Research Initiative Treatment Action (RITA!); Vol 9, No. 1 Summer 2003
Regis A. Vilchez, MD, and Janet S. Butel, PhD

Introduction

Immunodeficiency (whether congenital, iatrogenic, or caused by infection) increases the risk of some types of cancer, especially malignancies etiologically linked to DNA tumor viruses, such as herpesviruses and polyomavirus.¹, ², ³, ⁴ Indeed, immunosuppression associated with HIV infection substantially increases the risk of developing Kaposi's sarcoma and non-Hodgkin's lymphoma. These two malignancies and invasive cervical carcinoma are the only recognized AIDS-defining cancers.⁵ Hodgkin's lymphoma was not included as an AIDS-defining illness by the Center for Disease Control and Prevention HIV classification system,⁵ but data from several studies suggest that the risk of Hodgkin's lymphoma in persons with HIV infection is increased.⁶, ⁷, ⁸, ⁹

The introduction of highly active antiretroviral therapy (HAART) and prophylaxis against opportunistic diseases has significantly improved the survival of patients with HIV infection.¹⁰, ¹¹ HAART can cause a significant and sustained decrease in peripheral blood HIV RNA levels, as well as an increase in CD4 T cells.¹², ¹³, ¹⁴, ¹⁵ However, the influence of this therapy on AIDS-related lymphoproliferative disorders is less clear. ¹⁶, ¹⁷ Recent data from the United States and Western Europe have shown no significant decrease in the incidence of non-Hodgkin's and Hodgkin's lymphomas, in contrast to dramatic reductions in Kaposi's sarcoma among patients treated with HAART.¹¹, ^18-26 A meta-analysis of the incidence of cancers from selected cohorts²⁷ of HIV-infected patients from the periods of 1992 to 1996 and 1997 to 1999 by the International Collaboration on HIV and Cancer suggested a small decrease in systemic diffuse large cell lymphoma but no decreases in other types of non-Hodgkin's lymphoma. However, the analysis of lymphomas is limited by the lack of specific pathology information from some of the cohorts included in the meta-analysis.

While the goal of antiretroviral therapy is the suppression of HIV replication,²⁸, ²⁹ failure to accomplish this objective is common in clinical practice, occurring at a rate of 40% to 70%.³⁰, ³¹, ³² Also, data suggest that the continuing efficacy of present antiretroviral therapy may allow more HIV-infected patients to survive with long-term mild to moderate immunosuppression, thereby placing such patients at risk for the development of lymphoproliferative disorders such as Hodgkin's and non-Hodgkin's lymphomas. Indeed, recent data suggest that 23% to 50% of patients receiving HAART developed Hodgkin's and non-Hodgkin's lymphomas despite effective HIV suppression and high CD4 T cell counts.²⁵, ²⁶, ^33-36 These results substantiate that the development of lymphomas in HIV-infected individuals is a complex process not determined by HIV replication. In this review, we examine advances in understanding the biology and viral pathogenesis of lymphoproliferative disorders among HIV-infected patients.

Non-Hodgkin's Lymphoma

Non-Hodgkin lymphoma (NHL) is a common malignancy in HIV-infected patients and its incidence in that population may be increased up to 300 times.⁹,¹²,¹³ NHL incidence increases markedly with progression of HIV infection, although association with the level of CD4 lymphopenia is less pronounced than with other opportunistic infections. All populations at risk for HIV are also at risk for the development of lymphoma, in contrast to Kaposi's sarcoma, which is diagnosed primarily in homosexual or bisexual men. The NHL that occurs in HIV-infected patients can be divided into two categories: systemic and primary central nervous system lymphoma (see Table below). The genetic alterations of systemic NHL among HIV-infected patients include activation of oncogenes by chromosomal translocations (ie, c-myc and bcl-2) and/or inactivation of tumor suppressor genes (ie, p53).³ A recent analysis showed that, compared to HIV-negative cases, NHL among HIV-infected patients was more likely to be highly proliferative and to express p53.³⁶ These data suggest a different pathogenesis of NHL among HIV-infected patients as compared to uninfected patients.

