## Clear Cell RCC: Defining Features **Key Point:** Clear cell RCC (ccRCC) is the most common subtype (70–80% of RCCs) and arises from the proximal convoluted tubule epithelium, NOT the medulla. ### Correct Answer: Predominant Medullary Involvement Clear cell RCC typically arises in the **renal cortex** and often originates at the corticomedullary junction. Medullary involvement is NOT a characteristic feature; in fact, preservation of cortical architecture with infiltration is more typical. This option is factually incorrect and is the best answer. ### Why the Other Options Are Correct | Feature | Explanation | |---------|-------------| | **Lipid and glycogen accumulation** | The hallmark "clear cell" appearance results from abundant intracytoplasmic lipid and glycogen that are dissolved during routine histologic processing, leaving cells appearing empty under light microscopy. | | **CAIX expression** | VHL inactivation (mutation, deletion, or hypermethylation) leads to HIF-α accumulation, which drives CAIX transcription. CAIX is a hypoxia-inducible marker and is strongly positive in ~90% of ccRCC cases. | | **VHL gene inactivation** | VHL loss occurs in ~80–90% of sporadic ccRCC. This is the most frequent genetic alteration in ccRCC and is central to the pathogenesis of both sporadic and hereditary (von Hippel-Lindau syndrome) cases. | **High-Yield:** The VHL–HIF–VEGF axis is the dominant oncogenic pathway in ccRCC and explains the tumor's vascularity, angiogenesis, and responsiveness to anti-VEGF and mTOR inhibitors. **Clinical Pearl:** Patients with hereditary VHL syndrome have a ~70% lifetime risk of developing bilateral, multifocal ccRCC, often at a younger age than sporadic cases.
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