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.
Table 71–1. Differential Diagnosis of IgG4-Related Disease. ||Download (.pdf)
Table 71–1. Differential Diagnosis of IgG4-Related Disease.
- Systemic autoimmune conditions and vasculitides
- Sjögren syndrome
- Granulomatosis with polyangiitis (formerly Wegener granulomatosis)
- Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
- Giant cell arteritis/giant cell aortitis
- Takayasu arteritis
- Granulomatous disorders
- Fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis)
- Lymphoma, particularly MALT lymphoma
- Multicentric Castleman disease
- Adenocarcinoma of the pancreas
- Renal cell carcinoma
- Bronchoalveolar carcinoma of the lung
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.
Lacrimal Gland and Orbital Disease
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, below) observed in other organs.
IgG4-RD appears to cause approximately 10% of cases of “idiopathic” ascending aortitis, and is known to lead to complications such as aneurysm and dissection. Primary branch involvement of the thoracic aorta is less common than in other causes of large-vessel vasculitis, eg, Takayasu arteritis or giant cell aortitis.
Abdominal Aorta and Retroperitoneal Fibrosis
The abdominal aorta can also be involved by the syndrome of “inflammatory abdominal aortic aneurysm,” which overlaps to a large degree with retroperitoneal fibrosis and perianeurysmal fibrosis under a larger heading of chronic periaortitis.
Fibrosing Mediastinitis and Sclerosing Mesenteritis
These two conditions are rare entities that also have other causes (eg, histoplasmosis in the setting of fibrosing mediastinitis). However, small case series now document the relatively high frequency with which biopsies from patients with these disorders demonstrate the typical histopathologic and immunohistochemical staining patterns of IgG4-RD.
The pulmonary lesions of IgG4-RD remain rather poorly described but several small series have identified a remarkable diversity of clinical and radiologic presentations, making it clear that IgG4-RD can mimic many disorders with lung features. In some patients, lung lesions due to IgG4-related pulmonary disease are asymptomatic and are only diagnosed during broader work-up designed to exclude systemic causes of IgG4-RD manifestations in other organs. However, cough and dyspnea can also be presenting symptoms in patients with IgG4-RD. The diverse radiologic manifestations of IgG4-RD in the lung are described below.
For years it was recognized that a subset of patients with “primary sclerosing cholangitis” had disease that was responsive to glucocorticoids. Histopathologic evaluations of liver biopsies in such patients, interpreted now in the light of IgG4-RD, reveal IgG4-related cholangitis, characterized by lymphoplasmacytic infiltrates surrounding the bile ducts, and high IgG4/total IgG ratio among plasma cells in the lesions, storiform fibrosis, obliterative phlebitis, and modest tissue eosinophilia, all hallmarks of IgG4-RD. The distinction of IgG4-related sclerosing cholangitis from primary sclerosing cholangitis is crucial because of the differential responses to therapy that are characteristic of these separate conditions.
Type 1 autoimmune pancreatitis is the paradigm of organ involvement in IgG4-RD. In the setting of pancreatic masses, patients often have painless jaundice. As a result, many patients have undergone Whipple procedures for presumed adenocarcinoma of the pancreas. The classic demographic profile of such patients—middle-aged to elderly men—facilitates misdiagnosis in this setting because such a demographic profile is also typical of pancreatic cancer. In addition to icterus, patients may also have nonspecific abdominal pain, anorexia, weight loss, and features of IgG4-RD in extrapancreatic organs that may be overlooked. The radiologic features of type 1 autoimmune pancreatitis are discussed below. Type 1 autoimmune pancreatitis must be differentiated from type 2 disease, a condition with which it shares some clinical features but also vital pathologic distinctions.
Renal disease in IgG4-RD has two major clinical presentations: mass-like lesions that can mimic renal cell carcinoma and tubulointerstitial nephritis. A small number of cases to date have also been documented to have membranous glomerulonephritis (occurring simultaneously with tubulointerstitial disease), but the antibody specificity in such cases of glomerular disease appears to be different from that associated with idiopathic membranoproliferative glomerulonephritis. The mass lesions in IgG4-related kidney disease can be multiple and bilateral, and biopsy typically reveals tubulointerstitial nephritis. Laboratory findings in this setting are subnephrotic range proteinuria and mild to moderate hypocomplementemia of the third and fourth components of complement. The hypocomplementemia is consistent with the detection of immune complexes within the kidney by both immunofluorescence and electron microscopy. Azotemia occurs in a minority of patients and end-stage renal disease has been reported.
IgG4-RD has also been described in the pachymeninges, skin, prostate gland, pericardium, and middle ear. Bone-destructive lesions have been reported in the middle ear in some patients, mimicking granulomatosis with polyangiitis (formerly Wegener granulomatosis), chronic infection, and malignancy.
Most patients with IgG4-RD have elevated serum IgG4 concentrations, but the range varies widely. Approximately 30% of patients have normal serum IgG4 concentrations despite classic pathologic findings of IgG4-RD. One explanation for this finding in some patients is the prozone effect—a laboratory error (spuriously low result) induced by failure of the laboratory to perform a sufficient number of dilutions of the sample in the setting of a large quantity of analyte. Extremely limited data exist regarding the test characteristics of serum IgG4 concentrations in patients with potential IgG4-RD, and some of these data are confounded by clinical misclassification or laboratory error or both.
Monitoring IgG4 concentrations during glucocorticoid treatment yields unreliable data on disease activity. In most patients who have elevated IgG4 concentrations at baseline, glucocorticoid therapy lowered serum levels. In others, serum concentrations normalized. However, serum IgG4 concentrations remain abnormal in most. Patients can achieve clinical remissions without serum IgG4 concentrations normalizing and may relapse despite having normal serum IgG4 measurements. At the present time, the usefulness of serial serum IgG4 concentrations as a gauge of disease activity must be individualized for each patient.