Some NHL in HIV-infected patients has been attributed to deficient immune surveillance of oncogenic herpesviruses, such as Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8), or perhaps to chronic antigenic stimulation and defective immune regulation.¹,³⁸ EBV is suspected of playing a major causative role in primary central nervous system (CNS) NHL in HIV-infected patients, as most of those tumors contain EBV DNA, but it is detected less frequently (<40%) in systemic NHL in HIV-infected patients³⁸ (see Table below). EBV is found even less commonly in NHL from HIV-negative patients. HHV-8 is specifically associated with multicentric Castleman's disease and primary effusion lymphoma, which often occurs in a setting of profound immunosuppression.³⁸

Table. Characteristics of non-Hodgkin’s and Hodgkin’s lymphoma in patients with HIV infection during the HAART era.

Abbreviations: NHL, non-Hodgkin’s lymphoma; CNS, central nervous system; HAART, highly active antiretroviral therapy; EBV, Epstein-Barr virus; SV40, simian virus 40; HHV-8, human herpesvirus 8; ND, not determined.

As EBV and HHV-8 are absent from many forms of NHL, other viral agents such as polyomavirus simian virus 40 (SV40) have been investigated. Early studies reported the detection of polyomavirus SV40 DNA sequences in NHL from HIV-infected and non-HIV-infected patients, but the small size of the study populations, the lack of screening for other tumor viruses, and the limited confirmation of the detected viral sequences made it difficult to assess whether SV40 was associated with NHL.³⁹,⁴⁰ However, recent large and controlled studies demonstrated that SV40 tumor antigen (T-ag) DNA sequences were significantly associated with NHL in both HIV-infected and non-HIV-infected patients.³,⁴,⁴¹ In addition, EBV was found to be associated with 39% of systemic NHL from HIV-infected patients and with only 15% from the HIV-negative group,³ similar to rates reported previously.³⁸ Importantly, the observation of minimal instances of co-infection with SV40 and EBV and the lack of detection of SV40 in nonmalignant lymphoid samples and cancer control specimens suggest that SV40 may be contributing to the development of some NHL among HIV-infected patients.³

The lymphomagenic capacity of SV40 is well-established in laboratory animal models. In hamsters inoculated intravenously with SV40, lymphomas developed among 72% of the animals, compared to none in the control group.⁴² The lymphomas were of B cell origin as they expressed cell surface antigen and their histology was consistent with diffuse large cell type.⁴³ An etiologic role for the virus in the development of lymphomas was supported because SV40 T-ag was expressed in all tumor cells, animals with tumors developed antibody against SV40 T-ag, and neutralization of SV40 with specific antibody before virus inoculation prevented lymphoma development.⁴² SV40 oncogenesis is mediated in large part by the viral oncoprotein, T-ag, as a result of its binding and inactivation of tumor suppressor proteins in the p53 and pRb families.¹ The functional inactivation of these two important cell cycle control proteins stimulates host cells to proliferate. Other cellular effects may be mediated by SV40 in human B cells as well.⁴⁴,⁴⁵ Further studies are needed to define the mechanisms of SV40 interactions with human lymphocytes.

Hodgkin's Lymphoma

The association between HIV infection and the development of Hodgkin's lymphoma, which typically occurs in the age groups of patients most affected by HIV, has been slowly established because this malignancy is an uncommon cancer. An analysis⁷ of AIDS and cancer registry data from diverse regions of the United States conducted between 1978 and 1996 showed that Hodgkin's lymphoma occurred in a statistically significant excess in HIV-infected patients (relative risk [RR] 11.5; 95% confidence interval [95% CI], 10.6–12.5). More importantly, that analysis indicated a particular association with Hodgkin's lymphoma subtypes of mixed cellularity (RR, 18.3; 95% CI, 15.9–20.9) and lymphocyte depletion (RR, 35.3; 95% CI, 24.7–48.8).

There are very few studies that have analyzed Hodgkin's lymphoma during the HAART era,¹⁰,²⁰,²⁴ so assessing the incidence of this malignancy in HIV-infected patients since the introduction of HAART has been difficult. However, a recent investigation²⁶ showed that Hodgkin's lymphoma has a low incidence in HIV-infected patients receiving HAART (6.5 per 1,000 patients) and that no significant difference in the incidence of this malignancy was observed between patients receiving HAART and those naïve to antiretroviral therapy. The results further suggested that Hodgkin's lymphoma is an aggressive disease with unfavorable clinical outcome in HIV-infected patients.²⁶ Reports prior to the introduction of HAART described HIV-related Hodgkin's lymphoma as an atypical and more aggressive form of disease with unusual presentation and worse outcome compared with Hodgkin's lymphoma in patients with HIV-negative status.^6-9, ¹² Hodgkin's lymphoma in persons with HIV infection presented at an advanced stage, and commonly at extranodal sites. Mixed cellularity and lymphocyte depletion subtypes accounted for a greater proportion of the cases, and nodular sclerosing subtype for a lower proportion of cases, than in persons without HIV infection.^6-9, ¹² Recent data indicate that mixed cellularity and lymphocyte depletion subtypes continue to be the most frequent types of Hodgkin's lymphoma and that diffuse disease remains a common feature of this malignancy in the HAART era.²⁶ These clinical and histopathologic features of Hodgkin's lymphoma among HIV-infected patients may be the result of the alterations of CD4 T cells in this patient population.

