ReviewClinical, laboratory and imaging findings in Castleman's disease – The subtype decides
Introduction
Castleman's disease (CD) is a rare heterogenous lymphoproliferative disorder of unknown etiopathogenesis causing non-neoplastic lymphadenopathy. The disease was first described by Castleman et al. in 1956 as a large thymoma-like mass in the anterior mediastinum and later classified in a series of thirteen patients with unicentric localization [1]. In addition to the unicentric form of CD (uCD), Gaba et al. described in 1972 a disseminated or multicentric form of CD (mCD) [2]. This systemic disease is frequently associated with a general immunosuppression, and human herpesvirus-8 (HHV-8) or human immunodeficiency virus (HIV) infection [3]. Histopathologically, three forms can be discriminated: the hyaline vascular, the plasma cell-rich form, and a mixed variant [4].
In uCD, the hyaline-vascular type is known to be with almost 90% of cases the most predominant type, affecting mostly younger patients without a preference in sex. The mediastinum, the abdomen and the axillary and cervical lymph node regions are reported as the most common manifestations [5], [6]. But rare extranodal sites, such as larynx as well as intramuscular, subcutaneous, and intracranial locations, have been described additionally [7]. This form of CD is frequently asymptomatic and often accidentally discovered as a part of a chest X-ray [8], [9]. Laboratory alterations can be found only sporadically [10].
In contrast, mCD is a systemic disease [10], occurring in both an aggressive and a chronic persistent or chronic relapsing course. This form is considered to be a potentially malignant lymphoproliferative disease which may associate with the POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal-proteinaemia, skin changes) syndrome (11–30% of the patients with CD) [11], with HIV infection (estimated incidence in HIV-1 patients 2.3 per 10,000 patient-years in the pre-combination antiretroviral therapy (cART) era prior to 1996, and 8.3 per 10,000 patient-years since 2000) [12], with Kaposi's sarcoma (13% of HIV-negative patients with mCD up to 75% of HIV-positive patients with mCD [31]), or rarely with lymphoma (predominantly B-cell non-Hodgkin's lymphoma (B-NHL) with 71% of all reported cases of association CD-NHL) [13]. In most cases of mCD, histologically the plasma cell type is found. In general, elderly patients are more often affected by the multicentric form.
Though symptoms and laboratory findings vary depending on the variant of disease, both forms are related to an increased release of cytokines. Especially interleukin 6 (IL-6) is closely linked to the activity of the disease [14], [15]. A decrease in symptoms is always associated with a reduction in IL-6 levels, and vice versa [16].
The present work was intended to contribute to a better understanding of the rare and often unknown clinical picture of CD, paying special attention to the differences between the uCD and mCD. Improved knowledge on the signs and symptoms as well as laboratory and imaging findings of CD may accelerate its diagnosis and may enable an earlier adequate treatment.
Section snippets
Search strategy in MEDLINE and selection criteria for analysis
A MEDLINE search using the keyword “Castleman's disease” was conducted. Articles published until September 2011 were limited on German, English, French, and Italian language. For the current analysis, only case reports and case series were considered. Of 1799 articles retrieved, a total of 775 articles fulfilling these criteria were found. From these publications, a total 1133 cases were extracted for further analysis. From our own University Hospital two so far unpublished cases of CD were
Results
As shown in Fig. 1, we analyzed 1135 cases of CD which included two so far unpublished cases from our own facility. UCD was described in 719 patients and mCD in 416 patients.
Discussion
The present study aimed at characterizing in more detail the clinical, laboratory, radiological and therapeutic findings of the rare disorder CD paying special attention to the differences between its two variants, the unicentric and the multicentric forms. Until now, commonly case reports and studies with a limited number of patients reported on the typical characteristics of both forms of CD. In this work, 1135 case presentations of patients with CD including our own two so far unpublished
Practice points
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Clinical signs and symptoms as well as laboratory alterations are rare in uCD, but frequent in mCD, underlining its systemic nature.
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Histologically, the two forms of CD significantly differ, with predominance of the hyaline-vascular type in uCD and predominance of the plasma cell type and two-fold higher frequency of the mixed type in mCD.
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In uCD, the head and neck region is the most affected localization followed by the retroperitoneal space, whereas in mCD, axillary and abdominal manifestations
Research agenda
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A uniform therapy of mCD is not available and treatment recommendations are currently based on case reports, case series and a limited number of clinical trials.
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In light of the rarity of disease, large-scale randomized controlled trials will not be feasible. However, implementation of a registry of this rare disease may allow subtype-specific treatment recommendations in the future.
Conflict of interests
The authors have no relevant conflicts to disclose.
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Both authors contributed equally.