Skip to main content

Large Cell Lymphoma: Correlation of HIV Status and Prognosis with Differentiation Profiles Assessed by Immunophenotyping

Pathology & Oncology Research volume 19, pages 695–705 (2013)Cite this article

Abstract

Diffuse large B cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL) represent aggressive non-Hodgkin lymphomas, particularly in the setting of HIV infection. Since the introduction of highly active antiretroviral therapy (HAART), recent studies have documented improved survival outcome in patients with AIDS-related lymphomas. This study contributes a South African perspective by correlating the HIV status and prognosis of DLBCL and PBL with differentiation profiles assessed by immunophenotyping. Analysis of the morphologic, immunophenotypic and clinicopathologic features of 52 cases of DLBCL and 9 cases of de novo PBL was performed. The overall survival of patients with PBL was poorer than that of DLBCL (logrank p value 0.002). Despite HAART, the overall survival with DLBCL and HIV infection was significantly poorer than HIV negative patients with DLBCL (p value <0.001). Profound immunosuppression was evident in the HIV positive group as the mean CD4 count was 151 cells/mm3 in DLBCL and 61 cells/mm3 in PBL. HIV positive patients were significantly younger at presentation with greater likelihood of extranodal lymphoma. When Hans’ and Muris’ algorithmic stratification of DLBCL were applied, no statistical significance was demonstrated (p values 0.188 and 0.399 respectively). However, when Bcl-2 expression occurred in germinal center-type DLBCL (Hans’ defined), improved survival was conferred by the germinal center immunophenotype (p value 0.007). The study demonstrates that DLBCL and PBL have significant potential for aggressive behaviour and poor outcome in the setting of profound immunosuppression due to HIV infection. Further studies are required to assess the effect of targeted-immunotherapy (Rituximab) in combination with recent amendment of the South African national antiretroviral treatment guidelines which has created tremendous potential for improved survival in patients with AIDS-related non-Hodgkin B-cell lymphomas.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Stein H, Warnke RA, Chan WC, Jaffe ES, Chan JKC, Gatter KC, Campo E (2008) Diffuse large B cell lymphoma, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Thiele J, Vardiman JW (eds) World Health Organisation classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC Press, Lyon, pp 233–237

    Google Scholar 

  2. Hoffmann C, Tieman M, Schrader C, Janssen D, Wolf E, Vierbuchen M, Parwaresch R, Ernestus K, Plettenberg A, Stoehr A, Fatkenheuer G, Wyen C, Oette M, Horst HA (2005) AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping. Blood 106:1762–1769

    PubMed  CAS  Article  Google Scholar 

  3. Colomo L, Loong F, Rives S, Pittaluga S, Martínez A, López-Guillermo A, Ojanguren J, Romagosa V, Jaffe ES, Campo E (2004) Diffuse large B-cell Lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol 28:736–747

    PubMed  Article  Google Scholar 

  4. Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, Müller-Hermelink HK, Campo E, Braziel RM, Jaffe ES, Pan Z, Farinha P, Smith LM, Falini B, Banham AH, Rosenwald A, Staudt LM, Connors JM, Armitage JO, Chan WC (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103(1):275–282

    PubMed  CAS  Article  Google Scholar 

  5. Chang CC, McClintock S, Cleveland RP, Trzpuc T, Vesole DH, Logan B, Kajdacsy-Balla A, Perkins SL (2004) Immunohistochemical expression patterns of germinal center and activation B-cell markers correlate with prognosis in diffuse large B-cell lymphoma. Am J Surg Pathol 28:464–470

    PubMed  Article  Google Scholar 

  6. Tumwine LK, Agostinelli C, Campidelli C, Othieno E, Wabinga H, Righi S, Falini B, Piccaluga PP, Byarugaba W, Pileri SA (2009) Immunohistochemical and other prognostic factors in B cell non Hodgkin lymphoma patients, Kampala, Uganda. BMC Clin Pathol 9:1–7

    Article  Google Scholar 

  7. Amen F, Horncastle D, Elderfield K, Banham AH, Bower M, Macdonald D, Kanfer E, Naresh KN (2007) Absence of cyclin-D2 and Bcl-2 expression within the germinal centre type of diffuse large B-cell lymphoma identifies a very good prognostic subgroup of patients. Histopathology 51:70–79

