Immunohistochemical study of characteristics of bile duct dysplasia evaluated on the basis of expression of metastasis/invasion‐related factors and p53

Background/Purpose Bile duct carcinoma still continues to have an unfavorable prognosis, despite an improved rate of curative resection and the development of surgical techniques. We evaluated the expression of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and intercellular adhesive factors (E‐cadherin, α‐catenin, β‐catenin) in cancer, dysplastic lesions, and normal (nonatypical) epithelia (glandulous ducts) in patients with bile duct carcinoma. Positivity rates for these factors were compared among the three histological types to examine the characteristics of bile duct dysplasia. Methods Among 89 patients with bile duct carcinoma resected at our hospital during the past 10 years, we studied 18 patients who concurrently had a cancerous lesion, dysplastic lesion, and normal (nonatypical) epithelia adjoining each other in excised specimens. The immunohistochemical expressions of MMPs, TIMPs, E‐cadherin, α‐catenin, and β‐catenin were investigated. Results Positivity rates for MMP‐9, TIMP‐1, TIMP‐2, membrane type (MT) 1‐MMP, MT2‐MMP, and E‐cadherin were significantly higher in cancerous than in normal epithelium. Only the positivity rate for MT1‐MMP was significantly higher in dysplasia than in normal epithelium. Positivity for MMP‐related factors correlated with the degree of atypia of the bile duct epithelium. Differences between cancer and dysplasia were slightly greater than those between dysplasia and normal epithelium. Likelihood ratios between cancer and dysplasia, cancer and normal epithelium, and dysplasia and normal epithelium were higher than 5 for all metastasis‐related factors and higher than 10 for most factors. This finding suggests that a normal‐dysplasia‐carcinoma sequence underlies the development of bile duct cancer accompanied by dysplasia. Conclusions The phenotypic characteristics of dysplasia are closer to those of normal epithelium than to those of cancerous epithelium. A normal‐dysplasia‐carcinoma sequence is apparently involved in the development of bile duct cancer accompanied by dysplastic cells.