{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:44:15Z","timestamp":1788461055581,"version":"build-2803163510"},"reference-count":13,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,12]]},"abstract":"Gastrointestinal stromal tumors (GISTs) that lack kinase mutations often show loss of function of the succinate dehydrogenase (SDH) complex, due to germline mutation or promoter hypermethylation. SDH-deficient GISTs are exclusive to the stomach and have a multinodular architecture. It has been suggested that conventional risk stratification criteria may not predict outcome for this group of tumors, although data are limited. Here, we report the clinical, histologic, and genetic findings from a large cohort of 76 SDH-deficient GISTs diagnosed from 2005 to 2015, identified on the basis of histologic features or family history (45 female\/31 male; mean age at diagnosis 32 y; range 11 to 71 y; 10 patients 50 y of age or above). Immunohistochemistry for SDHB and SDHA showed loss of SDHB in all cases and loss of SDHA in 28 (37%) tumors. Tumor size ranged from 1.9 to 22.5 cm; the primary tumor was multifocal in 29%. Mitotic rate ranged from 1 to 80 per 5 mm2<\/jats:sup> (median 5.5). Lymph node metastases were found at primary resection in 14 (18%) patients. Twenty-four patients (32%) had distant metastases at presentation, and 52 of 70 patients (74%) with follow-up developed distant metastases, most often to the liver, but also bone, lungs, breast, and brain. Applying conventional criteria (size and mitotic rate), 60% to 82% of patients with tumors ranging from very low risk to high risk for progressive disease developed distant metastases, regardless of the category. Carney-Stratakis syndrome and Carney triad were diagnosed in 6 and 8 patients, respectively. Of 35 patients tested, 26 harbored SDH mutations (11 SDHA<\/jats:italic>, 8 SDHB<\/jats:italic>, 6 SDHC<\/jats:italic>, 1 SDHD<\/jats:italic>). Follow-up data available for 70 patients ranged from 1 month to 39.3 years: 20 patients had no evidence of disease (mean 6.1 y), 32 were alive with metastases (mean 10.9 y), and 18 died of disease (mean 7.0 y after diagnosis). In summary, SDH-deficient GISTs account for approximately 8% of gastric GISTs and are associated with a high rate of distant metastasis, regardless of conventional risk category. Many affected patients have germline SDH mutations (most often SDHA<\/jats:italic>). Identification of SDH-deficient GISTs is critical for prognostication and genetic counseling.<\/jats:p>","DOI":"10.1097\/pas.0000000000000685","type":"journal-article","created":{"date-parts":[[2016,6,24]],"date-time":"2016-06-24T16:10:51Z","timestamp":1466784651000},"page":"1616-1621","source":"Crossref","is-referenced-by-count":74,"title":["Conventional Risk Stratification Fails to Predict Progression of Succinate Dehydrogenase\u2013deficient Gastrointestinal Stromal Tumors"],"prefix":"10.1097","volume":"40","author":[{"given":"Emily F.","family":"Mason","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason L.","family":"Hornick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20230922","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1073\/pnas.1009199108","article-title":"Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations","volume":"108","author":"Janeway","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"R2-20230922","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/modpathol.2012.153","article-title":"Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors","volume":"26","author":"Wagner","year":"2013","journal-title":"Mod Pathol"},{"key":"R3-20230922","doi-asserted-by":"crossref","first-page":"268ra177","DOI":"10.1126\/scitranslmed.3009961","article-title":"Recurrent epimutation of SDHC in gastrointestinal stromal tumors","volume":"6","author":"Killian","year":"2014","journal-title":"Sci Transl Med"},{"key":"R4-20230922","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/ajmg.10235","article-title":"Familial paraganglioma and gastric stromal sarcoma: A new syndrome distinct from the Carney triad","volume":"108","author":"Carney","year":"2002","journal-title":"Am J Med Genet"},{"key":"R5-20230922","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1159\/000345672","article-title":"Carney triad","volume":"41","author":"Carney","year":"2013","journal-title":"Front Horm Res"},{"key":"R6-20230922","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/ejhg.2015.142","article-title":"Carney triad can be (rarely) associated with germline succinate dehydrogenase defects","volume":"24","author":"Boikos","year":"2016","journal-title":"Eur J Hum Genet"},{"key":"R7-20230922","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1111\/j.1365-2559.2012.04300.x","article-title":"Loss of succinate dehydrogenase subunit B (SDHB) expression is limited to a distinctive subset of gastric wild-type gastrointestinal stromal tumours: a comprehensive genotype-phenotype correlation study","volume":"61","author":"Doyle","year":"2012","journal-title":"Histopathology"},{"key":"R8-20230922","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1097\/PAS.0b013e3182260752","article-title":"Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age","volume":"35","author":"Miettinen","year":"2011","journal-title":"Am J Surg Pathol"},{"key":"R9-20230922","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1097\/PAS.0b013e31820e5f7d","article-title":"\u201cPediatric-type\u201d gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior","volume":"35","author":"Rege","year":"2011","journal-title":"Am J Surg Pathol"},{"key":"R10-20230922","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.5858\/2006-130-1466-GSTROM","article-title":"Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis","volume":"130","author":"Miettinen","year":"2006","journal-title":"Arch Pathol Lab Med"},{"key":"R11-20230922","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.6004\/jnccn.2007.2002","article-title":"NCCN Task Force report: management of patients with gastrointestinal stromal tumor (GIST)\u2014update of the NCCN clinical practice guidelines","volume":"5","author":"Demetri","year":"2007","journal-title":"J Natl Compr Canc Netw"},{"issue":"suppl 1","key":"R12-20230922","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1038\/modpathol.2013.173","article-title":"Gastrointestinal stromal tumors: what do we know now?","volume":"27","author":"Corless","year":"2014","journal-title":"Mod Pathol"},{"key":"R13-20230922","doi-asserted-by":"crossref","first-page":"5352","DOI":"10.1200\/JCO.2007.15.7461","article-title":"Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor","volume":"26","author":"Heinrich","year":"2008","journal-title":"J Clin Oncol"}],"container-title":["American Journal of Surgical Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/00000478-201612000-00005","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T22:15:11Z","timestamp":1695420911000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/00000478-201612000-00005"}},"subtitle":["A Clinicopathologic Study of 76 Cases"],"short-title":[],"issued":{"date-parts":[[2016,12]]},"references-count":13,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2016]]}},"URL":"https:\/\/doi.org\/10.1097\/pas.0000000000000685","relation":{},"ISSN":["0147-5185"],"issn-type":[{"value":"0147-5185","type":"print"}],"subject":[],"published":{"date-parts":[[2016,12]]}}}