Clinical and molecular characteristics of gastrointestinal stromal tumors in the pediatric and young adult population

Abstract

Gastrointestinal stromal tumors (GISTs) typically occur late in life; however, there also are reports of pediatric and young adult patients. This rare subset of GISTs has clinicopathologic and molecular features distinct from their adult counterparts. Most pediatric GIST patients are female and often present with multifocal tumors that are epithelioid in nature. Although these young patients often have metastatic disease, it progresses slowly. Most pediatric GISTs lack the gain-of-function mutation in KIT or PDGFRA commonly found in adult cases. Expression profiling and genomic studies of pediatric GISTs show distinct molecular signatures, suggesting a unique origin as compared with adult GISTs. We and others have shown that the insulin-like growth factor 1 receptor may have a prominent role in driving KIT/PDGFRA mutation-negative adult and pediatric GISTs, and clinical trials are currently being designed to exploit these types of discoveries.

Figure 1. Immunohistochemical Analysis of Tumor Tissues from a Carney Triad Patient

Expression of IGFIR (left panels) and KIT (right panels) in GIST tissue (top panels) and paraganglioma tissue (bottom panels) from a pediatric patient diagnosed with incomplete Carney triad.

Figure 2. Genetic and Cytogenetic Changes Associated with Pathogenesis of Pediatric and Adult GISTs

GISTs are thought to arise from the Interstitial Cells of Cajal (ICC), the pacemaker cells of the gut, or from interstitial mesenchymal precursor stem cells that also have the potential of giving rise to cells in the omentum and peritoneal surfaces. Pediatric GISTs are thought to develop independent from acquired mutations in KIT or PDGFRA. These tumors are frequently associated with increased expression of IGF1R, BAALC, FGF4, PLAG1 and NEL1. Adult GISTs and for some young adult GISTs develop as a result of an acquired mutation in KIT or PDGFRA and a series of sequential genetic and genomic abnormalities. Loss of chromosome 1p and monosomy 14 and 22 are two of the earliest cytogenetic changes that have been detected cytogenetically. MM - Muscularis Mucosae, CNVs - copy number variants. (Illustration by Karen Trush)