Epithelioid variant of gastrointestinal stromal tumor harboring PDGFRA mutation and MLH1 gene alteration: A case report

Abstract

Gastrointestinal stromal tumors (GISTs) are the most important and common mesenchymal tumors of the gastrointestinal tract, especially in the stomach. GISTs are usually driven by activating mutations in either KIT or PDGFRA genes. It is known that activating gene mutations predicts, to a certain extent, not only the morphology of the tumor cells but also a response to treatment with tyrosine kinase inhibitors. Here, we present a case of an epithelioid variant of GIST harboring PDGFRA and MLH1 gene alterations in the stomach of a 55‐year‐old Japanese woman. The tumor of 98 mm with multiple cysts showed exophytic growth from the gastric fundus. Histopathologically, it consisted of scattered medium‐sized epithelioid tumor cells in a loose myxoid background. Based on c‐kit and DOG‐1 immunoreactivity and a PDGFRA mutation (p.Trp559_Arg560del), the tumor was diagnosed as an epithelioid variant GIST. Interestingly, it had a gene alteration (p.Met524Ile) in the MLH1 gene of unknown pathogenicity. It was assigned to Group 3a (low risk for malignant behavior). After surgery, the patient has been on imatinib therapy and disease‐free for 10 months.

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

“…In a study conducted by Agaimy and colleagues where the authors evaluated a combined histomorphologicalimmunohistochemical pattern analysis of GIST with PDGFRA mutations, PDGFRA-mutant GIST were more frequently epithelioid compared to KIT-mutant GIST (p < 0.001) [24]. Of note, these results mirrored previous studies in this setting, where a higher frequency of epithelioid/mixed morphology as well as gastric location were observed in PDGFRAmutant GIST patients [18,19,24,25]. In addition, a non-statistically significant difference in sex distribution has been observed between cohorts defined by PDGFRA mutations, with a male predominance for exon 18 PDGFRA-mutant GIST.…”

“…The fate of this well-defined GIST population has recently changed with the advent of new drugs specifically directed to D842V mutations, such as crenolanib and especially avapritinib [14][15][16]. Furthermore, in recent years, the biological background of D842Vmutant GIST has been deeply investigated to better understand the molecular features of this peculiar subset of GIST, and some promising insights have emerged [17][18][19]. Hereinafter, we present a comprehensive overview on what D842V-mutant GIST have been, what they are now, and what they may be in the near future.…”

Identification of New Tumor-Related Gene Mutations in Chinese Gastrointestinal Stromal Tumors

“…Saito et al reported that MLH1 was hypermethylated in GIST ( Saito et al, 2008 ). A recent paper reported a GIST case who harbored a PDGFRA (p.Trp559_Arg560del) and a MLH1 (p.Met524Ile) mutation ( Kobayashi et al, 2019 ). Ravegnini et al investigated the influence of polymorphisms in several DNA repair genes on GIST susceptibility and characteristics, and showed that XPD rs13181, hOGG1 rs1052133 and XPF rs1800067 were associated with GIST susceptibility, whereas XPA rs1800975 and rs2808668 were associated with tumor size, tumor metastasis and mitotic index ( Ravegnini et al, 2016 ).…”

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“…Saito et al reported that MLH1 was hypermethylated in GIST (Saito et al, 2008). A recent paper reported a GIST case who harbored a PDGFRA (p.Trp559_Arg560del) and a MLH1 (p.Met524Ile) mutation (Kobayashi et al, 2019). Ravegnini et al investigated the influence of polymorphisms in several DNA repair genes on GIST susceptibility and characteristics, and showed that XPD rs13181, hOGG1 rs1052133 and XPF rs1800067 were associated with GIST susceptibility, whereas XPA rs1800975 and rs2808668 were associated with tumor size, tumor metastasis and mitotic index (Ravegnini et al, 2016).…”