Castleman disease: delineating the spectrum

Field: Medicine (Health Sciences)

Castleman disease (CD) is a spectrum of disorders that share common histopathological features. The localized form of CD is referred to as unicentric (UCD), and the systemic form as multicentric (MCD); the latter is characterized by episodic systemic inflammatory symptoms and reactive lymphadenopathy. MCD can be chaotic in behaviour and life-threatening, with multiorgan failure resulting from excessive secretion of interleukin 6 (IL6) and other proinflammatory cytokines. Infection with human herpes virus-8 (HHV-8) is well established as an aetiology of human immunodeficiency virus (HIV)-associated MCD and a significant proportion of HIV-negative MCD cases (Suda et al, 2001). Although the classification of MCD was previously based on HIV status, it is now based on HHV-8 status, as it was recently recognized that immunodeficiency associated with HIV infection or other immunocompromised states renders patients vulnerable to infection with HHV-8. Efforts are ongoing to identify other potential aetiologies in HHV-8 negative MCD, now referred to as idiopathic MCD (iMCD); possible aetiologies are viral, inflammatory or neoplastic disorders. As CD is rare, similar to other rare and orphan diseases, scientific and therapeutic progress is limited by suboptimal understanding of disease pathophysiology, a scarcity of data from prospective clinical trials and small numbers of patients reported in the literature, lowering statistical power and limiting meaningful analysis. In rare disorders, it is important to gain experience from larger series of affected patients and to establish collaborative investigations, in order to accelerate understanding of the disorder and its optimal management, and to unify terminologies defining disease subtypes, diagnostic criteria, classification and approach to treatment. In 2012, a group of physicians, researchers and patients was assembled to create the Castleman Disease Collaborative Network (CDCN), with an aim to accelerate progress in conducting research and delineating therapeutic options for CD (Fajgenbaum et al, 2016). This led to progress in our understanding of CD pathophysiology and classification, as well as therapeutic options: for example, IL6 inhibitors were recently approved for treatment of iMCD (Fajgenbaum et al, 2014). An international collaboration of clinicians and pathologists with expertise in CD has since published evidence-based consensus diagnostic criteria for iMCD (Fajgenbaum et al, 2017). A syndrome of thrombocytopenia, anasarca, bone marrow reticulin fibrosis, renal dysfunction and organomealy (TAFRO syndrome) was described in a subset of patients with iMCD. Proposed diagnostic criteria, classification and approach to treatment of TAFRO syndrome was published and the terminology “idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL-type)” applied to non-TAFRO iMCD (Masaki et al, 2016). The ambitious and impressive work presented in this issue by Oksenhendler and colleagues is an important contribution to furthering our understanding of clinical and pathological features, treatment and outcomes of CD. The paper “The full spectrum of Castleman Disease: 273 patients studied over 20 years”, is the largest series of CD patients published to date, other series being limited to double digits at most. The authors report near complete data on the 253 patients who proved to have CD, in whom the diagnosis was confirmed pathologically (Oksenhendler et al, 2017). Findings included 57 (23%) UCD, 169 (67%) HHV-8-positive MCD, including 140 (55%) who were HIV-positive, and 27 (10%) who were HHV-8 negative/iMCD. Most UCD patients were asymptomatic, whereas patients with iMCD and HHV-8 positive MCD had inflammatory symptoms, with a more aggressive course in HHV-8 positive MCD, particularly in those with HIV-infection. Twenty-six of 27 patients who were categorized as iMCD by the investigators proved to fulfil the more recently established criteria for iMCD. The diagnostic criteria for CD require a lymph node biopsy. A not infrequent problem that faces physicians in clinical practice is identifying accessible nodes for biopsy in patients who are suspected to have CD. Patients may present floridly ill and clinically unstable, with little in the way of peripheral tissue for biopsy, and the clinician may be faced with making a probable diagnosis and initiating treatment based on minor criteria and exclusion of other causes. In the future, the role of bone marrow biopsy in diagnosing MCD could be explored; there are currently no diagnostic criteria for this disorder on bone marrow biopsy. Moreover, it is not currently established whether the clinical features of such patients with probable MCD but who do not have a lymph node to biopsy differ significantly from the patients in the current series, and whether they might require a different treatment approach. The role of positron emission tomography (PET) scanning is explored in the Oksenhendler series, and could be further refined going forward. Finally, the impressive numbers of CD patients reviewed in this series notwithstanding, future efforts should include ongoing multicentre collaborations in order to evaluate significant numbers of patients over shorter time periods, and to establish up to date and effective treatment protocols for this rare but potentially life-threatening disorder. The authors have no relevant conflicts of interest to disclose.