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Archives of Pathology & Laboratory... May 2020Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs.... (Review)
Review
Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs. SDH-mutated GISTs lack mutations in the proto-oncogene receptor tyrosine kinase (also known as KIT, c-KIT, or CD117) or platelet-derived growth factor receptor α (PDGFR-α). These tumors have female predilection, affect children and young adults, and have a spectrum of behavior from indolent to progressive. These tumors have characteristic morphologic features including multinodular architecture, multiple tumors, lymphovascular involvement, and occasional lymph node metastasis. They can be seen in patients with Carney triad or Carney-Stratakis syndrome. Although a mutation in any one of the SDH subunits can be pathogenic, deficiency of a single subunit leads to loss of detectable SDH subunit B by immunohistochemistry, enabling a convenient, tissue-based screening method. The prognosis and the clinical course of these tumors is different from that of KIT- or PDGFR-α-mutated GISTs. Surgical management is considered the main line of treatment. SDH-mutated GISTs do not respond well to the common targeted therapy, with no objective tumor response to imatinib. The role of the pathologist in diagnosing these cases is imperative in management and subsequent follow-up.
Topics: Chondroma; Electron Transport Complex II; Gastrointestinal Stromal Tumors; Humans; Immunohistochemistry; Leiomyosarcoma; Lung Neoplasms; Membrane Proteins; Mutation; Paraganglioma; Paraganglioma, Extra-Adrenal; Prognosis; Proto-Oncogene Mas; Stomach Neoplasms; Succinate Dehydrogenase
PubMed: 31169996
DOI: 10.5858/arpa.2018-0370-RS -
Radiology. Cardiothoracic Imaging Aug 2020
PubMed: 33778605
DOI: 10.1148/ryct.2020200029 -
Archives of Pathology & Laboratory... Oct 2006Gastrointestinal stromal tumors (GISTs) are specific, generally Kit (CD117)-positive, mesenchymal tumors of the gastrointestinal tract encompassing a majority of tumors... (Review)
Review
CONTEXT
Gastrointestinal stromal tumors (GISTs) are specific, generally Kit (CD117)-positive, mesenchymal tumors of the gastrointestinal tract encompassing a majority of tumors previously considered gastrointestinal smooth muscle tumors. They are believed to originate from interstitial cells of Cajal or related stem cells.
OBJECTIVE
To review current clinicopathologically relevant information on GIST.
DATA SOURCES
Literature in Medline and authors' own experience.
CONCLUSIONS
GISTs usually occur in older adults (median age 55-60 years) and rarely in children in the second decade (<1%) throughout the gastrointestinal tract: 60% in stomach, 35% in small intestine, and less than 5% in rectum, esophagus, omentum, and mesentery; most GISTs in the latter 2 sites are metastatic. Five percent of GISTs occur in patients with neurofibromatosis type 1 syndrome (multiple small intestinal tumors) and in Carney triad (gastric epithelioid GISTs in young females). Familial GISTs occur in patients with inheritable germline Kit or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Histologically GISTs vary from spindle cell tumors to epithelioid and pleomorphic tumors. Most GISTs (95%) express Kit (CD117), CD34 (70%), and heavy caldesmon (80%), whereas 25% are positive for smooth muscle actin and less than 5% for desmin. Tumor size and mitotic activity are best predictive prognostic features; small intestinal tumors behave more aggressively than gastric tumors with similar parameters. Mutually exclusive gain-of-function Kit or PDGFRA mutations occur in a majority of GISTs representing in-frame deletions, point mutations, duplications and insertions. Mutations in Kit juxtamembrane domain (exon 11) are the most common in GISTs of all sites, whereas rare Kit extracellular domain (exon 9) Ala502-Tyr503 duplication is specific for intestinal GISTs. Mutations in PDGFRA have been identified in juxtamembrane (exon 12) and tyrosine kinase domains (exons 14 and 18), nearly exclusively in gastric GISTs, mostly in epithelioid variants. Some Kit and PDGFRA mutations have a prognostic value. Kit/PDGFRA tyrosine kinase inhibitor imatinib has been successfully used in the treatment of metastatic GISTs for more than 5 years. However, primary and acquired secondary resistance linked to certain types of Kit and PDGFRA mutations is limiting long-term success necessitating the use of alternative treatments.
Topics: Biomarkers, Tumor; Diagnosis, Differential; Gastrointestinal Stromal Tumors; Humans; Immunohistochemistry; Incidence; Intestinal Neoplasms; Intestine, Small; Mutation; Prognosis; Proto-Oncogene Proteins c-kit; Receptor, Platelet-Derived Growth Factor alpha; Stomach Neoplasms; Syndrome
PubMed: 17090188
DOI: 10.5858/2006-130-1466-GSTROM -
Frontiers in Endocrinology 2021Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and... (Review)
Review
Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All -deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the subunits. Gastrointestinal stromal tumors (GISTs) associated with deficiency are negative for mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. -deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the gene and may be due to germline mosaicism of the responsible genetic defect.
Topics: Adrenal Gland Neoplasms; Chondroma; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Leiomyosarcoma; Lung Neoplasms; Paraganglioma; Paraganglioma, Extra-Adrenal; Pheochromocytoma; Stomach Neoplasms; Succinate Dehydrogenase
PubMed: 34012423
DOI: 10.3389/fendo.2021.680609 -
Respiratory Care Dec 2014Endobronchial chondromas are rare benign tumors. They may be part of the Carney triad; however, isolated endobronchial chondromas can occur in the larynx, trachea, and...