In non-HIV-infected patients with Hodgkin's lymphoma, CD4 T cells predominate in the tumor microenvironment and may contribute, at least in part, to the modulation of the Hodgkin's lymphoma phenotype⁴⁶ and eventually to its clinical behavior.⁴⁷,⁴⁸ In contrast, among patients with HIV infection, the tumor microenvironment reportedly lacks the typical high proportion of CD4 T cells that may keep tumor cells and tissues under control and is characterized by an unusually high proportion of malignant cells.¹²,⁴⁹ Indeed, studies both prior to the introduction of HAART and in patients receiving HAART indicate that Hodgkin's lymphoma tends to develop in patients with a median CD4 T cell count of 200 cells/mm³.^6-9,¹²,²⁶

Immunodeficiency can play a negative role both in the clinical presentation and the outcome of HIV-infected patients with lymphoma.²⁶ A recent study compared the clinical features and prognosis of Hodgkin's lymphoma and NHL among HIV-infected patients.⁵⁰ The clinical presentation of these two lymphoproliferative disorders was similar, except for the decreased frequency of extranodal disease that was seen in patients with Hodgkin's lymphoma as compared to NHL (56% vs. 82%, p=0.02) and the increased frequency of bone marrow involvement in patients with Hodgkin's lymphoma as compared to NHL (50% vs. 20%, p=0.01). Complete remission and overall survival rates did not differ significantly, with estimated overall survival at 5 years of 24% in HIV-infected patients with Hodgkin's lymphoma and 23% in patients with NHL.

Data indicate that 50% of the patients with Hodgkin's lymphoma who were receiving HAART had detectable HIV RNA viral loads.²⁶ These findings support the hypothesis that factors promoting the development of lymphomas may not be related to immune dysfunction or may be associated with processes not affected by HAART. Indeed, EBV is suspected of playing a causative role in Hodgkin's lymphoma: as many as 70% of Reed-Sternberg cells are EBV-positive in HIV-infected patients, whereas only about one-third of these malignancies in the general population are EBV-positive²⁶ (see Table above). The precise role of EBV in Hodgkin's lymphoma among HIV-infected patients, however, requires further investigation.

Conclusion

Recent investigations suggest that Hodgkin's lymphoma and systemic NHL are significant causes of mortality among HIV-infected patients during the HAART era. As antiretroviral therapies improve the survival of HIV-infected patients, the risk of developing or dying from cancer may increase. Large and well-designed population-based studies will be needed to better define the spectrum of malignancies and the most effective strategies for screening and treatment in HIV-infected patients. In addition, further research is essential to define the role of DNA tumor viruses in the genesis of lymphoproliferative disorders among these patients.

Regis A. Vilchez, MD, and Janet S. Butel, PhD, are faculty researchers at Baylor College of Medicine and are affiliated with the Baylor Center for AIDS Research (CFAR).

References

1.Butel JS. Viral carcinogenesis: revelation of molecular mechanisms and etiology of human disease. Carcinogenesis. 2000 Mar; 21(3): 405-26.

2.Vilchez RA, Lednicky JA, Halvorson SJ, White ZS, Kozinetz CA, Butel JS. Detection of polyomavirus simian virus 40 tumor antigen DNA in AIDS-related systemic non-Hodgkin lymphoma. J Acquir Immune Defic Syndr. 2002 Feb 1; 29(2): 109-16.

3.Vilchez RA, Madden CR, Kozinetz CA, et al. Association between simian virus 40 and non-Hodgkin lymphoma. Lancet. 2002 Mar 9; 359(9309): 817-23.

4.Shivapurkar N, Harada K, Reddy J, et al. Presence of simian virus 40 DNA sequences in human lymphomas. Lancet. 2002 Mar 9; 359(9309): 851-2.

5.Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep. 1992;41:1-19.

6.Knopf KB, Locker GY. Hodgkin's disease and HIV infection. N Engl J Med. N Engl J Med. 1995 Jul 6; 333(1): 65-6.

