DOG1 and PKC-θ are useful in the diagnosis of KIT-negative gastrointestinal stromal tumors

Abstract

Pathological diagnosis of gastrointestinal stromal tumors (GISTs) is based on histological findings and immunohistochemical demonstration of the KIT protein. KIT-negative GISTs account for ∼5% of cases and cause diagnostic difficulties. In the era of imatinib therapy, a correct diagnosis of GISTs is important for therapeutic reasons regardless of KIT expression. Recently, DOG1 has been introduced as an important diagnostic marker with high sensitivity and specificity. In this study, immunohistochemical staining for DOG1 and protein kinase C-θ (PKC-θ) in whole tissue sections, and mutation analyses for KIT and PDGFRA were performed in 26 KIT-negative GISTs. Tissue microarrays of 112 KIT-positive GISTs were used as controls. Overall, 25 KIT-negative GISTs were located in the stomach, and 1 in the rectum. The histological subtype was spindle in 12, epithelioid in 11, and mixed in 3 cases. The expression of DOG1 and PKC-θ was positive in 24 (92%) and in 25 cases (96%), respectively. All 26 KIT-negative GISTs expressed either DOG1 or PKC-θ, and 23 cases (89%) were positive for both makers. PKC-θ was positive in two cases (8%), which lacked both KIT and DOG1 expressions. Mutation analysis showed PDGFRA exon 18 mutation in 15 cases (58%) and KIT exon 11 mutation in 1 case (4%), whereas the remaining 10 cases (39%) were wild type for both KIT and PDGFRA. The expression of DOG1 and PKC-θ showed no significant difference in KIT-negative and KIT-positive GISTs (P=1.000 and P=0.167, respectively). Our findings suggest that both DOG1 and PKC-θ can be used in the diagnosis of KIT-negative GISTs and they show positive staining even in KIT-negative tumors, which are wild type for KIT and PDGFRA on mutation analysis.