Gynecologic Malignancies¶
Chapter 94 | Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Chapter 94
Key Clinical Points¶
- Ovarian cancer is the leading cause of cancer death in American women, ranking behind lung, breast, colon, and pancreatic cancers.
- Cervical cancer is the second most common and most lethal malignancy in women worldwide; HPV infection (high-risk strains 16/18) is the primary initiating event.
- Epithelial ovarian cancers are divided into Type 1 (low-grade, indolent) and Type 2 (high-grade, aggressive, associated with TP53 mutation in 95% of cases).
- Primary debulking surgery aiming for R0 resection is the target outcome for ovarian cancer surgery.
- Platinum-based chemotherapy (Carboplatin + Paclitaxel) is standard for epithelial ovarian cancer; BEP (Bleomycin, Etoposide, Cisplatin) is standard for germ cell tumors.
- Germline BRCA1/2 mutations confer high risk for breast and ovarian cancer; prophylaxis involves salpingo-oophorectomy after childbearing.
- Cervical cancer screening relies on Pap smear and HPV testing; Gardasil-9 protects against 9 high-risk HPV types.
- Late relapse in testicular cancer (>2 years after chemotherapy) often represents chemotherapy-resistant disease requiring salvage surgery.
- Ascites and abdominal girth increase are hallmark signs of advanced ovarian cancer, often leading to late presentation.
- Immunotherapy with PD-1 blockers and PARP inhibitors (niraparib, olaparib) are used for HRD-positive ovarian cancer.
1. DEFINITION & CLASSIFICATION¶
Gynecologic malignancies encompass cancers of the female reproductive tract (ovary, fallopian tube, cervix, uterus, vulva). Classification is based on cell origin and histology.
• Ovarian Cancer: Epithelial (most common), germ cell, sex cord-stromal. • Cervical Cancer: Squamous cell carcinoma (80%), adenocarcinoma. • Uterine Corpus Cancer: Endometrial adenocarcinoma, leiomyosarcoma, carcinosarcoma. • Fallopian Tube Cancer: Serous histology. • Vulvar Cancer: Squamous cell carcinoma, melanoma.
1.1 Classification by Site¶
• Ovarian cancer: Epithelial (most common), germ cell, sex cord-stromal. • Cervical cancer: Squamous cell carcinoma (80%), adenocarcinoma. • Uterine corpus cancer: Endometrial adenocarcinoma, leiomyosarcoma, carcinosarcoma. • Fallopian tube cancer: Serous histology. • Vulvar cancer: Squamous cell carcinoma, melanoma. • Vaginal cancer: Squamous cell carcinoma. • Extragonadal germ cell tumors: Mediastinal or retroperitoneal.
1.2 Classification by Histology¶
• Type 1 Ovarian Cancers: Low-grade, indolent behavior (low malignant potential tumors, low-grade endometrioid, mucinous, clear cell). • Type 2 Ovarian Cancers: High-grade, aggressive (high-grade serous epithelial ovarian cancers). • Germ Cell Tumors: Dysgerminoma, immature teratoma, yolk sac tumor, choriocarcinoma. • Sex Cord-Stromal Tumors: Granulosa cell tumor, Sertoli-Leydig tumor, fibroma.
2. EPIDEMIOLOGY¶
Incidence and mortality vary by age, genetics, and geography.
• Ovarian Cancer: Lifetime risk ~1.6% (1 in 72). US incidence: ~19,710 cases/year; mortality >13,270/year. • Cervical Cancer: Global incidence >500,000/year; mortality >300,000/year. High-risk regions: Central/South America, Caribbean, sub-Saharan Africa. • Uterine Cancer: US incidence 66,200/year; mortality 13,030/year. Most common subtype: endometrioid (estrogen-linked). • Testicular Cancer: Non-germ cell tumors rare (>50 years). Extragonadal GCTs (~5% of cases): mediastinal or retroperitoneal.
