Female Reproductive System Ectocervix—nonkeratinizing squamous epithelium (estradiol stimulates growth, maturation, desquamation)

Transcription

Female Reproductive System
Ectocervix—nonkeratinizing squamous epithelium
(estradiol stimulates growth, maturation, desquamation)
Endocervix—mucous columnar epithelium
These two meet at the squamocolumnar junction (aka
transformation zone)
Metaplasia=one adult cell type replaced by another (most commonly, columnar→
squamous)
Squamous metaplasia occurs normally in the cervix, usually at the transformation
zone (columnar→ squamous)
More prominent in adolescence, pregnancy
Disorders of the Cervix:
I.
Inflammation
Acute cervicits—caused by gonorrhea, Chlamydia, candida, and trichomonas.
Chlamydia most common STD (may cause pus and yellowish discharge)
HSV-2—DNA virus, often asymptomatic on cervix (vulva and vagina also
involved) Important during pregnancy—can cause spontaneous abortion, fetal
morbidity and death
Chronic inflammation—common. For some reason, plasma cells and
lymphocytes accumulate subepithelially. If extensive→follicular cervicitis
II. Nabothian Cysts—inflammation and fibrosis may cover an “endocervical cleft” and
glands become dilated. Benign.
Nabothian Cyst
Koilocytosis (see below)
II. Endocervical Polyps—Inflammation of cervical folds, may cause abnormal
discharge or bleeding. Non-neoplastic.
III. HPV/Condyloma Acuminatum
STD, very common, many serotypes (6, 11, 16, 18, 31 involved in 75% of genital
tract infection)
Types 6, 11 typically involved in condyloma acuminatum (genital warts)—these
actually tend to be more benign in terms of causing atypia
Cause cervical epithelial abnormalities
Most infections are latent (asymptomatic), and most are self-limited or transient
Histology-- papillary growth with koilocytic change (perinuclear halos).
May have associated cellular atypia
IV. Premalignant and Malignant Change
Worldwide, 2nd leading cause of mortality, but incidence in US falling (why?)
Usually squamous cell, but sometimes adenocarcinoma or adenosquamous
carcinoma
A. Squamous Cell Carcinoma
60-80%, average age 50 years
Risk factors: Low SES, multiple partners/early age, multiparity, STDs, cigarettes
Results from a progression of condyloma (HPV) infection to CIN to invasive
lesions
HPV 6,11→condyloma acuminatum—visible warts, mostly benign or low-grade
HPV 16, 18, 31→high grade cervical cancer precursors and invasive squamous
cell carcinoma
Type 16—squamous, Type 18—squamous and glandular (adenoca)
How does HPV work? Viral oncogenes
E6
E7
Binds p53 tumor suppressor
Binds pRb—involved in cell cycle regulation
Causes p53 degradation
Accounts for most high-risk activity in malignant
transformation
HSV-2—may be linked to precursor dyplastic lesions and invasive cervical
cancer, but does not play a central role
B. Premalignant Squamous Lesions—Dysplasia and Carcinoma in Situ
Most invasive cervical cancers take a long time to grow (8-30 years) and can be
detected by routine pap smear—much lower rate of invasive cervical ca in the
screened population
Pap smear takes epithelial sample from transformation zone (squamocolumnar
jct)—this is where most squamous carcinomas occur.
Dysplasia=abnormalities in cytology and differentiation of cells. In cervix, this
means that some but not all of the squamous cells resemble cancer cells.
Classified as mild, moderate, and severe.
Carcinoma=all cells in the epithelium resemble cancer cells
In situ=within confines of epithelial basement membrane
Represents a continuum: dysplasia→carcinoma in situ→invasive cervical cancer
Cervical intraepithelial neoplasia (CIN) used to describe above:
o CIN 1=mild dysplasia
o CIN 2=moderate dysplasia
o CIN 3=severe dysplasia and carcinoma in situ
Squamous Intraepithelia lesion (SIL
o LSIL=low grade SIL; condyloma and CIN 1
o HSIL=high grade SIL; CIN 2 and 3
Detection: Pap smear—take a sample of the transitional zone with a tiny broom
and examine the cytology. Colposcopy—Look at the cervix with a microscope to
detect abnormalities. Biopsy
CIN—remember, no CINs are invasive yet—they are all in situ if they are truly
CIN! Therefore, patients have no symptoms, no gross lesions, and this is detected
by pap smear.
CINs may exhibit progression, regression, or persistence. Depends on HPV type,
and grade of lesion (e.g. 60% of CIN 1 regress; only 25% of CIN 3 regress)
C. Invasive Cervical Cancer
Small tumors—asymptomatic usually, detected by pap
Larger—may cause bleeding, bloody d/c, pain
Spread:
o Direct extension to pelvic tissues (parametrium, vagina). If advanced—
ureters and hydronephrosis
o Lymph spread pelvic lymph nodes→paraortic lymph nodes
o Hematogenous in advanced
Staging determines prognosis
Vulvar Diseases:
I.
Infectious
Gonorrhea—often subclinical, but may invade Bartholin’s, periurethral, or
vestibular glands. May cause Bartholin’s gland abscess, or travel up to fallopian
tubes and cause PID.
Syphilis→chancre (remember—painless)
HSV-2→vesicular eruption and ulcerations (ouch!)
HPV→condyloma acuminatum (genital warts)
II.
Dystrophy
Degenerative and hyperplastic conditions—idiopathic
Squamous hyperplasia—may have atypia
Lichen sclerosis—atrophy of epithelium, sclerosis, chronic inflammation
Pruritic—treat with steroids. Usually benign, but may cause carcinoma.
III.
Carcinoma in situ
Bowen’s disease
May be associated with CIN (25-30% of cases)
Very, very rare progression to invasive cancer
IV.
Invasive Squamous Cell Carcinoma
Most common malignant vulvar tumor
Older women (postmenopausal)
Inguinal-femoral lymph nodes
Vaginal Disease:
Mucous membrane with nonkeratinizing squamous epithelium. Epithelium
responds to estrogen (growth, increased glycogen)
I. Inflammation
Common. AKA vaginitis.
o Gardnerella vaginalis—most common, malodorous D/C (bacterial
vaginosis)
o Candida—Abx, DM, Steroids, pregnancy predispose. Pruritis and
exudates
o Trichomonas vaginalis—protozoan
o Treponema pallidum—syphilis, asymptomatic
II.
Cancer
Dysplasia and in situ carcinoma usually occur in women who have cervical CIN or
invasive cervical carcinoma
Invasive carcinoma is rare, typically in older women
Metastatic tumors from cervix, endometrium may recur in vagina
Endometrium/Myometrium

