Association of c-Met phosphorylation with micropapillary pattern and small cluster invasion in pT1-size lung adenocarcinoma

Lung adenocarcinomas with micropapillary pattern (MPP) are associated with frequent nodal metastasis. However, little is known about the mechanisms that underlie MPP-associated nodal metastasis. We have previously reported that pT1 lung adenocarcinomas with MPP are significantly associated with small cluster invasion (SCI) and lymphatic involvement. SCI is defined as markedly resolved acinar-papillary tumor structures with single or small clusters of carcinoma cells invading stroma within fibrotic foci. In this study, we hypothesized that c-Met activation may be involved in the MPP-SCI sequence, given that the c-Met tyrosine-kinase receptor and its ligand hepatocyte growth factor (HGF), play important roles in tumor cell motility and invasion. We analyzed 125 pT1-size lung adenocarcinomas for immunohistochemical expression of phosphorylated c-Met and its correlation with MPP, SCI, lymphatic involvement and prognosis. SCI was significantly more frequent in the MPP-positive group (P < 0.0001) and associated with lymphatic involvement (P < 0.0001) and nodal metastasis (P = 0.021). c-Met protein was detected in all tumors by immunohistochemistry as membranous and cytoplasmic staining. Phospho-c-Met (pc-Met) was positive in 119/125 tumors (95%) and expressed at high levels in 27 cases (22%). A high level of pc-Met expression was significantly associated with MPP (P = 0.01) and SCI (P = 0.0059). Moreover, in tumors with MPP or SCI, those expressing high levels of pc-Met were significantly more associated with lymphatic involvement. In p-Stage IA lung adenocarcinomas (n = 99), patients in the high pc-Met expression group showed significantly worse survival than patient in the low expression group (P = 0.0313). These results suggest that activation of c-Met through phosphorylation may be involved in MPP and SCI.