SDH-deficient GISTs represent the largest proportion of WT GISTs that lack KIT or PDGFRA mutations. The true frequency of SDH-deficient GISTs was reported to be approximately 7.4% to 7.7%[6-8]. This group encompasses most pediatric GISTs and two previously described syndromes: Carney-Stratakis syndrome and Carney triad.
Succinate dehydrogenase (SDH) is an enzyme complex composed of four protein subunits (SDHA, SDHB, SDHC, and SDHD). This complex acts at the interphase of the tricarboxylic acid cycle and electron transport chain. The SDH-complex participates in the Krebs cycle with subunit A (SDHA) being the catalytic unit responsible for the conversion of succinate to fumarate. Subunit B (SDHB) is an iron-sulfur protein that participates in the electron transport chain for the oxidation of ubiquinone to ubiquinol. Subunits C and D (SDHC and SDHD) are membrane-anchoring subunits. Remarkably, immunohistochemistry for SDHB becomes negative whenever there is bi-allelic inactivation of any component of SDH, which is very rare in the absence of syndromic disease[9]. Loss of SDHB, as tested by immunohistochemistry, is the most practical way to identify SDH-deficient tumors[3, 7]. 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.They can all be characterized as SDH-deficient tumors [9, 10].
SDH-deficient GISTs demonstrate unique clinical and pathological features, including an exclusively gastric location, absence of KIT or PDGFRA mutations, typically showed plexiform muscularis propria involvement, and epithelioid hypercellular morphology. Based on current experience, SDH-deficient GISTs occur mainly in the stomach and were more likely to occur in younger, female patients. In this report, we showed a colon mesentery tumor case in a three-month-old infant, which was the youngest patient also in an unusual location reported to date[3, 7, 8, 11]. Malignant tumors in infants and young children may represent a different subgroup because of their unique clinical features and biological behavior. The cause of the tumor is unclear. Whether it is associated with embryonic development needs more cases to study.
SDH-deficient GISTs are characterized by a distinctive multinodular/ plexiform architecture and epithelioid or mixed epithelioid and spindle cell morphology[4]. In our case, the “plexiform” pattern is apparent, and the tumor cells have mainly epithelioid cytology, which is consistent with the reports before and support for the diagnosis. Not surprisingly, IHC examinations for SDH-deficient GISTs showed positivity for CD117, CD34, DOG-1 and PDGFR, and negativity for SMA and S-100. Loss of SDHB expression is a consistent feature of SDH-deficient GISTs. The most important molecular change of SDH-deficient GISTs is SDH mutations followed by SDHC promoter hypermethylation[3, 12]. SDH mutations are often germline and most commonly A (about 30%), and B, C, or D (together 20%)[3, 6, 13]. It is unknown how mutations in the various SDH subunits may differentially regulate tumor biology. Patients with alterations of the SDHC gene may be less likely to develop distant metastases[6]. Besides, another feature of SDH-deficient GISTs is overexpression of insulin-like growth factor 1 receptor (IGF1R) gene, possibly by gene amplification. Chou A et al[14]used immunohistochemistry suggested that IGF1R is overexpressed in 100% of SDH-deficient GISTs but never in non-SDH deficient GISTs. In our case, the sequencing of SDHB showed synonymous mutation at position 169 of exon 1(C-A) and the mutation site agrees with the results of the previous study[15]. Although amino acid has not changed, synonymous mutation frequently acts as driver mutations in human cancers. Fran Supek et al. present robust statistical evidence in an analysis of > 3,000 cancer exomes and > 300 cancer genomes that synonymous mutations in exons may act through diverse molecular mechanisms, and are often associated with changes in splicing[16]. Marc Bennedbæk et al identified SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients and founded that all three SDHB missense variants were predicted as pathogenic. In silico splicing analysis indicates that this change could affect the splicing of exon 5[17]. Therefore, we speculate synonymous mutation of SDHB in our study may be pathogenic through the same mechanism. Besides, the tumor has an SDHA or SDHC alteration is also possible.
In addition, CCND2 amplification and amino acid missense mutation at position 932 of exon 19 of the PTCH1 gene was found. CCND2 belongs to the highly conserved cyclin family, forms a complex with CDK4 or CDK6, and functions as a regulatory subunit of the complex, whose activity is required for cell cycle G1/S transition. CCND2 amplification has been previously reported in GIST[18]. PTCH1 encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway, which is important in embryonic development and tumorigenesis[19]. Whether the changes in these two genes are related to the tumor needs more cases for further study.
SDH-deficient GISTs do not seem to have a marked tendency for familial occurrence, as compared with SDH mutation syndrome associated paragangliomas that show familial occurrence. Due to the rarity of SDH-deficient GISTs, treatment experience is limited,especially for pediatric patients. Complete surgical removal of the primary tumor and locoregional (omental or nodal) metastases should be performed whenever possible. There is no uniform about the adjuvant treatment of patients with SDH-deficient GISTs to date. Traditional cytotoxic chemotherapy is generally ineffective for SDH-deficient GISTs, as it is for KIT/PDGFRA mutant GISTs. SDH-deficient GISTs respond poorly to standard targeted therapy such as tyrosine kinase inhibitor drugs, neither the first line inhibitor imatinib mesylate nor a second line multikinase inhibitor sunitinib malate, although the stable disease has been observed in some cases[6, 8, 20]. Newer tyrosine kinase inhibitor drugs are potentially usable in SDH-deficient GISTs include regorafenib, nilotinib, and sorafenib[21]. Better molecular and clinical characterization could improve management.
Conventional risk stratification fails to predict the progression of SDH-deficient GISTs[6]. SDH deficient GISTs run a relatively indolent course despite their frequent lymph node or distant metastasis. Follow-up data shows some patients survived for 10~17 years after peritoneal metastases[7]. However, our case only survived for 5 months after surgery, which may be related to the unique nature of infant and young child malignancies. This case reminds us that such tumors should be vigilant and it is necessary to collect more cases to study the appropriate treatment.