Renal cell carcinoma is the most lethal of the genitourinary cancers, though most tumours are now found incidentally as small, localised masses. Most cases are sporadic and linked to obesity, smoking, and hypertension, but ~4–6% arise from autosomal dominant familial syndromes — most importantly von Hippel-Lindau, which defines the VHL–HIF–VEGF pathway central to RCC biology and therapy.
Epidemiology
- Incidence is rising (wider imaging use and rising obesity), with the greatest increase in small, localised masses (now >40% of new tumours). US incidence ~81,800 (2023, includes renal pelvis); Canada ~7,500 (2020, 10th most common).
- Mortality — US ~13,920 (2022); the most lethal GU malignancy, though 5-year survival is improving ~1%/year.
- 5-year relative survival by stage: localised 93%, regional 70%, distant 13%, all stages 75%.
- Demographics — M:F 1.75:1 (worse mortality in men); typical age 50–70 (median 64); more common in Black, American Indian, and Alaska Native populations. RCC in children and young adults is more often symptomatic, locally advanced, high-grade, and of unfavourable histology.
Risk Factors
Most RCC is sporadic. Four established risk factors: obesity (~30% of cases, tending to lower-grade/stage tumours), smoking (~20%), hypertension, and chronic renal failure / dialysis (controversial — consider delaying screening until the 3rd dialysis year). Others include a family history without a defined syndrome, chlorinated-solvent exposure, retroperitoneal radiation, and acquired cystic renal disease. Moderate alcohol, fruit/cruciferous-vegetable, and fatty-fish intake may be protective. ADPKD does not increase RCC risk.
Familial Syndromes
All are autosomal dominant and together account for ~4–6% of cases:
| Syndrome | Gene | Renal tumour | Key extra-renal features |
|---|---|---|---|
| Von Hippel-Lindau | VHL (3p25–26) | Clear cell RCC (bilateral, multifocal) + cysts | CNS/retinal haemangioblastomas, phaeochromocytoma, paraganglioma, pancreatic NETs/cysts, epididymal cystadenoma, endolymphatic sac tumour |
| Hereditary Papillary RCC | c-MET | Type 1 papillary (less aggressive) | — |
| Hereditary Leiomyomatosis & RCC* | Fumarate hydratase | Type 2 papillary or collecting duct | Cutaneous and uterine leiomyomas |
| Birt-Hogg-Dubé | Folliculin | Chromophobe, oncocytoma, hybrid tumours | Skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax |
| Succinate Dehydrogenase RCC* | SDHB/C/D | Clear cell, chromophobe, type 2 papillary, oncocytoma | Phaeochromocytoma / paraganglioma |
| Tuberous Sclerosis Complex | TSC1/2 | AML, ccRCC, oncocytoma, cysts | Adenoma sebaceum, shagreen patches, seizures, intellectual disability, retinal/CNS/cardiac lesions, pulmonary LAM |
| Cowden / PTEN | PTEN | ccRCC, papillary, chromophobe | Trichilemmomas, breast and thyroid malignancy |
| BAP1 tumour predisposition* | BAP1 | ccRCC | Uveal and cutaneous melanoma, mesothelioma, BCC |
*Renal cancers in these syndromes tend to be more aggressive.
Von Hippel-Lindau (1:30,000–40,000) — RCC develops in 35–70%, with early onset (median 40) and bilateral/multifocal disease; RCC is the leading cause of death in VHL. The VHL gene at 3p25–26 is the most common mutation in sporadic clear cell RCC. Normally the VHL complex degrades hypoxia-inducible factors (HIF); without VHL, HIF accumulates → VEGF overexpression → the neovascularity of ccRCC (and EPO-driven polycythaemia). Phaeochromocytoma occurs only in certain (type 2 VHL) families; offer affected patients genetic evaluation and presymptomatic screening.
Belzutifan (Welireg) — an oral HIF-2α inhibitor, the first drug approved specifically for VHL disease (2021); it blocks HIF-2α from binding ARNT, shutting off VEGF/EPO transcription. It is indicated for VHL-associated RCC, CNS haemangioblastomas, and pancreatic NETs not needing immediate surgery (Study 004 objective response ~36% RCC, ~30% haemangioblastoma, ~83% pNET). Key toxicity: anaemia (EPO suppression).
Other syndromes: HPRCC (c-MET tyrosine-kinase activation → less aggressive type 1 papillary); HLRCC (cutaneous leiomyomas and uterine fibroids in nearly all, RCC in only ~20% but unilateral, solitary, and aggressive — prompt surgery); and TSC (classic triad of seizures, adenoma sebaceum, and intellectual disability; 50% develop AMLs).
Self-Test
1. What proportion of RCC is familial? About 4–6%.
2. What are the clinical manifestations of VHL? Clear cell RCC and renal cysts, CNS/retinal haemangioblastomas, phaeochromocytoma, paraganglioma, pancreatic neuroendocrine tumours and cysts, epididymal cystadenoma, and endolymphatic sac tumours.
3. Gene and renal phenotype for HPRCC, HLRCC, Birt-Hogg-Dubé, and TSC? HPRCC — c-MET, type 1 papillary; HLRCC — fumarate hydratase, type 2 papillary (aggressive) with cutaneous/uterine leiomyomas; Birt-Hogg-Dubé — folliculin, chromophobe/oncocytoma with pulmonary cysts and pneumothoraces; TSC — TSC1/2, AMLs and ccRCC with adenoma sebaceum and seizures.
4. Explain the VHL–HIF pathway in RCC. Normally VHL targets HIF for degradation; with VHL loss, HIF accumulates and drives VEGF overexpression — the principal angiogenic factor in RCC.
5. What are the established risk factors for RCC? Obesity, smoking, hypertension, and chronic renal failure (plus acquired cystic disease and familial syndromes).