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In Reply:

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY

Baruch Brenner, David P. Kelsen

Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

The comments by Drs Grabowski and Scherubl about our recent review on small-cell carcinomas of the gastrointestinal tract¹ are very much appreciated. We agree that the significance of neuroendocrine differentiation in gastrointestinal carcinomas remains an important issue worthy of additional study. A fundamental issue is whether the presence in a gastrointestinal carcinoma of neuroendocrine differentiation, defined by immunohistochemistry, is a seminal feature that defines the clinical behavior and response to therapy, or whether it is instead the histologic appearance and its resemblance to the classic small-cell carcinoma phenotype, independent of the extent of neuroendocrine differentiation, that dictates the biology of the neoplasm.

Much of our knowledge about the biology of small-cell carcinoma has been gained through study these neoplasms in the lung, where small-cell carcinoma is more common than in any other anatomic location. Interestingly, the small-cell carcinomas that arise outside the lung, including those in the gastrointestinal tract, have similar pathologic features to their pulmonary homonyms, and an effort has been made to utilize the same pathologic criteria for the diagnosis of small-cell carcinoma, irrespective of the site of origin. This approach is particularly practical considering that many patients with small-cell carcinomas present at an advanced stage, without necessarily having a known primary site, and the diagnosis must be based on a biopsy of a metastatic focus. Available data indeed suggest that the clinical behavior, including the response to chemotherapy, is similar regardless of primary site, and many oncologists now treat small-cell carcinomas of the gastrointestinal tract in the same manner as those in the lung.

The definition of pulmonary small-cell carcinomas is purely morphologic; although immunohistochemical evidence of neuroendocrine differentiation can be found in 85% of cases,^2,3 it is not necessary to demonstrate neuroendocrine differentiation to establish the diagnosis.⁴ Thus, the official WHO-endorsed term remains "small-cell carcinoma,"⁴ not "small-cell neuroendocrine carcinoma." It has never been shown convincingly that there are any clinical or biologic differences between pulmonary small-cell carcinomas with documented neuroendocrine differentiation versus those without.⁵ Thus, all pulmonary small-cell carcinomas are treated (and prognosticated) similarly, irrespective of neuroendocrine differentiation. This approach has been extended to the GI tract,⁶ although as Drs Grabowski and Scherübl point out, their study of 20 colorectal small-cell carcinomas⁷ is perhaps the only one to systematically examine the relationship of neuroendocrine differentiation to prognosis. It is not clear why in their patient population, less than half (45%) of the tumors exhibited positive staining for neuroendocrine markers, whereas expression of neuroendocrine markers has been found in up to 95% of colorectal neuroendocrine carcinomas in other studies⁸ and in 86% of 21 colorectal small-cell carcinomas in our files (unpublished data). Given this high rate of neuroendocrine marker expression and the rarity of colorectal small-cell carcinomas, it may be difficult to assemble a large enough study to attempt to replicate the findings of Grabowski et al. Also, as the authors point out, their small cell carcinomas with neuroendocrine differentiation presented at a higher stage than those without,⁷ raising the possibility that the worse outcome could be explained entirely by the stage of the disease.

It is of interest to note that the presence of neuroendocrine differentiation is not at all specific to small-cell carcinomas. Not only do large-cell neuroendocrine carcinomas occur in the gastrointestinal tract,⁸ but conventional adenocarcinomas also commonly contain endocrine cells when studied by immunohistochemistry,^9-14 generally as widely scattered individual cells. In fact, using their definition of neuroendocrine differentiation (> 2% of the neoplastic cells staining for neuroendocrine markers), Grabowski et al found 17.2% of conventional colorectal carcinomas to have neuroendocrine differentiation.¹⁰ Other investigators have found neuroendocrine cells in up to 35% of colorectal carcinomas.¹³ The significance of this minor extent of neuroendocrine differentiation remains unclear, however. Although Grabowski et al found a worse prognosis for patients presenting with stage III colorectal carcinomas with a neuroendocrine cell component,¹⁰ those presenting at stage IV were not statistically different, and other investigators have failed to demonstrate prognostic significance to a minor neuroendocrine cell component.^9,12-14 Perhaps the discrepancies in these data relate to the differing criteria for the separation of non–neuroendocrine- versus neuroendocrine-containing carcinomas used by the various investigators.

