8.3 Genitourinary & Gynecologic Malignancies

1. Renal Cell Carcinoma

The classic triad of flank pain, hematuria and a palpable mass occurs in under 10% of patients and usually signals advanced disease. Most renal cell carcinomas today are found incidentally on imaging performed for another reason.

Clues that should prompt suspicion:

• Paraneoplastic syndromes are unusually common: hypercalcemia (parathyroid hormone-related peptide), erythrocytosis (autonomous erythropoietin production), hypertension (renin), Stauffer syndrome (non-metastatic hepatic dysfunction with elevated alkaline phosphatase that reverses after nephrectomy), fever and amyloidosis.
• A new left-sided varicocele that does not decompress when supine suggests left renal vein obstruction by tumor thrombus.

Risk factors: smoking, obesity, hypertension, acquired cystic disease of dialysis, and hereditary syndromes — von Hippel-Lindau disease (clear cell, often bilateral and multifocal, with hemangioblastomas and pheochromocytoma), Birt-Hogg-Dube syndrome and hereditary leiomyomatosis.

Diagnosis is radiologic, using contrast-enhanced CT or MRI; percutaneous biopsy is not routinely required before nephrectomy for a classic enhancing solid renal mass. Renal cell carcinoma is characteristically resistant to conventional cytotoxic chemotherapy; advanced disease is treated with immune checkpoint inhibitors and tyrosine kinase inhibitors. There is no recommended screening for the general population.

2. Bladder Cancer

Painless gross hematuria is the cardinal presentation, and the single most important teaching point is that it must be evaluated even if it resolves spontaneously and even if a urinary tract infection is present. Intermittency is characteristic of malignancy, not reassuring.

Evaluation of hematuria in an adult: urinalysis with microscopy to confirm true hematuria and assess for glomerular features (dysmorphic red cells, red cell casts, proteinuria), then cystoscopy plus upper tract imaging with CT urography for non-glomerular hematuria. Urine cytology supplements but does not replace cystoscopy.

Risk factors: cigarette smoking (the dominant modifiable factor), occupational aromatic amine exposure (dye, rubber, leather, painting), cyclophosphamide, pelvic radiation, and chronic irritation; chronic Schistosoma haematobium infection causes squamous cell carcinoma of the bladder.

Most tumors are non-muscle-invasive urothelial carcinoma at diagnosis, managed with transurethral resection and intravesical therapy — bacillus Calmette-Guerin for high-grade disease — with lifelong surveillance cystoscopy because recurrence is the rule.

3. Prostate Cancer

Screening is a shared decision, not a routine order. Prostate-specific antigen screening should be individualized after discussion of benefits and harms in men aged roughly 55 to 69, and is not recommended at age 70 and above. The harms — overdiagnosis of indolent disease and treatment-related incontinence and erectile dysfunction — are substantial and must be part of the conversation.

Diagnosis uses PSA and digital rectal examination, increasingly with multiparametric MRI before biopsy to target lesions and avoid unnecessary sampling. Grading uses the Gleason score and Grade Group.

Management by risk:

• Low-risk, low-volume disease: active surveillance with serial PSA, MRI and biopsy is preferred, because these cancers frequently never threaten life.
• Localized intermediate or high risk: radical prostatectomy or radiation with androgen deprivation.
• Metastatic: androgen deprivation therapy combined with an androgen-receptor pathway inhibitor or docetaxel.

Complications the internist manages: androgen deprivation causes osteoporosis (monitor bone density and supplement calcium and vitamin D), metabolic syndrome, cardiovascular risk, hot flashes and sarcopenia. Osteoblastic bone metastases are the classic pattern and may cause spinal cord compression; a bone scan is sensitive precisely because the lesions are blastic, in contrast to myeloma.

4. Testicular Cancer

The most common solid malignancy in men aged 15 to 35, and highly curable even when metastatic, which is why the exam treats a missed diagnosis as a serious error.

Presentation: a painless firm testicular mass or swelling. Any solid intratesticular mass is malignant until proven otherwise. A minority present with pain that is mistaken for epididymitis; failure to resolve on antibiotics requires ultrasound.

