Light-Chain 3A Autophagic Activity and Prognostic Significance in Non-small Cell Lung Carcinomas

Abstract

Lung carcinoma has a poor prognosis that is mainly predicted by the stage of the disease. Despite evaluation of various prognostic factors, the role of autophagy, a self-degradative process involved in the turnover of cytoplasmic material, remains unexplored in lung malignancy. Autophagic activity was investigated in 115 patients with non-small cell lung carcinoma treated with surgery (64 squamous cell carcinomas, 24 adenocarcinomas of mixed subtype, 18 large cell carcinomas, 9 uncommon types). The median overall survival was 32 months (range, 2-102 months). We used the MAP1LC3A antibody and a standard immunohistochemical technique. Autophagic activity was correlated with clinical and pathologic parameters. Immunohistochemical examination revealed three patterns of autophagic activity: diffuse cytoplasmic, cytoplasmic perinuclear, and "stone-like" structures (SLSs), which are dense, rounded cytosolic structures typically enclosed within light-chain 3 (LC3) A-positive vacuoles. A high SLS count was associated with a reduction of the overall median survival from 88 to 15 months and constituted the strongest independent variable in multivariate analysis. Interestingly, a high presence of SLS defined significantly poor prognosis within stage I and II, whereas a similar trend was noted within stage III. The other two patterns of LC3A reactivity were not correlated with prognosis. Exaggerated autophagy, as indicated by the intense presence of SLSs, is strongly correlated with a poor outcome in non-small cell lung carcinoma, suggesting possibly that autophagy functions as a survival tool in cancer cells.