Diagnosis and management of lymphomas and other cancers in HIV-infected patients

Key Points

  • Lymphomas represent the most frequent malignancy among HIV-infected people

  • The most common lymphomas that arise in HIV-associated patients are Burkitt lymphoma, diffuse large B-cell lymphomas, and Hodgkin lymphoma—the latter is the most common non AIDS-defining cancer type

  • Some rare types of lymphomas, such as primary effusion lymphomas, occur nearly exclusively in people with HIV and/or AIDS

  • Non AIDS-defining cancers are mostly infection-related, and exhibit histopathological and immunophenotypical features similar to those observed in HIV-negative patients

  • The combination of cART and antineoplastic treatment has provided remarkable results in the most common lymphomas that arise in HIV-infected patients

  • In people with HIV and/or AIDS, improved screening strategies are required to actively detect oncogenic viruses, precancerous lesions, and early stage malignant disease

Abstract

Despite the introduction of highly active antiretroviral therapy or combination antiretroviral therapy (HAART and cART, respectively) patients infected with HIV might develop certain types of cancer more frequently than uninfected people. Lymphomas represent the most frequent malignancy among patients with HIV. Other cancer types that have increased in these patients include Kaposi sarcoma, cancer of the cervix, anus, lung and liver. In the post-HAART era, however, patients with HIV have experienced a significant improvement in their morbidity, mortality and life expectancy. This Review focuses on the different types of lymphomas that generally occur in patients with HIV. The combination of cART and antineoplastic treatment has resulted in remarkable prolongation of disease-free survival and overall survival among patients with HIV who develop lymphoma. However, the survival in these patients still lags behind that of patients with lymphoma who are not infected with HIV. We also provide an update of epidemiological data, diagnostic issues, and strategies regarding the most-appropriate management of patients with both HIV and lymphomas.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: HIV-associated Burkitt lymphoma.
Figure 2: HIV-associated DLBCL.
Figure 3: AIDS and non AIDS-defining cancers.

References

  1. 1

    IARC in IARC Monograph on the Evaluation of Carcinogenic Risk to Humans. Vol. 100 Part B (IARC, Lyon, France, 2012).

  2. 2

    de Martel, C. et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 13, 607–615 (2012).

    Google Scholar 

  3. 3

    Grulich, A. E., van Leeuwen, M. T., Falster, M. O. & Vajdic, C. M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370, 59–67 (2007).

    Google Scholar 

  4. 4

    Moore, P. S. & Chang, Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat. Rev. Cancer 10, 878–889 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  5. 5

    Simard, E. P., Pfeiffer, R. M. & Engels, E. A. Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States. Cancer 117, 1089–1096 (2011).

    Google Scholar 

  6. 6

    Shiels, M. S. et al. The epidemic of non-Hodgkin lymphoma in the United States: disentangling the effect of HIV, 1992–2009 Cancer Epidemiol. Biomarkers Prev. 22, 1069–1078 (2013).

    PubMed Central  PubMed  Google Scholar 

  7. 7

    Polesel, J. et al. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS 22, 301–306 (2008).

    Google Scholar 

  8. 8

    Serraino, D. et al. Survival after AIDS diagnosis in Italy, 1999–2006: a population-based study. J. Acquir. Immune Defic. Syndr. 52, 99–105 (2009).

    Google Scholar 

  9. 9

    Mbulaiteye, S. M. et al. Spectrum of cancers among HIV-infected persons in Africa: the Uganda AIDS-Cancer Registry Match Study. Int. J. Cancer 118, 985–990 (2006).

    CAS  Google Scholar 

  10. 10

    Ablanedo-Terrazas, Y., Alvarado- De La Barrera, C. & Reyes-Teran, G. Towards a better understanding of Kaposi sarcoma-associated immune reconstitution inflammatory syndrome. AIDS 27, 1667–1669 (2013).

    Google Scholar 

  11. 11

    Maurer, T., Ponte, M. & Leslie, K. HIV-associated Kaposi's sarcoma with a high CD4 count and a low viral load. N. Engl. J. Med. 357, 1352–1353 (2007).

    CAS  Google Scholar 

  12. 12

    Mani, D., Neil, N., Israel, R. & Aboulafia, D. M. A retrospective analysis of AIDS-associated Kaposi's sarcoma in patients with undetectable HIV viral loads and CD4 counts greater than 300 cells/mm (3). J. Int. Assoc. Physicians AIDS Care (Chic.) 8, 279–285 (2009).

