In this study we evaluated clinicopathologically 66 succinate dehydrogenase (SDH) deficient gastric GISTs, defined here by immunohistochemical negativity for SDHB, one of the normally ubiquitously expressed subunits of the SDH complex. Based on knowledge of the impact of loss of any SDH – subunits inactivation of the entire SDH complex in other tumors associated with SDH-deficiency, especially paragangliomas 11,17
– it is appropriate to designate this group as SDH-deficient GISTs.
We found SDH-deficient GISTs exclusively among gastric GISTs (66/756, 8.7%). However, this overestimates the true frequency, as the analysis was in part targeted to GISTs of young patients. Based on an unselected sample, we estimate that the true frequency of SDHB-deficient GISTs among all gastric GISTs is 7.5%. While most GISTs in young patients (≤21 years of age) were SDH-deficient, approximately half of them in patients at ages 21–30 years were SDH-deficient, whereas this was only rarely the case in GISTs of older adults. Previous studies have found SDH-deficient (SDHB-negative) pediatric, Carney Triad or Carney Stratakis syndrome-associated GISTs 8,10,17
along with rare examples of similar adult GISTs (3%) in one study.10
While there was an overall female predominance, the gender distribution was equal in age groups > 30 years in our study.
There are a number of histologic clues to SDH-negative status. These include epithelial hypercellular histology, plexiform growth pattern in the muscularis propria, and lymphovascular invasion and lymph node metastases that are otherwise rare in gastric GISTs. In fact, the “plexiform” muscularis propria involvement resembles that often seen in gastric glomus tumors, in some of the nodules may be intravascular.23
Similar patterns were recently also reported in rare adult GISTs resembling pediatric GISTs, but their SDHB-status was not known.33
Immunohistochemically SDH-deficient GISTs are distinctive for strong KIT expression, in contrast to many gastric epithelioid GISTs that show weaker KIT expression. They also are more often CD34-positive than gastric epithelioid GISTs but almost never express alpha smooth muscle actin that is present in 23% gastric GISTs, at least focally. 24
A molecular genetic clue to SDH-deficient GIST is lack of KIT and PDGFRA mutations (wild type), found here in all analyzed SDH-deficient GISTS, similar to previous observations on a smaller number of cases. 17
Also, these tumors seem to be unrelated to the rare KIT/PDGFRA-wild type GISTs carrying BRAF mutations found in adult patients, more often with intestinal GISTs. 2,16
Clinical behavior of SDH-deficient GISTs largely mirrors pediatric and Carney triad GISTs due to their predominant occurrence at a young age. In our study cohort, 10 of 54 patients with follow-up (19%) developed liver metastases and 7 patients died of disease. Many patients were alive with disease during long-term follow-up. Long latency from primary tumor to metastasis is common, and the longest interval from primary tumor to liver metastasis was 42 years in our study, illustrating the chronic course and need for life-long follow-up. Gastric recurrences, very rare in adult gastric GISTs, are common in SDH-deficient GISTs often ultimately leading to subtotal gastrectomy; they do not seem to have adverse prognostic significance. Neither are lymphovascular invasion, lymph node metastases, or peritoneal micrometastases ominous signs in this group, as many patients with them survived for long times.
SDH-deficient GISTs are unpredictable and metastatic disease may occur in tumors with favorable histologic parameters; two such patients died of disease. In our experience, many patients with metastatic GISTs ≤ 5 cm with mitotic counts ≤ 5/50 HPFs (group 2 GISTs) are SDH-deficient GISTs. On other hand, some patients with SDH-deficient GISTs with mitotic activity in excess of 10/50 HPFs, have uneventful survival again illustrating their unpredictability. The fact that 4 of 7 patients who died of tumor were male in this heavily female dominated group, may suggest that male patients have more aggressive course of disease. The very small number of older adults with SDH-deficient GISTs limits prognostic conclusions, although, with one exception, all patients had a favorable outcome. In many ways: tumor multiplicity, predilection to gastric antrum, potential occurrence of nodal metastases, chronic, somewhat unpredictable course but ultimately low long-term tumor mortality, SDH-deficient GISTs resemble Carney triad-associated and pediatric GISTs in general.5,25,32,38
Carney triad (gastric GIST, pulmonary chondroma, and paraganglioma) is a non-hereditary tumor syndrome including at least of the following: gastric GIST, pulmonary chondroma, and paraganglioma, at varying time intervals. It has a strong predilection to young females.5,38
In this study, we identified only 2 patients with pulmonary chondroma and 2 other patients with paraganglioma. Even if the frequency of Carney triad may be underestimated in our series, the findings suggest that Carney triad is not very common among the SDH-deficient GISTs. Carney triad patients do not have SDH germline mutations, but SDH-deficiency may be mediated by allelic losses in SDH, and losses in chromosome 1p36, the locus of SDHB, may be the alternative mechanism for loss of function of the SDH complex. 21