2.1 Ovarian Cancer Epidemiology¶
• Lifetime risk: ~1.6% (1 in 72). • US incidence: ~19,710 cases/year. • Mortality: >13,270/year. • Peak incidence: Women aged 50–60 years. • Familial risk: BRCA1/2, Lynch syndrome.
2.2 Cervical Cancer Epidemiology¶
• Global incidence: >500,000/year. • US incidence: ~13,960 cases/year. • Mortality: ~4,300/year. • HPV prevalence: Primary risk factor (high-risk strains 16/18).
2.3 Uterine Cancer Epidemiology¶
• US incidence: 66,200/year. • Mortality: 13,030/year. • Risk factors: Obesity, unopposed estrogen exposure, tamoxifen use.
2.4 Testicular Cancer Epidemiology¶
• Extragonadal GCTs: ~5% of cases (mediastinal/retroperitoneal). • Klinefelter’s syndrome: Increased risk of mediastinal nonseminomatous GCTs.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Key etiologic factors include genetic mutations and environmental exposures.
• HPV Infection: Primary cause of cervical cancer (high-risk strains 16/18; E6/E7 inactivate p53/RB). • BRCA1/2 Mutations: Drive ovarian and breast cancer (46–87% breast risk, 39–63% ovarian risk). • Estrogen Exposure: Promotes endometrial cancer (obesity, tamoxifen use). • TP53 Mutation: Characteristic of Type 2 ovarian cancers (95% cases).
3.1 HPV and Cervical Cancer¶
• Primary cause: High-risk HPV strains (16/18; >20 high-risk types). • Mechanism: E6/E7 inactivate p53/RB, disrupting cell cycle checkpoints. • Progression: Persistent infection → dysplasia → carcinoma over years. • HPV-negative cancers: KRAS, ARID1A, PTEN mutations.
3.2 Ovarian Cancer Genetics¶
• Type 1: KRAS, BRAF, PTEN, PIK3CA mutations (low-grade). • Type 2: BRCA1/2 loss, TP53 mutation (95% cases; high-grade serous). • Lynch Syndrome: MSH2, MLH1, PMS2 mutations increase risk. • Other genes: NF1, RB1, CDK12.
3.3 Endometrial Cancer Genetics¶
• Type 1 (Estrogen-linked): Endometrioid subtype; driven by estrogen overexposure. • Type 2: Serous/clear cell; TP53 loss. • Genetic risk: BRCA1/2, Lynch syndrome.
3.4 Testicular Cancer Genetics¶
• Klinefelter’s syndrome: Increased mediastinal nonseminomatous GCT risk. • Hematologic disorders: Rare association with AML.
4. CLINICAL FEATURES¶
Symptoms vary by cancer type and stage.
• Ovarian Cancer: Late presentation with GI symptoms (bloating, early satiety), ascites, abdominal girth increase. • Cervical Cancer: Asymptomatic until advanced; postcoital bleeding, foul discharge. • Uterine Cancer: Postmenopausal vaginal bleeding; sarcomas cause pelvic pain/masses. • Testicular Cancer: Palpable mass; torsion/hemorrhage may present acutely.
4.1 Ovarian Cancer Symptoms¶
• Early stage: Often asymptomatic. • Advanced stage: Nausea, bloating, constipation, abdominal pain. • Signs: Ascites (rapid abdominal girth increase). • Physical exam: Pelvic discomfort, urinary/bowel changes.
4.2 Cervical Cancer Symptoms¶
• Early cancer: Asymptomatic. • Invasive carcinoma: Postcoital bleeding, intermenstrual bleeding, foul discharge. • Pain: Pelvic/sacral pain (lateral extension), flank pain (hydronephrosis).
4.3 Uterine Cancer Symptoms¶
• Postmenopausal: Vaginal bleeding. • Premenopausal: Atypical intermenstrual bleeding. • Sarcomas: Pelvic pain, large masses. • Stromal tumors: Estrogen production (breast tenderness, precocious puberty).
4.4 Testicular Cancer Symptoms¶
• Mass: Palpable abdominal/pelvic mass. • Pain: Torsion/hemorrhage (acute presentation). • Hormonal: Virilization in sex cord-stromal tumors. • Metastasis: Rare; most common in advanced prostate cancer/melanoma.
