Histopathology, morphometry, tritiated thymidine incorporation and immunohistochemistry were studied in 221 esophageal biopsies from subjects with cytologica hyperplasia in Linxian, China. A spectrum of 7 morphologic entities were found: (1) normal/near normal (NN); (2) basal cell hyperplasia 0 (BHO); (3) simple hyperplasia (SH); (4) mixed basal and spinous cell hyperplasia (MBS); (5) basal cell hyperplasia 1 (BH1); (6) dysplasia (D); and (7) non-proliferative lesion (NP). Forty percent of the biopsies had combinations of histologic types. The thickness of the epithelium was increased in SH, MBS, and BH1, but not in BHO and NP. Elongation of papillae was frequently seen in SH, MBS, BH1, and D. Papillary bleeding was very prevalent in the esophageal specimens studied. A variety of cellular changes were found in peripapillary areas especially when bleeding occurred. [3H]-thymidine labeling index was dramatically increased in the entire epithelium in dysplasia, and also increased in cell layer 3 of MBS, BH1 and D. Blood group antigen LeY and lectin WGA showed consistent positivity in cellular membranes of the squamous cells, and these changes occurred before gross morphologic alterations. These findings provide a hypothesis for the sequence of pathogenetic events leading to esophageal carcinoma, and define each step with corresponding biomarkers for cancer prevention studies.