Pediatric GIST
| Information on Pediatric GIST: A subset of GIST occurs in the pediatric age group. The incidence of pediatric GIST is smaller than in adults. Significant clinical and genetic differences are noted between adult and pediatric forms of GIST. Pediatric cases of GIST typically affect females and are located with predilection in the stomach as multiple nodules. Histologically, they often have an epithelioid morphology and genetically most tumors lack mutations in the KIT or PDGFRA genes. In contrast, sporadic adult GIST have a more balanced distribution between stomach and small bowel, have often a spindle cell morphology and show in a significant number of cases an activating mutation either in KIT or PDGFRA oncogenes. However the KIT receptor is activated and expressed in the majority of cases of both adult and pediatric tumors.Pediatric GISTs are associated with a high risk of local recurrence at the gastric stump after partial gastrectomy, most likely due to their multicentric distribution. Also a dis-proportionally high incidence of regional lymph node metastasis is noted in pediatric, as compared with adult patients, possibly related to the common epithelioid histology. Although it is difficult to evaluate their clinical outcome due to the limited number of cases studied to date, it appears that children with GIST follow a more indolent course, even after developing recurrence and even in the absence of imatinib therapy. Even more difficult is the assessment of imatinib response in pediatric population with GIST. The lack of enthusiasm so far encountered in treating children with GIST with imatinib is also based on prior experience with the adult GIST patients carrying a KIT/PDGFRA wild-type genotype, who have been found not to respond to imatinib therapy.
There has been much progress made over the last several years with the investigation of pediatric GIST. Dr. Andrew Godwin of Fox Chase Cancer Center and Dr. Cristina Antonescu of Memorial Sloan Kettering Cancer Center have been leading the primary investigations. The most prominent result has been the identification of the IGF-1R mutation as being overexpressed in pediatric/wild type GIST. Additionally, the National Institute of Health has created a center for pediatric GIST patients to have their cases studied by a panel of GIST experts. For more info, please vist www.pediatricgist.cancer.gov/. There is also a list serv designed specifically for pediatric GIST. Please visit www.gistsupport.org and click on the tab for Pediatric Gist & Carney’s Triad to sign up for this valuable communication tool.
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Publications and Resources: J Pediatr Hematol Oncol. 2005 Apr;27(4):179-187. Gastrointestinal Stromal Tumors in Children and Young Adults: A Clinicopathologic, Molecular, and Genomic Study of 15 Cases and Review of the Literature |
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Pediatric GIST – by Dr. Christina Antonescu Gastrointestinal stromal tumors (GISTs) occurring in the pediatric age group are extremely rare and form a distinct clinical and molecular subset from the adult tumors. Almost all GISTs diagnosed in children have a predilection for girls, multifocal gastric location and lack oncogenic mutations in KIT/PDGFRA genes. Only infrequently boys are affected and in this setting their tumors might not always resemble the typical pediatric GIST phenotype, showing variability in extra-gastric location and/or KIT/PDGFRA mutations. Regardless of these clinicopathologic variations, all pediatric GISTs show consistent biochemical activation and overexpression by immunohistochemistry of the KIT receptor tyrosine kinase. Morphologically the tumors have either a predominantly epithelioid or mixed epithelioid-spindle cell appearance.In contrast with adult GIST, pediatric tumors tend to have a multinodular growth within the stomach, with partial excisions being often followed by local recurrence at the gastric stump. Another important distinction from the adult counterpart is their indolent clinical behavior, even in the presence of loco-regional or distant metastatic disease. Long term follow-up of these patients in the pre-imatinib era showed a prolonged survival with slow growth and tumor progression even in the absence of targeted kinase inhibition. These findings suggest a distinct tumor biology of GISTs affecting children, with possibly alternative molecular mechanisms and signaling pathways downstream of KIT receptor. Although no definitive data exists on the response of pediatric GIST to imatinib therapy, the experience in adults suggests that wild-type GIST patients are the least responsive genomic subset. And since the overwhelming majority of pediatric GIST shows a wild-type genotype there is justifiable concern related to similar ineffectiveness of this targeted therapy in children with GIST. Thus the potential use of alternative, more broad-based, kinase inhibitors, such as sunitinib, has been questioned as the first-line therapy in metastatic pediatric GIST. Our GIST research laboratory investigates various strategies to identify novel therapeutic targets in pediatric tumors that can provide additional options for management. Gene expression profiling of wild-type pediatric GISTs is used for mining candidate genes for targeted therapies, compared to wild-type adults GISTs. Furthermore, imatinib-alternative drugs, such as nilotinib, sorafenib and dasatinib are being tested for their efficacy in an in vitro murine Ba/F3 cell system expressing the wild-type KIT. |
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