FDG-PET scan of the patient with type 1 AIP. FDG accumulates in the pancreas body to tail, gall bladder, right parotid gland, and median and inguinal lymph nodes before steroid therapy (a). After steroid therapy, pancreatic enlargement and FDG accumulation are improved. Accumulation of the gall bladder, right parotid gland, and inguinal lymph nodes is disappeared. Accumulation of median lymph nodes is also decreased (b). FDG-PET scan is useful to detect extra pancreatic lesions and evaluate steroid therapy
Histopathological Features of IgG4-Related Lymphadenopathy
In general, IgG4-RD (including type 1 AIP) appears to have three major histopathological features, including (1) dense lymphoplasmacytic infiltrate, (2) storiform fibrosis, and (3) obliterative phlebitis . In 2011, an international symposium on IgG4-RD was held in Boston . Consensus statement on the pathology of IgG4-related disease was proposed in 2012. This statement proposed a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance and importance of tissue IgG4 counts and IgG4/IgG ratios. This statement also descried that the isolated presence of IgG4-positive plasma cells or an elevated IgG4/IgG ratio constitutes relatively nonspecific findings.
Several studies of these morphological and immunohistological findings of IgG4-related lymphadenopathy have been performed [31, 32, 35–38]. Furthermore, the histopathological features of IgG4-related lymphadenopathy differ from those of extranodal sites in that there is usually no sclerosis or phlebitis. Lymph node showed no unique features of inflammation. Fibrosis is only seen in inflammatory pseudotumor-like lesions. Five histological patterns are recognized: type I, multicentric Castleman disease-like; type II, follicular hyperplasia; type III, interfollicular expansion; type IV, progressive transformation of germinal center; and type V, nodal inflammatory pseudotumor-like [31, 32, 36–38]. IgG4-positive cells are located in both the germinal centers and interfollicular zone. In case of type IV pattern, IgG4-positive cells infiltrate predominantly within the germinal centers .
Type I: Multicentric Castleman Disease-Like
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 %) . 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 . 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 .
Type II: Follicular Hyperplasia
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].
IgG4-related lymphadenopathy (type II: follicular hyperplasia). This lymph node is surgical specimen from regional lymph nodes of IgG4-related sialadenitis. FDG-PET scan of this patient is presented in Fig. 20.1. (a) The lymph node shows reactive follicular hyperplasia. Immunostaining shows numerous IgG4-positive cells (b) and IgG-positive cells (c) in the interfollicular zone and germinal centers. The IgG4/IgG ratio in this case is over 40 %
Type III: Interfollicular Expansion
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].
IgG4-related lymphadenopathy (type III: interfollicular expansion). Systemic lymphadenopathy appears synchronously with type1 AIP in this patient. These figures show surgical specimen of cervical lymph nodes. The lymph node shows interfollicular expansion. (a) Immunohistochemical staining shows that CD20 (b) and 79a (c) positive cells exist in lymphoid follicle. CD3 T cells exists in the interfollicular zone (d). Large numbers of IgG4-positive cells appeared mainly in the interfollicular zone (e, f)
Type IV: Progressive Transformation of Germinal Centers
Type V: Inflammatory Pseudotumor-Like
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].
AIP is a new clinical entity of pancreatic disorder. Type 1 AIP is recognized as one of pancreatic manifestations of IgG4-RD. Lymphadenopathy accompanied with type 1 AIP is well known, but that with type 2 is unclear. Further studies are needed to clarify the pathogenesis of lymphadenopathy, including the role of IgG4.