Pulmonary Adenocarcinomas with Signet Ring Cell (SRC) Features: A Clinicopathologic and Molecular Study
Jennifer M Boland, Jin S Jang, Jason A Wampfler, Xiaoke Wang, Michele R Erickson-Johnson, Andre M Oliveira, Ping Yang, Jin Jen, Eunhee S Yi. Mayo Clinic, Rochester, MN
Background: Pulmonary adenocarcinomas (ADCA) with SRC features (SRC+) have been associated with poor outcome and ALK rearrangement (ALK+). However, their clinicopathologic characteristics and molecular profile are not well known. Herein, we systematically reviewed pulmonary ADCAs for SRCs and evaluated clinical and molecular features of SRC+ cases.
Design: Surgically treated lung ADCAs (n=764) in 3 cohorts representing distinct patient groups were reviewed by 2 pulmonary pathologists: never smoker cohort (n=300), a 2006-7 patient cohort with 5-year follow-up (n=223), and a cohort generated from a pathology search enriched for lepidic growth (n=557). SRC+ tumors had >10% SRCs agreed by both pathologists and were TTF1+, cytoplasmic mucin+, and CDX2-. ALK immunohistochemistry (IHC) was performed on all SRC+ cases and ALK status was confirmed by FISH for cases with any IHC positivity. DNA was extracted from SRC+ cases, and samples were run on MassArray based Lung Cancer Mutations Screening Panel (LuCaMSP), which tests for 179 individual mutations in 10 genes including EGFR, KRAS, BRAF, ERBB2, JAK2, AKT1, AKT2, KIT, MET and PIK3CA; positive results were confirmed by gene sequencing.
Results: Fifty-two of 764 cases (7%) were SRC+, which were more likely to occur in men and have higher stage. The 300 never smokers included 226 women (75%); 27 cases (9%) were SRC+, which were more likely to be ALK+ than SRC- cases (33% vs 5%, p<0.0001). LuCaMSP analysis on 25 SRC+ cases in this cohort showed the following mutations in ALK- cases: 7 EGFR, 3 KRAS, and 4 MET (1 case had both ALK and MET R970C). SRC+ never smokers were more likely to have lung cancer progression and death: median progression-free survival 2.2 vs. 5.0 years (p=0.0001), median overall survival 3.5 vs. 7.6 (p=0.0038). The 223 patients treated in 2006-7 had 123 women (55%), and 19 (9%) were SRC+. The 557 lepidic enriched cases occurred in 314 women (56%), and 27 (5%) were SRC+. Analysis of the later 2 cohorts yielded the following results: no significant difference in smoking status (never- vs. ever-smokers); confirmation that SRC+ cases are more likely to be ALK+; crude 5-year survival rates were 8%-16% inferior in SRC+ cases compared to the SRC- cases, although not reaching statistical threshold; LuCaMSP analysis is ongoing, and 3 of 4 examined cases have KRAS mutations.
Conclusions: SRC+ ADCA of lung are associated with male gender and higher stage. Shorter survival was observed in SRC+ cases for all 3 cohorts but was only statistically significant in the never-smoker cohort. SRC+ cases in all cohorts were more likely to be ALK+.
Monday, March 4, 2013 2:15 PM
Proffered Papers: Section D, Monday Afternoon