The Carney triad (CT) is gastrointestinal stromal tumor (GIST), paraganglioma, and pulmonary chondroma. The GISTs of CT show different clinical, molecular, and morphologic features to usual adult GISTs but are similar to the majority of pediatric GISTs. We postulated that these GISTs would show negative staining for succinate dehydrogenase B (SDHB). We performed SDHB immunohistochemistry on GISTs arising in 5 individuals with CT, 1 child, 7 individuals with GIST in young adulthood including 2 with germline KIT mutations, 3 individuals with neurofibromatosis 1, one 63-year-old female with multifocal gastric epithelioid GIST with lymph node metastases, and 104 consecutive unselected individuals with apparently sporadic GIST. The GISTs and paragangliomas arising in CT, the pediatric GIST, and the multifocal gastric GIST from the 63-year-old showed negative SDHB staining. GISTs from the 7 young adults and 3 with neurofibromatosis were SDHB positive. Of the unselected GISTs, 101 (97%) were positive. One of the negative GISTs arose in a 48-year-old female with previous recurrent multifocal gastric GISTs and the other 2 arose in females also in their 40s with gastric GISTs with epithelioid morphology. We conclude that negative staining for SDHB is characteristic of the GISTs of CT and the subgroup of pediatric GISTs which it resembles. Furthermore, when negative staining occurs in apparently sporadic GISTs in adults, the GISTs show morphologic and clinical features similar to pediatric and CT type GISTs. GISTs may therefore be divided into type 1 (SDHB positive) and type 2 (SDHB negative) subtypes.
"Paragangliomas These tumours arise from the neuroendocrine paraganglia that occur along the paravertebral axis from the base of the skull through to the pelvis (Fig. 1), and are divided into those that derive from the parasympathetic paraganglia (HNPGLs) or those from sympathetic paraganglia (TAPGLs). Approximately 40% of all PGLs are associated with SDH deficiency (Gill et al. 2010a), and those associated with SDHB mutations (PGL4) are at higher risk of malignancy (Timmers et al. 2007). "
"Furthermore, germline SDH mutation presenting with pituitary neoplasia is extremely rare (none in 309 consecutive adenomas). This is in contrast to pheochromocytoma/paraganglioma, in which SDH deficiency occurs in up to 15% of cases arising in an unselected population (3% in adrenal pheochromocytomas and up to 40% in extra-adrenal parangangliomas),9 and gastric GIST, in which SDH deficiency occurs in 5% to 7.5% of all cases,6,13 and more in keeping with the low incidence of succinate dehydrogenase deficiency in renal cancer, which is estimated to be 0.6%.27 On this basis it is hard to justify IHC screening for SDHB in all pituitary tumors as has been suggested for all pheochromocytomas/paragangliomas as well as GISTs and renal carcinomas with compatible morphology.4,6–8,15 "
[Show abstract][Hide abstract] ABSTRACT: Germline mutations in the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are established as causes of pheochromocytoma/paraganglioma, renal carcinoma, and gastrointestinal stromal tumor. It has recently been suggested that pituitary adenomas may also be a component of this syndrome. We sought to determine the incidence of SDH mutation in pituitary adenomas. We performed screening immunohistochemistry for SDHB and SDHA on all available pituitary adenomas resected at our institution from 1998 to 2012. In those patients with an abnormal pattern of staining, we then performed SDH mutation analysis on DNA extracted from paraffin-embedded tissue, fresh frozen tissue, and peripheral blood. One of 309 adenomas (0.3%) demonstrated an abnormal pattern of staining, a 30 mm prolactin-producing tumor from a 62-year-old man showing loss of staining for both SDHA and SDHB. Examination of paraffin-embedded and frozen tissues confirmed double-hit inactivating somatic SDHA mutations (c.725_736del and c.989_990insTA). Neither of these mutations was present in the germline. We conclude that, although pathogenic SDH mutation may occur in pituitary adenomas and can be identified by immunohistochemistry, it appears to be a very rare event and can occur in the absence of germline mutation. SDH-deficient pituitary adenomas may be larger and more likely to produce prolactin than other pituitary adenomas. Unless suggested by family history and physical examination, it is difficult to justify screening for SDH mutations in pituitary adenomas. Surveillance programs for patients with SDH mutation may be tailored to include the possibility of pituitary neoplasia; however, this is likely to be a low-yield strategy.
The American journal of surgical pathology 04/2014; 38(4):560-6. DOI:10.1097/PAS.0000000000000149 · 5.15 Impact Factor
"Recently those GISTs associated with Carney Triad, Carney-Stratakis syndrome, along with young and pediatric GISTs have been documented to have a loss of succinate dehydrogenase subunit B (SDHB) expression, a mitochondrial protein [41–43]. On the basis of the SDHB expression, it has been recently proposed that GISTs could be differentiated into 2 characteristic subgroups: type 1 SDHB-positive and type 2 SDHB-negative . "
[Show abstract][Hide abstract] ABSTRACT: Aims:
The objectives of this study were (a) to report our experience regarding the association between neurofibromatosis type 1 (NF1) and gastrointestinal stromal tumors (GISTs); (b) to provide a systematic review of the literature in this field; and (c) to compare the features of NF1-associated GISTs with those reported in sporadic GISTs.
We reported two cases of NF1-associated GISTs. Moreover we reviewed 23 case reports/series including 252 GISTs detected in 126 NF1 patients; the data obtained from different studies were analyzed and compared to those of the sporadic GISTs undergone surgical treatment at our centre.
NF1 patients presenting with GISTs had a homogeneous M/F ratio with a mean age of 52.8 years. NF1-associated GISTs were often reported as multiple tumors, mainly incidental, localized at the jejunum, with a mean diameter of 3.8 cm, a mean mitotic count of 3.0/50 HPF, and KIT/PDGFR α wild type. We reported a statistical difference comparing the age and the symptoms at presentation, the tumors' diameters and localizations, and the risk criteria of the NF1-associated GISTs comparing to those documented in sporadic GISTs.
NF1-associated GISTs seem to have a distinct phenotype, specifically younger age, distal localization, small diameter, and absence of KIT/PDGRF α mutations.
International Journal of Surgical Oncology 12/2013; 2013:398570. DOI:10.1155/2013/398570
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