The suggestion of Grabowski and Scherübl that in either small-cell carcinomas or in adenocarcinomas, the presence of neuroendocrine differentiation is associated with an adverse prognosis is provocative and raises the possibility that neuroendocrine differentiation rather than cellular morphology may drive the tumor's biology. Of course, to fully evaluate this possibility, it would be necessary to perform a multivariate statistical analysis incorporating the histologic diagnosis (small-cell carcinoma, large-cell neuroendocrine carcinoma, adenocarcinoma), grade, stage, treatment, and other factors; such a study has yet to be performed.

One of the most important aspects of the small-cell carcinoma phenotype is the correlation with chemotherapy response. Most colorectal carcinomas judged to be small-cell carcinomas or other high-grade neuroendocrine carcinomas are now treated with a cisplatin or carboplatin plus etoposide or irinotecan regimen, similar to pulmonary small-cell carcinomas, whereas adenocarcinoma is treated with fluorouracil-based regimens, including irinotecan or oxaliplatin. Even if the presence of scattered neuroendocrine cells in conventional adenocarcinomas were proven to be an adverse prognostic factor, it is not at all clear that these patients should be treated with "small-cell carcinoma chemotherapy." In the study showing prognostic significance of neuroendocrine differentiation,¹⁰ only 19 of 116 patients with stages III and IV colorectal carcinoma received chemotherapy, and the specific regimens were not provided, so no assessment could be made of the potential impact of focal neuroendocrine differentiation in response to various chemotherapeutic regimens.

We believe that in our current state of understanding, small-cell carcinomas remain a pathologically cohesive group with distinctive morphologic and molecular features, both in gastrointestinal tract and elsewhere. Their aggressive biology (despite some initially favorable responses to chemotherapy typically used in small-cell lung carcinoma) has been abundantly documented in the literature. Whether the presence of neuroendocrine differentiation per se represents a defining feature of these tumors remains to be proven, but the clinical management of gastrointestinal small cell carcinomas cannot yet be directed by the results of immunohistochemical staining for neuroendocrine markers. Thus, although we agree with Grabowski and Scherubl that staining for neuroendocrine markers should be performed (at least to increase our experience with these rare tumors), we are not convinced the results are clinically useful.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

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6. Capella C, Solcia E, Sobin LH, et al: Endocrine tumours of the colon and rectum, in Hamilton SR, Aaltonen LA (eds): Pathology and Genetics of Tumours of the Digestive System. Lyon, France, IARC Press, 2000, pp 137-139

7. Grabowski P, Schonfelder 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]

8. Bernick PE, Klimstra DS, Shia J, et al: Neuroendocrine carcinomas of the colon and rectum. Dis Colon Rectum 47:163-169, 2004[CrossRef][Medline]

9. Ferrero S, Buffa R, Pruneri G, et al: The prevalence and clinical significance of chromogranin A and secretogranin II immunoreactivity in colorectal adenocarcinomas. Virchows Arch 426:587-592, 1995[Medline]

10. 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]

11. Hamada Y, Oishi A, Shoji T, et al: Endocrine cells and prognosis in patients with colorectal carcinoma. Cancer 69:2641-2646, 1992[CrossRef][Medline]

12. Lapertosa G, Baracchini P, Delucchi F: Prevalence and prognostic significance of endocrine cells in colorectal adenocarcinomas. Pathologica 86:170-173, 1994[Medline]

13. Mori M, Mimori K, Kamakura T, et al: Chromogranin positive cells in colorectal carcinoma and transitional mucosa. J Clin Pathol 48:754-758, 1995[Abstract/Free Full Text]

14. Smith DM, Haggitt RC: The prevalence and prognostic significance of argyrophil cells in colorectal carcinomas. Am J Surg Pathol 8:123-128, 1984[Medline]

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