Dr. Antonescu is a member of the LRG Research Team. This article is part of a series written by each of the key team members.
Although GISTs occurring in the pediatric age group are extremely rare, comprising no more than two to three percent of cases, they constitute a distinct clinical and molecular subset from the adult tumors. We and others have previously described the characteristic features of this rare type of sarcoma in children, with strong predominance for females and wild-type genotype for KIT and PDGFRA (1). Pediatric GISTs are preferentially located in the stomach as multiple nodules and histologically have either an epithelioid or mixed spindle and epithelioid morphology (1, 2). Of interest is that unlike in adults, the majority of GISTs in pediatric patients follow an indolent course, in spite of the high rate of metastasis to the peritoneal cavity and liver. Furthermore, metastasis to loco-regional lymph nodes is common in pediatric GIST patients and rare in adults (1).
Since our initial report comprising five female patients with wild-type gastric GIST, we have expanded our analysis to 17 children. This includes five male patients, one of whom had a solitary small bowel tumor. In this larger cohort, we confirm that pediatric GIST is more prevalent in females, who develop multiple tumors within the stomach, without associated interstitial cell of Cajal hyperplasia. Microscopically, these tumors often show an epithelioid morphology, with a variable proliferation index. All female patients and about two-thirds of male patients lack activating mutations in KIT/ PDGFRA. Our experience is in concordance with Miettinen et al. (2), who identified a wild-type KIT/PDGFRA genotype in all 13 pediatric GISTs analyzed, although sequencing analysis was not performed in the only pediatric male patient. Activating mutations were found, however, in two of our five male patients, one in the juxtamembrane domain of KIT receptor and the other in the kinase domain of PDGFRA. In the study by Price et al., two of their five pediatric patients were males, and one of them harbored a novel point mutation in codon 456 of KIT exon 9, while the other was wild-type (3). In spite of the overwhelming prevalence of wild-type genotype, pediatric GIST tumors consistently overexpress KIT protein, as evidenced by the strong immunostaining for CD117 (1,4) and KIT phosphorylation on biochemical assays. This finding is further supported by the high KIT mRNA expression on transcriptional profiling. The mechanism of constitutive activation of the KIT protein in these cases remains unclear. The transcriptional signature of pediatric GIST is distinct from adult wild-type or gastric GISTs (Figure 1). The top ranked genes overexpressed in the pediatric subset include: BAALC, FGF4, PLAG1, IGF1R, NELL1, and CRLF1.
The association of multifocal gastric GIST with paragangliomas and pulmonary chondromas affecting mostly females is diagnostic of Carney’s triad (5). Although mostly sporadic, a few familial cases were included in the original cohort of Carney’s triad (6). More recently it was recognized that the autosomal dominant inheritance of the dyad “paraganglioma and gastric GIST”, or the “Carney-Stratakis syndrome” (CSS), represents a separate condition which affects both males and females and lacks the association with pulmonary chondromas (7). Mutations of the genes coding for succinate dehydrogenase (SDH) subunits, typically associated with familial paragangliomas, are most likely implicated in the pathogenesis of CSS (8). Once cases of CSS are eliminated, there are no inherited cases of the Carney’s triad. The significant overlap between clinicopathologic features of pediatric GIST and Carney’s triad, such as female predisposition, multifocal gastric location requiring multiple gastric operations and relatively long survival (even in the presence of lymph node or peritoneal/ liver metastatic disease) suggests a pathogenetic link. Thus, at least a subset of the pediatric GIST patients may represent a form fruste of Carney’s triad. Indeed, longer follow-up in some patients reveals the development of a second neoplasm, diagnostic of this syndrome. Furthermore, in a recent comprehensive genetic analysis of 41 tumors from 37 patients with Carney’s triad, sequencing analysis for the entire coding region of KIT, PDGFRA, SDHA, SDHB, SDHC, and SDHD failed to identify any activating mutations (9). This result parallels the findings of a wild-type genotype in the majority of pediatric GIST patients.
