Prognostic impact of cancer-associated active fibroblasts and invasive architectural patterns on early-stage lung adenocarcinoma

Background: Invasion is a crucial indicator of the prognosis in lung adenocarcinoma. The 2015 WHO classification of lung tumors defined invasion of adenocarcinoma mainly by the presence of non-lepidic histological subtypes including papillary, acinar, micropapillary and solid patterns, and the presence of cancer-associated active fibroblasts (CAF). In this study, we focused specifically on early-stage lepidic adenocarcinoma with CAF to evaluate its prognostic significance. Methods: We included 1032 resected cases of lung adenocarcinoma, which consisted of pathological stage IA invasive cancer and adenocarcinoma in situ (AIS). Invasive adenocarcinoma was classified into two subgroups according to the type of invasion, INV-1 and INV-2. We defined INV-1 as adenocarcinoma of a non-lepidic histological subtype with or without CAF, and INV-2 as lepidic adenocarcinoma with CAF. The clinicopathological characteristics and prognosis were retrospectively analyzed. Results: Included cases were classified into 696 (67.4 %) INV-1, 170 (16.5 %) INV-2, and 166 (16.1 %) AIS. The estimated 5-year recurrence-free probabilities of INV-1, INV-2, and AIS were 92.9 %, 100 %, and 100 %, respectively (p< 0.001). Although there were significant differences between INV-1 and INV-2 in terms of gender (more males in INV-1, p = 0.039), smoking habit (more smokers in INV-1, p= 0.046), and lymphovascular invasion (more invasion in INV-1, p < 0.001), there was no difference between AIS and INV-2. Conclusion: The presence of CAF is not always associated with a worse prognosis, and therefore it does not seem appropriate to include the presence of CAF alone in diagnostic criteria for invasion in early-stage lung adenocarcinoma.y