Expression of Neuroendocrine Markers in Undifferentiated Carcinomas of the Gastrointestinal Tract

Abstract

TO THE EDITOR: In the July 1, 2004, issue of the Journal of Clinical Oncology, Brenner et al have provided an excellent review on small-cell undifferentiated carcinomas of the gastrointestinal tract. However, we want to point out that immunohistochemical staining for neuroendocrine markers is often positive in undifferentiated gastrointestinal cancers. In a recent series of 20 undifferentiated colorectal cancers, representing 0.8% of 2,530 colorectal cancers treated at a single institution, nine (45%) of the 20 undifferentiated cancers were found to express neuroendocrine markers. Interestingly, neuroendocrine marker–positive undifferentiated cancers differed from neuroendocrine marker–negative undifferentiated cancers in the expression of epidermal growth factor receptor (EGFR). Although none of the nine neuroendocrine marker–positive cancers stained positive for EGFR expression, the 11 neuroendocrine marker–negative cancers expressed EGFR immunohistochemically (see Fig 1). Moreover, neuroendocrine differentiation was of prognostic relevance. Neuroendocrine marker–negative undifferentiated colorectal cancers were diagnosed at an earlier stage and had a more favorable overall survival than neuroendocrine marker–positive undifferentiated colorectal carcinomas (45% v 11% survivors after 2 years; P .001). The latter manifested at an earlier age (51.9 years v 63.6 years), a finding that may well reflect their aggressive tumor biology. Noteworthy is the fact that partial neuroendocrine differentiation also predicts a less favorable clinical course in Dukes’ C colorectal adenocarcinoma. Undifferentiated neuroendocrine carcinomas are not thought to derive from benign orthotopic neuroendocrine epithelial cells; instead, the most favored concept currently is that they are of stem cell origin. This means that a single epithelial cell, even if malignant, can give rise to all cell types seen in the colorectal epithelium. This concept also explains the occurrence of bior multiphenotypic tumors. In line with this notion, Vortmeyer et al observed identical genetic alterations in synchronous poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. We suggest that the expression of neuroendocrine markers should be evaluated in undifferentiated carcinomas of the gastrointestinal tract, because neuroendocrine differentiation is of prognostic value and will probably have therapeutic implications in the near future.