Endometrium lines innermost cavity of uterus, changes according to monthly
menstrual cycle
Glands and stroma responsive to estrogen and progesterone secreted by ovaries
Proliferative phase: Days 1-14, estrogen-dependent. Growth of glands and stroma
Secretory phase (Luteal): Days 15-28, estrogen and progesterone from corpus luteum,
secretions into glands and stromal edema. Gland growth ceases, glands become
tortuous and spiral arteries present.
During pregnancy, the endometrium undergoes additional changes: “decidual reaction
of stroma”—stromal cells enlarged with prominent borders; “Arias-Stella
phenomenon”—large, hyperchromatic nuclei bulge into glands.
Exogenous hormones (e.g. OCPs) also produce effects: Progestins in oral
contraceptives result in secretory gland changes and eventual atrophy, stroma
becomes decidua-like. Estrogens cause endometrial proliferation.
Endometrial Pathology:
Abnormal uterine bleeding encompasses a variety of pathologic processes. Usually
presents as bleeding not associated with a period. Causes include: Dysfunctional
uterine bleeding, pregnancy complications, inflammation, atrophy, exogenous
hormones, lesions (leiyomyomas, polyps, hyperplasia, carcinoma), or systemic
bleeding disorders.
I. Dysfunctional Uterine Bleeding
Defined as dysfunctional and excessive bleeding with no organic cause. Put another
way, it means abnormal bleeding as a disturbance in the proper function of the
reproductive organs, rather than due to a lesion of the uterus or endometrium.
These are most often due to anovulatory cycles or luteal phase defects.
In an anovulatory cycle, there is excessive and prolonged estrogenic stimulation
without the development of a progestational phase (the follicles develop, but there is
no ovulation and therefore no corpus luteum to release progesterone). So proliferation
and bleeding occur. Most common when menstrual cycles are likely to be irregular—
menarche and menopause.
II. Inflammation
Causes bleeding and infertility
Endometritis=endometrial inflammation. Chronic—PID, pregnancy, or abortion.
Acute—recent pregnancy or abortion; IUD placement, cervical stenosis, or tumor.
If chronic, may cause infertility. See plasma cells in stroma.
III. Polyps

