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Q1: Cell of origin, subtypes and classification (2 min)
Define renal cell carcinoma. What is its cell of origin and the commonest histological subtype? List the major subtypes with their genetic drivers and relative frequencies. How are hereditary RCC syndromes distinguished from sporadic RCC (VHL, hereditary papillary RCC, Birt-Hogg-Dube, HLRCC, tuberous sclerosis)? Reproduce the Bosniak cyst classification.
Expected: adenocarcinoma of the proximal convoluted tubule; clear-cell ~75 percent (VHL, 3p25); papillary type 1 (MET, trisomy 7) and type 2 (FH, HLRCC); chromophobe (FLCN, Birt-Hogg-Dube); collecting-duct and medullary (sickle-cell trait). Bosniak I, II, IIF (~5 to 10 percent, follow-up), III (~50 percent, biopsy or excise), IV (~90 percent, surgery).
Q2: Risk factors and clinical presentation (3 min)
List the major risk factors for RCC (recall SOAP plus dialysis and genes). Describe the classic triad and its current frequency. Why is the modern presentation different? Describe the paraneoplastic syndromes of RCC and their mediators (polycythaemia/EPO, hypercalcaemia/PTHrP, Stauffer syndrome). Why does a new left varicocele that does not empty on lying down in a man raise suspicion for a left renal tumour?
Expected: smoking, obesity, age, hypertension, dialysis (acquired cystic), VHL. Triad of haematuria, flank pain, palpable mass now rare (under 10 percent), most incidental on imaging. Paraneoplastic EPO (polycythaemia), PTHrP (hypercalcaemia), Stauffer (non-metastatic reversible cholestasis). Left testicular vein drains into the left renal vein; tumour thrombus obstructs it producing a non-reducible left varicocele.
Q3: Pathophysiology (2 min)
Describe the VHL-HIF molecular cascade in clear-cell RCC. Which hypoxia-response genes are upregulated and what phenotype do they produce? Why is RCC chemo-resistant? Describe the routes of spread and why the renal vein and IVC pattern is characteristic.
Expected: bi-allelic VHL loss on 3p25 disables the E3 ubiquitin ligase that destroys HIF-alpha in normoxia; HIF accumulates and drives VEGF (angiogenesis, golden-yellow hypervascular tumour), GLUT-1 (Warburg glycolysis, clear cytoplasm), EPO (polycythaemia), CA-IX. Chemo-resistant due to P-glycoprotein / MDR-1 pumps and low proliferative index. Spread: direct capsular, renal vein to IVC tumour thrombus, lymphatic (para-aortic), haematogenous (lung cannonball, bone, liver, brain).
Q4: Investigations and staging (2 min)
What is the imaging modality of choice for characterising a renal mass, and what CT criterion defines a solid RCC? Reproduce the IMDC prognostic criteria. List the staging investigations. When is renal mass biopsy indicated?
Expected: multiphase contrast-enhanced CT; enhancement of over 15 to 20 Hounsfield units defines a solid mass suspicious for RCC. IMDC: one point each for time-to-treatment under 1 year, KPS under 80, haemoglobin below normal, calcium above normal, neutrophils and platelets above normal (favourable 0, intermediate 1 to 2, poor 3 to 6). Staging: CT abdomen/pelvis, CT chest, bloods (FBC, U&E, LFT, calcium), MRI for IVC thrombus, bone scan if symptomatic. Biopsy for metastatic disease before systemic therapy, surveillance enrolment, suspected lymphoma/infection.
Q5: Management and landmark trials (2 min)
Outline the management of localised RCC. What are the modern first-line agents for metastatic RCC, and which landmark trials established them? Why is RCC chemo-resistant? Reproduce the dose of sunitinib and the regimen.
Expected: localised — partial nephrectomy (T1, nephron-sparing), radical nephrectomy (T2 or central), thermal ablation (RFA, cryoablation for small tumours in unfit patients), active surveillance for small renal masses with limited life expectancy. Metastatic — chemo-resistant; first-line ICI combinations: nivolumab + ipilimumab (CheckMate 214, PMID 29562145), pembrolizumab + axitinib (KEYNOTE-426, PMID 30779529), pembrolizumab + lenvatinib (CLEAR, PMID 33616314). Sunitinib 50 mg once daily, 4 weeks on / 2 weeks off (PMID 17215529). Cytoreductive nephrectomy selective in the immunotherapy era (CARMENA).