Immunohistochemical Evaluation of Precursor Lesions of Gallbladder Carcinoma in Cholecystectomy Specimens with Stones

Abstract

Objective: Gallbladder carcinoma is an aggressive malignancy with poor prognosis, particularly in high-incidence regions. This study evaluated the immunohistochemical expression of p16, p53, COX-2, and HER2/neu in precursor epithelial lesions of the gallbladder and assessed their potential role in gallbladder carcinogenesis.

Materials and Methods: A total of 1500 cholecystectomy specimens with gallstones were reviewed over two years. Histopathological examination identified epithelial precursor lesions, including hyperplasia, metaplasia, and dysplasia. Thirty cases each of hyperplasia, metaplasia, and dysplasia were subjected to immunohistochemical analysis for p16, p53, COX-2, and HER2/neu. Immunoreactivity was assessed using staining intensity, percentage positivity, and H-score. HER2/neu expression was evaluated using a modified breast cancer scoring system. Statistical significance was set at p < 0.05.

Results: Precursor epithelial lesions were identified in 287/1500 (19%) cases, comprising hyperplasia (8%), metaplasia (9%), and dysplasia (2%). p16 expression was significantly higher in dysplasia (96%) compared with hyperplasia (10%) and metaplasia (13%) (p < 0.001). p53 expression was observed only in dysplasia (16%) (p < 0.05). COX-2 expression was detected in all dysplasia cases and in 23% of metaplasia and 16.6% of hyperplasia cases (p < 0.001). HER2/neu positivity was seen in 27% of dysplasia, 13% of metaplasia, and 6.6% of hyperplasia cases, suggesting an early molecular alteration in gallbladder carcinogenesis.

Conclusion: The findings support a stepwise progression from metaplasia to dysplasia in gallbladder carcinogenesis. Careful histopathological and immunohistochemical evaluation of cholecystectomy specimens may aid in identifying high-risk precursor lesions. Our findings suggest a sequential molecular model in which HER2/neu alteration occurs early, p16 dysregulation marks establishment of dysplasia, and p53 accumulation indicates progression. This panel-based approach provides better insight into gallbladder carcinogenesis than individual markers.