Multicentric Castleman Disease



Multicentric Castleman Disease


Pei Lin, MD





Key Facts


Terminology



  • Systemic lymphoproliferative disease occurs in patients with immunodeficiency or immune dysregulation and is usually associated with human herpesvirus type 8 (HHV8) infection


Etiology/Pathogenesis



  • HHV8 (KSHV) infection important



    • Virus has pleiotropic effects, including encoding homolog of IL-6


  • Immunodeficiency (e.g., HIV) plays important role


  • POEMS syndrome is commonly associated with MCD


Clinical Issues



  • Lymphadenopathy constant; any lymph node group


  • B symptoms in over 95% of patients


  • Splenomegaly in ˜ 75%; hepatomegaly ˜ 50%


  • Patients with MCD have increased frequency of other neoplasms



    • Plasmablastic lymphoma, Kaposi sarcoma, primary effusion lymphoma


Microscopic Pathology



  • Sheets of plasma cells in interfollicular zones


  • Extensive vascular proliferation


  • Blurring of boundary between mantle zone and interfollicular area


  • HHV8(+) cells are usually localized in mantle zones of follicles



    • Plasmablasts or immunoblasts


Ancillary Tests



  • LANA1 antibody recognizes HHV8(+) cells


  • Monoclonal Ig gene rearrangements







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.


TERMINOLOGY


Abbreviations



  • Multicentric Castleman disease (MCD)


Synonyms



  • Angiofollicular lymph node hyperplasia


  • Angiomatous lymphoid hamartoma


  • Giant lymph node hyperplasia


Definitions



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



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


ETIOLOGY/PATHOGENESIS


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


CLINICAL ISSUES


Epidemiology



  • 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)


Presentation



  • 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


Treatment



  • Chemotherapy and steroids have been used for patients with MCD



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


Prognosis



  • 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


IMAGE FINDINGS


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


MICROSCOPIC PATHOLOGY


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


ANCILLARY TESTS


Immunohistochemistry



  • 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

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

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