Poorly Differentiated Clusters in Colorectal Adenocarcinomas Share Biological Similarities with Micropapillary Patterns as well as Tumor Buds

In colorectal carcinoma, poorly differentiated clusters (PDCs) are a poor prognostic indicator and show morphological continuity and behavioral similarities to micropapillary patterns (MPPs) as well as tumor buds (TBs). Epithelial-mesenchymal transition (EMT) and inhibition of cancer-stromal interactions may contribute to the development of PDCs. To clarify the biological nature of PDCs, we examined immunohistochemical stainings for β-catenin, Ki-67, E-cadherin, epithelial cell adhesion molecule (EpCAM), MUC1, and epithelial membrane antigen (EMA), which are associated with EMT and cancer-stromal interactions. The expression frequencies and patterns of PDCs, TBs, and differentiated neoplastic glands from the tumor center (TC) were compared. In the study group (117 cases), the nuclear β-catenin staining index was higher in PDCs (37.3%) and TBs (43.3%) than in neoplastic glands from TC (8.9%, P < 0.001). The mean Ki-67 labeling index in TC was 71.5%, whereas it was decreased in PDCs (31.2%) and TBs (10.2%, P < 0.001). E-cadherin and EpCAM displayed a tendency to be found along the cell membrane in TC samples (91.5% and 92.3%, respectively), whereas they showed loss of membranous staining in PDC (44.4% and 36.8%, respectively) and TB samples (60.7% and 68.4%, respectively). An inside-out pattern for MUC1 and EMA was frequently observed in PDC (48.7% and 45.3%, respectively) and TB samples (46.2% and 45.3%, respectively), but not in TC samples. Our data demonstrate that there is a pathogenetic overlap among PDCs, TBs, and MPPs and suggest that they might represent sequential growth patterns that branch from common biological processes such as dedifferentiation and alteration in cancer-stromal interactions.