Multicentric Castleman disease: Where are we now?

doi:10.1053/j.semdp.2016.05.006

Seminars in Diagnostic Pathology

Volume 33, Issue 5, September 2016, Pages 294-306

https://doi.org/10.1053/j.semdp.2016.05.006 Get rights and content

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.

Section snippets

Historical background

In 1954, Castleman and Towne¹ reported the first case of Castleman disease presenting as a large mediastinal mass in a 40-year-old male patient. Histological examination revealed hyperplastic lymphoid tissue with hyalinized germinal centers that mimic Hassall corpuscles. In a subsequent report of 12 more cases, Castleman et al.² further characterized the clinicopathologic findings. The patients all presented with enlarged mediastinal masses with none or only mild nonspecific systemic symptoms.

Hyaline vascular Castleman disease

Hyaline vascular type comprises more than 90% of unicentric Castleman disease. It has a broad range of age distribution from pediatric to elderly patients. There is no predilection for either gender. Most patients present with a localized mass without constitutional symptoms or laboratory abnormalities. The mediastinum is the most common location, although the disease can also occur in extrathoracic sites such as the abdomen or neck.4, 14 Surgical excision is the treatment of choice, and

KSHV/HHV8-associated multicentric Castleman disease

Although MCD was initially separated from unicentric CD by its multifocal nature, it is now clear that it represents a different disease with different pathogenesis and much worse clinical outcome. Virtually all MCD cases in HIV-positive patients are associated with KSHV/HHV8, although KSHV/HHV8-positive MCD can also occur in HIV-negative patients. The patients typically present with flares of symptoms including fever, sweats, fatigue, cachexia, lymphadenopathy, splenomegaly, cytopenia, and

KSHV/HHV8-negative idiopathic multicentric Castleman disease

Since the discovery of KSHV/HHV8 in MCD,¹² intensive investigations have established the causative role of KSHV/HHV8 in the pathogenesis of MCD in all HIV-positive cases as well as in some HIV-negative patients. However, for the remaining cases of MCD that are negative for KSHV/HHV8, the etiology remains obscure. Those cases have been collectively denoted as idiopathic MCD (iMCD).¹³

Like KSHV/HHV8-associated MCD, iMCD is also characterized by proinflammatory hypercytokinemia. Several cytokines

Conclusions

In this article, we reviewed the current knowledge of Castleman disease, with an emphasis on MCD that is often diagnostically challenging. The challenges arise from several sources. First, the pathological findings are not specific, and can be seen in many conditions. Secondly, the presentation is heterogeneous. The heterogeneity may result from different disease stages or interplay between different etiologic cytokines. Thirdly, the associated viruses, including HIV, KSHV/HHV8, and even EBV

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Published by Elsevier Inc.

Multicentric Castleman disease: Where are we now?

Abstract

Section snippets

Historical background

Hyaline vascular Castleman disease

KSHV/HHV8-associated multicentric Castleman disease

KSHV/HHV8-negative idiopathic multicentric Castleman disease

Conclusions

Blood

Blood

Mod Pathol

Blood

Mod Pathol

Semin Oncol

Curr Opin Virol

Hum Immunol

Blood

J Biol Chem

J Biol Chem

Cancer Cell

Blood

Cancer Cell

Blood

Virology

Am J Pathol

Blood

Blood

Blood

J Mol Biol

Blood

Blood

Cytokine

Blood

Blood

Hum Pathol

Blood

CASE records of the Massachusetts General Hospital weekly clinicopathological exercises: case 40011

N Engl J Med

Localized mediastinal lymphnode hyperplasia resembling thymoma

Cancer

Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations

Cancer

A systemic lymphoproliferative disorder with morphologic features of Castleman׳s disease. Pathological findings in 15 patients

Am J Surg Pathol

Systemic lymphoproliferative disorder with morphologic features of Castleman׳s disease. Immunoperoxidase study of cytoplasmic immunoglobulins

Arch Pathol Lab Med

A systemic lymphoproliferative disorder with morphologic features of Castleman׳s disease: clinical findings and clinicopathologic correlations in 15 patients

J Clin Oncol

Hypervascular follicular hyperplasia and Kaposi׳s sarcoma in patients at risk for AIDS

N Engl J Med

Multicentric angiofollicular lymph node hyperplasia (Castleman׳s disease) followed by Kaposi׳s sarcoma in two homosexual males with the acquired immunodeficiency syndrome (AIDS)

Am J Clin Pathol

Generalized lymphadenopathy with morphologic features of Castleman׳s disease in an HIV-positive man

Cancer

Multicentric Castleman׳s disease in HIV infection: a clinical and pathological study of 20 patients

AIDS

Castleman׳s disease and related disorders

Semin Diagn Pathol

Surgery in Castleman׳s disease: a systematic review of 404 published cases

Ann Surg

Follicular dendritic cell sarcoma. Clinicopathologic analysis of 17 cases suggesting a malignant potential higher than currently recognized

Cancer

Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman׳s disease of the nasopharynx: tracing its evolution by sequential biopsies

Histopathology

A chromosomal abnormality in hyaline vascular Castleman׳s disease: evidence for clonal proliferation of dysplastic stromal cells

Am J Surg Pathol

Hyaline vascular Castleman׳s disease with HMGIC rearrangement in follicular dendritic cells: molecular evidence of mesenchymal tumorigenesis

Am J Surg Pathol

Monoclonality and polyclonality of plasma cells in Castleman׳s disease of the plasma cell variant

Histopathology

An immunohistological and genotypic study of the plasma cell form of Castleman׳s disease

Histopathology

Plasmablastic lymphoma and related disorders

Am J Clin Pathol

Recent advances in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease

Curr Opin Oncol

Immunophenotypic analysis of the Kaposi sarcoma herpesvirus (KSHV; HHV-8)-infected B cells in HIV+ multicentric Castleman disease (MCD)

Histopathology