PKCθ expression in gastrointestinal stromal tumor

Abstract

Gastrointestinal stromal tumor is characterized by a gain of function mutation of KIT gene and the expression of c-kit protein, but in 5% of cases, c-kit expression is negative although histological findings of gastrointestinal stromal tumor are most suspicious. The existence of c-kit-negative gastrointestinal stromal tumors points to the need of additional markers for making the diagnosis. In this study, we studied the expression of PKCh and correlated their expression with other immunohistochemical profiles of gastrointestinal stromal tumors and evaluated their usability as a diagnostic marker. For this purpose, 220 gastrointestinal stromal tumors were immunohistochemically stained for PKCh, c-kit, CD34, a-smooth muscle actin and S-100 protein. Additionally, genetic studies of KIT and PDGFRA genes were performed using c-kit-negative or PKCh-negative cases. All the 220 masses were either PKCh-positive or c-kit-positive. PKCh was positive in 212 (96%) cases and c-kit was positive in 216 (98%) cases in the cytoplasm of tumor cells with a diffuse staining pattern. Out of 212 PKChpositive GISTs, 208 (98%) cases were c-kit-positive, 174 (82%) cases were CD34-positive, 62 (29%) cases were SMA-positive and S-100 protein was positive in 54 cases (26%). Genetic analyses on eight PKCh-negative cases showed exon 11 mutations of KIT gene in four cases. Two PKCh-positive and c-kit-negative GISTs showed mutations of PDGFRA gene. Our study shows that PKCh is a useful marker and it may play a role in the development of gastrointestinal stromal tumors. Together with c-kit, PKCh immunostaining can be used as an important diagnostic tool in the pathologic diagnosis of gastrointestinal stromal tumors with its high specificity and sensitivity.

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

“…PKC-y is also reported to be expressed in schwannoma, malignant peripheral nerve sheath tumor, and Ewing's sarcoma/primitive neuroectodermal tumor. 19,28 In our series, all cases of mesenteric fibromatosis, PDGFRA, platelet-derived growth factor receptor-a; NR, not reported.…”

“…19,21 In previous studies with KIT-negative GISTs, 3-4% was negative for the new DOG1 antibody. 5,27 PKC-y was positive in two cases (8%) and completely negative for both KIT and DOG1 in this study, which was helpful in validating these cases as GISTs.…”

“…Four of these KIT-negative tumors were reported in a previous study. 19 Small biopsy specimens and tumors obtained after treatment with imatinib were excluded from this study. Pathological reports and hematoxylin and eosin-stained slides were reviewed in all cases, and estimated tumor characteristics included location, size, histological subtype, and mitotic count per 50 high power fields.…”

“…18 Several studies have been reported on the utility of PKC-y in identifying KIT-negative GISTs and in discriminating this subset of GISTs from other soft tissue tumors. [18][19][20][21] However, high background staining and expression in schwannomas have limited its diagnostic utility. 2 In our experience, an optimal setting of the staining conditions can remove these problems and yield greater sensitivity and specificity in the diagnosis of KIT-negative GISTs.…”

“…2 In our experience, an optimal setting of the staining conditions can remove these problems and yield greater sensitivity and specificity in the diagnosis of KIT-negative GISTs. 19 In this study, the clinicopathological and molecular features of 26 KIT-negative GISTs were analyzed. Immunostaining of DOG1 and PKC-y and mutational analysis for KIT and PDGFRA genes in KIT-negative GISTs were performed, and compared with KIT-positive GISTs.…”