Abstract Purpose: Lung cancer in people who have never smoked (LCINS) is biologically distinct from smoking-related lung cancer yet remains histologically under-characterized. Prognostic frameworks, including the International Association for the Study of Lung Cancer (IASLC) grading system for non-mucinous adenocarcinoma, were developed in smoker-dominant cohorts and remain untested in LCINS. We characterized the LCINS histologic landscape and, within non-mucinous adenocarcinoma, evaluated the prognostic value of IASLC grade and additional histologic features. To our knowledge, this is the first large-scale study dedicated exclusively to LCINS histopathology. Methods: We established the LCINS histologic landscape using the Sherlock-Lung study. Sherlock-Lung H intense/not intense, “intense” indicating high lymphocyte density) for their impact on overall survival (OS) in Sherlock-Lung, and IASLC grade and STAS for OS and disease-free survival (DFS) in MSK. Results: LCINS were predominantly adenocarcinomas (84%; 75% non-mucinous), whereas carcinoid tumors accounted for 8%. In Sherlock-Lung (median follow-up 52 months; 202 deaths), Grades 1-2 had significantly better 5- and 10-year OS versus Grade 3 (HR5 years=0.30, 95%CI 0.18-0.50; HR10 years=0.36, 95%CI 0.24-0.53), most strongly in stage I (HR10 years=0.29, 95%CI 0.16-0.53; pinteraction=0.03). Intense TILs independently improved long-term OS (HR5 years=0.64, 95%CI 0.36-1.11; HR10 years=0.51, 95%CI 0.30-0.86). In MSK (median follow-up 43 months; 21 deaths, 30 DFS events), grades 1-2 showed consistently better OS and DFS, although not statistically significant (OS: HR5 years=0.91, 95%CI 0.28-3.02; DFS: HR5 years=0.61, 95%CI 0.26-1.43) and STAS was not associated with either endpoint. Conclusion: In the largest LCINS cohort to date, we defined distinct histologic features and verified the prognostic value of the IASLC grading system, with Grade 3 indicating worse survival. TIL assessment further refined risk stratification, highlighting the need for further smoking-specific histological evaluation and larger prospective studies. Citation Format: Thi-Van-Trinh Tran, Monjoy Saha, Huu Phuc Hoang, Praphulla Bhawsar, Robert Homer, Marina K. Baine, Lynette M. Sholl, Philippe Joubert, Charles Leduc, William Travis, Ruth Pfeiffer, Jonas S. Almeida, David R. Jones, Gaetano Rocco, Soo Ryum Yang, Maria Teresa Landi. Distinct Histology of Lung Cancer inpeople who have never smokedand Prognostic Determinants in Non-Mucinous Adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1302.
Tran et al. (Fri,) studied this question.