Lower Genital Tract Pathology Vulva,

Vagina, and Cervix

Husni Maqboul, MD
 Vulva
⬧ Vulvitis

⬧ Non-neoplastic epithelial disorders

⬧ Tumors
 Vulvitis
Causative agents
⬧ Contact “eczymatous” dermatitis
⬧ Human papillomavirus: Condyloma
acuminatum, VIN, and Carcinoma.
⬧ Herpes simplex virus: Herpes Genitalis
(painful vesicular/ulcerative lesions).
⬧ Neisseria gonorrhoeae: Gonorrhea (purulent
infection of the vulvovaginal glands)
⬧ Treponema pallidum: Syphilis (chancre and
condyloma lata)
 Vulvar Leukoplakia

⬧ Leukoplakia: A descriptive clinical term;

refers to a white plaque or patch on a
mucosal surface
⬧ Causes of vulvar leukoplakia:
1. Vitiligo (loss of pigment)
2. Inflammatory dermatosis: p.e. psoriasis
3. Squamous intraepithelial neoplasms of the
vulva (VIN) and invasive carcinoma
4. Paget’s disease
Leukoplakia
 Non-neoplastic epithelial
disorders (Vulvar dystrophies)
⬧ Lichen Sclerosus: Thinned epidermis,
hyperkeratosis, dermal fibrosis, and
band-like superficial perivascular
mononuclear cell infiltrate.
– All age groups, mostly postemenopausal
– May lead to labial stiffness and atrophy
and constriction of vaginal orifice
 Non-neoplastic epithelial
disorders (Vulvar dystrophies)
⬧ Lichen Simplex Chronicus : (“Squamous
Hyperplasia”,“Hyperplastic dystrophy”)
– Thickened epidermis and hyperkeratosis.
– Mild mononuclear cell dermal
inflammation.
– No cytologic atypia.
 Vulvar Tumors
Condylomas (anogenital warts)
⬧ Condyloma lata: Flat, moist, minimally
elevated lesion. Rare today, seen in
secondarysyphilis.
⬧ Condyloma acuminatum: elevated or flat.

They occur anywhere in the anogenital surface,

singly or in multiple sites, they range from mm
to cm, pink to brown.
 Condyloma Acuminata
⬧ Epithelial thickening.
⬧ Hyperkeratosis and parakeratosis.
⬧ Complex branching papillary
architecture.
⬧ Koilocyte/koilocytosis: Dark, enlarged,
and wrinkled nuclei with cytoplasmic
perinuclear “vacuolization”
⬧ HPV (6 and 11) *.
Condyloma
 Vulvar Intraepithelial Neoplasia
(VIN)
⬧ Squamous cell dysplasia of the vulva
without stromal invasion.
⬧ Dysplasia: nuclear “atypia”, increased number
of mitosis, and loss of differentiation
(“maturation”).
1. VIN I: mild dysplasia, lower third.- HPV 11,
6, ( codyloma related)
2. VIN II: moderate dysplasia, lower two thirds.
3. VIN III (CIS): Severe dysplasia, full
thickness.
 Vulvar Carcinoma
⬧ Stromal invasion.
⬧ 3% of all female genital cancers, > 60
years of age.
⬧ Increasing Incidence of VIN (40-60 y).
⬧ 90% of malignancies are squamous cell
carcinomas, 10%: adenocarcinomas, basal
cell carcinomas, and melanomas.
 Vulvar Carcinoma
Two “biologic” forms:

1) HPV related (90%):

⬧ Younger age group (40-60y)
⬧ Contain cancer associated HPV types (16,
18).
⬧ Often multicentric, with in-situ components
⬧ 10-30 % coexist with squamous tumor in
cervix or vagina.
⬧ Association with cigarette smoking.
⬧ “Poorly differentiated” (Basaloid)
 Vulvar Carcinoma
2) Non-HPV related
⬧ Older women.
⬧ Usually unicentric.
⬧ Associated with vulvar dystrophies
(squamous cell hyperplasia or lichen
sclerosus).
⬧ Infrequently associated with HPV other carcinogens?.