5. DIFFERENTIAL DIAGNOSIS¶
Key differentials include benign and malignant entities.
• Adnexal Masses: Ovarian cancer vs. Krukenberg tumors (metastatic GI), dermoid cysts, PID abscess. • Cervical Lesions: CIN vs. HPV infection, polyps, chlamydia. • Uterine Masses: Leiomyoma vs. leiomyosarcoma, endometrial cancer, adenomyosis.
5.1 Adnexal Mass Differential¶
• Ovarian cancer: Epithelial, germ cell, stromal. • Benign: Cysts, fibromas, dermoid cysts. • Metastatic: Krukenberg tumors (colon, appendix, stomach, breast). • Borderline: Low malignant potential tumors. • Inflammatory: PID, abscess.
5.2 Cervical Lesion Differential¶
• Cervical cancer: Squamous cell, adenocarcinoma. • Precancerous: CIN (CIN1–3). • Infection: HPV, herpes, chlamydia. • Polyps: Cervical polyps.
5.3 Uterine Mass Differential¶
• Leiomyoma: Benign smooth muscle tumor. • Leiomyosarcoma: Malignant smooth muscle tumor. • Endometrial cancer: Adenocarcinoma. • Sarcoma: Carcinosarcoma, leiomyosarcoma. • Adenomyosis: Benign condition.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic approach includes imaging, lab tests, and histology.
• Laboratory Tests: CA-125 (ovarian cancer), AFP (yolk sac tumors), hCG (choriocarcinoma), LDH (seminomas). • Imaging: Ultrasound (adnexal mass), CT (hydronephrosis, lymph nodes), MRI (uterine extension), scrotal ultrasound (extragonadal GCTs). • Staging: Clinical exam + imaging (FIGO staging for ovarian/cervical/uterine cancers).
6.1 Laboratory Tests¶
• CA-125: Elevated in ovarian cancer (not specific). • AFP: Elevated in yolk sac tumors. • hCG: Elevated in choriocarcinomas. • LDH: Elevated in seminomas. • Genetic testing: BRCA1/2, HRD status for ovarian cancer.
6.2 Imaging¶
• Ultrasound: Complex adnexal mass identification. • CT: Hydronephrosis, intraperitoneal disease, lymph nodes. • MRI: Uterine extension, paracervical spread. • PET: Not routinely used. • Scrotal ultrasound: Excludes gonadal primary in extragonadal GCTs.
6.3 Staging Criteria¶
• Ovarian Cancer: Stage I (ovary), II (pelvis), III (peritoneum), IV (parenchymal metastases). • Cervical Cancer: Stage I (cervix), II (upper vagina/paracervical), III (lower vagina/pelvic wall), IV (bladder/rectum/distant). • Uterine Cancer: Stage I (corpus), II (cervix), III (pelvic wall), IV (bladder/rectum).
Table 1: Staging and Survival Summary - Ovarian: I (88–95%), II (70–80%), III (20–40%), IV (10–20%). - Endometrial: I (>90%), II (~75%), III (45–60%), IV (~20%). - Cervix: I (Carcinoma in situ: 100%), II (Invades beyond uterus but not to pelvic wall or lower 1/3 of vagina: 65%), III (Extends to pelvic wall and/or lower third of vagina, or hydronephrosis), IV (Invades mucosa of bladder or rectum or extends beyond the true pelvis: 7%).
6.4 Diagnostic Algorithms¶
• Ovarian Cancer: Laparoscopic evaluation → surgery → debulking → chemotherapy → maintenance. • Cervical Cancer: Pap smear → HPV testing → colposcopy → biopsy → staging → treatment (surgery/radiation). • Uterine Cancer: Endometrial biopsy → hysterectomy + sentinel lymph node biopsy.
7. MANAGEMENT & TREATMENT¶
Management plans vary by cancer type and specific clinical indicators.
