Clear cell renal cell carcinoma
- Lesion
The commonest kidney cancer of adults: loss of the VHL gene makes cells behave as if starved of oxygen, building vessels and storing lipid.
What it is
Renal cell carcinomas arise from tubular epithelium and make up most adult kidney cancers; clear cell carcinoma is the commonest type. Smoking, obesity, hypertension, acquired cystic disease and occupational exposures raise the risk. Almost all clear cell tumours lose the short arm of chromosome 3 and inactivate VHL, sporadically or in von Hippel-Lindau disease. Without VHL, hypoxia-inducible factor builds up and turns on VEGF, growth factors and glucose uptake, which explains the rich vascular network and the yellow lipid-rich cells.
Structure
- Cells with clear cytoplasm full of lipid and glycogen, in nests separated by a delicate, richly branched capillary network.
- Nuclear grade (WHO/ISUP) uses nucleolar prominence; sarcomatoid and rhabdoid areas mean high grade.
- Immunohistochemistry: PAX8, CA-IX (box-like), CD10 positive.
Step by step
- One VHL copy is lost with the 3p deletion; the other is mutated or silenced by methylation.
- Without VHL protein, HIF is not tagged for destruction even when oxygen is normal.
- HIF switches on VEGF, PDGF and TGF-α: angiogenesis and autocrine growth.
- Cells shift to glycolysis and store lipid and glycogen, so they look clear.
- Mutations in chromatin regulators (PBRM1, SETD2, BAP1) drive progression.
- The vascular tumour invades veins and spreads by blood to lungs and bone.
Clinical notes
- Often found incidentally on imaging done for other reasons.
- Drugs against VEGF and mTOR, and immune checkpoint inhibitors, follow directly from this biology.
- In Latin America and the Caribbean, smoking accounts for a share of kidney and bladder cancers.
Test yourself
Think of the answer, then tap the question to see it.
Which gene is inactivated in nearly all clear cell renal cell carcinomas?
VHL on the short arm of chromosome 3.
How does VHL loss explain the vascularity of the tumour?
HIF accumulates and induces VEGF and other angiogenic factors.
Which three paraneoplastic syndromes occur with renal cell carcinoma?
Polycythemia from erythropoietin, hypercalcemia from PTH-related protein and hypertension from renin.
Elsewhere in DurgiPedia
- Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis
- Tumour angiogenesis
- Paraneoplastic syndromes: the table to know
- Pathways of spread and the usual metastatic sites
Connections
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Renal cell carcinoma: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2025); Renal Cell Cancer Treatment (PDQ®)–Patient Version (National Cancer Institute, 2025).
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Representative model, for educational purposes only.