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Signet Ring Cells in Gastric Carcinomas Are Derived from Neuroendocrine Cells

Karin Bakkelund, Reidar Fossmark, Ivar Nordrum and Helge Waldum

Department of Cancer Research and Molecular Medicine (KB,RF,HW) and Department of Laboratory Medicine, Children's and Women's Health (IN), Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway, and Department of Medicine (RF,HW) and Department of Pathology and Medical Genetics (IN), St. Olavs Hospital, Trondheim, Norway

Correspondence to: Karin Bakkelund, Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), N-7006, Trondheim, Norway. E-mail: karin.bakkelund{at}ntnu.no

Adenocarcinomas are malignant tumors with glandular growth and/or supposed intracellular mucin as identified by periodic acid-Schiff (PAS) positivity. Gastric signet ring cell carcinomas are classified as diffuse type. A proportion of diffuse-type adenocarcinomas have previously been suggested to be of neuroendocrine origin. In the present study we examined gastric signet ring cell carcinomas for neuroendocrine differentiation. Of 11 gastric signet ring cell carcinomas, 8 contained areas with PAS-positive signet ring cells that also were immunoreactive for one or several neuroendocrine markers: synaptophysin, chromogranin A, and histidine decarboxylase, the latter an enterochromaffin-like (ECL) cell marker. Whereas PAS positivity was located in the central cytoplasm, neuroendocrine immunoreactivity was often located as a rim surrounding an otherwise non-immunoreactive cytoplasm, presumed to represent the area with PAS-positive material. These findings indicate that signet ring cell carcinomas could be of neuroendocrine origin. We propose that signet ring cell carcinomas develop by gradual dedifferentiation from ECL cells via signet ring cells with neuroendocrine immunoreactivity toward signet ring cells where the cytoplasm mainly consists of PAS-positive material. This finding could have implications for the classification and understanding of gastric carcinogenesis. (J Histochem Cytochem 54:615–621, 2006)

Key Words: signet ring cells • neuroendocrine differentiation • chromogranin A • synaptophysin • histidine decarboxylase • 5-hydroxytryptamine • somatostatin

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