23: Clinical and imaging findings in individuals with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) and utility of FH/2SC staining in the identification of FH-deficient piloleiomyomas

Background: Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) has phenotypic manifestations that include uterine leiomyomas, piloleiomyomas, and aggressive renal cell carcinoma (RCC). At a single tertiary academic center, we aimed to identify clinical, histopathologic, and imaging findings in HLRCC families, and assess the utility of fumarate hydratase (FH) and 2-succinocysteine (2SC) immmunohistochemistry (IHC) on piloleiomyomas as a prelude to genetic referral.

Methods: We retrospectively reviewed 29 probands who met major clinical criteria for HLRCC (i.e. multiple cutaneous leiomyomas) or whom had a documented FH germline mutation. HLRCC positive family members of the 29 probands were also included in the analysis if records were available. Thirty-nine individual records were reviewed (ages 4-75 years). FH germline mutations were documented in 28 individuals. A separate search of institutional pathology archives identified 64 piloleiomyomas from 41 patients between 1995 to 2023 on which FH/2SC IHC was performed.

Results: 28 of 39 individuals who had renal imaging were reviewed; 54% (15/28) exhibited renal cysts, 7% (2/28) angiomyolipomas, and 11% (3/28) adrenal adenomas. First or second-degree relatives with RCC were reported in 18% (5/29) of evaluable families with HLRCC. Piloleiomyomas were present in 63% (12/19) of women and 94% (16/17) of men over age 10. Uterine leiomyomas were present in 88% (15/17) of evaluable women over age 10 and 76% (13/17) underwent hysterectomy or myomectomy.

From our separate search of our institutional pathology archive, FH-deficiency/2SC-positivity was found in 41/64 piloleiomyomas and 18/41 patients. FH-loss and positive 2SC staining was demonstrated in 100% (12/12) of piloleiomyomas from individuals with more than one piloleiomyoma. Six solitary, piloleiomyomas from 6 different individuals, with unknown HLRCC status, were FH-deficient by IHC.

Conclusions: Our study underscores the role of FH/2SC in identifying FH-deficient piloleiomyomas to aid in appropriate genetic referral. Notably, we report two HLRCC patients with angiomyolipomas, including a case of bilateral angiomyolipomas.