Fumarate Hydratase-Deficient Uterine Leiomyomas in Appalachian Women: A Case Series Highlighting Cancer Disparities in Underserved White Populations

Uterine leiomyomas are highly prevalent, yet specific variants, such as fumarate hydratase (FH)-deficient leiomyomas, are rare and clinically significant due to their association with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). Diagnosis of this subtype relies on identifying unique histopathological features and confirming loss of FH expression or positive S-(2-succino)-cysteine (2SC) staining. This diagnostic challenge is compounded in underserved regions like Appalachia, where health inequities and limited access to specialist care can hinder the management of hereditary conditions. We present a case series of three Appalachian women diagnosed with FH-deficient, 2SC-positive uterine leiomyomas, analyzing their presentation, histopathology, and follow-up within the context of regional healthcare disparities. Histopathological analysis in all cases revealed characteristic features such as focal nuclear atypia, bizarre nuclei, and staghorn vessels. Despite findings warranting genetic evaluation, including significant family histories of cancer in two patients, referral for genetic analysis was inconsistent. These cases illustrate the diagnostic complexity of FH-deficient leiomyomas and underscore the barriers to genetics-based care in Appalachia. Our findings emphasize the critical need for heightened clinical suspicion for atypical leiomyomas, implementation of reflex testing, and improved access to genetic services to optimize outcomes for this underserved population.