Multicentric Castleman disease: Where are we now?

Abstract

Multicentric Castleman disease (MCD) encompasses a spectrum of conditions that give rise to overlapping clinicopathological manifestations. The fundamental pathogenetic mechanism involves dysregulated cytokine activity, which causes systemic inflammatory symptoms as well as lymphadenopathy. The histological changes in lymph nodes resemble in part the findings originally described in the unicentric forms Castleman disease, both hyaline vascular and plasma cell variants. In MCD caused by Kaposi sarcoma-associated herpesvirus/human herpesvirus-8 (KSHV/HHV8), the cytokine over activity is caused by viral products, which can also lead to atypical lymphoproliferations and potential progression to lymphoma. In cases negative for KSHV/HHV8, so-called idiopathic MCD, the hypercytokinemia can result from various mechanisms, which ultimately lead to different constellations of clinical presentations and varied pathology in lymphoid tissues. In this article, we review the evolving concepts and definitions of the various conditions under the eponym of Castleman disease, and summarize current knowledge regarding the histopathology and pathogenesis of lesions within the MCD spectrum.

International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease

“…9 We sometimes observed the "lollipop sign" of prominent blood vessels radially penetrating GCs and "budding" or "twinning" of follicles, which involves $2 GCs located within a single follicle. 5,9 Historically, many features of this group would be described as consistent with the "hyaline vascular" (HV) histopathologic subtype of MCD. However, many hematopathologists consider HV to only occur in UCD based on the classic descriptions by Benjamin Castleman, and a few HV-UCD features, such as FDC dysplasia and sclerotic vessels, are not often observed in MCD.…”

“…5 Other virally-associated lymphoproliferations or uncontrolled infections that should be considered include Epstein-Barr virus (EBV)-associated lymphoproliferative disorders, such as infectious mononucleosis or chronic active EBV infection, but low levels of EBV are not necessarily exclusionary.…”

“…Virallyencoded interleukin (IL)-6 and human IL-6 are implicated in disease pathogenesis. [4][5][6][7][8] HHV-8-negative/iMCD is less well understood and has no specific biomarkers. Currently, iMCD is diagnosed when a constellation of nonspecific but characteristic lymph node histopathologic features commonly described as "hyaline vascular," "plasmacytic," or "mixed" are observed in patients with appropriate clinical features.…”

Muscle-specific receptor tyrosine kinase (MuSK) myasthenia gravis associated with castleman disease

“…4 Furthermore, recent studies have revealed that patients with multi-centric CD exhibit elevated serum concentrations of IgG4 and interleukin-6, and abundant infiltration of IgG4-positive cells in the affected organs. 5 MuSK antibodies are primarily associated with IgG4, in contrast to acetylcholine receptor antibodies, which are primarily associated with IgG1 or IgG3.…”

Unraveling Castleman: progress in a complex process

“…2 It is a rarely encountered, poorly understood, lymphoproliferative disorder that really comprises a broad spectrum of clinicopathologic entities and has widely variable therapeutic outcomes. 3 Unicentric and multicentric variants have been described. Unicentric CD (UCD) is confined to one lymph node region and is usually treated by lymph node excision; inflammatory symptoms are mild and typically abate with lymph node removal.…”