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

Visceral pleural invasion (VPI) of lung cancer is defined as involvement by tumor cells into the elastic laminae of visceral pleura. In both AJCC staging system and CAP cancer protocol, VPI is classified as below: 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/outer) elastic lamina, rather than the internal/inner elastic lamina, serves 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 external versus internal elastic lamina of visceral pleura. We retrospectively reviewed the clinicopathological characteristics of 1,217 lung cancer patients with surgically resected non-mucinous 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 internal elastic lamina), PL-i (tumor invading into or beyond internal elastic lamina and beneath external elastic lamina), PL-e (tumor invading into or beyond external elastic lamina but not reaching parietal pleura), and PL-p (tumor invading through elastic laminae and reaching parietal pleura). We analyzed the relationship between categories of VPI and prognosis, along with other pertinent clinical and histopathological parameters. 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, while 5-year recurrence-free survival rates were 88.1%, 85.8%, 55.8%, and 48.6%, respectively. PL-e showed significant differences in univariate analyses in overall survival analysis whereas in disease-free survival analysis, PL-e showed significant differences in both univariate and multivariate analyses. Tumor cells invading external elastic lamina (PL-e) was a significant prognostic factor for recurrence and associated with worse overall survival for pulmonary non-mucinous invasive adenocarcinoma, compared to tumor cells invading beneath 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.