IgG4-related disease: what a hematologist needs to know

Abstract

IgG4-related disease is a fibro-inflammatory condition that can affect nearly any organ system. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. This review focuses on the hematologic manifestations of IgG4-related disease, including lymphadenopathy, eosinophilia, and polyclonal hypergammaglobulinemia. The disease can easily be missed by unsuspecting hematologists, as patients may present with clinical problems that mimic disorders such as multicentric Castleman disease, lymphoma, plasma cell neoplasms and hypereosinophilic syndromes. When IgG4-related disease is suspected, serum protein electrophoresis and IgG subclasses are helpful as initial tests but a firm histological diagnosis is essential both to confirm the diagnosis and to rule out mimickers. The central histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate enriched with IgG4-positive plasma cells (with an IgG4/IgG ratio >40%), storiform fibrosis, and obliterative phlebitis. Importantly for hematologists, the latter two features are seen in all tissues except bone marrow and lymph nodes, making these two sites suboptimal for histological confirmation. Many patients follow an indolent course and respond well to treatment, but a significant proportion may have highly morbid or fatal complications such as periaortitis, severe retroperitoneal fibrosis or pachymeningitis. Corticosteroids are effective but cause new or worsening diabetes in about 40% of patients. Initial response rates to rituximab are high but durable remissions are rare. More intensive lymphoma chemotherapy regimens may be required in rare cases of severe, refractory disease, and targeted therapy against plasmablasts, IgE and other disease biomarkers warrant further exploration.

Figure 1.

Manifestations of IgG4-related disease by organ system. The most common primary disease features are indicated in bold.

Figure 2.

Lymph nodes in IgG4-related disease. (A,B) An example of the interfollicular pattern of IgG4-related lymphadenopathy, with mature plasma cells, many expressing IgG4, distributed between benign follicles. (A) Hematoxylin and eosin stain. (B) IgG4 immunohistochemistry. (C) A needle core lymph node biopsy from a different case with the interfollicular pattern (hematoxylin and eosin stain). (D,E) A case of IgG4-lymphadenoapthy with a progressive transformation of the follicular center pattern, with the plasma cells within the follicle proper. (D) Hematoxylin and eosin stain. (E) IgG4 immunohistochemistry. (F) An example of a mass-like lesion (inflammatory pseudotumor) with dense fibrosis and associated follicular hyperplasia in a case of IgG4-lymphadenoapthy (hematoxylin and eosin).

Figure 3.

Serum protein electrophoresis showing electrophoretic patterns for four patients with mild to gross elevations in IgG4 concentration in between two for patients with low IgG4 concentration. The physicochemical properties of the IgG4 heavy chain result in a relative anodal position (shift toward albumin) of the gamma globulins when the IgG4 becomes the predominant gamma globulin. Apart from IgG4, IgA immunoglobulins are frequently observed in the boundary between the beta and gamma regions. Monoclonal bands may also migrate in this region as shown in the gel (the monoclonal gammopathy in this case is an IgG1 monoclonal band that has physicochemical properties that are atypical for IgG1 immunoglobulins, which are normally found in a more cathodal position). NC: normal control, MG: monoclonal gammopathy.

Figure 4.

Bone marrow specimens involved by IgG4-related disease. Both cases show mature plasma cells distributed throughout the marrow. Ancillary studies established that these plasma cells were polyclonal, excluding a plasma cell neoplasm. (A,C) Hematoxylin and eosin stains. (B,D) IgG4 immunohistochemistry.