⬧ “Well differentiated” (keratinized cytoplasm

and keratin pearls).
 Vulvar Carcinoma
⬧ Initially a leukoplakia-type lesion, progresses to
overt exophytic (elevated) or endophytic
(ulcerated) lesion.
⬧ Management and prognosis depend on size of
tumor, depth of invasion, lymphatic
involvement , and presence of metastasis.
⬧ STAGE
⬧ 5 year survival:
Stage I (tumor < 2 cm): 60-80%
Larger tumor with metastasis: 10%
Vulvar Carcinoma - Ulcerated
Vulva Carcinoma - Exophytic
 Vulvar Carcinoma

● FIGO I (T1 NO MO) Tumor confined to the vulva or perineum, <2 cm,
negative LN
● FIGO II (T2 MO NO) Tumor confined to the vulva and/or perineum, > 2cm,
negative LN
● FIGO III (T3 MO NO, T1,2,3 N1 MO)
Tumor of any size with:
adjacent spread to lower urethra or anus (T3) or unilateral lymph node spread
(N1)
● FIGO IV A (T1,2,3 NO MO, T4 any N MO) Tumor invades upper urethra,
bladder mucosa, rectal mucosa, or pelvic bone (T4), or bilateral lymph node
spread (N2)
● FIGO IV B (Any T any N, M1) Any distant metastasis, including pelvic
lymph nodes
 Vulvar Carcinoma
⬧ FIGO I (T1 N0 M0) Tumor confined to the vulva or perineum,
<2 cm, negative LN
⬧ FIGO II (T2 M0 Tumor confined to the vulva and/or
perineum,
N0) > 2cm, negative LN
⬧ FIGO III (T3 M0 N0, T1,2,3 N1 M0) Tumor of any size with:
adjacent spread to lower urethra or anus (T3) or unilateral lymph node
spread (N1)
⬧ FIGO IV A (T1,2,3 N0 M0, T4 any N M0) Tumor invades upper
urethra, bladder mucosa, rectal mucosa, or pelvic bone (T4), or
bilateral lymph node spread (N2)
⬧ FIGO IV B (Any T any N, M1) Any distant metastasis, including
pelvic lymph nodes
 Vulvar Carcinoma
⬧ Surgery: treatment of choice for early
stage lesions
Local excision, radical vulvectomy,
groin/pelvic LN dissection
⬧ Radiotherapy: stage III and IV tumors
⬧ Chemotherapy: Metastatic disease (low
response rate)
 Extramammary Paget’s Disease
⬧ Intraepithelial (adeno)carcinoma
⬧ Vulvar and perianal area.
⬧ Large pleomorphic cells lying singly or in
small clusters in epidermis.
⬧ Cytoplasmic mucopolysacharides: periodic
acid-Schiff (PAS) and mucin positivity, (S-100
:negative)*.
⬧ Solitary or multiple.
⬧ If confined to epithelium: may persists for
years without invasion*.
Paget’s Disease
 Vulvar Melanoma
⬧ Malignant Melanoma
⬧ 5-10% of all vulvar malignancies
⬧ 50-60 years of age
⬧ Capable of metastasis. 5 year survival: 32%
⬧ Proliferation of Malignant Melanocytes
⬧ Differential Diagnosis: Paget’s disease
⬧ S-100(+), mucicarmin(-), PAS(-)
⬧ Prognosis depends on depth of invasion
Melanoma
 Pathology of the Vagina
It is seldom the site of primary disease. It is
more often secondarily involved in the
spread of cancer or infections from vulva,
cervix, bladder , rectum.
⬧ Vaginitis
⬧ Vaginal intraepithelial neoplasia (VAIN)
and Squamous cell carcinoma.
⬧ Sarcoma Botryoides
 Vaginitis
⬧ Usually transient.
⬧ Leukorrhea*
⬧ Diabetes mellitus, systemic antibiotic therapy,
post abortion or pregnancy,, elderly patients,
immunocompromised patients (p.e. AIDS)
⬧ Gonorrhea, Candida Albicans, and
Trichomona vaginalis
⬧ Nonspecific atrophic vaginits*
 Vaginal Intraepithelial Neoplasia(VAIN) and
Carcinoma
● Uncommon, VAIN are graded I, Il, and III (~VIN)
● Elderly females (>60 y) ! HPV infection
● Preexisting or concurrent cervical or vulvar neoplasia or carcinoma
is sometimes present.
● Mostly Squamous cell carcinoma
Clear Cell adenocarcinoma
● Intrauterine exposure to diethylstilbestrol: Vaginal adenosis and
Vaginal clear cell adenocarcinoma
 Vaginal Intraepithelial Neoplasia
(VAIN) and Carcinoma
⬧ Uncommon, VAIN are graded I, II, and III (~VIN)
⬧ Elderly females (>60 y)
⬧ Preexisting or concurrent cervical or vulvar
neoplasia or carcinoma is sometimes present.
⬧ Intrauterine exposure to diethylstilbestrol: Vaginal
adenosis and Vaginal clear cell adenocarcinoma
 Sarcoma Botryoides

