 8
 3. Small Cell Squamous Carcinoma REFERENCES
- Morphologically cannot differentiate from 1. Powerpoint Lecture 2012
undifferentiated small cell “neuroendocrine” 2. 2013B Trans
carcinoma, most aggressive, no keratin 3. Recording
- Similar to small cell ca of the lungs 4. Robbins 8th edition
Adenocarcinoma, Cervix
 15% of cervical cancer cases
 Adenocarcinoma in situ is the precursor lesion
 Pap screening is less effective in detecting these cancers
 Tall columnar glandular cells with basally oriented nuclei and
apical cytoplasmic mucin
 Resembles endocervical mucinous glandular epithelium with
atypia, pleomorphism, mitoses, invasion
 Malignant endocervical cells with large, hyperchromatic nuclei
and relatively mucin-depleted cytoplasm resulting in dark
appearance of glands
Adenosquamous Carcinoma, Cervix
- Mixture of malignant squamous and glandular components
(contiguous)
- More aggressive tumor
Clear Cell Adenocarcinoma
- Similar to clear cell carcinoma of the ovary
- Vagina or cervix may be involved
- Adenocarcinoma variant with clear cytoplasm and
“hobnailing” of the nuclei
- Related to maternal DES exposure

Fig. 26. Adenosquamous CA, cervix

Fig. 27. Clear cell adenocarcinoma

SECTION B UERMMMC Class 2014 Pathology 8 | 8