Diagnosis and Management of Primary Effusion Lymphoma in the Immunocompetent and Immunocompromised Hosts

Abstract

Primary effusion lymphoma (PEL) is an uncommon non-Hodgkin lymphoma associated with human herpes virus-8 (HHV-8) that grows mainly in serous body cavities. The most common presentation of PEL is that of a young immunocompromised male with shortness of breath, as the pleural cavity is most commonly affected. Diagnosis is primarily based on fluid cytology in which PEL cells display variable morphology and a null lymphocyte immunophenotype; however, evidence of HHV-8 infection within the neoplastic cell is essential. Patients have commonly been treated with systemic multidrug chemotherapy and antiretroviral therapy if they were HIV positive or were immunocompromised for other reasons. In the immunocompetent patient, there have been no agreed-upon pathways for management of this condition. Progression of disease is common and median survival is approximately 6 months. Novel intrapleural treatments with antiviral agents such as intracavity cidofovir have shown to be effective in controlling local disease, and ongoing clinical trials may provide some promise in the treatment for this condition.

Keywords

primary effusion lymphoma - immunocompromised - immunocompetent - HHV-8 - chemotherapy

• References

• 1 Knowles DM, Inghirami G, Ubriaco A, Dalla-Favera R. Molecular genetic analysis of three AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible pathogenetic role of the Epstein-Barr virus. Blood 1989; 73 (3) 792-799
• 2 Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009; 1: 523-531
• 3 Carbone A, Gaidano G. HHV-8-positive body-cavity-based lymphoma: a novel lymphoma entity. Br J Haematol 1997; 97 (3) 515-522
• 4 Knowles DM, Chadburn A. Lymphadenopathy and the lymphoid neoplasms associated with the acquired immune deficiency syndrome (AIDS). In: Knowles DM, , ed. Neoplastic Hematopathology. Baltimore, MD: Williams & Wilkins; 1992: 773
• 5 Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N Engl J Med 1995; 332 (18) 1186-1191
• 6 Said JW, Tasaka T, Takeuchi S , et al. Primary effusion lymphoma in women: report of two cases of Kaposi's sarcoma herpes virus-associated effusion-based lymphoma in human immunodeficiency virus-negative women. Blood 1996; 88 (8) 3124-3128
• 7 Adiguzel C, Bozkurt SU, Kaygusuz I, Uzay A, Tecimer T, Bayik M. Human herpes virus 8-unrelated primary effusion lymphoma-like lymphoma: report of a rare case and review of the literature. APMIS 2009; 117 (3) 222-229
• 8 Little RF, Gutierrez M, Jaffe ES, Pau A, Horne M, Wilson W. HIV-associated non-Hodgkin lymphoma: incidence, presentation, and prognosis. JAMA 2001; 285 (14) 1880-1885
• 9 Simonelli C, Spina M, Cinelli R , et al. Clinical features and outcome of primary effusion lymphoma in HIV-infected patients: a single-institution study. J Clin Oncol 2003; 21 (21) 3948-3954
• 10 Boulanger E, Gérard L, Gabarre J , et al. Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS. J Clin Oncol 2005; 23 (19) 4372-4380
• 11 Boulanger E, Daniel MT, Agbalika F, Oksenhendler E. Combined chemotherapy including high-dose methotrexate in KSHV/HHV8-associated primary effusion lymphoma. Am J Hematol 2003; 73 (3) 143-148
• 12 Nador RG, Cesarman E, Chadburn A , et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood 1996; 88 (2) 645-656
