Neuroendocrine cell differentiation of poorly differentiated colorectal adenocarcinoma correlates with liver metastasis

Abstract

Abstract. Poorly differentiated (PD) adenocarcinoma often retains the capacity for neuroendocrine (NE) cell differentiation; however, it is difficult to distinguish the NE cell differentiation by routine hematoxylin and eosin staining. It is important to detect the presence of NE cell differentiation in advanced colorectal carcinomas because these carcinomas have been shown to produce distant metastasis at the time of diagnosis and to have a particularly poor prognosis. In this study, the characteristics of PD adenocarcinoma with NE cell differentiation and its biological metastatic mechanisms were investigated. Forty-eight of 2204 colorectal cancer patients, diagnosed as having PD adenocarcinoma (2.2%) were enrolled in this study. Immunohistochemical analysis was performed with anti-chromogranin A anti-synaptophysin, anti-CD34, anti-D2-40, and anti-VEGF antibodies. The clinicopathological factors for PD adenocarcinoma with NE cell differentiation were compared with those for PD adenocarcinoma without NE cell differentiation. Microvessel density (MVD) was assessed using immunostained slides with anti-CD34 antibody and vascular endothelial growth factor (VEGF) expression in PD adenocarcinoma with NE cell differentiation was confirmed by in situ hybridization. By immunohistochemical staining for chromogranin A and synaptophysin, NE cell differentiation was detected in eight of 48 patients (16.7%) with PD adenocarcinoma. The frequency of liver metastasis at the time of diagnosis was significantly higher in patients having PD adenocarcinoma with NE cell differentiation (p=0.03). Moreover, MVD and VEGF expression level tended to be higher in patients having PD adenocarcinoma with NE cell differentiation (p=0.13 and 0.068, respectively). NE cell differentiation in PD adenocarcinoma may produce liver metastasis through microvessel formation in the tumor induced by VEGF. In PD colorectal adenocarcinoma, immunohistochemical analysis of NE markers is important for establishing the presence of NE cell differentiation and further study is necessary to evaluate the effectiveness of anti-angiogenic drugs to PD adenocarcinoma with NE cell differentiation.

Is neuroendocrine differentiation a prognostic factor in poorly differentiated colorectal cancer?

“…Similar findings were reported in a meta-analysis by Zeng et al [4]. Intriguingly, some studies have indicated that CRC with NED was correlated with liver metastasis and advanced tumor stages [3, 5]. …”

“…It is known that PDCRC is usually associated with a poor prognosis. NED is often found in PDCRC [5]. The prognosis of PDCRC with NED is currently still unclear.…”

Current concepts in neuroendocrine cancer metabolism

“…In a tumor displaying NED, focal clusters of NE-like cells secrete small molecules and peptides that bind to receptors expressed on the surface of juxtaposed non-NE cells, resulting in increased cellular proliferation [18,19]. The expression of NE features has been demonstrated in many cancers, including adenocarcinomas of the lung, prostate, and colon [7,20,21]. Studies have shown that lung adenocarcinomas with NED are associated with significantly shorter survival compared to lung adenocarcinomas without NED [20,22].…”

Extracellular Lumican Inhibits Pancreatic Cancer Cell Growth and Is Associated with Prolonged Survival after Surgery

“…In melanoma, decreased lumican expression correlates with increased tumor growth and progression (3, 4), and increased lumican expression impedes tumor cell migration and invasion by directly interacting with the α2β1 integrin (5) and decreasing pFAK phosphorylation (6). In neuroendocrine tumors of the colon, lumican expression in the cytoplasm is negatively correlated with tumor grade (7). In contrast, in high-grade breast cancer (8, 9) and pancreatic cancer (10), lumican is overexpressed within the stroma and is typically indicative of advanced tumors and associated with poor prognostic outcomes.…”