Several specific staining techniques have been developed for identifying neuroendocrine cells. The traditional ones are the argentaffin and argyrophil reactions. The argentaffin reaction as described by Masson characterizes endocrine cells that can take up and reduce silver ions.9 Argentaffin-positive staining is typically found in midgut carcinoid tumors and generally is assumed to be associated with the presence of serotonin. For example, argyrophilic reaction with the Grimelius technique is preferentially found in foregut and appendiceal neuroendocrine tumors. An argentaffin reaction is very specific for neuroendocrine cells, whereas an argyrophilic reaction is much more sensitive.

Immunohistochemical techniques have greatly facilitated the characterization of neuroendocrine tissues by using monoclonal or polyclonal antibodies against neuron-specific enolase, chromogranin A, and synaptophysin.31 These markers are important for the differential diagnosis and can also be elevated in the serum and thus used as tumor markers for follow-up. Diagnosis of well-differentiated neuroendocrine tumors is usually easy because of their characteristic uniform cell pattern with round nuclei and eosinophilic cytoplasm on hematoxylin and eosin staining.13 Discrimination of atypical carcinoids and poorly differentiated or small cell neuroendocrine tumors may be difficult because they look like metastatic tumors from the lungs or other sites. The same applies for neuroendocrine carcinomas of the colon, which may resemble poorly differentiated colon cancers or lymphomas.

Typical neuroendocrine tumors have a yellow-grayish color and can demonstrate various morphologic patterns, such as insular growth with solid nests; trabecular growth; glandular growth with alveolar, acinar, or pseudoglandular pattern; and a mixed or undifferentiated growth.32 Although these different patterns can be seen in neuroendocrine tumors from all sites, foregut and hindgut tumors show preferentially a trabecular pattern and midgut carcinoids show an insular pattern. Foregut neuroendocrine tumors almost always stain positively for thyroid transcription factor 1 (TTF-1), whereas gastrointestinal carcinoids do not. Staining for TTF-1 can, therefore, help identify the site of origin when it is not known. The various growth patterns do not affect the prognosis, which is determined more by tumor location (Fig. 86-2).

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