Purpose: We aimed to develop prognostic biomarkers for gastrointestinal stromal tumors (GIST) using a proteomic approach. Experimental Design: We examined the proteomic profile of GISTs using two-dimensional difference gel electrophoresis. The prognostic performance of biomarker candidates was examined using a large-scale sample set and specific antibodies. Results: We identified 43 protein spots whose intensity was statistically different between GISTs with good and poor prognosis. Mass spectrometric protein identification showed that the 43 spots corresponded to 25 distinct gene products. Eight of the 43 spots derived from pfetin, a potassium channel protein, and four of the eight pfetin spots had a high discriminative power between the two groups.Western blotting and real-time PCR showed that pfetin expression and tumor metastasis were inversely related.The prognostic performance of pfetin was also examined by immunohistochemistry on 210 GISTcases.The 5-year metastasis-free survival rate was 93.9% and 36.2% for patients with pfetin-positive and pfetin-negative tumors, respectively (P < 0.0001).Univariate and multivariate analyses revealed that pfetin expression was a powerful prognostic factor among the clinicopathologic variables examined, including risk classification and c-kit^or platelet-derived growth factor receptor A mutation status. Conclusions: These results establish pfetin as a powerful prognostic marker for GISTs and may provide novel therapeutic strategies to prevent metastasis of GIST.

In soft tissue sarcomas, the diagnosis of malignant fibrous histiocytoma (MFH) has been a very controversial issue, and MFH is now considered to be reclassified into pleomorphic subtypes of other sarcomas. To characterize MFH genetically, we used an oligonucleotide microarray to analyze gene expression in 105 samples from 10 types of soft tissue tumors. Spindle cell and pleomorphic sarcomas, such as dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor (MPNST), fibrosarcoma and MFH, showed similar gene expression patterns compared to other tumors. Samples from those five sarcoma types could be classified into respective clusters based on gene expression by excluding MFH samples. We calculated distances between MFH samples and other five sarcoma types (dedifferentiated liposarcoma, myxofibrosarcoma, leiomyosarcoma, MPNST and fibrosarcoma) based on differentially expressed genes and evaluated similarities. Three of the 21 MFH samples showed marked similarities to one of the five sarcoma types, which were supported by histological findings. Although most of the remaining 18 MFH samples showed little or no histological resemblance to one of the five sarcoma types, 12 of them showed moderate similarities in terms of gene expression. These results explain the heterogeneity of MFH and show that the majority of MFHs could be reclassified into pleomorphic subtypes of other sarcomas. Taken together, gene expression profiling could be a useful tool to unveil the difference in the underlying molecular backgrounds, which leads to a rational taxonomy and diagnosis of a diverse group of soft tissue sarcomas.

The separation of benign reactive mesothelium (RM) from malignant mesothelial proliferation can be a major challenge. A number of markers have been proposed, including epithelial membrane antigen, p53 protein, and P-glycoprotein. To date, however, no immunohistochemical marker that allows unequivocal discrimination of RM from malignant pleural mesothelioma (MPM) has been available. A family of glucose transporter isoforms (GLUT), of which GLUT-1 is a member, facilitate the entry of glucose into cells. GLUT-1 is largely undetectable by immunohistochemistry in normal epithelial tissues and benign tumors, but is expressed in a variety of malignancies. Thus, the expression of GLUT-1 appears to be a potential marker of malignant transformation. Recently, in fact, some studies have shown that GLUT-1 expression is useful for distinguishing benign from malignant lesions. The purpose of the present study was to evaluate the diagnostic utility of GLUT-1 expression for diagnostic differentiation between RM and MPM. Immunohistochemical staining for GLUT-1 was performed in 40 cases of RM, 48 cases of MPM, and 58 cases of lung carcinoma. Immunohistochemical GLUT-1 expression was seen in 40 of 40 (100%) MPMs, and in all cases the expression was demonstrated by linear plasma membrane staining, sometimes with cytoplasmic staining in addition. GLUT-1 expression was also observed in 56 out of 58 (96.5%) lung carcinomas. On the other hand, no RM cases were positive for GLUT-1. GLUT-1 is a sensitive and specific immunohistochemical marker enabling differential diagnosis of RM from MPM, whereas it cannot discriminate MPM from lung carcinoma. Modern Pathology (2007) 20, 215-220.

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