Multicentric Castleman Disease

Multicentric Castleman Disease

Pei Lin, MD

Lymph node involved by multicentric Castleman disease, HHV8(+) in an HIV(+) patient. Scattered hyaline-vascular follicles are present.

Lymph node involved by multicentric Castleman disease in an HIV(+) patient. Antibody specific for latency-associated nuclear antigen (LANA-1) of HHV8 shows positive immunoblasts within the mantle zone.



  • Multicentric Castleman disease (MCD)


  • Angiofollicular lymph node hyperplasia

  • Angiomatous lymphoid hamartoma

  • Giant lymph node hyperplasia


  • Systemic lymphoproliferative disease that occurs in patients with immunodeficiency or immune dysregulation

    • Usually associated with human herpesvirus type 8 (HHV8) infection


Infectious Agents

  • HHV8

    • a.k.a. Kaposi sarcoma herpesvirus (KSHV)

    • γ-herpesvirus with estimated seroprevalence of 25% in USA

    • Virus load in peripheral blood mononuclear cells correlates with disease severity

    • HHV8 encodes for homolog of human interleukin-6 (IL-6)

    • Viral IL-6 stimulates human IL-6 induced cellular pathways

    • Human IL-6 is B-cell growth factor that regulates differentiation of B lymphocytes to plasma cells

      • Regulates T-cell function and induces C-reactive protein (CRP) production by hepatocytes

      • Endogenous pyrogen

    • B cells derived form MCD overexpress IL-6 receptor CD126

      • Cells within lymph nodes express high levels of IL-6

      • This suggests paracrine and autocrine mechanisms involved in pathophysiology of MCD

  • Immunodeficiency or immune dysregulation/dysfunction

    • HIV infection

      • Most HIV(+) patients with MCD are HHV8(+)

    • Wiskott-Aldrich syndrome

    • Autoimmune diseases or phenomena

      • Associated with autoantibody-induced paraneoplastic pemphigus

      • Associated with myasthenia gravis

    • POEMS syndrome

      • Peripheral neuropathy, organomegaly, endocrinopathy, monoclonal M protein, skin lesions

      • Serologic evidence of HHV8(+) in many patients

      • Poorly understood syndrome associated with immune dysregulation



  • Incidence

    • MCD occurs most often in HIV(+) patients with AIDS

      • Therefore, incidence correlates with that of AIDS

  • Age

    • Broad age range

  • Gender

    • More often in males (correlates with AIDS)


  • Lymphadenopathy is constant finding; any lymph node group can be involved

    • Peripheral, abdominal, or mediastinal lymphadenopathy

  • B-type symptoms in over 95% of patients

    • Fever, night sweats, weight loss

  • Splenomegaly in ˜ 75%, hepatomegaly in ˜ 50%

  • Edema, body cavity effusions, and skin rash in subset of patients

  • Central nervous system abnormalities in small patient subset

  • Higher risk for coexistent chronic infections

    • Epstein-Barr virus, hepatitis C, CMV

Laboratory Tests

  • Abnormal serum findings

    • Elevated serum IL-6 levels during symptomatic episodes

    • Elevated erythrocyte sedimentation rate

    • Elevated lactate dehydrogenase (LDH) levels

    • Hypergammaglobulinemia

  • Hematologic

    • Cytopenias

      • Anemia &/or thrombocytopenia


  • Chemotherapy and steroids have been used for patients with MCD

    • Not very effective for MCD patients who are HIV(+) or have POEMS syndrome


  • Poor in patients with POEMS syndrome or HIV infection

    • Patients usually die within a few months of diagnosis

Frequently Associated Neoplasms

  • Plasmablastic lymphoma (PBL)

    • HHV8(+) patients; often also EBV(+)

    • PBL usually involves lymph nodes and spleen; leukemia rare

    • Can affect HIV(-) patients in HHV8 endemic regions (Africa and Mediterranean countries)

  • Kaposi sarcoma

    • More common in HIV(+) patients

  • Primary effusion lymphoma (PEL)

    • Occurs in HHV8(+) patients

    • Usually coinfected with EBV

  • Glomeruloid hemangioma

    • Distinctive skin tumor highly suggestive of POEMS syndrome

  • Increased frequency of classical Hodgkin lymphoma (HL), diffuse large B-cell lymphoma, mantle cell lymphoma, and peripheral T-cell lymphoma

    • Mixed cellularity is most common type of classical HL


Radiographic Findings

  • Lymphadenopathy and hepatosplenomegaly

  • CT scan: Lesions enhance with IV contrast

  • PET scan: ˜ 50-60% of lesions have increased FDG uptake

  • Radiographic findings are not specific

    • Biopsy required for diagnosis


Histologic Features

  • Lymph nodes

    • Most MCD cases have features that fit best as plasma cell variant

    • Hyaline-vascular follicles are also usually present

      • Others in past have designated these cases as mixed or transitional type of CD

      • These changes are part of spectrum of plasma cell (PC) variant

  • Sheets of polytypic plasma cells in interfollicular regions

  • Extensive vascular proliferation

  • Some features of HHV8(+) MCD differ from HHV8(-) plasma cell variant

    • Greater degree of lymphocyte depletion

      • Particularly in HIV(+) patients

    • Blurred border between mantle zones and surrounding interfollicular areas

    • Plasma cells in MCD can be immature and atypical (plasmablasts)

  • HHV8(+) cells can be small or large with features of immunoblasts or plasmablasts

    • Usually located in mantle zones

    • These cells can form small nodules or “microlymphomas”

      • Observed in subset of cases

      • During early stage of disease, plasma cells are polytypic or monotypic

      • During later stage of disease, plasma cells are monotypic

      • Usually express monotypic Igλ

    • HHV8(+) cases with distinctive plasmablasts have been called “plasmablastic variant of CD”

  • Bone marrow involvement by MCD

    • Bland plasmacytosis is common

      • Can mimic plasma cell myeloma

    • HHV8(+) cells can be identified in bone marrow

Cytologic Features

  • MCD

    • Touch imprints and smears show plasma cells, plasmablasts, and lymphocytes

  • MCD with PBL

    • Monotonous proliferation of plasmablasts

  • HHV8(+) immunohistochemistry can be performed on smears/imprints



  • Can detect HHV8(+) cells using LANA1 antibody

    • Latency associated nuclear antigen (LANA)

  • HHV8(+) cells can be small lymphocytes, immunoblasts, or plasmablasts

    • Plasmablasts are usually polytypic but can be monotypic; IgM(+)

  • In subset of cases, follicular dendritic cells (FDRCs) are HHV8(+)

  • Plasma cells are usually polytypic but can be monotypic

  • Interfollicular areas show T cells without aberrancy

  • Follicles show B cells and increased CD21(+) FDRCs

Molecular Genetics

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Multicentric Castleman Disease

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