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Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review
Markku Miettinen1, Jerzy Lasota1
1Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
Abstract:
Loss of function of the succinate dehydrogenase complex characterizes a rare group of human tumors including some gastrointestinal stromal tumors, paragangliomas, renal carcinomas, and pituitary adenomas, and these can all be characterized as SDH-deficient tumors. Approximately 7.5% of gastric gastrointestinal stromal tumors are SDH-deficient and not driven by KIT/PDGFRA mutations, as are most other GISTs. The occurrence of SDH-deficient GISTs is restricted to stomach, and they typically occur in children and young adults representing a spectrum of clinical behavior from indolent to progressive. Slow progression is a common feature even after metastatic spread has taken place, and many patients live years with metastases. SDH-deficient GISTs have characteristic morphologic features including multinodular gastric wall involvement, often multiple separate tumors, common lymphovascular invasion, and occasional lymph node metastases. Diagnostic is the loss of succinate dehydrogenase subunit B (SDHB) from the tumor cells and this can be practically assessed by immunohistochemistry. SDHA is lost in cases associated with SDHA mutations. Approximately half of the patients have SDH subunit gene mutations, often germline and most commonly A (30%), and B, C or D (together 20%), with both alleles inactivated in the tumor cells according to the classic tumor suppressor gene model. Half of the cases are not associated with SDH-mutations and epigenetic silencing of the SDH complex is the possible pathogenesis. Extensive genomic methylation has been observed in these tumors, which is in contrast with other GISTs. SDH-loss causes succinate accumulation and activation of pseudohypoxia signaling via overexpression of HIF-proteins. Activation of insulin-like growth factor 1-signaling is also typical of these tumors. SDH-deficient GISTs are a unique group of GISTs with an energy metabolism defect as the key oncogenic mechanism. This article is part of a Directed Issue entitled: Rare Cancers.
Insights
Succinate dehydrogenase-deficient tumors, including rare gastrointestinal stromal tumors (GISTs), result from energy metabolism defects. These tumors, often found in young patients, show slow progression and characteristic genetic or epigenetic changes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Succinate dehydrogenase (SDH) complex dysfunction defines a rare subset of human tumors, including specific gastrointestinal stromal tumors (GISTs).
- SDH-deficient GISTs are distinct from common GISTs, lacking KIT/PDGFRA mutations and predominantly affecting the stomach in pediatric and young adult populations.
- These tumors exhibit unique clinical and morphological features, including slow progression, multinodular growth, and lymphovascular invasion.
Purpose of the Study:
- To characterize the unique features of SDH-deficient GISTs.
- To explore the underlying genetic and epigenetic mechanisms driving SDH-deficient GIST pathogenesis.
- To highlight the diagnostic markers and clinical behavior of these rare tumors.
Main Methods:
- Immunohistochemistry to assess the loss of SDH subunits (SDHB, SDHA).
- Genetic analysis to identify mutations in SDH subunit genes (SDHA, SDHB, SDHC, SDHD).
- Genomic analysis to investigate epigenetic alterations like methylation.
Main Results:
- Loss of SDHB expression via immunohistochemistry is a key diagnostic indicator.
- Approximately 50% of SDH-deficient GISTs harbor germline or somatic mutations in SDH subunit genes.
- The remaining cases are associated with epigenetic silencing of the SDH complex, characterized by extensive genomic methylation.
- SDH-loss leads to succinate accumulation, pseudohypoxia signaling (HIF-protein overexpression), and activation of IGF-1 signaling.
Conclusions:
- SDH-deficient GISTs represent a distinct clinicopathological and molecular subtype of GIST.
- Defects in energy metabolism, driven by SDH complex dysfunction, are the primary oncogenic mechanism.
- Understanding these mechanisms is crucial for diagnosing and potentially treating this rare cancer subset.
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