The Morphologic and Molecular Heterogeneity of Fumarate Hydratase–deficient Leiomyomas: Integrative Molecular Profiling of Uterine Smooth Muscle Tumors With Histologic Feature Correlation

The morphologic features of uterine smooth muscle tumors (USMTs) are subject to interobserver variability and are complicated by consideration of features of fumarate hydratase deficiency (FHd) and other morphologic subtypes, with difficult cases occasionally diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP). We compare immunohistochemical findings and detailed morphologic analysis of 45 USMTs by 4 fellowship-trained gynecologic pathologists with comprehensive molecular analysis, focusing on FHd leiomyomas (n=15), compared to a variety of other USMTs with overlapping morphologic features, including 9 STUMPs, 8 usual-type leiomyomas (ULM), 11 apoplectic leiomyomas, and 2 leiomyomas with bizarre nuclei (LMBN). FHd leiomyomas, defined by immunohistochemical (IHC) loss of FH and/or 2SC accumulation, showed FH mutations and/or FH copy loss in all cases, with concurrent TP53 mutations in 2 tumors. Severe and/or symplastic-type cytologic atypia was seen more often in FHd leiomyomas with only FH copy loss (6/8, and 2/2 with concurrent TP53 mutations) compared to those with FH mutations (2/7) and typically showed increased genomic instability. This subset of FHd tumors often showed morphologic overlap with STUMPs and LMBN, but all cases of FHd tumors showed 2SC accumulation and/or FH loss by IHC. In conclusion, we highlight the importance of investigating USMTs with severe and/or symplastic-type cytologic atypia with FH and 2SC IHC, as many of these tumors are FH-deficient via focal deep deletion (2-copy loss) of the FH locus. In addition, we report the presence of concurrent TP53 mutations in FHd tumors with more severe cytologic atypia; further data about clinical outcomes for these tumors are needed.