SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors

Gaal, José; Stratakis, Constantine A.; Carney, J. Aidan; Ball, Evan; Korpershoek, Esther; Lodish, Maya; Levy, Isaac; Xekouki, Paraskevi; Nederveen, Francien H. van; Bakker, Michael A. den; O’Sullivan, Maureen; Dinjens, Winand N.M.; Krijger, Ronald R. de

doi:10.1038/modpathol.2010.185

Cited by 182 publications

(164 citation statements)

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“…[13][14][15] Furthermore, loss of expression of SDHB by immunohistochemistry is a consistent feature of SDH-deficient GIST, whereas SDHB expression is intact in KIT-mutant GISTs. 14,[27][28][29] A similar genotype/immunophenotype correlation has also been noted in paragangliomas, with mutations in SDHB, SDHC, or SDHD, leading to loss of SDHB expression. 13,30 Recently, loss of expression of both SDHA and SDHB by immunohistochemistry in paragangliomas was shown to correlate specifically with mutations in the SDHA gene.…”

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confidence: 62%

“…[11][12][13]28,29 This group of tumors was formerly referred to as 'type 2' or 'pediatric-type' GIST because of their distinctive pathological features, wild-type KIT and PDGFRA status, and prevalence among GISTs arising in patients o18 years of age. 29,32 Because this type of GIST also arises in adult patients (overall accounting for the majority of such tumors), the term 'SDH-deficient GIST' is increasingly applied, reflecting the underlying biochemical and, in some cases, genetic lesions.…”

Section: Discussionmentioning

confidence: 99%

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Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

et al. 2013

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Gastrointestinal stromal tumors (GISTs) are usually driven by mutations in KIT or PDGFRA, although 15% of GISTs in adults and 490% in children lack such mutations. The majority of gastric KIT/PDGFRA wild-type GISTs show distinctive morphological and clinical features and loss of expression of succinate dehydrogenase (SDH) B. Only a small subset of SDHB-deficient GISTs carries loss-of-function mutations in SDHB, SDHC, or SDHD. Because of the complexity of its locus (15 exons) and the presence of three pseudogenes, SDHA is rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of expression of SDHA in a small group of paragangliomas. We sought to determine whether immunohistochemistry for SDHA could identify GISTs with SDHA mutations. Tumors (n ¼ 33) with pathological features of SDH-deficient GIST were analyzed for expression of SDHA and SDHB by immunohistochemistry, and SDHA exons were sequenced from tumors lacking SDHA expression. Exons harboring somatic mutations were examined in DNA from corresponding normal tissue. All 33 tumors showed loss of SDHB expression. A total of 9 out of 33 (27%) tumors also lacked expression of SDHA. SDHA-deficient GISTs affected five men and four women (median age 38 years). SDHA expression was intact in the 24 remaining tumors, including those with known SDHB (n ¼ 3) or SDHC (n ¼ 2) mutations. Nonsense (n ¼ 8) or missense (n ¼ 1) mutations in SDHA were identified in all SDHA-deficient tumors. Heterozygous mutations were also found in DNA from normal tissues from six patients with available material. Somatic loss of the second allele has been found in seven tumors, five by loss of heterozygosity, one by a 13-bp deletion, and one by a missense mutation. Loss of SDHA expression in GIST reliably predicts the presence of SDHA mutations, which represent a relatively common cause of SDH-deficient GIST in adults. Immunohistochemistry for SDHA can be used to select patients for SDHA-specific genetic testing.

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confidence: 62%

Section: Discussionmentioning

confidence: 99%

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

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“…17 SDH functions not only in mitochondrial energy generation, but the genes encoding this enzyme also act as tumor suppressors. SDH consists of the subunits SDHA, SDHB, SDHC and SDHD.…”

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confidence: 99%

“…20,21 In addition, Carney-Stratakis and Carney triad associated and wild-type pediatric GISTs can be recognized by SDHB immunohistochemistry. 17,22 In this work, we performed SDHA immunohistochemistry on 33 wild-type GISTs, including nine pediatric/adolescent GISTs, in order to investigate whether immunohistochemistry could identify SDHA-mutated GISTs.…”

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SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors

et al. 2013

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Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-a. However, a small subset of GISTs lacks such mutations and is termed 'wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C4T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.

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“…The newly recognized Carney Stratakis is a dyad; patients have germline mutations of the succinate dehydrogenase subunits B (SDHB), C (SDHC) and D (SDHD) and develop multifocal GISTs and multicentric PGLs. 49,50 The GISTs in these syndromes are quite interesting as they lack staining for SDHB (whereas regular GISTs have it) and lack KIT mutations, features they share with pediatric GISTs 51 ( Figure 9). …”

Section: Gastrointestinal Stromal Tumormentioning

confidence: 99%

Gastrointestinal tract spindle cell lesions—just like real estate, it's all about location

Voltaggio

Montgomery

2015

Modern Pathology

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Interpretation of gastrointestinal tract mesenchymal lesions is simplified merely by knowing in which anatomic layer they are usually found. For example, Kaposi sarcoma is detected on mucosal biopsies, whereas inflammatory fibroid polyp is nearly always in the submucosa. Gastrointestinal stromal tumors (GISTs) are generally centered in the muscularis propria. Schwannomas are essentially always in the muscularis propria. Mesenteric lesions are usually found in the small bowel mesentery. Knowledge of the favored layer is even most important in interpreting colon biopsies, as many mesenschymal polyps are encountered in the colon. Although GISTs are among the most common mesenchymal lesions, we will concentrate our discussion on other mesenchymal lesions, some of which are in the differential diagnosis of GIST, and point out some diagnostic pitfalls, particularly in immunolabeling.

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SDHB immunohistochemistry: a useful tool in the diagnosis of Carney–Stratakis and Carney triad gastrointestinal stromal tumors

Cited by 182 publications

References 17 publications

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors

Gastrointestinal tract spindle cell lesions—just like real estate, it's all about location

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