• 13 Valencia ME, Martinez P, Moreno V, Laguna F, Lahoz JG. AIDS-related body cavity-based lymphomas, herpesvirus-8 and HIV infection: a study of seven cases. AIDS 1999; 13 (18) 2603-2605
• 14 Yiakoumis X, Pangalis GA, Kyrtsonis MC , et al. Primary effusion lymphoma in two HIV-negative patients successfully treated with pleurodesis as first-line therapy. Anticancer Res 2010; 30 (1) 271-276
• 15 Brimo F, Michel RP, Khetani K, Auger M. Primary effusion lymphoma: a series of 4 cases and review of the literature with emphasis on cytomorphologic and immunocytochemical differential diagnosis. Cancer 2007; 111 (4) 224-233
• 16 Jones D, Ballestas ME, Kaye KM , et al. Primary-effusion lymphoma and Kaposi's sarcoma in a cardiac-transplant recipient. N Engl J Med 1998; 339 (7) 444-449
• 17 Ascoli V, Mastroianni CM, Galati V , et al. Primary effusion lymphoma containing human herpesvirus 8 DNA in two AIDS patients with Kaposi's sarcoma. Haematologica 1998; 83 (1) 8-12
• 18 Tumwine LK, Lalitha R, Agostinelli C , et al. Primary effusion lymphoma associated with human herpes virus-8 and Epstein Barr virus in an HIV-infected woman from Kampala, Uganda: a case report. J Med Case Reports 2011; 5: 60
• 19 Honda M, Morikawa T, Yamaguchi Y , et al. A case of a primary effusion lymphoma in the elderly. Nippon Ronen Igakkai Zasshi 2009; 46 (6) 551-556
• 20 Ascoli V, Scalzo CC, Danese C, Vacca K, Pistilli A, Lo Coco F. Human herpes virus-8 associated primary effusion lymphoma of the pleural cavity in HIV-negative elderly men. Eur Respir J 1999; 14 (5) 1231-1234
• 21 Testa A, Baiocchini A, Comandini UV , et al. Fatal sclerosing peritonitis associated with primary effusion lymphoma after liver transplantation: a case report. Transplant Proc 2010; 42 (9) 3849-3853
• 22 Moore PS, Chang Y. Kaposi's sarcoma (KS), KS-associated herpesvirus, and the criteria for causality in the age of molecular biology. Am J Epidemiol 1998; 147 (3) 217-221
• 23 Shebl FM, Dollard SC, Pfeiffer RM , et al. Human herpesvirus 8 seropositivity among sexually active adults in Uganda. PLoS One 2011; 6 (6) e21286
• 24 Baillargeon J, Leach CT, Deng JH, Gao SJ, Jenson HB. High prevalence of human herpesvirus 8 (HHV-8) infection in South Texas children. J Med Virol 2002; 67 (4) 542-548
• 25 Jenson HB. Human herpesvirus 8 infection. Curr Opin Pediatr 2003; 15 (1) 85-91
• 26 Sullivan RJ, Pantanowitz L, Casper C, Stebbing J, Dezube BJ. HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effusion lymphoma, and multicentric Castleman disease. Clin Infect Dis 2008; 47 (9) 1209-1215
• 27 Dupin N, Fisher C, Kellam P , et al. Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Proc Natl Acad Sci U S A 1999; 96 (8) 4546-4551
• 28 Carbone A, Gloghini A, Vaccher E , et al. Kaposi's sarcoma-associated herpesvirus DNA sequences in AIDS-related and AIDS-unrelated lymphomatous effusions. Br J Haematol 1996; 94 (3) 533-543
• 29 Friborg Jr J, Kong W, Hottiger MO, Nabel GJ. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 1999; 402 (6764) 889-894
• 30 Ballestas ME, Chatis PA, Kaye KM. Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 1999; 284 (5414) 641-644
• 31 Sun Q, Zachariah S, Chaudhary PM. The human herpes virus 8-encoded viral FLICE-inhibitory protein induces cellular transformation via NF-kappaB activation. J Biol Chem 2003; 278 (52) 52437-52445
