Multicentric Castleman's Disease

Polyadenopathy is the most distinct characteristic of the disease. In many patients, three or more lymph nodes are affected. Since MCD is associated with a systemic inflammatory response, affected individuals typically present with fatigue, fever, chills and night sweats. Some patients claim nausea and vomiting, and chronic loss of appetite may result in weight loss. An increased vascular permeability, possibly triggered by VEGF, may provoke peripheral edema, pleural effusion or ascites. Pleural effusion is commonly associated with dyspnea and cough. Physical examination of MCD patients frequently reveals hepatosplenomegaly, and in fact, hepatic insufficiency may contribute to hypoalbuminemia and subsequent formation of edema. Jaundice may be noted. Additional complaints consistent with MCD are xerostomia, rash and neurological deficits [8]. MCD may progress to non-Hodgkin lymphoma, particularly in patients infected with HIV.

Patients may claim remission and recurrence, but the disease may also follow a progressive course. Moreover, considerable shares of MCD patients present with comorbidities. AIDS and Kaposi sarcoma result from infections with HIV and HHV8, respectively. Accordingly, patients presenting with symptoms consistent with MCD should be queried as to a possible prior diagnosis of HIV or HHV8 infection. If such an infection has not been confirmed previously and subsequent diagnostic measures support the diagnosis of MCD, the respective tests should be ordered. Further entities commonly seen in MCD patients are POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) and paraneoplastic pemphigus [9].

Generally, blood samples are obtained next. Laboratory findings typical of MCD are:

• Autoimmune hemolytic anemia
• Pancytopenia
• Polyclonal hypergammaglobulinemia
• Hypoalbuminemia
• Elevated C-reactive protein
• Enhanced levels of IL-6 and VEGF

Distinct diagnostic schemes have been proposed to assure a diagnosis of MCD [8] [10]. Those schemes are mainly based on the presence of fever and a determined number of additional clinical symptoms as well as on the detection of elevated C-reactive protein and other anomalies in blood biochemistry, but they have been shown to be of limited sensitivity [11]. Thus, it is strongly recommended to perform a histopathological analysis of a lymph node biopsy sample. Then, clinical, serological, laboratory and histological results should be interpreted as a whole.

The diagnostic workup of MCD patients further comprises the application of imaging techniques to precisely assess which lymph nodes are affected. Some of them may cause local mass effects besides contributing to systemic inflammation. In severe cases, symptomatic therapy is also required for complications like pleural effusion. Plain radiography is often utilized to visualize intrathoracic pathologies, but computed tomography scans may be more sensitive to this end. The latter is also employed for abdominal examinations.

Due to the crucial role of IL-6 in MCD pathogenesis, immunotherapy with monoclonal antibodies directed against this cytokine or its receptor is considered a first-line option. Siltuximab or tocilizumab may be administered to this end. Furthermore, thalidomide may be applied to suppress IL-6-mediated pro-inflammatory events. Bortezomib has been used with similar intentions. Rituximab is a monoclonal antibody directed against CD20, a surface antigen expressed by B cells, and is frequently used instead of the aforementioned compounds. Immunotherapy may be combined with corticosteroids - prednisone is commonly prescribed - or chemotherapeutics like cyclophosphamide or etoposide. Chemotherapy is generally reserved for severe cases and aggressive disease. Underlying viral infectious diseases may be treated with virostatics like cidofovir, ganciclovir or valganciclovir. Treatment recommendations have not yet been established and thus, therapeutic regimens encountered in the literature vary considerably [4]. Recurrence after cessation of drug therapy is likely and many patients require life-long maintenance therapy.

Contrary to UCD, surgical resection of affected lymphatic tissue is generally not an option promising cure of MCD. However, space-occupying lesions causing complications may be resected.

A patient's prognosis depends on their status regarding an infection with HIV and the subtype of MCD as assessed by histopathological analyses of tissue specimens. To date, MCD patients who test positive for HIV still have a poor prognosis. According to a retrospective study considering more than 400 cases of MCD, none of the HIV-positive patients presented with the hyaline vascular variant of the disease and their 3-year disease-free survival rate was nearly 28% [8]. Histopathologically similar cases in HIV-negative patients were associated with a disease-free survival rate of 46%.

The etiology of MCD is only poorly understood. The disease may be related to present infections with HIV and human herpesvirus-8 (HHV8, also referred to as Kaposi's sarcoma-associated herpesvirus). In fact, patients who suffer from immunodeficiency due to an infection with HIV are prone to an infection with HHV8, an opportunistic pathogen. Thus, it is not uncommon for MCD patients to test positive for both viruses. Dysregulated cytokine release has been identified as a major pathomechanism in MCD and it has been suggested that HIV and HHV8 may induce an inappropriate immune response [2]. In detail, persistent B cell activation due to virus replication in these cell populations, virus-mediated effects on lymphocyte differentiation as well as the production of a viral homologue of IL-6 by HHV8, all imply immunopathogenic mechanisms to be involved in the onset of MCD. Still, MCD patients may test negative for HIV and HHV8 [3]. This form of the disease is deemed idiopathic. Viral infections with pathogens distinct from those known to be associated with the disease, immune disorders as well as neoplasms have been suggested to account for these cases, but reliable evidence has not yet been provided to this end.

