Association of Platelet-Derived Growth Factor Receptor α Mutations with Gastric Primary Site and Epithelioid or Mixed Cell Morphology in Gastrointestinal Stromal Tumors

Abstract

Most gastrointestinal stromal tumors (GISTs) carry activating mutations of the KIT gene encoding the receptor tyrosine kinase KIT. In a previous study we were able to show an association between the lack of KIT mutations (wild-type GISTs) and the presence of a significant epithelioid tumor component. A very recent study described the occurrence of PDGFRalpha mutations in KIT wt GISTS. Therefore, we studied a panel of 87 GISTs for mutations in the hot spot regions of the PDGFRalpha gene with single strand conformation polymorphism analysis and sequencing and correlated the PDGFRalpha status with pathomorphological data. We detected 20 cases with exon 18 mutations but none with exon 12 mutations. The mutations were located in the second kinase domain of PDGFRalpha with 16 point mutations, and four larger deletions of 9 to 12 bp. All cases with mutations in the PDGFRalpha gene revealed wild-type KIT in common regions of mutation, ie, exons 9 and 11. Most interestingly, the occurrence of PDGFRalpha mutations was significantly associated with a higher frequency of epithelioid or mixed morphology (18 of 20 cases, P < 0.0001) and gastric location (all cases, P = 0.0008). Our data indicate that GISTs represent distinctive entities, differing in genetic, biological, and morphological features.

Gastrointestinal stromal tumors: what do we know now?

“…Further, as discussed below, both genotypes are associated with cytogenetic changes that are distinctive for GIST. 37,43 Despite these molecular similarities, PDGFRAmutant GISTs do show features distinctive from KIT-mutant GISTs, including differences in gene expression profile, 39,44 a striking predilection for the stomach, variable (sometimes negative) expression of KIT, 20,41,[45][46][47][48] and a generally lower potential for malignancy. 49 Morphologically, however, PDGFRAmutant GISTs are not reliably distinguishable from KIT-mutant GISTs ( Figure 1).…”

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival

“…On the other hand, the predominance of the epithelioid/mixed phenotypes in PDGFRA-mutant GISTs demonstrated in several previous studies 7,8,[13][14][15] suggests a primary commitment of this subset of GISTs toward an epithelioid phenotype. This view is supported by the generally favorable clinical course of PDGFRAmutated GISTs, which contrasts with our findings in epithelioid/mixed KIT-mutant GISTs.…”

“…6 On the other hand, the majority of PDGFRA-mutated GISTs display epithelioid or mixed (predominantly epithelioid) phenotypes. 7,8 Intriguingly, data on the correlation of the histological subtype with the clinical outcome have been inconsistent. The presence of an epithelioid/mixed morphology/ component in GISTs was associated with malignant behavior in GISTs in several studies.…”

“…6,[9][10][11][12] On the other hand, PDGFRA-mutated epithelioid GISTs frequently exhibit a less aggressive behavior. 7,8,[13][14][15] Recently, we identified a morphological shift from spindled to epithelioid phenotype in GISTs that were composed of well-circumscribed spindled and epithelioid components. 16 The epithelioid component displayed unfavorable histological features (higher cellularity, higher mitotic activity and higher Ki67 index), and was associated with more aggressive clinical course.…”

Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas

“…2,20,21 PDGFRA-mutated GISTs show a preference for gastric location, epithelioid morphology, variable or absent KIT expression by immunohistochemistry (IHC), and a more indolent clinical behavior. 21,22 In about 10% of patients, no detectable mutation is identified in either KIT or PDGFRA. In particular, GISTs that occur in pediatric or neurofibromatosis type I patients are nearly always wild type (ie not mutated) for both genes.…”