Original ArticlesNovel Histologic Classification of Small Tumor Cell Nests for Lung Adenocarcinoma With Prognostic and Etiological Significance Small Solid Nests and Pure Micropapillary NestsSaito, Ryoko MD, PhD*,†; Ninomiya, Hironori MD, PhD*; Okumura, Sakae MD‡; Mun, Mingyon MD, PhD‡; Sasano, Hironobu MD, PhD†; Ishikawa, Yuichi MD, PhD*,§Author Information *Division of Pathology, The Cancer Institute, The Cancer Institute Hospital, Japanese Foundation for Cancer Research ‡Department of Thoracic Surgical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research §Department of Pathology, Mita Hospital, International University of Health and Welfare, Tokyo †Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan R.S. and Y.I.: carried out the conception and design and helped in manuscript writing. Y.I. and H.S.: helped in administrative support. H.N., S.O., M.M., and Y.I.: helped in the provision of study materials or patients. R.S. and Y.I.: collected and assembled data. R.S., H.N., S.O., M.M., H.S., and Y.I.: conducted data analysis and interpretation. Conflicts of Interest and Source of Funding: Supported partly by Grants-in-Aid for Scientific Research (Kakenhi) from Japan Society for the Promotion of Science (JSPS) (Y.I.: 19H03446), grants from Japan Agency for Medical Research and Development (AMED) (Y.I.: 18ck0106335h0002), and by funding for mesothelioma projects entrusted by the Ministry of Environment, Japan (Y.I.). Y.I. received research funds from Daiichi Sankyo Co. Ltd and is a consultant for Fujirebio Inc. For the remaining authors none were declared. Correspondence: Yuichi Ishikawa, MD, PhD, Department of Pathology, Mita Hospital, International University of Health and Welfare, 1-4-3 Mita, Minato-ku, Tokyo 108-8329, Japan (e-mail: [email protected]). The American Journal of Surgical Pathology: May 2021 - Volume 45 - Issue 5 - p 604-615 doi: 10.1097/PAS.0000000000001696 Buy SDC Metrics Abstract Small tumor cell nests such as micropapillary nests are histologic poor prognostic markers for adenocarcinomas of various organs, including the lung. However, for the lung, the association of micropapillary patterns with smoking is controversial, which may be because of a vague definition of micropapillary patterns. This study clarifies the implications of small tumor cell nests by introducing a new dichotomic classification based on the glandular polarity of tumor cells: pure micropapillary nests (pMPs), preserving glandular polarity, and small solid nests (SSNs), lacking polarity. We examined the clinicopathologic factors in 436 resected adenocarcinomas, and analyzed the overall survival between groups classified by either the presence or absence of pMPs and SSNs. pMP was positively associated with nonsmoking–related features such as epidermal growth factor receptor mutations and thyroid transcription factor 1 expression. By contrast, SSN was positively associated with smoking-related features such as KRAS mutations and hepatocyte nuclear factor-4a expressions. Besides, pMP and SSN were significant and independent indicators of poor prognosis in all stages. SSN was an indicator in stage I too, whereas pMP was not. Furthermore, prognoses of the group with SSN were significantly worse than those of pMP-only group. In conclusion, the present study has revealed 2 completely different patterns of small tumor cell nests in lung adenocarcinoma, the nonsmoking–related pMPs, and the smoking-related SSNs, by considering glandular polarity. MPP should include only pMPs, and SSNs should be in a solid pattern. This novel classification might boast clinical significance as a potent poor prognostic marker as well as a factor reflecting etiological and genetic characters. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.