Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 1;44(5):385-397.
doi: 10.1097/PGP.0000000000001101. Epub 2025 Jan 13.

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

Julianne M Szczepanski  1 , David B Chapel  1 , Tao Huang  1 , Trinh Pham  2 , Rahul Mannan  1   3 , Rohit Mehra  1   3   4 , Andrew P Sciallis  5 , Scott Tomlins  1 , Stephanie L Skala  1   4 , Aaron M Udager  1   3   4
Affiliations

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

Julianne M Szczepanski et al. Int J Gynecol Pathol. .

Abstract

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.

Keywords: Fumarate hydratase–deficient leiomyoma; Leiomyoma with bizarre nuclei; Smooth muscle tumor of uncertain malignant potential; Uterine smooth muscle tumor.

PubMed Disclaimer

Conflict of interest statement

S.A.T. is a co-founder of and current Chief Medical Officer for Stata Oncology. The remaining authors declare no conflict of interest.

References

    1. Bell SW, Kempson RL, Hendrickson MR. Problematic uterine smooth muscle neoplasms. A clinicopathologic study of 213 cases. Am J Surg Pathol 1994;18:535–558.
    1. Lim D, Alvarez T, Nucci MR, et al. Interobserver variability in the interpretation of tumor cell necrosis in uterine leiomyosarcoma. Am J Surg Pathol 2013;37:650–658.
    1. Harrison WJ, Andrici J, Maclean F, et al. Fumarate hydratase-deficient uterine leiomyomas occur in both the syndromic and sporadic settings. Am J Surg Pathol 2016;40:599–607.
    1. Miettinen M, Felisiak-Golabek A, Wasag B, et al. Fumarase-deficient uterine leiomyomas: an immunohistochemical, molecular genetic, and clinicopathologic study of 86 cases. Am J Surg Pathol 2016;40:1661–1669.
    1. Pors J, Weiel JJ, Devereaux KA, et al. Fumarate hydratase deficiency should be considered in the differential diagnosis of uterine and extrauterine smooth muscle tumors of uncertain malignant potential (STUMP). Int J Gynecol Pathol 2022;41:268–275.

Substances

Supplementary concepts