Fumarate hydratase-deficient uterine leiomyomas occur in both the syndromic and sporadic settings

Wesley J. Harrison, Juliana Andrici, Fiona Maclean, Raha Madadi-Ghahan, Mahtab Farzin, Loretta Sioson, Christopher W. Toon, Adele Clarkson, Nicole Watson, Justine Pickett, Michael Field, Ashley Crook, Katherine Tucker, Annabel Goodwin, Lyndal Anderson, Bhuvana Srinivasan, Petr Grossmann, Petr Martinek, Ondrej Ondič, Ondřej HesKiril Trpkov, Roderick J. Clifton-Bligh, Trisha Dwight, Anthony J. Gill*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Citations (Scopus)

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome secondary to germline fumarate hydratase (FH) mutation presents with cutaneous and uterine leiomyomas, and a distinctive aggressive renal carcinoma. Identification of HLRCC patients presenting first with uterine leiomyomas may allow early intervention for renal carcinoma. We reviewed the morphology and immunohistochemical (IHC) findings in patients with uterine leiomyomas and confirmed or presumed HLRCC. IHC was also performed on a tissue microarray of unselected uterine leiomyomas and leiomyosarcomas. FH-deficient leiomyomas underwent Sanger and massively parallel sequencing on formalin-fixed paraffin-embedded tissue. All 5 patients with HLRCC had at least 1 FH-deficient leiomyoma: defined as completely negative FH staining with positive internal controls. One percent (12/1152) of unselected uterine leiomyomas but 0 of 88 leiomyosarcomas were FH deficient. FHdeficient leiomyoma patients were younger (42.7 vs. 48.8 y, P=0.024) and commonly demonstrated a distinctive hemangiopericytomatous vasculature. Other features reported to be associated with FH-deficient leiomyomas (hypercellularity, nuclear atypia, inclusion-like nucleoli, stromal edema) were inconstantly present. Somatic FH mutations were identified in 6 of 10 informative unselected FH-deficient leiomyomas. None of these mutations were found in the germline. We conclude that, while the great majority of patients with HLRCC will have FHdeficient leiomyomas, 1% of all uterine leiomyomas are FH deficient usually due to somatic inactivation. Although IHC screening for FH may have a role in confirming patients at high risk for hereditary disease before genetic testing, prospective identification of FH-deficient leiomyomas is of limited clinical benefit in screening unselected patients because of the relatively high incidence of somatic mutations.

Original languageEnglish
Pages (from-to)599-607
Number of pages9
JournalAmerican Journal of Surgical Pathology
Volume40
Issue number5
DOIs
Publication statusPublished - May 2016
Externally publishedYes

Keywords

  • Fumarate hydratase
  • Fumarate hydratase-deficient leiomyoma
  • HLRCC
  • Leiomyoma

Fingerprint Dive into the research topics of 'Fumarate hydratase-deficient uterine leiomyomas occur in both the syndromic and sporadic settings'. Together they form a unique fingerprint.

Cite this