Essentials of Diagnosis
- IgG4-related disease (IgG4-RD) is a potentially multi-organ 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; 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%). One explanation for the finding of normal serum IgG4 concentrations may be the prozone phenomenon, a spuriously low result reported sometimes when the analyte (IgG4) is actually present at exceptionally high concentrations. This problem may be circumvented by diluting test samples sufficiently.
- Serum IgG4 concentrations sometimes correlate with disease activity.
- 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-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 autoimmune pancreatitis. In 2003, extrapancreatic manifestations were identified in patients with this pancreatic disease, and IgG4-RD has now been described 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 bear striking similarities across organs. In 2011, recommendations for the nomenclature of individual organ system manifestations were put forth following an international symposium on this condition.
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. 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, among other cases of inflammation within organs that until recently has been considered to be of obscure origin.
The etiology of IgG4-RD remains unknown. There is no definitive evidence for a link with autoimmunity. Many patients have overlaps with allergic conditions, such as asthma and allergic rhinitis. Few population-based studies of IgG4-RD have been performed and the disease epidemiology remains poorly described, but certain striking demographic features are evident. Cases in children are rare but described. Approximately 60–80% of patients are males older than the age of 50, but some variations on these demographic features occur in the different organs affected by IgG4-RD. For example, in the case of IgG4-RD affecting the organs of the head and neck, women appear to be affected as frequently as men. Much remains unknown about the behavior of IgG4 in vivo and the nature of its role in IgG4-RD (primary or secondary) remains to be fully defined.
Clinical Findings
The major symptoms and differential diagnoses of each organ lesion are summarized in Table 71–1. IgG4-RD usually presents subacutely and most patients are not constitutionally ill, but a minority of patients have strong clinical manifestations of systemic inflammation at diagnosis, eg, fevers and elevations of acute phase reactants. IgG4-RD is often identified through findings observed unexpectedly by the radiologist or pathologist.
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IgG4-RD sometimes remains confined to one organ, eg, the salivary or lacrimal glands, for many years. However, some patients have major clinical disease in one organ but less obvious or even subclinical involvement in other organs. As an example, although patients with autoimmune pancreatitis generally have pancreatic dysfunction as a major clinical manifestation, careful scrutiny by physical examination, urinalysis, cross-sectional imaging, positron emission tomography (PET) scanning, or other evaluations may unveil disease in the lungs, kidneys, lymph nodes, or other organs.
Multi-organ disease may be evident at diagnosis but can also evolve metachronously, over months to years. Spontaneous improvement, sometimes leading to at least temporary clinical resolution in certain organ system manifestations, can occur.
Tumefactive lesions and allergic disease are common manifestations of IgG4-RD. IgG4-RD account for a variable proportion of tumorous swellings in organs such as the orbits, salivary and lacrimal glands, lungs, kidneys, and other organs. One series and other clinical experience indicate, for example, that 25–50% of orbital pseudotumors fall within the spectrum of IgG4-RD. Allergic features such as atopy, eczema, asthma, and modest peripheral eosinophilia also accompany IgG4-RD in up to 40% of patients.
The clinical manifestations of each of the commonly involved organs are discussed below.
Both the submandibular and parotid glands can be affected by IgG4-RD. The disease has a particular predilection to involve the submandibular glands bilaterally and in isolation (Plate 57), a point that frequently helps distinguish it from Sjögren syndrome. The usual symptom at presentation is glandular swelling, with variable degrees of discomfort and tenderness that range from mild to substantial. Xerostomia often results from chronic sclerosing sialadenitis but this is less frequent than in Sjögren syndrome. The entity once known as “Mikulicz disease,” used nonspecifically to designate swelling of the submandibular, parotid, and lacrimal glands that was not associated with cancer, is probably more accurately called IgG4-RD in most cases.
Many cases of “idiopathic” orbital pseudotumor in the past, including those involving the lacrimal gland (Plate 58), have not been subjected to biopsy. Even if biopsied, IgG4 staining has seldom been performed. Consequently, the frequency with which IgG4-RD affects the orbit has been overlooked until recently. Substantial proptosis can result from IgG4-RD involvement of the orbit, even in the setting of lacrimal disease alone. Such proptosis is one of several manifestations through which IgG4-RD mimics granulomatosis with polyangiitis (formerly Wegener granulomatosis). Orbital disease associated with IgG4-RD occasionally extends into the sinuses or the cavernous sinus, and disease originating from those sites can also affect the orbit. Vision loss can ensue if the blood supply to the optic nerve is disrupted by the mass effect.
Riedel thyroiditis, a disorder associated with fibrosis and woody enlargement of the thyroid gland, was of obscure etiology until recently when the link between this condition and IgG4-RD was ascertained. Riedel thyroiditis has been known for decades to occur in association with fibrotic lesions in other organs, eg, the lacrimal glands, retroperitoneum, and mediastinum, in the context of an entity labeled “multifocal fibrosclerosis.” IgG4-RD now appears to account for the majority of such cases.
IgG4-RD can be associated with tender or nontender lymphadenopathy, with or without other organ manifestations of the disease. The diagnosis of IgG4-RD is difficult to make on the basis of a lymph node biopsy alone, as lymph nodes seldom undergo the degree of “storiform fibrosis” (see Special Tests, Biopsy
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