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  • IgG4-related disease (IgG4-RD) is a multiorgan disease with highly characteristic pathology findings and immunostaining characteristics across involved tissues.

  • Organ system involvement may be confined to single organs but in many cases evolves over months to years to involve multiple organs in either a sequential or simultaneous fashion.

  • Commonly involved organs include the salivary glands (submandibular, parotid); the orbits and lacrimal glands; the thyroid gland; the lymph nodes; the thoracic and abdominal aorta; the mediastinum, retroperitoneum, and mesentery; and the lungs, biliary tree, pancreas, and kidneys.

  • IgG4-RD has also been reported in the pachymeninges, the skin, and the prostate gland.

  • Serum IgG4 concentrations are elevated in most patients (approximately 70%). In patients with exceptionally high serum IgG4 concentrations—usually those with multiorgan disease—the prozone phenomenon can lead to a spuriously low result. This problem may be circumvented by diluting test samples sufficiently.

  • If elevated at the time of diagnosis, serum IgG4 concentrations are generally a good biomarker. Other useful biomarkers in individual patients include IgG1, IgE, and complement levels (C3 and C4).

  • Histopathologic hallmarks: lymphoplasmacytic tissue infiltrate, storiform fibrosis, obliterative phlebitis, germinal center formation, and mild to modest tissue eosinophilia.

  • Immunostaining characteristics: A high percentage of plasma cells stain positively for IgG4.

General Considerations

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition recognized in the first decade of this century and now identified increasingly across a wide array of organ systems. The condition is characterized by a tendency to form tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and, often but not always, elevated serum IgG4 concentrations. The first organ within the spectrum of IgG4-RD to be linked with elevations in serum IgG4 concentrations was the pancreas. Pancreatic involvement by IgG4-RD is now termed type 1 IgG4-related autoimmune pancreatitis. In 2003, extrapancreatic manifestations were identified in patients with this pancreatic disease, and IgG4-RD is now known to occur in virtually every organ system: the biliary tree, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin. The histopathologic features are similar across organs, with some organs or body regions (eg, the retroperitoneum) demonstrating a higher degree of fibrosis at the time of diagnosis.

One consequence of the recognition of IgG4-RD is that many medical conditions once viewed as separate conditions isolated to single organs are now acknowledged to be part of the IgG4-RD spectrum. Examples of this include “Mikulicz syndrome,” “Küttner tumor,” and Riedel thyroiditis, once regarded to be conditions limited to the major salivary and lacrimal glands alone; to the submandibular glands alone; or to the thyroid gland alone. In addition, IgG4-RD also accounts for substantial percentages of diseases characterized by the presence of pseudotumors or fibrotic lesions of previously unclear etiologies. IgG4-RD is responsible for significant proportions of cases of orbital pseudotumors, retroperitoneal fibrosis, and sclerosing mesenteritis.

The etiology of IgG4-RD remains unknown ...

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