Fumarate Hydratase-deficient Uterine Smooth Muscle Tumors: A 6-Year Prospective Analysis of Morphology-based Screening and Patient Outcomes.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant disorder caused by germline fumarate hydratase (FH) pathogenic variants (PVs), characterized by cutaneous leiomyomas, early-onset uterine leiomyomas, and aggressive papillary renal cell carcinoma. While FH-deficient (FH-d) uterine leiomyomas have been proposed as a screening tool for identifying patients, prospective studies remain limited. Over a 6-yr study period, 1838 uterine smooth muscle tumors (uSMTs) were evaluated at our institution and prospectively screened for FH-d morphologic features. Seventy-one tumors (3.9%) showed features suggestive of FH-deficiency, prompting FH immunohistochemistry (IHC), which confirmed FH loss in 41 cases (58%). Among 41 patients with FH-d tumors, the median patient age was 43 yr, and most underwent hysterectomy for symptomatic leiomyomas, abnormal vaginal bleeding, or pelvic pain. Thirty-six patients (88%) had 2 or more leiomyomas, while 5 had a single tumor. The cohort included 39 FH-d leiomyomas, 1 uterine smooth muscle tumor of uncertain malignant potential (STUMP), and 1 FH-d adenomyoma, a previously unreported entity. Genetic counseling was offered to 36 of 41 (88%) patients. Fifteen patients declined testing or did not follow up with the genetic counseling appointment. Among 19 patients tested for FH and other hereditary cancer-related genes, 5 (26%) had FH germline pathogenic mutations, and 1 patient had a variant of unknown significance. Pelvic MRI in mutation carriers showed no abnormalities. In conclusion, FH-d uSMTs represented 2.2% of all uSMTs in our series. A combined morphologic and IHC screening approach can effectively identify patients at risk for HLRCC, facilitating genetic counseling and family screening.