Differences in Cell Proliferation and Prognostic Significance of Proliferating Cell Nuclear Antigen and Ki-67 Antigen Immunoreactivity in in Situ and Invasive Carcinomas of the Extrahepatic Biliary Tract

Background: Cell proliferative activity is an important indicator of growth and behavior of various human tumors. Immunostaining of tissue sections with proliferating cell nuclear antigen (PCNA) and Ki-67 antibodies appears to be reliable in the assessment of tumor cell proliferation. This study examined differences in cell kinetics between neoplastic and nonneoplastic lesions of the gallbladder and biliary tract using an antibody against PCNA and Ki-67.

Methods: There were a total of 27 cancer cases comprising patients with invasive carcinoma of the gallbladder (n = 13), common bile duct (n = 5) and ampulla of Vater (n = 8). Cases of chronic cholecystitis (n = 11) from the nonneoplastic group; carcinoma in situ (CIS) of the gallbladder (n = 4) and ampulla (n = 6) from the noninvasive group. Cell cycle activity was determined in sections of routinely formalin fixed, paraffin processed, biopsy material using immunohistochemical stains for the monoclonal PCNA, PC10, KI-67, and MIB-1. The expression of PCNA and MIB-1 in these conditions was determined by calculating the percentage of cell nuclei that stained positively to obtain the PCNA and MIB-1 indices, respectively.

Results: The PCNA and MIB-1 indices in chronic cholecystitis were significantly lower than those obtained in both moderately and poorly differentiated adenocarcinoma of the gallbladder (P < 0.001). Similarly, cases of ampullary and gallbladder CIS had significantly lower PCNA and MIB-1 indices than the invasive carcinoma cases (P < 0.001). There was a strong correlation between PCNA and MIB-1 expression (r = 0.828, r2 = 0.686; P = 0.001), although the PCNA index was generally higher than that of MIB-1. The poorly differentiated adenocarcinomas of the gallbladder had higher mean PCNA and MIB-1 indices but reduced patient survival when compared with the moderately differentiated carcinomas.

Conclusions: In conclusion, gallbladder, ampulla, and common bile duct carcinomas have significantly higher PCNA and MIB-1 indices than CIS and nonneoplastic lesions. Because tumors with higher PCNA or MIB-1 indices are associated with a poorer prognosis, both PCNA and MIB-1 may be useful markers of tumor cell proliferative activity and biologic behavior in gallbladder, ampullary, and common bile duct carcinomas.