Primary Effusion Lymphoma (PEL) and Solid Variant of PEL



Primary Effusion Lymphoma (PEL) and Solid Variant of PEL


Francisco Vega, MD, PhD










Cytospin of primary effusion lymphoma (PEL) showing medium- to large-sized lymphoid cells with abundant finely vacuolated cytoplasm and irregular nuclei. (Courtesy W. Chen, MD.)






Cell block of primary effusion lymphoma (PEL) showing that virtually all neoplastic cells strongly HHV8(+). The neoplastic cells were CD20(−). Detecting evidence of HHV8 infection is essential for the diagnosis of PEL.


TERMINOLOGY


Abbreviations



  • Primary effusion lymphoma (PEL)


Synonyms



  • Body cavity-based lymphoma


  • Kaposi sarcoma-associated herpesvirus (KSHV)-associated lymphoma


Definitions



  • Human herpes virus 8 (HHV8)-associated large B-cell neoplasm most often involving body cavities



    • Pleural, pericardial, or peritoneal cavity


  • HHV8(+) lymphomas indistinguishable from PEL rarely present as solid tumor mass



    • These tumors are designated as extracavitary or solid variants of PEL


ETIOLOGY/PATHOGENESIS


Infectious Agents



  • PEL arises from HHV8-infected B cells that are frequently coinfected by Epstein-Barr virus (EBV)


  • HHV8 virus



    • γ herpes double-stranded DNA lymphotropic virus


    • Endemic in sub-Saharan Africa and Mediterranean region


    • In addition to PEL, HHV8 is associated with



      • Kaposi sarcoma


      • Multicentric Castleman disease (MCD)


      • MCD-associated plasmablastic lymphoma


    • Encodes number of homologues of cellular genes



      • Involved in cell proliferation and apoptosis


Clinical Associations



  • HIV infection or other severe acquired immunodeficiencies



    • Preexisting acquired immunodeficiency syndrome (AIDS) is very common


  • PEL also can occur in patients without immunodeficiency



    • Elderly patients in 8th to 9th decades in HHV8 endemic areas



      • Usually these tumors are EBV(−)


  • Rare cases of PEL are associated with hepatitis C &/or B


Pathogenesis



  • In PEL, B-cell differentiation program is blocked



    • In part due to overexpression of activated B-cell factor 1 (ABF-1) and inhibitor of differentiation 2 (ID2)



      • These molecules inhibit E2A (B-cell transcription factor)


      • E2A inhibition downregulates B-cell specific genes


    • Restoration of E2A activity in PEL induces apoptosis of tumor cells


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Rare



      • 0.3% of all aggressive lymphomas in HIV(−) patients


      • 4% of all HIV-related lymphomas


Presentation



  • Lymphoma cells grow in pleural, peritoneal, &/or pericardial effusions


  • Usually no distinct extracavitary tumor masses &/or organomegaly


  • Frequent B symptoms


  • Symptoms commonly result from massive malignant effusion



    • Dyspnea is frequent (from pleural or pericardial disease)



    • Abdominal distension (from peritoneal disease)


  • Systemic dissemination can occur during course of disease


  • Associated with clinical and laboratory findings of severe immunosuppression



    • Marked depletion of CD4(+) T cells


  • Involvement of central nervous system and bone marrow is rare


  • Standard Ann Arbor staging is not useful as, by definition, all PEL cases are stage IV


  • Some patients have coexistent Kaposi sarcoma


  • HHV8(+) lymphomas can present as masses involving organs (extracavitary or solid variant of PEL)



    • Gastrointestinal tract most frequently involved


    • Lymph nodes can be involved


    • Patients with extracavitary mass often develop malignant effusion over disease course


Treatment



  • Highly active antiretroviral therapy (HAART) improves prognosis


  • Intracavitary cidofovir (antiviral agent that inhibits replication of HHV8) with interferon-α


  • Traditional chemotherapy, usually cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)


  • Bortezomib, a proteosome inhibitor that inhibits NFkB pathway


  • Antivirals (valganciclovir)


  • Rituximab probably has no role in patients with PEL



    • CD20 is usually negative


Prognosis



  • Usually poor; median survival < 6 months


IMAGE FINDINGS


Radiographic Findings



  • Bilateral or unilateral pleural effusion


  • Pericardial effusion, peritoneal effusion


  • Slight thickening of parietal pleura, pericardium, or peritoneum


  • Absence of solid tumor masses, parenchymal abnormalities, or mediastinal enlargement


MICROSCOPIC PATHOLOGY


Histologic Features



  • Diagnosis is usually made on cytological preparations of involved effusion fluid


  • Biopsy specimens of cavity lining tissue also may show small number of neoplastic cells adherent to mesothelial surfaces


  • Large lymphoid cells with round to irregular nuclei, prominent nucleoli, and variable morphology



    • Immunoblastic



      • Round nuclei with centrally located nucleoli


    • Plasmablastic



      • Eccentric nuclei with abundant cytoplasm, sometimes with perinuclear hof


    • Anaplastic



      • Multinucleated and Reed-Sternberg-like cells


Cytologic Features



  • Medium- to large-sized atypical cells, many with irregular nuclear contours, prominent nucleoli, and abundant cytoplasm (± vacuolated)


  • Cytomorphologic appearances ranging from immunoblastic to anaplastic and exhibiting frequent plasmablastic differentiation


ANCILLARY TESTS


Immunohistochemistry



  • HHV8(+) is essential for diagnosis


  • Plasma cell-associated markers(+)



    • CD138, VS38c, IRF-4/MUM1


    • CD38, EMA


  • Cytoplasmic Ig λ light chain(+/−)


  • CD30(+), CD45/LCA(+/−)


  • Notch(+) in most cases



    • Nuclear and cytoplasmic pattern of expression



  • Pan-B-cell markers(−)



    • CD19, CD20, CD79a, pax-5


  • CD15(−), LMP-1(−)


  • CD10(−), Bcl-6(−)


Flow Cytometry



  • Similar immunophenotype to that observed by immunohistochemistry


  • Results



    • CD45/LCA(+), CD71(+)


    • HLA-DR(+); CD23(+) in ˜ 20%


    • Surface Ig light chain expression is rare


    • CD19(−), CD20(−), CD22(−)



      • ˜ 10% of cases have dim CD20 expression


    • CD10(−), FMC7(−)


    • Aberrant T-cell markers are positive in subset of cases



      • CD45RO (˜ 90%), CD7 (˜ 30%), CD4 (˜ 20%)


      • CD2(−), CD3(−), CD5(−), CD8(−)


Cytogenetics



  • Usually complex karyotype


  • No recurrent chromosomal abnormalities identified


In Situ Hybridization



  • EBER(+) in ˜ 80% of cases


Array CGH



  • Gains of Iq21-41, 4q28-35, 7q, 8q, 11, 12, 17q, 19p, 20q


  • Losses of 4q, 11q25, 14q32



    • Amplification of selectin-P ligand (12q24.11)

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Primary Effusion Lymphoma (PEL) and Solid Variant of PEL
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