Pathologic significance of immunoglobulin G4-positive plasma cells in extrahepatic cholangiocarcinoma.

Immunoglobulin G4-related sclerosing cholangitis is histologically characterized by the infiltration of immunoglobulin G4-positive plasma cells and sclerosing change. Moreover, several cases of carcinoma accompanied by immunoglobulin G4-positive cells in tissue and increased serum immunoglobulin G4 levels have been reported, but the association between cancer-associated immunity and an immunoglobulin G4 reaction is still unclear. In this study, we examined the infiltration of immunoglobulin G4-positive cells in extrahepatic cholangiocarcinoma and the pathologic significance of the immunoglobulin G4 reaction found in cancer tissues in terms of the evasion of immune surveillance by regulatory T cells. Immunohistochemistry for immunoglobulin G4, forkhead box P3, CD4, and CD8 was performed using 68 surgical specimens from patients with extrahepatic cholangiocarcinoma, and positive cells were investigated, particularly within and around cancerous tissues. Consequently, although immunoglobulin G4+ cells were few (average, <10 cells/high-power field) in most cases, 10 or more and 50 or more cells were found in 37% and 6% of cases, respectively. Immunoglobulin G4+ cells were predominantly found in the invasive front of carcinoma tissue. In the cases with 10 or more immunoglobulin G4+ cells, forkhead box P3+ regulatory T cells were also distinguishable, and a positive correlation was found between the forkhead box P3+/CD4+ ratio and immunoglobulin G4+ cell count, but few CD8+ cells invaded cancer cells (<10 cells). In conclusion, extrahepatic cholangiocarcinomas are often accompanied by the significant infiltration of immunoglobulin G4+ cells, and the immunoglobulin G4 reaction showed a positive and negative correlation with forkhead box P3+ and CD8+ cells, respectively, suggesting the evasion of immune surveillance associated with CD8+ cytotoxic T cells via the regulatory function of forkhead box P3+ regulatory T cells.