Succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs. SDH-mutated GISTs lack mutations in the proto-oncogene receptor tyrosine kinase (also known as KIT, c-KIT, or CD117) or platelet-derived growth factor receptor α (PDGFR-α). These tumors have female predilection, affect children and young adults, and have a spectrum of behavior from indolent to progressive. These tumors have characteristic morphologic features including multinodular architecture, multiple tumors, lymphovascular involvement, and occasional lymph node metastasis. They can be seen in patients with Carney triad or Carney-Stratakis syndrome. Although a mutation in any one of the SDH subunits can be pathogenic, deficiency of a single subunit leads to loss of detectable SDH subunit B by immunohistochemistry, enabling a convenient, tissue-based screening method. The prognosis and the clinical course of these tumors is different from that of KIT- or PDGFR-α–mutated GISTs. Surgical management is considered the main line of treatment. SDH-mutated GISTs do not respond well to the common targeted therapy, with no objective tumor response to imatinib. The role of the pathologist in diagnosing these cases is imperative in management and subsequent follow-up.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They are most common in the stomach (50%–60%) and small intestine (30%–35%) and are less frequent in the colon and rectum (5%) and the esophagus (<1%).1 Most GISTs occur in older adults and are driven by KIT or platelet-derived growth factor receptor α (PDGFR-α) activating mutations. Wild-type GISTs (WT-GISTs) lack such mutations. These tumors are seen primarily in children (85%–90%) and in a small percentage of adults (10%–15%).2,3 Standard GIST therapies (tyrosine kinase inhibitors) are less efficacious in WT-GISTs.
Succinate dehydrogenase (SDH)–deficient GISTs are a unique group of GISTs with an energy metabolism defect as the key oncogenic mechanism.8,9 SDH-deficient GISTs have different clinical, morphologic, and molecular characteristics from other GISTs. The SDH complex (mitochondrial complex or succinate reductase) is composed of 4 subunits: SDHA, SDHB, SDHC, and SDHD. Approximately half of pediatric WT-GISTs have mutations in one of these subunits, with SDHA mutations being the most common.4 Mutations of SDHA, SDHB, SDHC, and SDHD reported in SDH-deficient GISTs are listed in Table 1.
SDHA and SDHB are the catalytic components of succinate reductase enzyme, and SDHC and SDHD are the anchoring components that attach the SDH to the inner mitochondrial membrane.5 The SDH complex participates in the Krebs cycle, with subunit A being the catalytic unit responsible for conversion of succinate to fumarate. Subunit B participates in the electron transport chain for oxidation of ubiquinone to ubiquinol, and SDHC and SDHD are membrane-anchoring subunits. Loss of the mitochondrial SDH complex through mutations in SDHA, SDHB, SDHC, or SDHD leads to an accumulation of succinate, which results in overexpression of hypoxia-inducible factor (HIF) proteins and increased transcription of HIF-1a–regulated genes and decreased DNA demethylation. There is an increase in DNA methylation similar to that seen in gliomas and leukemias with isocitrate dehydrogenase IDH1 and IDH2 mutations.6,7 Activation of insulin-like growth factor 1 signaling is also typical of SDH-deficient GISTs. Not all SDHB-immunonegative GISTs harbor an SDH gene mutation; these tumors may have other genetic defects in the SDH pathway.10
SDH-deficient GISTs usually present before the age of 40 years, whereas other GISTs only rarely affect young people. Tumors with loss of SDHB expression by immunohistochemistry can be subdivided into 2 groups, one with SDH gene mutations and others with loss of SDHB by immunostain without SDH mutations. Those with SDH mutations occur in young adults, are gastric in location, and have a female preponderance (>2:1). Those with loss of SDHB by immunostain without SDH mutations occur in the pediatric age group and young adults, are gastric in location, and occur exclusively in females.10 SDH-deficient GISTs occur almost exclusively in the stomach, and although any part of the stomach can be involved, there is predilection to the distal stomach and antrum.