Focal overgrowths of glands and stroma,
benign
No malignant potential, may occur at any
age but most common in the
perimenopausal patient
IV. Hyperplasia
Proliferation of endometrial epithelium→abnormal gland shapes and sizes.
Due to unopposed estrogen stimulation of the endometrium
Hyperplasia→atypia→adenocarcinoma
Classification: Without atypia—simple or complex, with atypia—simple or complex
o Hyperplasia in all forms exhibits glands with irregular shapes and sizes
o Atypia—cytologic change within cells
Occurs in peri- and post-menopausal women, causes abnormal bleeding.
Increased risk of developing endometrial adenocarcinoma
V. Adenocarcinoma
Endometrial carcinoma—most common cancer of female reproductive tract
Usually postmenopausal, presents with abnormal uterine bleeding
Estrogen-related—so risk factors make sense: anovulation, exogenous estrogens,
obesity, HTN, DM, nulliparity, granulosa-cell ovarian tumors.
May have squamous component—adenocanthoma contains benign squamous,
malignant adeno- elements, adenosquamous carcinoma—malignant adeno- and
squamous elements
Endometrial adenocarcinoma with clear cell or serous cell features with high nuclear
grade=poor prognosis, aggressive—often not estrogen-related.

Prognosis—Depth of myometrial invasion most important factor in stage I, also
depends on nuclear grade, differentiation, histologic type, vascular invasion.
Invades myometrium and cervix, pelvic lymph nodes, hematogenous in late stages
VI. Sarcomas
Uncommon, but BAD
Malignant mixed mullerian—rare, highly malignant, mixed carcinomatous and
sarcomatous elements (cartilage, rhabdomyoblasts), older women, poorly
differentiated
Leiomyosarcoma
Stromal sarcoma
Myometrial Pathology:
I. Leiomyomas
AKA fibroid tumors—most common tumor, benign smooth muscle tumor occurring
in reproductive years
May cause uterine enlargement, bleeding, pain, and infertility
Grow rapidly during pregnancy, often regress after menopause
II. Adenomyosis
Endometrial glands and stroma grow where they don’t belong—in the myometrium.
Uterine enlargement, pelvic pain, dysmenorrheal, menorrhagia.
Ovary/Fallopian Tube
Mesothelium—surface epithelium covering ovary
Germ cells—Present from birth, gone after menopause
Sex cord-stromal cells—Granulosa, theca, and mesenchymal cells

