Pathology of the female genital tract

Female genital tract
vulva, vagina, cervix, corpus uteri
and ovary
Zoltán Sápi MD, PhD
1st Department of Pathology and Experimental Cancer Research
Infections
Candida
Causes vulvovaginitis; 10% of women are carriers
Risk factors: diabetes, oral contraceptives,
Clinical: small white surface patches with
leukorrhea and itching
Pseudohyphae formed by elongated budding yeast
Herpes simplex virus
Sexually transmitted disease characterized
by labial ulcers with punched out centers
Can be extremely painful
Papules in vulva, progress to vesicles,
later coalescent than ulcers
Also affects vagina and cervix
Usually HSV2 in young women
1/3 are symptomatic (lesions 3-7 days after sex);
lesions heal in 1-3 weeks,
but virus is latent in regional nerve ganglia
2/3 suffer recurrences (less painful)
Neisseria gonorrhea
Affects entire gynecologic tract in adults except vagina; only children get vaginitis
Causes infertility
Begins in Bartholin’s glands or other vestibular or periurethral glands,
then spreads to cervix, tubes, ovaries
Micro: acute suppurative reaction
Trichomonas vaginalis
Large, flagellated, ovoid protozoan
Purulent discharge, local discomfort, "strawberry" cervix (fiery red with thin epidermis)
Infection limited to epithelium and lamina propria
Treated with metronidazole
Tumors
Bartholin’s cyst
Often secondary to gonorrhea or other acute inflammation which causes abscess
then obstruction of duct
Painful; may be huge; seen in all ages, but often women age 40 or more
May be associated with accessory breast tissue
May have mucocele-like changes,
Treatment: excise in older women because of risk of adenoid cystic carcinoma;
otherwise marsupialize
Micro: squamous and urothelial epithelium common, but may be destroyed by
inflammatory infiltrate
Marsupialization is a relatively straightforward procedure that can be performed
in about 15 minutes, using local anesthesia. After sterile preparation of the cyst and
surrounding area, a scalpel is used to make a vertical elliptic incision just inside or
outside the hymenal ring.
Angiomyofibroblastoma
Benign vulvar tumor, resemble Bartholin’s gland cyst
Gross: well circumscribed, 0.5 to 12.0 cm
Micro: circumscribed tumor with alternating hypercellular and hypocellular areas,
spindle cells and plump stroma cells with eosinophilic cytoplasm that aggregate
around small blood vessels; no atypia; rare/no mitotic figures;
Positive stains: vimentin, desmin
Desmin
Condyloma acuminatum
Sexual transmitted disease, lesions may be multiple and coalesce
Vulvar, vaginal, perianal, perineal
Human papillomavirus (HPV)
Different from condyloma latum of syphilis
Flat condyloma more common than condyloma accuminatum
Regress, except in immunocompromised
Treatment: CO2 laser, podophyllin application
Micro: complex papillary arrangement of well differentiated squamous cells with
intact basement membranes
Typical papilliferous warts affecting
the vulva, vagina and cervix
Squamous cell carcinoma
95% of vulvar carcinomas
Mean age 60-74, rare in women younger than 30 years
Risk factors: large number of sexual partners, cigarette smoking, immunodeficiency
Two types: HPV related (younger women, often basaloid or warty histology)
and non-HPV related
Usually on labia majora, also labia minora, clitoris
20% metastasize to regional inguinal nodes
Treatment: wide local excision with 1 cm margins if small
or radical vulvectomy with bilateral lymph node dissection
Prognosis: 5 year survival 50-75%; based on lymph node status
Gross specimen, radical vulvectomy with 4 tumors
Cervix-normal histology
Squamocolumnar junction: where squamous and glandular epithelium meets;
usually in exocervix; nearby reserve cells are involved in squamous metaplasia,
dysplasia and carcinoma
Micro anatomy of the uterine cervix: 1= Nulliparous, 2= Multiparous
(A: external os, pink area = non keratinized squamous epithelium,
purple area = glandular epithelium composed of
one layer of mucin secreting and ciliated cells).
Endocervical polyp
2-5% of adult women
Usually multigravida age 30-59 years
Produces bleeding or mucoid discharge
Probably secondary to chronic inflammation and not neoplastic
Gross: usually single, up to 1 cm; rarely mimics malignant tumor
Endocervical polyp covered by a single
layer of mucinous epithelium.