• Ovarian Cancer: 1. Initial Treatment: Diagnostic surgery → Primary debulking → Platinum complex + taxane chemotherapy. 2. Maintenance Therapy: Based on HRD status (HRD abnormal → Poly-(ADP-ribose)-polymerase inhibitor for 2 years). 3. Relapse Management: - If Platinum-Sensitive (relapse <6 months after last platinum dose) → Interval surgery → Carboplatin with either liposomal doxorubicin, paclitaxel, or gemcitabine → Subsequent Remission → Maintenance therapy and Bevacizumab. - If Platinum-Resistant/Recurrent (relapse >6 months after last platinum dose) → Single-agent treatments (e.g., Liposomal doxorubicin, topotecan). • Cervical Cancer: Treatment based on staging (surgery/radiation). • Uterine Cancer: Hysterectomy + sentinel lymph node biopsy.
Ovarian Management Pathway¶
- Initial: Diagnostic surgery → Primary debulking → Platinum complex + taxane.
- Maintenance: HRD abnormal → PARP inhibitor (2 years).
- Relapse Decision:
- Relapse < 6 months post-platinum → Platinum-Sensitive → Interval surgery → Carboplatin + liposomal doxorubicin/paclitaxel/gemcitabine.
- Relapse > 6 months post-platinum → Platinum-Resistant → Single agents (e.g., Liposomal doxorubicin, topotecan).
8. COMPLICATIONS & PROGNOSIS¶
Management of complications and assessment of metastatic spread.
• Neurologic Toxicities (Table 6): - Acute encephalopathy (delirium): Methotrexate, Cisplatin, Vincristine, Asparaginase, Procarbazine, 5-Fluorouril (± levamisole), Cytarabine (high-dose), Nitrosoureas (high-dose or arterial), Ifosfamide, Etoposide (high-dose), Bevacizumab (PRES), CAR-T cells. - Chronic encephalopathy (dementia): Methotrexate, Carmustine, Cytarabine, Fludarabine. - Visual loss: Tamoxifen, Gallium nitrate, Cisplatin, Fludarabine. - Cerebellar dysfunction/ataxia: 5-Fluorouril (± levamisole), Cytarabine, Procarbazine. - Seizures: Methotrexate, Etoposide (high-dose), Cisplatin, Vincristine, Asparaginase, Nitrogen mustard, Carmustine, Dacarbazine (intraarterial or high-dose), Busulfin (high-dose). - Myelopathy (IT drugs): Methotrexate, Cytarabine, Thiotepa. - Peripheral neuropathy: Vinca alkaloids, Cisplatin, Procarbazine, Etoposide, Teniposide, Cytarabine, Taxanes, Suramin, Bortezomib.
• Metastatic Spread: - Epidural spread (Figure 13). - Leptomeningeal metastases (Figure 15). - Frequency of Nervous System Metastases (Table 5): Lung (Brain 41%, LM 17%, ESCC 15%); Breast (Brain 19%, LM 57%); Melanoma (Brain 10%, LM 12%, ESCC 4%); Prostate (Brain 1%, LM 1%); GIT (Brain 7%, ESCC 5%); Renal (Brain 3%, LM 2%); Lymphoma (LM 10%, ESCC 10%); Other (Brain 11%, ESCC 18%).
Neuro-oncology Context¶
• Genetic Syndromes (Table 3): - Cowden's: PTEN; Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), meningioma, astrocytoma; associated with Breast, endometrial, thyroid cancer, trichilemmomas. - Gardner's: APC; Medulloblastoma, glioblastoma, craniopharyngioma; associated with Familial polyposis, multiple osteomas, skin and soft tissue tumors. - Li-Fraumeni: p53; Gliomas, medulloblastomas, Sarcomas, breast cancer, leukemias. - MEN1: Menin; Pituitary adenoma, malignant schwannomas, Parathyroid and pancreatic islet cell tumors. - NF1: NF1/neurofibromin. - NF2: NF2/merlin; Bilateral vestibular schwannomas, astrocytomas, multiple meningiomas, ependymomas. - TSC: TSC1/TSC2. - Turcot (Apca): APCa; Gliomas, medulloblastomas. - [hMLH1]: hMLH1 (ch3p21); Adenomatous colon polyps, adenocarcinoma. - [VHL]: VHL gene (ch3p25).
