Tumor Cell Invasion of the External Elastic Lamina Designates Visceral Pleural Invasion and Predicts Poorer Patient Outcomes in Pulmonary Nonmucinous Invasive Adenocarcinoma

Introduction: Visceral pleural invasion (VPI) of lung cancer is defined as involvement by tumor cells into the elastic laminae of the visceral pleura. In both the American Joint Committee on Cancer staging system and the College of American Pathologists cancer protocol, VPI is classified as follows: PL-0 for tumors that do not invade the elastic lamina; PL-1 for tumors that invade the elastic lamina but not up to the pleural surface; PL-2 for tumors that invade up to the pleural surface without involvement of adjacent anatomic structures; and PL-3 for tumors that invade the parietal pleura. Staging of tumors smaller than 3 cm in size will be upgraded from T1 to T2 if VPI (PL-1 or PL-2) is present. Currently, it is recommended that tumor cells invading the outmost (external or outer) elastic lamina, rather than the internal or inner elastic lamina, serve as the criterion for diagnosing VPI. Nevertheless, there is scarce evidence supporting this widely adopted recommendation. Real-world experiences are needed to further validate the clinical significance of lung cancer invading the external versus internal elastic lamina of the visceral pleura. Methods: We retrospectively reviewed the clinicopathologic characteristics of 1217 patients with lung cancer with surgically resected nonmucinous invasive adenocarcinoma between 2011 and 2016. Using the scheme with two-layered elastic laminae, VPI was categorized into PL-n (no pleural invasion; tumor involvement beneath the internal elastic lamina), PL-i (tumor invading into or beyond the internal elastic lamina and beneath the external elastic lamina), PL-e (tumor invading into or beyond the external elastic lamina but not reaching the parietal pleura), and PL-p (tumor invading through the elastic laminae and reaching the parietal pleura). We analyzed the relationship between categories of VPI and prognosis, along with other pertinent clinical and histopathologic parameters. Results: The 5-year overall survival rates were 89.7% for patients with PL-n, 89.5% for PL-i, 71.3% for PL-e, and 53.3% for PL-p, whereas the 5-year recurrence-free survival rates were 88.1%, 85.8%, 55.8%, and 48.6%, respectively. PL-e demonstrated significant differences in univariate analyses in the overall survival analysis, whereas in the disease-free survival analysis, PL-e demonstrated significant differences in both univariate and multivariate analyses. Conclusions: The tumor cell invading the external elastic lamina (PL-e) was a significant prognostic factor for recurrence and associated with worse overall survival for pulmonary nonmucinous invasive adenocarcinoma, compared with the tumor cell invading beneath the external elastic lamina (PL-i). This study provides evidence supporting the use of the outmost external elastic lamina involvement as the landmark of visceral pleural invasion in current clinical practice.