Premalignant / preinvasive lesions of cervix
Human papilloma virus (HPV) of cervix
Causes spectrum of changes ranging from condyloma accuminatum
to invasive squamous cell carcinoma
Family of 100+ viral types; nonenveloped viruses, 55 nm in diameter
Transmitted sexually; has predilection for metaplastic squamous epithelium
Koilocytosis / koilocytotic atypia: related to expression of viral E4 protein and
this causes disruption in cytoplasmic keratin matrix
Koilocyte is superficial or immature squamous cell with sharply outlined perinuclear
vacuoles, dense and irregular staining peripheral cytoplasm, enlarged nucleus with
undulating nuclear membrane and rope-like chromatin; often bi- or multinucleation and variation in nuclear size
Low risk HPV subtypes (associated with genital condyloma and low grade SIL): 6, 11, 40,
High risk HPV subtypes (associated with high grade SIL and invasive carcinoma): 16, 18, 31, 33
HPV 18: associated with lesions of glandular origin and small cell neuroendocrine carcinoma
recommended endocervical curettage
Squamous cells with a perinuclear empty cavity
surrounded by cytoplasmic thickening and with moderate
nuclear enlargement: typical koilocytes.
Bethesda System 2001 for Cervicovaginal Cytology reporting
Specimen adequacy
Assessment of specimen adequacy (satisfactory and unsatisfactory):
1 - Adequate number of squamous cells
2 - The presence or absence of endocervical cells should be reported;
3 - Specimen with more than 75% of cells obscured by inflammation and bacteria is unsatisfactory.
Interpretation/result
Negative for Intraepithelial Lesion or Malignancy (NILM)
Organisms
• Trichomonas vaginalis
• Fungal organisms morphologically consistent with Candida species
• Shift in flora suggestive of bacterial vaginosis
• Bacteria morphologically consistent with Actinomyces species
• Cellular changes associated with Herpes simplex virus
Other non-neoplastic findings (optional to report, list is not inclusive)
• Reactive cellular changes associated with:
- inflammation (includes typical repair)
- irradiation
- Intrauterine contraceptive device (IUD)
• Glandular cells status post hysterectomy
• Atrophy
Epithelial Cell Abnormalities
SQUAMOUS CELL
• Atypical squamous cells
- of undetermined significance (ASC-US)
• Low grade squamous intraepithelial lesion (LSIL)
- encompassing HPV/mild dysplasia/CIN I
• High grade squamous intraepithelial lesion (HSIL)
- encompassing: moderate and severe dysplasia/CIN2/CIN3/CIS
• Squamous cell carcinoma
GLANDULAR CELL
• Atypical
- endocervical cells (NOS or specify in comment)
- endometrial cells (NOS or specify in comment)
- glandular atypical cells of undetermined significance (AGUS)
• Atypical
- endocervical cells, favor neoplastic
- glandular cells, favor neoplastic
• Endocervical Adenocarcinoma in situ
• Adenocarcinoma
- endocervical
- endometrial
- extrauterine
- not otherwise specified (NOS)
Squamous intraepithelial lesions (SIL), of cervix - general (CIN)
Invasive carcinoma is usually preceded by SIL, which may exist for 20 years before tumor
becomes invasive
Often occurs in teenagers and young women (mean age 26 years in one study)
Low grade SIL (LSIL): usually euploid or polypoid, 2/3 regress, 1/6 are unchanged, 1/6 progress
High grade SIL (HSIL): usually aneuploid, less regression; 1/3 become invasive at 9 years
Treatment for LSIL: controversial since most lesions regress
Treatment for HSIL: conization, cryosurgery, laser; long term followup is necessary
CIN 1 with mild koilocytosis, disorganization of the lower third
CIN 2-3: organization is disturbed in the lower two-thirds
and the cells display a high degree of nuclear and cellular
of the epithelium and koilocytes in the upper third.
abnormalities with typical and atypical mitoses.
HPV vaccination
Gardasil: HPV 6, 11 and 16,18, not containing all HPV! ~70% immunity
Cervarix: HPV 16, 18
•15 – 25 years, ideal for vaccination
• Around 12 year; it is questionable (no experience)
•First have to test the HPV; if HPV infected there is no effect
•Side effects?