    Google Scholar 

  13. 13

    Unemori, P. et al. Immunosenescence is associated with presence of Kaposi's sarcoma in antiretroviral treated HIV infection. AIDS 27, 1735–1742 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  14. 14

    Bhatia, K., Shiels, M. S., Berg, A. & Engels, E. A. Sarcomas other than Kaposi sarcoma occurring in immunodeficiency: interpretations from a systematic literature review. Curr. Opin. Oncol. 24, 537–546 (2012).

    PubMed Central  PubMed  Google Scholar 

  15. 15

    Vaccher, E. et al. Improvement of systemic human immunodeficiency virus-related non-Hodgkin lymphoma outcome in the era of highly active antiretroviral therapy. Clin. Infect. Dis. 37, 1556–1564 (2003).

    Google Scholar 

  16. 16

    Barta, S. K. et al. Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients. Blood 122, 3251–3262 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  17. 17

    Chao, C. et al. Survival of non-Hodgkin lymphoma patients with and without HIV infection in the era of combined antiretroviral therapy. AIDS 24, 1765–1770 (2010).

    PubMed Central  PubMed  Google Scholar 

  18. 18

    Gopal, S. et al. Temporal trends in presentation and survival for HIV-associated lymphoma in the antiretroviral therapy Era. J. Natl Cancer Inst. 105, 1221–1229 (2013).

    PubMed Central  PubMed  Google Scholar 

  19. 19

    Raphael, M., Said, J., Borish, B., Cesarman, E. & Harris, N. L. in WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn (eds Swerdlow, S. H. et al.) 340–342 (IARC, Lyon, 2008).

    Google Scholar 

  20. 20

    Kaplan, L. D. HIV-associated lymphoma. Best Pract. Res. Clin. Haematol. 25, 101–117 (2012).

    CAS  Google Scholar 

  21. 21

    Carbone, A., Cesarman, E., Spina, M., Gloghini, A. & Schulz, T. F. HIV-associated lymphomas and gamma-herpesviruses. Blood 113, 1213–1224 (2009).

    CAS  Google Scholar 

  22. 22

    Roschewski, M. & Wilson, W. H. EBV-associated lymphomas in adults. Best Pract. Res. Clin. Haematol. 25, 75–89 (2012).

    PubMed Central  PubMed  Google Scholar 

  23. 23

    Carbone, A. et al. Immunophenotypic and molecular analyses of acquired immune deficiency syndrome-related and Epstein–Barr virus-associated lymphomas: a comparative study. Hum. Pathol. 27, 133–146 (1996).

    CAS  Google Scholar 

  24. 24

    Shiels, M. S. et al. Cancer burden in the HIV-infected population in the United States. J. Natl Cancer Inst. 103, 753–762 (2011).

    PubMed Central  PubMed  Google Scholar 

  25. 25

    Franceschi, S. et al. Kaposi sarcoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. Br. J. Cancer 99, 800–804 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  26. 26

    Franceschi, S. et al. Changing patterns of cancer incidence in the early and late-HAART periods: the swiss HIV cohort study. Br. J. Cancer 103, 416–422 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. 27

    Dal Maso, L. et al. Pattern of cancer risk in persons with AIDS in Italy in the HAART era. Br. J. Cancer 100, 840–847 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  28. 28

    Polesel, J. et al. Cancer incidence in people with AIDS in Italy. Int. J. Cancer 127, 1437–1445 (2010).

    CAS  Google Scholar 

  29. 29

    Guiguet, M. et al. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): a prospective cohort study. Lancet Oncol. 10, 1152–1159 (2009).

    CAS  Google Scholar 

  30. 30

    [No authors listed] 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm. Rep. 41, 1–19 (1992).

  31. 31

    Ancelle-Park, R. A., Alix, J., Downs, A. M. & Brunet, J. B. Impact of 1993 revision of adult/adolescent AIDS surveillance case-definition for Europe. National Coordinators for AIDS Surveillance in 38 European countries. Lancet 345, 789–790 (1995).

    CAS  PubMed  Google Scholar 

  32. 32

    Sahasrabuddhe, V. V., Shiels, M. S., McGlynn, K. A. & Engels, E. A. The risk of hepatocellular carcinoma among individuals with acquired immunodeficiency syndrome in the United States. Cancer 118, 6226–6233 (2012).

    PubMed Central  PubMed  Google Scholar 

  33. 33

    Martin, C. P., Fain, M. J. & Klotz, S. A. The older HIV-positive adult: a critical review of the medical literature. Am. J. Med. 121, 1032–1037 (2008).

    Google Scholar 

  34. 34

    Stein, L. et al. The spectrum of human immunodeficiency virus-associated cancers in a South African black population: results from a case–control study, 1995–2004 Int. J. Cancer 122, 2260–2265 (2008).