• Glioma Molecular Alterations (Table 4): - Astrocytoma, IDH-mutant: IDH1, IDH2. - Oligodendroglioma, IDH-mutant, 1p/19q-codeleted: IDH1, IDH2, 1p/19q. - Glioblastoma, IDH wild type: Chromosome 7 gain and 10 loss, TERT, EGFR. - Diffuse low-grade glioma, MAPK pathway-altered: BRAF V600E mutation, BRAF fusion, FGFR mutation.
9. KEY PEARLS & HIGH-YIELD POINTS¶
• Ovarian Cancer: High suspicion for advanced disease if ascites or rapid abdominal girth increase is present. • Cervical Cancer: HPV 16 and 18 are the primary drivers of malignancy; early detection via Pap/HPV screening is critical. • Germ Cell Tumors: Use BEP (Bleomycin, Etoposide, Cisplatin) as standard chemotherapy. • Testicular Cancer: Late relapse (>2 years post-treatment) suggests resistance and requires salvage surgery. • Genetic Syndromes: Cowden's syndrome (PTEN mutation) is specifically associated with endometrial cancer.
Reference Tables¶
TABLE 94-1 Staging and Survival in Gynecologic Malignancies¶
Harrison's 22e, p.711
| STAGE | OVARIAN | 5-YEAR SURVIVAL, % | ENDOMETRIAL | 5-YEAR SURVIVAL, % | CERVIX | 5-YEAR SURVIVAL, % |
|---|---|---|---|---|---|---|
| 0 | — | — | Carcinoma in situ | 100 | ||
| Confined to ovary | 88–95 | Confined to corpus | >90 | Confined to uterus | ||
| II | Confined to pelvic organs | 70–80 | Involves corpus and cervix |
~75 | Invades beyond uterus but not to pelvic wall |
65 |
| Intra-abdominal spread to omentum, diaphragm, or lymph nodes |
20–40 | Extends outside the uterus but not outside the true pelvis |
45–60 | Extends to pelvic wall and/ or lower third of vagina, or hydronephrosis |
||
| IV | Spread outside abdominal cavity, parenchymal spread, and pleural effusion cytology |
10–20 | Extends outside the true pelvis or involves the bladder or rectum |
~20 | Invades mucosa of bladder or rectum or extends beyond the true pelvis |
7 |
TABLE 95-1 Symptoms and Signs at Presentation of Brain Tumors Generalized Impaired cognitive function Hemiparesis…¶
Harrison's 22e, p.716
| HIGH-GRADE GLIOMA (%) | LOW-GRADE GLIOMA (%) | MENINGIOMA (%) | METASTASES (%) | |
|---|---|---|---|---|
| Generalized | ||||
| Impaired cognitive function | 50 | 10 | 30 | 60 |
| 40 | 10 | 36 | ||
| Headache | 50 | 40 | 37 | 50 |
| Lateralizing | ||||
| 20 | 70+ | 17 | ||
| Aphasia | 20 | <5 | — | 18 |
| — | — | — |
TABLE 95-2 Genetic Syndromes Associated with Primary Brain Tumors SYNDROME Cowden’s syndrome¶
Harrison's 22e, p.717
| SYNDROME | INHERITANCE | GENE/PROTEIN | ASSOCIATED TUMORS |
|---|---|---|---|
| Cowden’s syndrome | AD | Mutations of PTEN (ch10p23) | Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease), meningioma, astrocytoma |
| Breast, endometrial, thyroid cancer, trichilemmomas | |||
| Sporadic Hereditary |
Mutations in INI1/SNF5 (ch22q11) | ||
| Gardner’s syndrome | AD | Mutations in APC (ch5q21) | Medulloblastoma, glioblastoma, craniopharyngioma |
