Ovarian and Endometrial Cancer

Ovarian cancer — non-modifiable

• **Germline BRCA1/BRCA2 mutation**: loss of homologous recombination repair; the single strongest hereditary driver, and the reason NCCN recommends genetic testing for all women with epithelial ovarian cancer regardless of family history
• Lynch syndrome (mismatch repair deficiency): raises risk of ovarian (often endometrioid/clear cell) plus colorectal and endometrial cancer
• Incessant ovulation: early menarche, late menopause, and nulliparity mean more ovulatory epithelial repair cycles → more DNA damage; age is the dominant risk factor overall
• Endometriosis: chronic inflammation and ARID1A loss predispose specifically to clear cell and endometrioid histology

Ovarian cancer — modifiable/protective

• Combined oral contraceptives: ovulation suppression produces a durable, duration-dependent risk reduction — the classic protective factor in stems
• Multiparity, breastfeeding, tubal ligation/opportunistic salpingectomy: also ovulation- or fallopian-tube-related; ACOG endorses opportunistic salpingectomy at benign pelvic surgery, since high-grade serous cancer arises in the fimbria

Endometrial cancer — unopposed estrogen (mostly modifiable)

• Obesity: adipose aromatase converts androstenedione to estrone with no progesterone opposition — the most common and most testable risk factor
• Chronic anovulation/PCOS: persistent proliferative endometrium without a luteal progesterone phase
• Unopposed estrogen therapy: estrogen alone in a woman with a uterus; a progestin must be added
• Tamoxifen: estrogen agonist at the endometrium while antagonist at breast
• Estrogen-secreting tumors: granulosa cell tumor presenting with postmenopausal bleeding
• Diabetes and metabolic syndrome: hyperinsulinemia lowers SHBG, raising free estrogen

Endometrial cancer — non-modifiable

• Lynch syndrome: endometrial cancer is frequently the sentinel cancer; NCCN recommends universal MMR/MSI tumor screening
• Age, nulliparity, early menarche/late menopause
• Type II (serous/clear cell): *TP53*-driven, arises in atrophic endometrium of older, thin women and after prior pelvic radiation — estrogen exposure is irrelevant here

OVARIAN CANCER

• BRCA1/BRCA2 mutations (~10-15% of cases): Impair homologous recombination DNA repair, increasing genomic instability and malignant transformation; confer 35-70% lifetime risk
• High-grade serous carcinoma (HGSC) pathway: TP53 mutations (~96% of cases) drive rapid malignant transformation; accounts for 70% of ovarian cancer deaths
• Low-grade serous carcinoma pathway: KRAS/BRAF mutations promote gradual progression from benign to borderline to invasive tumors
• Clear cell and mucinous subtypes: Associated with ARID1A and KRAS mutations; often present at earlier stages but may have worse prognosis
• Ovarian surface epithelium transformation: Repeated ovulation causes inflammation, DNA damage, and malignant transformation of epithelial cells
• PARP inhibitor sensitivity: BRCA-mutant and homologous recombination-deficient tumors depend on PARP for DNA repair, making them exquisitely sensitive to PARP inhibitors

ENDOMETRIAL CANCER

• Type I (endometrioid, ~80% of cases): Associated with estrogen excess and unopposed estrogen stimulation; mutations in PTEN, PIK3CA, KRAS, ARID1A; generally lower grade and better prognosis
• Type II (serous/clear cell, ~10% of cases): TP53 mutations drive aggressive behavior; NOT estrogen-driven; poor prognosis regardless of stage
• Lynch syndrome (3-5% of cases): Mismatch repair (MLH1, MSH2, MSH6, PMS2) deficiency causes microsatellite instability (MSI-high); increases endometrial cancer risk to 40-60%
• Unopposed estrogen mechanism: In type I cancers, continuous estrogen stimulation without progesterone opposition increases mitotic activity and malignant transformation
• POLE mutations: Ultra-mutated tumors with improved prognosis despite molecular complexity
• Molecular classification (TCGA): Four subtypes (POLE ultramutated, MSI-hypermutated, copy-number low, copy-number high) predict prognosis better than traditional histology

