Historical and pathological overview of Castleman disease

Abstract

Castleman disease consists of several lymphoproliferative subtypes that share some histological features in the lymph nodes. On the other hand, numerous clinical findings and etiologies make the disease challenging to understand. The origin of the disease is the hyaline vascular-type unicentric Castleman disease (UCD), first reported by Benjamin Castleman et al. in 1954. Although UCD is characterized by localized lesions and lack of symptoms, multicentric Castleman disease (MCD) with multiple lesions and systemic symptoms was reported by Frizzera in 1983. MCD is further divided according to KSHV/HHV8 infection status. In KSHV/HHV8-related MCD, viral infection signals lead to excessive cytokine production, and cause clinical and pathologic abnormalities. Some cases of plasma cell-type KSHV/HHV8-negative MCD can be found in association with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes), which is a paraneoplastic syndrome. The others are idiopathic MCD, which are currently considered a heterogeneous group of diseases with overlapping pathological and clinical features. In this article, we summarize the historical evolution of Castleman disease to help understand the disease concept. We also review the latest ideas and definitions of the subtypes within the MCD spectrum and summarize the histopathological findings.

Keywords: Castleman disease; TAFRO syndrome; idiopathic multicentric Castleman disease; idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia.

Fig. 1

Chronological history of Castleman disease (reference numbers: 1-10, 12). Abbreviations: CD, Castleman disease; HV, hyaline vascular; PC, plasma cell; UCD, unicentric CD; iMCD, idiopathic multicentric CD; Kaposi sarcoma associated herpesvirus/human herpes virus 8.

Fig. 2

Classification of Castleman disease (CD). CD is divided into several subtypes according to its clinical presentation, histological findings, and etiology. iMCD itself encompasses a heterogeneous group of diseases. iMCD with TAFRO symptoms has been established as an independent entity, and it usually shows hypervascular-type histology. iMCD without TAFRO-symptoms is defined as iMCD-NOS, and usually shows plasma cell-type histology with varying degrees of vascularization. Abbreviations: UCD, unicentric CD; MCD, multicentric CD; HV, hyaline vascular; PC, plasma cell; iMCD, idiopathic MCD; POEMS, polyneuropathy, organomegaly, endocrinopathy, M-proteins, and skin changes; KSHV/HHV-8, Kaposi sarcoma associated herpesvirus/human herpes virus 8; TAFRO, thrombocytopenia, anasarca, myelofibrosis, renal dysfunction and organomegaly; NOS, not otherwise specified; HyperV, hypervascular; IPL, idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia.

Fig. 3

Histological findings of HV-UCD. (a, H&E) Follicles with an atrophic germinal center and increased vascularity in the interfollicular area are shown. (b, CD21 staining) CD21 immunostaining reveals prominent follicular dendritic cells. (c and d, H&E) The atrophied germinal center is penetrated by blood vessels with hyalinized walls, and the vessels often show radial or dendritic morphology. (e, H&E) Altered follicle structures with expanded mantle zones are shown. (f, H&E) Broad hyalinized collagen fibers are present in the lesion.

Fig. 4

Atypical dendritic cells in the germinal center and interfollicular area are seen in HV-UCD. (a and b, H&E) Multinucleated giant cells resembling Warthin–Finkeldey cell are observed in the germinal center area and interfollicular area. These cells are positive for CD21 (c) and CXCL13 (d) and correspond to dysplastic dendritic cells.

Fig. 5

Lymph node histology in a patient with a plasma cell neoplasm associated with POEMS syndrome. (a, H&E) Prominent plasma cell proliferation and hypervascularization in the interfollicular area are observed. In situ hybridization for Igκ (b) and Igλ (c) revealed lambda light chain restriction.

Fig. 6

Histological findings of KSHV/HHV8-associated MCD. (a, H&E) Increased number of plasmablasts (arrowheads) in the mantle cell zones is observed. (b, HHV8-encoded latent nuclear antigen-1) Immunostaining for HHV8 highlights the infected plasmablasts.

Fig. 7

Concepts of TAFRO syndrome and iMCD-TAFRO. “TAFRO syndrome” includes iMCD-TAFRO and a group associated with other comorbidities.

Fig. 8

Histological findings of iMCD-TAFRO. (a, H&E) The involved lymph node is mildly enlarged (scale bar: 1000 μm). (b-d, H&E) Regressed germinal center and marked hypervascularization with plump endothelial cells in the interfollicular area are shown. Hyalinization of vessel wall is not apparent. (e, H&E) Hypercellular bone marrow. (f, H&E) Megakaryocytic hyperplasia is observed. (g, Silver impregnation staining) Silver staining highlights reticulin fibrosis.

Fig. 9

Histological findings in a patient with systemic lupus erythematosus. (a and b, H&E) Lymph node biopsy revealed an atrophic germinal center. In the expanded interfollicular area, prominent vascular proliferation and sheet-like plasmacytosis are observed.

Fig. 10

Histological findings of iMCD-NOS (plasma cell-type iMCD). (a, H&E) The interfollicular area is markedly expanded. (b, H&E) Sheet-like plasma cell proliferation is seen in the expanded interfollicular area, accompanied by hemosiderin deposition. (c, H&E) Russel bodies (center of the image) are often observed, reflecting increased immunoglobulin production. (d, IL-6 immunostaining) Immunostaining of IL-6 is strongly positive in plasma cells in the interfollicular area and in B cells in the germinal center.