[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [General pathology](https://durgical.com/en/general-pathology/) › [Kidney](https://durgical.com/en/general-pathology/areas/kidney/) › Clear cell renal cell carcinoma # 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. Updated Nov 12, 2026 ## Key points - Clear cell type: most renal cell carcinomas; arises from proximal tubule. - 3p loss and VHL inactivation; also PBRM1, SETD2, BAP1 chromatin genes. - Gross: solitary, spherical, golden-yellow with hemorrhage, necrosis and cysts; tends to invade the renal vein and grow up the vena cava. - Classic triad (pain, mass, hematuria) occurs in only a minority; hematuria is the most reliable sign. - Paraneoplastic: polycythemia (erythropoietin), hypercalcemia (PTHrP), hypertension (renin), Cushing, feminization. - Metastasizes to lung and bone most often; may present with metastasis. ## 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. ## Memory aid Lose 3p, lose VHL, keep HIF on: the cell thinks it is suffocating and builds vessels. ## 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. [Add to my cards (3)](https://durgical.app/estudiar/?add=/en/general-pathology/clear-cell-renal-cell-carcinoma/) [More Pathology questions →](https://durgical.com/en/practice/?f=pathology) ## Elsewhere in DurgiPedia - [Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis](https://durgical.com/en/general-pathology/tumour-suppressor-genes-rb-tp53-apc-brca-and-the-two-hit-hypothesis/) - [Tumour angiogenesis](https://durgical.com/en/general-pathology/tumour-angiogenesis/) - [Paraneoplastic syndromes: the table to know](https://durgical.com/en/general-pathology/paraneoplastic-syndromes-the-table-to-know/) - [Pathways of spread and the usual metastatic sites](https://durgical.com/en/general-pathology/pathways-of-spread-and-the-usual-metastatic-sites/) ## Connections ## Related 5 - [Papillary, chromophobe and the rarer renal cell carcinomas](https://durgical.com/en/general-pathology/papillary-chromophobe-and-the-rarer-renal-cell-carcinomas/) - [Benign kidney tumours](https://durgical.com/en/general-pathology/benign-kidney-tumours/) - [Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis](https://durgical.com/en/general-pathology/tumour-suppressor-genes-rb-tp53-apc-brca-and-the-two-hit-hypothesis/) - [Tumour angiogenesis](https://durgical.com/en/general-pathology/tumour-angiogenesis/) - [Hereditary cancer syndromes: the table to know](https://durgical.com/en/general-pathology/hereditary-cancer-syndromes-the-table-to-know/) ## Related conditions 6 - [Renal cell carcinoma](https://durgical.com/en/conditions/renal-cell-carcinoma/) - [Hypercalcaemia of malignancy](https://durgical.com/en/conditions/hypercalcaemia-of-malignancy/) - [Paraneoplastic syndromes](https://durgical.com/en/conditions/paraneoplastic-syndromes/) - [Tobacco use disorder](https://durgical.com/en/conditions/tobacco-use-disorder/) - [Obesity](https://durgical.com/en/conditions/obesity/) - [Chronic kidney disease](https://durgical.com/en/conditions/chronic-kidney-disease/) [← All of general pathology](https://durgical.com/en/general-pathology/) 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](https://medlineplus.gov/ency/article/000516.htm) (MedlinePlus, US National Library of Medicine, 2025); [Renal Cell Cancer Treatment (PDQ®)–Patient Version](https://www.cancer.gov/types/kidney/patient/kidney-treatment-pdq) (National Cancer Institute, 2025). ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/general-pathology/clear-cell-renal-cell-carcinoma/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/clear-cell-renal-cell-carcinoma/