OVARIAN CANCER

• Vague abdominal symptoms (classic presentation): Bloating, early satiety, abdominal/pelvic pain, increased abdominal girth—often attributed to benign causes; 75% present at stage III-IV
• Ascites: Fluid accumulation causing abdominal distension; indicates advanced disease
• Pelvic/abdominal mass: Noted on exam or imaging; may be asymptomatic
• Constitutional symptoms: Unintentional weight loss, fatigue, night sweats (late presentation)
• GI symptoms: Constipation, diarrhea, nausea from peritoneal involvement
• Pleural effusion: Right-sided in advanced disease; can cause dyspnea
• Important pearl: Early-stage ovarian cancer is often ASYMPTOMATIC—diagnosis frequently delayed until advanced stage due to vague symptomatology and deep pelvic location

ENDOMETRIAL CANCER

• Abnormal uterine bleeding (90% of patients): Postmenopausal bleeding is cardinal sign; perimenopausal irregularity also concerning; abnormal vaginal bleeding in reproductive-age women
• Vaginal discharge: Blood-tinged or serosanguinous discharge
• Pelvic pain/cramping: May indicate advanced disease or cervical stenosis
• Pelvic mass or enlarged uterus: On examination; suggests advanced disease
• Constitutional symptoms: Late presentation with weight loss, fatigue
• Important pearl: Postmenopausal bleeding is endometrial cancer until proven otherwise—any postmenopausal woman with bleeding requires evaluation (transvaginal ultrasound or endometrial biopsy)

OVARIAN CANCER

• Transvaginal ultrasound (TVUS): First-line imaging; evaluates ovarian morphology (size >3 cm, thick septations, solid components, papillations suggest malignancy)
• CA-125 level: Elevated in 80% of advanced ovarian cancer; NOT diagnostic alone and can be elevated in benign conditions (endometriosis, fibroids, menses, peritonitis); combined with TVUS improves specificity
• Risk of Malignancy Index (RMI): RMI = CA-125 × menopausal status × ultrasound score; RMI >200 indicates high risk requiring gynecologic oncology referral
• Staging laparotomy/laparoscopy: Required for surgical diagnosis and staging; includes omentectomy, biopsies, fluid cytology, comprehensive staging
• CT abdomen/pelvis: Evaluates metastatic disease, ascites, lymph nodes; used after diagnosis for treatment planning
• Diagnostic criteria: Ovarian cancer confirmed by pathology; staging per FIGO system (I-IV based on extent of disease)
• Important consideration: Elevated CA-125 + ovarian mass = presumed ovarian cancer; definitive diagnosis by surgical exploration/pathology, not by imaging or labs alone

ENDOMETRIAL CANCER

• Transvaginal ultrasound (TVUS): Measures endometrial thickness; thickness >4 mm in postmenopausal women concerning for malignancy (though 10% of thick endometria are benign)
• Endometrial biopsy: Gold standard for diagnosis in symptomatic women; performed in office with Pipelle catheter; high sensitivity (90-99%)
• Dilation and curettage (D&C): Can be performed for diagnostic evaluation, especially if biopsy inconclusive or cervical stenosis present
• Hysteroscopy: Allows direct visualization and biopsy if suspicion high; may improve diagnostic accuracy
• MRI pelvis: Used for staging to assess myometrial invasion, cervical involvement, and lymph node status after diagnosis
• Chest imaging and labs: CT chest to evaluate for metastatic disease; CBC, CMP for baseline before treatment
• Staging: Surgical staging (total abdominal hysterectomy, bilateral salpingo-oophorectomy, lymph node assessment) determines FIGO stage and prognosis

OVARIAN CANCER

• Stage I disease (early-stage, favorable):
• Surgery alone: Comprehensive staging laparotomy with TAH/BSO, omentectomy, peritoneal biopsies for grade 1, stage IA disease
• Adjuvant chemotherapy: Consider for stage IB-IC or grade 2-3 tumors; 3-6 cycles of carboplatin/paclitaxel (TC) improves survival

• Stage II-IV disease (advanced, requires chemotherapy):
• Neoadjuvant chemotherapy (NACT): 3 cycles carboplatin AUC 5-6 + paclitaxel 175 mg/m² IV given before surgery when optimal debulking unlikely; improves outcomes vs. upfront surgery
• Primary debulking surgery: Hysterectomy, BSO, omentectomy, peritoneal stripping, bowel resection as needed; goal = residual tumor <1 cm ("optimal debulking")
• Adjuvant chemotherapy: 6 cycles carboplatin + paclitaxel after surgery; continuation maintenance paclitaxel (weekly) improves PFS

• Platinum-sensitive relapse (recurrence >6 months after platinum-free interval):
• Re-treatment with platinum-based chemotherapy (carboplatin/paclitaxel); consider bevacizumab (anti-VEGF mon

