Immunohistochemical profiling of receptor tyrosine kinases, MED12, and TGF-βRII of surgically resected small cell lung cancer, and the potential of c-kit as a prognostic marker

// Hiroshi Yokouchi 1 , Hiroshi Nishihara 2 , Toshiyuki Harada 3 , Takashi Ishida 1,4 , Shigeo Yamazaki 5 , Hajime Kikuchi 6 , Satoshi Oizumi 6,7 , Hidetaka Uramoto 8,9 , Fumihiro Tanaka 8 , Masao Harada 7 , Kenji Akie 10 , Fumiko Sugaya 11 , Yuka Fujita 12 , Kei Takamura 13 , Tetsuya Kojima 14 , Mitsunori Higuchi 15,16 , Osamu Honjo 11,17 , Yoshinori Minami 18 , Naomi Watanabe 19 , Aya Goto 20 , Hiroyuki Suzuki 16 , Hirotoshi Dosaka-Akita 21 , Hiroshi Isobe 14 , Masaharu Nishimura 6 and Mitsuru Munakata 1 1 Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, Japan 2 Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 3 Center for Respiratory Diseases, JCHO Hokkaido Hospital, Sapporo, Japan 4 Clinical Oncology Center, Fukushima Medical University Hospital, Fukushima, Japan 5 Department of Thoracic Surgery, Keiyukai Sapporo Hospital, Sapporo, Japan 6 First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan 7 Department of Respiratory Medicine, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan 8 Second Department of Surgery, University of Occupational and Environmental Health, Kita-kyushu, Japan 9 Department of Thoracic Surgery, Kanazawa Medical University, Uchinada, Japan 10 Department of Respiratory Disease, Sapporo City General Hospital, Sapporo, Japan 11 Department of Respiratory Medicine, Teine Keijinkai Hospital, Sapporo, Japan 12 Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan 13 First Department of Medicine, Obihiro Kosei Hospital, Obihiro, Japan 14 Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo, Japan 15 Department of Thoracic Surgery, Fukushima Red Cross Hospital, Fukushima, Japan 16 Department of Thoracic Surgery, Fukushima Medical University, Fukushima, Japan 17 Department of Respiratory Medicine, Sapporo-Kosei General Hospital, Sapporo, Japan 18 Respiratory Center, Asahikawa Medical University, Asahikawa, Japan 19 Department of Internal Medicine, Sunagawa City Medical Center, Sunagawa, Japan 20 Center for Integrated Science and Humanities, Fukushima Medical University, Fukushima, Japan 21 Department of Medical Oncology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Correspondence to: Hiroshi Yokouchi, email: // Keywords : small-cell lung cancer, surgery, MED12, c-kit, immunohistochemistry Received : June 13, 2016 Accepted : December 01, 2016 Published : December 31, 2016 Abstract The limited number of available treatments for patients with small-cell lung cancer (SCLC) has prompted us to further investigate the biology of SCLC by molecular profiling. We collected formalin-fixed paraffin-embedded tumor samples from 127 patients with SCLC, who had undergone surgery at 16 institutions between January 2003 and January 2013, and analyzed the association between disease-specific survival and protein expression of c-kit, c-Met, epidermal growth factor receptor, human EGFR-related 2, vascular endothelial growth factor receptor II, anaplastic lymphoma kinase, mediator complex subunit 12 (MED12), and transforming growth factor beta receptor II (TGF-βRII) by immunohistochemistry (IHC). Of the 125 evaluable samples, all tumors expressed MED12, and 123 samples (98.4%) expressed TGF-βRII. MED12 was highly expressed in the nucleus in 92% of the positive samples while TGF-βRII was highly expressed in the cytoplasm in 55% of the positive samples. High c-kit expression was an independent favorable prognostic marker confirmed by multivariate analysis (hazard ratio: 0.543, 95% confidence interval: 0.310–0.953, p = 0.033). Both the relapse free-survival and overall survival of patients who underwent adjuvant chemotherapy were statistically longer in those with high c-kit expression (n = 38) than those with intermediate, low, or no c-kit expression ( n = 19) (not reached vs 11.6 months, p = 0.021; not reached vs 25.9 months, p = 0.028). IHC for c-kit may offer a prognostic marker for early-stage SCLC, and the results for MED12 and TGF-βRII may suggest the biological characteristics of SCLC. Further investigation of the roles of their related molecules in early stage SCLC is required.