Multicentric Castleman’s disease: expert opinion

Castleman’s disease (CD) is not a single entity, but a group of disorders that share some morphological and, in part, clinical features. It is characterised by localised or generalised lymphadenopathy, and in the case of multicentric Castleman’s disease (MCD), often accompanied by organomegaly and a broad range of clinical symptoms, with characteristic morphological findings and absence of lymphocyte clonality. Altogether, CD is rare, with the unicentric form clearly being predominant. For MCD, estimates on incidence and prevalence are difficult due to the lack of reliable registry data and the difficulties in diagnosing the disease. A recent study by Robinson and colleagues (see selected reading) gave an estimated ten-year prevalence rate of 2.4/million for the US.

Clinically, one discriminates the unicentric form presenting as a solitary mass lesion, for example, in the mediastinum, usually without systemic symptoms, often in young adults, and the multicentric form, which is usually accompanied by a variety of systemic symptoms. Morphologically, the unicentric form corresponds to hyaline vascular CD (Figure 1), and the multicentric form to the plasma cell variant (Figure 2). Although morphologically cases with mixed features can be observed, the use of the term ‘CD of mixed type’ is discouraged, because the two forms represent two pathogenetically distinct disorders.

Unicentric CD of hyaline vascular type is regarded as a disorder of follicular dendritic cells, which show features of dysplasia and clonal cytogenetic abnormalities, whereas the lymphocyte population is reactive and lacks clonal gene rearrangements. Further evidence for its derivation from follicular dendritic cells is the occurrence of tumours/sarcomas of follicular dendritic cells arising in the background of hyaline vascular CD. The causes for unicentric/hyaline vascular CD are unknown.

Multicentric CD is usually of the plasma cell variant, but morphologically an overlap with the unicentric form can sometimes be observed, with the appearance of typical regressed germinal centres with concentric ‘onion-skin’ arrangement of lymphoid cells. However, a mandatory feature of the plasma cell type of CD is a massive proliferation of plasma cells in the interfollicular area. Of note, MCD is not a morphological diagnosis, but a clinico-pathological syndrome that requires both typical clinical findings as well as an appropriate morphology in a lymph node biopsy. The plasma cell variant of MCD can be observed in three distinct settings:

In this disorder, osteosclerotic plasma cell myeloma (showing sclerotic bone lesions, in contrast to the osteolytic lesions of conventional myeloma), usually of lambda light chain restriction, is accompanied by a range of paraneoplastic symptoms, which can include Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder and Skin changes (POEMS). Other symptoms include extracellular volume overload (manifesting as oedema, ascites and pleural effusions), papilloedema and thrombocytosis or erythrocytosis.

All forms, however, are characterised by a hyperinflammatory syndrome caused by overproduction of cytokines, mainly interleukin-6 (IL-6), which results in a variety of constitutional symptoms, disturbances of microcirculation with extracellular fluid accumulations, haematological disturbances and other abnormal laboratory findings. In HHV8-associated MCD, viral homologue of IL-6 is considered to trigger the systemic symptoms.

Unicentric CD is diagnosed by the pathologist when a mass lesion is excised, usually under the suspicion of a malignancy, for example, lymphoma.

Patients with MCD, due to the mostly non-specific symptoms, often present with a long history of varying complaints of uncertain aetiology, and the differential diagnosis includes malignancies, mainly lymphoma due to the lymphadenopathy and organomegaly, autoimmune disorders and chronic infectious disease. In contrast to unicentric CD of hyaline vascular subtype, which is in most cases a straightforward morphological diagnosis, histopathology alone is not sufficient for diagnosis of MCD, because similar lymph node patterns may be observed in a variety of settings, and the diagnosis requires the presence of both typical clinical findings and appropriate morphology. Therefore, to secure a diagnosis of MCD requires close collaboration between clinician and pathologist.

Prognosis of unicentric CD is excellent, and surgical removal of the mass is the treatment of choice.

For MCD, prognosis is much more guarded, and depends on the underlying condition. Prognosis for HHV8+ MCD in HIV infection is generally poor, both due to the underlying immunodeficiency and the emergence of HHV8-associated malignant lymphoma, but has improved significantly in recent years with treatments targeting proliferating B-cells, such as rituximab. In idiopathic MCD, treatments blocking the effects of IL-6 overproduction have shown promise and have resulted in an improved outlook for the patients. Although epidemiological survival data are lacking, recent surveys have found a ten-year survival rate of around 40%, up from less than 15% two decades earlier.

A broad range of laboratory abnormalities can be encountered in MCD, including anaemia, elevated erythrocyte sedimentation rate, increased C-reactive protein and fibrinogen, positive anti-nuclear antibodies and autoantibodies against blood cells, proteinuria, hypoalbuminaemia, polyclonal hypergammaglobulinaemia, and thrombocytosis or thrombopenia. Elevations of IL-6 and vascular endothelial growth factor are the only alterations that point more strongly to a diagnosis of MCD, but there is no pathognomonic laboratory finding for MCD.

Lymph nodes in hyaline vascular CD show a very characteristic pattern with regressed germinal centres with concentrically arranged lymphocytes in expanded mantle zones, surrounded by a hypervascular interfollicular zone (Figure 1). The regressed germinal centres are often perforated by a radial vessel, the so-called ‘lollipop’ phenomenon. Lymph nodes in MCD are less characteristic, and both hyperplastic as well as regressed germinal centres can be observed. A constant feature of MCD is the interfollicular expansion of polytypic plasma cells (Figure 2). In HHV8-associated MCD, immunostaining for the viral protein, LANA, identifies scattered positive plasmablasts in the mantle zones of follicles (Figure 3).

Rituximab is highly effective in treating HHV-8-associated MCD. Occasionally, etoposide, doxorubicin, and/or antivirals are also used.

There are four main treatment categories:

Over the last decade, treatments directly targeting IL-6 have been employed. Tocilizumab, an anti-IL-6 receptor mAb that is approved to treat iMCD in Japan, has demonstrated effectiveness at inducing and maintaining remission. Siltuximab (Sylvant®) is a novel chimeric human-murine IgG mAb that binds and neutralises human IL-6 with high specificity and affinity, and which has recently been approved by the US Food and Drug Administration and European Medicines Agency. It demonstrated durable tumour and symptomatic response at a significantly higher rate compared with placebo in the first randomised Phase II study in MCD (34% versus 0%; p=0.0012; see selected reading). Both mAbs have shown clinical activity in iMCD and are potential candidates for frontline therapy. However, they require life-long administration and are not effective in all patients.

For idiopathic MCD, identification of the cause(s) of the characteristic hypercytokinaemia (IL-6 elevation) is certainly the most burning question. However, it may well be that there is more than one causative pathway. In terms of therapy, introduction of anti-IL-6 treatments has been a major, and significant, milestone.