Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm

// Cheol Keun Park 1 , Ji Soo Park 2 , Hyo Song Kim 2 , Sun Young Rha 2 , Woo Jin Hyung 3 , Jae-Ho Cheong 3 , Sung Hoon Noh 3 , Sang Kil Lee 4 , Yong Chan Lee 4 , Yong-min Huh 5 , Hyunki Kim 1 1 Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea 2 Division of Medical Oncology, Yonsei Cancer Center, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 3 Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea 4 Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea 5 YUMS-KRIBB Medical Convergence Research Institute, Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea Correspondence to: Hyunki Kim, email: kimhyunki@yuhs.ac Keywords: gastric cancer, receptor tyrosine kinase, amplification, screening algorithm Received: June 17, 2016 Accepted: September 17, 2016 Published: September 27, 2016 ABSTRACT Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR , HER2 , and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age ( P < 0.001), differentiated histology ( P = 0.001), intestinal or mixed type by Lauren classification ( P < 0.001), lymphovascular invasion ( P = 0.026), and mutant-pattern of p53 ( P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification , based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification . In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.