    PubMed  CAS  Article  Google Scholar 

  8. Muris JJF, Meijer CJLM, Vos W, van Krieken JH, Jiwa NM, Ossenkoppele GJ, Oudejans JJ (2006) Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma. J Pathol 208:714–723

    PubMed  CAS  Article  Google Scholar 

  9. Choi WW, Weisenburger DD, Greiner TC, Piris MA, Banham AH, Delabie J, Braziel RM, Geng H, Iqbal J, Lenz G, Vose JM, Hans CP, Fu K, Smith LM, Li M, Liu Z, Gascoyne RD, Rosenwald A, Ott G, Rimsza LM, Campo E, Jaffe ES, Jaye DL, Staudt LM, Chan WC (2009) A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res 15:5494–5502

    PubMed  CAS  Article  Google Scholar 

  10. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511

    PubMed  CAS  Article  Google Scholar 

  11. Madan R, Gormley R, Dulau A, Xu D, Walsh D, Ramesh KH, Cannizaro L, Tamas EF, Kumar P, Sparano J, LeValley A, Xue X, Bhattacharyya PK, Ioachim HL, Ratech H (2006) AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles. Mod Pathol 19:438–446

    PubMed  CAS  Article  Google Scholar 

  12. Banks PM, Keller RH, Li C-Y, White WL (1978) Case report malignant lymphoma of plasmablastic identity: a neoplasm with both “immunoblastic” and plasma cellular features. Am J Med 64(5):906–909

    PubMed  CAS  Article  Google Scholar 

  13. Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, Huhn D, Schmidt-Westhausen A, Reichart PA, Gross U, Stein H (1997) Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 89:1413–1420

    PubMed  CAS  Google Scholar 

  14. Stein H, Harris NL, Campo E (2008) Plasmablastic lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Thiele J, Vardiman JW (eds) World Health Organisation classification of tumours of haematopoietic and lymphoid tissues, 4th edn. IARC Press, Lyon, pp 256–257

    Google Scholar 

  15. Desai J, Mitnick RJ, Henry DH, Llena J, Sparano JA (1999) Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-Hodgkin lymphoma. Cancer 86(9):1840–1847

    PubMed  CAS  Article  Google Scholar 

  16. Sarker D, Thirlwell C, Nelson M, Gazzard B, Bower M (2003) Leptomeningeal disease in AIDS-related non-Hodgkin’s lymphoma. AIDS 17:861–865

    PubMed  Article  Google Scholar 

  17. Republic of South Africa. Department of Health. National Antiretroviral Treatment Guidelines. Jacana, 2004. Available from http://southafrica.usembassy.gov/media/2004‐doh‐art‐guidelines.pdf

  18. Warnke RA, Strauchen JA, Burke JS, Hoppe RT, Campbell BA, Dorfman RF (1982) Morphologic types of diffuse large B-cell lymphoma. Cancer 50:690–695

    PubMed  CAS  Article  Google Scholar 

  19. Ambinder RF (2001) Epstein-Barr virus associated lymphoproliferations in the AIDS setting. Eur J Cancer 10:1209–1216

    Article  Google Scholar 

  20. Nyman H (2010) Prognostic molecular factors and algorithms in diffuse large B-cell lymphoma. [Academic thesis] University of Helsinki

  21. Chan JKC (2007) Tumors of the lymphoreticular system—part A: the lymph node. In: Fletcher CDM (ed) Diagnostic histopathology of tumors vol 2, 3rd edn. Churchill-Livingstone Elsevier, London, pp 1139–1288

    Google Scholar 

  22. Antinori A, Cingolani A, Alba L, Ammassari A, Serraino D, Ciancio BC, Palmieri F, De Luca A, Larocca LM, Ruco L, Ippolito G, Cauda R (2001) Better response to chemotherapy and prolonged survival in AIDS-related lymphomas responding to highly active antiretroviral therapy. AIDS 15:1483–1491

