title: Long-term prognosis of patients with pediatric pheochromocytoma.
abstract: A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.
authors.affiliation: 2nd Department of Medicine, University of Freiburg, Freiburg, Germany Department of Surgery, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany Department of Medicine, Familial Cancer Clinic and Oncoendocrinology, University of Padova, Padova, Italy Center for Endocrinological Investigations (CEDIE), Hospital de Ninos R. Gutierrez, Buenos Aires, Argentina Department of Surgery, Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany Department of Hypertension, Institute of Cardiology, Warsaw, Poland Department of Endocrinology, University of Lorraine, Nancy, France Division of Pediatric Surgery, Department of Pediatrics, University Hospital of Padova, Padova, Italy Pediatric Oncology, Division of Hematology and Oncology, Department of Pediatrics, University Hospital of Padova, Padova, Italy Department of Endocrinology, University Medical Center, University of Duisburg and Essen, Essen, Germany Department of Pediatrics, Hospital Great Ormond Street, London, UK 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary Institute of Otorhinolaryngology, NAMS of Ukraine, Kiev, Ukraine Department of Endocrinology, University of Riga, Riga, Latvia Department of Endocrinology, La Timone Hospital, Aix-Marseille University, Marseille, France Department of Nuclear Medicine, University Hospital Timone, Marseilles, France Section for Preventive Medicine, Department of Nephrology and General Medicine, University of Freiburg, Freiburg, Germany Department of Visceral Surgery, University of Freiburg, Freiburg, Germany Department of Pediatrics, University of Freiburg, Freiburg, Germany Department of Pathology, University Medical Center, University of Duisburg and Essen, Essen, Germany Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Birke
authors.initials: B
authors.lastname: Bausch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Wellner
authors.forename: Dirk
authors.initials: D
authors.lastname: Bausch
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Marta
authors.initials: M
authors.lastname: Barontini
authors.forename: Gabriela
authors.initials: G
authors.lastname: Sanso
authors.forename: Martin K
authors.initials: MK
authors.lastname: Walz
authors.forename: Mariola
authors.initials: M
authors.lastname: Peczkowska
authors.forename: Georges
authors.initials: G
authors.lastname: Weryha
authors.forename: Patrizia
authors.initials: P
authors.lastname: Dall'igna
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cecchetto
authors.forename: Gianni
authors.initials: G
authors.lastname: Bisogno
authors.forename: Lars C
authors.initials: LC
authors.lastname: Moeller
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.forename: Attila
authors.initials: A
authors.lastname: Patocs
authors.forename: Karoly
authors.initials: K
authors.lastname: Rácz
authors.forename: Dmitry
authors.initials: D
authors.lastname: Zabolotnyi
authors.forename: Svetlana
authors.initials: S
authors.lastname: Yaremchuk
authors.forename: Iveta
authors.initials: I
authors.lastname: Dzivite-Krisane
authors.forename: Frederic
authors.initials: F
authors.lastname: Castinetti
authors.forename: David
authors.initials: D
authors.lastname: Taieb
authors.forename: Angelica
authors.initials: A
authors.lastname: Malinoc
authors.forename: Ernst
authors.initials: E
authors.lastname: von Dobschuetz
authors.forename: Jochen
authors.initials: J
authors.lastname: Roessler
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Schmid
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008017:Life Expectancy; D008137:Longitudinal Studies; D008297:Male; D010235:Paraganglioma / Q000235:genetics / Q000473:pathology*; D010673:Pheochromocytoma / Q000235:genetics / Q000473:pathology*; D017422:Sequence Analysis, DNA
chemical_list: D004273:DNA, Neoplasm
keywords: germline mutations; long-term follow-up; pheochromocytoma; relapse