title: Fumarate Hydratase-deficient Renal Cell Carcinoma Is Strongly Correlated With Fumarate Hydratase Mutation and Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome.
abstract: Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinomas (RCC) are difficult to diagnose prospectively. We used immunohistochemistry (IHC) to identify fumarate hydratase (FH)-deficient tumors (defined as FH negative, 2-succinocysteine [2SC] positive) in cases diagnosed as "unclassified RCC, high grade or with papillary pattern," or "papillary RCC type 2," from multiple institutions. A total of 124 tumors (from 118 patients) were evaluated by IHC for FH and 2SC. An FH deficiency was found in 24/124 (19%) cases. An indeterminate result (only 1 marker abnormal) was found in 27/124 (22%) cases. In a tissue microarray of 776 RCCs of different types, only 2 (0.5%) tumors, initially considered papillary type 2, were FH deficient. FH mutations were found in 19/21 FH-deficient tumors (with confirmed germline mutations in 9 of 9 tumors in which germline status could be assessed) and in 1/26 FH-indeterminate tumors identified by IHC. No FH mutations were found in 2/21 FH-deficient RCCs, 25/26 FH-indeterminate RCCs, and 10/10 RCCs demonstrating FH expression by IHC. Patients with FH-deficient RCC had a median age of 44 years (range, 21 to 65 y). Average tumor size was 8.2 cm (range, 0.9 to 18 cm). FH-deficient RCCs were characterized by at least focal macronucleoli and demonstrated 2 or more growth patterns in 93% cases. Papillary was the most common (74%) and dominant (59%) pattern, whereas other common patterns included: solid (44%), tubulocystic (41%), cribriform (41%), and cystic (33%). At presentation, 57% were stage ≥pT3, 52% had positive nodes, and 19% had distant metastases. After a mean follow-up of 27 months (range, 1 to 114 mo), 39% of patients were dead of disease, and 26% had disease progression. We conclude that FH and 2SC are useful IHC ancillary tools, which allow recognition of FH-deficient RCC.
authors.affiliation: *Calgary Laboratory Services and University of Calgary, Calgary, AB, Canada §§McGill University, Montreal, QC, Canada †Charles University, Pilsen, Czech Republic ‡Institute of Pathology, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany ∥University Clinic Bonn, Germany §Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH ‡‡University of Michigan, Ann Arbor, MI ∥∥University of South Carolina School of Medicine, Columbia, SC ¶University of Florence, Florence, Italy #Pitié-Salpêtrière Hospital, Paris, France **Hopital Cochin, APHP, Université Paris Descartes, Paris, France ††Barts Cancer Institute, Queen Mary University of London, London, United Kingdom ¶¶Sullivan Nicolaides Pathology, Gold Coast, Qld, Australia ***Mater Hospital, South Brisbane, Qld, Australia ##Douglass Hanly Moir Pathology, North Ryde, NSW, Australia †††Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.
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authors.lastname: Trpkov
authors.forename: Ondrej
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authors.lastname: Hes
authors.forename: Abbas
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authors.lastname: Agaimy
authors.forename: Michael
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authors.lastname: Bonert
authors.forename: Petr
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authors.lastname: Martinek
authors.forename: Cristina
authors.initials: C
authors.lastname: Magi-Galluzzi
authors.forename: Glen
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authors.lastname: Kristiansen
authors.forename: Christine
authors.initials: C
authors.lastname: Lüders
authors.forename: Gabriella
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authors.lastname: Nesi
authors.forename: Eva
authors.initials: E
authors.lastname: Compérat
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Berney
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.forename: Fadi
authors.initials: F
authors.lastname: Brimo
authors.forename: Arndt
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authors.lastname: Hartmann
authors.forename: Arjumand
authors.initials: A
authors.lastname: Husain
authors.forename: Norma
authors.initials: N
authors.lastname: Frizzell
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hills
authors.forename: Fiona
authors.initials: F
authors.lastname: Maclean
authors.forename: Bhuvana
authors.initials: B
authors.lastname: Srinivasan
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000209:etiology; D003545:Cysteine / Q000031:analogs & derivatives / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D005649:Fumarate Hydratase / Q000172:deficiency* / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000209:etiology; D018231:Leiomyomatosis / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008661:Metabolism, Inborn Errors / Q000150:complications*; D008875:Middle Aged; D009123:Muscle Hypotonia / Q000150:complications*; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D011596:Psychomotor Disorders / Q000150:complications*; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D046888:Tissue Array Analysis; D014594:Uterine Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology*; D055815:Young Adult
chemical_list: C511650:S-(2-succinyl)cysteine; D005649:Fumarate Hydratase; D003545:Cysteine