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Stem
A 58-year-old male heavy smoker (40 pack-years) presents to the outpatient department with three weeks of painless gross haematuria, right flank discomfort, and unintentional weight loss of 6 kg over two months. On examination he is plethoric; blood pressure is 168/96 mmHg; a hard, non-tender mass is ballotable in the right flank on bimanual palpation. Bloods: haemoglobin 188 g/L (haematocrit 0.58), corrected calcium 2.95 mmol/L, alkaline phosphatase 320 U/L with normal bilirubin and albumin, eGFR 68. Contrast-enhanced CT of the abdomen shows a 9 cm heterogeneous, hypervascular solid mass arising from the upper pole of the right kidney, with enhancement of 50 Hounsfield units between non-contrast and corticomedullary phases and a filling defect in the right renal vein. CT chest shows three well-circumscribed rounded pulmonary nodules in both lung fields.
Questions
a) What is the most likely diagnosis and list four clinical features from the stem that support it? (2 marks)
Renal cell carcinoma (clear-cell subtype) of the right kidney with renal vein tumour thrombus and pulmonary (cannonball) metastases. Supporting features: (i) the classic triad of painless haematuria, flank pain and a palpable flank mass; (ii) paraneoplastic polycythaemia (haemoglobin 188 g/L, haematocrit 0.58 — ectopic erythropoietin); (iii) paraneoplastic hypercalcaemia (corrected calcium 2.95 mmol/L — PTHrP); (iv) the large hypervascular enhancing upper-pole renal mass with renal vein thrombus and cannonball lung metastases on imaging; plus risk factors of smoking and hypertension.
b) Outline the molecular pathogenesis of the clear-cell subtype and explain the paraneoplastic polycythaemia. (2 marks)
Clear-cell RCC is driven by bi-allelic inactivation of the VHL tumour-suppressor gene on chromosome 3p25 (a Knudson two-hit mechanism: one allele lost by 3p deletion, the second by point mutation or promoter methylation). The VHL protein normally forms part of an E3 ubiquitin-ligase complex that recognises hydroxylated HIF-alpha and targets it for proteasomal degradation in normoxia. Loss of VHL allows HIF-alpha to accumulate, dimerise with HIF-beta and drive transcription of hypoxia-response genes including VEGF (angiogenesis), GLUT-1 (Warburg glycolysis — clear cytoplasm), carbonic anhydrase IX, and erythropoietin (EPO). The ectopic EPO production by the tumour — arising in the very cell whose physiological role is EPO regulation — explains the paraneoplastic polycythaemia.
c) List the staging investigations required and reproduce the Bosniak, IMDC, or TNM classification relevant to this patient. (3 marks)
Staging: multiphase contrast-enhanced CT abdomen/pelvis (already done — defines primary, renal vein thrombus, nodal and adrenal/liver disease), CT chest (cannonball metastases), full blood count, U&E, LFT, calcium and coagulation; consider MRI for the renal vein/IVC thrombus level; renal mass biopsy is not required if imaging is classical and surgery or systemic therapy is planned (here metastatic disease may warrant biopsy before systemic therapy). TNM: this is at least T2 (>7 cm, confined to kidney) with renal vein involvement (T3a) — so T3a — and M1 (lung metastases), making it Stage IV. IMDC criteria (one point each for time-to-treatment under 1 year, KPS under 80, haemoglobin below normal, calcium above normal, neutrophils and platelets above normal): this patient has a normal KPS (presumed 90), normal haemoglobin (actually polycythaemic), raised calcium — placing him in at least intermediate-risk. IMDC drives first-line systemic therapy choice.
d) Outline the definitive management and the key agents with regimens. (3 marks)
This is metastatic RCC, which is chemo-resistant; management is by systemic immunotherapy/targeted therapy under a urology-oncology MDT, with a possible role for cytoreductive nephrectomy in selected fit patients with limited metastatic burden. First-line for intermediate-risk metastatic clear-cell RCC is an immune checkpoint inhibitor combination: nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA-4) per CheckMate 214 (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then nivolumab maintenance), OR pembrolizumab plus axitinib (KEYNOTE-426), OR pembrolizumab plus lenvatinib (CLEAR — strongest OS/PFS benefit). Tyrosine-kinase inhibitor monotherapy (sunitinib 50 mg daily, 4 weeks on / 2 weeks off; or pazopanib, cabozantinib) is an alternative, particularly for favourable-risk disease. Manage the paraneoplastic hypercalcaemia (aggressive isotonic saline 3 to 6 L/day plus IV zoledronic acid 4 mg). Consider palliative metastasectomy or radiotherapy for symptomatic bone/brain metastases; monitor and treat immunotherapy-related adverse events (pneumonitis, colitis, hepatitis, endocrinopathies) with corticosteroids.