Multiple Gastrointestinal Stromal Tumors: Clinicopathologic and Genetic Analysis of 12 Patients

Abstract

Multiple gastrointestinal stromal tumors (GISTs) are extremely rare and usually associated with type 1 neurofibromatosis and familial GIST. The aim of this study was to investigate the clinical, phenotypic, and genetic characteristics of multiple GISTs to gain insights into their underlying pathogenesis and clinical behavior. Forty-seven paraffin blocks of multiple GISTs from 12 patients were analyzed. Genomic DNA was extracted from the tumor and normal mucosa and mutations for 4 exons of KIT gene and 3 exons of PDGFRA gene were determined. Among 12 patients with multiple GISTs, 5 were sporadic, 2 were familial with germline mutations of KIT gene, and 5 were associated with type 1 neurofibromatosis. All but 1 sporadic and familial multiple GISTs showed mutations of KIT gene shared by the same mutation on each GIST mass within a patient. But in 1 sporadic case, different types of KIT mutations were observed. Two familial multiple GIST cases showed diffuse involvement of the gastrointestinal tract with diffuse hyperplasia of interstitial cell of Cajal. Multiple GISTs associated with type 1 neurofibromatosis were located in the jejunum and harbored no mutations of KIT or PDGFRA. Different types of KIT gene mutation found in our case raise a possibility that recurrence of GISTs within a gastrointestinal tract may have a chance to be a rare occurrence of multiple primary GISTs instead of true recurrence. Multiple GISTs show unique clinical, phenotypic, and genotypic characteristics that are dependent on the particular underlying mechanisms, but the overall prognosis is favorable regardless of the numbers or phenotype of GISTs.

Gastrointestinal stromal tumors: what do we know now?

“…[51][52][53][54][55][56] Most arise in the small intestine and they do not readily metastasize. 51 The majority of these GISTs are wild type for KIT and PDGFRA, but as expected they do show either somatic mutation or loss of the remaining wild-type NF1 allele, resulting in signaling through the MAP kinase cascade (Figure 3b).…”

“…26,27 These mice also develop GIST-like tumors. Diffuse ICC hyperplasia has been described in several kindreds with heritable mutations in KIT (Table 2), and is associated with dysphagia and the development of multiple GISTs, 26,29,53,[73][74][75][76][77][78] although many of the tumors do not follow a malignant course.…”

“…The large pool of micro-GISTs in the general population likely explains the multiple reported cases in which two or more genotypically distinct GISTs are found in a patient during a single surgical procedure. 53,79,84 Chromosomal and Molecular Alterations During GIST Progression of GISTs demonstrate either monosomy of chromosome 14, or partial loss of 14q. 37,[85][86][87][88][89] Interestingly, these chromosome 14 abnormalities are observed in both KIT-mutant and PDGFRA-mutant GISTs.…”

Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors

“…30,31,33,34,[36][37][38][39][40]43,44,46,49 KIT-Val559Ala mutation is the most frequent type, which has been detected in five families. 33,34,38,39,49 Recently, we found a germline mutation at exon 11, KIT-Tyr553Cys, in a 68-yearold woman with multiple GISTs.…”

“…30 To our knowledge, B20 families with germline c-kit gene mutations and multiple GISTs have been reported so far. [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] Thirteen families including the first case have the c-kit gene mutation at exon 11, 30,31,33,34,[36][37][38][39][40]43,44,46,49 three families at exon 13, 32,45,48 three families at exon 17 35,42,47 and one family at exon 8. 41 In addition to multiple GISTs, patients of these families have hyperplasia of ICCs in the gut wall.…”