Disease-related

• Malignant bowel obstruction (emergency): peritoneal carcinomatosis encases bowel serosa; presents with progressive vomiting, obstipation, and air–fluid levels — the most common terminal event in ovarian cancer
• Malignant ascites and pleural effusion: tumor-driven VEGF increases peritoneal capillary permeability; a cytology-positive pleural effusion makes disease stage IV
• Venous thromboembolism (emergency): adenocarcinoma tissue factor and mucin produce a hypercoagulable state; unexplained dyspnea, tachycardia, or unilateral leg swelling should prompt imaging. ASCO guidance favors low-molecular-weight heparin or a DOAC over warfarin for cancer-associated VTE
• Ureteral obstruction/hydronephrosis: pelvic mass or nodal bulk compresses the ureter; rising creatinine with a dilated collecting system
• Anemia and hemorrhage: chronic bleeding in endometrial cancer; brisk hemorrhage from an advanced uterine or cervical-extension tumor is an emergency
• Ovarian mass torsion or rupture (emergency): acute severe unilateral pain with an adnexal mass and absent Doppler flow

Treatment-related

• Neutropenic fever after carboplatin/paclitaxel (emergency): nadir roughly 7–14 days post-infusion; single temperature elevation with ANC <500 requires immediate empiric antipseudomonal beta-lactam per IDSA febrile neutropenia guidance
• Carboplatin hypersensitivity: IgE-mediated, characteristically appearing after repeated cycles (often cycle 6 or later) — anaphylaxis is treated with intramuscular epinephrine 0.3 mg
• Paclitaxel peripheral neuropathy: microtubule stabilization damages long axons; stocking-glove numbness that may require dose reduction
• Bevacizumab: GI perforation, hemorrhage, hypertension, impaired wound healing (perforation is an emergency): VEGF blockade impairs mucosal and endothelial repair; new peritonitis in a patient on bevacizumab is perforation until excluded
• PARP inhibitor myelosuppression and secondary MDS/AML: cumulative marrow genotoxicity; persistent cytopenias warrant marrow evaluation
• Surgical menopause and lymphedema: BSO abruptly removes estrogen (vasomotor symptoms, bone loss); pelvic lymphadenectomy disrupts drainage — sentinel node mapping in endometrial cancer reduces this risk

• Postmenopausal bleeding = endometrial cancer until disproven: the single best next step is endometrial sampling (office biopsy) or transvaginal ultrasound per ACOG; a stripe ≤4 mm is reassuring, but persistent or recurrent bleeding still requires tissue, because type II serous cancers arise in a thin, atrophic endometrium
• CA-125 is not a screening test: the USPSTF recommends against ovarian cancer screening in asymptomatic average-risk women — TVUS plus CA-125 does not reduce mortality and generates harmful surgery. CA-125 is for triage of a known mass and for tracking treatment response
• The classic association examiners test: BRCA1/2 links high-grade serous ovarian/fallopian tube cancer to breast cancer, and NCCN recommends germline testing in every woman with epithelial ovarian cancer. Risk-reducing bilateral salpingo-oophorectomy after childbearing is the definitive prevention, done earlier for BRCA1 than BRCA2
• Lynch syndrome: endometrial cancer is often the first cancer; MMR/MSI testing of the tumor is standard, and a positive result should trigger colonoscopy surveillance and family testing
• Buzzwords: psammoma bodies → serous carcinoma; Call-Exner bodies → granulosa cell tumor (estrogen excess → precocious puberty or postmenopausal bleeding); Schiller-Duval bodies → yolk sac tumor (elevated AFP); signet-ring cells in bilateral ovaries → Krukenberg tumor from gastric primary; Meigs syndrome → benign ovarian fibroma + ascites + right pleural effusion, which mimics but is not cancer
• Tamoxifen distractor: it is an endometrial agonist and raises endometrial cancer risk, yet asymptomatic users are not screened with ultrasound — evaluate only if bleeding occurs. Raloxifene does not carry this risk
• Endometrial hyperplasia with atypia is the true precursor lesion and frequently harbors occult carcinoma; hysterectomy is definitive, with progestin therapy (levonorgestrel IUD) reserved for fertility preservation
• Don't confuse the two cancers' presentation: ovarian cancer presents late with bloating and early satiety; endometrial cancer presents early with bleeding — which is why survival differs so sharply