IgG4-related sclerosing disease, an emerging entity: a review of a multi-system disease

Abstract

Immunoglobulin G4-related systemic disease (IgG4-RSD) is a recently defined emerging entity characterized by a diffuse or mass forming inflammatory reaction rich in IgG4-positive plasma cells associated with fibrosclerosis and obliterative phlebitis. IgG4-RSD usually affects middle aged and elderly patients, with a male predominance. It is associated with an elevated serum titer of IgG4, which acts as a marker for this recently characterized entity. The prototype is IgG4-related sclerosing pancreatitis or autoimmune pancreatitis (AIP). Other common sites of involvement are the hepatobiliary tract, salivary gland, orbit, and lymph node, however practically any organ can be involved, including upper aerodigestive tract, lung, aorta, mediastinum, retroperitoneum, soft tissue, skin, central nervous system, breast, kidney, and prostate. Fever or constitutional symptoms usually do not comprise part of the clinical picture. Laboratory findings detected include raised serum globulin, IgG and IgG4. An association with autoantibody detection (such as antinuclear antibodies and rheumatoid factor) is seen in some cases. Steroid therapy comprises the mainstay of treatment. Disease progression with involvement of multiple organ-sites may be encountered in a subset of cases and may follow a relapsing-remitting course. The principal histopathologic findings in several extranodal sites include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosis and obliterative phlebitis, along with atrophy and destruction of tissues. Immunohistochemical staining shows increased IgG4+ cells in the involved tissues (>50 per high-power field, with IgG4/IgG ratio >40%). IgG4-RSD may potentially be rarely associated with the development of lymphoma and carcinoma. However, the nature and pathogenesis of IgG4-RSD are yet to be fully elucidated and provide immense scope for further studies.

Fig. 1

The gross photograph of pancreas shows an ill-defined firm lesion in the head of the pancreas (arrow) with yellow-tan and fibrotic cut surface. The lesion extends into the peripancreatic fat tissue.

Fig. 2

Microscopic features of IgG4-related sclerosing pancreatitis. (A) Pancreatic lobules are replaced by severe inflammatory cell infiltration and fibrosis. Sclerosis of interlobular septa enhances lobular architecture of pancreas (H&E stain, original magnification ×40). (B) The lobular interstitium is infiltrated by plasma cells, lymphocytes, and a variable number of eosinophils. Residual atrophic pancreatic acini are identified (right upper corner, arrow; H&E stain, original magnification ×400). (C) Obliterative phlebitis is characterized by perivenular and intravenular inflammatory cell infiltrate with fibrous obliteration of the lumen (H&E stain, original magnification ×200). (D) IgG4 immunostain shows markedly increased IgG4-positive plasma cells (>50 plasma cells/HPF; immunohistochemical stain, original magnification ×200). IgG4, immunoglobulin G4; HPF, high-power fields.

Fig. 3

Microscopic features of IgG4-related sclerosing cholangitis. (A) Intrahepatic bile ducts are infiltrated by lymphoplasmacytes with variable numbers of eosinophils, intermixed with collagen fibers (H&E stain, original magnification ×400). (B) Lymphoplasmacytes are infiltrating in the perivenular soft tissue of large veins, resulting in vascular wall destruction and luminal obliteration (H&E stain, original magnification ×200). (C) The bile duct lumen undergoes stenosis due to the periductal fibrosis and inflammation (H&E stain, original magnification ×40). (D) Numerous plasma cells are positive for IgG4 (immunohistochemical stain, original magnification ×200). IgG4, immunoglobulin G4.

Fig. 4

Microscopic features of IgG4-associated inflammatory pseudotumor of ureter. (A) Fibroinflammatory lesion involves the entire ureteral wall and extends into periureteral adipose tissue (H&E stain, original magnification ×12.5). (B) Abundant plasma cells are intermixed with scattered histiocytes, fibroblasts and collagen fibers (H&E stain, original magnification ×400). (C) Obliterative phlebitis is identified in the periureteral adipose tissue (H&E stain, original magnification ×100). (D) A significant subset of plasma cells is positive for IgG4 (immunohistochemical stain, original magnification ×200). IgG4, immunoglobulin G4.

Fig. 5

Microscopic features of IgG4-related lymphadenopathy, type I. (A) Multicentric Castleman disease-like pattern with interfolicular expansion (H&E stain, ×40). (B) Perivascular sclerosis and hyalinized venules in lymphoid follicles are identified (H&E stain, ×100). (C) The interfollicular area is infiltrated by plasma cells intermixed with collagen fibers (H&E stain, ×400). (D) Many plasma cells are positive for IgG4 (immunohistochemical stain, ×200). IgG4, immunoglobulin G4.