Unexpected aggressiveness in VHL-associated clear cell renal cell carcinoma: insights from two patients highlighting...

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome predisposing to renal cell carcinoma (RCC), typically considered more indolent than sporadic RCC. The '3 cm rule' has guided nephron-sparing interventions, as tumours smaller than 3 cm rarely metastasise. However, accumulating evidence suggests this paradigm is not universal, with some VHL-associated RCCs demonstrating aggressive biological behaviour despite their small size. We report two cases of aggressive clear cell RCC (ccRCC) in patients with suspected VHL. The first case involved a middle-aged male presenting with bilateral renal tumours, an inferior vena cava tumour thrombus and synchronous liver metastases. He underwent right radical nephrectomy with thrombectomy and contralateral partial nephrectomy, with histopathology confirming ccRCC, WHO/ISUP grade 2, with metastatic deposits. The second case was a young male with a large unilateral renal mass showing sarcomatoid and rhabdoid differentiation, WHO/ISUP grade 4, staged pT3a, consistent with aggressive ccRCC. Both presentations deviated from the traditionally indolent course of VHL-associated RCC, underscoring the heterogeneity of tumour biology. These cases highlight the limitations of strict size-based management, emphasising the importance of vigilant surveillance, histopathological assessment and early genetic evaluation. Recognition of aggressive variants is essential to optimise surgical planning and multidisciplinary management in VHL patients.