A 58-year-old man with a 20-year history of smoking presents with hematuria and flank pain. Imaging reveals a solid renal mass. Histopathology shows polygonal cells with clear cytoplasm arranged in nests separated by a delicate vascular network. Which is the most common histological subtype of renal cell carcinoma in this patient?

Explanation

## Most Common Histological Subtype of RCC ### Clear Cell RCC — The Predominant Form **Key Point:** Clear cell renal cell carcinoma (ccRCC) accounts for 70–80% of all renal cell carcinomas, making it by far the most common subtype encountered in clinical practice. ### Histopathological Features of Clear Cell RCC - **Cytoplasm:** Abundant lipid and glycogen → clear or "empty" appearance on H&E staining - **Architecture:** Nested or acinar pattern separated by a delicate fibrovascular network - **Nuclear grade:** Varies from low to high; Fuhrman grading applies - **Immunohistochemistry:** Positive for PAX8, CA IX; negative for cytokeratin 7 ### Risk Factors and Associations | Risk Factor | Association | | --- | --- | | Smoking | 2–3× increased risk | | Obesity | Increased risk, especially in women | | Hypertension | Independent risk factor | | Chronic kidney disease | Increased incidence | | Von Hippel–Lindau (VHL) syndrome | Nearly 100% develop ccRCC by age 60 | | Hereditary papillary RCC | Familial papillary subtype | **High-Yield:** The VHL gene (chromosome 3p25) is inactivated in ~80% of sporadic ccRCC, leading to HIF-α accumulation and VEGF overexpression — the basis for anti-VEGF and mTOR inhibitor therapy. ### Clinical Pearl Clear cell RCC has the worst prognosis among RCC subtypes when matched for stage, due to higher rates of metastasis and aggressive biology. The classic triad of hematuria, flank pain, and constitutional symptoms occurs in only ~10% of cases; most are now detected incidentally on imaging. ### Comparison with Other Subtypes | Subtype | Frequency | Key Features | Prognosis | | --- | --- | --- | --- | | Clear cell | 70–80% | Clear cytoplasm, VHL mutation, VEGF-driven | Worst (stage-matched) | | Papillary | 10–15% | Papillary architecture, MET/CDKN1B mutations | Intermediate | | Chromophobe | 5% | Pale cytoplasm, "vegetable cells," binucleate | Better than ccRCC | | Oncocytoma | 3–5% | Benign, eosinophilic, mitochondria-rich | Excellent (benign) | **Warning:** Oncocytoma is benign and is NOT a true renal cell carcinoma — it does not metastasize. However, it can be confused with chromophobe RCC or eosinophilic variant of ccRCC on imaging and even histology.