Succinate Dehydrogenase-Deficient GISTs: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 66 Gastric GISTs With Predilection to Young Age

Most gastrointestinal stromal tumors (GISTs) are driven by KIT or PDGFRA-activating mutations, but a small subset is associated with loss of function of the succinate dehydrogenase (SDH) complex of mitochondrial inner membrane proteins. This occurs by germline mutations of the SDH subunit genes and hitherto unknown mechanisms. SDH-deficient GISTs especially include pediatric GISTs and those associated with Carney triad (CT) or Carney-Stratakis syndromes (CSSs); the latter 2 also include paraganglioma as a component. SDH-deficient GISTs were identified in this study on the basis of immunohistochemical loss of succinate dehydrogenase subunit B (SDHB), which signals functional loss of the SDH complex. We found 66 SDH-deficient GISTs among 756 gastric GISTs, with an estimated frequency of 7.5% of unselected cases. Nearly, all gastric GISTs in patients <20 years, and a substantial percentage of those in patients <40 years, but only rare GISTs in older adults were SDH deficient. There was a female predominance of over 2:1. Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations. SDH-deficient GISTs were often multiple and typically showed plexiform muscularis propria involvement and epithelioid hypercellular morphology. They were consistently KIT-positive and DOG1/Ano 1-positive and almost always smooth muscle actin negative. Tumor size and mitotic activity varied, and the tumors were somewhat unpredictable with low mitotic rates developing metastases. Gastric recurrences occurred in 11 patients, and peritoneal and liver metastases occurred in 8 and 10 patients, respectively. Lymph node metastases were detected in 5 patients, but lymphovascular invasion was present in >50% of cases studied; these 2 were not related to adverse outcome. Seven patients died of disease, but many had long survivals, even with peritoneal or liver metastases. All 378 nongastric GISTs and 34 gastric non-GIST mesenchymal tumors were SDHB positive. SDH-deficient GISTs constitute a small subgroup of gastric GISTs; they usually occur in children and young adults, often have a chronic course similar to that of pediatric and CT GISTs, and have potential association with paraganglioma, necessitating long-term follow-up.

[1]  R. Casadio,et al.  SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. , 2011, Journal of the National Cancer Institute.

[2]  M. Heinrich,et al.  “Pediatric-type” Gastrointestinal Stromal Tumors in Adults: Distinctive Histology Predicts Genotype and Clinical Behavior , 2011, The American journal of surgical pathology.

[3]  J. Lasota,et al.  Succinate Dehydrogenase Subunit B (SDHB) Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists): Implications for the SDHB Expression Based Classification of Gists , 2011, Journal of Cancer.

[4]  C. Antonescu,et al.  Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations , 2010, Proceedings of the National Academy of Sciences.

[5]  P. Bénit,et al.  SDHA is a tumor suppressor gene causing paraganglioma. , 2010, Human molecular genetics.

[6]  H. Morreau,et al.  Low penetrance of a SDHB mutation in a large Dutch paraganglioma family , 2010, BMC Medical Genetics.

[7]  A. Chou,et al.  Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. , 2010, Human pathology.

[8]  D. Winge,et al.  Succinate dehydrogenase - Assembly, regulation and role in human disease. , 2010, Mitochondrion.

[9]  A. Chou,et al.  Immunohistochemistry for SDHB Divides Gastrointestinal Stromal Tumors (GISTs) into 2 Distinct Types , 2010, The American journal of surgical pathology.

[10]  W. Young,et al.  Gastric Stromal Tumors in Carney Triad Are Different Clinically, Pathologically, and Behaviorally From Sporadic Gastric Gastrointestinal Stromal Tumors: Findings in 104 Cases , 2010, The American journal of surgical pathology.

[11]  J. Carney,et al.  Carney triad: a syndrome featuring paraganglionic, adrenocortical, and possibly other endocrine tumors. , 2009, The Journal of clinical endocrinology and metabolism.

[12]  E. van Marck,et al.  An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. , 2009, The Lancet. Oncology.

[13]  A. Vénisse,et al.  The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. , 2009, The Journal of clinical endocrinology and metabolism.

[14]  J. Carney,et al.  The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): molecular genetics and clinical implications , 2009, Journal of internal medicine.

[15]  C. Stratakis,et al.  SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma–paraganglioma syndromes , 2009, Journal of internal medicine.

[16]  Narasimhan P. Agaram,et al.  Novel V600E BRAF mutations in imatinib‐naive and imatinib‐resistant gastrointestinal stromal tumors , 2008, Genes, chromosomes & cancer.

[17]  J. Lasota,et al.  Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours , 2008, Histopathology.

[18]  M. Mata,et al.  Cells silenced for SDHB expression display characteristic features of the tumor phenotype. , 2008, Cancer research.

[19]  Narasimhan P. Agaram,et al.  Molecular Characterization of Pediatric Gastrointestinal Stromal Tumors , 2008, Clinical Cancer Research.

[20]  C. Stratakis,et al.  Familial gastrointestinal stromal tumors and germ-line mutations. , 2007, The New England journal of medicine.

[21]  E. Campo,et al.  Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. , 2007, The Journal of clinical endocrinology and metabolism.

[22]  E. Gottlieb,et al.  Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer , 2006, Oncogene.

[23]  W. Young,et al.  Functioning Paraganglioma and Gastrointestinal Stromal Tumor of the Jejunum in Three Women: Syndrome or Coincidence , 2006, The American journal of surgical pathology.

[24]  H. Prokisch,et al.  Leigh syndrome caused by mutations in the flavoprotein (Fp) subunit of succinate dehydrogenase (SDHA) , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[25]  L. Sobin,et al.  Gastrointestinal Stromal Tumors of the Stomach in Children and Young Adults: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 44 Cases With Long-Term Follow-Up and Review of the Literature , 2005, The American journal of surgical pathology.

[26]  J R Griffiths,et al.  Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. , 2005, Human molecular genetics.

[27]  Sandro Santagata,et al.  A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas , 2005, PLoS genetics.

[28]  N. Socci,et al.  Gastrointestinal Stromal Tumors in Children and Young Adults: A Clinicopathologic, Molecular, and Genomic Study of 15 Cases and Review of the Literature , 2005, Journal of pediatric hematology/oncology.

[29]  L. Sobin,et al.  Gastrointestinal Stromal Tumors of the Stomach: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 1765 Cases With Long-term Follow-up , 2005, The American journal of surgical pathology.

[30]  S. Hirota,et al.  Absence of c‐kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients , 2004, The Journal of pathology.

[31]  Samuel Singer,et al.  PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors , 2003, Science.

[32]  L. Sobin,et al.  Gastrointestinal Glomus Tumors: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 32 Cases , 2002, The American journal of surgical pathology.

[33]  P. Rustin,et al.  The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. , 2001, American journal of human genetics.

[34]  S. Hirota,et al.  Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. , 1998, Science.

[35]  M. O'sullivan,et al.  SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors , 2011, Modern Pathology.

[36]  Jean-Yves Scoazec,et al.  BRAF mutation status in gastrointestinal stromal tumors. , 2010, American journal of clinical pathology.

[37]  J. Ellison,et al.  Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD , 2008, European Journal of Human Genetics.

[38]  L. Aaltonen,et al.  Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. , 2004, American journal of human genetics.