Retrospective review of hereditary leiomyomatosis and renal cell cancer at a single institution.

Abstract

10621 Background: Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is an autosomal dominant syndrome caused by loss-of-function mutations in the Fumarate Hydratase ( FH ) gene. HLRCC poses an elevated risk for skin leiomyomas, uterine fibroids, pheochromocytomas, paragangliomas, and renal cell cancer (RCC), particularly FH-deficient RCC and potentially clear cell RCC. It is recommended that patients with personal and/or family history of a single skin leiomyoma, multiple FH-deficient (by immunohistochemistry (IHC)) uterine fibroids, pheochromocytoma, paraganglioma, or FH-deficient RCC be tested for, among other genes, germline FH mutations, with yearly surveillance with abdominal imaging being the recommendation if positive. To better describe this patient population, we present our experience with high-volume referrals for HLRCC testing at a single institution. Methods: We performed retrospective chart review (2017-present) of all patients referred for HLRCC testing at the Hereditary Renal Cell Carcinoma & VHL Disease Clinic and the Hemangioblastoma Center at the Massachusetts General Cancer Center. The study was approved by the Massachusetts General Brigham IRB. Results: We herein describe the largest, to our knowledge, series of HLRCC patients (67) at a single institution. While the majority (30, 45%) of cases were referred due to an incidental genetic finding either on prenatal screening or through a comprehensive multi-cancer gene panel sent for hereditary cancer screening, 31% (21) of patients were referred after being found to have an HLRCC-related lesion. Of this subset, the most common first HLRCC-related lesion was a uterine fibroid that was FH-deficient by IHC (13), followed by an equal number of skin leiomyomas (4) and RCCs (4). Importantly, we calculate the rate of patients later confirmed to have an HLRCC diagnosis (pathogenic variant by genetic sequencing) based on referral reason: patients referred for uterine fibroids deficient in FH by IHC, 59.1% (13 of 21); patients referred for RCC either with loss of FH by IHC or papillary RCC, 80% (4 of 5); patients referred with cutaneous leiomyomas deficient in FH by IHC, 66.7% (4 of 6); and patients with family members with known diagnosis of HLRCC, 83.3% (15 of 18). Mutations in positive HLRCC cases either caused premature termination by nonsense or frameshift (18, 26.9%), point mutations by missense (22, 32.8%), or had an AAA duplication at c.1431_1433, causing a lysine duplication at amino acid residue 477 of the fumarate hydratase protein (20, 22.9%), the last of which has ongoing discussion of true association with HLRCC. One patient was indeed seen to have papillary RCC with this mutation, supporting the association of c.1431_1433dupAAA with HLRCC. Conclusions: In sum, we describe populations characteristics, common reasons for referral, and likelihood of genetic testing confirmation for patients with concern for HLRCC.