Squamous cell carcinoma of cervix
4,500 deaths/year in US, #8 cause of cancer death in women in US (was #1 in 1940's);
still #1 in other countries
Reduction due to Papanicolaou smear test to detect premalignant lesions
(1 million cases of SIL detected per year in US, 13,000 new invasive carcinomas,)
Mean age 51 years, uncommon before age 30 years but most are ages 45-55 years
Risk factors: early age at first intercourse, multiple sexual partners,
male partner with multiple prior sexual partners, history of HSIL, cigarette smoking,
high risk HPV types for cervical carcinoma: 16, 18, 31, 33
Prognostic factors: clinical stage, nodal status, size of largest node and number of
involved nodes, tumor size, depth of invasion, endometrial extension, parametrial involvement
Treatment: surgery, radiation therapy, radioactive implants (for early lesions), pelvic extenteration
Gross appearance of a cervical squamous cell
carcinoma that is still limited to the cervix (stage I).
Adenocarcinoma of cervix
5-15% of invasive cervical carcinomas
Incidence increasing in US, now up to 25% of cervical cancers, due to decreasing rates
of squamous cell carcinoma and difficulty in diagnosis using current screening methods
Usually associated with in-situ adenocarcinoma
Suspected but still unproven association with oral contraceptives
30-50% false negative reports by cytology
Often vaginal bleeding, pelvic pain
Spreads first to pelvic structures, then pelvic lymph nodes; metastases to ovaries,
upper abdomen, distant organs
Survival by stage: I-79%, II-37%, III/IV-less than 9%
Gross: exophytic mass, ulcerated plaque or barrel-shaped cervix (diffuse enlargement)
Micro: often well differentiated; may also be poorly differentiated, papillary, endometrioid
Endometrium
Endometritis
Ascendent
Acut, chronic (plasma cells)
IUD (chronic)
Chlamidia, Mycoplasma, Neiserria
Infertility
Arias-Stella reaction
Extrauterine pregnancy
Gestational trophoblastic disease
Hormonal therapy (nonpregnant patient)
Adenomyosis
Endometrial glands and stroma within the myometrium not connected to normal endometrium.
Metrorrhagia, dysmenorrhoea, pain (menstruation)
Endometriosis
Surface of the uterus and outside of uterus (ovary, peritoneum, lymph node, lung, bone)
Regurgitation, metaplastic (coelomic epithelia) theory and/or vascular dissemination
Endometrial gland, endometrial stroma (CD10), hemosiderin (not metastasis!)
A lot of different symptoms connected to menstruation cycle
Endometrial curettage
Curettage is method of choice for sampling localized lesions and to evaluate
infertile or dysmenorrheic patients
Fractional curettage: separate sampling from endometrial and endocervical cavities
during same procedure; do endocervix first to minimize contamination
Helpful clinical information: patient’s age, date and characteristics of last and current
menstrual period, use of hormones/steroids
Dysfunctional uterine bleeding (DUB)
A clinical term, not a pathologist term.
Known causes: endometriosis, submucous myoma, endometrial polyp (5-15%),
cancer (5-15% of postmenopausal bleeding), anovulatory cycle, chronic
inflammation, ectopic pregnancy, endometrial hyperplasia
Endometrial hyperplasia
Proliferation of glands of irregular size and shape
with an increase in the gland to stroma ratio
compared with proliferative endometrium
Usually in perimenopausal women, usual
predecessor to endometrial carcinoma
Risk of developing carcinoma is greater with
complex or atypical changes
Simple hyperplasia, complex hyperplasia,
atypical hyperplasia
Endometrial polyp
pedunculated or sessile
thick-walled vessels + glands + stroma
Stromal cells: rearrangement of 6p21 chromosomal region
Bleeding, increased risk for carcinoma if atypical
Endometrial carcinoma
Most common gynecologic malignancy in US; incidence is increasing
Usually (80%) arises in postmenopausal women with symptoms of bleeding
Associated with obesity, diabetes, hypertension, infertility, failure of ovulation,
dysfunctional uterine bleeding, prolonged estrogen use, tamoxifen therapy.
Major types of endometrial carcioma are:
endometrioid: increased estrogen level; PTEN, KRAS, b. katenin, DNA mismatch repair
serous: P53 mutation
Spread/metastases: cervix (direct extension), ovary, vagina and lung, liver, bone,
nodal metastases to pelvic and para-aortic nodes.