There are a few controversial points regarding the prediction of outcome in pediatric GIST. The conventional criteria for assessing risk of malignancy, such as tumor size, mitotic activity and anatomic location are not reliable in pediatric GIST. These patients frequently present with multiple nodules within the stomach, thus the largest tumor dimension cannot be easily defined. Furthermore, we noted a wide range of variability in proliferation index between patients and even among multiple tumors from the same patient. Our experience is similar with that of Miettinen (2), who noted that some pediatric patients with GIST developed metastasis despite being classified as low risk by criteria established in adult GIST. Similarly, most of our patients with a low proliferation index (<5MF/50HPFs) eventually progressed with recurrent disease within the peri-gastric lymph nodes, peritoneal cavity or liver. These findings suggest that GISTs in children are unpredictable, being more prone to metastasis than comparable gastric tumors in adults. Secondly, the biology of pediatric GIST appears to be more indolent than the adult counterpart, with long-term survival even in the presence of metastatic disease and without kinase inhibition therapy.
GIST in young adults is a heterogeneous entity, with some cases resembling the clinicopathologic features of pediatric disease, while most are more in keeping with the adult counterpart. Although there is still a female sex and gastric location predominance, up to one-third of cases occur in male patients and in an extra-gastric location. About two-thirds of GISTs from young adults show the presence of KIT/PDGFRA mutation, with a similar distribution as in adult tumors, most in KIT exon 11, few in KIT exon 9, and rare in PDGFRA exon 12. The remaining one-third of GIST in young adults lack KIT/PDGFRA mutations, being mostly located in the stomach and occurring in female patients. It is this subset of young adult GIST patients that shares clinicopathologic feaGIST. By gene expression analysis also, these tumors cluster together with the pediatric GIST group, distinct from other adult wild-type GIST samples. The same distinctive set of genes found to be up-regulated in pediatric GIST are also found to be overexpressed in the GISTs from young adults. These findings suggest that a subset of GISTs occurring in patients younger than thirty years old may be biologically related to pediatric GIST. However, the majority of cases recapitulate closely the adult GIST phenotype.
Extrapolating from the adult experience, in which the wild-type genomic subset is the least sensitive to imatinib inhibition, the question still remains if pediatric GISTs, which typically lack KIT/PDGFRA mutations, will respond to imatinib. This question remains unresolved due to the rarity of pediatric GIST and its indolent natural history, both of which preclude large clinical trials. Anecdotal evidence based mainly on case reports shows poor clinical responses to imatinib (10). Preliminary data on a few patients suggest that sunitinib may have a better activity on pediatric wild-type GIST. Effective agents for pediatric GIST are needed. Also of interest is that the pattern of excruciating somatic soft tissue and bone pain seen in some children treated with imatinib and/ or sunitinib, has not been previously described in imatinib-treated children with other diseases, such as pediatric CML and ALL (11). Our in vitro data suggest that second generation kinase inhibitors are more effective than imatinib against wild-type KIT transfected cells.
In summary, although pediatric GIST was initially regarded as a homogenous clinical and genetic subset with a predilection for females, gastric location and wild-type genotype, the analysis of additional cases expanded this view. Up to one third of cases may occur in males and these can harbor activating KIT/ PDGFRA mutations and occur in the small bowel. With longer follow-up it is now becoming clear that some pediatric patients eventually develop secondary neoplasms diagnostic for Carney’s triad, obscuring the distinction from the more common form of pediatric GIST. However, the gene expression profiles of pediatric tumors is distinct from the wild-type adult GIST and includes overexpression of BAALC, IGF1R, FGF4, PLAG1 and NELL1. A subset of GISTs occurring in young adults share clinicopathologic features as well as a similar gene expression profile with the pediatric counterpart. Our in vitro data suggest that second generation kinase inhibitors are superior to imatinib therapy against wild-typeT KIT transfected cells. It remains to be determined, if these newer generation, broad-based inhibitors will prove efficacious in pediatric GIST patients as well.
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