• 32 Sullivan R, Dezube BJ, Koon HB. Signal transduction targets in Kaposi's sarcoma. Curr Opin Oncol 2006; 18 (5) 456-462
• 33 Stebbing J, Pantanowitz L, Dayyani F, Sullivan RJ, Bower M, Dezube BJ. HIV-associated multicentric Castleman's disease. Am J Hematol 2008; 83 (6) 498-503
• 34 Chen YB, Rahemtullah A, Hochberg E. Primary effusion lymphoma. Oncologist 2007; 12 (5) 569-576
• 35 Swanton C, Mann DJ, Fleckenstein B, Neipel F, Peters G, Jones N. Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. Nature 1997; 390 (6656) 184-187
• 36 Russo JJ, Bohenzky RA, Chien MC , et al. Nucleotide sequence of the Kaposi sarcoma-associated herpesvirus (HHV8). Proc Natl Acad Sci U S A 1996; 93 (25) 14862-14867
• 37 Horenstein MG, Nador RG, Chadburn A , et al. Epstein-Barr virus latent gene expression in primary effusion lymphomas containing Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8. Blood 1997; 90 (3) 1186-1191
• 38 Nicholas J. Human herpesvirus 8-encoded proteins with potential roles in virus-associated neoplasia. Front Biosci 2007; 12: 265-281
• 39 Chang H, Dittmer DP, Shin YC, Hong Y, Jung JU. Role of Notch signal transduction in Kaposi's sarcoma-associated herpesvirus gene expression. J Virol 2005; 79 (22) 14371-14382
• 40 Lan K, Murakami M, Choudhuri T , et al. Intracellular activated Notch1 can reactivate Kaposi's sarcoma associated herpes virus from latency. Virology 2006; 351: 393-403
• 41 Lan K, Choudhuri T, Murakami M, Kuppers DA, Robertson ES. Intracellular activated Notch1 is critical for proliferation of Kaposi's sarcoma-associated herpesvirus-associated B-lymphoma cell lines in vitro. J Virol 2006; 80 (13) 6411-6419
• 42 Wang HY, Fuda FS, Chen W, Karandikar NJ. Notch1 in primary effusion lymphoma: a clinicopathological study. Mod Pathol 2010; 23 (6) 773-780
• 43 Matolcsy A, Nádor RG, Cesarman E, Knowles DM. Immunoglobulin VH gene mutational analysis suggests that primary effusion lymphomas derive from different stages of B cell maturation. Am J Pathol 1998; 153 (5) 1609-1614
• 44 Walts AE, Shintaku IP, Said JW. Diagnosis of malignant lymphoma in effusions from patients with AIDS by gene rearrangement. Am J Clin Pathol 1990; 94 (2) 170-175
• 45 Chadburn A, Cesarman E, Jagirdar J, Subar M, Mir RN, Knowles DM. CD30 (Ki-1) positive anaplastic large cell lymphomas in individuals infected with the human immunodeficiency virus. Cancer 1993; 72 (10) 3078-3090
• 46 Delsol G, Gatter KC, Stein H , et al. Human lymphoid cells express epithelial membrane antigen. Implications for diagnosis of human neoplasms. Lancet 1984; 2 (8412) 1124-1129
• 47 Boulanger E, Agbalika F, Maarek O , et al. A clinical, molecular and cytogenetic study of 12 cases of human herpesvirus 8 associated primary effusion lymphoma in HIV-infected patients. Hematol J 2001; 2 (3) 172-179
• 48 Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the committee on Hodgkin's disease classification. Cancer Res 1971; 31 (11) 1860-1861
• 49 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992; 41 (RR-17) 1-19
• 50 Komanduri KV, Luce JA, McGrath MS, Herndier BG, Ng VL. The natural history and molecular heterogeneity of HIV-associated primary malignant lymphomatous effusions. J Acquir Immune Defic Syndr Hum Retrovirol 1996; 13 (3) 215-226
• 51 Pastore RD, Chadburn A, Kripas C, Schattner EJ. Novel association of haemophagocytic syndrome with Kaposi's sarcoma-associated herpesvirus-related primary effusion lymphoma. Br J Haematol 2000; 111 (4) 1112-1115