    CAS  Google Scholar 

  35. 35

    De Paoli, P. Novel virally targeted therapies of EBV-associated tumors. Curr. Cancer Drug Targets 8, 591–596 (2008).

    PubMed  Google Scholar 

  36. 36

    Chan, A. T. et al. Azacitidine induces demethylation of the Epstein–Barr virus genome in tumors. J. Clin. Oncol. 22, 1373–1381 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Gulley, M. L. & Tang, W. Laboratory assays for Epstein–Barr virus-related disease. J. Mol. Diagn. 10, 279–292 (2008).

    PubMed Central  PubMed  Google Scholar 

  38. 38

    De Paoli, P., Pratesi, C. & Bortolin, M. T. The Epstein Barr virus DNA levels as a tumor marker in EBV-associated cancers. J. Cancer Res. Clin. Oncol. 133, 809–815 (2007).

    CAS  PubMed  Google Scholar 

  39. 39

    Van Baarle, D. et al. Absolute level of Epstein–Barr virus DNA in human immunodeficiency virus type 1 infection is not predictive of AIDS-related non-Hodgkin lymphoma. J. Infect. Dis. 186, 405–409 (2002).

    CAS  PubMed  Google Scholar 

  40. 40

    Tedeschi, R. et al. Assessment of immunovirological features in HIV related non-Hodgkin lymphoma patients and their impact on outcome. J. Clin. Virol. 53, 297–301 (2012).

    Google Scholar 

  41. 41

    Carbone, A. et al. Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8-positive solid lymphomas: a tissue-based variant of primary effusion lymphoma. J. Mol. Diagn. 7, 17–27 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. 42

    Chadburn, A., Wilson, J. & Wang, Y. L. Molecular and immunohistochemical detection of Kaposi sarcoma herpesvirus/human herpesvirus-8. Methods Mol. Biol. 999, 245–256 (2013).

    CAS  Google Scholar 

  43. 43

    Shamay, M. et al. CpG methylation as a tool to characterize cell-free Kaposi sarcoma herpesvirus DNA. J. Infect. Dis. 205, 1095–1099 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  44. 44

    Carbone, A. & De Paoli, P. Cancers related to viral agents that have a direct role in carcinogenesis: pathological and diagnostic techniques. J. Clin. Pathol. 65, 680–686 (2012).

    Google Scholar 

  45. 45

    Friborg, J. Jr, Kong, W., Hottiger, M. O. & Nabel, G. J. p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402, 889–894 (1999).

    CAS  Google Scholar 

  46. 46

    Liu, J., Martin, H. J., Liao, G. & Hayward, S. D. The Kaposi's sarcoma-associated herpesvirus LANA protein stabilizes and activates c-Myc. J. Virol. 81, 10451–10459 (2007).

    CAS  PubMed Central  PubMed  Google Scholar 

  47. 47

    Gloghini, A., Dolcetti, R. & Carbone, A. Lymphomas occurring specifically in HIV-infected patients: from pathogenesis to pathology. Semin. Cancer Biol. 23, 457–467 (2013).

    CAS  Google Scholar 

  48. 48

    Fiorentini, S., Marini, E., Caracciolo, S. & Caruso, A. Functions of the HIV-1 matrix protein p17. New Microbiol. 29, 1–10 (2006).

    CAS  Google Scholar 

  49. 49

    Giagulli, C. et al. Opposite effects of HIV-1 p17 variants on PTEN activation and cell growth in B cells. PLoS ONE 6, e17831 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  50. 50

    Hussain, S. K. et al. Serum biomarkers of immune activation and subsequent risk of non-Hodgkin B cell lymphoma among HIV-infected women. Cancer Epidemiol. Biomarkers Prev. 22, 2084–2093 (2013).

    CAS  Google Scholar 

  51. 51

    Breen, E. C. et al. B-cell stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B-cell lymphoma. Cancer Epidemiol. Biomarkers Prev. 20, 1303–1314 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  52. 52

    Appay, V. & Sauce, D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J. Pathol. 214, 231–241 (2008).

    CAS  Google Scholar 

  53. 53

    Takeshita, S. et al. Induction of IL-6 and IL-10 production by recombinant HIV-1 envelope glycoprotein 41 (gp41) in the THP-1 human monocytic cell line. Cell. Immunol. 165, 234–242 (1995).

    CAS  Google Scholar 

  54. 54

    Sabbah, S. et al. T-cell immunity to Kaposi sarcoma-associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells. Blood 119, 2083–2092 (2012).

