Based on histological and immunohistochemical examination of various organs of patients with autoimmune pancreatitis (AIP), a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prostate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AIP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4-related sclerosing diseases. This disease includes AIP, sclerosing cholangitis, cholecystitis, sialadenitis, retroperitoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AIP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunostaining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.
An elevated serum titer of immunoglobulin G4 (IgG4), the least common (3% to 6%) of the 4 subclasses of IgG, is a surrogate marker for the recently characterized IgG4-related sclerosing disease. The syndrome affects predominantly middle-aged and elderly patients, with male predominance. The patients present with symptoms referable to the involvement of 1 or more sites, usually in the form of mass lesions. The prototype is IgG4-related sclerosing pancreatitis (also known as autoimmune pancreatitis), most commonly presenting as painless obstructive jaundice with or without a pancreatic mass. Other common sites of involvement are the hepatobiliary tract, salivary gland, orbit, and lymph node, but practically any organ-site can be affected, such as retroperitoneum, aorta, mediastinum, soft tissue, skin, central nervous system, breast, kidney, prostate, upper aerodigestive tract, and lung. The patients usually have a good general condition, with no fever or constitutional symptoms. Common laboratory findings include raised serum globulin, IgG, IgG4, and IgE, whereas lactate dehydrogenase is usually not raised. Some patients have low titers of autoantibodies (such as antinuclear antibodies and rheumatoid factor). The disease often shows excellent response to steroid therapy. The natural history is characterized by the development of multiple sites of involvement with time, sometimes after many years. However, the disease can remain localized to 1 site in occasional patients. The main pathologic findings in various extranodal sites include lymphoplasmacytic infiltration, lymphoid follicle formation, sclerosis and obliterative phlebitis, accompanied by atrophy and loss of the specialized structures of the involved tissue (such as secretory acini in pancreas, salivary gland, or lacrimal gland). The relative predominance of the lymphoplasmacytic and sclerotic components results in 3 histologic patterns: pseudolymphomatous, mixed, and sclerosing. Immunostaining shows increased IgG4+ cells in the involved tissues (>50 per high-power field, with IgG4/IgG ratio >40%). The lymph nodes show multicentric Castleman disease-like features, reactive follicular hyperplasia, interfollicular expansion, or progressive transformation of germinal centers, with the unifying feature being an increase in IgG4+ plasma cells on immunostaining. The nature and pathogenesis of IgG4-related sclerosing disease are still elusive. Occasionally, the disease can be complicated by the development of malignant lymphoma and possibly carcinoma.
Core tip: IgG4-related sclerosing cholangitis (IgG4-SC) has become a third distinct clinical entity of sclerosing cholangitis. The diffuse cholangiographic abnormalities observed in IgG4-SC may resemble those observed in primary sclerosing cholangitis (PSC), and the presence of segmental stenosis suggests cholangiocarcinoma (CC). IgG4-SC responds well to steroid therapy, whereas PSC is only effectively treated with liver transplantation, and CC requires surgical intervention. IgG4-SC should be carefully diagnosed based on a combination of characteristic clinical, serological, morphological, and histopathological features after cholangiographic classification and targeting of a disease for differential diagnosis.