title: Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum.
abstract: BACKGROUND
  Mutations in genes encoding the subunits of succinate dehydrogenase (SDH) can lead to pheochromocytoma/paraganglioma formation. However, SDH mutations have also been linked to nonparaganglionic tumors.
  
  
  OBJECTIVE
  The objective was to investigate which nonparaganglionic tumors belong to the SDH-associated tumor spectrum.
  
  
  METHODS
  This was a retrospective cohort study.
  
  
  METHODS
  The setting was a tertiary referral center.
  
  
  METHODS
  Patients included all consecutive SDHA/SDHB/SDHC and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center who were affected by non-pheochromocytoma/paraganglioma solid tumors.
  
  
  METHODS
  Main outcome measures were SDHA/SDHB immunohistochemistry, mutation analysis, and loss of heterozygosity analysis of the involved SDH-encoding genes.
  
  
  RESULTS
  Twenty-five of 35 tumors (from 26 patients) showed positive staining on SDHB and SDHA immunohistochemistry. Eight tumors showed negative staining for SDHB and positive staining for SDHA: a pancreatic neuroendocrine tumor, a macroprolactinoma, two gastric gastrointestinal stromal tumors, an abdominal ganglioneuroma, and three renal cell carcinomas. With the exception of the abdominal ganglioneuroma, loss of heterozygosity was detected in all tumors. A prolactinoma in a patient with a germline SDHA mutation was the only tumor immunonegative for both SDHA and SDHB. Sanger sequencing of this tumor revealed a somatic mutation (p.D38V) as a likely second hit leading to biallelic inactivation of SDHA. One tumor (breast cancer) showed heterogeneous SDHB staining, positive SDHA staining, and retention of heterozygosity.
  
  
  CONCLUSIONS
  This study strengthens the etiological association of SDH genes with pituitary neoplasia, renal tumorigenesis, and gastric gastrointestinal stromal tumors. Furthermore, our results indicate that pancreatic neuroendocrine tumor also falls within the SDH-related tumor spectrum.
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Nicolasine D
authors.initials: ND
authors.lastname: Niemeijer
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Papathomas
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Korpershoek
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Oudijk
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bayley
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Jeroen C
authors.initials: JC
authors.lastname: Jansen
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Winand N M
authors.initials: WN
authors.lastname: Dinjens
authors.affiliation: Department of Endocrinology and Metabolic Diseases (N.D.N., E.P.M.C.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Department of Pathology (T.G.P., E.K., L.O., W.N.M.D., R.R.d.K.) Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; Department of Pathology (R.R.d.K.), Reinier de Graaf Hospital, 2625 AD Delft, The Netherlands; and Departments of Pathology (H.M.), Human Genetics (J.P.B.), Clinical Genetics (F.J.H.), and Otorhinolaryngology (J.C.J.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Eleonora P M
authors.initials: EP
authors.lastname: Corssmit
mesh_terms: D000328:Adult; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology; D012189:Retrospective Studies; D013385:Succinate Dehydrogenase / Q000235:genetics*
chemical_list: D013385:Succinate Dehydrogenase