Recently, epidemiological data regarding MCD have been provided for the United States [4]. Although most cases were described in Caucasians, this observation may represent the demographic composition of the population rather than a racial predilection. People of African and Asian descent have also been diagnosed with the disease. About 60% of all patients were males. The median age of symptom onset was 55 years, but young adults were also shown to suffer from the disease. Of note, MCD has occasionally been reported in pediatric patients [5]. In some instances, MCD at a young age may be explained by immunodeficiency due to virus infection, but this does not apply to all such cases. Based on data collected, the overall incidence of MCD has been estimated to be 0.15 per million person-years. Prolonged survival of HIV patients due to improvements of therapy may eventually be accompanied by an increasing incidence of MCD [6].

Histopathologists distinguish three subtypes of CD, and analyses to this end are of prognostic value [7]. On one hand, lymphofollicular hyperplasia may be accompanied by prominent capillary hyalinization. The latter feature is why this form of the disease is known as hyaline vascular CD. In other patients, capillary hyalinization cannot be observed. Instead, plasma cells are arranged concentrically ("onion skin-like patterns") around the secondary follicles of lymph nodes. Moreover, plasma cells predominate in interfollicular regions, and consequently, this variant has been designated plasma cell MCD. A detailed characterization of B lymphocytes observed in tissue samples obtained from MCD patients allowed for the identification of a plasmablastic form of the disease. Plasma cells prevail in these specimens, too, but show an abnormal morphology with prominent nucleoli. Plasmablastic MCD behaves aggressively and is most common in HIV-positive patients.

The pathophysiological hallmark of MCD is hypercytokinemia, and patients generally present with increased serum concentrations of IL-6. This cytokine promotes B cell differentiation into plasma cells and stimulates the proliferation of this subpopulation of lymphocytes. Furthermore, IL-6 may trigger an acute phase response and fever as well as the vascular endothelial growth factor (VEGF). VEGF, in turn, induces angiogenesis. VEGF expression has been shown in lymph nodes of MCD patients, but could not be proven in samples obtained from a control group. Further studies are required, though, to clarify how VEGF is involved in MCD pathogenesis.

Because MCD is frequently associated with HIV infection, particularly AIDS; measures to prevent contracting the sexually transmitted disease may also reduce the individual risk of developing MCD. Such measures comprise the use of condoms and the reduction of sexual partners. Because the risk of HIV transmission is highest during anal sexual intercourse, men who have sex with men are considered a risk group, and this may indeed explain the observed predilection for males in studies regarding MCD. Implementation of needle-exchange programs may help to reduce HIV transmission among people abusing illicit drugs; patients who inject drugs should be advised to never share their needles with anyone.

In general, Castleman's disease refers to a rare disease primarily characterized by lymphadenopathy. It has first been described by the US-American pathologist Benjamin Castleman in 1954. Castleman and colleagues published a case report depicting a man with enlarged mediastinal lymph nodes [1]. Subsequent histopathological analyses revealed benign hyperplasia of these lymph nodes, while additional alterations of lymphatic tissues were not detected. Today, this entity is known as unicentric Castleman's disease (UCD). In contrast, patients may also develop polyadenopathy due to cytokine disorders and a systemic inflammatory response, and they are diagnosed with multicentric Castleman's disease (MCD). Whereas lymph node specimens obtained from either UCD or MCD patients share some common features, the latter are more prone to become symptomatic. Furthermore, MCD may progress to lymphoma and therapy is a major challenge. Besides monoclonal antibodies directed at cytokines produced in excess, chemotherapeutic drugs are administered in case of an aggressive lymphoproliferative disease. MCD patients may also receive antiviral treatment since viral infectious diseases seem to predispose for or effectively trigger this disorder. In fact, the outcome largely depends on the underlying disease, with patients infected with human immunodeficiency virus (HIV) having the poorest prognosis.

Multicentric Castleman's disease (MCD) is a rare systemic disorder of largely unknown etiology. Patients affected by MCD typically present with fatigue, fever, chills and night sweats, and may note swelling of lymph nodes in distinct regions of their body. Because lymph nodes are not necessarily palpable, the latter condition may only be recognized after imaging studies. Additionally, MCD patients may suffer from peripheral edema, breathing difficulties and cough as well as jaundice. These symptoms result from an excess inflammatory response. In detail, MCD is associated with dysregulated cytokine release, and these mediators stimulate subpopulations of immune cells to differentiate and proliferate. As has been indicated above, the precise trigger of these pathophysiological events remains unknown. However, there is a significant correlation between MCD and present infections with the human immunodeficiency virus (HIV) and/or human herpesvirus-8. The former causes AIDS, the latter is related to specific forms of cancer. Some MCD patients test negative for both pathogens, though.

Diagnosis of MCD involves clinical, laboratory and histopathologic studies. Thus, if a patient presents with symptoms consistent with MCD, their physician will obtain blood samples and perform a biopsy of an affect lymph node. Detailed examination of biopsy samples is of prognostic value since distinct subtypes of MCD are related to better or worse outcomes. In general, poorest outcomes are to be expected in HIV-positive patients. Therapy comprises immunomodulatory medication directed against excess cytokines, corticosteroids to reduce inflammation, chemotherapeutics to prevent further proliferation of lymphocytes, and antiviral therapy to treat the underlying disease. Some patients may require life-long maintenance therapy to avoid relapses. This is of particular importance since MCD patients are at relatively high risks of developing non-Hodgkin lymphoma, a type of malignant neoplasm originating from immune cells.

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