    CAS  Google Scholar 

  55. 55

    Piriou, E. et al. Loss of EBNA1-specific memory CD4+ and CD8+ T cells in HIV-infected patients progressing to AIDS-related non-Hodgkin lymphoma. Blood 106, 3166–3174 (2005).

    CAS  Google Scholar 

  56. 56

    Liapis, K. et al. The microenvironment of AIDS-related diffuse large B-cell lymphoma provides insight into the pathophysiology and indicates possible therapeutic strategies. Blood 122, 424–433 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  57. 57

    Giffin, L. & Damania, B. KSHV: Pathways to tumorigenesis and persistent infection. Adv. Virus Res. 88, 111–159 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  58. 58

    Ensoli, B. et al. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature 371, 674–680 (1994).

    CAS  Google Scholar 

  59. 59

    Meckes, D. G. Jr & Raab-Traub, N. Microvesicles and viral infection. J. Virol. 85, 12844–12854 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  60. 60

    Meckes, D. G. Jr et al. Modulation of B-cell exosome proteins by gamma herpesvirus infection. Proc. Natl Acad. Sci. USA 110, E2925–E2933 (2013).

    CAS  Google Scholar 

  61. 61

    de Oliveira, D. E., Ballon, G. & Cesarman, E. NF-kappaB signaling modulation by EBV and KSHV. Trends Microbiol. 18, 248–257 (2010).

    CAS  Google Scholar 

  62. 62

    Cesarman, E. Pathology of lymphoma in HIV. Curr. Opin. Oncol. 25, 487–494 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  63. 63

    Chadburn, A., Abdul-Nabi, A. M., Teruya, B. S. & Lo, A. A. Lymphoid proliferations associated with human immunodeficiency virus infection. Arch. Pathol. Lab. Med. 137, 360–370 (2013).

    CAS  Google Scholar 

  64. 64

    Hamilton-Dutoit, S. J. et al. Epstein–Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency. Am. J. Pathol. 143, 1072–1085 (1993).

    CAS  PubMed Central  PubMed  Google Scholar 

  65. 65

    Touitou, R. et al. Heterogeneous Epstein–Barr virus latent gene expression in AIDS-associated lymphomas and in type I Burkitt's lymphoma cell lines. J. Gen. Virol. 84, 949–957 (2003).

    CAS  Google Scholar 

  66. 66

    Chadburn, A. et al. Immunophenotypic analysis of AIDS-related diffuse large B-cell lymphoma and clinical implications in patients from AIDS Malignancies Consortium clinical trials 010 and 034. J. Clin. Oncol. 27, 5039–5048 (2009).

    PubMed Central  PubMed  Google Scholar 

  67. 67

    Dunleavy, K. et al. The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood 115, 3017–3024 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  68. 68

    Gaidano, G. et al. Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma. Blood 102, 1833–1841 (2003).

    CAS  Google Scholar 

  69. 69

    Tirelli, U. et al. Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J. Clin. Oncol. 13, 1758–1767 (1995).

    CAS  Google Scholar 

  70. 70

    Biggar, R. J. et al. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108, 3786–3791 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  71. 71

    Gloghini, A. & Carbone, A. Why would the incidence of HIV-associated Hodgkin lymphoma increase in the setting of improved immunity? Int. J. Cancer 120, 2753–2754 (2007).

    CAS  Google Scholar 

  72. 72

    Carbone, A., Cabras, A. & Gloghini, A. HIV-associated Hodgkin's lymphoma. Antiapoptotic pathways and mechanisms for immune escape by tumor cells in the setting of improved immunity. Int. J. Biol. Markers 22, 161–163 (2007).

    CAS  Google Scholar 

  73. 73

    Deeken, J. F. et al. The rising challenge of non-AIDS-defining cancers in HIV-infected patients. Clin. Infect. Dis. 55, 1228–1235 (2012).

    PubMed Central  PubMed  Google Scholar 

  74. 74

    Novak, R. M. et al. Immune reconstitution inflammatory syndrome: incidence and implications for mortality. AIDS 26, 721–730 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  75. 75

    Rajasuriar, R. et al. Persistent immune activation in chronic HIV infection: do any interventions work? AIDS 27, 1199–1208 (2013).

    PubMed Central  PubMed  Google Scholar 

  76. 76

    Kowalkowski, M. A., Mims, M. P., Amiran, E. S., Lulla, P. & Chiao, E. Y. Effect of immune reconstitution on the incidence of HIV-related Hodgkin Lymphoma. PLoS ONE 8, e77409 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  77. 77

    Vega, F. et al. Plasmablastic lymphomas and plasmablastic plasma cell myelomas have nearly identical immunophenotypic profiles. Mod. Pathol. 18, 806–815 (2005).

