Background/Purpose: Some of clinical features of the plasma cell type of human herpesvirus-8-negative multicentric Castleman’s disease (idiopathic MCD or iMCD) are similar to those of IgG4-related disease (IgG4-RD). These conditions are associated with lymphadenopathy (LAD), a polyclonal hypergammaglobulinemia, as well as constitutional symptoms (e.g., weight loss, fatigue). The histologic features of iMCD LAD overlap with those of IgG4-related LAD. This has led to suspicion that iMCD is either overdiagnosed in some institutions or underdiagnosed in others, or that variation in disease expression across countries may alter clinical disease phenotypes. Levels of acute phase reactants, particularly the C-reactive protein (CRP), have been proposed as useful in discriminating iMCD from IgG4-RD.

Methods: American and Japanese clinicians and pathologists exchanged pathology slides of 60 cases (30 cases from the US, 30 from Japan) accompanied by clinical vignettes. Japanese investigators submitted 15 cases in which they suspected a diagnosis of iMCD and 15 cases they felt were typical IgG4-RD. Cases considered iMCD had at least focal extranodal manifestations. US investigators submitted 12 cases considered to represent IgG4-RD with an elevated CRP and 18 IgG4-RD cases with normal CRP. All investigators were blinded to CRP and IL-6 concentrations as well as treatment responses. The US investigators were blinded to the designated diagnoses of the Japanese cases. The diagnosis of iMCD was evaluated based on expert pathology opinion as well as recently published diagnostic criteria (Fajgenbaum, Blood 2017).

Results: Of the 15 suspected iMCD cases from Japan, 14 had mixed nodal and extranodal manifestations and 1 had pure extranodal abnormalities. All but one had elevated serum IgG4 concentrations. Twelve (80%) had extensive extranodal polyclonal plasma cell infiltrates with increased IgG4-positive plasma cells affecting the kidneys, lungs, and skin that were similar to the lymph node appearance. Nine (60%) fulfilled iMCD diagnostic criteria. When reviewed by expert American pathologists, however, the histopathology of all suspected iMCD cases were considered to be a nonspecific, reactive process characterized by a nonspecific plasmacytic infiltrate without regressed follicles. No association was observed between CRP elevations in the US IgG4-RD cases and whether or not the Japanese investigators considered the case to be IgG4-RD (P=0.5). None of the US IgG4-RD cases were considered iMCD by the Japanese investigators.

Conclusion: A condition characterized by multifocal LAD with polyclonal IgG4+ plasma cell infiltrates, extranodal lesions of similar histologic appearance, and elevated inflammatory markers mimics IgG4-RD and iMCD but is often not clearly classifiable as either condition even with iMCD diagnostic criteria. Although these and similar cases are commonly reported as iMCD, future studies using alternative but common nosology are critical to better characterize them. Furthermore, the diagnosis of IgG4-RD was agreed on regardless of the CRP concentration, suggesting that CRP can be elevated in otherwise typical IgG4-RD and that CRP is not a useful measure to distinguish iMCD and IgG4-RD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-multi-organ-inflammatory-condition-with-features-of-idiopathic-multicentric-castlemans-disease-and-igg4-related-disease-an-unrecognized-mimicker-of-igg4-rd/