Structural and biological properties of a papillary component generating a micropapillary component in lung adenocarcinoma

Abstract

Lung adenocarcinoma with a micropapillary component (MPC) is an aggressive subtype of adenocarcinoma with a papillary component. The aim of this study was to explore the pathobiological properties of a papillary component which generates MPC. We reviewed the 445 cases of resected primary lung adenocarcinoma and confirmed all of the MPC(+) cases ( n = 150) were found only in the cases of adenocarcinoma with a papillary component ( n = 228) and no features of the MPC were detected in any of the other histological subtypes without papillary component. Even in the cases of adenocarcinoma with a papillary component, the MPC(+) group ( n = 150) had significantly poorer outcome than the MPC(−) group ( n = 78) ( P < 0.0001). When this MPC(+) cases were divided into grade 0–2 according to the proportion of the tumor occupied by the MPC, the stage I patients with grade 2 MPC had a significantly poorer outcome than the stage I patients with grade 0 or grade 1 MPC. By considering the histological characteristics that MPC has always structural continuity with papillary component, we evaluated the pathobiological profile of (1) MPC, (2) papillary component which generate MPC [PC MPC(+)], and (3) papillary component without MPC [PC MPC(−)]. The mean width of the stalks in the PC MPC(+) was significantly smaller than in the PC MPC(−) (17.64 ± 9.53 vs. 26.07 ± 10.16 μm, P < 0.001). Although staining for CD34 and collagen IV showed that MPC lacked both fibrovascular stalks and basement membranes, staining for cleaved caspase 3 showed that apoptotic cells were rare in the MPC (1.0%), and the expression levels of the adhesion molecules E-cadherin, β-catenin, and CD44 were similar in all three lesions. The immunohistochemical staining scores of hypoxic marker GLUT-1 in the MPC, PC MPC(+), and PC MPC(−) were 69, 26, and 8.6, respectively, and the differences between the MPC and PC MPC(+) and between the PC MPC(+) and PC MPC(−) were significant ( P = 0.001 and 0.025, respectively). These results indicated that the biological behavior of the papillary component which generates MPC is different from the papillary component without MPC in terms of structural alternation and hypoxic state, and the difference may be related to the aggressive behavior of MPC(+) adenocarcinoma.