Elsevier

The Lancet Haematology

Volume 3, Issue 4, April 2016, Pages e163-e175
The Lancet Haematology

Articles
Idiopathic multicentric Castleman's disease: a systematic literature review

https://doi.org/10.1016/S2352-3026(16)00006-5Get rights and content

Summary

Background

Multicentric Castleman's disease describes a group of poorly understood lymphoproliferative disorders driven by proinflammatory hypercytokinaemia. Patients have heterogeneous clinical features, characteristic lymph node histopathology, and often deadly multiple organ dysfunction. Human herpesvirus 8 (HHV8) causes multicentric Castleman's disease in immunosuppressed patients. The cause of HHV8-negative multicentric Castleman's disease is idiopathic; such cases are called idiopathic multicentric Castleman's disease. An absence of centralised information about idiopathic multicentric Castleman's disease represents a major challenge for clinicians and researchers. We aimed to characterise clinical features of, treatments for, and outcomes of idiopathic multicentric Castleman's disease.

Methods

We did a systematic literature review and searched PubMed, the Cochrane database, and ClinicalTrials.gov from January, 1995, with keywords including “Castleman's disease” and “giant lymph node hyperplasia”. Inclusion criteria were pathology-confirmed Castleman's disease in multiple nodes and minimum clinical and treatment information on individual patients. Patients with HHV8 or HIV infection or diseases known to cause Castleman-like histopathology were excluded.

Findings

Our search identified 626 (33%) patients with HHV8-negative multicentric Castleman's disease from 1923 cases of multicentric Castleman's disease. 128 patients with idiopathic multicentric Castleman's disease met all inclusion criteria for the systematic review. Furthermore, aggregated data for 127 patients with idiopathic multicentric Castleman's disease were presented from clinical trials, which were excluded from primary analyses because patient-level data were not available. Clinical features of idiopathic multicentric Castleman's disease included multicentric lymphadenopathy (128/128), anaemia (79/91), elevated C-reactive protein (65/79), hypergammaglobulinaemia (63/82), hypoalbuminaemia (57/63), elevated interleukin 6 (57/63), hepatomegaly or splenomegaly (52/67), fever (33/64), oedema, ascites, anasarca, or a combination (29/37), elevated soluble interleukin 2 receptor (20/21), and elevated VEGF (16/20). First-line treatments for idiopathic multicentric Castleman's disease included corticosteroids (47/128 [37%]), cytotoxic chemotherapy (47/128 [37%]), and anti-interleukin 6 therapy (11/128 [9%]). 49 (42%) of 116 patients failed first-line therapy, 2-year survival was 88% (95% CI 81–95; 114 total patients, 12 events, 36 censored), and 27 (22%) of 121 patients died by the end of their observed follow-up (median 29 months [IQR 12–50]). 24 (19%) of 128 patients with idiopathic multicentric Castleman's disease had a diagnosis of a separate malignant disease, significantly higher than the frequency expected in age-matched controls (6%).

Interpretation

Our systematic review provides comprehensive information about clinical features, treatment, and outcomes of idiopathic multicentric Castleman's disease, which accounts for at least 33% of all cases of multicentric Castleman's disease. Our findings will assist with prompt recognition, diagnostic criteria development, and effective management of the disease.

Funding

None.

Introduction

Castleman's disease was first described in case reports published in the 1950s.1, 2 The initial report featured a constellation of histological findings in one region of lymph nodes; case reports describing more than one affected region of lymph nodes were published in the 1970s.3 The observation that Castleman's disease can arise in more than one region gave rise to the first major distinction in the classification of the disease: unicentric versus multicentric. Unicentric Castleman's disease has been treated by surgical lymph node excision, which is curative for most patients.4, 5 By contrast, systemic treatment is needed to control multicentric Castleman's disease effectively.

A sharp increase in reported cases of multicentric Castleman's disease emerged in the 1980s, when the disease was noted in immunocompromised patients with HIV-1 infection.6, 7, 8, 9 In these patients, the disease was frequently associated with Kaposi's sarcoma,10 leading to the discovery that human herpesvirus 8 (HHV8)—also known as Kaposi's sarcoma herpesvirus—caused multicentric Castleman's disease in this subgroup.11, 12 Replication of HHV8 in germinal centre lymph node plasmablasts expresses viral interleukin 6, human interleukin 6, and several other proinflammatory proteins, which cause the characteristic histopathological changes noted in patients with multicentric Castleman's disease and lead to multiple organ dysfunction.13, 14 The pathological role of HHV8—irrespective of HIV infection—has prompted a reclassification of Castleman's disease based on HHV8 status.15, 16

