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Fumarate Hydratase–deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings

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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.
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Keywords: HLRCC; fumarate hydratase; fumarate hydratase–deficient leiomyoma; leiomyoma

Document Type: Research Article

Affiliations: 1: University of Sydney, Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research 2: Douglass Hanly Moir Pathology 3: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Department of Anatomical Pathology 4: University of Sydney, Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Histopath Pathology, North Ryde 5: Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research 6: Familial Cancer Clinic, Royal North Shore Hospital, St Leonards 7: Department of Medical Oncology, Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick 8: University of Sydney, Department of Medical Oncology, Concord Hospital, Concord West 9: University of Sydney, Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW 10: Department of Anatomical Pathology, Mater Hospital, South Brisbane, Qld, Australia 11: Šikl’s Department of Pathology, University Hospital, Faculty of Medicine in Pilsen, Charles University in Prague, Prague, Czech Republic 12: Department of Pathology and Laboratory Medicine, Calgary Laboratory Services, University of Calgary, Calgary, AB, Canada 13: University of Sydney, Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney 14: University of Sydney, Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, Department of Anatomical Pathology

Publication date: May 1, 2016

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