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Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Joaquina Baranda, Stafinur Atay, Andrew K. Godwin
Carney triad (CT) is a very rare disease with synchronous or metachronous occurrence of at least three different tumor entities; gastric gastrointestinal stromal tumor (GIST), paraganglioma (PGL), and pulmonary chondroma [80–82]. Recently, esophageal leiomyomas and adrenal cortical adenomas have been added as components of the syndrome [83, 84]. GISTs in this syndrome lack mutations in KIT/PDGFRA/BRAF and are unusual in that they are multifocal tumors affecting the stomachs of young female patients. Importantly, this condition is never inherited. Lymph node or liver metastases may occur but do not necessarily portend a rapidly progressive malignant course. These features are similar to pediatric GISTs (described below), raising the likelihood that pediatric GISTs may be an attenuated or atypical form of Carney’s triad. KIT protein expression has been variably reported in the GISTs of Carney’s triad [46, 85–87].
Imaging of the adrenal glands
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Although patients with pheochromocytoma may present with hypertension, palpitations, headache, diaphoresis, and flushing, 10% of patients are asymptomatic. In patients with incidentally discovered pheochromocytoma, 53% have hypertension [30]. The diagnosis is made clinically by measuring metanephrines (i.e., metanephrine plus normetanephrine) and parent catacholamines. Urinary catecholamines and their metabolites, metanephrines, vanillyl-mandelic acid (VMA), and homovanillic acid (HVA), are rarely used because of low sensitivity and specificity. Pheochromocytomas are associated with a number of syndromes, including multiple endocrine neoplasia type 2, von Hippel–Lindau syndrome, neurofibromatosis, tuberous sclerosis, and Sturge–Weber syndrome (Figure 27.8). Extra-adrenal pheochromocytoma can occur anywhere along the sympathetic chain, with the periadrenal, the para-aortic, and the ureterocystic junction being common locations. Familial paraganglioma is associated with parasympathetic tumors at the carotid bifurcation or glomus jugulare at the base of the skull. Carney’s triad is a constellation of extra-adrenal pheochromocytoma, gastrointestinal stromal tumor (GIST) of the stomach, and pulmonary chondroma.
Deciding on the duration of adjuvant therapy in gastrointestinal stromal tumor
Published in Expert Review of Anticancer Therapy, 2021
Peter Whooley, Erika Correa, Margaret von Mehren
SDH deficient tumors can present as multi-focal tumors and with lymph node involvement that is uncommon for other primary GIST. While these features might suggest a more aggressive course, some have an indolent behavior and persist for many years without significant morbidity or mortality. This is particularly true of tumors that are part of the Carney triad, constituted by GIST, pulmonary chondromas, and paragangliomas, which have altered methylation rather than mutations [6,11]. In contrast, tumors with mutations in the SDH family of genes, can have a more aggressive biology and be associated with germline mutations. The Carney Stratakis Dyad consists of GIST and paragangliomas, including pheochromocytomas [12]. GIST in NF-1 patients or carrying a mutation in this gene, can present with multi-focal disease; they tend to be rather indolent as well [13]. Little is known about other mutations and prognosis given the relative rarity of these tumors.