Common clinical manifestations of SDH-deficient GISTs are similar to those of other gastric tumors, including gastrointestinal bleeding and epigastric discomfort. Occasional patients diagnosed with SDH-deficient GISTs have shown symptoms related to metastatic tumors in the abdomen or liver.11 In general, these tumors pursue an indolent course and may sometimes be fatal. Tumors can be multiple and synchronous. SDH-mutated GISTs can be seen in association with Carney triad or Carney-Stratakis syndrome associated with paraganglioma and/or chondroma. All tumors in patients with Carney triad or Carney-Stratakis syndrome have SDH abnormalities (SDHA or SDHC germline mutations).2,11,12 Carney-Stratakis syndrome includes occurrence of GIST and paraganglioma in the context of SDH germline mutation and is hereditary.13,14 Carney triad includes the combination of GIST and pulmonary chondroma, paraganglioma, or both, without SDH mutations or hereditary basis.15,16 Differences from non–SDH-deficient GISTs are summarized in Table 2.
PATHOLOGIC FEATURES OF SDH-MUTATED GISTS
Tumor size is varied, with most cases ranging from 1.5 to 12 cm (median, 5.0 cm). The location is almost exclusively in the stomach (antrum is the most common location, with lesser curvature second, followed by posterior wall/lesser sac, and to a lesser extent the greater curvature/fundus, fundus, cardia, or upper stomach). These tumors are typically multinodular, plexiform, and sometimes bilobed masses, often divided by fibrous septa. Cut section of these tumors varies from yellowish to pale tan to pink and brown, and may have focal areas of hemorrhage or cystic degeneration. These multinodular tumors involve the muscularis propria as apparently separate nodules, which has been referred to as microplexiform pattern (Figure 1).10 Some cases can have ulceration present. The cytomorphology is most often either epithelioid or mixed spindled/epithelioid (Figure 2). Few SDH-mutated GIST cases with spindle cell and rare cases with pleomorphic cytology have also been described. The tumors are generally hypercellular with back-to-back cells, without significant nuclear pleomorphism (Figure 3). Mitotic rate may reach more than 5 per 5 mm2, and occasionally atypical mitoses can be seen. Features commonly seen in adult GISTs like palisaded vacuolated or sclerosing morphology are rarely encountered. Nuclear vacuolization is usually focal and present in most cases, but palisading is very rare. Coagulative necrosis is also very rare and not linked with survival. Omental/peritoneal micrometastasis can occur at the time of presentation, as can lymph node metastasis. Lymphovascular invasion around tumor nodules is common.13,17
The differential diagnosis for SDH-deficient GISTs is similar to that of other gastrointestinal stromal tumors and includes carcinoma, perivascular epithelioid cell tumor, melanoma, epithelioid leiomyosarcoma, epithelioid angiosarcoma, glomus tumor, and even neuroendocrine tumor when the tumor shows epithelioid morphology. The differential diagnosis in the rare case with predominantly spindle morphology includes smooth muscle tumor, inflammatory myofibroblastic tumor, plexiform fibromyxoma, and fibromatosis, among others. As with other KIT/PDGFR-α GISTs, the diagnosis of SDH-mutated GIST can be made by use of discovered on GIST 1 (DOG1) and cluster of differentiation (CD117)/KIT, which would be positive (Figure 4, A and B). These GISTs express KIT/CD117 equally as strongly as KIT-mutant GISTs. They are uniformly immunohistochemically positive for DOG1 and for CD34. However, they rarely if ever express smooth muscle actin, which is present in 30% of GISTs in general.
