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Expression of Neuroendocrine Markers in Undifferentiated Carcinomas of the Gastrointestinal Tract

Medizinische Klinik I, Charité—Campus Benjamin Franklin, Berlin, Germany

To the Editor:

In the July 1, 2004, issue of the Journal of Clinical Oncology, Brenner et al¹ 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.² 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.³

View larger version (143K): [in this window] [in a new window]   Fig 1. Immunohistochemical detection of epidermal growth factor receptor (EGFR) -expression in undifferentiated colorectal cancers. (A) Lack of EGFR-staining in an undifferentiated colorectal carcinoma with neuroendocrine features (representative slide of a total of nine cancers); (B) positive immunohistochemical staining for EGFR (in red color) in an undifferentiated colorectal carcinoma without neuroendocrine features (representative slide of a total of eleven cancers) The cutoff for immunohistochemical EGFR-positivity was set at 10% or more EGFR-positive tumor cells. Bar = 100 µm.

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.

Authors' Disclosures of Potential Conflicts of Interest

The following authors and their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Hans Scherubl, AstraZeneca. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.

REFERENCES

1. Brenner B, Tang LH, Klimstra DS, et al: Small-cell carcinomas of the gastrointestinal tract: A review. J Clin Oncol 22:2730-2739, 2004[Abstract/Free Full Text]

2. Grabowski P, Schönfelder J, Ahnert-Hilger G, et al: Expression of neuroendocrine markers: A signature of human undifferentiated carcinoma of the colon and rectum. Virchows Arch 441:256-263, 2002[CrossRef][Medline]

3. Grabowski P, Schindler I, Anagnostopoulos I, et al: Neuroendocrine differentiation is a relevant prognostic factor in stage III-IV colorectal cancer. Eur J Gastroenterol Hepatol 13:405-411, 2001[CrossRef][Medline]

4. Helpap B, Kollermann J: Immunohistochemical analysis of the proliferative activity of neuroendocrine tumors from various organs: Are there indications for a neuroendocrine tumor-carcinoma sequence? Virchows Arch 438:86-91, 2001[CrossRef][Medline]

5. Brittan M, Wright NA: Stem cell in gastrointestinal structure and neoplastic development. Gut 53:899-910, 2004[Free Full Text]

6. Vortmeyer AO, Lubensky IA, Merino MJ, et al: Concordance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. J Natl Cancer Inst 89:1448-1453, 1997[Abstract/Free Full Text]

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  David S. Klimstra, Jinru Shia, Laura Tang, Baruch Brenner, and David P. Kelsen
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