Renal haemangioblastoma: a clinicopathologic and molecular characterization of 8 cases supporting the presence of recurrent MTOR pathway alterations.

Renal haemangioblastoma is a very rare mesenchymal neoplasm that remains incompletely characterized despite its inclusion in the WHO classification. In this study, we investigate the clinicopathologic and molecular features of renal haemangioblastoma. The cohort comprised 8 patients (six male, two female) with a median age of 47 years (range: 29-63). No patients had a known history of a tumour predisposition syndrome. The tumours ranged in size from 1.3 to 8.0 cm (median: 4.0 cm). Histologically, the tumours were well circumscribed and composed of epithelioid/polygonal cells with clear-to-palely eosinophilic and often multivacuolated cytoplasm. In other areas, the tumour cells were more spindled. A prominent vascular pattern was frequently present. Two tumours were closely associated with renal cell carcinoma (RCC); the latter demonstrated features characteristic of RCC with fibromyomatous stroma (FMS). Targeted DNA sequencing was successfully performed on 7 tumours, revealing that most (5/7; 71%) harboured one or more alterations involving mTOR pathway genes. A total of 9 mTOR pathway alterations were identified, affecting MTOR (n = 3), TSC1 (n = 4), TSC2 (n = 1) and PTEN (n = 1). Immunohistochemistry for glycoprotein nonmetastatic B (GPNMB) was positive in 5/6 tumours assessed, including one tumour that lacked an identifiable mTOR pathway alteration by sequencing. This study contributes further understanding to the pathogenesis of renal haemangioblastoma and supports that it exists on a spectrum with RCC with haemangioblastoma-like features and RCC with FMS.