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.

*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 Prague Prague Czech Republic ∥∥Department of Pathology and Laboratory Medicine Calgary Laboratory Services University of Calgary Calgary AB Canada

Zobrazit více v PubMed

Reed WB, Walker R, Horowitz R.Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol. 1973;53:409–416. PubMed

Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30:406–410. PubMed

Launonen V, Vierimaa O, Kiuru M, et al. Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A. 2001;98:3387–3392. PubMed PMC

Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet. 2003;12:1241–1252. PubMed

Merino MJ, Torres-Cabala C, Pinto P, et al. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol. 2007;31:1578–1585. PubMed

Toro JR, Nickerson ML, Wei MH, et al. Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet. 2003;73:95–106. PubMed PMC

Sanz-Ortega J, Vocke C, Stratton P, et al. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. Am J Surg Pathol. 2013;37:74–80. PubMed PMC

Martinek P, Grossmann P, Hes O, et al. Genetic testing of leiomyoma tissue in women younger than 30 years old might provide an effective screening approach for the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). Virchows Arch. 2015;467:185–191. PubMed

Payson M, Leppert P, Segars J. Epidemiology of myomas. Obstet Gynecol Clin North Am. 2006;33:1–11. PubMed PMC

Alsolami S, El-Bahrawy M, Kalloger SE, et al. Current morphologic criteria perform poorly in identifying hereditary leiomyomatosis and renal cell carcinoma syndrome-associated uterine leiomyomas. Int J Gynecol Pathol. 2014;33:560–567. PubMed

Reyes C, Karamurzin Y, Frizzell N, et al. Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S-(2-succino)-cysteine immunohistochemistry. Mod Pathol. 2014;27:1020–1027. PubMed PMC

Chen YB, Brannon AR, Toubaji A, et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. Am J Surg Pathol. 2014;38:627–637. PubMed PMC

Bardella C, El-Bahrawy M, Frizzell N, et al. Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status. J Pathol. 2011;225:4–11. PubMed

Trpkov K, Hes O, Agaimy A, et al. IHC screening of unclassified RCC detects tumors associated with HLRCC. Mod Pathol. 2015;28:263A.

Chen YB, Kong MX, Bialik A, et al. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-associated renal cancer: a comparison of fumarate hydratase (FH) and S-(2-succino)-cysteine (2SC) immunohistochemistry as ancillary tools. Mod Pathol. 2015;28:271–318.

Bennett JA, Chiang S, Chen Y-B, et al. Leiomyoma with bizarre nuclei: correlation between morphology and fumarate/S-(2-succino)-cysteine expression. Mod Pathol. 2015;28:276A.

Buelow B, Cohen J, Joseph NM, et al. Immunohistochemistry for 2SC and FH in cutaneous leiomyomas may aid in identification of patients with HLRCC (hereditary leiomyomatosis and renal cell carcinoma syndrome). Mod Pathol. 2015;28:117A. PubMed

Gill AJ. Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology. 2012;44:285–292. PubMed

Barker KT, Spendlove HE, Banu NS, et al. No evidence for epigenetic inactivation of fumarate hydratase in leiomyomas and leiomyosarcomas. Cancer Lett. 2006;235:136–140. PubMed

Barker KT, Bevan S, Wang R, et al. Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas. Br J Cancer. 2002;87:446–448. PubMed PMC

Lehtonen R, Kiuru M, Vanharanta S, et al. Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol. 2004;164:17–22. PubMed PMC

Ylisaukko-oja SK, Kiuru M, Lehtonen HJ, et al. Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer. 2006;119:283–287. PubMed

Kiuru M, Lehtonen R, Arola J, et al. Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res. 2002;62:4554–4557. PubMed

Alam NA, Olpin S, Leigh IM. Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer. Br J Dermatol. 2005;153:11–17. PubMed

Uterine leiomyoma with RAD51B::NUDT3 fusion: a report of 2 cases

New developments in existing WHO entities and evolving molecular concepts: The Genitourinary Pathology Society (GUPS) update on renal neoplasia

Report From the International Society of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers: III: Molecular Pathology of Kidney Cancer

Molecular Genetics of Renal Cell Tumors: A Practical Diagnostic Approach

Immunohistochemical and selected genetic reflex testing of all uterine leiomyosarcomas and STUMPs for ALK gene rearrangement may provide an effective screening tool in identifying uterine ALK-rearranged mesenchymal tumors

Tubulocystic Carcinoma of the Kidney With Poorly Differentiated Foci: A Frequent Morphologic Pattern of Fumarate Hydratase-deficient Renal Cell Carcinoma