Carney-Stratakis syndrome (CSS) is a rare hereditary syndrome combining gastric GIST and paraganglioma. In contrast to Carney triad, it has a more equal gender distribution. The pathogenesis is based on a loss-of-function germline mutation in SDH subunits B, C, or D, and functional loss of the other allele based on currently poorly understood mechanisms. 28,29
Lack of familial tumor history and SDHB, C, or D (germline) mutations (analyzed in 10 patients in this study) suggests that SDHB-deficient GISTs are not commonly associated with CSS. However, we were not able to analyze DNA from two male patients with GIST and paraganglioma, good candidates for CSS. However, 54% of patients with paragangliomas, commonly SDH-deficient tumors, were found to have germline SDH mutations in one study. 3
In their rarity of SDH germline mutations, despite SDH-deficient status, GISTs differ from paragangliomas, for which SDH-deficiency generally signals a germline mutation. 26
Very recently, loss-of-function SDHA germline mutations were reported in two gastric KIT/PDGFRA wildtype GISTs 27
indicating that mutations of this subunit should also be screened in SDH-negative GISTs. SDHA mutations have been previously found in one patient with a cathecholamine-secreting adrenal paraganglioma. 4
Previously SDHA loss-of function mutation was reported in Leigh syndrome featuring a severe neurodegenerative disorder. 15
Renal onkocytoma was diagnosed in one patient with an SDH-deficient GIST. Renal cell carcinoma has been reported to be associated with SDHB paraganglioma syndrome, and this tumor is also otherwise known to be associated with pseodohypoxia pathway.36
Esophageal leiomyoma or adrenal adenoma, other tumors seen in Carney Triad, 5
were not encountered in our patients.
The pathogenesis-based definition, SDH-deficient GIST, common to GISTs of Carney triad, Carney-Stratakis syndrome and pediatric GISTs in general, obtained by a single immunostain for SDHB, seems to be more efficient than the identification of a syndrome based on the accompanying tumors, paragangliomas and pulmonary chondromas, or young age only. First, different components of these syndromes can present over a long period of time making life-long follow-up necessary to observe the complete syndrome phenotype. Secondly, based knowledge on the related paraganglioma syndromes also associated with SDH-deficiency, these syndromes may have incomplete to low penetrance, perhaps in only 30%, making it more difficult to observe familial disease without germline mutation analysis. 13
Thirdly, there are pediatric GISTs other than SDH-deficient GISTs; these comprise the very rare non-gastric GISTs at a young age. Similar gene expression profiles reported in CT, CSS, pediatric GISTs, and a small number of adult GISTs also seem to support the unifying concept of SDH-deficient GIST. 1
SDHB-deficient GISTs seem to exclusively occur in the stomach, and none of the GISTs from other locations were SDHB-negative. This included the rare non-gastric GISTs in young populations, NF1-associated GISTs, and sporadic, non-gastric wild-type GISTs, whose pathogenesis remains poorly understood. However, one report described two small intestinal (jejunal) GISTs in paraganglioma patients. 30
Although these cases were negative for SDH subunit mutations, immunohistochemical testing for SDHB was not yet available, leaving it open whether these jejunal GISTs were SDH-deficient.
For treatment, patients with SDH-deficient GISTs should undergo complete tumor resection with attention to secondary lesions and peritoneal and nodal metastases. For adjuvant therapy, they may require different approach than KIT/PDGFRA mutated GISTs that typically respond to imatinib mesylate, the first line KIT tyrosine kinase inhibitor. Instead, second generation tyrosine kinase inhibitors, such as sunitib malate, may be more effective, as noted for pediatric GISTs.1
Lifelong follow-up is necessary for the potential of liver metastases and accompanying tumors, especially paragangliomas, for which also radiologic screening might be indicated. In this retrospective study, only a few patients received imatinib for some periods of time and no one sunitinib, so that data are insufficient for further comments on effectiveness of tyrosine kinase inhibitor treatment, especially in view of generally slow natural course of disease.
In conclusion, we analyzed a series of 66 gastric SDH-deficient GISTs. Most patients were young, with a small population of older adults. Only 4 patients had accompanying tumors defining Carney triad, and none of the patients was found to have germline mutations of SDH subunits defining Carney-Stratakis syndrome. SDH-deficient GISTs are KIT/PDGFRA wild type, typically have plexiform muscularis propria involvement, epithelioid morphology, lymphovascular invasion, and some also have lymph node metastases. Multiple synchronous or asynchronous tumors are common leading to gastric recurrences. Potential, somewhat unpredictable development of liver metastases (in 20% of patients) after long latency and asynchronous paragangliomas necessitate long-term follow-up.