Low-Malignant-Potential Adenocarcinoma: A Histological Category with a Significantly Better Prognosis than Other Solid Adenocarcinomas at IA Stage

Introduction: Low-malignant-potential adenocarcinoma has been defined as a type of non-mucinous tumor, which has a total tumor size measuring ≤ 3 cm, exhibits ≥ 15% lepidic growth, lacks non-predominant high-grade patterns (≥10% cribriform, ≥5% micropapillary, ≥5% solid), has an absence of angiolymphatic or visceral pleural invasion, spread through air spaces (STAS), necrosis and >1 mitosis per 2 mm2. The aim of this study is to validate, with regard to cancer-specific survival (CSS) and disease-free survival (DFS), the proposed definition of LMP adenocarcinoma in an independent external cohort of lung adenocarcinoma patients having undergone surgical resection, and having presented with a long follow-up period. Methods: Clinicopathological characteristics of patients who underwent lung resection for adenocarcinoma from 1 January 2005 to 31 December 2014 were retrospectively analyzed. Patients with ground-glass opacity (GGO) and part-solid tumors, minimally invasive adenocarcinoma (MIA), adenocarcinoma in situ (AIS), tumors ≥5 cm in size, nodal involvement and/or distant metastases, patients who underwent neoadjuvant treatment, and those who had an incomplete follow-up or a follow-up shorter than 60 months were excluded. The proposed criteria for low-malignant-potential adenocarcinoma (LMPA) were tumor size ≤ 3 cm, invasive size ≥ 0,5 cm, lepidic growth ≥ 15%, and absence of the following: mitosis (>1 per 2 mm2), mucinous subtype, angiolymphatic invasion, visceral pleural invasion, spread through air spaces (STAS) and tumor necrosis. End points were disease-free survival (DFS) and cancer-specific survival (CSS). The log-rank test was used to assess differences between subgroups. Results: Out of 80 patients meeting the proposed criteria, 14 (17.5%) had the LMPA characteristics defined. The mean follow-up time was 67 ± 39 months. A total of 19 patients died, all in the non-LMPA category, and 33 patients experienced recurrence: 4 (28.5%) with LMPA and 29 (43.9%) with non-LMPA. Log-rank analysis showed 100% 10-year CSS for patients with LMPA and 77.4% for patients without LMPA, with this difference being statistically significant (p-value = 0.047). Univariate analysis showed a significant association with the cStage (AJCC eighth edition), both for CSS (p value = 0.005) and DFS (p-value = 0.003). LMPA classification did not show a statistically significant impact on CSS and DFS, likely due to the limited number of events (CSS p-value = 0.232 and DFS p-value = 0.213). No statistical association was found for CSS and DFS with pT, the number of resected nodes (< or >10) or the number of resected N2 stations (< or >2). Conclusions: Our study confirmed the prognostic role of LMPA features, with a low risk of recurrence and a good CSS and DFS. The criteria for diagnosis are replicable and feasible for application. The clinical implications of these findings, such as pre-operative prediction and surveillance scheduling, may be the topic of future prospective studies.