Possible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypes
Published in Journal of Neurogenetics, 2018
Succinate dehydrogenase subunit B (SDHB) is one of the ubiquitously expressed proteins in the mitochondria. The lack of SDHB expression was observed in cases of Carney triad and Carney Stratakis syndrome-associated gastrointestinal stromal tumors (GISTs) (OMIM#606864) (Pasini et al., 2008; Price, Zielenska, Chilton-MacNeill, Smith, & Pappo, 2005). GISTs arise in NF1 patients 150-times more often than they do in the general population (Bajor, 2009). Similar to the majority of adult GISTs, NF1-associated GISTs express SDHB; however, unlike the majority of GISTs, they do not respond well to imatinib treatment (Wang, Lasota, & Miettinen, 2011). This observation raised the possibility that SDHB could be a candidate modifier of the phenotypic variation in NF1. Sciacovelli et al. (2013) proposed that inhibition of SDH with the mitochondrial chaperone TRAP1 could promote neoplastic growth. TRAP1 expression is restricted to the mitochondria and has a protective role in oxidative stress. TRAP1 is highly expressed in many tumors, and therefore, may also be a crucial factor in NF1 tumors. Cancer cells require a high amount of oxygen so that they can expand their own blood supply rapidly (Gilkes, Semenza, & Wirtz, 2014). Yet, because their growth rate is so high, cancer cells have acquired a mechanism, known as the Warburg effect, which decreases the rate of mitochondrial respiration (Frezza & Gottlieb, 2009) to allow the cells to grow in a hypoxic condition (Hsu & Sabatini, 2008). This effect is initiated by the induction of hypoxia-inducible transcription factor-1 (HIF1), which is activated by hypoxia together with the accumulation of succinate and fumarate, the Krebs cycle metabolites (Selak et al., 2005). HIF1 decreases the influx of pyruvate to the Krebs cycle and activates glycolysis (Semenza, 2010). Specifically, TRAP1, an evolutionarily conserved chaperone of the heat-shock protein 90 family (Altieri, Stein, Lian, & Languino, 2012), downregulates mitochondrial respiration by reducing the activity of SDH, which in turn stabilizes HIF1 by increasing succinate levels (Sciacovelli et al., 2013).
New insights into the clinical management of advanced gastrointestinal stromal tumors
Published in Expert Opinion on Pharmacotherapy, 2021
More recently, it has been shown that the majority of wild-type GIST are characterized by a loss of expression of the succinate dehydrogenase B (SDHB) resulting from mutations or epigenetic inactivation of the SDHA, SDHB, SDHC, or SDHD gene in one of the SDH family members (A, B, C, or D), or from epigenetic inactivation [40–42]. SDH-deficient GISTs can be sporadic, with no other clinical manifestations, but more frequently present as one of two classes of syndromic GISTs, Carney triad and Carney–Stratakis syndrome [43–45]. Carney-Stratakis syndrome, an inherited predisposition syndrome to multiple gastric GISTs and paragangliomas, is caused by SDHx germline mutations [40,46–48]. Surveillance for paragangliomas and other tumors is indicated for patients with inherited SDH-deficient GISTs [49]. Carney-triad, a non-heritable syndrome characterized by multiple gastric GISTs, paragangliomas and pulmonary chondromas, is generally associated with epigenetic SDH inactivation through SDHC hypermethylation [42–50], and has been rarely associated with germline SDH mutations [51]. These SDH-deficient GISTs have specific clinical features including age at diagnosis <40 years, female predominance, preferential gastric location, and multifocality [40]. Treatment of patients with SDH-deficient GIST is challenging given their resistance to imatinib. Sunitinib and regorafenib have been shown to provide some disease control but their efficacy remains modest in this setting. Interestingly, several studies have shown that SDH-def GIST are characterized by an overexpression of IGF-1 R [52–54]. The results of a phase II study investigating linsitinib, an oral kinase inhibitor with specificity for IGF-1 R and the insulin receptor (IR), in patients with advanced SDH-deficient GIST have been recently reported [55]. Ten of 19 patients eligible for efficacy analysis experience tumor shrinkage. The clinical benefit rate, defined as the proportion of patients with stable disease >9 months, partial response, or complete response was 40%. Nine-month progression-free and overall survival rates at 9 months were 52% and 80%, respectively [55]. These results appear as promising given the fact that all the patients enrolled in the study were refractory to previous tyrosine kinase inhibitors. However, the authors were not available to identify any predictive biomarkers of clinical benefit. In particular, no correlation was found between IGF-IR expression levels and clinical efficacy. Further studies are needed to assess the relevance of this approach as a single agent or in combination.