Several patterns of acute phase reactant levels are observed in IgG4-RD. Only a small percentage (approximately 10%) have striking elevations of both the erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP). It is more common, however, for both of these measurements to be normal. Because the ESR is often affected by the level of hypergammaglobulinemia, another common pattern observed is a moderate to high elevation of the ESR in the setting of a normal CRP. Neither the ESR nor the CRP appears to be a reliable biomarker across the spectrum of disease activity in IgG4-RD.
Mild to moderate peripheral eosinophilia is a common finding in the blood of patients with IgG4-RD, just as eosinophilia is frequently present within the tissue of affected organs. Peripheral eosinophilias of 20% of the total white blood cell count are typical of IgG4-RD.
Mild hypocomplementemia of both the third and fourth components of complement can be detected in IgG4-RD, particularly in those patients with renal disease. Presumably this finding is indicative of immune complex deposition within the kidney and other organs, although additional studies of this phenomenon and the nature of immune complexes detectable at sides of disease are required.
Subnephrotic range proteinuria is typical of the tubulointerstitial disease of IgG4-RD.
Chest radiographs are often the route through which unsuspected pulmonary disease is identified. However, other imaging studies of the lungs are more useful in delineating the nature and extent of pulmonary involvement in IgG4-RD.
CT scans are useful in three major settings in IgG4-RD: pulmonary disease, pancreatic disease, and renal disease.
CT scans have identified a number of pleuropulmonary lesions that are characteristic of IgG4-RD. These include nodules, ground-glass opacities, interstitial lesions leading sometimes to honeycombing, thickening of the bronchovascular bundle, and pleural thickening. These radiologic lesions may mimic many forms of rheumatologic, oncologic, or infectious disease (see Table 71–1).
Abdominal CT scans may reveal a “sausage-shaped” pancreas, sometimes accompanied by an echogenic halo of surrounding edema. The pancreas is typically diffusely enlarged. The classic radiologic presentation in the proper clinical setting is strongly suggestive of type 1 (IgG4-related) autoimmune pancreatitis, but biopsy is essential in atypical presentations to exclude pancreatic carcinoma.
A high percentage of patients with type 1 (IgG4-related) autoimmune pancreatitis have IgG4-related kidney disease as well. Diffusely enlarged kidneys may be evident, and pseudotumors may resemble renal cell carcinoma strongly. IgG4-related pseudotumors within the kidney typically have a hypoattenuated appearance on CT.
Positron Emission Tomography (PET)
Total body PET imaging appears to be a sensitive modality for defining the extent of disease in IgG4-RD. Additional studies are required to define its sensitivity to change following treatment and its role as an outcome measure in studies of this disease.
Magnetic Resonance Imaging (MRI)
MRI is most useful in the evaluation of patients with the two most common neurologic manifestations of IgG4-RD: namely, pachymeningitis and hypophysitis. MRI can also identify perineural encasement by IgG4-related inflammation that may be symptomatic or asymptomatic.
The crux of an IgG4-RD diagnosis is the nature of the histopathologic findings in a biopsy from an affected organ. Misdiagnoses of IgG4-RD result if excessive emphasis is placed on moderate serum concentration elevations of IgG4 or overreliance on the finding of IgG4-positive plasma cells in tissue.
A key morphologic feature of IgG4-RD is a dense lymphoplasmacytic infiltrate that is organized in a storiform pattern (Plates 59 and 60). “Storiform” refers to a matted, irregularly whorled pattern of fibrosis. The fibrosis appears to swirl past cellular elements of the tissues as water flowing by rocks in a stream. Other histopathologic hallmarks are obliterative phlebitis, a mild to moderate eosinophil infiltrate, and the presence of germinal centers. The inflammatory lesion frequently forms a tumefactive mass that is associated with tissue destruction.
Some histopathologic findings are distinctly unusual in IgG4-RD, and their presence should conjure other potential diagnoses. Such findings include necrosis, granulomatous inflammation, and significant collections of neutrophilic inflammation.
The histologic appearance of IgG4-RD is highly characteristic and essential to the diagnosis, but this may be clinched by the findings of immunostaining studies. The ratio of IgG4-positive plasma cells to the total number of plasma cells within tissue (ie, the IgG4/total IgG ratio) is usually high (0.4 to 0.8 or higher). Such high ratios are particularly remarkable when one considers that in normal individuals IgG4 comprises approximately 4% of the circulating immunoglobulin pool. Among patients with IgG4-RD whose tissues are biopsied at stages of advanced fibrosis, as is true of many patients with retroperitoneal fibrosis, for example, the link to IgG4-RD may be more difficult to establish because of smaller overall numbers of plasma cells. However, the IgG4:total IgG ratio remains high in that setting.
Both clinicians and pathologists must bear in mind that IgG4-positive cells are found in a wide variety of inflammatory infiltrates and that the detection of significant numbers of IgG4-positive plasma cells is not diagnostic of IgG4-RD. However, a diffuse IgG4-positive plasma cell infiltrate with more than 30 IgG4-positive cells/HPF and an IgG4:IgG ratio greater than 50% provides compelling evidence of IgG4-RD, particularly in conjunction with the appropriate histopathologic appearance.
The inflammatory infiltrate is composed of an admixture of T- and B-lymphocytes. Whereas B cells are typically organized in germinal centers, the T cells are distributed diffusely throughout the lesion. All immunoglobulin subclasses may be represented within involved tissue, but IgG4 predominates. Clonality studies are required to exclude these malignancies.