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Imaging in multicentric Castleman's disease.

Multicentric Castleman's disease (MCD) is an uncommon lymphoproliferative disorder that presents with fevers, anaemia and multifocal lymphadenopathy, and nowadays it is most commonly diagnosed in individuals infected with human immunodeficiency virus type-1 (HIV). The first description of Castleman's disease appeared as a case record of the Massachusetts General Hospital in the New England Journal of Medicine in 1954 [1]. Benjamin Castleman, the pathologist at Massachusetts General Hospital, subsequently described 13 cases of asymptomatic localised mediastinal masses demonstrating lymph node hyperplasia resembling thymoma in 1956 [2]. The localised form usually presents in young adults with isolated masses in the mediastinum, neck or abdomen and systemic manifestations are rare. In contrast, HIV-associated MCD presents with polylymphadenopathy and frequently multi-organ involvement, is associated with systemic features, and follows a more aggressive natural history. Patients often present with generalised malaise, night sweats, rigors, fever, anorexia and weight loss but occasionally may present with pancytopenia and organ failure (particularly respiratory and renal), as well as shock requiring admission into intensive care units.

On examination, patients have diffuse lymphadenopathy, hepatosplenomegaly, and may have ascites, oedema and effusions both pulmonary and pericardial. The clinical manifestations include an acute interstitial pneumonitis [3,4] and haemophagocytic syndrome [5], and less frequently neuropathic problems including polyneuropathies, leptomeningeal and CNS infiltration, as well as myasthenia gravis [6]. Laboratory investigations may reveal thrombocytopenia, anaemia, hypoalbuminaemia and hypergammaglobulinaemia.

MCD is a relapsing and remitting disease and the definition of an 'attack' has been proposed as a combination of fever and a raised serum C-reactive protein in the absence of other aetiology, plus three of the following symptoms: peripheral lymphadenopathy, splenomegaly, oedema, pleural effusion, ascites, cough, nasal obstruction, xerostomia, rash, central neurological symptoms, jaundice or autoimmune haemolytic anaemia [7].

There is an association between MCD and AIDS-associated Kaposi's sarcoma (KS) caused by human herpesvirus 8 (HHV8) or Kaposi's sarcoma herpesvirus (KSHV). This virus is also present in all cases of HIV-associated MCD [8] and many of the features of this condition can be explained by its presence. The diagnosis of MCD is established histologically by lymph node biopsy or if necessary splenectomy. The characteristic features are interfollicular plasmablasts that express the HHV8 latent nuclear antigen (LANA). These plasmablasts also express high levels of light-chain restricted IgM, but are polyclonal and do not contain somatic mutations in their IgV genes, suggesting that they arise from naive B-lymphocytes [9]. Occasionally, these plasmablasts join together to form clusters or 'microlymphomas' and may progress to monoclonal plasmablastic lymphomas [10].

The radiological features of HIV-associated MCD have been described in a small series of nine patients, using predominantly the CT scan findings [11], and the extent of organ involvement may be derived from the larger clinical studies of HIV-associated MCD [7,12,13]. The common features include generalised lymph node enlargement (Figure 1), which is present in very nearly all cases, and splenomegaly (Figure 2), which was present in all patients who had a spleen in situ, whilst hepatomegaly was a less universal finding present in 75-85% of patients [11,13]. In general, following the administration of intravenous contrast medium, the enlarged lymph nodes enhanced avidly. Pulmonary radiological abnormalities, usually interstitial pneumonitis, were found in 45-65% (Figure 3) [11,13]. In a separate clinical series the pulmonary manifestations of HIV-associated MCD have been addressed in 12 patients, and the most common finding was an acute reticulo-nodular interstitial pneumonitis; pleural effusions were also frequently present [3]. Table 1 gives an updated review of the CT radiology findings in 42 patients with newly diagnosed, histologically confirmed HIV-associated MCD.

Despite these observations, CT scan findings are not sufficiently reliable to establish a diagnosis of MCD, which requires histological confirmation. The differential diagnosis in people with HIV who present with these clinical findings includes many opportunistic infections, persistent generalised lymphadenopathy and lymphoma. HIV-associated MCD may also be complicated by the co-existence or subsequent development of non-Hodgkin's lymphoma, follicular dendritic cell sarcoma, Hodgkin's disease, and another KSHV-driven neoplasm, primary effusion lymphoma [14-17]. Newer imaging techniques have therefore been studied in patients with HIV-associated MCD in an attempt to improve diagnostic accuracy. Positron emission tomography (PET) uses the glucose analogue 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG), which is taken up and retained by metabolically active cells. It produces a metabolic body map demonstrating increased activity of normal glycolytic pathway-using tissues but also hypermetabolic pathological processes. PET scanning produces limited anatomical localisation which is significantly improved by using combined PET-CT imaging to anatomically localise the functional information. A few studies have investigated the role of FDG-PET in the diagnosis of Castleman's disease although the majority of these very small studies are either in unifocal Castleman's disease or in HIV-negative MCD [18-22].





PET-CT has recently been introduced into the clinical management algorithm for HIV-associated MCD. Results for seven HIV-seropositive patients with active MCD, either newly diagnosed or relapsed, showed that 36% of lymph node groups included radiologically enlarged nodes on CT scan, whilst 63% of lymph node groups showed enhanced FDG uptake on PET-CT scan (Figure 4). These findings suggest that FDG PET-CT may be more sensitive than CT alone in detecting MCD. In contrast, in two scans from patients in remission, there were no enlarged lymph nodes on CT scan but 11% of lymph nodes demonstrated enhanced FDG uptake, suggesting that FDG PET-CT may be less sensitive in monitoring disease activity than CT (results submitted for publication). These limitations of FDG PET-CT are well known in terms of uptake in reactive or infected nodes and this uptake in HIV-positive patients can be highly variable in persistent generalised lymphadenopathy [23]. Nevertheless, these preliminary findings suggest that FDG PET-CT may assist in the monitoring of disease activity in MCD along with the familiar clinical and laboratory tools and the more recently introduced plasma HHV8 DNA viral load measurement [24,25].


