Recurrent mTOR pathway alterations in renal cell carcinoma with hemangioblastoma-like features: A multi-institutional...

Renal hemangioblastoma (HB) is a rare extra-central nervous system mesenchymal neoplasm molecularly defined by recurrent mTOR pathway alterations and lacking VHL abnormalities, distinct from its central nervous system counterpart. While rare renal cell carcinomas (RCCs) exhibiting HB-like features have been documented, their clinicopathological spectrum, biological behavior, and molecular underpinnings remain incompletely characterized. This study characterizes a multi-institutional series of 9 cases of RCC with HB-like features. All tumors presented as well-circumscribed, solitary renal masses (median size, 2.6 cm), with 8 out of 9 cases demonstrating thick fibromuscular capsules. All cases uniformly lacked necrosis, mitotic activity, and vascular invasion. Histologically, the tumors demonstrated a variable proportion of the RCC component (5-50% tumor volume, mean:10%) with clear to pale eosinophilic cells forming tubules, acini, or tubulocystic structures blending with the dominant HB-like component; one case showed discrete compartmentalization of the RCC component, forming distinct papillary and tubulocystic structures adjacent to HB-like areas. Immunohistochemically, RCC components expressed epithelial markers (AE1/AE3, cytokeratin 7, CAM5.2), while HB-like components expressed stromal markers (α-inhibin, S100 protein). Critically, both components consistently expressed PAX8, vimentin, carbonic anhydrase IX, CD10, neuron-specific enolase, and GPNMB (8/9). Targeted next-generation sequencing revealed universal mTOR pathway alterations: mutually exclusive MTOR mutations (5 cases) or TSC2 mutations (4 cases), with no VHL alterations or 3p25 deletions identified. Over a median follow-up of 50 months (range, 4-114 months), all patients remained disease-free. Our study confirms that RCC with HB-like features represents a distinct morphological pattern within the HB to RCC with fibromyomatous stroma continuum and establishes its expanded morphological spectrum and indolent biological behavior.