    PubMed  CAS  Article  Google Scholar 

  23. Navarro JT, Ribera JM, Oriol A (2001) Influence of highly active antiretroviral therapy on response to treatment and survival in patients with acquired immunodeficiency syndrome-related non-Hodgkin’s lymphoma treated with CHOP. Br J Haematol 112:909–915

    PubMed  CAS  Article  Google Scholar 

  24. Besson C, Goubar A, Gabarre J, Rozenbaum W, Pialoux G, Châtelet FP, Katlama C, Charlotte F, Dupont B, Brousse N, Huerre M, Mikol J, Camparo P, Mokhtari K, Tulliez M, Salmon‐Céron D, Boué F, Costagliola D, Raphaël M (2001) Changes in AIDS-related lymphoma since the era of highly active antiretroviral therapy. Blood 98:2339–2344

    Google Scholar 

  25. Seaberg EC, Wiley D, Martínez‐Maza O, Chmiel JS, Kingsley L, Tang Y, Margolick JB, Jacobson LP, Multicenter AIDS Cohort Study (MACS) (2010) Cancer incidence in the multicenter AIDS cohort study before and during the HAART era 1984–2007. Cancer 116(23):5507–5516

    Google Scholar 

  26. Franceschi S, Lise M, Clifford GM, Rickenbach M, Levi F, Maspoli M, Bouchardy C (2010) Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study. Br J Cancer 103(3):416–422

    PubMed  CAS  Article  Google Scholar 

  27. Republic of South Africa. Department of Health. The South African Antiretroviral Treatment Guidelines 2010. Available from http://www.uj.ac.za/EN/CorporateServices/ioha/Documentation/Documents/ART%20Guideline.pdf

  28. van Eeden A. New HIV treatment guidelines: 15 August 2011 [Internet] Available from http://www.samedical.org/newsroom/media-releases/archived-media-releases/new-hiv-treatment-guidelines-15-august-2011.html

  29. Evison J, Jost J, Ledergerber B, Jost L, Strasser F, Weber R (1999) HIV-associated non-Hodgkin’s lymphoma: highly active antiretroviral therapy improves remission rate of chemotherapy. AIDS 13:732–734

    PubMed  CAS  Article  Google Scholar 

  30. Thiessard F, Morlat P, Marimoutou C, Labouyrie E, Ragnaud JM, Pellegrin JL, Dupon M, Dabis F, the Groupe d’Epidémiologie Clinique du SIDA en Aquitaine (GECSA) (2000) Prognostic factors after non-Hodgkin’s lymphoma in patients infected with the human immunodefciency virus: aquitaine cohort, France. Cancer 88:1696–1702

    PubMed  CAS  Article  Google Scholar 

  31. Coiffier B (2001) Diffuse large cell lymphoma. Curr Opin Oncol 13:325–334

    PubMed  CAS  Article  Google Scholar 

  32. Habermann TM, Weller EA, Morrison VA et al (2006) Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 24:3121–3127

    PubMed  CAS  Article  Google Scholar 

  33. Pfreundschuh M, Trumper L, Osterborg A et al (2006) CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379–391

    PubMed  CAS  Article  Google Scholar 

  34. Sehn LH, Donaldson J, Chhanabhai M et al (2005) Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23:5027–5033

    PubMed  CAS  Article  Google Scholar 

  35. Hockenbery D, Nunez G, Milliman C et al (1990) Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336

    PubMed  CAS  Article  Google Scholar 

  36. Cory S (1995) Regulation of lymphocyte survival by the bcl-2 gene family. Annu Rev Immunol 13:513–543

    PubMed  CAS  Article  Google Scholar 

  37. Reed JC (1997) Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semin Hematol 34:9–19

    PubMed  CAS  Google Scholar 

  38. Obermann EC, Csato M, Dirnhofer S, Tzankov A (2009) BCL2 gene aberration as an IPI-independent marker for poor outcome in non-germinal-centre diffuse large B cell lymphoma. J Clin Pathol 62:903–907

    PubMed  CAS  Article  Google Scholar 

  39. Hermine O, Haioun C, Lepage E, d’Agay MF, Briere J, Lavignac C, Fillet G, Salles G, Marolleau JP, Diebold J, Reyas F, Gaulard P (1996) Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’s lymphoma. Blood 87:265–272

