Small cluster invasion: a possible link between micropapillary pattern and lymph node metastasis in pT1 lung adenocarcinomas

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. In this study, we investigated how small micropapillary clusters of carcinoma cells present in tumoral alveolar spaces lead to increased lymph node metastasis. We analyzed 146 cases of pT1 lung adenocarcinomas with reference to the presence of MPP, small cluster invasion (SCI), and lymphatic involvement. SCI was defined as markedly resolved acinar-papillary tumor structures with single or small clusters of carcinoma cells invading stroma within fibrotic foci. The MPP-positive group (88/146 cases) was associated with significantly more frequent nodal metastasis and significantly worse survival. Moreover, SCI was significantly more frequent in the MPP-positive group (71/88 cases) than MPP-negative group (10/58 cases) and was significantly associated with lymphatic involvement (p < 0.0001) and nodal metastasis (p = 0.0073). The SCI-positive group showed significantly worse survival (5-year survival, 70%) than the SCI-negative group (91%, p = 0.0017). Carcinoma cells undergoing SCI demonstrated the same characteristic MUC-1 expression on the outer surface of cell clusters as those undergoing MPP. Thus, SCI could link MPP to nodal metastasis; carcinoma cells with MPP tend to undergo SCI in scars and invade lymphatics in pT1 lung adenocarcinomas.