GIST occurred in 7 % of patients with NF1 in a study utilizing Swedish health registry data [6, 7]. The median age of GIST diagnosis in NF1 patients is 49 years and it appears GIST occurs slightly more often in females than in males. GIST occurring in the setting of NF1 are located in the small bowel, have a spindle cell morphology, can be multiple, and often have a background of interstitial cells of Cajal hyperplasia. Prognosis is usually good when tumors are small and have a low mitotic rate which is the more common scenario [8]. There is little information to inform medical management of GIST occurring in patients with NF1. Imatinib does not seem to be effective. There is a case report with response to sunitinib [7, 9].

Approximately 10 % of GIST occurring in adults [10] and 85 % of GIST occurring in children [11] lack an activating mutation in the tyrosine kinases – KIT, PDGFR, BRAF –typically mutated in GIST. This type of GIST has been called “wildtype GIST” or “pediatric GIST.” Now that the biology of these GIST tumors is better understood, the preferred terminology for this group is “SDH-deficient GIST.” As discussed in greater detail in the chapter “Surgical Pathology of Gastrointestinal​ Stromal Tumors:​ Correlation with Clinical and Molecular Subtypes,” SDH-deficient GIST is defined by absence of immunohistochemical (IHC) staining for succinate dehydrogenase B (SDHB). The SDH-ubiquinone complex is a component of the Krebs cycle and the respiratory chain. It is a heteroligomer composed of subunits A, B, C, and D. Inactivation of any one of the three SDH subunits results in destabilization of the SDH complex, loss of enzymatic function, and absence of IHC staining for SDHB [12].

There appears to be two mechanisms through which SDH inactivation occurs, germline or somatic inactivating mutations [13] and methylation of the SDHC in this context refers to gene: succinate dehydrogenase complex (SDHC) promoter leading to silencing of SDHC expression [14]. We have called GIST with germline or somatic mutations in SDHA, SDHB, SDHC, or SDHD (also indicated by SDHX) SDH-mutant GIST and GIST with methylation of the SDHC promoter SDH-epimutant GIST [15]. As described in further detail below, it is important to recognize SDH-deficient GIST and to determine which subtype of SDH-deficient GIST a patient has because SDH-deficient GIST has unique epidemiologic (Fig. 1) and clinical features with implications for prognosis and clinical management.

Approximately 70 % of SDH-deficient GIST have an SDHX mutation and thus are best categorized as SDH-mutant GIST. The SDH subunit mutated in these SDH-mutant GIST is SDHA in 54 % of cases, SDHB in 25 % of cases, SDHC in 19 % of cases, and SDHD in 2 % of cases. Approximately 80 % of patients with SDH-mutant GIST will have the identified SDHX mutation in the germline while the remaining 20 % appear to have the SDHX mutation present in the tumor only. The median age of GIST presentation in SDH-mutant GIST is 23 (range 7–58), much younger than the age of presentation for KIT and PDGFRA mutant GIST. About 60 % of patients presenting with SDH-mutant GIST are female. All SDH-mutant GIST occur in the stomach with 40 % of these gastric tumors being multifocal (more than one discrete gastric tumor) at the time of presentation. Approximately 30 % of patients with SDH-mutant GIST will have metastatic disease at presentation with lymph nodes being the most common site of metastatic disease followed by liver and peritoneum [15].

As discussed in much greater detail in the section SDH-deficient GIST, approach to cancer screening section later in this chapter, germline SDHX mutations cause hereditary paraganglioma, reviewed in [16]. Consequently, these patients are at risk for other cancers especially paraganglioma and pheochromocytoma.

Approximately 30 % of SDH-deficient GIST have SDHC promoter hypermethylation and thus are best categorized as SDH-epimutant GIST. The median age of GIST presentation in SDH-epimutant GIST is 15 (range 8–50). Almost all of the patients presenting with SDH-epimutant GIST are female. Thus SDH-epimutant GIST is the predominant subtype occurring in young females. All SDH-epimutant GIST occur in the stomach with 72 % of these gastric tumors being multifocal at the time of presentation. Approximately 40 % of patients with SDH-epimutant GIST will have metastatic disease at presentation with liver and lymph nodes being the most common site of metastatic disease followed by peritoneum [15].