Cysts and masses—not all ovarian masses are malignant. Both benign and malignant
conditions, however, may cause cyst formation with ovarian enlargement. May be
very small to quite large
Causes of ovarian cysts/masses: follicular cyst and corpus luteum cysts (functional,
normal part of menses); polycystic ovaries, endometriosis, benign neoplasms,
malignant neoplasms (usually epithelial tumors).
I. Polycystic Ovary Disease (Stein-Leventhal Syndrome)
Anovulation with menometrorrhagia or oligomenorrhagia—ovarian follicles develop
but ovulation does not occur→multiple cystic follicles→polycystic ovaries
But this is not caused by ovarian dysfunction; rather it occurs due to dysregulated
FSH and LH at the pituitary
Hirsutism
Infertility
Obesity (sometimes)
II. Endometriosis
Endometrium grows where it does not belong (what is this like?)
Endometrial glands and stroma outside the uterine corpus—ovary, pelvic peritoneum,
uterine ligaments, rectovaginal septum common sites. Less common—cervix, vagina,
vulva, bladder, skin. Very rarely lungs, pleura.
Most often occurs in childbearing years, associated with fewer and later pregnancies.
Cause of infertility
Symptoms—dysmenorrheal (pain with periods), pelvic pain, pain during intercourse
(dyspareunia), irregular bleeding. Symptoms may not correlate with extent of disease.
Etiology
o Most likely—retrograde menses get pushed up through fallopian tubes and
out onto ovaries
o Intraoperative implantation (definitely occurs)
o Lymphatic/vascular spread
o Metaplastic theory—pelvic peritoneum undergoes metaplasia to endometrium
(unlikely)
Pathology—benign endometrial tissue with glands and stroma. Responsive to
estrogen just like endometrium—may have hemorrhage in sites, and undergoes cyclic
changes.
o Ovaries—common site. “powder burns”=focal, small hemorrhages, versus the
“chocolate cyst”=large, cystic lesions filled with old blood, aka
endometriomas. Often accompanied by adhesions onto fallopian
tube→infertility
III. Ovarian Tumors
Benign and malignant
Surface/Epithelial Germ Cell
Sex
Steroid cell
Metastatic to
cord/Stromal
(Lipid)
ovary
70%
15-20%
5-10%
5%
3-5% malignant 2-3%
5%
95% of all
malignant
malignant
Benign > 20
Malignant >50
Serous
Teratoma
Fibroma
Variable
Mucinous
Dysgerminoma
GranulosaTheca cell
Endometriod
Endodermal
Sertoli-Leydig
sinus
cell
Clear Cell
Choriocarcinoma
Brenner
Cystadenofibroma
1. Epithelial Tumors
Unknown etiology, but OCs and multiparity are protective
Familial cases, associated with BRCA-1 and 2 (BRCA-1 most often)
Benign, malignant, and borderline
o Benign=cystadenoma; Malignant=cystadenocarcinoma
o Borderline=tumors of low malignant potential, about 20% of mucinous and
serous carcinomas. Not malignant because absence of stromal invasion,
cellular atypia present. Better prognosis than malignant, but still 20% cause
death.
Serous—most common type of benign and malignant, often bilateral
o Often contain psammoma bodies—calcifications
o Serous type fluid lined by tubal-like epithelium
Mucinous—benign and malignant
o Often benign, may be enormous
Endometrioid adenocarcinoma—second most common malignant type, 15% from
endometriomas, better prognosis
Brenner—almost always benign
Pathology—Most epithelial tumors are cystic
o Papillary growth common, lining cysts
Bilaterality—serous>endometrioid>mucinous
Survival: carcinoma=30%, borderline=80%
Symptoms: Often asymptomatic until very late stage. Pain, pelvic mass, abdominal
enlargement
Screening:
o CA-125—present in most serous and endometrioid carcinomas, better for
following patients than diagnosis
o Transvaginal U/S
o Proteomics, LPA, tumor-associated antigens
Spread:
o Aortic, pelvic lymph nodes
o Directly onto peritoneal surfaces, causing ascites
o 30-45% 5-year survival
o Stage is best prognostic indicator
2. Germ Cell Tumors
From primitive germ cells of ovaries
Majority are benign mature cystic teratomas (aka dermoid cysts)
o Very common, young women, may be bilateral
o Path—3 layers: endoderm, ectoderm, mesoderm
o May contain cartilage, bone (teeth), hair, sebaceous material, respiratory
epithelium, neuroglia, skin appendages
Other tumors—all malignant but rare, occur in teens or 20s
o Unilateral and rapid-growing, large
o Tumor markers may be produced (AFP, B-HCG)
o Dysgerminoma most common malignant germ cell tumor
o If treat with surgery and chemotherapy, often long-term remissions and cure
3. Sex cord-stromal tumors
Granulosa cell tumor
o Rare, usually postmenopausal
o Low grade malignant potential; but if large, advanced stage, and/or
ruptures (causing hemoperitoneum)→poor prognosis
o May produce estrogens which affect endometrium→endometrial
hyperplasia and neoplasms
o Mostly unilateral
o Path=Call-Exner bodies (small, distinctive, gland-like structures filled
with an acidophilic material) and coffee bean shaped nuclei with
longitudinal grooves
Thecoma and Fibroma
o Benign, solid, fibrous tumors with spindle cells
o Peri- and post-menopausal
o Thecomas have lipid in the cytoplasm (which may have estrogenic
effects), fibromas do not
o Meigs’ Syndrome—ascites and pleural effusion occur with fibrous tumor
and disappear with removal of tumor
Sertoli-Leydig tumors
o Rare, mimic patterns in developing testes!
o Therefore, androgenic→hirsutism, virilization
o Usually benign, but may be malignant if poorly differentiated
Steroid (lipid) cell tumors
o Rare, usually benign
o Resemble theca-lutein cells
o Often estrogenic
Mets
o Endomterium, breast, stomach, colon
o Krukenbug tumor—metastatic signet-ring carcinoma, usually from
stomach
Fallopian Tube
Site of fertilization by sperm. Three portions—
infundibulum, ampulla, isthmus. Ciliated and
secretory cells.
VERY RARE site of neoplasms
Inflammation is common, though→pelvic
inflammatory disease (PID)
PID most commonly caused by STDs, but may
occur following abortion or pregnancy
Infection—gonorrhea, Chlamydia most
common. Pregnancy—strep, staph.
Acute phase of PID (suppurative salpingitis)—acute inflammation of fallopian tube, often
spreads to ovary and causes salpingo-oophoritis. Tube distended with inflammatory cells
Chronic PID—Tubo-ovarian abscess may form, or healing with fibrosis and scarring.
Complications of PID—vary with phase. Acute—bacterial peritonitis and bacteremia;
chronic—tubo-ovarian abscess, hydrosalpinx (dilated tube).
End-stage PID—tubal occlusion, adhesions→infertility.

Ectopic Pregnancy
o Pregnancy occurs outside of endometrium, most commonly in the fallopian tube.
o PID is a risk factor, as well as adhesions, endometriosis, prior tubal surgery.
o Pregnancy may grow through wall and rupture→intra-abdominal hemorrhage,
pregnancy loss, acute abdomen
o Ectopic pregnancy is a medical emergency