**3. Pathology**

Two distinct variants have been described in CD: the hyaline vascular and plasma cell variant. Where features of both these varieties occur, it is referred to as the mixed type or variant [2,5].

The hyaline vascular variant is characterised by follicles which show prominent vascular proliferation and hyalinization of the central portion. There is concentric layering of the lymphocytes at the periphery of the follicles (mantle zone) – referred to as 'target follicles' and imparting a classical 'onion-skin' appearance (see Figure 1). Another feature of this variety is the presence of prominent sclerotic blood vessels which penetrate radially into the germinal centres and transfix it,resulting in a 'lollypop'follicle appearance (see Figure 2). The interfollic‐ ular stroma is also prominent, with numerous hyperplastic vessels, plasma cells, eosinophils, and immunoblasts. The hyaline vascular variety is most commonly associated with UCD [2,6].

The plasma cell variant is characterised by a diffuse interfollicular plasma cell proliferation. Intermingled with the plasma cells are immunoblasts, lymphocytes, and histiocytes. Features of the hyaline vascular variant are typically inconspicuous or absent. This variety is most commonly associated with MCD [2,5,6]. The histopathological characteristic of MCD is the presence of large, abnormal plasmablasts located within the mantle zones of involved lymph nodes [13,14].

of patients in 1956 [1]. It is a heterogeneous disorder, manifesting clinically as a unicentric (solitary; localised) or multicentric disease and pathologically as hyaline vascular, plasma cell

The multicentric variety is aetiologically linked to human herpes virus-8 (HHV-8) [7]. It is strongly associated with immunosuppression and is now being encountered with increasing

This review will focus on CD, with particular reference to Multicentric Castleman's disease (MCD), and it will include a description of the disease as seen at Chris Hani Baragwanath Academic Hospital (CHBAH), Johannesburg, South Africa over a 25-year period (1990 to 2014). The renewed interest in MCD stems from its association with HIV, particularly in areas such as sub-Saharan Africa where HIV has reached pandemic proportions, with South Africa being home to approximately 6.4 million people living with HIV/AIDS (acquired immunodeficiency

Castleman's disease (CD), from being rare, is now more commonly encountered. In the last three decades since the discovery of HIV, the incidence of MCD has progressively increased over time. The median age at presentation of MCD is 40 (21–67) years, with a male predomi‐ nance of 90%, based on a systematic review of published cases in the literature up to 2007 [10]. A younger age at presentation is noted in HIV-seropositive individuals with MCD compared

Two distinct variants have been described in CD: the hyaline vascular and plasma cell variant. Where features of both these varieties occur, it is referred to as the mixed type or variant [2,5]. The hyaline vascular variant is characterised by follicles which show prominent vascular proliferation and hyalinization of the central portion. There is concentric layering of the lymphocytes at the periphery of the follicles (mantle zone) – referred to as 'target follicles' and imparting a classical 'onion-skin' appearance (see Figure 1). Another feature of this variety is the presence of prominent sclerotic blood vessels which penetrate radially into the germinal centres and transfix it,resulting in a 'lollypop'follicle appearance (see Figure 2). The interfollic‐ ular stroma is also prominent, with numerous hyperplastic vessels, plasma cells, eosinophils, and immunoblasts. The hyaline vascular variety is most commonly associated with UCD [2,6]. The plasma cell variant is characterised by a diffuse interfollicular plasma cell proliferation. Intermingled with the plasma cells are immunoblasts, lymphocytes, and histiocytes. Features of the hyaline vascular variant are typically inconspicuous or absent. This variety is most commonly associated with MCD [2,5,6]. The histopathological characteristic of MCD is the

frequency in patients with HIV (human immunodeficiency virus) infection [8].

or mixed variants [2–6].

248 Immunopathology and Immunomodulation

syndrome) [9].

**3. Pathology**

**2. Epidemiology**

to HIV-seronegative MCD [11,12].

The mixed variant or type of CD shares morphological features between the hyaline vascular variant and plasma cell variant. It is classically encountered in MCD and is typically seen in HIV-associated MCD [4,5].

**Figure 1.** Haematoxylin and Eosin stained section of lymph node (100× magnification) showing the concentric layering of lymphocytes in the mantle zone of the lymphoid follicle – 'onion-ring' appearance

The pathogenesis of CD involves an interplay between viruses, namely HHV-8 and HIV, cytokines such as IL-6 (interleukin-6) and IL-10, and growth factors such as VEGF (vascular endothelial growth factor) [15,16].

Multicentric Castleman's disease (MCD) is aetiologically linked to HHV-8 [7]. Human Herpesvirus 8 is a gamma herpes virus and the causative organism in KS [17]. Soulier et al, 1995 [7], showed that HHV-8 sequences were detected in lymph nodes in 14/14 (100%) cases of HIVassociated MCD, compared to 7/17 (41%) cases with HIV-negative MCD. Other studies have demonstrated an almost universal association of HHV-8 with HIV-associated MCD [11,18].

Interleukin-6 levels are increased in CD. A raised CRP, a surrogate marker for IL-6, anaemia, hypergammaglobulinemia, plasmacytosis, splenomegaly, and lymphadenopathy are all

**Figure 2.** Haematoxylin and Eosin stained section of lymph node (200× magnification) showing the radially penetrat‐ ing blood vessels transfixing the germinal centre – 'lollipop' appearance

**Figure 3.** Human Herpesvirus-8 immunohistochemical stain showing mantle zone concentricity and distinct HHV-8 positive nuclear staining of lymphoid cells in the mantle zone (100× magnification)

associated with elevated levels of IL-6 [15,16]. Increased VEGF expression is also noted in CD and is likely to be responsible for the increased angiogenesis component of the disease [19].

The diagnosis of CD is based on a combination of compatible clinical features together with distinct histopathological features characteristic of the disease. Importantly, other benign and malignant disorders with overlapping clinical and histological features should be excluded. Recently, diagnostic criteria have been proposed for patients with MCD, particularly in association with HIV [20,21]. These include the French ANRS (Agence Nationale de Recher‐ chesurle SIDA) criteria and the National Cancer Institute (NCI) criteria [20,21]. The diagnostic criteria devised by these two groups complement the histopathological findings and are particularly useful in those with idiopathic MCD. However, in HIV and HHV-8 associated MCD, the histopathological diagnosis has been made much easier due to the presence of DNA tests to detect HHV-8 in the blood and HHV-8 immunostaining of the tissue. Thus, Bower et al, 2014 [22], suggest that in these individuals a triad of 'B' symptoms, elevated plasma HHV-8 levels and histopathological findings should suffice in making the diagnosis of MCD.
