Female Reproductive Pathology

PCOS and unopposed estrogen

Polycystic ovary syndrome. PCOS combines hyperandrogenism (hirsutism, acne), oligo-ovulation and polycystic ovaries, usually with insulin resistance and obesity. An increased LH:FSH ratio drives theca cells to overproduce androgens, and hyperinsulinemia amplifies ovarian androgen output and lowers SHBG. Excess androgen is aromatized peripherally to estrone, while anovulation means no corpus luteum and no progesterone.

Treatment. Combined OCPs regulate cycles and protect the endometrium; metformin addresses insulin resistance; letrozole or clomiphene induces ovulation for fertility; spironolactone treats hirsutism.

PCOS anovulation means unopposed estrogen, raising the risk of endometrial hyperplasia and carcinoma. Obesity, estrogen-only therapy, tamoxifen and estrogen-secreting granulosa cell tumors act the same way.

Uterine pathology

Endometriosis. Endometrial glands and stroma lie outside the uterus, most often on the ovary and pelvic peritoneum, and bleed with each cycle. Patients have dysmenorrhea, dyspareunia, dyschezia and infertility. Ovarian implants form "chocolate cysts" (endometriomas), and peritoneal implants look like powder burns. Laparoscopy is diagnostic. Proposed origins include retrograde menstruation, coelomic metaplasia and lymphatic or vascular spread.

Adenomyosis. Endometrial tissue within the myometrium produces a diffusely enlarged, boggy, tender uterus with menorrhagia and dysmenorrhea; hysterectomy is curative.

Leiomyoma (fibroid). The most common tumor of the female reproductive tract, more common in Black women: benign smooth-muscle tumors, often multiple, with a whorled cut surface. They are estrogen-sensitive, growing in pregnancy and regressing after menopause, and cause menorrhagia and bulk symptoms. They do not transform into leiomyosarcoma, which arises de novo as a single necrotic, hemorrhagic mass in older women.

Endometrial hyperplasia. Unopposed estrogen (obesity, PCOS, anovulation, estrogen-only therapy, tamoxifen) causes endometrial glandular proliferation that presents as abnormal or postmenopausal bleeding. Atypical (complex) hyperplasia is the direct precursor of endometrioid carcinoma; nuclear atypia is the feature that predicts progression.

Endometrial carcinoma. The most common gynecologic malignancy in the US; it classically presents with postmenopausal bleeding, and endometrial biopsy makes the diagnosis. Type I (endometrioid) is estrogen-driven, arises from hyperplasia in perimenopausal women, and is associated with PTEN mutations and Lynch syndrome. Type II (serous) is estrogen-independent, arises in older women with atrophic endometrium, carries p53 mutations and is more aggressive.

Ovarian tumors

Epithelial tumors. Surface epithelial tumors are the most common ovarian tumors and the most common ovarian cancers. Serous cystadenocarcinoma, often bilateral with psammoma bodies, is the most common malignant type and is linked to BRCA mutations. Presentation is typically late, with a pelvic mass and ascites, and CA-125 is used to monitor disease. Fewer lifetime ovulations (pregnancy, breastfeeding, OCP use) lower risk.

Germ cell tumors. These affect children and young women. Dysgerminoma is the most common malignant germ cell tumor, the female counterpart of seminoma, with sheets of uniform "fried egg" cells and LDH as its marker. Yolk sac tumor secretes AFP, shows glomeruloid Schiller-Duval bodies and occurs in children. Choriocarcinoma secretes β-hCG. Mature cystic teratoma (dermoid cyst) is the most common germ cell tumor; it contains tissues from all three germ layers and can form struma ovarii, which may cause hyperthyroidism.

Sex cord-stromal tumors. Granulosa cell tumor secretes estrogen and shows Call-Exner bodies, causing precocious puberty in girls or postmenopausal bleeding and endometrial hyperplasia in older women. Sertoli-Leydig cell tumor secretes androgens and causes virilization. Ovarian fibroma is a benign, hormonally inactive tumor of spindle-shaped fibroblasts.

Meigs and Krukenberg. Meigs syndrome is the triad of an ovarian fibroma, ascites and a right-sided pleural effusion that resolves after the tumor is removed. A Krukenberg tumor is bilateral ovarian metastasis of mucin-secreting signet-ring cells, classically from a gastric (or colon) primary.

Cervix, vagina and vulva

HPV oncogenesis. High-risk HPV types 16 and 18 cause cervical dysplasia at the transformation zone. The viral E6 protein degrades p53 and E7 inactivates Rb, releasing the cell cycle. Koilocytes (cells with wrinkled nuclei and perinuclear halos) are the cytologic hallmark on the Pap smear. Smoking, multiple partners and immunosuppression (HIV) raise the risk; vaccination prevents infection.

Cervical carcinoma. Usually squamous cell and HPV-related (adenocarcinoma is less common), it presents with postcoital bleeding. Pap smear and HPV testing catch precancer. Advanced disease invades laterally and can obstruct the ureters, causing hydronephrosis and postrenal failure, a common cause of death.

Vaginal and vulvar lesions.

• Clear cell adenocarcinoma of the vagina: linked to in utero DES exposure.
• Sarcoma botryoides (embryonal rhabdomyosarcoma): grape-like vaginal masses in girls under 4; desmin-positive.
• Lichen sclerosus: thin, white, parchment-like vulvar skin that slightly raises squamous cell carcinoma risk.
• Extramammary Paget disease: pruritic, red, crusted vulvar plaques from intraepithelial adenocarcinoma cells.

Gestational trophoblastic disease

Hydatidiform moles. A complete mole forms when an empty egg is fertilized and the paternal genome duplicates, giving a 46,XX karyotype that is entirely paternal. There are no fetal parts; the uterus is large for dates with a snowstorm or cluster-of-grapes appearance, β-hCG is very high, and about 2% progress to choriocarcinoma. A partial mole arises when a normal egg is fertilized by two sperm, giving a triploid karyotype (such as 69,XXX) with fetal parts and a low malignant risk. Very high hCG can cause hyperemesis, early preeclampsia, theca-lutein cysts and hyperthyroidism. Treatment is suction curettage with serial β-hCG monitoring.

Choriocarcinoma. A malignant tumor of cytotrophoblast and syncytiotrophoblast without villi. It can follow a mole, a normal pregnancy or an abortion, secretes β-hCG and spreads hematogenously to the lungs.