If any component of the mitochondrial complex 2 (that is, SDHA, SDHB, SDHC, SDHD, or SDHAF2) is lost, then the entire SDH complex either becomes unstable or does not form, releasing the SDHB subunit into the cytoplasm, where it degrades rapidly. The loss of expression of SDHB can be detected by immunohistochemistry. Numerous commercially available antibodies for SDHB are available, of which SDHB rabbit polyclonal HPA002868 (Sigma-Aldrich Corp) is the most often used antibody. Cases can be classified as SDH-deficient GISTs by use of SDHB immunostain (Figure 5).1,11 SDH-deficient GISTs lack SDHB expression in the tumor cells, but stromal and vascular elements should be positive to verify adequate immunohistochemical detection. Mutations in SDHA are the most common encountered in SDH-deficient GISTs (approximately 30%). These can be identified by loss of the SDHA immunostain along with SDHB immunohistochemical staining on the histologic sections. There is a strong correlation between immunohistochemically observed loss of SDHA and SDHA mutations. An equal proportion of cases (∼30%) carry mutations in the other 3 subunits combined.1 Attempts to use SDHC and SDHD immunohistochemistry to separate mutations in SDHB, SDHC, and SDHD have been unsuccessful so far.
SDH deficiency and KIT or PDGFR-α mutations are mutually exclusive, except for a few case reports that describe both KIT and PDGFR-α mutation in GISTs exhibiting SDH deficiency.18 Mutations in the SDH subunits are also mutually exclusive with mutations in BRAF or neurofibromatosis (NF1). Approximately half of patients with SDH-mutated GISTs have mutations in one of the SDH subunits, with the most common being in SDHA genes.1
SDHA MUTATION–ASSOCIATED GISTS
The most commonly mutated SDH subunit in SDH-deficient GISTs is SDHA, with an estimated frequency of approximately 30% of all SDH-deficient GISTs. Most of these cases are germline mutations, and there is excellent correlation with loss of SDHA expression by immunohistochemistry.10,19–23
The most common recurrent SDHA mutation translates to protein abrogation R31X. Simultaneous allelic loss at the SDHA locus at 5p15 has been detected with comparative genomic hybridization. Tumor suppressor genes in SDHA mutation seem to be under a classic 2-hit hypothesis. Loss of SDHA protein expression is associated with both truncating and missense germline mutations. SDHA mutation–associated GISTs occur at an older age than other SDH-deficient GISTs, with the median age of presentation in the largest series being 34 years.19
SDHB, SDHC, AND SDHD MUTATION–ASSOCIATED GISTS
SDH DEFICIENCY WITHOUT SDH SUBUNIT MUTATIONS
Up to half of SDH-deficient GISTs (cases that are negative for SDHB by immunohistochemistry) lack SDH subunit mutations. This estimated percentage of WT-GISTs might not be accurate, as the proportion of cases comprehensively analyzed for mutations remains small and some larger deletions might be undetected in the analytical systems used.19
METHYLATION IN SDH-DEFICIENT GISTS
The methylation status of these tumors showed that SDH-deficient tumors have a hypermethylator phenotype, whereas tumors with KIT or PDGFR-α mutations have a methylation pattern consistent with normal tissues. SDH deficiency shortens the Krebs cycle, which eventually affects mitochondrial respiration. This leads to continued malignant proliferation. Succinate accumulation continues because of SDH deficiency leading to a pseudohypoxic state, which then triggers HIF-1a. This step leads to activating angiogenesis that supports tumor formation. Thus, succinate accumulation will lead to a-ketoglutarate (a-KG) inhibition, as it is structurally like succinate. This in return leads to inhibition of the ten-eleven translocation (TET) family of DNA hydroxylases.15,20 DNA demethylation depends on essential elements like 5-hydroxymethylcytosine. Via TET, 5-methylcytosine is converted via TET to 5-hydroxymethylcytosine. Thus, SDH deficiency leads to succinate accumulation that potentially inhibits TET-family proteins and subsequently leads to changes in DNA methylation and ultimately in gene expression.17
CURRENT TREATMENT AND PROGNOSIS
Wild-type GIST is an indolent disease and most patients survive with disease progression.27 Different studies have concluded a good median survival of approximately 10 years.17,19 Studies have found that current National Institutes of Health risk stratification criteria might not be appropriate for use on SDH-mutated GISTs.
