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 that 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.

Keywords: Acquired immune deficiency syndrome; Castleman disease; Human herpesvirus type-8; Interleukin-6; Kaposi sarcoma-associated herpesvirus; TAFRO syndrome.

Figure 1. Classification of Castleman disease

UCD: unicentric Castleman disease; MCD: multicentric Castleman disease; HV: hyaline vascular; PC: plasma cell; iMCD: idiopathic multicentric Castleman disease.

Figure 2. Hyaline vascular Castleman disease

A. H&E stain showing the hyaline vascular changes of the lymphoid follicles including the penetrating hyalinized vessels, layered mantle cells and twinning of the germinal centers. B. H&E stain showing occasional dysplastic follicular dendritic cells within the follicles.

Figure 3. Multicentric Castleman disease

A. Low magnification shows marked vascular proliferation in the paracortex, with increased vascularity within a reactive germinal center. B. High magnification H&E stain showing the plasmablastic cells in the mantle zone. C. Immunohistochemical stain for KSHV/HHV-8 encoded LANA-1 highlighting the infected plasmablasts in the mantle zone. D. Immunostain for vIL-6 showing that the plasmablasts express vIL-6. E-F. Immunohistochemical stains for immunoglobulin κ and λ light chains showing restricted expression of λ light chain in the plasmablasts (arrow), while the plasma cells in the interfollicular areas are polyclonal.

Figure 4. Germinotropic lymphoproliferative disorder

A–B: H&E stains showing confluent aggregates of atypical plasmablasts within the involved germinal centers. C. Immunohistochemical stain for KSHV/HHV-8 encoded LANA-1 highlighting the atypical plasmablasts. D. In-situ hybridization for EBV-encoded RNAs (EBER) showing co-infection of EBV in the atypical plasmablasts.

Figure 5. Histologic features of the plasma cell variant of idiopathic multicentric Castleman disease (iMCD) and TAFRO syndrome

A–B: plasma cell variant of iMCD; C-F: TAFRO syndrome. A: H&E stain showing sheets of plasma cells in the interfollicular areas with relatively well formed germinal centers in plasma cell variant of iMCD. B. CD138 stain highlighting sheets of interfollicular plasma cells. C. H&E stain showing prominent vascular proliferation and atrophic germinal centers in TAFRO syndrome. D. CD138 demonstrating a lesser extent of plasmacytosis in the interfollicular areas. E. H&E stain highlighting marked vascular proliferation with plump endothelial cells. F. Bone marrow biopsy/aspirate showing megakaryocytic hyperplasia with occasional emperipolesis in megakaryocytes.