Research in context

Evidence before this study

Before undertaking this study, we were aware of no attempts in published medical literature to characterise idiopathic multicentric Castleman's disease systematically. Although case reports, case series, and clinical trials in idiopathic multicentric Castleman's disease have been published, analysis of these data in aggregate has not been described for clinical features, treatment responses, outcomes, or associations with cancer. We searched PubMed and the Cochrane database between January, 1995, and May, 2013, with the terms: “castleman”, “Castleman's”, “angiofollicular hyperplasia”, “giant lymph node hyperplasia”, “lymph node hamartoma”, “follicular lymphoreticuloma”, “benign giant lymphoma”, “angiomatous lymphoid hamartoma”, “angiofollicular mediastinal lymph node hyperplasia”, “angioimmunoblastic lymphadenopathy with dysproteinemia”, “benign giant lymphoma”, or “idiopathic plasmacytic lymphadenopathy with polyclonal hypergammaglobulinemia”. We retrieved reports published in English and references from relevant reports of all published cases of multicentric Castleman's disease. We searched ClinicalTrials.gov with the terms “Castleman disease” or “Castleman's disease”. A smaller set of terms was used for ClinicalTrials.gov because the number of characters in a search field is restricted. We included cases from reports published in English that contained: pathology-confirmed Castleman's disease in multiple nodes; negative testing for HHV8; and minimum clinical and treatment information on individual patients. Reports were excluded if they referred to: unicentric Castleman's disease, presence of only one mass, or complete remission after surgical resection of one mass, or a combination of these; positive testing for HIV or HHV8; or diagnosis of another disease that could account for the Castleman-like histopathological features—eg, systemic lupus erythematosus or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin abnormalities). 2184 eligible reports were retrieved for review.

Added value of this study

Our study is, to our knowledge, the first and largest systematic characterisation of the clinical features, associated diseases, treatment responses, and outcomes of HHV8-negative idiopathic multicentric Castleman's disease. This information is important because it provides an evidence base with which to establish diagnostic criteria, inform clinical decisions, and focus research efforts. Our review showed that effectiveness of first-line treatment was highly variable across treatment regimens, the disease is deadly, and associated malignant diseases are common.

Implications of all the available evidence

Patients with idiopathic multicentric Castleman's disease should be monitored closely to assess their response to treatment, identify the earliest signs of disease activity, and detect development of malignant diseases. Translational research studies are needed urgently to elucidate the pathophysiology of idiopathic multicentric Castleman's disease and identify novel treatment options for patients who do not respond to anti-interleukin 6 therapy.

A subset of patients show histopathological changes characteristic of multicentric Castleman's disease and clinical features overlapping with HHV8-associated multicentric Castleman's disease but do not have HIV or HHV8 infection.17 In these cases of so-called idiopathic multicentric Castleman's disease, a hypercytokinaemic proinflammatory state arises similar to that seen in patients with HHV8-associated multicentric Castleman's disease, but the cause and pathogenesis are unknown. Compared with HHV8-associated multicentric Castleman's disease, idiopathic multicentric Castleman's disease is more difficult to diagnose, can have unique clinical features, and responds to different treatments.18 The previous idea that multicentric Castleman's disease is driven by benign, interleukin 6-secreting lymph node tumours has shifted: the new model of pathogenesis suggests that enlarged lymph nodes and their characteristic histological features are reactive changes to hypercytokinaemia, often including interleukin 6. Current hypotheses for the cause of idiopathic multicentric Castleman's disease include pathological autoantibodies or germline mutations in genes that regulate the innate immune system (autoimmune/autoinflammatory hypothesis), a small population of malignant cells (paraneoplastic hypothesis), or an undiscovered virus other than HHV8 (viral hypothesis).16

Scant data exist regarding the epidemiology of idiopathic multicentric Castleman's disease. In a study of the epidemiology of multicentric Castleman's disease,19 researchers used an insurance claims database and estimated that 6500–7700 new cases of Castleman's disease are diagnosed every year in the USA, with about 1650 cases of multicentric disease. HHV8 status was not specified.19 Published medical research rarely acknowledges the HHV8-negative subgroup of multicentric Castleman's disease.20