Endobronchial chondromas are rare benign tumors. They may be part of the Carney triad; however, isolated endobronchial chondromas can occur in the larynx, trachea, and bronchi. We report a case of an endobronchial chondroma in a 61-y-old man with an incidental 5-mm endobronchial polypoid lesion at the proximal left main bronchus that was later found to be an endobronchial chondroma. Flexible bronchoscopy demonstrated a pedunculated, vascularized, pink mass. An excisional biopsy revealed a well-circumscribed lesion with nodular areas of mature cartilage and myxoid tissue confirmatory of an endobronchial chondroma. We reviewed a total of 23 cases of isolated endobronchial chondromas reported in the medical literature. Despite their rarity, endobronchial chondromas should be considered in the differential diagnosis of endobronchial tumors. Prompt recognition and resection of endobronchial chondromas is important to prevent airway obstruction and its associated complications.
Topics: Biopsy; Bronchial Neoplasms; Bronchoscopy; Chondroma; Humans; Incidental Findings; Male; Middle Aged; Radiography
PubMed: 25233382
DOI: 10.4187/respcare.02673 -
Molecular and Cellular Endocrinology Jul 2018In this report, we review the relationship between succinate dehydrogenase (SDH) deficiency and the epigenome, especially with regards to two clinical conditions. Carney... (Review)
Review
In this report, we review the relationship between succinate dehydrogenase (SDH) deficiency and the epigenome, especially with regards to two clinical conditions. 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. This condition affects mostly females and it is never inherited. Another disease that shares two of the tumor components of CT, namely GIST and PGL is the Carney-Stratakis syndrome (CSS) or dyad. CSS affects both genders during childhood and adolescence. We review herein the main clinical features and molecular mechanisms behind those two syndromes that share quite a bit of similarities, but one is non-hereditary (CT) whereas the other shows an autosomal-dominant, with incomplete penetrance, inheritance pattern (CSS). Both CT and CSS are caused by the deficiency of the succinate dehydrogenase (SDH) enzyme. The key difference between the two syndromes is the molecular mechanism that causes the SDH deficiency. Most cases of CT show down-regulation of SDH through site-specific hyper-methylation of the SDHC gene, whereas CSS cases carry inactivating germline mutations within one of the genes coding for the SDH subunits A, B, C, or D (SDHA, SDHB, SDHC, and SDHD). There is only partial overlap between the two conditions (there are a few patients with CT that have SDH subunit mutations) but both lead to increased methylation of the entire genome in the tumors associated with them. Other tumors (outside CT and CSS) that have SDH deficiency are associated with increased methylation of the entire genome, but only in CT there is site-specific methylation of the SDHC gene. These findings have implications for diagnostics and the treatment of patients with these, often metastatic tumors.
Topics: Carcinogenesis; Chondroma; Epigenomics; Germ-Line Mutation; Humans; Leiomyosarcoma; Lung Neoplasms; Paraganglioma, Extra-Adrenal; Stomach Neoplasms; Succinate Dehydrogenase
PubMed: 28739378
DOI: 10.1016/j.mce.2017.07.018 -
JCEM Case Reports Feb 2024
PubMed: 38405102
DOI: 10.1210/jcemcr/luae016 -
World Journal of Gastroenterology Feb 2015Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still... (Review)
Review
Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor 1α may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Gastrointestinal Stromal Tumors; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Molecular Targeted Therapy; Receptor, IGF Type 1; Receptors, Somatomedin; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Stomach Neoplasms; Succinate Dehydrogenase
PubMed: 25741136
DOI: 10.3748/wjg.v21.i8.2303 -
Endocrinology, Diabetes & Metabolism... Mar 2021Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma...
SUMMARY
Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC.
LEARNING POINTS
The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes. Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs. Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants. Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.
PubMed: 33839693
DOI: 10.1530/EDM-20-0170 -
Endocrine-related Cancer Jun 2015Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other...
Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr. For the present study, we examined mitochondrial structure in human tumors and GI tissue (GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), those with isolated GIST (n=1), and those with CSS caused by SDHC (n=1) and SDHD (n=2) mutations were studied by electron microscopy (EM). Samples of GIT from mice with a heterozygous deletion in Sdhb (Sdhb(+) (/-), n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located, round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GISTs of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained an increased number of mitochondria with a 'hypoxic' phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities, and were of variable size. Occasionally, mitochondria were small and round; rarely, they were thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. A similar mitochondrial hypoxic phenotype was seen in Sdhb(+) (/-) mice. We concluded that tissues from SDH-deficient tumors, those from mouse GIT, and those from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still-elusive CTr defect(s) is(are) likely to affect mitochondrial function, just like germline SDH-deficiency does.
Topics: Adolescent; Adult; Animals; Child; Chondroma; Electron Transport Complex II; Female; Humans; Leiomyosarcoma; Lung Neoplasms; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Mitochondria; Paraganglioma, Extra-Adrenal; Stomach Neoplasms; Succinate Dehydrogenase; Young Adult
PubMed: 25808178
DOI: 10.1530/ERC-15-0069