Which diagnosis can explain this patient’s multisystem condition?
Answer: Immunoglobulin G4–related disease (IgG4-RD).
The Diagnostic Test
The diagnosis was made following a careful review of the submandibular gland biopsy. Both the histopathology slides and additional immunostains of the existing tissue sample (re-cuts of the tissue block) were essential to establishing the diagnosis.
The submandibular biopsy revealed a gland largely replaced by a lymphoplasmacytic infiltrate: reactive lymphoid follicles surrounded by small lymphocytes and plasma cells (see Figure 3A). In addition, there was striking storiform fibrosis (see Figure 3B), obliterative phlebitis, and scattered eosinophils. Immunostaining of the tissue for IgG4 and IgG demonstrated more than 100 IgG4-positive plasma cells per high-power field and an IgG4:total IgG ratio of 0.92. This biopsy was diagnostic of IgG4-RD.
What Is IgG4-RD?
IgG4-RD is a fibroinflammatory condition 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.1 IgG4-RD was not recognized to be an overarching, systemic condition until 2003, when extrapancreatic manifestations were identified in patients with autoimmune pancreatitis.2 The first use of the term “autoimmune pancreatitis” was in 1995.3 Autoimmune pancreatitis, known by a variety of other names up until then, including sclerosing pancreatitis, was linked to elevated serum IgG4 concentrations in 2001.4
Is This a New Disease?
No. Scrutiny and reinterpretation of the medical literature in light of the emerging knowledge of this newly recognized disorder indicates that IgG4-RD has been known by other names, generally while being regarded as an entity isolated to an individual organ system. A disorder termed “multisystemic fibrosclerosis” in the 1960s probably represents—in most cases—IgG4-RD. Table 2 displays a list of previously recognized conditions known by other names that comprise (or may comprise) parts of the IgG4-RD spectrum.
Common Clinical Manifestations
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. A list of the common clinical manifestations in a broad variety of organ systems is shown in Table 3. The histopathologic features of this disease bear striking similarities across organs, regardless of the site of involvement.1 IgG4-RD is therefore analogous to sarcoidosis, another systemic disease in which diverse organ manifestations are linked by unique histopathology.