In a study by Mason and Hornick,28 it was seen that conventional risk stratification failed to predict disease progression in patients with SDH-deficient GIST. In this study, regardless of risk category, approximately 60% to 80% of patients developed distant metastases.
In a study done by Weldon et al,27 the presence of metastasis and elevated mitotic rate were found to have a strong effect on the outcome. Unlike KIT/PDGFR-α–mutated GISTs, WT-GISTs' margin of resection status did not affect event-free survival. Resections with negative gross margins that are positive microscopically have shown no significant difference in 4-year recurrence-free survival compared with negative margins on microscopic examination.27
Despite low overall mortality, disease progression and recurrence occur frequently. Unlike KIT-mutated GISTs, which are generally responsive to tyrosine kinase inhibitor, SDH-mutated GISTs respond poorly to imatinib because of lack of activating tyrosine kinase mutations.1,27
Surgery remains the most important form of treatment of nonmetastatic WT-GIST and is recommended by the National Comprehensive Cancer Network.3 Besides helping with local disease control, surgery at initial presentation is crucial to secure tissue for pathologic diagnosis and genotyping. A frequent manifestation of WT-GIST is gastrointestinal hemorrhage, and surgery at presentation is often required. In the setting of recurrent disease, data support the role of surgery in the event of symptoms such as pain, bleeding, perforation, obstruction, or other clinically significant issues.27
Some investigations have assessed systemic therapy for patients with WT-GIST. Data published from the National Institutes of Health WT-GIST clinic demonstrated no objective tumor response to imatinib, but a superior response to sunitinib.29 Mechanistically, it appears that the absence of functional SDH complex drives increased vascular endothelial growth factor receptor (VEGFR) and insulin growth factor receptor (IGF1R) signaling via hypoxia-inducible factor 1α transcriptional activity. This mechanism may account for the efficacy of sunitinib, which has inhibitory effects on both VEGFR and IGF1R, in SDH-deficient GIST, and predicts potential alternative therapeutic angles targeting these receptors or their downstream effectors.1
A 2016 study by Ben-Ami et al30 noted potential improvement of progression-free survival with regorafenib among patients with unresectable SDH-deficient GIST after failure of prior therapy with a tyrosine kinase inhibitor.
Experimental agents that are based on the biology of SDH-deficient GISTs and could be useful in the future, but are not yet available except on a trial basis, include insulin-like growth factor 1- receptor inhibitor OSI-906 (linsitinib), and heat shock protein inhibitors.31
SDH-mutant GISTs account for approximately 10% of gastric GISTs. Expression of KIT and/or DOG1 remains a highly sensitive method for identification of GISTs in the setting of SDH deficiency. Diagnosis can be established by loss of detectable SDHB by immunohistochemistry, enabling a convenient and tissue-based screening method. SDH-deficient GISTs are characteristically multinodular, most commonly have either exclusively epithelioid or mixed spindled/epithelioid cytomorphology, and are almost exclusively gastric. Whereas other GISTs rarely present with lymphovascular invasion or lymph node metastasis, these occur frequently in SDH-deficient GISTs. Tumor cells show loss of the SDH complex because of both germline and somatic mutations in the SDH subunit genes. 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 increased genomic methylation, different from conventional KIT/PDGFR-α–mutant GISTs. SDH-deficient GISTs are usually restricted to the stomach, occur predominantly at a young age, and are clinically heterogeneous, with some patients having other SDH-deficient tumors, especially paragangliomas.
SDH-deficient GISTs show primary resistance to imatinib, but reliable evidence for the use of alternative tyrosine kinase inhibitors is difficult to ascertain because of the infrequency of cases and the difficulty of assessing meaningful treatment responses in a subpopulation with often-indolent disease. Anecdotal responses of pediatric GISTs to sunitinib have been reported.
The authors have no relevant financial interest in the products or companies described in this article.