    Google Scholar 

  78. 78

    Pantanowitz, L., Pihan, G., Carbone, A. & Dezube, B. J. Differentiating HIV-associated non-Hodgkin's lymphomas with similar plasmacellular differentiation. J. HIV Ther. 14, 24–33 (2009).

    Google Scholar 

  79. 79

    Pantanowitz, L. & Dezube, B. J. Editorial comment: hemophagocytic syndrome—an HIV-associated quagmire. AIDS Read. 17, 500–502 (2007).

    Google Scholar 

  80. 80

    Stein, H. & Dallenbach, F. in Neoplastic Hematopathology (ed. Knowles, D. M.) 675–714 (Williams & Wilkins, Baltimore, MA, 1992).

    Google Scholar 

  81. 81

    Delecluse, H. J. et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 89, 1413–1420 (1997).

    CAS  Google Scholar 

  82. 82

    Gatter, K. C. & Warnke, R. A. in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues 3rd edn (eds Jaffe, E. S., Harris, N. L., Stein, H. & Vardiman, J. W.) 171–174 (IARC Press, Lyon, France, 2001).

    Google Scholar 

  83. 83

    Stein, H., Harris, N. L. & Campo, E. in WHO classification of Tumours of Haematopoietic and Lymphoid Tissues 4th edn (eds Swerdlow, S. H. et al.) 256–257 (IARC Press, Lyon, France, 2008).

    Google Scholar 

  84. 84

    Castillo, J., Pantanowitz, L. & Dezube, B. J. HIV-associated plasmablastic lymphoma: lessons learned from 112 published cases. Am. J. Hematol. 83, 804–809 (2008).

    Google Scholar 

  85. 85

    Pantanowitz, L., Carbone, A. & Dezube, B. J. in Plasmablastic lymphoma. An Emergent Disease with Poor Prognosis (ed. Pantanowitz, L.) 3–15 (VDM Verlag Dr Muller, Saarbrücken, Germany, 2010).

    Google Scholar 

  86. 86

    Colomo, L. et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am. J. Surg. Pathol. 28, 736–747 (2004).

    Google Scholar 

  87. 87

    Jung, C. P. et al. Uncommon hematologic malignancies. Case 1. Plasmablastic leukemia in HIV-associated multicentric Castleman's disease. J. Clin. Oncol. 21, 4248–4249 (2003).

    Google Scholar 

  88. 88

    Goedhals, J., Beukes, C. A. & Cooper, S. The ultrastructural features of plasmablastic lymphoma. Ultrastruct. Pathol. 30, 427–433 (2006).

    CAS  Google Scholar 

  89. 89

    Reid-Nicholson, M. et al. Plasmablastic lymphoma: cytologic findings in 5 cases with unusual presentation. Cancer 114, 333–341 (2008).

    Google Scholar 

  90. 90

    Bogusz, A. M. et al. Plasmablastic lymphomas with MYC/IgH rearrangement: report of three cases and review of the literature. Am. J. Clin. Pathol. 132, 597–605 (2009).

    CAS  Google Scholar 

  91. 91

    Carbone, A., Gloghini, A. & Gaidano, G. Is plasmablastic lymphoma of the oral cavity an HHV-8-associated disease? Am. J. Surg. Pathol. 28, 1538–1540 (2004).

    Google Scholar 

  92. 92

    Seliem, R. M. et al. HHV-8+, EBV+ multicentric plasmablastic microlymphoma in an HIV+ Man: the spectrum of HHV-8+ lymphoproliferative disorders expands. Am. J. Surg. Pathol. 31, 1439–1445 (2007).

    Google Scholar 

  93. 93

    Cesarman, E., Chang, Y., Moore, P. S., Said, J. W. & Knowles, D. M. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N. Engl. J. Med. 332, 1186–1191 (1995).

    CAS  Google Scholar 

  94. 94

    Chadburn, A. et al. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Am. J. Surg. Pathol. 28, 1401–1416 (2004).

    Google Scholar 

  95. 95

    Carbone, A., Cesarman, E., Gloghini, A. & Drexler, H. G. Understanding pathogenetic aspects and clinical presentation of primary effusion lymphoma through its derived cell lines. AIDS 24, 479–490 (2010).

    PubMed Central  PubMed  Google Scholar 

  96. 96

    Klein, U. et al. Gene expression profile analysis of AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic derivation and identifies PEL-specific transcripts. Blood 101, 4115–4121 (2003).

    CAS  Google Scholar 

  97. 97

    Morassut, S. et al. HIV-associated human herpesvirus 8-positive primary lymphomatous effusions: radiologic findings in six patients. Radiology 205, 459–463 (1997).

