Fumarate Hydratase Mutations and Alterations in Leiomyoma with Bizarre Nuclei

Qing Zhang, Kate Poropatich, Julianne Ubago, Jia Xie, Xiuhua Xu, Norma Frizzell, Julie Kim, Beihua Kong, Jian Jun Wei*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Leiomyoma with bizarre nuclei (LM-BN), is a variant of uterine smooth muscle tumor with atypical histologic features. Although some LM-BN share several significant genetic alterations with leiomyosarcoma, including p16 and p53, the underlying tumorigenesis of LM-BN remains largely unknown. As we previously reported, LM-BN can be divided into 2 subtypes, type I and type II, based on different nuclear features. Type I LM-BN have similar histologic features as uterine smooth muscle tumors with fumarate hydratase (FH) alterations. In this study, we examined FH expression and FH mutations in 77 LM-BN (40 type I cases and 37 type II cases). FH expression was examined by immunohistochemistry using S-(2-succino)-cysteine antibodies (2SC, a protein modification associated with FH inactivation and subsequent fumarate accumulation) and FH antibodies (FH gene products). Seventy-two LM-BN tumors underwent Sanger sequencing to detect FH mutations. We found that 51% (39/77) of LM-BN showed FH alterations detected by immunohistochemistry with both 2SC and FH. Mutational analysis showed that 21% (15/72) of LM-BN harbored FH gene mutations. Further analysis revealed that 85% (34/40) of those with FH alterations were type I LM-BN while 19% (7/37) were type II LM-BN. Our findings suggest that over half of histologically diagnosed LM-BN may be related to FH alterations or FH mutations and the majority of these have the characteristic histologic features of type I LM-BN.

Original languageEnglish (US)
Pages (from-to)421-430
Number of pages10
JournalInternational Journal of Gynecological Pathology
Issue number5
StatePublished - Sep 1 2018


  • Fumarate hydratase
  • Gene mutation
  • Immunohistochemistry
  • Leiomyoma with bizarre nuclei
  • Uterine smooth muscle tumor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Obstetrics and Gynecology

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