| Familial polyposis, multiple osteomas, skin and soft tissue tumors | |||
| AD | Mutations in Patched 1 gene (ch9q22.3) | ||
| Li-Fraumeni syndrome | AD | Mutations in p53 (ch17p13.1) | Gliomas, medulloblastomas Sarcomas, breast cancer, leukemias, others |
| AD | Mutations in MSH2, MSH1, MSH6, PMS2 | ||
| Multiple endocrine neoplasia 1 (Wermer’s syndrome) |
AD | Mutations in Menin (ch11q13) | Pituitary adenoma, malignant schwannomas Parathyroid and pancreatic islet cell tumors |
| AD | Mutations in NF1/neurofibromin (ch17q12-22) |
||
| NF2 | AD | Mutations in NF2/merlin (ch22q12) | Bilateral vestibular schwannomas, astrocytomas, multiple meningiomas, ependymomas |
| AD | Mutations in TSC1/TSC2 (ch9q34/16) | ||
| Turcot syndrome | AD | Mutations in APCa (ch5) | Gliomas, medulloblastomas |
| AR | hMLH1 (ch3p21) | Adenomatous colon polyps, adenocarcinoma | |
| AD | Mutations in VHL gene (ch3p25) |
TABLE 95-3 Summary of Gliomas and Relevant Molecular Alterations¶
Harrison's 22e, p.718
| TUMOR TYPE | CHARACTERISTIC MOLECULAR ALTERATIONS |
|---|---|
| Adult-Type Diffuse Gliomas | |
| Astrocytoma, IDH-mutant | IDH1, IDH2 |
| Oligodendroglioma, IDH-mutant, 1p/19q-codeleted |
IDH1, IDH2, 1p/19q |
| Glioblastoma, IDH wild type | Chromosome 7 gain and 10 loss, TERT, EGFR |
| Pediatric-Type Diffuse High-Grade Gliomas | |
| Pediatric-Type Diffuse Low-Grade Gliomas | |
| Diffuse low-grade glioma, MAPK pathway-altered |
MAPK pathway genes (BRAF V600E mutation, BRAF fusion, FGFR mutation) |
TABLE 95-4 Frequency of Nervous System Metastases for Common Primary Tumors Lung Breast Melanoma Prostate GIT Renal…¶
Harrison's 22e, p.723
| BRAIN (%) | LM (%) | ESCC (%) | |
|---|---|---|---|
| Lung | 41 | 17 | 15 |
| 19 | 57 | ||
| Melanoma | 10 | 12 | 4 |
| 1 | 1 | ||
| GIT | 7 | — | 5 |
| 3 | 2 | ||
| Lymphoma | <1 | 10 | 10 |
| 7 | 1 | ||
| Other | 11 | — | 18 |
TABLE 95-5 Neurologic Toxicities Caused by Agents Commonly Used in Patients with Cancer Acute encephalopathy (delirium)¶
Harrison's 22e, p.726
| Acute encephalopathy (delirium) Methotrexate (high-dose IV, IT) Cisplatin Vincristine Asparaginase Procarbazine 5-Fluorouracil (± levamisole) Cytarabine (high-dose) Nitrosoureas (high-dose or arterial) Ifosfamide Etoposide (high-dose) Bevacizumab (PRES) CAR-T cells Chronic encephalopathy (dementia) Methotrexate Carmustine Cytarabine Fludarabine Visual loss Tamoxifen Gallium nitrate Cisplatin Fludarabine Cerebellar dysfunction/ataxia 5-Fluorouracil (± levamisole) Cytarabine Procarbazine |
Seizures Methotrexate Etoposide (high-dose) Cisplatin Vincristine Asparaginase Nitrogen mustard Carmustine Dacarbazine (intraarterial or high-dose) Busulfan (high-dose) Myelopathy (IT drugs) Methotrexate Cytarabine Thiotepa Peripheral neuropathy Vinca alkaloids Cisplatin Procarbazine Etoposide Teniposide Cytarabine Taxanes Suramin Bortezomib |
|---|---|