Clinicopathological Analysis between IgG4-related and Non-IgG4- related DiseasesOccurring in Various Organs and Tissues: Re- evaluation of ComprehensiveDiagnostic Criteria and Usefulness of Interleukin-6 Immunostaining

Comprehensive diagnostic criteria for IgG4-related diseases are widely accepted. However, clinicopathological features of probable and possible Ig4-related and non-IgG4-related diseases, which are subdivided by comprehensive diagnostic criteria, are not fully understood.IgG4-related disease (IgG4-RD) is a recently identified systemic fibro-sclerotic disease of unknown etiology. It exhibits multiple organ involvement,causes symmetrical or asymmetrical organomegaly,and forms nodular or hypertrophic lesions concurrently or metachronously. IgG4-RD has several typical characteristics such as predominant occurrence in middle-aged men; presence of antinuclear antibodies; high incidence of allergic diseases; eosinophilia; elevation of serum gammaglobulins, IgG, IgG4, and IgE; and good response to steroid therapy. Histologically, IgG4-RD is characterized by lymphoplasmacytic infiltration,lymphoid follicle formation, eosinophil infiltration,IgG4-positive plasma cell infiltration, storiform fibrosis (SF), and obliterative phlebitis (OP)(1,2).Useful diagnostic tool to distinguish between IgG4-related and non-IgG4-related diseases and prediction of therapeutic responsiveness for IgG4-related disease is required. The purpose of this study is to clarify these diagnostic problems. Methods: The clinicopathological features and expression of interleukin-6 and glycoprotein 130 were analyzed in 94 and 34 cases of IgG4-related and non-IgG4-related diseases,respectively. Results: Probable IgG4-related cases showed decreased plasma cell number, increased eosinophils and mast cell numbers, and marked fibrosis. Marked fibrosis and inflammatory cell infiltration were not observed in possible IgG4-related cases. Although most non-IgG4-related cases matched the comprehensive diagnostic criteria, completely or partially, could be easily differentiated based on histological findings, multicentric Castleman’s disease exhibited findings closely similar to those of IgG4-related disease. Immunohistochemical expression of interleukin-6 in IgG4-related disease was significantly lower than that in multicentric Castleman’s disease. Comprehensive diagnostic criteria could be effectively applied to IgG4-related disease occurring in various organs and tissues and was applied to biopsied and surgically resected specimens, although histological information was limited in the biopsied specimen. Relapsed cases after steroid therapy showed a higher incidence of multiple organ involvement and lower incidences of storiform fibrosis and obliterative phlebitis than the non-relapsed cases. Conclusion: Probable IgG4-related disease was considered as the advanced phase of definite IgG4-related disease. Possible IgG4-related disease had to undergo repeat biopsy or surgical excision of other organs. Careful consideration of clinical information and immunostaining for interleukin-6 may be crucial to distinguish between IgG4-related and multicentric Castleman’s diseases. It is useful to assess the fibrosis grade to evaluate the disease progression and the therapeutic responsiveness for IgG4- related disease occurring in various organs and tissues.