Lewis system alterations in gastric carcinogenesis. Alterations in the expression of type 1 blood group-related antigens (Lewis a and b) were examined immunohistochemically in 371 consecutives gastric biopsy and 80 surgical specimens from patients of gastric carcinoma. The ABH and Lewis phenotype and secretor status of the patients were correlated with histologic findings. An anomalous expression of Lewis a antigen was found in 88 of 249 gastric biopsy specimens of Lewis (a-b+) phenotype patients. The prevalence of this anomaly increased with the evolution of the premalignant process, in agreement with the commonly accepted model of gastric carcinogenesis. Thus, anomalous Lewis a antigen appeared in 66.6% of gastric dysplasia cases, in 64.6% of intestinal metaplasia, in 15.4% of atrophic gastritis, and in 7.4% of superficial gastritis. No alterations were found in subjects with normal gastric mucosa. Forty-seven of the 49 Lewis (a-b+) phenotype gastric carcinoma patients showed antigenic alterations in tumor cells (anomalous Lewis a antigen in 36 and loss of Lewis antigens in 11). In 26 of these gastric specimens an anomalous Lewis a antigen was present in areas of intestinal metaplasia and/or dysplasia away from the area of neoplastic transformation. The expression of Lewis a antigen in Lewis (a-b+) phenotype patients is a frequent phenomenon in gastric neoplastic cells and could result from the blocked synthesis of Lewis b antigen with accumulation of its precursors. These findings suggest that, during gastric carcinogenesis, antigenic alterations may precede neoplastic transformation. An anomalous Lewis a antigen could constitute a significant index of severity of the histologic lesion and contribute to identifying high-risk individuals. 