Abstract
Background and Aims: A proportion of diffuse gastric carcinoma according to the Lauren classification system has signet ring cell morphology. Signet ring cells are characterized by a peripherally placed nucleus and a central amorphous substance, which is reported to be mucin based on Periodic Acid Schiff positivity (PAS). PAS is not a specific staining method for mucin, and it stains several substances including various glycoproteins. Neuroendocrine expression has previously been reported in tumour cells in diffuse type gastric cancer. Methods: PAS, PAS-Diastase, Alcian blue and cytokeratin stainings were undertaken. Relevant gastrointestinal mucins (MUC1, 2, 3, 4, 5AC, 6 and MUC13) were assessed by immunohistochemistry and in situ hybridization (ISH) by the use of a new and improved ISH method. The neuroendocrine properties were evaluated by mRNA and protein expression of the general neuroendocrine markers chromogranin A, synaptophysin as well as Regenerating islet-derived family member 4 (Reg-IV). Results: All cases had cytokeratin positive tumor cells that also were PAS and PAS-Diastase and Alcian blue positive. No mucin mRNA or protein expression was observed in signet ring tumor cells including the amorphous substance in any of the nine cases. Focal or diffuse expression of mucin by immunohistochemistry was observed in non-signet ring tumors cells in five out of nine cases. All cases showed immunoreactivity to synaptophysin, and seven out of nine cases immunoreactivity to chromogranin A in signet ring and non-signet ring tumor cells. Chromogranin A and Reg-4 mRNA expression was observed in tumor cells in all samples with retained mRNA. Conclusions: The lack of MUC protein and mRNA in signet ring tumor cells suggests the amorphous substance is not mucin. The in situ hybridization method utilized in this study has several specificity steps and clear advantages over conventional methods. The discrepancy between mucin mRNA and protein expression suggest that the focal or diffuse positivity in non-signet ring tumor cells by immunohistochemistry could be non-specific. The abundant expression of the general neuroendocrine markers CgA and synaptophysin, and CgA as well as Reg-4 mRNA in tumour cells gives support to a neuroendocrine origin. In conclusion, these findings question exocrine expression in these tumours and do not lend support to the view that these tumours are mixed adenoneuroendocrine carcinomas (MANEC).
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