Review
Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) – A review

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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.

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Although GISTs occur most frequently in the stomach and small intestine, they can present anywhere in the gastrointestinal tract with a lower frequency. Epidemiologic studies suggest that GISTs have an annual incidence of at least 14–20 per million people. However, minimal clinically indolent tumors are probably much more common based on studies on surgical excisions for unrelated tumors and autopsy studies, in which as many as 10–25% study subjects harbored an incidental minimal GIST. GISTs show phenotypic similarity with gastrointestinal Cajal cells. These mesenchymal cells are the functional intermediaries between autonomic nervous system and smooth muscle cells. Like Cajal cells, GISTs are almost uniformly KIT-expressing, and KIT receptor tyrosine kinase is a centrally important signaling molecule regulating cell proliferation and apoptosis (Corless et al., 2011, Miettinen and Lasota, 2013a).

Most GISTs are driven by oncogenic KIT or PDGFRA receptor tyrosine kinase activating mutations. This mechanism has been successfully countered by tyrosine kinase inhibitor treatment as the first example of targeted therapy for a solid tumor. Approximately 10–15% of all GISTs lack KIT or PDGFRA mutations and are therefore called wild type GISTs in reference to KIT and PDGFRA mutation status (Lasota and Miettinen, 2008, Corless et al., 2011). SDH-deficient GISTs are the largest group of KIT/PDGFRA wild type GISTs (Janeway et al., 2011, Miettinen et al., 2011). Neurofibromatosis 1-associated GISTs are also KIT/PDGFRA wild type, but they are not SDH-deficient (Wang et al., 2011).

Deficiencies in the succinate dehydrogenase complex characterize subsets of certain types of human tumors, most importantly gastrointestinal stromal tumors, paragangliomas, renal cell carcinomas, and pituitary adenomas (Barletta and Hornick, 2012, Gill, 2012; Hoekstra and Bayley, 2013). In these tumors that we call “succinate dehydrogenase deficient” the succinate dehydrogenase complex is inactivated in the tumor cells. In many cases, this happens via combination of a loss-of-function germline mutations in one of the SDH subunit genes and somatic loss-of-function mutations in the tumor cells, leading into inactivation of both alleles according to the principle of classic tumor suppressor genes. In some cases the mechanism of inactivation is unclear and possibly related to epigenetic silencing. Although SDH-complex is essential for life, haploinsufficiency is tolerated and compensated. However, disruption of both alleles by compound heterozygotic germline SDHA mutations causes a severe neurodegenerative syndrome, Leigh syndrome (Parfait et al., 2000) and a homozygous loss-of-function SDHB mutation a leukodystrophy (Alston et al., 2012).

Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex located in the inner mitochondrial membrane and is entirely encoded by chromosomal DNA. The SDH-complex participates in the Krebs cycle with subunit A (SDHA) being the catalytic unit responsible for conversion of succinate to fumarate. Subunit B (SDHB) is an iron sulphur protein that participates in the electron transport chain for the oxidation of ubiquinone to ubiquinol, and subunits C and D (SDHC and SDHD) are membrane-anchoring subunits (Rutter et al., 2010).

Studies on paragangliomas and GISTs indicate that loss of any SDH-subunit renders the complex inactive, and it has been found that any paraganglioma associated with an SDH-mutation (usually germline syndrome) lacks SDHB subunit. Therefore, loss of SDHB, as tested by immunohistochemistry, is the most practical way to identify SDH-deficient tumors (van Nederveen et al., 2009, Gill et al., 2010a, Gill et al., 2010b, Gill et al., 2011).

In this paper, we review the epidemiology, clinical features, histopathology, and molecular pathology of SDH-deficient gastrointestinal stromal tumors (GISTs).

