Neuroendocrine differentiation is often seen in colorectal cancer. It is an independent prognostic factor in stage III-IV colorectal cancer.

The frequency and prognostic significance of neuroendocrine marker expression in undifferentiated colorectal cancers has not yet been studied in great detail. Therefore, the survival of 20 patients with small cell undifferentiated colorectal cancers, treated at our institution between 1982 and 1997 (0.8% of all operated colorectal carcinomas), was correlated with the extent of neuroendocrine differentiation. Chromogranin A, synaptophysin, syntaxin1, VAMP2, SNAP25 and alpha/beta-SNAP were used as neuroendocrine markers. Based on the degree of immunoreactivity for these marker proteins, tumors were separated into group 0 (<2% cells stained positive for neuroendocrine markers) and group 1 (>2% cells stained positive). Patients were followed up for at least 5 years or until death. Of 20 (45%) undifferentiated colorectal tumors, 9 expressed neuroendocrine markers (group 1). Only one patient of this group survived for 2 years (11%), whereas the 2-year-survival rate was 45.4% in group 0. Of the 11 patients in group 0, 9 were diagnosed with UICC stages I-III, whereas 8 of 9 tumors with expression of neuroendocrine markers were diagnosed with UICC stage IV ( P=0.002). Our results show that neuroendocrine differentiation is often seen in small cell undifferentiated colorectal cancer. It correlates with a more aggressive course of the disease.

Deregulation of cell death pathways contributes to tumor development and to the clinical course of cancer disease. In patients with liver metastases of colorectal cancer, we have previously shown that an intact p53/BAX apoptotic pathway is a positive prognostic factor. Therefore, the purpose of our study was to determine the prognostic value of BAX protein expression and the mutational status of its upstream regulator p53 in primary colorectal adenocarcinoma. To this end, we analyzed retrospectively tumor samples of 116 patients who underwent surgery for colorectal adenocarcinoma and had a follow-up for a minimum of 5 years or until death (UICC Stage III: 59 patients, UICC Stage IV: 57 patients). Tumors were screened for p53 mutations and investigated for BAX protein expression. Overall median survival was 17 months. As expected, patients with UICC III tumors survived longer than patients with UICC IV tumors: 69 months vs. 8 months (p < 0.0001). UICC III tumors with high BAX expression were associated with a significantly better prognosis (p ‫؍‬ 0.009) than BAX low expressing tumors. The combined p53/BAX pathway analysis for the UICC Stage III group revealed the worst outcome for patients with a disrupted p53/ BAX pathway (i.e., BAX low/p53 mutated; p ‫؍‬ 0.004). In contrast, no significant effect of the p53/BAX status on survival was found in UICC IV tumors. Our study in primary adenocarcinoma of the colorectum shows for the first time that a disrupted p53/BAX pathway is associated with a poor clinical outcome in UICC III tumors. These data also confirm our previous report on the relevance of an intact p53/BAX pathway in liver metastasis of colorectal cancer. Nevertheless, we were not able to confirm this finding in the heterogenous subgroup of UICC IV tumors of the colorectum. Our study therefore provides the basis for the analysis of defects in p53/BAX (and additional genes) in a prospective trial that is the logical basis for future risk-adapted therapies.

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