    CAS  Google Scholar 

  98. 98

    Katano, H. et al. Human herpesvirus 8-associated solid lymphomas that occur in AIDS patients take anaplastic large cell morphology. Mod. Pathol. 13, 77–85 (2000).

    CAS  Google Scholar 

  99. 99

    Pan, Z. G. et al. Extracavitary KSHV-associated large B-cell lymphoma: a distinct entity or a subtype of primary effusion lymphoma? Study of 9 cases and review of an additional 43 cases. Am. J. Surg. Pathol. 36, 1129–1140 (2012).

    Google Scholar 

  100. 100

    Carbone, A. et al. Extracavitary KSHV-positive solid lymphoma: a large B-cell lymphoma within the spectrum of primary effusion lymphoma. Am. J. Surg. Pathol. 37, 1460–1461 (2013).

    PubMed Central  PubMed  Google Scholar 

  101. 101

    Fend, F. et al. Early lesions in lymphoid neoplasia. J. Hematop. 5, 169–199 (2012).

    Google Scholar 

  102. 102

    Tirelli, U. et al. Epidemiological, biological and clinical features of HIV-related lymphomas in the era of highly active antiretroviral therapy. AIDS 14, 1675–1688 (2000).

    CAS  Google Scholar 

  103. 103

    Mounier, N., Spina, M. & Gisselbrecht, C. Modern management of non-Hodgkin lymphoma in HIV-infected patients. Br. J. Haematol. 136, 685–698 (2007).

    CAS  Google Scholar 

  104. 104

    State of the art oncology in Europe. Staroncology [online], (2014).

  105. 105

    Kaplan, L. D. et al. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N. Engl. J. Med. 336, 1641–1648 (1997).

    CAS  Google Scholar 

  106. 106

    Ratner, L. et al. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy. J. Clin. Oncol. 19, 2171–2178 (2001).

    CAS  Google Scholar 

  107. 107

    Mounier, N. et al. AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy. Blood 107, 3832–3840 (2006).

    CAS  Google Scholar 

  108. 108

    Sparano, J. A. et al. Phase II trial of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group Trial (E1494). J. Clin. Oncol. 22, 1491–1500 (2004).

    CAS  Google Scholar 

  109. 109

    Little, R. F. et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood 101, 4653–4659 (2003).

    CAS  Google Scholar 

  110. 110

    Levine, A. M. Management of AIDS-related lymphoma. Curr. Opin. Oncol. 20, 522–528 (2008).

    CAS  Google Scholar 

  111. 111

    Dunleavy, K. & Wilson, W. H. How I treat HIV-associated lymphoma. Blood 119, 3245–3255 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  112. 112

    Spina, M. et al. Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide in HIV-associated non-Hodgkin lymphoma: pooled results from 3 phase 2 trials. Blood 105, 1891–1897 (2005).

    CAS  Google Scholar 

  113. 113

    Boue, F. et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. J. Clin. Oncol. 24, 4123–4128 (2006).

    CAS  Google Scholar 

  114. 114

    Ribera, J. M. et al. Safety and efficacy of cyclophosphamide, adriamycin, vincristine, prednisone and rituximab in patients with human immunodeficiency virus-associated diffuse large B-cell lymphoma: results of a phase II trial. Br. J. Haematol. 140, 411–419 (2008).

    CAS  Google Scholar 

  115. 115

    Sparano, J. A. et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 115, 3008–3016 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  116. 116

    Levine, A. M. et al. Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047. J. Clin. Oncol. 31, 58–64 (2013).

    CAS  Google Scholar 

  117. 117

    Lim, S. T. et al. AIDS-related Burkitt's lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: significant differences in survival with standard chemotherapy. J. Clin. Oncol. 23, 4430–4438 (2005).

    CAS  Google Scholar 

  118. 118

    Lim, S. T., Karim, R., Tulpule, A., Nathwani, B. N. & Levine, A. M. Prognostic factors in HIV-related diffuse large-cell lymphoma: before versus after highly active antiretroviral therapy. J. Clin. Oncol. 23, 8477–8482 (2005).

    Google Scholar 

  119. 119

    Miralles, P. et al. Prognosis of AIDS-related systemic non-Hodgkin lymphoma treated with chemotherapy and highly active antiretroviral therapy depends exclusively on tumor-related factors. J. Acquir. Immune Defic. Syndr. 44, 167–173 (2007).

    Google Scholar 

  120. 120

    Kaplan, L. D. et al. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-malignancies consortium trial 010. Blood 106, 1538–1543 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  121. 121

    Barta, S. K., Lee, J. Y., Kaplan, L. D., Noy, A. & Sparano, J. A. Pooled analysis of AIDS malignancy consortium trials evaluating rituximab plus CHOP or infusional EPOCH chemotherapy in HIV-associated non-Hodgkin lymphoma. Cancer 118, 3977–3983 (2012).