    PubMed  CAS  Google Scholar 

  40. Gascoyne R, Adomat S, Krajewski S, Krajewska M, Horsman DE, Tolcher AW, O’Reilly SE, Hoskins P, Coldman AJ, Reed JC, Connors JM (1997) Prognostic significance of bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin’s lymphoma. Blood 90:244–251

    PubMed  CAS  Google Scholar 

  41. Barrans SL, Carter I, Owen RG, Davies FE, Patmore RD, Haynes AP, Morgan GJ, Jack AS (2002) Germinal center phenotype and bcl-2 expression combined with the International Prognostic Index improves patient risk stratification in diffuse large B-cell lymphoma. Blood 99:1136–1143

    PubMed  CAS  Article  Google Scholar 

  42. Ohshima K, Kawasaki C, Muta H, Muta K, Deyev V, Haraoka S, Suzumiya J, Podack ER, Kikuchi M (2001) CD10 and Bcl10 expression in diffuse large B-cell lymphoma: CD10 is a marker of improved prognosis. Histopathology 39(2):156–162

    PubMed  CAS  Article  Google Scholar 

  43. Liu YJ, Johnson GD, Gordon J, Maclennan IC (1992) Germinal centres in T-cell-dependent antibody responses. Immunol Today 13:17–21

    PubMed  CAS  Article  Google Scholar 

  44. Cutrona G, Dono M, Pastorino S, Ulivi M, Burgio VL, Zupo S, Roncella S, Ferrarini M (1997) The propensity to apoptosis of centrocytes and centroblasts correlates with elevated levels of intracellular myc protein. Eur J Immunol 27:234–238

    PubMed  CAS  Article  Google Scholar 

  45. Cutrona G, Leanza N, Ulivi M, Melioli G, Burgio VL, Mazzarello G, Gabutti G (1999) Expression of CD10 by human T cells that undergo apoptosis both in vitro and in vivo. Blood 94(9):3067–3076

    PubMed  CAS  Google Scholar 

  46. Cutrona G, Tasso P, Dono M, Roncella S, Ulivi M, Carpaneto EM, Fontana V, Comis M, Morabito F, Spinelli M, Frascella E, Boffa LC, Basso G, Pistoia, Ferrarini M (2002) CD10 is a marker for cycling cells with propensity to apoptosis in childhood ALL. Br J Cancer 86(11):1776–1785

    PubMed  CAS  Article  Google Scholar 

  47. Lossos IS, Jones CD, Warnke R, Natkunam Y, Kaizer H, Zehnder JL, Tibshirani R, Levy R (2001) Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. Blood 98:945–951

    PubMed  CAS  Article  Google Scholar 

  48. Winter JN, Weller EA, Horning SJ, Krajewska M, Variakojis D, Habermann TM, Fisher RI, Kurtin PJ, Macon WR, Chhanabhai M, Felgar RE, Hsi ED, Medeiros LJ, Weick JK, Reed JC, Gascoyne RD (2006) Prognostic significance of Bcl-6 protein expression in DLBCL treated with CHOP or R-CHOP: a prospective correlative study. Blood 107:4207–4213

    PubMed  CAS  Article  Google Scholar 

  49. Levine AM (2006) AIDS-related lymphoma. Semin Oncol Nurs 22:80–89

    PubMed  Article  Google Scholar 

  50. Castillo J, Pantanowithz L, Dezube BJ (2008) HIV-associated plasmablastic lymphoma: a literature review of 112 cases. Am J Hematol 83:804–809

    PubMed  Article  Google Scholar 

  51. Flaitz CM, Nichols, Walling DM, Hicks MJ (2002) Case report. Plasmablastic lymphoma: an HIV-associated entity with primary oral manifestations. Oral Oncol 38:96–102

    PubMed  CAS  Article  Google Scholar 

  52. Chabay P, De Matteo E, Lorenzetti M, Gutierrez M, Narbaitz M, Aversa L, Preciado MV (2009) Case report: vulvar plasmablastic lymphoma in a HIV-positive child: a novel extraoral localisation. J Clin Pathol 62:644–646