Idiopathic multicentric Castleman's disease is diagnosed clinicopathologically,21 yet no official criteria exist for its diagnosis, and symptoms are poorly defined. Typically, idiopathic multicentric Castleman's disease is diagnosed when characteristic Castleman-like lymph node histopathological features are recorded, HHV8 testing is negative, and other well defined diseases that are known to cause these histopathological features are excluded. Commonly reported clinical features are fever, night sweats, weight loss, lymphadenopathy, ascites, pleural effusions, and hepatosplenomegaly. A subset of patients with idiopathic multicentric Castleman's disease has emerged in the past few years with a syndrome known as TAFRO, characterised by thrombocytopenia, ascites, fever, reticulin fibrosis in bone marrow, organomegaly, and normal amounts of γ-globulin. First described in Japan in 2010,22 TAFRO has gained recognition, with more than 35 cases reported in Japan,23, 24, 25 Europe,26, 27 and the USA.28

The four commonly recognised histopathological variants of Castleman's disease are hyaline vascular, plasma cell, mixed pathology, and plasmablastic. Plasmablastic lymph node changes are connected exclusively with HHV8-associated multicentric Castleman's disease and will not be discussed further here. Hyaline vascular lymph node changes are characterised by hyalinised vessels that penetrate small, atrophic, germinal centres. Around these germinal centres are concentric rings of small lymphocytes that comprise a widened mantle zone. Plasma cell and mixed pathology variants are characterised by hyperplastic germinal centres and a proliferation of plasma cells in interfollicular regions, and some hyaline vascular features.

Various treatments have been used for patients with idiopathic multicentric Castleman's disease (panel). Corticosteroids, immunomodulatory or immunosuppressive agents, and cytotoxic chemotherapy have served historically as the mainstay of treatment, borrowing from regimens in lymphoma and multiple myeloma. More recently, biological anti-interleukin 6 treatments have been developed. Siltuximab, which targets interleukin 6 directly, has been approved for idiopathic multicentric Castleman's disease in the USA, Canada, and Europe, after findings of a double-blind, placebo-controlled, phase 2 trial showing significantly higher durable tumour response (lymph node regression) and symptomatic response (2% complete response and 32% partial response) compared with placebo (0%; p=0·0012).29 Tocilizumab, which targets the interleukin 6 receptor, was approved in Japan in 2005 and has been used off-label around the world for idiopathic multicentric Castleman's disease. In an open-label prospective study of 28 patients on tocilizumab, ten (43%) of 23 patients with enlarged lymph nodes at baseline saw a decrease in size below 10 mm after 16 weeks.30, 31, 32

The presence of clinical and histological features helps to distinguish idiopathic multicentric Castleman's disease from other similar disorders, but an understanding of the frequency of these features is needed to aid accurate characterisation and identification of cases of this disease. Furthermore, an absence of aggregated clinical information and scant understanding of the cause of idiopathic multicentric Castleman's disease has made treatment and management decisions challenging. The sparseness of data on idiopathic multicentric Castleman's disease is an impediment to the delivery of timely and optimum care. We aimed to do the most comprehensive review to date of published medical literature about idiopathic multicentric Castleman's disease, to summarise diagnostic features, prognosis, and treatment modalities associated with this rare and fatal disease.

Section snippets

Search strategy and selection criteria

We did a systematic literature review of clinical features, associated diseases, treatment regimens, and outcomes of idiopathic multicentric Castleman's disease. We identified cases for this review by searching PubMed and the Cochrane database between January, 1995, and May, 2013, with the terms “castleman”, “Castleman's”, “angiofollicular hyperplasia”, “giant lymph node hyperplasia”, “lymph node hamartoma”, “follicular lymphoreticuloma”, “benign giant lymphoma”, “angiomatous lymphoid

Results

Figure 1 shows how we applied our inclusion and exclusion criteria. Our systematic review of work published since 1995 identified 1923 patients with multicentric Castleman's disease. 808 (42%) patients were HHV8-positive, HIV-positive, or both; 489 (25%) were HIV-negative and had unknown HHV8 status; and 626 (33%) patients were HHV8-negative. Thus, HHV8-negative multicentric Castleman's disease accounted for at least a third of all published cases of multicentric Castleman's disease.

128

Discussion

The analysis presented here represents the most comprehensive summary, to date, of clinical data in idiopathic multicentric Castleman's disease, advancing our understanding of the disease in many respects. First, our review of the scientific literature shows that at least a third of all published cases of multicentric Castleman's disease are negative for HHV8 and HIV and are, therefore, idiopathic. Thus, idiopathic multicentric Castleman's disease represents a considerable disease entity that

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