Expression of p21 protein may be a better prognostic factor than p53 protein expression in patients with advanced gastric carcinoma.

We have examined the occurrence of apoptotic cell death in formalin‐fixed, paraffin‐embedded human gastric carcinoma specimens by the terminal deoxynucleotidyl transferase (TdT)‐mediated dUTP‐biotin nick end labeling (TUNEL) method. The specificity of the TUNEL signals was confirmed by the omission of either TdT or biotinylated dUTP as negative controls, and by pretreatment with DNase I as a positive control. Careful observation of routine hematoxylin and eosin‐stained sections showed a few tumor cells with apoptosis, especially in well‐differentiated carcinomas. Intense TUNEL signals were frequently observed even in ordinary, non‐pyknotic nuclei of tumor cells, and occasionally also in nuclear fragments corresponding to apoptotic bodies. Apoptotic indices (number of apoptotic cells/total number of tumor cells) ranged between 7.7 and 14.5% (mean, 10.9%) in nine well‐differentiated carcinomas and between 2.7 and 7.5% (mean, 4.0%) in five which were poorly differentiated, the mean number being significantly higher in the former (P<0.01). No apparent correlation was found between apoptosis and the expression of proliferating cell nuclear antigen, P53 or Ley in the present study. This high frequency of apoptosis, implying cell loss, may be related to the slow‐growing nature of well‐differentiated carcinomas. Poorly differentiated carcinomas, including scirrhous gastric carcinomas, showed a lower incidence of apoptosis, indicating the existence of an escape mechanism from the process.

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We examined the existence and distribution of apoptotic cells in human gastric mucosa, chronic gastritis, adenomatous dysplasias and carcinomas in 15 surgically removed stomachs in which dysplasia and carcinoma were found simultaneously. Serial sections were cut for immunohistochemistry for p53 oncoprotein and Ki-67 antigen, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labelling (TUNEL). TUNEL signal-positive apoptotic cells were rare in normal mucosa, while a few apoptotic cells were noted in gastritic mucosa and intestinal metaplasia, intermingled with Ki-67 antigen-positive cells forming a generative cell zone. This suggests the cell-cycle-dependent apoptosis of gastric mucosa. The frequency of apoptotic cells per crypt was higher in incomplete than in complete metaplasia, implying greater underlying DNA damage in the former. TUNEL indices (TI: percentage of TUNEL-positive cells in tumour cells) were slightly higher in adenomatous dysplasias (4.9 +/- 2.1) than in carcinoma (3.9 +/- 1.1), but there was no no statistical difference. Ki-67 indices (KI: percentage of Ki-67 antigen-positive cells in tumour cells) were significantly (P < 0.05) higher in carcinomas than in dysplasias. Thus, gastric adenomatous dysplasias were characterized by relatively higher TI and lower KI, which might reflect a more static growth potential. The expression of p53 oncoprotein in cancer cells is thought to be an apoptosis-suppressing event, although its precise role remains to be elucidated. Overall, these results indicate that apoptosis plays a crucial part in the morphogenesis of gastritic mucosa including intestinal metaplasia, and that the process is correlated both with tumourigenesis and with proliferative activity.