title: Fumarate Hydratase-deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings.
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. FH-deficient 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 FH-deficient 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.
authors.affiliation: *University of Sydney ¶¶Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney †Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research §Department of Anatomical Pathology ¶Familial Cancer Clinic, Royal North Shore Hospital, St Leonards ‡Douglass Hanly Moir Pathology ∥Histopath Pathology, North Ryde #Department of Medical Oncology, Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick **Department of Medical Oncology, Concord Hospital, Concord West ††Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW ‡‡Department of Anatomical Pathology, Mater Hospital, South Brisbane, Qld, Australia §§Šikl's Department of Pathology, University Hospital, Faculty of Medicine in Pilsen, Charles University in Prague, Prague, Czech Republic ∥∥Department of Pathology and Laboratory Medicine, Calgary Laboratory Services, University of Calgary, Calgary, AB, Canada.
authors.forename: Wesley J
authors.initials: WJ
authors.lastname: Harrison
authors.forename: Juliana
authors.initials: J
authors.lastname: Andrici
authors.forename: Fiona
authors.initials: F
authors.lastname: Maclean
authors.forename: Raha
authors.initials: R
authors.lastname: Madadi-Ghahan
authors.forename: Mahtab
authors.initials: M
authors.lastname: Farzin
authors.forename: Loretta
authors.initials: L
authors.lastname: Sioson
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Toon
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.forename: Nicole
authors.initials: N
authors.lastname: Watson
authors.forename: Justine
authors.initials: J
authors.lastname: Pickett
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.forename: Ashley
authors.initials: A
authors.lastname: Crook
authors.forename: Katherine
authors.initials: K
authors.lastname: Tucker
authors.forename: Annabel
authors.initials: A
authors.lastname: Goodwin
authors.forename: Lyndal
authors.initials: L
authors.lastname: Anderson
authors.forename: Bhuvana
authors.initials: B
authors.lastname: Srinivasan
authors.forename: Petr
authors.initials: P
authors.lastname: Grossmann
authors.forename: Petr
authors.initials: P
authors.lastname: Martinek
authors.forename: Ondrej
authors.initials: O
authors.lastname: Ondič
authors.forename: Ondřej
authors.initials: O
authors.lastname: Hes
authors.forename: Kiril
authors.initials: K
authors.lastname: Trpkov
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Clifton-Bligh
authors.forename: Trisha
authors.initials: T
authors.lastname: Dwight
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D018231:Leiomyomatosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D008875:Middle Aged; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary; D010641:Phenotype; D011379:Prognosis; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D013577:Syndrome; D046888:Tissue Array Analysis; D014594:Uterine Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; D005649:Fumarate Hydratase