"Pediatric-type" gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior.
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.
- SourceAvailable from: Margherita Nannini[Show abstract] [Hide abstract]
ABSTRACT: KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumours (GISTs) showed a response rate to imatinib ranging from 0 to 25%. Nilotinib is a new-generation tyrosine kinase inhibitor that has demonstrated clinical activity in pretreated GIST patients. At present, no correlation between nilotinib activity and clinical/pathological/molecular features is available. We report on two WT GIST patients resistant to imatinib and sunitinib, and enrolled in the CAMN107A2201 study who achieved an impressive disease control by nilotinib. Both patients have germ-line mutations in the SDHA gene. In April 2004, a 39-year-old woman presented gastric GIST with multiple liver metastases and was treated with imatinib 400 mg/day, followed by imatinib 800 mg/day and then sunitinib. In August 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. In March 2005, a 27-year-old woman started imatinib 600 mg/day and then sunitinib for gastric GIST with multiple liver and lung metastases. In October 2007, because of disease progression, she was enrolled in the CAMN107A2201 study and assigned to the nilotinib 800 mg/day arm. One patient still showed stable disease after 46 months of treatment according to the Response Evaluation Criteria In Solid Tumors, and a partial response after 9 months according to Choi's criteria. The other patient still showed stable disease after 42 months according to Response Evaluation Criteria In Solid Tumors. At present, they continue to receive nilotinib. We report very long-term disease stabilization under nilotinib treatment in two pretreated WT GIST patients. In-vitro studies and clinical analyses are warranted to evaluate a potential correlation between nilotinib activity and WT genotype or other clinical/pathological features.Anti-cancer drugs 03/2012; 23(5):567-72. · 2.23 Impact Factor
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ABSTRACT: The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone incorporates changes in tumor classification, as well as new genetic insights into the pathogenesis of many different tumor types that have emerged over the 11 years since the publication of the prior volume. This article reviews changes in the classification of soft tissue and bone sarcomas as well as tumors of intermediate biologic potential in the 2013 World Health Organization volume, new molecular insights into these tumors, and associated surgical and clinical implications. Cancer 2014. © 2014 American Cancer Society.Cancer 03/2014; · 5.20 Impact Factor
Article: Gastrointestinal stromal tumour.[Show abstract] [Hide abstract]
ABSTRACT: Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms that arise in the gastrointestinal tract, usually in the stomach or the small intestine and rarely elsewhere in the abdomen. They can occur at any age, the median age being 60-65 years, and typically cause bleeding, anaemia, and pain. GISTs have variable malignant potential, ranging from small lesions with a benign behaviour to fatal sarcomas. Most tumours stain positively for the mast/stem cell growth factor receptor KIT and anoctamin 1 and harbour a kinase-activating mutation in either KIT or PDGFRA. Tumours without such mutations could have alterations in genes of the succinate dehydrogenase complex or in BRAF, or rarely RAS family genes. About 60% of patients are cured by surgery. Adjuvant treatment with imatinib is recommended for patients with a substantial risk of recurrence, if the tumour has an imatinib-sensitive mutation. Tyrosine kinase inhibitors substantially improve survival in advanced disease, but secondary drug resistance is common.The Lancet 04/2013; · 39.21 Impact Factor