• 52 Shipp MA, Yeap BY, Harrington DP , et al. The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with the M-BACOD regimen. J Clin Oncol 1990; 8 (1) 84-93
• 53 Evans WE, Pratt CB. Effect of pleural effusion on high-dose methotrexate kinetics. Clin Pharmacol Ther 1978; 23 (1) 68-72
• 54 Wan SH, Huffman DH, Azarnoff DL, Stephens R, Hoogstraten B. Effect of route of administration and effusions on methotrexate pharmacokinetics. Cancer Res 1974; 34 (12) 3487-3491
• 55 Navarro WH, Kaplan LD. AIDS-related lymphoproliferative disease. Blood 2006; 107 (1) 13-20
• 56 Oksenhendler E, Clauvel JP, Jouveshomme S, Davi F, Mansour G. Complete remission of a primary effusion lymphoma with antiretroviral therapy. Am J Hematol 1998; 57 (3) 266
• 57 Hocqueloux L, Agbalika F, Oksenhendler E, Molina JM. Long-term remission of an AIDS-related primary effusion lymphoma with antiviral therapy. AIDS 2001; 15 (2) 280-282
• 58 Spina M, Gaidano G, Carbone A, Capello D, Tirelli U. Highly active antiretroviral therapy in human herpesvirus-8-related body-cavity-based lymphoma. AIDS 1998; 12 (8) 955-956
• 59 An J, Sun Y, Fisher M, Rettig MB. Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. Leukemia 2004; 18 (10) 1699-1704
• 60 Sarosiek KA, Cavallin LE, Bhatt S , et al. Efficacy of bortezomib in a direct xenograft model of primary effusion lymphoma. Proc Natl Acad Sci U S A 2010; 107 (29) 13069-13074
• 61 U.S. National Institute of Health. Bortezomib and antiviral therapy followed by effusion drainage, bevacizumab, and combination chemotherapy in treating patients with primary effusion lymphoma. Available at: http://clinicaltrials.gov/ct2/show/NCT00217503 . Accessed April 4, 2012
• 62 Waddington TW, Aboulafia DM. Failure to eradicate AIDS-associated primary effusion lymphoma with high-dose chemotherapy and autologous stem cell reinfusion: case report and literature review. AIDS Patient Care STDS 2004; 18 (2) 67-73
• 63 Won JH, Han SH, Bae SB , et al. Successful eradication of relapsed primary effusion lymphoma with high-dose chemotherapy and autologous stem cell transplantation in a patient seronegative for human immunodeficiency virus. Int J Hematol 2006; 83 (4) 328-330
• 64 Halfdanarson TR, Markovic SN, Kalokhe U, Luppi M. A non-chemotherapy treatment of a primary effusion lymphoma: durable remission after intracavitary cidofovir in HIV negative PEL refractory to chemotherapy. Ann Oncol 2006; 17 (12) 1849-1850
• 65 Luppi M, Trovato R, Barozzi P , et al. Treatment of herpesvirus associated primary effusion lymphoma with intracavity cidofovir. Leukemia 2005; 19 (3) 473-476
• 66 Stingaciu S, Ticchioni M, Sudaka I, Haudebourg J, Mounier N. Intracavitary cidofovir for human herpes virus-8-associated primary effusion lymphoma in an HIV-negative patient. Clin Adv Hematol Oncol 2010; 8 (5) 367-374
• 67 Moyo TK, Richards KL, Damania B. Use of cidofovir for the treatment of HIV-negative human herpes virus-8-associated primary effusion lymphoma. Clin Adv Hematol Oncol 2010; 8 (5) 372-374
• 68 Casper C, Wald A. The use of antiviral drugs in the prevention and treatment of Kaposi sarcoma, multicentric Castleman disease and primary effusion lymphoma. Curr Top Microbiol Immunol 2007; 312: 289-307
• 69 Alexandrakis MG, Passam FH, Kyriakou DS, Bouros D. Pleural effusions in hematologic malignancies. Chest 2004; 125 (4) 1546-1555