Treatment: Total abdominal hysterectomy with bilateral salpingo-oophorectomy
Survival: 5 year survival by stage: 1 - 95%, 2 - 85%, 3-65%, 4-20%
Gross: lush, polypoid endometrium with yellow necrotic areas
Leiomyoma
Present in 25% of women during reproductive years
More common in blacks than whites; usually multiple in blacks
In 77% at autopsy; 84% of tumors are multicentric
Clinically apparent lesions are more common in nulliparous, postmenopausal women
May interfere with pregnancy or block ureters if large
Estrogen responsive; may regress after menopause or castration, enlarge during pregnancy
Treatment: myomectomy, leuprolide acetate depot that shrinks the tumor
Gross: sharply circumscribed, round, firm, gray-white, whorled cut surface; often shells out
Micro: whorled (fascicular) pattern of smooth muscle bundles separated by well
vascularized connective tissue, usually less than 5 mitotic figures per 10 high power fields,
no significant atypia.
Leiomyosarcoma
Rare, probably not derived from leiomyomas
Peaks at ages 40-69 years, mean 54 years
If spread beyond uterus, few survive long term
Tend to recur, 50% metastasize to lung, bone, brain, other; lymph node involvement unusual
5 year survival 40%; anaplastic only 10%; minimal survival if extend beyond uterus;
Gross: bulky, fleshy tumor invading into myometrial wall or polypoid tumor projecting
into lumen, hemorrhagic or necrotic; grossly appear invasive
Micro: hypercellular tumors composed of spindle cells resembling smooth muscle
cells with moderate to severe pleomorphism, 10+ mitotic figures per 10 high power fields and/or
necrosis!
The irregular nature of this mass suggests
that is not just an ordinary leiomyoma.
Polycystic ovary disease (PCO)
Multiple cystic follicles, covered by a dense fibrous capsule
Associated with endometrial hyperplasia, well differentiated adenocarcinoma
If idiopathic, have “masculine” response to LHRH agonist nafarelin, suggesting
abnormal regulation of ovarian enzymes; known causes are congenital adrenal
hyperplasia, ovarian neoplasms, primary hyperthyroidism
Treatment: cortisol, clomiphene citrate; formerly did wedge resections
Stein-Leventhal syndrome: polycystic ovaries and oligomenorrhea / sterility;
persistent anovulation, obesity (40%), hirsutism (50%), rarely virilism
Gross: large ovaries (2x normal), numerous subcortical cysts
Micro: hyperplastic theca interna, few corpora lutea or corpora albicantia
Ovarian Tumors - general
#5 cause of cancer death in women; incidence has not changed recently
80% benign (usually ages 20-45)
90% of malignancies are carcinoma, 80% have spread beyond the ovary at diagnosis
Risk factors for carcinoma: nulliparity, family history, childhood gonadal dysgenesis,
Negative risk factors: pregnancy before age 25
Classification:
surface epithelial (65%),
germ cell (15%),
sex cord-stroma (10%),
metastases (5%)
Benign, borderline or malignant; malignant may be invasive or non-invasive
Most malignant tumors are surface epithelial (90%)
Bilateral carcinomas: serous (65%), metastatic (>50%), endometrioid (40%),
mucinous (20%)
Symptoms: lower abdominal pain, abdominal enlargement,
increased pressure on adjacent organs
CA-125: a high molecular weight glycoprotein present in 80% of serous and
endometrioid carcinomas
Metastases from primary ovarian tumors
Contralateral ovary, peritoneal surfaces,
para-aortic/pelvic nodes, liver, lung, pleura, omentum, diaphragm
umbilical metastasis, may be first manifestation of disease
Metastases are associated with ascites, intestinal obstruction, ureteral involvement
and hydronephrosis
Coexistence with uterine carcinoma: uncommon; may reflect metastases from uterus
or ovary
Treatment: must examine peritoneal cavity for proper staging
Benign, borderline tumors: unilateral salpingo-oophorectomy
Malignant tumors: bilateral salpingo-oophorectomy with total abdominal hysterectomy
Prognosis: 5 year survival: 35%
Poor prognosis: high stage, high tumor grade, mixed endometrioid worse than
pure endometrioid, serous tumors without psammoma bodies worse than
with psammoma bodies; aneuploid tumors worse than diploid, epithelial worse
than sex cord stromal
Serous tumors
25% of all ovarian tumors
60% benign, 15% borderline, 25% malignant
Serous cystadenoma
Benign; 25% bilateral
Gross: smooth glistening cyst wall; papillary tumors have papillary projections on
outer surface or protruding into cystic cavity
Micro: usually small, multilocular, simple papillary processes
Serous borderline tumors (serous - low malignant potential)
Younger women, often pregnant, rarely have malignant behavior
Bilateral in 1/3 if include microscopic tumors
5 year survival of 100% if confined to ovary; 90% if involves peritoneum
Serous borderline and invasive carcinomas have different
genetic aberrations!
