Castleman disease

Abstract

Castleman disease (CD), a heterogeneous group of disorders that share morphological features, is divided into unicentric CD and multicentric CD (MCD) according to the clinical presentation and disease course. Unicentric CD involves a solitary enlarged lymph node and mild symptoms and excision surgery is often curative. MCD includes a form associated with Kaposi sarcoma herpesvirus (KSHV) (also known as human herpesvirus 8) and a KSHV-negative idiopathic form (iMCD). iMCD can present in association with severe syndromes such as TAFRO (thrombocytopenia, ascites, fever, reticulin fibrosis and organomegaly) or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder and skin changes). KSHV-MCD often occurs in the setting of HIV infection or another cause of immune deficiency. The interplay between KSHV and HIV elevates the risk for the development of KSHV-induced disorders, including KSHV-MCD, KSHV-lymphoproliferation, KSHV inflammatory cytokine syndrome, primary effusion lymphoma and Kaposi sarcoma. A CD diagnosis requires a multidimensional approach, including clinical presentation and imaging, pathological features, and molecular virology. B cell-directed monoclonal antibody therapy is the standard of care in KSHV-MCD, and anti-IL-6 therapy is the recommended first-line therapy and only treatment of iMCD approved by the US FDA and EMA.

Figure 1.. Common pathogenic mechanisms in KSHV-MCD and other KSHV-associated diseases.

Schematic picture of a lymph node follicle with Kaposi sarcoma (KS) herpesvirus (KSHV)-infected B cell plasmablast. These cells express KSHV lytic proteins and some express the cell surface receptor CD20. The KSHV-positive plasmablasts also express high amounts of both human IL-6 (hIL-6) and viral IL-6 (vIL-6). It is hypothesized that both of these cytokines can in turn elicit other cells (for example, plasma cells in the lymph node) to secrete vascular endothelial growth factor (VEGF) or that the KSHV-infected cells themselves express VEGF. VEGF can then induce the endothelial cells that are present in the lymph node to proliferate and to secrete more hIL-6 in a feedforward loop that augments the proliferation of both B cells and endothelial cells in the lymph node. Elevated levels of other cytokines, such as IL-10, IL-1β and TNF, are also observed in KSHV-multicentric Castleman disease (MCD) and other KSHV-associated diseases. KSHV contributes to the development of several lymphoid proliferations, especially primary effusion lymphoma and its variants, through a group of virally encoded proteins (not shown).

Figure 2.. Unicentric Castleman disease.

a | A lymphoid follicle with vascular transformation (VT) of the germinal centre (GC). b | Lymphoid follicle in which the GC is replaced by a CD21+ dense meshwork of dysplastic follicular dendritic reticulum cells (DRC) and vascular channels with high endothelium. Magnification x10 (both images).

Figure 3.. Histological features of the plasma cell variant of iMCD.

a | Haematoxylin and eosin staining shows sheets of plasma cells in the interfollicular areas with relatively well-formed germinal centres in plasma cell variant of idiopathic multicentric Castleman disease (iMCD). b | Plasma cells in the interfollicular areas are strongly stained for CD. Adapted with permission from ref., Elsevier.

Figure 4.. KSHV-MCD and KSHV-MCD with concurrent KS.

a | The lymphoid follicle has a high degree of vascular proliferation. It also has typical penetrating hyalinized vessels (PHV). The inset shows plasmablasts in the mantle zone. b | Latency-associated nuclear antigen (LANA1) staining shows the characteristic Kaposi sarcoma (KS) herpesvirus (KSHV)-positive plasmablasts (brown) in the mantle zone. Magnification x10 (panels a and b); insets magnification x40. c | Marked interfollicular endothelial proliferation consistent with KS. d | Plasmablast infected cells (brown). e | In the mantle zone, typical endothelial cells are positive for LANA1 (arrows). In the follicular mantle, some large atypical cells, consistent with plasmablasts, are also positive for LANA1 (circled). f | KS spindle cells (brown) in the tumour. Magnification x20 (panels c and e); x60 (panels d and f). MCD, multicentric Castleman disease.

Figure 5.. The management of UCD.

The figure highlights the guidelines of the optimal treatment for resectable and unresectable unicentric Castleman disease (UCD). iMCD, idiopathic multicentric Castleman disease.

Figure 6.. Management of iMCD.

The figure provides an overview of the management of severe and non-severe (mild or moderate) idiopathic multicentric Castleman disease (iMCD) based on available publications–. Adapted with permission from ref., Elsevier.