The pathology of IgG4-related disease: critical issues and challenges

IgG4-related disease (IgG4-RD) is a chronic and relapsing disease. The diagnosis of IgG4-RD is based on a combination of features that include clinical, imaging, serologic, histology, and immunohistochemistry. Nonetheless, histopathology has emerged as the gold standard for the diagnosis of IgG4-RD. Guidelines for the pathologic diagnosis of this condition have been published by an international group of experts: a triumvirate of histologic features allows for a confident diagnosis of IgG4-RD to be made in most cases: (1) a dense lymphoplasmacytic infiltrate, (2) storiform-type fibrosis, and (3) obliterative phlebitis. Elevated numbers of IgG4-positive plasma cells are essential for the diagnosis, but this feature is not sufficient in, and of, itself. IgG4-positive plasma cells are also seen in a variety of inflammatory and neoplastic diseases. An elevated IgG4 to IgG ratio, more than 40%, improves the specificity of this stain. A wide range of inflammatory and neoplastic diseases including antineutrophil cytoplasmic antibody (ANCA)-related vasculitis, chronic infections, mesenchymal neoplasms, carcinoma, and lymphoma should be excluded before arriving at a diagnosis of IgG4-RD. This review aims to provide the histopathologist with a set of practical guidelines for the diagnosis of IgG4-RD, and also addresses the many controversies associated with the diagnostic aspects of this disease.