Gastrointestinal Stromal Tumors in Children and Young Adults: A Clinicopathologic, Molecular, and Genomic Study of 15 Cases and Review of the Literature

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Journal of Pediatric Hematology/Oncology (Impact Factor: 0.9). 04/2005; 27(4):179-87. DOI: 10.1097/01.mph.0000157790.81329.47
Source: PubMed


Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the intestinal tract that typically occur in adults over the age of 40 years. GISTs in younger patients are rare and not well characterized. The objective was to define the characteristics of GISTs in children and young adults (<30 years old). Clinicopathologic and molecular features, including KIT/PDGFRA genotype, in GISTs from 5 children and 10 young adults were analyzed. Gene expression analysis was performed on 5 gastric tumor samples from 2 children, 2 gastric tumors from young adults, and 10 gastric GISTs from older adults using an U133A Affymetrix platform (22,000 genes). All five pediatric GISTs occurred in girls, involved the stomach as multiple nodules, showed predominantly an epithelioid morphology, often involved lymph nodes, and lacked KIT or PDGFRA mutations. Although all five patients developed recurrence (four in the liver, three in the peritoneum, and two in both sites), four are still alive with disease. Of the 10 GISTs in young adults, half occurred in the small bowel and had spindle cell morphology, and one case had lymph node metastasis. KIT mutations were identified in seven cases, four in exon 11 and three in exon 9. Seven patients developed recurrence, and at last follow-up two patients had died of disease. Gene expression analysis showed high expression of PHKA1, FZD2, NLGN4, IGF1R, and ANK3 in the pediatric and young adult versus older adult cases. GISTs that occur in children are a separate clinicopathologic and molecular subset with predilection for girls, multifocal gastric tumors, and wild-type KIT/PDGFRA genotype. In contrast, GISTs in young adults are a more heterogeneous group, including cases that resemble either the pediatric or the older adult-type tumors. The distinct gene expression profile suggests avenues for investigation of pathogenesis and potential therapeutic strategies.

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Available from: Leonard H Wexler, Aug 21, 2014
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    • "KIT mutations were identified in seven cases, four in exon 11 and three in exon 9. GISTs that occur in children are a separate clinicopathologic and molecular subset with predilection for girls, multifocal gastric tumors, and wild-type KIT/PDGFRA genotype. In contrast, GISTs in young adults are a more heterogeneous group, including cases that resemble either the pediatric or the older adult-type tumors [31]. "
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    ABSTRACT: Objective Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. We report a case of gastrointestinal stromal tumor in a small intestine, initially suspected for leiomyosarcoma given that gastrointestinal stromal tumors in young patients are limited due to their rarity. Method A 30-year-old Caucasian ethnic Albanian female from Kosovo presented with abdominal pain, nausea and vomiting. Subsequently, the tumor was detected in the small intestine, as an infiltrating mass approximately 10 cm in diameter. The tumor has been resected en bloc and the duodenojejunal terminal-terminal anastomosis has been performed. Results The tumor was large, intramural mass, with fish-flesh to tan-brown appearance, as well as with foci of hemorrhage and necrosis. Histologically, the tumor showed transmural growth, deep infiltrative pattern and malignant feature, with dense cellularity, plump spindle cells, within variably hyalinized and edematous stroma. In addition, tumor was composed of frequent areas with epitheloid morphology. The immunohistochemistry results showed high expression of c-KIT (CD117), CD34 and Vimentin, whereas α-smooth muscle actin was focally positive. Desmin and S100 protein were negative. Conclusion Given, that GIST in young adults represents a more heterogeneous group, there should be made more efforts in investigating its pathogenesis and potential more specific treatment.
    26th European Congress of Pathology, ExcCel, London, United Kingdom; 08/2014
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    • "The natural history of these tumors nevertheless appears to be more indolent than adult GISTs, as patients can survive for many years with metastatic disease (Miettinen et al., 2005a). Interestingly, many of the characteristics of GISTs in the pediatric population (e.g., female predilection, predominance of gastric, multi-focal tumors of epithelioid morphology ) are not as clearly defined in the more heterogeneous group of young adult (i.e., 21–30 years) GIST patients (Miettinen et al., 2005a; Prakash et al., 2005; Agaram et al., 2008a; Rink and Godwin, 2009), suggesting that some but not all of the patients in this age group may more properly be considered with the pediatric group. "
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    ABSTRACT: Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.
    Frontiers in Oncology 05/2013; 3:117. DOI:10.3389/fonc.2013.00117
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    • "GIST is considered to be a solitary tumor and the occurrence of multiple primary lesions is very rare, restricted to familial GISTs [4], pediatric forms [5], or district syndromes such as type 1 neurofibromatosis (NF1) or von Recklinghausen disease [6] or Carney's syndrome [7]. All these are well-defined entities that can be easily distinguished from common sporadic GISTs based on their peculiar clinicopathological features. "
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    ABSTRACT: This report describes a patient with synchronous sporadic gastrointestinal stromal tumors (GISTs) in the stomach and jejunum. A 71-year-old Japanese male presented with a 2-year history of occasional melena and general fatigue. Computed tomography of the abdomen demonstrated an enhanced extramural gastric tumor, 4 cm in diameter. Endoscopic examination revealed a jejunal submucosal tumor. He was referred to the surgical outpatient clinic for surgical treatment of an extramural gastric tumor and a jejunal submucosal tumor. Laparotomy allowed the identification of a nut-sized extramural tumor at the stomach and a thumb's head-sized tumor on the jejunum. Partial resections of the stomach and jejunum were performed. Histopathological and immunohistochemical examination revealed that these tumors were GISTs. Although no molecular analysis was performed, the immunohistochemical staining patterns of these two tumors were different from each other. Therefore, the final diagnosis was synchronous sporadic GISTs in the stomach and jejunum. This patient has survived without recurrence for approximately 12 years since complete resection.
    Case Reports in Gastroenterology 03/2013; 7(1):69-74. DOI:10.1159/000348754
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