    CAS  Google Scholar 

  122. 122

    Antinori, A. et al. Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. Update 2011. New Microbiol. 35, 113–159 (2012).

    CAS  Google Scholar 

  123. 123

    Ministero della salute. HIV and AIDS prevention [online].

  124. 124

    National comprehensive cancer network [online].

  125. 125

    Rudek, M. A., Flexner, C. & Ambinder, R. F. Use of antineoplastic agents in patients with cancer who have HIV/AIDS. Lancet Oncol. 12, 905–912 (2011).

    PubMed Central  PubMed  Google Scholar 

  126. 126

    Pham, P. A. & Flexner, C. Emerging antiretroviral drug interactions. J. Antimicrob. Chemother. 66, 235–239 (2011).

    CAS  Google Scholar 

  127. 127

    Zolopa, A. et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS ONE 4, e5575 (2009).

    PubMed Central  PubMed  Google Scholar 

  128. 128

    Gopal, S. et al. Association of early HIV viremia with mortality after HIV-associated lymphoma. AIDS 27, 2365–2373 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  129. 129

    Tirelli, U. & Bernardi, D. Impact of HAART on the clinical management of AIDS-related cancers. Eur. J. Cancer 37, 1320–1324 (2001).

    CAS  Google Scholar 

  130. 130

    Re, A. et al. High-dose therapy and autologous peripheral blood stem cell transplantation as salvage treatment for AIDS-related lymphoma: long-term results of the Italian Cooperative Group on AIDS and Tumors (GICAT) study with analysis of prognostic factors. Blood 114, 1306–1313 (2009).

    CAS  Google Scholar 

  131. 131

    Diez-Martin, J. L. et al. Comparable survival between HIV+ and HIV- non-Hodgkin and Hodgkin lymphoma patients undergoing autologous peripheral blood stem cell transplantation. Blood 113, 6011–6014 (2009).

    CAS  Google Scholar 

  132. 132

    Balsalobre, P. et al. Autologous stem-cell transplantation in patients with HIV-related lymphoma. J. Clin. Oncol. 27, 2192–2198 (2009).

    Google Scholar 

  133. 133

    Krishnan, A. et al. HIV status does not affect the outcome of autologous stem cell transplantation (ASCT) for non-Hodgkin lymphoma (NHL). Biol. Blood Marrow Transplant. 16, 1302–1308 (2010).

    PubMed Central  PubMed  Google Scholar 

  134. 134

    Michieli, M., Mazzucato, M., Tirelli, U. & De Paoli, P. Stem cell transplantation for lymphoma patients with HIV infection. Cell Transplant. 20, 351–370 (2011).

    Google Scholar 

  135. 135

    Bayraktar, U. D. et al. Outcome of patients with relapsed/refractory acquired immune deficiency syndrome-related lymphoma diagnosed 1999–2008 and treated with curative intent in the AIDS Malignancy Consortium. Leuk. Lymphoma 53, 2383–2389 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  136. 136

    Noy, A. Controversies in the treatment of Burkitt lymphoma in AIDS. Curr. Opin. Oncol. 22, 443–448 (2010).

    PubMed Central  PubMed  Google Scholar 

  137. 137

    Galicier, L. et al. Intensive chemotherapy regimen (LMB86) for St Jude stage IV AIDS-related Burkitt lymphoma/leukemia: a prospective study. Blood 110, 2846–2854 (2007).

    CAS  Google Scholar 

  138. 138

    Wang, E. S. et al. Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma. Cancer 98, 1196–1205 (2003).

    CAS  Google Scholar 

  139. 139

    Noy, A., Kaplan, L. & Lee, J. Feasibility and toxicity of a modified dose intensive R-CODOX-M/IVAC for HIV-associated Burkitt and atypical Burkitt lymphoma (BL): preliminary results of a prospective multicenterphase II trial of the AIDS Malignancy Consortium (AMC) [abstract]. Blood 114, a3673 (2009).

    Google Scholar 

  140. 140

    Dunleavy, K. & Wilson, W. H. Implications of the shifting pathobiology of AIDS-related lymphoma. J. Natl Cancer Inst. 105, 1170–1171 (2013).

    Google Scholar 

  141. 141

    Simonelli, C. et al. Prognostic factors in human herpesvirus 8-related lymphoproliferative disorders associated with HIV infection. J. Clin. Oncol. 24, 209; author reply 209–210 (2006).

