Pulmonary adenocarcinoma with signet ring cell features: a comprehensive study from 3 distinct patient cohorts

Comprehensive biological characteristics of pulmonary adenocarcinomas with signet ring cell features (SRC⁺) are not well known. Herein, we systematically evaluated clinical and molecular features of SRC⁺ cases with particular attention to smoking status. Surgically treated lung adenocarcinomas (n=763) with follow-up ≥5 years in 3 cohorts were reviewed: all patients in 2006 to 2007 ("all-comers," n=222; 168 ever-smokers), a never-smoker cohort (n=266), and a cohort of ever-smokers (n=275). SRC⁺ tumors had ≥10% of SRCs agreed by 2 pathologists. SRC⁺ cases were tested for rearrangement of ALK and ROS1, as well as 187 known mutations in 10 oncogenes including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET, and PIK3CA. Overall, 53 of 763 cases (7%) were SRC⁺. In the 2006 to 2007 "all comer" cohort, 9% were SRC⁺. In the never-smoker cohort, 9% were SRC⁺. In the smoker cohort, 3% were SRC⁺. Univariable analysis showed that SRC⁺ never-smokers had shorter overall and disease-free survival (P=0.006 and 0.0004, respectively), but the significance faded in the multivariable analysis. For the other 2 cohorts, crude 5-year survival was decreased by 6% to 27% in SRC⁺ cases without reaching statistical significance. In SRC⁺ tumors, KRAS mutation was most common (29%), followed by ALK (26%), EGFR (18%), ROS1 (6%), BRAF (6%), and PIK3CA (3%). In summary, SRC⁺ tumors in never-smokers had a worse survival by univariable analysis only. SRC⁺ cases seemed enriched for ALK⁺ and ROS1⁺, and other mutations were generally in keeping with the patient's smoking status.