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Renal cell carcinoma — clear cell and other subtypes
In most clear cell kidney cancers the VHL gene is inactive, HIF accumulates and drives VEGF — so metastatic treatment combines immunotherapy with VEGFR inhibitors; localised disease is treated by partial or radical nephrectomy.
Why it matters in the exam
Kidney cancer questions in the bank focus mainly on biology: how VHL loss causes angiogenesis, which hereditary syndromes are linked to kidney cancer (VHL, Lynch and others), and when to refer a young patient for genetic testing. The clinical questions cover risk groups in metastatic disease, first-line choice and treatment of the papillary subtype.
A common distractor is thinking kidney cancer responds to classic chemotherapy or conventionally fractionated radiation — it is relatively resistant to both, but responds well to SBRT and immunotherapy. Paraneoplastic findings such as polycythaemia and hypercalcaemia also appear in the scenarios.
Key points
- Loss of VHL activity causes HIF accumulation and activation of VEGF and PDGF — the biological basis of therapy with VEGFR inhibitors and HIF-2α inhibitors.
- A small localised tumour is treated by partial nephrectomy, and after high-risk surgery adjuvant pembrolizumab is given.
- In metastatic disease first line is combination immunotherapy, guided by IMDC risk groups.
- The papillary subtype is treated with cabozantinib because of the role of the MET pathway, and in non-clear cell subtypes a clinical trial is also worth considering.
- A young patient, bilateral tumours or recurrent tumours require work-up for VHL and other hereditary syndromes.
Summary table
| Issue | Key points | Exam detail |
|---|---|---|
| Biology | VHL loss prevents HIF degradation, and HIF drives VEGF and PDGF | Belzutifan inhibits HIF-2α; tyrosine kinase inhibitors block VEGF receptors |
| Hereditary syndromes | VHL: kidney cancer, brain and retinal haemangioblastomas, phaeochromocytoma and pancreatic cysts | Also FH, BHD, tuberous sclerosis and BAP1; age 46 or less — genetic work-up |
| Localised disease | Partial nephrectomy for T1; radical nephrectomy for large tumours | Adjuvant pembrolizumab for one year in high-risk clear cell |
| Risk groups in metastatic disease (IMDC) | Less than one year from diagnosis to treatment, poor performance status, low haemoglobin, high calcium, high neutrophils and platelets | In the MSKCC model high LDH replaces neutrophils and platelets |
| First-line metastatic clear cell | PD-1 inhibitor with a VEGFR inhibitor (axitinib, cabozantinib or lenvatinib), or nivolumab with ipilimumab | A sarcomatoid component responds especially well to immunotherapy |
| Papillary subtype | Cabozantinib | The MET pathway matters in this subtype |
| Paraneoplastic syndromes | Polycythaemia from erythropoietin, hypercalcaemia from PTHrP, abnormal liver tests without metastases | The classic triad: haematuria, flank pain and mass — rare today |
In the full version for subscribers
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Sources
- NCCN Clinical Practice Guidelines in Oncology: Kidney Cancer, 2026 — Systemic therapy for relapsed or stage IV disease
- ESMO Clinical Practice Guideline: Renal cell carcinoma, 2024 — Diagnosis, treatment and follow-up
- DeVita, Hellman and Rosenberg's Cancer: Principles and Practice of Oncology, 12th ed. (2023) — Cancer of the kidney
Sources are given for further reading; the text is written afresh and not copied from them.
Reviewed by the Examqo AI Professor · 2026-11-06. The text may contain errors; when in doubt, check the source.