Young-Soo Park

ROS1 Receptor Tyrosine Kinase, a Druggable Target, is Frequently Overexpressed in Non-Small Cell Lung Carcinomas Via Genetic and Epigenetic Mechanisms

BackgroundMicroarray analyses have revealed significantly elevated expression of the proto-oncogene ROS1 receptor tyrosine kinase in 20–30xa0% of non-small cell lung carcinomas (NSCLC). Selective and potent ROS1 kinase inhibitors have recently been developed and oncogenic rearrangement of ROS1 in NSCLC identified.MethodsWe performed immunohistochemical evaluation of expression of ROS1 kinase and its downstream molecules in 399 NSCLC cases. ROS1 expression in primary and recurring lesions of 92 recurrent NSCLC cases was additionally analyzed. To elucidate mechanism of expression, two ROS1-nonexpressing NSCLC cell lines (Calu6 and H358) and fresh frozen tissues from 28 consecutive NSCLC patients were examined for ROS1 promoter methylation status and ROS1 expression.ResultsOverall expression rate of ROS1 was 22xa0% (19xa0% for adenocarcinomas and 25xa0% for nonadenocarcinomas) in NSCLC. ROS1 expression was a worse prognostic factor for overall survival in adenocarcinomas of stage I NSCLC. In recurred NSCLC, ROS1 expression was significantly higher in recurring tumors (38xa0%) than primary tumors (19xa0%). Two NSCLC cell lines showed increased ROS1 expression after treatment with 5-aza-2′deoxycytidine and/or trichostatin A. Among the 14 adenocarcinomas examined, two (14xa0%) showed more than twice the level of ROS1 expression in tumor tissue than was observed in matched normal tissue and statistically significant differences in the ROS1 promoter methylation level.ConclusionsA subset of NSCLC revealed overexpression of ROS1 receptor tyrosine kinase, possibly in relation to epigenetic changes. ROS1 expression was an independent prognostic factor for overall survival in adenocarcinomas of stage I NSCLC. Further studies are needed to validate our results.

Pathologic Discordance of Differentiation Between Endoscopic Biopsy and Postoperative Specimen in Mucosal Gastric Adenocarcinomas

AbstractBackgroundTumor differentiation is a major determinant of endoscopic resection in mucosal gastric cancers, and the treatment decision is usually based on a preoperative endoscopic biopsy. However, in a proportion of patients, the pathologic assessment of differentiation differs between the endoscopic biopsy and postgastrectomy specimen. This discrepancy is important in that it may lead to an additional radical gastrectomy after endoscopic resection or unnecessary operation for patients who could have been treated with endoscopic resection. This study aimed to investigate the frequency of such cases and to identify risk factors for discordance in patients with mucosal gastric adenocarcinoma.nMethodsThe clinicopathologic characteristics of 1,326 patients who underwent curative gastrectomy for mucosal gastric cancer at Asan Medical Center from 2007 to 2011 were retrospectively reviewed.ResultsThe overall discordance was 21.5xa0% (285 cases), and clinically significant discordant rate was 11.9xa0% (157 cases). Ninety-nine tumors (7.5xa0%) with differentiated histology on preoperative biopsy were found to be undifferentiated on postoperative pathology. Additionally, 58 patients (4.4xa0%) with undifferentiated histology on preoperative biopsy exhibited differentiated histology postoperatively. Multivariate analysis revealed that age, sex, tumor location, size, and gross pattern were associated with overall pathologic discordance. In patients with clinically significant discordance, only tumor location (cardia) and size (>2xa0cm) were independent factors for discordance.ConclusionsConsidering a high discordance rate of differentiation between biopsy samples and resected specimens in mucosal cancer in cardia, performing endoscopic resection for confirmative diagnosis of differentiation before total gastrectomy can be a good option.

Biomarkers of EBV-positive Gastric Cancers: Loss of PTEN Expression is Associated with Poor Prognosis and Nodal Metastasis

BackgroundEpstein–Barr virus-positive gastric carcinoma (EBVGC) constitutes approximately 10xa0% of all gastric carcinoma cases. While distinct molecular features have been characterized previously, there have not been studies identifying their clinical utility. The purpose of this study was to investigate the immunohistochemistry (IHC) profile of EBVGC and to evaluate the potential clinicopathologic and prognostic significance of each marker.MethodsClinicopathologic characteristics of 234 patients (203 males and 31 females) who underwent curative gastrectomy for EBVGCs from 1998 to 2013 at Asan Medical Center, were reviewed, and IHC for ARID1A, PTEN, PD-L1, p53, p16INK4a, MLH1, and MSH2 were performed on tissue microarrays. These markers along with several tumor characteristics, e.g., lymphovascular invasion and the extent of differentiation, were analyzed for significant associations as well as any prognostic significance by multivariate analysis.ResultsIn multivariate analysis, PTEN loss was as an independent factor associated with poor prognosis (pxa0=xa00.011). Furthermore, PTEN loss was an independent risk factor for nodal metastasis (pxa0=xa00.038). No other biomarkers, ARID1A, PD-L1, p53, p16INK4a, MLH1, or MSH2, demonstrated significant prognostic value.ConclusionsPTEN loss in EBVGC is a poor prognostic factor associated with mortality and nodal metastasis in EBVGCs. Evaluation of PTEN expression may be helpful to determine the most appropriate treatment strategy, especially for endoscopically resected EBVGCs.

655PCOMPARISON OF HER2 IMMUNOHISTOCHEMICAL STAINING IN PRIMARY SIGNET RING CELL CARCINOMA; PATHWAY VERSUS HERCEPTEST

ABSTRACT Aim: Trastuzumab has shown efficacy in gastric cancers with HER2 amplification. Immunohistochemical (IHC) staining is used for screening and in situ hybridization (ISH) is done as adjunct. One the FDA approved IHC method, PATHWAY, occasionally shows strong nuclear and/or cytoplasmic staining, which should not be considered positive. This can sometimes be misinterpreted as true membranous staining especially in signet ring cell carcinoma (SRC) because the cytoplasms of these tumor cells are marginated against the membrane. We compared the IHC staining results in SRC with other FDA approved IHC method (HercepTest) and confirmed the results with ISH. Methods: Stage IV primary gastric SRC was retrospectively collected from 2009 to 2012. We analyzed 157 patients who had tumor tissue available for IHC and ISH. After scoring HER2 IHC (PATHWAY and HercepTest), all score 2+ and 3+ cases and those showing discrepancy between two IHC methods were confirmed with silver ISH (SISH). Results: Twenty-five cases (15.9%) showed discrepancy (concordance rate = 67.5%; k = 0.275) between two IHC methods. The concordance rate of IHC 3+ and HER2 amplification by SISH was 100% in HercepTest (k = 1.000) but 15.8% in PATHWAY (k = 0.018). These discrepancies were caused by strong nuclear/cytoplasmic staining which was observed only in PATHWAY method (10.2%) and none of these showed HER2 amplification by SISH. Conclusions: Misinterpretation of HER2 IHC can lead to unnecessary administration of trastuzumab. Since interpretation of IHC using PATHWAY method can be erred in gastric SRC, other staining method or ISH confirmation should be considered. Disclosure: All authors have declared no conflicts of interest.