A Case of Gastric Amphicrine Signet-Ring Cell Carcinoma

Feyrter ¹ first proposed the concept of the “endocrine epithelial system” to indicate the coexistence of endocrine and exocrine secretory products in single cells. Later, Ratzenhoffer and Leb ² advocated the use of the word “amphicrine” (Gk: amphi- means “both” or “double”) to refer to cells that synchronously exhibit the endocrine and exocrine phenotypes. Investigators have reported the amphicrine phenotype in physiological and pathological cells, including those present in tumors of the gastrointestinal tract. However, few reports have described amphicrine differentiation in gastric cancer.^3-5 Therefore, the pathobiological and clinicopathological features of amphicrine gastric cancer remain unclear. Here, we report a case of amphicrine gastric cancer.

A woman in her sixth decade of life underwent follow-up for 10 years after surgical treatment for breast cancer. She had no signs of Helicobacter pylori on a urea breath test or history of intake of any proton pump inhibitors. She presented with anemia and had undergone upper endoscopy.

She appeared to have a gastric tumor in the corpus. Tissue specimen biopsy revealed a poorly cohesive carcinoma that sparsely coexisted with signet-ring cell carcinoma cells. Subsequently, the patient underwent total gastrectomy with lymph node dissection. The resected tumor measured 5.0 cm × 4.0 cm in size (Figure 1). The tumor had extended to the surface of the serosa with regional lymph node metastasis. The patient was accordingly diagnosed with T_4aN₂M₀, Stage-IIIA (8th edition of tumor–node–metastasis staging by the American Joint Committee on Cancer/Union for International Cancer Control) gastric cancer.

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Figure 1.

Because the present tumor was located in the greater curve of the corpus, the resected stomach was opened along the lesser curvature of the stomach. The tumor was found in the corpus within the square range highlighted by the blue line (A). Histopathological examination revealed that a carcinoid-like tumor cell nest was located in the center of the tumor, within the red circle, while signet-ring cell carcinoma cells were distributed in the whole area of the tumor, within the black circle (B).

In surgically resected tissue specimens, a poorly cohesive carcinoma harboring 2 distinct phenotypes of signet-ring cell carcinoma cells were detected—cells with eosinophilic and somewhat granular cytoplasm (Figure 2A) or pale cytoplasm (Figure 2B). We also observed a carcinoid-like tumor cell nest around the signet-ring cells (Figure 2C).

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Figure 2.

Poorly cohesive carcinoma harboring 2 distinct phenotypes of signet-ring cell carcinoma cells—cells with eosinophilic and somewhat granular cytoplasm (A and B). Note the signet-ring cell carcinoma with eosinophilic granules indicated by black arrow. We also observed a carcinoid-like tumor cell nest (black arrowheads) around the signet-ring cells (C). Note the synaptophysin immunoreactivity in the carcinoid-like nested tumor cells (black arrowheads) and also in the signet-ring cell carcinoma cells (D). We confirmed the coexistence of synaptophysin immunoreactivity and Alcian blue (pH 2.5) staining in individual signet-ring cell carcinoma cells, which harbored eosin-stained abundant granular cytoplasm in a mirror image tissue section (E). Both chromogranin and CD56 immunoreactivity were found in cancer cells (F and G, respectively). Interestingly, the CD44v9 immunoreactivity was found in the present gastric cancer cells (H). Scale bar: 100 µm. White arrow indicates the same tubular structure to facilitate quick understanding of tissue location.

Subsequently, we performed immunohistochemical staining using a specific antibody against synaptophysin, an integrated part of the neuroendocrine secretory granule membrane, which is broadly used as a protein marker for neuroendocrine cells. ⁶ Immunohistochemical staining was performed as previously reported. ⁷ Notably, both carcinoid-like nested tumor cells and signet-ring cell carcinoma cells were stained by anti-synaptophysin antibody (Figure 2D). As expected, signet-ring cell carcinoma cells exhibited periodic acid–Schiff and/or Alcian blue (AB) (pH 2.5) positivity. We confirmed the coexistence of synaptophysin immunoreactivity and AB staining in individual signet-ring cell carcinoma cells, which harbored eosin-stained abundant granular cytoplasm (Figure 2E). In addition, we also found chromogranin and CD56 immunoreactivity in the present cancer cells (Figure 2F and G). These findings indicated that the poorly cohesive carcinoma contained amphicrine signet-ring cell carcinoma cells with eosinophilic cytoplasm.

CD44 variant 9 (CD44v9) marks a population of cancer stem cells, which are able to form tumors as well as regenerate the original tumor heterogeneity. ⁸ Subsequently, immunohistochemical staining was performed using specific antibody to CD44v9 (Cat No. CAC-LKG-M001, Cosmo Bio, Tokyo, Japan). Interestingly, we found CD44v9 immunoreactivity in signet-ring cell carcinoma cells (Figure 2H). The presence of CD44v9-expressing cells might suggest that the present amphicrine cell would have a phenotype of progenitor cell. To our knowledge, this is also the first report of amphicrine signet-ring cell carcinoma with eosinophilic cytoplasm.