Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei

Abstract

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.

Comparative analysis of AKT and the related biomarkers in uterine leiomyomas with MED12, HMGA2, and FH mutations

“…Fresh frozen and/or formalin‐fixed and paraffin‐embedded tumor, and myometrial tissues were used. The genotypes of the selected ULM with MED12 mutations, HMGA2 overexpression and biallelic FH inactivation have been reported in previous studies …”

“…After genotype was determined by gene mutation analysis ( MED12 exon 2) and immunohistochemistry ( HMGA2 overexpression and loss of FH ), the cases from each of three gene mutations were selected for this study including 25 ULM with MED12 mutations, and 15 ULM with HMGA2 overexpression. We also selected 27 ULM with loss of FH expression in our collection of leiomyoma with bizarre nuclei . Histologically, MED12 ULM showed varied cellularity of smooth muscle cells with prominent extracellular matrix and low vasculature (Figure ; H/E).…”

“…15 FH ULM exhibit characteristic histologic features in leiomyomas of bizarre nuclei. 16,17 Further investigation of the molecular and histological difference in ULM with different driver gene mutations may assist in understanding biological and medical significance and aid in clinical management.…”

High grade infiltrative adenocarcinomas of renal cell origin: New insights into classification, morphology, and molecular pathogenesis

“…Variable stromal edema has been described, as has schwannoma‐like nuclear palisading . In particular, it seems that a significant subset of atypical or bizarre leiomyomas show FH deficiency …”

“…50,51 In particular, it seems that a significant subset of atypical or bizarre leiomyomas show FH deficiency. 52,53 One of the challenges of dealing with this syndrome, from the surgical pathologist's standpoint, is that tumors with morphologic and cytologic features very suggestive of the syndrome seem to come to sign-out without available documentation of any personal or family history of the syndrome or any data regarding presence or absence of its stigmata. [54][55][56] This is important, because the pathologist's role for recognition, triage, and referral for definitive genetic testing of hereditary RCC is essential and growing, 57 and has been supported by data showing strong association between histologic findings and positive testing.…”