7.Frish M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA. 2001 Apr 4; 285(13): 1736-45.

8.Hessol NA, Katz MH, Liu JY, Buchbinder SP, Rubino CJ, Holmberg SD. Increased incidence of Hodgkin disease in homosexual men with HIV infection. Ann Intern Med. 1992 Aug 15; 117(4): 309-11.

9.Knowles DM, Chamulak GA, Subar M, et al. Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS). The New York University Medical Center experience with 105 patients (1981-1986). Ann Intern Med. 1988 May; 108(5): 744-53.

10.Palella FJ, Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998 Mar 26; 338(13): 853-60.

11.National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia. HIV/AIDS, hepatitis C and sexually transmitted infections in Australia: Annual surveillance report 1999.

12.Knowles DM. Etiology and pathogenesis of AIDS-related non--Hodgkin's lymphoma. Hematol Oncol Clin North Am. 1996 Oct; 10(5): 1081-109.

13.Sandler AS, Kaplan L. AIDS lymphoma. Curr Opin Oncol. 1996 Sep; 8(5): 377-85.

14.Li TS, Tubiana R, Katlama C, Calvez V, Ait Mohand H, Autran B. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet. 1998 Jun 6; 351(9117): 1682-6.

15.Pezzotti P, Pappagallo M, Phillips AN, et al. Response to highly active antiretroviral therapy according to duration of HIV infection. J Acquir Immune Defic Syndr. 2001 Apr 15; 26(5): 473-9.

16.Matthews GV, Bower M, Mandalia S, Powles T, Nelson MR, Gazzard BG. Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy. Blood. 2000 Oct 15; 96(8): 2730-4.

17.Rabkin CS. AIDS and cancer in the era of highly active antiretroviral therapy (HAART). Eur J Cancer. 2001 Jul; 37(10): 1316-9.

18.Mocroft A, Vella S, Benfield TL, et al. Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet. 1998 Nov 28; 352(9142): 1725-30.

19.Jacobson LP, Yamashita TE, Detels R, et al. Impact of potent antiretroviral therapy on the incidence of Kaposi's sarcoma and non-Hodgkin's lymphomas among HIV-1-infected individuals. Multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr. 1999 Aug 1; 21 Suppl 1: S34-41.

20.Jones JL, Hanson DL, Dworkin MS, Ward JW, Jaffe HW. Effect of antiretroviral therapy on recent trends in selected cancers among HIV-infected persons. Adult/Adolescent Spectrum of HIV Disease Project Group.
J Acquir Immune Defic Syndr. 1999 Aug 1; 21 Suppl 1: S11-7.

21.Ledergerber B, Egger M, Erard V, et al. AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study. JAMA. 1999 Dec 15; 282(23): 2220-6.

22.Ledergerber B, Telenti A, Egger M. Risk of HIV related Kaposi's sarcoma and non-Hodgkin's lymphoma with potent antiretroviral therapy: prospective cohort study. Swiss HIV Cohort Study. BMJ. 1999 Jul 3; 319(7201): 23-4.

23.Mocroft A, Katlama C, Johnson AM, et al. AIDS across Europe, 1994-98: the EuroSIDA study. Lancet. 2000 Jul 22; 356(9226): 291-6.

24.Vilchez RA, Kozinetz CA, Butel JS. The changing incidence of four AIDS-related malignancies in a large urban center. AIDS Patient Care STDs. 2001 Aug; 15(8): 405-6.

25.Vilchez RA, Kozinetz CA, Jorgensen JL, Kroll MH, Butel JS. AIDS-related systemic non-Hodgkin's lymphoma at a large community program. AIDS Res Hum Retroviruses. 2002 Mar 1; 18(4): 237-42.

26.Vilchez RA, Finch CJ, Jorgensen JL, Butel JS. The clinical epidemiology of Hodgkin lymphoma in HIV-infected patients in the highly active antiretroviral therapy (HAART) era. Medicine. 2003 Mar; 82(2): 77-81.

27.International Collaboration on HIV and Cancer. Highly active antiretroviral therapy and incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst. 2000 Nov 15; 92(22): 1823-30.

28.Carpenter CC, Cooper DA, Fischl MA, et al. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel. JAMA. 2000 Jan 19; 283(3): 381-90.

29.Centers for Disease Control and Prevention. Vol. 47, No. 28 - MMWR Weekly Jul 31, 1998 / 47(29);619.