    PubMed  CAS  Article  Google Scholar 

  53. Radhakrishnan R, Suhas S, Kumar RV, Krishnanand G, Srinivasan R, Rao NN (2005) Plasmablastic lymphoma of the oral cavity in an HIV-positive child. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100:725–731

    PubMed  Article  Google Scholar 

  54. Gogia A, Bakhshi S (2010) Letter to the editor. Plasmablastic lymphoma of oral cavity in an HIV negative child. Pediatr Blood Cancer 55:390–391

    PubMed  Article  Google Scholar 

  55. Pather S, MacKinnon D, Padayachee RS (2012) Plasmablastic lymphoma in paediatric patients: Clinicopathologic study of three cases. Ann Diagn Pathol. Accepted for publication Aug 2012

  56. Scheper MA, Nikitakis NG, Fernandes R, Gocke CD, Ord RA, Sauk JJ (2005) Oral plasmablastic lymphoma in an HIV-negative patient: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100:198–206

    PubMed  Article  Google Scholar 

  57. Lin F, Zhang K, Quiery AT, Prichard J, Schuerch C (2004) Plasmablastic Lymphoma of the cervical lymph nodes in a human immunodeficiency virus-negative patient. A case report and review of the literature. Arch Pathol Lab Med 128:581–584

    PubMed  Google Scholar 

  58. Guan B, Zhang X, Hu W, Rao Q, Wang Y, Zhu Y, Wang H, Ma H, Zhou H, Zhou X (2011) Plasmablastic lymphoma of the oral cavity in an HIV-negative patient. Ann Diagn Pathol 15(6):436–440

    PubMed  Article  Google Scholar 

  59. Chetty R, Hlatswayo N, Muc R, Sabaratnam R, Gatter K (2003) Plasmablastic lymphoma in HIV + patients: an expanding spectrum. Histopathology 42:605–609

    PubMed  CAS  Article  Google Scholar 

  60. Dong HY, Scadden DT, de Leval L, Tang Z, Isaacson PG, Harris NL (2005) Plasmablastic lymphoma in HIV-positive patients: an aggressive Epstein-Barr virus–associated extramedullary plasmacytic neoplasm. Am J Surg Pathol 29:1633–1641

    PubMed  Article  Google Scholar 

  61. Rochford R, Hobbs MV, Garnier JL, Cooper NR, Cannon MJ (1993) Plasmacytoid differentiation of Epstein-Barr virus-transformed B cells in vivo is associated with reduced expression of viral latent genes. Proc Natl Acad Sci U S A 90:352–356

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgments

This study was made possible by a research grant (number 93874) from the National Health Laboratory Service, South Africa, which is most appreciatively acknowledged. This presentation has also been supported, in part, by a fellowship/grant from the Fogarty International Center/USNIH: grant # 3U2RTW007373 ICOHRTA and 3U2RTW007370‐05S1.

The academic inspiration of Professor Dhirendra Govender (HOD; Anatomical Pathology, UCT) is gratefully acknowledged.

Author information

Affiliations

  1. Division of Anatomical Pathology, National Health Laboratory Service, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa

    Sugeshnee Pather & Heather McLeod

  2. Department of Radiation Oncology, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa

    Zainab Mohamed

  3. Division of Anatomical Pathology, National Health Laboratory Service, Red Cross Children’s Hospital, University of Cape Town, Cape Town, South Africa

    Komala Pillay

Authors
  1. Sugeshnee Pather
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zainab Mohamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heather McLeod
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Komala Pillay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sugeshnee Pather.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pather, S., Mohamed, Z., McLeod, H. et al. Large Cell Lymphoma: Correlation of HIV Status and Prognosis with Differentiation Profiles Assessed by Immunophenotyping. Pathol. Oncol. Res. 19, 695–705 (2013). https://doi.org/10.1007/s12253-013-9632-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-013-9632-2

Keywords

  • Diffuse large B cell lymphoma
  • Plasmablastic lymphoma
  • Prognosis
  • HAART
  • HIV
  • CD4
  • Bcl-2
  • CD38