Type I is frequently characterized by systemic lymphadenopathy. The architecture of the lymph node is preserved, and the lymph node shows varying degrees of interfollicular expansion with normal to hyperplastic germinal centers and penetration by hyalinized blood vessels. The interfollicular zone shows increased high endothelial venules, abundant plasma cells, and scattered eosinophils. These features are similar to those of multicentric Castleman disease, especially in the presence of multifocal lymphadenopathy, hypergammaglobulinemia, and elevated serum IgG4 levels [31, 32, 35–40]. Usually, multicentric Castleman disease shows small and regressive germinal centers without eosinophil infiltration. Multicentric Castleman disease sometimes fulfills the diagnostic criteria for IgG4-RD and abundant IgG4-positive plasma cell infiltration (especially an IgG4/IgG-positive plasma cell ratio >40 %) [40]. Therefore, a pathological diagnosis is difficult to make using histological findings alone. The morphological features are also similar to those of autoimmune disease-associated lymphadenopathy as seen in rheumatoid arthritis [41, 42] and the so-called idiopathic plasmacytic lymphadenopathy with polyclonal hypergammaglobulinemia [43]. Sato et al. proposed the concept of hyper IL-6 syndrome such as multicentric Castleman disease, rheumatoid arthritis, and other immune-associated conditions. In hyper-IL-6 syndromes, abnormalities of laboratory data showed elevated serum levels of IgG, IgA, and IgM; C-reactive protein (CRP); thrombocytosis; anemia; hypoalbuminemia; and hypocholesterolemia. In contrast, IgG4-RD does not show these abnormalities. They conclude that laboratory data is crucial to differentiate between IgG4-related disease and hyper IL-6 syndrome [37].

Type II is frequently showed in the regional lymph nodes of IgG4-RD. The histopathological findings of the lymph nodes usually show reactive follicular hyperplasia. The reactive follicles consist of a germinal center surrounded by a discrete mantle zone. The interfollicular zone may or may not show plasmacytosis, with eosinophils (Fig. 20.2) [31, 32, 35–38].

Type III is also characterized by systemic lymphadenopathy. The lymph nodes show marked interfollicular expansion. Lymphoid follicles often are atrophic. High endothelial venules exist in expanded interfollicular zones where small lymphocytes, immunoblasts, plasmablasts, mature plasma cells, immature plasma cells, and eosinophils infiltrate. Interfollicular expansion-type lymphadenopathy is similar to angioimmunoblastic T-cell lymphoma, but definite cytologic atypia, clusters of clear cells, CD10⁺ T cells, T-cell receptor gene rearrangement, or CD21⁺ follicular dendritic cell proliferation is not observed (Fig. 20.3) [31, 32, 35–38].

Type IV is characterized as a benign reactive follicular hyperplasia of unknown origin. This type usually shows hyperplastic follicles, and lymph nodes show severalfold enlarged follicles and a distinct mantle zone but no expansion of the interfollicular zone [31, 32, 35–38].

Type V is rare and characterized by focal replacement of the hyalinized fibrous tissue. A few residual lymphoid parenchyma shows hyperplastic germinal centers and focally dense lymphoplasmacytic infiltrations. Small lymphocytes, plasma cells, and eosinophils infiltrate the hyalinized fibrous tissue [31, 32, 35–38].