Evaluation:

1. Scrotal ultrasound
2. Serum tumor markers before orchiectomy: alpha-fetoprotein, beta-human chorionic gonadotropin, lactate dehydrogenase
3. Radical inguinal orchiectomy — both diagnostic and therapeutic

Transscrotal biopsy or orchiectomy is contraindicated because it violates the scrotal lymphatic drainage and alters the pattern of spread. This is a favorite exam point.

Marker interpretation: pure seminoma never produces alpha-fetoprotein. An elevated alpha-fetoprotein in a tumor that looks like seminoma histologically means it contains non-seminomatous elements and must be treated as a non-seminoma. Beta-hCG may be modestly elevated in seminoma.

Risk factors: cryptorchidism (risk persists in the contralateral testis and after orchiopexy), prior testicular cancer, family history. Sperm banking should be discussed before treatment.

5. Ovarian Cancer

There is no effective screening test, and this is a heavily tested negative: neither CA-125 nor transvaginal ultrasound reduces mortality in average-risk women, and both generate harmful false positives leading to unnecessary surgery.

Presentation is nonspecific and late — bloating, early satiety, pelvic or abdominal pain, urinary urgency — which is why most disease presents at an advanced stage with ascites and carcinomatosis.

Hereditary risk drives management. BRCA1 and BRCA2 mutations confer substantially elevated risk, as does Lynch syndrome. For known carriers, risk-reducing bilateral salpingo-oophorectomy is recommended, generally at ages 35 to 40 for BRCA1 and 40 to 45 for BRCA2 after childbearing. A family history of breast and ovarian cancer should trigger genetic counseling.

Protective factors include combined oral contraceptive use, multiparity and breastfeeding. Treatment is cytoreductive surgery with platinum-taxane chemotherapy, with PARP inhibitor maintenance in homologous recombination-deficient disease.

6. Endometrial Cancer

The most common gynecologic malignancy in the United States, and unusually favorable because it announces itself early.

Postmenopausal bleeding is endometrial cancer until proven otherwise and always requires evaluation — transvaginal ultrasound with an endometrial thickness threshold, or direct endometrial biopsy. Any bleeding after menopause, however slight, qualifies.

Risk factors all reduce to unopposed estrogen exposure:

• Obesity — peripheral aromatization of androgens; the dominant modifiable risk factor
• Chronic anovulation / polycystic ovary syndrome
• Nulliparity, early menarche, late menopause
• Estrogen therapy without a progestin in a woman with a uterus
• Tamoxifen — an estrogen agonist at the endometrium
• Lynch syndrome — lifetime risk approaching that of colorectal cancer; endometrial cancer is frequently the sentinel malignancy in affected women

Combined oral contraceptives and progestin-containing intrauterine devices are protective. Routine screening is not recommended, even in tamoxifen users; the recommendation is prompt evaluation of any abnormal bleeding.

7. Cervical Cancer

Almost entirely attributable to persistent high-risk human papillomavirus infection, particularly types 16 and 18 — which makes it both preventable by vaccination and detectable by screening.

Screening combines cytology and HPV testing at guideline-defined intervals beginning at age 21, with primary HPV testing increasingly preferred in older cohorts. HPV vaccination does not change screening recommendations for those already vaccinated.

Presentation when screening fails: postcoital bleeding, abnormal vaginal bleeding, or malodorous discharge. Advanced disease causes obstructive uropathy from ureteral involvement, which is a common cause of death.

Immunosuppression, including HIV infection, increases risk and progression rate and mandates more frequent screening.

8. Vulvar Cancer

Uncommon, and important chiefly because it is frequently misdiagnosed as a benign dermatosis for months or years. A persistent vulvar plaque, ulcer, pruritus or pigmented lesion that does not respond to topical therapy requires biopsy rather than another prescription.

Two pathways: an HPV-related pathway in younger women and a non-HPV pathway arising in lichen sclerosus in older women — which is why lichen sclerosus warrants surveillance rather than indefinite empiric treatment.

9. Urologic and Gynecologic Cancer Screening: What Is and Is Not Recommended

The pattern to internalize: for most genitourinary and gynecologic cancers, the evidence supports rapid evaluation of a specific symptom rather than population screening. Cervical cancer is the outlier, because a long, detectable pre-invasive phase makes screening effective.