"Pediatric-type" Gastrointestinal Stromal Tumors in Adults: Distinctive Histology Predicts Genotype and Clinical Behavior

Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
The American journal of surgical pathology (Impact Factor: 4.59). 02/2011; 35(4):495-504. DOI: 10.1097/PAS.0b013e31820e5f7d
Source: PubMed

ABSTRACT Gastrointestinal stromal tumors (GISTs) rarely affect children, mainly girls. Pediatric GISTs typically arise in the stomach as multifocal tumors with a multinodular growth pattern, epithelioid morphology, lymph node metastases, an absence of KIT and PDGFRA gene mutations, and indolent behavior. Occasional GISTs in adults show similar features. Such tumors are not widely recognized. GISTs with a multinodular growth pattern in patients over the age of 18 years were retrieved from surgical and consultation files. Hematoxylin and eosin-stained slides were reviewed, immunohistochemistry was performed, and KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12, 14, and 18) genes were screened for mutations. Clinical follow-up was obtained. Sixteen cases were identified, affecting 13 women and 3 men (median age, 31.5 y; range, 19 to 56 y), all in the stomach. The mean tumor size was 5.4 cm (range, 1.8 to 11 cm); 4 were multifocal. All tumors showed a multinodular or plexiform architecture and epithelioid (N=3) or mixed epithelioid and spindle cell (N=13) morphology. Five tumors had vascular invasion; 6 had focal necrosis. Mitotic activity ranged from 3 to 156/50 high-power fields (8 tumors had ≤5/50 high-power fields). Using Armed Forces Institute of Pathology risk stratification, categories for primary tumors were: none (N=2), very low risk (N=3), low risk (N=3), moderate risk (N=3), and high risk (N=5). By immunohistochemistry, all tumors were positive for KIT, 82% DOG1, 72% CD34, 18% caldesmon, 9% S-100, 8% smooth muscle actin, and 0% desmin. All tumors were wild type for KIT and PDGFRA in the exons that were screened. At primary resection, 9 patients (56%) had lymph node metastases and 3 patients had liver metastases. Follow-up ranged from 16 months to 16 years (median, 5 y). Two tumors recurred locally in the stomach and 7 patients developed subsequent metastases to the lymph nodes (N=5), liver (N=3), and peritoneum/omentum (N=3). Primary tumors from 7 patients with metastases were Armed Forces Institute of Pathology low risk, very low risk, or no risk of recurrence. None of the metastatic tumors responded to treatment with imatinib mesylate. One patient died of disseminated liver and intra-abdominal metastases and the remaining patients were alive at last follow-up. Gastric GISTs in adults with a multinodular or plexiform growth pattern and epithelioid or mixed morphology are similar to pediatric GISTs. Unlike conventional adult GISTs, this distinctive subset predominantly affects women, often metastasizes to lymph nodes, and lacks mutations in KIT and PDGFRA. Current risk assessment criteria do not reliably predict behavior for this group. Although metastases are common and most tumors are imatinib resistant, they pursue a relatively indolent clinical course. Recognition of "pediatric-type" GISTs in adults is critical for prognosis, appropriate therapy, and follow-up.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Connective tissue tumors located inside the abdomen are a rare heterogeneous group of tumors, except for gastro-intestinal stromal tumors. They may be benign, malignant, or intermediate in terms of biologic potential. Pathologists have to remember the list of all the lesions possibly involved, with their immunohistochemical characteristics, and to know which molecular analyses are needed, with which expected results, and by which team they can be performed. The main tumor types are discussed with diagnostic tools and treatment consequences. Copyright © 2014. Published by Elsevier Masson SAS.
    Annales de Pathologie 12/2014; DOI:10.1016/j.annpat.2014.11.007 · 0.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. The discovery that these tumors, formerly thought of smooth muscle origin, are indeed better characterized by specific activating mutation in genes coding for the receptor tyrosine kinases (RTKs) CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with RTK inhibitors has made GISTs the typical example of the integration of basic molecular knowledge in the daily clinical activity. The information on the mutational status of these tumors is essential to predict (and subsequently to plan) the therapy. As resistant cases are frequently wild type, other possible oncogenic events, defining other "entities," have been discovered (e.g., succinil dehydrogenase mutation/dysregulation, insuline growth factor expression, and mutations in the RAS-RAF-MAPK pathway). The classification of disease must nowadays rely on the integration of the clinico-morphological characteristics with the molecular data.
    11/2014; 1:43. DOI:10.3389/fmed.2014.00043
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.