Histologic Grade and STAS As Key Predictors Of Distant Recurrence In Resected Early-Stage Lung Adenocarcinoma: A Single-Center Study

Alessandro Bonis^1,2Giulia Pagliarini²Giovanni Comacchio²Marco Mammana²Federica Pezzuto³Vincenzo Verzeletti²Enrica Pellizzer²Alessandro Berni²Stefano Silvestrin²Giorgio Cannone²Eleonora Faccioli²Alessandro Rebusso²Marco Schiavon²Samuele Nicotra²Andrea Dell'Amore^1,2*Fiorella Calabrese³FEDERICO REA²

• ¹University of Padova, Padova, Italy
• ²Thoracic Surgery Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Padova, Italy
• ³Pathology Unit, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Padova, Italy

Early-stage lung adenocarcinoma (ADC) is curable by surgical resection in the majority of cases. However, unexpectedly, some patients experience distant disease relapse. Emerging evidence suggests that microscopic tumor characteristics may increase the risk of tumor relapse. Consequently, we aimed to test different microscopic variables to assess their association with distant recurrence (DR).The evaluation of all cases of radically treated stage I-IIA ADCs from 2016 to 2020) was conducted. Clinical and pathological variables were assessed for their association with DR using univariable and multivariable logistic regression.Results. A total of 259 patients were treated (214 lobectomies and 45 segmentectomies). After resection, 54 patients relapsed, 28 of whom had distant recurrences (DR). Spread through air spaces (STAS) was detected in 48% of samples, while vascular invasion (VI) was present in 53%, which was 17% more frequent in those with DR. Tumor size was larger in patients with recurrence, with the largest tumors observed in those with local recurrence (25.5 mm in local vs. 23.5 mm in DR; p=0.028). G3 ADCs were more prevalent in DR cases, accounting for 48% of samples. In univariate regression, surgical margins, LVI, necrosis, G3 primary tumors, and STAS were significant factors. In multivariate analysis, only STAS and G3 remained significant (p=0.07 and p<0.01, respectively).Conclusions. STAS, LVI, necrosis, and G3 histology appear to influence distant recurrence after resection of stage I-IIA ADCs. G3 and STAS remained significant in multivariate analysis, suggesting that alveolar spread and dedifferentiated ADCs represent aggressive tumor types prone to distant recurrence.