What is the etiopathogenesis of Castleman's disease?

Etiopathogenesis of Castleman's Disease

Overview of Pathogenic Mechanisms

Castleman's disease is a heterogeneous group of lymphoproliferative disorders driven by dysregulated interleukin-6 (IL-6) signaling, with distinct pathogenic mechanisms depending on the subtype: HHV-8-associated disease involves viral-driven cytokine production, while idiopathic multicentric Castleman disease (iMCD) remains poorly understood but involves aberrant immune activation and hypercytokinemia. 1, 2

Classification-Based Pathogenesis

The etiopathogenesis varies significantly by disease subtype:

Unicentric Castleman Disease (UCD)

• Localized lymph node hyperplasia with non-clonal lymphoproliferation, typically representing a reactive process rather than a systemic disorder 1, 3
• The exact trigger for the localized immune dysregulation remains unknown 3

HHV-8-Associated Multicentric Castleman Disease (HHV-8-MCD)

• Human herpesvirus-8 (HHV-8) directly drives pathogenesis through viral IL-6 (vIL-6) production, which mimics human IL-6 and triggers systemic inflammatory responses 1, 2
• Strong association with HIV infection, where immunosuppression allows HHV-8 reactivation and uncontrolled viral replication 2, 3
• The virus infects B cells and induces polyclonal B-cell proliferation through continuous cytokine stimulation 2

Idiopathic Multicentric Castleman Disease (iMCD)

• Etiology remains unknown, but characterized by excessive IL-6 production from an unidentified source 1, 2
• IL-6 receptor polymorphisms may contribute to disease susceptibility and severity 2
• Two distinct clinical-pathologic subtypes exist: iMCD-TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly) and iMCD-NOS (not otherwise specified), suggesting potentially different pathogenic mechanisms within the idiopathic category 1

Central Role of IL-6 Dysregulation

IL-6 hypersecretion is the final common pathway driving the systemic manifestations across all MCD subtypes:

• IL-6 induces hepatic acute-phase protein synthesis, leading to elevated C-reactive protein, fibrinogen, and hepcidin (causing anemia) 1
• Promotes B-cell proliferation and plasma cell differentiation, resulting in hypergammaglobulinemia and lymphadenopathy 1, 2
• Drives VEGF production, contributing to vascular permeability, edema, and organomegaly 1
• The success of anti-IL-6 therapies (siltuximab, tocilizumab) validates IL-6 as the central pathogenic mediator 4, 5

Histopathological Substrate

Three histological patterns exist, though they do not strictly correlate with clinical behavior:

• Hyaline vascular type: characterized by follicular hyperplasia with hyalinized vessels penetrating germinal centers 1, 2
• Plasmacytic type: marked by sheets of plasma cells in interfollicular regions, more commonly associated with systemic symptoms 1, 2
• Mixed cellularity type: features of both patterns 2, 3

Associated Conditions and Secondary Forms

Castleman's disease can occur as a secondary phenomenon in several conditions:

• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) may be associated with Castleman-like lymph node changes 6, 1
• Immune complex-mediated MPGN (membranoproliferative glomerulonephritis) can be triggered by Castleman disease through chronic antigenemia 7
• Mixed cryoglobulinemia has been reported in association with Castleman disease 7

Key Pathogenic Uncertainties

Despite advances, critical gaps remain:

• The trigger for IL-6 overproduction in iMCD is unknown, distinguishing it from HHV-8-MCD where viral IL-6 is the clear driver 2, 3
• Genetic susceptibility factors beyond IL-6 receptor polymorphisms have not been identified 2
• Why some patients develop life-threatening TAFRO variant while others have indolent disease remains unexplained 1
• The relationship between histological subtype and clinical behavior is inconsistent and poorly understood 2, 3