🟠 Renal Cell Carcinoma
Pathology, subtypes, presentation, paraneoplastic syndromes, staging, surgical management, systemic therapy — MRCS high-yield.
Overview & Pathology
Definition
Renal cell carcinoma (RCC) is a malignant tumour arising from the renal tubular epithelium of the renal cortex. It accounts for approximately 85% of all primary renal malignancies in adults (the remainder being urothelial carcinoma of the renal pelvis, Wilms’ tumour in children, and rare sarcomas).
| Feature | Detail |
|---|---|
| Incidence | ~13,000 new cases/year in the UK; 3rd most common urological cancer after prostate and bladder |
| Peak age | 6th–7th decade; male:female ~2:1 |
| 5-year survival | Localised: ~90%; locally advanced: ~65%; metastatic: ~12% |
| Bilateral/multifocal | Sporadic cases unilateral; VHL syndrome → bilateral, multifocal |
| Historical name | Hypernephroma (Grawitz tumour) — misnomer, previously thought to arise from adrenal rests |
Risk Factors
| Risk Factor | Mechanism / Notes |
|---|---|
| Smoking | Most important modifiable risk — doubles risk; clear cell subtype most affected |
| Obesity | BMI >35 increases risk ~1.5–2× — adipokines, insulin resistance, inflammation |
| Hypertension | Independent risk factor; possibly direct renal tubular damage |
| Von Hippel-Lindau (VHL) disease | Autosomal dominant. VHL gene (3p25) mutation → bilateral, multifocal clear cell RCC in nearly 100% by age 60. Also: haemangioblastomas, phaeochromocytoma, endolymphatic sac tumours, clear cell renal cysts, pancreatic cysts/NETs |
| Hereditary papillary RCC | MET proto-oncogene mutation → bilateral type 1 papillary RCC |
| Birt-Hogg-Dubé syndrome | FLCN gene → chromophobe RCC + oncocytoma hybrids; pulmonary cysts; fibrofolliculomas |
| Tuberous sclerosis | TSC1/TSC2 → angiomyolipomas (most common), cysts, rarely RCC |
| Chronic kidney disease / dialysis | Acquired cystic disease of the kidney → increased RCC risk (~30× in dialysis patients) |
| Analgesic nephropathy | Long-term phenacetin/NSAID use → urothelial and renal parenchymal carcinoma |
RCC is not a single disease — subtypes have distinct molecular biology, behaviour, and therapeutic sensitivities. The WHO 2022 classification recognises multiple entities; the most important for MRCS are:
- VHL gene loss (chr 3p25) in ~80% — even sporadic cases
- VHL loss → ↑ HIF → ↑ VEGF/PDGF → highly vascular tumour
- Bright yellow/gold on cut section (lipid-rich cytoplasm)
- Most common subtype in VHL syndrome
- Most responsive to VEGF-targeted therapy and immunotherapy
- Worst prognosis among common subtypes when high grade
- Type 1: MET mutations; sporadic or hereditary (HPRCC); better prognosis
- Type 2: Fumarate hydratase (FH) mutations; more aggressive; associated with hereditary leiomyomatosis and RCC (HLRCC)
- Frothy/foamy cytoplasm; papillary architecture
- Often multifocal and bilateral
- Less vascular than clear cell — less responsive to VEGF therapy
- Arises from intercalated cells of collecting duct
- Large pale cells with prominent cell membranes (“plant cell” appearance)
- Associated with Birt-Hogg-Dubé syndrome
- Best prognosis of the three main subtypes — rarely metastasises
- Hale’s colloidal iron stain positive
- Arises from principal cells of the collecting duct
- Aggressive; often metastatic at presentation
- Poor prognosis; poor response to standard therapies
- Medullary location — arises near the renal hilum
- Benign renal tumour — NOT a true RCC, but clinically important
- Cannot be reliably distinguished from chromophobe RCC on imaging
- Classic “spoke-wheel” pattern of central scar on CT (not pathognomonic)
- Biopsy can assist but can be non-diagnostic
- Small lesions: active surveillance; larger: nephron-sparing surgery
VHL Pathway — Why Clear Cell RCC is So Vascular
The VHL tumour suppressor gene (chr 3p25) normally promotes degradation of HIF-1α (hypoxia-inducible factor). When VHL is lost (mutated or deleted), HIF-1α accumulates regardless of oxygen levels → upregulation of VEGF, PDGF, TGF-α, GLUT-1 → pathological angiogenesis → highly vascular tumour. This explains:
- Why clear cell RCC enhances brightly on CT with contrast (arterial phase)
- Why VEGF/mTOR pathway inhibitors (sunitinib, pazopanib, everolimus) are effective in clear cell RCC
- Why VHL syndrome causes bilateral, multifocal clear cell RCC — every cell carries one germline VHL mutation; somatic loss of the second allele drives tumorigenesis in many cells