Differences of tumor microenvironment between stage I lepidic-positive and lepidic-negative lung adenocarcinomas

Lepidic growth is a noninvasive component of lung adenocarcinoma. Many adenocarcinoma cases contain coexistent lepidic and nonlepidic (invasive) components (lepidic-growth positive [Lep+] adenocarcinoma); however, some cases comprise only nonlepidic components (lepidic-growth negative [Lep-] adenocarcinoma). The aim of this study was to investigate the biological differences between the invasive components of Lep+ and Lep- adenocarcinoma.

We investigated the clinicopathologic characteristics of 232 adenocarcinomas (116 size-matched tumor pairs from Lep+ and Lep- adenocarcinomas). We then evaluated the cancer cell-specific expression levels of cancer stem cell, hypoxia, and invasion molecules in these lesions. The number of tumor-promoting stromal cells, including podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor-associated macrophages, was also analyzed.

Among cases with size-matched invasive components, significant differences were shown in total tumor size and predominant subtype in invasive component between Lep+ and Lep- adenocarcinomas. The expression levels of hypoxia-related molecules were significantly lower in Lep+ adenocarcinomas (glucose transporter 1: 0 vs 10, P < .01; carbonic anhydrase IX: 0 vs 0 [mean, 4.7 vs 14.1], P = .01). The number of podoplanin-positive cancer-associated fibroblasts and CD204-positive tumor-associated macrophages was significantly lower in Lep+ adenocarcinomas (podoplanin-positive cancer-associated fibroblasts: 0 vs 0 [mean: 1.6 vs 11.6], P < .01; CD204-positive tumor-associated macrophages: 8.7 vs 24.7, P < .01).

Our results indicated that lower cancer cell-specific expression levels of hypoxia markers and a smaller number of tumor-promoting stromal cells in invasive component were characteristic features of Lep+ adenocarcinomas.