[1.] Castleman B, Towne VW. Case records of the Massachusetts General Hospital: case no. 40231. N Engl J Med, 1954, 250, 1001-1005.

[2.] Castleman B, Iverson L, Menendez V. Localized mediastinal lymph-node hyperplasia resembling thymoma. Cancer, 1956, 9, 822-830.

[3.] Guihot A, Couderc LJ, Agbalika F et al. Pulmonary manifestations of multicentric Castleman's disease in HIV infection: a clinical, biological and radiological study. Eur Respir J, 2005, 26, 118-125.

[4.] Guihot A, Couderc LJ, Rivaud E et al. Thoracic radiographic and CT findings of multicentric Castleman disease in HIV-infected patients. J Thorac Imaging, 2007, 22, 207-211.

[5.] Yates JA, Zakai NA, Griffith RC et al. Multicentric Castleman disease, Kaposi sarcoma, hemophagocytic syndrome, and a novel HHV8-lymphoproliferative disorder. AIDS Read, 2007, 17, 596-598, 601.

[6.] Day JR, Bew D, Ali M et al. Castleman's disease associated with myasthenia gravis. Ann Thorac Surg, 2003, 75, 1648-1650.

[7.] Gerard L, Berezne A, Galicier L et al. Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman's disease: ANRS 117 CastlemaB Trial. J Clin Oncol, 2007, 25, 3350-3356.

[8.] Soulier J, Grollet L, Oksenhendler E et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood, 1995, 86, 1276-1280.

[9.] Du MQ, Liu H, Diss TC et al. Kaposi sarcoma-associated herpesvirus infects monotypic (IgM lambda) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood, 2001, 97, 2130-2136.

[10.] Dupin N, Diss TL, Kellam P et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood, 2000, 95, 1406-1412.

[11.] Hillier JC, Shaw P, Miller RF et al. Imaging features of multicentric Castleman's disease in HIV infection. Clin Radiol, 2004, 59, 596-601.

[12.] Bower M, Powles T, Williams S et al. Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med, 2007, 147, 836-839.

[13.] Oksenhendler E, Duarte M, Soulier J et al. Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients. AIDS, 1996, 10, 61-67.

[14.] Chan JK, Tsang WY, Ng CS. Follicular dendritic cell tumor and vascular neoplasm complicating hyaline-vascular Castleman's disease. Am J Surg Pathol, 1994, 18, 517-525.

[15.] Zarate-Osorno A, Medeiros LJ, Danon AD, Neiman RS. Hodgkin's disease with coexistent Castleman-like histologic features. A report of three cases. Arch Pathol Lab Med, 1994, 118, 270-274.

[16.] Kojima M, Nakamura S, Shimizu K et al. Nodal marginal zone B-cell lymphoma resembling plasmacytoma arising from a plasma cell variant of localized Castleman's disease: a case report. Apmis, 2002, 110, 523-527.

[17.] Venizelos I, Tamiolakis D, Simopoulos C et al. Diffuse large B-cell lymphoma arising from a multicentric mixed variant of Castleman's disease. Indian J Cancer, 2004, 41, 135-137.

[18.] Murphy SP, Nathan MA, Karwal MW. FDG-PET appearance of pelvic Castleman's disease. J Nucl Med, 1997, 38, 1211-1212.

[19.] Kunishima S, Taniguchi H, Koh T et al. F-18 fluorodeoxyglucose positron emission tomography in mesenterial Castleman's lymphoma. Clin Nucl Med, 2001, 26, 789-790.

[20.] Blockmans D, Maes A, Stroobants S et al. FDG positron emission tomographic scintigraphy can reveal Castleman's disease as a cause of inflammation. Clin Nucl Med, 2001, 26, 975-976.

[21.] Reddy MP, Graham MM. FDG positron emission tomographic imaging of thoracic Castleman's disease. Clin Nucl Med, 2003, 28, 325-326.

[22.] Enomoto K, Nakamichi I, Hamada K et al. Unicentric and multicentric Castleman's disease. Br J Radiol, 2007, 80, e24-26.

[23.] O'Doherty MJ, Barrington SF, Campbell M et al. PET scanning and the human immunodeficiency virus-positive patient. J Nucl Med, 1997, 38, 1575-1583.

[24.] Stebbing J, Pantanowitz L, Dayyani F et al. HIV-associated multicentric Castleman's disease. Am J Hematol, 2008, 83, 498-503.

[25.] Dieval C, Bonnet F, Mauclere S et al. Multicentric Castleman disease: use of HHV8 viral load monitoring and positron emission tomography during follow-up. Leuk Lymphoma, 2007, 48, 1881-1883.

Correspondence to: Professor Mark Bower, Department of Oncology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK Email
Table 1: CT scan findings in 42 HIV-seropositive patients with
newly diagnosed histologically confirmed MCD.

 Number Percentage (%)

Lymphadenopathy 42/42 10
Hepatomegaly 28/42 67
Splenomegaly 39/41 * 95
Pulmonary involvement 17/42 40
Pulmonary infiltrates 11/42 26
Bilateral pleural effusion 6/42 14

* One patient had undergone a splenectomy for ITP prior to
developing MCD.
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Title Annotation:LEADING ARTICLE
Author:Barker, Robert; Kazmi, Fahrad; Bower, Mark
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:4EUUK
Date:Sep 1, 2008
Previous Article:Imaging techniques for Kaposi's sarcoma.
Next Article:HIV and the liver.

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