The histochemical pattern of gamma-glutamyltransferase (GGT) was studied in benign and malignant tumors produced by two different experimental protocols, two-stage carcinogenesis and complete carcinogenesis. Six percent of all papillomas produced by two-stage carcinogenesis were GGT positive, whereas 14% of benign tumors produced by complete carcinogenesis exhibited GGT-positive areas. The incidence of GGT-positive papillomas in the two-step carcinogenesis protocol increased up to wk 28 of treatment. After 32 wk, the incidence decreased abruptly, coinciding with an abrupt increase in the incidence of squamous cell carcinomas. On the other hand, the incidence of GGT-positive benign tumors produced during the course of complete carcinogenesis increased gradually up to wk 32 of treatment, coinciding with the increased incidence of squamous cell carcinomas. The incidence of GGT-positive keratoacanthomas and GGT-positive papillomas produced with the complete carcinogenesis protocol exhibited different patterns, suggesting different histogenesis and biological behavior of these two types of tumors. In addition, the labeling index of GGT-positive areas was lower (17 +/- 3%) than that of the GGT-negative areas (41 +/- 0.18%) of the same papillomas, indicating that the presence of GGT may be related to abnormal keratocyte differentiation rather than to proliferative changes.