borderline
benign serous cystadenoma with
multiloculation, the inner surface is smooth,
with only a solitary papillation
many papillations on the inner surface
Serous cystadenocarcinoma / carcinoma
5 year survival of 70% if confined to ovary; drops to 25% if involves peritoneum
65% bilateral
Gross: solid, hemorrhagic, necrotic
Micro: nuclear atypia and stratification, glandular complexity, branching papillary fronds,
frequent mitoses, stromal invasion
Psammoma bodies: calcium concretions with concentric laminations (better prognosis)
Molecular: frequent loss of heterozygosity of p53 and BRCA1 loci
Bilateral ovarian serous carcinoma
solid serous carcinoma
cystadenocarcinoma
Mucinous tumors
15% of ovarian neoplasms, rare before puberty or after menopause
80% are benign, 10% are borderline and 10% are carcinomas
Compared to serous neoplasms, have more cysts, larger size (up to 25kg), more often
unilateral, filled with sticky, gelatinous fluid rich in glycoproteins
Mucinous cystadenoma
Micro: tall, columnar, nonciliated cells, basal nuclei, abundant intracellular mucin
Usually endocervical type; also intestinal type
Mucinous borderline tumors
Micro: resemble villous or tubular adenomas of intestines; endocrine cells common;
are noninvasive with intraglandular or intracystic epithelial proliferations
Mucinous cystadenocarcinoma / carcinoma
77% are ovarian metastases, 23% are ovarian primaries,
Features favoring primary ovarian carcinoma vs. metastasis are: unilateral,
"expansile" pattern of invasion, complex papillary pattern, size > 10 cm, smooth
external surface, microscopic cystic glands, accompanying teratoma, endometriosis
Definition: stromal invasion distinguishes these tumors from borderline tumors
Survival: 95% for stage 1 vs. 32% for stages 2+
Distant metastases are rare
Gross: primary tumors are usually unilateral, > 10 cm, smooth capsule, cystic and
solid areas of tumor evenly distributed throughout ovary without discrete nodularity
Micro: stromal invasion; also more solid growth, atypia, stratification
Sex cord-stromal tumors - general
5% of ovarian neoplasms, 7% of malignant ovarian neoplasms
Derived from ovarian stroma, itself derived from sex cords of embryonic gonad
Positive stains: mullerian inhibiting substance, alpha-inhibin (>95%)
Granulosa cell tumor - adult
Differentiation towards follicular granulosa cells
Usually women age 15+ years; 75% associated with hyperestrogenism,
causes precocious puberty in children, metrorrhagia,
endometrial hyperplasia / carcinoma (usually well differentiated and superficial),
breast fibrocystic changes in adults
10 year survival >90%; tends to recur locally, up to 20 years later
5-25% risk of malignancy, cannot predict from histology
Micro: small, bland, cuboidal to polygonal cells in various patterns,
including Call-Exner bodies
Partly cystic and partly solid yellowish
tumor with an area of hemorrhage
many Call-Exner bodies
Germ cell tumors - general
20% of ovarian tumors; resemble germ cell tumors in testis
Usually children and young adults
Usually benign cystic teratomas
but choriocarcinoma, dysgerminoma, embryonal carcinoma,
Teratoma
mature, immature (tissue resembles embryonal or fetal tissue), malignant
Teratoma-mature
Defined as containing only adult tissues
Usually teenage women (solid) or children (cystic)
Excellent prognosis, even if peritoneal implants present
Dermoid cyst: usually means teratoma resembles skin; some use dermoid cyst and
mature teratoma interchangeably
Micro: ectodermal structures in 100%, mesodermal in 93%,
endodermal in 71%; skin and glial tissue common
Struma ovarii
Monodermal teratoma composed of mature thyroid tissue