Like other GIST, SDH-deficient GIST arise from the interstitial cells of Cajal and, therefore, are in the muscularis propria layer of the gastrointestinal tract deep to the submucosa. In the case of SDH-deficient GIST, patients present with one or multiple intramural masses in the stomach. Because children with GIST essentially all have SDH-deficient GIST, information gleaned from case series of pediatric GIST has relevance to SDH-deficient GIST. In a summation of pediatric GIST series and case reports, by far the most common manifestations at the time of initial presentation are gastrointestinal bleeding and anemia or symptoms related to it such as fatigue. Patients can also have abdominal pain and a palpable abdominal mass or abdominal distension [21]. Staging which should be performed with ¹⁸FDG-PET-CT reveals metastatic disease involving the gastric lymph nodes, liver, or peritoneum in 30–40 % of patients. If liver metastases are present, magnetic resonance imaging (MRI) can be helpful to establish a baseline appearance for correlation with later imaging assessment of response to treatment. Chest X-ray should be obtained at diagnosis to evaluate for the presence of pulmonary chondromas which occur in the setting of Carney Triad (Fig. 2).

The diagnosis of SDH-deficient GIST should be suspected in patients presenting with GIST at a young age (<40 years), whenever a patient presents with multifocal gastric tumors and when lymph nodes are involved with metastases at the time of diagnosis. The recommended approach for biopsy of SDH-deficient GIST is endoscopic, ultrasound-guided biopsy of the gastric masses except when presentation with massive hemorrhage or perforation necessitates emergency surgery. Endoscopic biopsy of GIST is discussed in detail in the chapter “Endoscopic Evaluation of Gastrointestinal​ Stromal Tumors.”

The pathologic features of SDH-deficient GIST are discussed in detail in the chapter “Surgical Pathology of Gastrointestinal​ Stromal Tumors:​ Correlation with Clinical and Molecular Subtypes.” Epitheilioid morphology and a multinodular or plexiform pattern are pathologic features suggesting a diagnosis of SDH-deficient GIST. In addition, SDH-deficient GIST should be considered when molecular testing of tumor reveals nosomatic mutations in KIT, PDGFRA, and BRAF. SDH-deficient GIST have strong membranous IHC staining for KIT and DOG1. The key pathologic feature confirming a diagnosis of SDH-deficient GIST is absence of IHC staining for SDHB [22]. SDHB IHC should be performed on GIST presenting in young patient, when multifocal GIST is present, when pathologic features are suggestive of SDH-deficient GIST, and when features of SDH-deficient GIST are not present but tumor sequencing does not reveal kinase mutations. It is also possible to perform IHC for SDHA. IHC staining for SDHA is absent in SDH-deficient GIST caused by germline or somatic mutations in SDHA [23, 24]. Sequencing tumor for mutations in KIT, PDGFRA, BRAF, SDHA, SDHB, SDHC, and SDHD can be very helpful in determining optimal treatment approaches, prognosis, and whether referral to a cancer predisposition program for genetic testing is indicated. Testing for mutations in KIT and PDGFRA and, when negative, for mutations in SDH genes is recommended in the National Comprehensive Cancer Network (NCCN) Guidelines [25].

As SDH-deficient GIST has only recently been identified as a distinct entity, there is limited data on the clinical course or prognosis of this entity. Because children with GIST essentially all have SDH-deficient GIST, information gleaned from case series of pediatric GIST has relevance to SDH-deficient GIST. A review of literature on pediatric GIST suggests that most SDH-deficient GIST have an indolent course. Despite the fact that many patients develop multiple disease recurrences or present with metastatic disease, patients can survive with active disease for many years [21]. In one of the largest series of pediatric GIST reported to date, with a mean duration of follow up of almost 5 years,10 of 12 patients (83 %) developed metastatic disease yet only one died as a consequence of GIST. Half of the patients were alive with disease and the mean duration of survival with disease was almost 6 years [26].

A comprehensive study of 84 patients with SDH-deficient GIST led by the NIH collected follow-up data on a cohort of patients who attended a clinic dedicated to assessment of patients with pediatric or wild-type GIST. In 63 patients with SDH-mutant GIST, after a median follow-up from diagnosis of 6 (range 1–44) years, 3 had died (8–24 years after initial diagnosis). In the 21 patients with SDH-epimutant GIST, after a median follow-up of 9 (range 1–32) years, 1 patient died 6 years after diagnosis [15]. Patients with SDHA mutant GIST appear to have an excellent prognosis [27].