TEACHING CASE 1

Relevant clinical history:
The specimen is a gastric biopsy from a 48 year old male with an apparent mass in the greater curvature of the stomach.

H&E-stained sections reveal the presence of carcinoid-like nests in the lamina propria, adjacent to glandular elements that show intestinal type metaplastic changes. However, an argyrophil stain was performed and reported to be negative on the cells of interest. The nature of the cell nests in the lamina propria is uncertain and needs to be determined. Could these represent gastric carcinoma?

Results of immunohistochemistry studies:

Cytokeratin:	The cell nests in the lamina propria are identified as epithelial in nature, as they show strong, uniform expression of cytokeratins, as identified with the AE1/AE3 monoclonal antibody cocktail, which identifies a broad range of cytokeratins. A non-neoplastic 'intestinalized' gland is shown at the top of the image, and the tumor at the bottom.
Cytokeratin 20:	The tumor cells are further demonstrated to lack expression of either cytokeratin 7 or cytokeratin 20. In this image, the positive immunostaining of the intestinalized gland with antibodies to cytokeratin 20 contrasts with the absence of immunostaining of the directly adjacent tumor. The absence of cytokeratin 7 and 20 is characteristic of a subset of epithelial tumors, including renal cell carcinoma, prostate carcinoma, hepatocellular carcinoma, and most neuroendocrine carcinomas.
Synaptophysin:	The diagnosis of a neuroendocrine carcinoma is confirmed by demonstrating uniform, strong expression of the protein, synaptophysin by all the tumor cells. Note complete absence of immunostaining of the non-neoplastic intestinalized glands embedded in the tumor. Chromogranin A was also uniformly expressed by these tumor cells.
Ki-67 antigen:	The diagnosis of well differentiated neuroendocrine carcinoma is confirmed by also demonstrating that this neuroendocrine carcinoma has a very low Ki67-defined cell proliferation rate. Note the dearth of positive tumor cell nuclei, compared with the relatively high Ki67-defined cell proliferation rate, as expected, in the intestinalized gland, probably corresponding to a crypt region. Thus, these cells mark as low grade neuroendocrine carcinoma, most consistent with carcinoid tumor in this clinicopathologic setting. The explanation of the reported negative argyrophil stains is uncertain, but the immunostains performed here may be more sensitive in identifying neuroendocrine differentiation.