Cyclin D1 overexpression is remarkably frequent in several human carcinomas and is believed to be a critical event in oncogenesis. We examined cyclin D1 expression, p53 expression, and the Ki-67 labeling index by immunostaining in human gallbladder mucosa in conditions varying from normal to malignant tissue. We also examined K-ras codon 12 mutations in these tissues with a two-step polymerase chain reaction. Nuclear cyclin D1 overexpression was observed in 48% of carcinomas occurring independently of adenoma, but not in adenomas, carcinomas arising in adenomas, or nonneoplastic lesions. Cytoplasmic cyclin D1 overexpression was observed in about 15% of abnormal specimens, irrespective of the type of epithelial abnormality. Carcinomas showing nuclear cyclin D1 overexpression had significantly higher Ki-67 labeling indexes than those with no overexpression. Moderately to poorly differentiated adenocarcinomas showed a higher incidence of nuclear cyclin D1 overexpression than papillary to well differentiated carcinomas. Specimens with cyclin D1 overexpression showed a high incidence of lymph permeation, venous permeation, and lymph node metastasis. We conclude that nuclear cyclin D1 overexpression is a critical event importantly associated with cell proliferation and invasive growth in gallbladder carcinogenesis, and that cyclin D1 immunostaining may become a useful marker for evaluating gallbladder carcinomas.

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