title: Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers.
abstract: We addressed uncertainties regarding hereditary leiomyomatosis and renal cell carcinoma (HLRCC) by exploring all French cases, representing the largest series to date. Fumarate hydratase (FH) germline testing was performed with Sanger sequencing and qPCR/MLPA. Enzyme activity was measured when necessary. We carried out whenever possible a pathology review of RCC and S-(2-succino)-cysteine (2SC)/fumarate hydratase immunohistochemistry. We estimated survival using non-parametric Kaplan-Meier. There were 182 cases from 114 families. Thirty-seven RCC were diagnosed in 34 carriers (19%) at a median age of 40. Among the 23 RCC with pathology review, 13 were papillary type 2. There were 4 papillary RCC of unspecified type, 3 unclassified, 2 tubulocystic, and 1 collecting duct (CD) RCC, all 2SC+ and most (8/10) FH-. Of the remaining 14, papillary type 2, papillary unspecified, CD, and clear cell histologies were reported. The vast majority of RCC (82%) were metastatic at diagnosis or rapidly became metastatic. Median survival for metastatic disease was 18 months (95%CI: 11-29). 133 cases (73%) had a history of cutaneous leiomyomas, 3 developed skin leiomyosarcoma. Uterine leiomyomas were frequent in women (77%), but no sarcomas were observed. Only 2 cases had pheochromocytomas/paraganglioma.
  
  
  CONCLUSIONS
  Our findings have direct implications regarding the identification and management of HLRCC patients.
authors.affiliation: Réseau Expert National pour Cancers Rares de l'Adulte PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Ecole Pratique des Hautes Etudes F-75014 Paris, Laboratoire de Génétique Oncologique EPHE, INSERM U1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.|Département de Médecine Oncologique, Institut de Cancérologie de Lorraine Alexis Vautrin, Nancy, France.
authors.forename: M
authors.identifier: http://orcid.org/0000-0001-6412-932X
authors.initials: M
authors.lastname: Muller
authors.affiliation: Réseau Expert National pour Cancers Rares de l'Adulte PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Service d'Anatomie Pathologique, Hôpitaux Universitaires Paris Sud, AP-HP, Le Kremlin-Bicêtre, France.
authors.forename: S
authors.initials: S
authors.lastname: Ferlicot
authors.affiliation: Département de Biopathologie, Service de Génétique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: M
authors.initials: M
authors.lastname: Guillaud-Bataille
authors.affiliation: Unité de Biostatistiques et d'Epidémiologie, Gustave Roussy, Université Paris-Saclay, Villejuif, France.|INSERM U1018, CESP, Université Paris-Saclay, Villejuif, France.
authors.forename: G
authors.initials: G
authors.lastname: Le Teuff
authors.affiliation: Département de Biopathologie, Service d'Anatomie-Pathologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Genestie
authors.affiliation: Réseau Expert National pour Cancers Rares de l'Adulte PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: S
authors.initials: S
authors.lastname: Deveaux
authors.affiliation: Service de Biologie Moléculaire, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
authors.forename: A
authors.initials: A
authors.lastname: Slama
authors.affiliation: Service de Dermatologie, Centre Hospitalier Lyon Sud, Lyon, France.
authors.forename: N
authors.initials: N
authors.lastname: Poulalhon
authors.affiliation: Réseau Expert National pour Cancers Rares de l'Adulte PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: B
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: L
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Département de Génétique Moléculaire, Hôpital Bichat-Claude Bernard, Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Soufir
authors.affiliation: Réseau Expert National pour Cancers Rares de l'Adulte PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Service de Dermatologie, Hôpital Cochin, AP-HP, Paris, France.|Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: M-F
authors.initials: MF
authors.lastname: Avril
authors.affiliation: Ecole Pratique des Hautes Etudes F-75014 Paris, Laboratoire de Génétique Oncologique EPHE, INSERM U1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.|Inserm UMR 892, CNRS UMR 6299, Centre de Recherche en Cancérologie Nantes-Angers, Institut de Recherche en Santé, Université de Nantes, Nantes, France.
authors.forename: B
authors.initials: B
authors.lastname: Gardie
authors.affiliation: Service d'Oncologie Médicale, Hôpital Henri Mondor, Créteil, France.
authors.forename: C
authors.initials: C
authors.lastname: Saldana
authors.affiliation: Service d'Anatomie-Pathologique, Hôpital Henri Mondor, AP-HP, Créteil, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Allory
authors.affiliation: Réseau Expert National pour Cancers Rares de l'Adulte PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Centre de Recherche Cardiovasculaire, INSERM, UMR970, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Service de Génétique, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
authors.forename: A-P
authors.initials: AP
authors.lastname: Gimenez-Roqueplo
authors.affiliation: Département de Biopathologie, Service de Génétique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: B
authors.initials: B
authors.lastname: Bressac-de Paillerets
authors.affiliation: Réseau Expert National pour Cancers Rares de l'Adulte PREDIR AP-HP/INCa, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.|Ecole Pratique des Hautes Etudes F-75014 Paris, Laboratoire de Génétique Oncologique EPHE, INSERM U1186, Gustave Roussy, Université Paris-Saclay, Villejuif, France.|Faculté de Médecine Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: S
authors.initials: S
authors.lastname: Richard
authors.affiliation: Département de Médecine Oncologique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: P R
authors.initials: PR
authors.lastname: Benusiglio
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002648:Child; D005260:Female; D005602:France; D005649:Fumarate Hydratase / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D018231:Leiomyomatosis / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D007890:Leiomyosarcoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010673:Pheochromocytoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012878:Skin Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D014594:Uterine Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D005649:Fumarate Hydratase
keywords: fumarate hydratase; hereditary neoplastic syndromes; leiomyomatosis; leiomyosarcoma; pheochromocytoma; renal cell carcinoma