⬧ Embryonal rhabdomyosarcoma.
⬧ Infants and children under 5 years of age.
⬧ Anterior wall of vagina.
⬧ Rapid growing polypoid grape-like mass.
⬧ “Small blue round” cells that tend to cluster
beneath the mucosal surface.
⬧ “Strap cells”
 Uterine Cervix

⬧ Cervicitis

⬧ Tumors
 Cervicitis
⬧ “Erosions” and development of the transformation
zone (T zone). Nabothian cysts.
⬧ Infectious and non-infectious cervicitis
⬧ Vaginal flora, Chlamydia trachomatis,
Ureaplasma urealyticum, Trichomonas
vaginalis, Candida species, Neisseria
gonorrhoeae, Herpes simplex II, and HPV.
 Cervicitis
⬧ Acute nonspecific: postpartum,
Staphylococci/Streptococci
⬧ Nonspecific (chronic) cervicitis
⬧ Gross: reddening, swelling, and granularity
around margins of external cervical os.
⬧ Microscopy: Hyperplasia and reactive atypia of
epithelium, no dysplasia, glycogen depletion
(false positive Schiller test). Mononuclear cell
infiltrate, nabothian cysts. Viral inclusions
(HSV). Plasma cells in C. trachomatis.
Schilling test
 Cervicitis
⬧ Leukorrhea
⬧ Culture interpretation*.
⬧ If severe >>>differentiation from
carcinoma: colposcopy and biopsy.
⬧ Subsoil for carcinogenesis?
⬧ May lead to sterility (fibrosis/
unfavorable medium for sperm).
 Endocervical polyp
⬧ Inflammatory polypoid masses, cm.
⬧ Smooth surface composed of columnar
mucus-secreting cells (endocervical
epithelium) with underlying cystically
dilated glands filled with mucus. Stromal
edema inflammatory mononuclear cells.
⬧ Squamous metaplasia and ulceration.
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma
⬧ Cervical cancer was the most frequent
form of cancer around the world.
⬧ Impact of Papanicolaou screening:
Decrease incidence of invasive tumors and
increase incidence in the detection of
precursors (dysplasias/CINs) lesions.
⬧ Do all dysplasias (precursors lesions)
progress to invasive cancer?
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma
⬧ Importance of early detection, adequate
follow up and management.
⬧ Histologic grading of precursor
lesions:
1. CIN I: Mild dysplasia
2. CIN II: Moderate dysplasia
3. CIN III : Severe dysplasia/carcinoma in
situ
 Cervical Intraepithelial Neoplasia (CIN) and
Carcinoma
SIL - squamous intraepithelial lesion :
1) LOW GRADE SQUAMOUS
INTRAEPITHELIAL LESIONS - productive infection
[CIN I and Condylomas (koilocytosis)]
Not considered precancerous
Most HPV infection cleared by the age 20
 Cervical Intraepithelial Neoplasia (CIN) and
Carcinoma
SIL - squamous intraepithelial lesion :
2) HIGH GRADE SQUAMOUS
INTRAEPITHELIAL LESIONS
[CIN I, CIN I/CISI]
Increased proliferation, arrested maturation and decreased viral
replication
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma
Cytologic grading of precursor
lesions
1) LOW GRADE SQUAMOUS
INTRAEPITHELIAL LESIONS
[CIN I and Condylomas (koilocytosis)]
2) HIGH GRADE SQUAMOUS
INTRAEPITHELIAL LESIONS
[CIN II, CIN III/CIS]
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma
Natural History
⬧ Different studies = different populations
= different results
⬧ CIN I: 50 to 60% regress, persists 30%,
and progress to CIN III 20%. 1 to 5%
become invasive.
⬧ CIN III: 33% regress, progression varies
from 6 to 74%.
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma
⬧ Peak incidence
1. CIN : 30 Y
2. Invasive carcinoma: 45 y
⬧ Risk factors
1. Early age at first intercourse
2. Multiple sexual partners
3. A male partner with multiple previous sexual
partners
4. Persistent infection by high risk HPV
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma
⬧ Higher incidence in lower
socioeconomic groups
⬧ Rarity among virgins
⬧ Multiple pregnancies