Section snippets

Terminology, epidemiology and clinical features of SDH-deficient GISTs

SDH-deficient GIST implies a gastrointestinal stromal tumor that has a loss of succinate dehydrogenase complex function as the oncogenic mechanism, instead of KIT or PDGFRA-activating mutations, as seen in a great majority of GISTs in general. This group encompasses most pediatric GISTs and two previously described syndromes: Carney–Stratakis syndrome and Carney triad.

Carney–Stratakis syndrome includes occurrence of GIST and paraganglioma in the context of SDH-germline mutation and is

Pathology of SDH-deficient GISTs

Characteristic of SDH-deficient GISTs is a relatively high frequency of tumor multiplicity with many patients showing coalescent or separate tumor nodules involving the gastric wall. Although SDH-deficient GISTs can involve any part of the stomach, there is some predilection to distal stomach and antrum. Occurrence of lymph node metastases is a feature almost restricted to SDH-deficient GISTs among all GISTs, although this is still seen in a minority of patients, 10% or less (Miettinen et al.,

Clinical aspects of SDH-deficient GISTs

Clinically SDH-deficient GISTs are a heterogeneous group ranging from indolent tumors that never recur or metastasize to those that are metastatic at presentation and some of these are fatal in a few years. These tumors do not follow well the predictions of behavior made for GISTs based on mitotic activity and tumor size and therefore a separate set of criteria should be developed for them in the future.

While SDH-deficient GISTs that are relatively small and contain low mitotic activity (<5 

Genetic background and its clinical correlation

At least half of SDH-deficient GISTs contain loss-of-function SDH subunit germline and somatic mutations. These mutations include frame shift deletions leading to premature stop codons, missense, and nonsense mutations and occasionally splice site mutations. SDH-complex mutations reported in non-syndromic GISTs are listed in Table 1.

SDH deficiency without SDH subunit mutation

Up to half of SDH-deficient GIST appears to lack SDH-subunit mutations. However, this number may be too high as the number of cases comprehensively analyzed for mutation remains relatively small and also because some larger deletions may have remained undetected in the used analytical systems more geared toward detection of single nucleotide changes or small deletions.

Methylation in SDH-deficient GISTs

Independent of SDH gene status, all SDH-deficient GISTs have a high frequency of gene methylation, in comparison with KIT or PDGFRA mutant GIST. Markedly higher number of hyper than hypomethylations were detected in a screening for a large number of genes via Golden Gate® Assay for Methylation (Illumina, Inc.). Similar methylation patterns were also detected in IDH1-mutant gliomas, tumors with another Krebs cycle deficiency (Killian et al., 2013). Therefore, Krebs cycle enzyme deficiency may

Biochemical consequences of SDH-deficient status

Most of this work is based on in vitro studies and studies of paraganglioma cells or cells artificially rendered SDH-deficient. Unfortunately, no cell line exists yet to allow dynamic experimental studies on SDH-deficient GIST cells.

SDH-deficient cells accumulate succinate and this inhibits processing of HIF1-alpha by prolyl hydroxylase, which leads to HIF1-alpha overexpression and HIF transport (translocation) into nuclei (Brière et al., 2005, Selak et al., 2005). Overexpressed HIF proteins

Treatment of SDH-deficient GISTs

Due to the rarity of SDH-deficient GISTs, treatment experience is limited to a very small number of patients. Complete surgical removal of the primary tumor and locoregional (omental or nodal) metastaes should be performed whenever possible. The adjuvant treatment of patients with SDH-deficient GISTs is evolving and to date there is no uniform standard or recommendations for treating these patients. One of the complicating factors is difficulty of clinically determining what constitutes

Conclusion

SDH-deficient GISTs comprise a subgroup of a relatively rare tumor type and show a number of clinically and biologically unique features. Tumor cells have the loss of the SDH-complex, either by the combination of germline and somatic mutations in the SDH-subunit genes, or unknown possibly epigenetic mechanisms. Mutation of any subunit, most commonly SDHA, leads to loss of the complex that can be reliably detected by immunohistochemistry for SDHB. SDH-deficient GISTs have an increased genomic

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