30.Deeks SG, Barbour JD, Martin JN, Swanson MS, Grant RM. Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection. J Infect Dis. 2000 Mar; 181(3): 946-53.

31.Jones JL, Hanson DL, Dworkin MS, Ward JW, Jaffe HW. Effect of antiretroviral therapy on recent trends in selected cancers among HIV-infected persons. Adult/Adolescent Spectrum of HIV Disease Project Group.
J Acquir Immune Defic Syndr. 1999 Aug 1; 21 Suppl 1: S11-7.

32.Lucas GM, Chaisson RE, Moore RD. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions. Ann Intern Med. 1999 Jul 20; 131(2): 81-7.

33.Tam HK, Zuo-Feng Z, Jacobson LP, et al. Effect of highly active antiretroviral therapy on survival among HIV-infected men with Kaposi sarcoma or non-Hodgkin lymphoma. Int J Cancer. 2002 Apr 20; 98(6): 916-22.

34.Gerard L, Galicier L, Maillard A, et al. Systemic non-Hodgkin lymphoma in HIV-infected patients with effective suppression of HIV replication: persistent occurrence but improved survival. J Acquir Immune Defic Syndr. 2002 Aug 15; 30(5): 478-84.

35.Navarro JT, Ribera JM, Oriol A, Tural C, Milla F, Feliu E. Improved outcome of AIDS-related lymphoma in patients with virologic response to highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2003 Mar 1; 32(3): 347-8.

36.Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003 Jun 15; 101(12): 4653-9.

37.Carbone A, Gloghini A, Capello A, Gaidano G. Genetic pathways and histogenetic models of AIDS-related lymphomas. Eur J Cancer. 2001 Jul; 37(10): 1270-5.

38.Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization classification of tumors. Pathology and genetics of tumors of hematopoietic and lymphoid tissues. Lyon: IARC Press, 2001.

39.Martini F, Dolcetti R, Gloghini A, et al. Simian-virus-40 footprints in human lymphoproliferative disorders of HIV- and HIV+ patients. Int J Cancer. 1998 Dec 9; 78(6): 669-74.

40.Rizzo P, Carbone M, Fisher SG, et al. Simian virus 40 is present in most United States human mesotheliomas, but it is rarely present in non-Hodgkin's lymphoma. Chest. 1999 Dec; 116(6 Suppl): 470S-473S.

41.David H, Mendoza S, Konishi T, Miller CW. Simian virus 40 is present in human lymphomas and normal blood. Cancer Lett. 2001 Jan 10; 162(1): 57-64.

42.Diamandopoulos GT. Leukemia, lymphoma, and osteosarcoma induced in the Syrian golden hamster by simian virus 40. Science. 1972 Apr 14; 176(31): 173-5.

43.Coe JE, Green I. B-cell origin of hamster lymphoid tumors induced by simian virus 40. J Nat Cancer Inst. 1975 Jan; 54(1): 269-70.

44.Kanki T. Immortalization of human primary B lymphocytes by simian virus 40 early region DNA. Hybridoma. 1994 Aug; 13(4): 327-30.

45.Classon M, Henriksson M, Sumegi J, Klein G, Hammaskjold ML. Elevated c-myc expression facilitates the replication of SV40 DNA in human lymphoma cells. Nature. 1987 Nov 19-25; 330(6145): 272-4.

46.Carbone A, Gloghini A, Gaidano G, et al. Expression status of BCL-6 and syndecan-1 identifies distinct histogenetic subtypes of Hodgkin's disease. Blood. 1998 Oct 1; 92(7): 2220-8.

47.Munker R, Hasenclever D, Brosteanu O, Hiller E, Diehl V. Bone marrow involvement in Hodgkin's disease: an analysis of 135 consecutive cases. German Hodgkin's Lymphoma Study Group. J Clin Oncol. J Clin Oncol. 1995 Feb; 13(2): 403-9.

48.Smolewski P, Robak T, Krykowski E, et al. Prognostic factors in Hodgkin's disease: multivariate analysis of 327 patients from a single institution. Clin Cancer Res. 2000 Mar; 6(3): 1150-60.

49.International Agency for Research on Cancer (IARC). IARC monographs on the evaluation of carcinogenic risks to humans: human immunodeficiency virus and human T cell lymphotrophic viruses. Volume 67. Lyon: IARC/World Health Organization, 1996.

50.Re A, Casari S, Cattaneo C, et al. Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer. 2001 Dec 1; 92(11): 2739-45.

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