⬧ >>>>>>>>>>>>>>>STD
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma
⬧ HPV: 85-90% of lesions
⬧ Serotypes:
1. High risk: 16, 18, 31, and 33.
2. Low risk (associated with condylomas):
6, 11, 42, and 44.
⬧ Integration of viral genes into host
genome>>transcription>>translation of
specific proteins that inactivate TP53 and
retinoblastoma tumor suppressor genes.
 Cervical Intraepithelial Neoplasia (CIN) and
Carcinoma
● Integration of viral genes into host genome >> transcription
>> translation of specific proteins E6 and E7 that inactivate
TP53 and retinoblastoma tumor suppressor genes respectively
● Allows continuous replication of the virus
● Other mutations such as LKB1 in 20%
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma

⬧ Viral infection does not mean that a

women will develop cancer.
⬧ 10-15% HPV: negative
⬧ Other carcinogens, genetic factors,
host immunity, cigarette smoking.
Cervical Intraepithelial Neoplasia
(CIN) and Carcinoma
⬧ T zone
⬧ High grade dysplasia/HPV 16 and 18
⬧ Viral isolation and typing do not predict
the course.
⬧ Follow up: cytology, colposcopy (acetic
acid test), biopsy*.
Invasive Carcinoma
Invasive Carcinoma of the Cervix
⬧ 80-95%: Squamous cell carcinomas
⬧ Multifactorial disease
⬧ Preventable
⬧ Gross (macroscopic appearance)
Fungating (exophytic) Ulcerative
(endophytic)
Infiltrative
 Invasive Carcinoma of the Cervix
“Route of invasion”:
1. Underlying stroma
2. Obliteration of os
3. Endocervical canal
4. Lower uterine segment
5. Wall of fundus
6. Broad ligament
7. Rectum or bladder
8. Ureters
9. Lymph nodes
10. Lungs, bones, liver
Invasive Carcinoma of the Cervix
⬧ Squamous cell carcinoma
Well to poorly differentiated
⬧ Adenocarcinomas
⬧ Adenosquamous carcinomas
⬧ Staging
Invasive Carcinoma of the Cervix
⬧ CIS: Asymptomatic, Leukorrhea
⬧ Carcinoma: Vaginal bleeding, leukorrhea,
painful coitus, and dysurea
⬧ DX: Colposcopy: acetic acid test, Bx
⬧ Mortality: Related to local extension*:
ureter obstruction or invasion of bladder or
rectum.
Invasive Carcinoma of the Cervix
⬧ Importance of early diagnosis
⬧ Time….?
⬧ 5-year survival rate:
1. Stage 0 (CIS): 100%
2. Stage I: 85% to 90%
3. Stage II: 70 to 75%
4. Stage III: 35%
5. Stage IV: 10%
Invasive Carcinoma of the Cervix
⬧ Stage 0: Carcinoma in situ
⬧ Stage I: Tumor confined to the cervix
⬧ Stage II: Tumor extends beyond the cervix
but not onto the pelvic side wall
⬧ Stage III: Tumor extends to the pelvic side
wall or to the lower one third of vagina, or
causes hydronephrosis, or a nonfunctioning
kidney
⬧ Stage IV: Tumor extends beyond true pelvis, or
biopsy-proved involvement of bladder or rectal
mucosa.
Invasive Carcinoma of the Cervix
Management
⬧ LEEP
⬧ Conization
⬧ Hysterectomy
⬧ Pelvic exenteration
⬧ Radiotherapy
exenteration
exenteration
Body of Uterus
Pathology
 Body of the Uterus
⬧ Endometritis
⬧ Adenomyosis
⬧ Endometriosis
⬧ Dysfunctional uterine bleeding
⬧ Endometrial hyperplasia
⬧ Endometrial polyps
⬧ Leiomyomas and leiomyosarcomas
⬧ Endometrial carcinomas
 Endometritis
⬧ Clinical settings:
1. Chronic gonorrheal pelvic disease
2. Tuberculosis
3. Retained Product of conception
4. IUD
5. Spontaneously
⬧ Histology: Irregular disposition and
proliferation of endometrial glands, plasma
cells and lymphocytes in the stroma
 Adenomyosis
⬧ Growth of the basal layer of endometrium
(glands and stroma) down into the
myometrium between the muscle bundles
⬧ Thick myometrium: reactive hypertrophy
⬧ Nonfunctional: no bleeding*
⬧ Menorrhagia, dysmenorrhea, and
premenstrual pain
 Endometriosis
⬧ Infertility, dysmenorrhea, pelvic pain.
⬧ Foci of endometrial tissue in pelvis
(ovaries, pouch of Douglas, uterine
ligaments, tubes, rectovaginal septum).
⬧ Sometimes in umbilicus, LNs, lungs,
skin, heart, bone.
⬧ Theories of genesis: Regurgitation,
metaplastic, and lymphovascular
 Endometriosis
⬧ Theories of genesis:
1. Regurgitation: menstrual backflow
through fallopian tubes and
subsequent implantation
2. Metaplastic: metaplasia of coelomic
epithelium
3. Lymphovascular dissemination
 Endometriosis
⬧ Functional endometrium: cyclic bleeding

