Original ArticlesInsulinoma-associated Protein 1 (INSM1) Is a Better Marker for the Diagnosis and Prognosis Estimation of Small Cell Lung Carcinoma Than Neuroendocrine Phenotype Markers Such as Chromogranin A, Synaptophysin, and CD56Sakakibara, Rie MD, PhD*,†,‡; Kobayashi, Maki PhD*,†; Takahashi, Naoko BSc*,†; Inamura, Kentaro MD, PhD*,†; Ninomiya, Hironori MD, PhD*,†; Wakejima, Ryo MD*,†; Kitazono, Satoru MD, PhD§; Yanagitani, Noriko MD, PhD§; Horiike, Atsushi MD, PhD§,∥; Ichinose, Junji MD, PhD¶; Matsuura, Yosuke MD, PhD¶; Nakao, Masayuki MD, PhD¶; Mun, Mingyon MD, PhD¶; Nishio, Makoto MD, PhD§; Okumura, Sakae MD¶; Motoi, Noriko MD, PhD#; Ito, Takaaki MD, PhD**; Miyazaki, Yasunari MD, PhD‡; Inase, Naohiko MD, PhD‡; Ishikawa, Yuichi MD, PhD*,†Author Information *Division of Pathology, The Cancer Institute Departments of †Pathology §Thoracic Medical Oncology ¶Thoracic Surgical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research ‡Department of Respiratory Medicine, Tokyo Medical and Dental University ∥Department of Medicine, Division of Medical Oncology, Showa University School of Medicine #Department of Pathology, National Cancer Center Hospital, Tokyo **Department of Pathology and Experimental Medicine, Kumamoto University, Kumamoto, Japan Present address: Yuichi Ishikawa, MD, PhD, Department of Pathology, School of Medicine, International University of Health and Welfare, 1-4-3 Mita, Minato-ku, Tokyo 108-8329, Japan. Conflicts of Interest and Source of Funding: Parts of this study were supported financially by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, including Grant Numbers JP16K08679 (K.I.), JP26430149 (H.N.), and JP15H04714 and 19H03446 (Y.I.) grants from the Japan Society for the Promotion of Science; the Ministry of Health, Labour and Welfare, Japan; the Ministry of the Environment, Japan; the Japan Agency for Medical Research and Development. Y.I. received research grants from Daiichi Sankyo Co. Ltd and is a consultant for Fujirebio Inc. M.N. received grants and personal fees from Ono Pharmaceutical, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Pfizer, grants and personal fees from Chugai Pharmaceutical, grants, and personal fees from Eli Lilly, grants and personal fees from Taiho Pharmaceutical, grants and personal fees from AstraZeneca, grants and personal fees from Boehringer-Ingelheim, grants and personal fees from MSD, grants and personal fees from Novartis, personal fees from Daiichi Sankyo Healthcare, personal fees from Merck Serono, grants from Astellas, outside the submitted work. N.M. received personal fees (for a lecture, advisory board) from Bristol-Myers Squibb, Miraca Life Sciences, AstraZeneca, Chugai Pharmaceutical, MSD, Agilent and Novartis; institutional research funding from Roche Diagnostics. K.I. received a research grant from Konica Minolta Inc. A.H. received a personal fee for a lecture from Chugai Pharmaceutical, AstraZeneca, Chugai Pharma, MSD, Pfizer, Boehringer-Ingelheim, and Ono Pharmaceutical. N.Y. is a consultant for Chugai Pharma. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Yuichi Ishikawa, MD, PhD, Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan (e-mail: firstname.lastname@example.org). Online date: February 28, 2020 The American Journal of Surgical Pathology: June 2020 - Volume 44 - Issue 6 - p 757-764 doi: 10.1097/PAS.0000000000001444 Buy Metrics Abstract To diagnose small cell lung carcinoma (SCLC), neuroendocrine (NE) phenotype markers such as chromogranin A, synaptophysin, and CD56 are helpful. However, because they are dispensable, SCLCs occur without apparent NE phenotypes. Insulinoma-associated protein 1 (INSM1) is a transcription factor for NE differentiation and has emerged as a single practical marker for SCLC. Using the surgical samples of 141 pulmonary NE tumors (78 SCLCs, 44 large cell NE carcinomas, and 19 carcinoids), and 246 non-NE carcinomas, we examined the immunohistochemical expression and prognostic relevance of INSM1 in association with NE phenotype markers. We evaluated its sensitivity and specificity for SCLC diagnosis, as well as its usefulness to diagnose SCLC without NE marker expression and to estimate the prognosis. INSM1 was expressed in SCLCs (92%, 72/78), large cell NE carcinomas (68%, 30/44), and carcinoids (95%, 18/19). In addition, among SCLCs with no expression of NE phenotype markers (n=12), 9 (75%) were positive for INSM1. These data suggest the superiority of INSM1 to the phenotype markers. Only 7% of adenocarcinomas (9/134) and 4% of squamous cell carcinomas (4/112) were positive for INSM1. SCLC with low-INSM1 expression (n=28) had a significantly better prognosis (P=0.040) than the high-INSM1 group (n=50). Our study revealed that INSM1 is highly sensitive and specific to detect SCLC and can estimate prognosis. INSM1 will be a promising marker for SCLC. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.