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.