⬧ Complications:Fibrosis,adhesions: pain,
sterility

⬧ Gross: red-blue to yellow-brown nodules,

chocolate cysts in ovaries

⬧ Microscopy: Endometrial glands, stroma, and

hemosiderin deposition
 Dysfunctional Uterine Bleeding

⬧ Abnormal bleeding with no organic

lesion
⬧ Etiology of uterine bleeding varies with
age: prepuber,adolescence, reproductive
age, perimenopause, and postmenopause.
 Dysfunctional Uterine Bleeding
⬧ Three functional groups (E/P)
1. Anovulatory cycles

2. Inadequate luteal phase

3. Contraceptive induced bleeding

4. ? Endometrial disorders
 Anovulatory Cycles
⬧ Common at both ends of reproductive life
⬧ Hypothalamic-pituitary axis, thyroid, or
adrenal dysfunction
⬧ Functioning ovarian producing lesion,
malnutrition, obesity, stress, debilitating
disease
⬧ Persistence of proliferative “growth” until
endometrium collapse, spiral arteries
rupture, and bleeding occurs.
 Inadequate Luteal Phase
⬧ Corpus luteum fail to mature normally or
regress prematurely: less progesterone is
produced: delay and inadequate secretory
phase
Contraceptive Induced Bleeding
⬧ Imbalance in the ratio Estrogen/Progesterone
 Endometrial Hyperplasia
⬧ Estrogen>>>>Progesterone: Polycystic
ovaries(Stein-Leventhal syndrome), cortical stromal
hyperplasia, granulosa-theca ovarian tumors
⬧ Simple Hyperplasia
⬧ Complex Hyperplasia without atypia
⬧ Complex Hyperplasia with atypia: 20/25% risk of
carcinoma
⬧ Continuum of changes based on duration and level of
estrogen excess
⬧ Causes irregular uterine bleeding
⬧ Biopsy and follow up
Endometrial Hyperplasia
 Endometrial Polyps
⬧ Uterine bleeding
⬧ Gross: Sessile(rarely pedunculated) rounded
lesions: 0.5 to 3 cm
⬧ Microscopy: Surface lined by columnar
epithelium, stroma (monoclonal stromal cells
with rearrangement of 6p21) with thick-walled
vessels, and endometrial glands some of which
appear cystically dilated.
⬧ Occur at any age, but common around
menopause
Endometrial Polyp
 Leiomyoma
⬧ Benign smooth muscle tumor
⬧ “Fibroids”, “Myomas”
⬧ 30 to 50% of women during reproductive life.
⬧ More frequent in African American than in
whites.
⬧ Estrogen stimulates their growth
⬧ Involutes after menopause
⬧ Monoclonal, 40% have nonrandom
chromosomal abnormalities
 Leiomyoma

⬧ Gross: Well circumscribed, firm, gray, white mass.

