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