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Ann Thorac Surg 1996;62:809-810
© 1996 The Society of Thoracic Surgeons
DR WILLIAM H. WARREN (Chicago, IL): I want to congratulate Dr Rusch on a very fine presentation and for providing me with a copy of the manuscript in advance for discussion.
This is a very ambitious project that attempts to bridge the disciplines of molecular biology and thoracic surgery. A great deal has been accomplished in basic biology over the past 10 years and attempts to explore its clinical relevance is timely and can only advance our understanding of tumor biology.
I wish to underscore several important points made by Dr Rusch and colleagues. First is the acknowledgment of the entity of large cell carcinomas with predominantly neuroendocrine differentiation, as we had recognized in our original classification of neuroendocrine tumors in 1983. The tumors may go unrecognized were it not for the almost routine use of neuroendocrine markers in our laboratory. Up to 20% of these large cell carcinomas, currently called simply large cell undifferentiated carcinoma, in fact have predominantly neuroendocrine differentiation when studied. The majority of the remaining 80% of these tumors have either exocrine or mixed exocrine/neuroendocrine patterns of differentiation. In our experience, as in the experience of Rusch and colleagues, large cell neuroendocrine carcinomas are extremely aggressive tumors that may respond to chemotherapy currently used for small cell neuroendocrine carcinoma. It remains to be seen if these tumors, stage for stage, are more aggressive than their exocrine counterparts. My first question is, were these large cell tumors studied to confirm that they were in fact neuroendocrine and distinguish them from the other population? In any study on neuroendocrine differentiation (especially those dealing with poorly differentiated neuroendocrine carcinomas), these tumors must be confirmed as neuroendocrine in nature either by immunohistochemistry or by electron microscopy.
The identification of aggressive neuroendocrine tumors behaving like small cell neuroendocrine carcinoma but currently included among tumors called non-small cell lung cancer is relevant, and I propose that we adopt the more useful and more accurate classification of neuroendocrine versus nonneuroendocrine tumors rather than small cell versus non-small cell lung cancer.
The molecular markers used in this study were chosen presumably because at some time they were reported to be markers of proliferative activity. I submit, however, that these profiles simply confirm what pathologists already know, namely that carcinoids are indolent tumors and that the more aggressive tumors can be identified by mitotic rate, vascular invasion, and presence of necrosis. A much more useful study, from a clinical point of view, would be to study the pattern of light microscopy of these tumors if they are similar by hematoxylin and eosin staining to large cell carcinomas of a similar stage and treating them in a similar fashion and assess the prognostic significance of these molecular markers. Have you looked at any nonneuroendocrine lung cancers and compared their profile with respect to these markers with those of these neuroendocrine carcinomas?
DR RUSCH: Thank you, Dr Warren, for your incisive comments. The tumors selected for this study were already clearly identified by light microscopy as neuroendocrine tumors or tumors with neuroendocrine features. Some form of neuroendocrine immunohistochemical staining was usually done to confirm the light microscopic findings. However, as we have both discussed standard neuroendocrine stains (chromogranin, synaptophysin, and neuron-specific enolase) do not uniformly distinguish among these groups of tumors.
We did not do a complete retrospective review of all primary lung tumors, because the number of tumors available for review during this 10-year period at Memorial Hospital would have been prohibitively large. Moreover, the Lung Cancer Study Group found that tumors diagnosed as ordinary non-small cell lung cancers by light microscopy but found incidentally to have positive neuroendocrine immunohistochemical staining do not have a different prognosis. Therefore, it seems important to distinguish between these tumors and tumors that are neuroendocrine by light microscopy.
The choice of molecular "markers" used in this study was very specific. The expression of the retinoblastoma gene is abnormal in almost all small cell lung cancers and in about a third of non-small cell lung cancers. The pattern of expression of p53 and the EGF receptor is different in small cell compared with non-small cell lung cancer. P53 mutation or overexpression occurs in approximately half of non-small cell lung cancers and far less frequently in small cell lung cancers. EGF receptor overexpression is seen in about half non-small cell lung cancers and rarely in small cell lung cancers. In contrast to standard neuroendocrine immunohistochemical stains, staining for Rb, p53, and EGF receptor does not just identify that a tumor has neuroendocrine features. It reflects the molecular genesis of these tumors.
Related Article
Ann. Thorac. Surg. 1996 62: 798-809.
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