Whorled cut surface.
Singly or multiple. Few cm to large masses.
Intramucosal, intramural, and/or subserosal location.
Parasitic leiomyomas
⬧ Microscopy: Interlacing bundles of smooth muscle cells.
Foci of ischemic necrosis, fibrosis, cyst degeneration,
hemorrhage, and calcification are not uncommon.
Leiomyoma
Leiomyoma
 Leiomyoma
⬧ Asymptomatic
⬧ If Symptoms: Bleeding (menorrhagia) or
“mass effect”
⬧ Progression to sarcomas?
 Leiomyosarcoma
⬧ Usually solitary tumors
⬧ Derived from mesenchymal myometrial
cells
⬧ Gross:
1. Bulky masses infiltrating uterine wall
2. Polypoid lesions projecting into uterine
cavity
3. Discrete tumors(~ leiomyomas)
Leiomyosarcoma
 Leiomyosarcoma
⬧ Microscopy: Increased cellularity,
mitosis, nuclear atypia, and necrosis.
⬧ Recurrence and metastasis are not
uncommon
⬧ 5 year survival rate: 40%
Leiomyosarcoma
 Endometrial Carcinoma
⬧ Most frequent cancer of the female genital
tract in USA
⬧ 55 to 65 y (uncommon <40y)
⬧ Risk factors:
1. Obesity: synthesis of estrogen in fat
deposits
2. Diabetes
3. Hypertension
4. Infertility: anovulatory cycles
 Endometrial Carcinoma
⬧ Hyperestrinism : HRT, estrogen
secretingovarian tumors, etc.
⬧ Background of endometrial hyperplasia
⬧ 20%: no Hyperestrinism and no
hyperplasia: older patients, poor
prognosis
 Endometrial Carcinoma
⬧ Gross:
⬧ Diffuse thickening of uterine wall:
Infiltrative
⬧ Exophytic form
⬧ Filling of the endometrial cavity with a
firm to soft partially necrotic tumor.
⬧ Myometrium invasion/ serosa/ LN
 Endometrial Carcinoma
⬧ Adenocarcinomas (Adenocarcinomas
with squamous metaplasia,
Adenoacanthoma, Adenosquamous
carcinoma)

⬧ Endometrioid
⬧ Papillary serous carcinoma
⬧ Clear cell adenocarcinoma
 Endometrial Carcinoma

● Endometrioid 80%
- Association with estrogen excess in the setting of
endometrial hyperplasia in perimenopausal
- 70% PTEN and mismatch gene mutation
- Germline Cowden and Lynch mutations
 Endometrial Carcinoma

● Serous carcinoma 15%

- In endometrial atrophy in older postmenopausal
women.
- Less common but more aggressive
- More prominent cytologic atypia
- TP53 mutations
- Precursor lesion : serous endometrial intraepithelial
carcinoma (SEIC) that is positive for TP53 mutation
 Endometrial Carcinoma
⬧ Grade: Degree of cytologic
differentiation. GH1, G2, and G3
⬧ Stage: Spread of the tumor
1. I: Confined to corpus
2. II: Extension to cervix
3. III: Extension outside the uterus , but
still confined to pelvis
4. IV: Extension outside the pelvis
 Endometrial Carcinoma
⬧ Leukorrhea and irregular bleeding in a
postmenopausal patient
⬧ Enlargement of uterus and fixation to
surrounding structures
⬧ Late metastasizing neoplasm to LN and
other organs
⬧ 5-year survival rate:
1. Stage I: 90%
2. Stage II: 30 to 0%
3. Stage III and IV: less than 20%