Does lung adenocarcinoma subtyping offer clinical benefits?-a retrospective population-based cohort study from Sweden.

Background: Classification of lung adenocarcinoma into subtypes is relatively recent and not universally practiced. Consequently, large representative studies describing clinical outcomes are rare, failing to pervasively present the advantages of subtyping, which might potentially improve treatment and survival. Although many related studies have been published, few of them include large patient numbers of unselected adenocarcinoma subtypes, which has probably resulted in discrepant results. We describe the situation in Sweden with the largest study on a European population with a focus on survival. Methods: Patient data were obtained from the Swedish Cancer Registry from 2005 to 2021, accounting for 1,418 patients, less than 5% of the reference group 'adenocarcinoma not otherwise specified (NOS)'. All reported adenocarcinoma patients were included from the cancer registry, with complete national coverage of patients and pathological verification of diagnoses. Non-parametric survival estimates were calculated using the Kaplan-Meier method and testing for linear consistency using Weibull modelling. Results: Survival was generally better for women compared to men and this was most prominent for early-stage cancers. Female 5-year survival decreased in order, lepidic [59%, 95% confidence interval (CI): 55-65%], papillary (51%, 95% CI: 40-64%), invasive mucinous (46%, 95% CI: 32-66%), colloid (36%, 95% CI: 30-43%) and adenocarcinoma NOS (24%, 95% CI: 24-25%). Male 5-year survival for lepidic (46%, 95% CI: 40-53%) and colloid subtypes (22%, 95% CI: 16-29%) was significantly lower than female survival. Survival slopes for T1, T2, N0, M0 cases of lepidic, papillary and adenocarcinoma NOS were almost linear, suggesting homogeneous diagnostics. Survival kinetics were in agreement with Weibull modelling k-values of 1.00 or slightly higher, implying that mortality increased slowly with time, only moderately faster than for the background population of similar age. Conclusions: The present study is among the largest ones so far published on unselected stages of adenocarcinoma subtypes. Our findings demonstrate a significant female survival advantage across most adenocarcinoma subtypes. Survival in T1 and T2 classes with N0 and M0 for lepidic, papillary and adenocarcinoma NOS was close to linear, suggesting that patients are homogeneously diagnosed and treated. Survival benefits of lepidic and papillary subtypes over adenocarcinoma NOS give justification for adenocarcinoma subclassification, and independently validate the prognostic advantage of lepidic and papillary subtypes proposed in the World Health Organization (WHO) 2021 adenocarcinoma grading classification.