Lymphadenopathy of IgG4-related disease: an underdiagnosed and overdiagnosed entity

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Lymphadenopathy is a common occurrence in IgG4-related disease; it can appear before, concurrent with, or after the diagnosis of this disease, which is characterized by tumefactive sclerosing inflammatory lesions predominantly affecting extranodal sites, such as the pancreas, salivary gland, and lacrimal gland. Although multiple lymph node groups are commonly involved, constitutional symptoms are absent. The lymph nodes can show a broad morphologic spectrum, including multicentric Castleman disease-like (type I), follicular hyperplasia (type II), interfollicular expansion (type III), progressive transformation of germinal centers (type IV), and inflammatory pseudotumor-like (type V). All are characterized by an increase in IgG4+ plasma cells (>100 per high power field) and IgG4/IgG ratio (>40%). IgG4-related lymphadenopathy is both an underdiagnosed and overdiagnosed entity. The former is because of the fact that this entity has not been characterized until recently, while the latter results from pathologists' enthusiasm in diagnosing “new” entities and the lack of specificity of the morphologic and immunophenotypic features of IgG4-related lymphadenopathy. It is prudent to render this diagnosis only for patients with known IgG4-related disease or in the presence of corroborating clinical and laboratory findings (such as elderly men, systemic lymphadenopathy, elevated serum IgG4, IgG, and IgE but not IgM and IgA, and low titers of autoantibodies). Outside these circumstances, a descriptive diagnosis of “reactive lymphoid hyperplasia with increased IgG4+ cells” accompanied by a recommendation for follow-up will be appropriate because IgG4-related disease will likely ensue only in a minority of such patients.

Section snippets

Occurrence of lymphadenopathy in IgG4-related disease

A mere 10 years ago, Kamisawa et al1, 2 proposed the existence of a new disease entity characterized by tumefactive sclerosing inflammation of multiple organs, tissue infiltration by IgG4+ plasma cells, elevated serum IgG4 levels, and favorable response to steroid therapy. This disease has now come to be known as “IgG4-related disease,” after multiple revisions in terminology over the years.3, 4, 5, 6, 7 Although IgG4-related disease affects predominantly extranodal sites, in particular

Clinical features of IgG4-related lymphadenopathy

As depicted in Figure 1, there are 4 scenarios whereby lymphadenopathy occurs in IgG4-related disease (Figure 1).9, 10, 11, 12, 15, 16, 17

In scenario A, regional lymph nodes are found in excision specimens of involved organs (such as pancreas or submandibular gland). The lymph nodes may or may not be enlarged, and they rarely produce symptoms.

In scenario B, systemic lymphadenopathy represents part of the initial presentation of IgG4-related disease, or is discovered on work-up of the patients

Should IgG4 immunostain be performed routinely on all reactive lymph nodes so as not to miss IgG4-related lymphadenopathy?

The more we learn about IgG4-related disease, the more we realize that an increase in IgG4+ cells and IgG4/IgG ratio is not all that specific when taken in isolation. With widespread application of IgG4 and IgG immunostains on reactive lymph nodes in recent years, many other diseases and even nonspecific reactive lymphadenopathies have occasionally been found to show high IgG4+ cell count and high IgG4/IgG ratio, but the significance of the IgG4+ cell infiltrate in such cases is unclear.

Conclusions

Our understanding of IgG4-related disease is still evolving. It is likely that the diagnostic approach to IgG4-related lymphadenopathy will have to be modified in future with the availability of new data.

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