    Google Scholar 

  142. 142

    Castillo, J. J. et al. Human immunodeficiency virus-associated plasmablastic lymphoma: poor prognosis in the era of highly active antiretroviral therapy. Cancer 118, 5270–5277 (2012).

    Google Scholar 

  143. 143

    Reid, E. G. Bortezomib-induced Epstein–Barr virus and Kaposi sarcoma herpesvirus lytic gene expression: oncolytic strategies. Curr. Opin. Oncol. 23, 482–487 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  144. 144

    Bhatt, S. et al. Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J. Clin. Invest. 123, 2616–2628 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  145. 145

    Bhatt, S. et al. CD30 targeting with brentuximab vedotin: a novel therapeutic approach to primary effusion lymphoma. Blood 122, 1233–1242 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  146. 146

    Vaccher, E., Spina, M. & Tirelli, U. Clinical aspects and management of Hodgkin's disease and other tumours in HIV-infected individuals. Eur. J. Cancer 37, 1306–1315 (2001).

    CAS  Google Scholar 

  147. 147

    Carbone, A., Spina, M., Gloghini, A. & Tirelli, U. Classical Hodgkin's lymphoma arising in different host's conditions: pathobiology parameters, therapeutic options, and outcome. Am. J. Hematol. 86, 170–179 (2011).

    Google Scholar 

  148. 148

    Martis, N. & Mounier, N. Hodgkin lymphoma in patients with HIV infection: a review. Curr. Hematol. Malig. Rep. 7, 228–234 (2012).

    Google Scholar 

  149. 149

    Xicoy, B. et al. Results of treatment with doxorubicin, bleomycin, vinblastine and dacarbazine and highly active antiretroviral therapy in advanced stage, human immunodeficiency virus-related Hodgkin's lymphoma. Haematologica 92, 191–198 (2007).

    CAS  Google Scholar 

  150. 150

    Montoto, S. et al. HIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era. J. Clin. Oncol. 30, 4111–4116 (2012).

    PubMed Central  PubMed  Google Scholar 

  151. 151

    Spina, M. et al. Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection. Blood 100, 1984–1988 (2002).

    CAS  Google Scholar 

  152. 152

    Hentrich, M. et al. Stage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study. J. Clin. Oncol. 30, 4117–4123 (2012).

    Google Scholar 

  153. 153

    Younes, A. Brentuximab vedotin for the treatment of patients with hodgkin lymphoma. Hematol. Oncol. Clin. North Am. 28, 27–32 (2014).

    Google Scholar 

  154. 154

    Silverberg, M. J. et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS 23, 2337–2345 (2009).

    PubMed Central  PubMed  Google Scholar 

  155. 155

    Deeks, S. G. HIV infection, inflammation, immunosenescence, and aging. Annu. Rev. Med. 62, 141–155 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  156. 156

    Achenbach, C. J. et al. Mortality after cancer diagnosis in HIV-infected individuals treated with antiretroviral therapy. AIDS 25, 691–700 (2011).

    PubMed Central  PubMed  Google Scholar 

  157. 157

    Berretta, M. et al. Hepatocellular carcinoma in HIV-infected patients: check early, treat hard. Oncologist 16, 1258–1269 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  158. 158

    Lim, C. et al. Standardized care management ensures similar survival rates in HIV-positive and HIV-negative patients with hepatocellular carcinoma. J. Acquir. Immune Defic. Syndr. 61, 581–587 (2012).

    PubMed  Google Scholar 

  159. 159

    Chiao, E. Y., Giordano, T. P., Richardson, P. & El-Serag, H. B. Human immunodeficiency virus-associated squamous cell cancer of the anus: epidemiology and outcomes in the highly active antiretroviral therapy era. J. Clin. Oncol. 26, 474–479 (2008).

    Google Scholar 

  160. 160

    Rengan, R., Mitra, N., Liao, K., Armstrong, K. & Vachani, A. Effect of HIV on survival in patients with non-small-cell lung cancer in the era of highly active antiretroviral therapy: a population-based study. Lancet Oncol. 13, 1203–1209 (2012).

    PubMed  Google Scholar 

  161. 161

    Bower, M. et al. The effect of HAART in 254 consecutive patients with AIDS-related Kaposi's sarcoma. AIDS 23, 1701–1706 (2009).

    Google Scholar 

  162. 162

    Cattelan, A. M. et al. Acquired immunodeficiency syndrome-related Kaposi's sarcoma regression after highly active antiretroviral therapy: biologic correlates of clinical outcome. J. Natl Cancer Inst. Monogr. 28, 44–49 (2001).

    Google Scholar 

  163. 163

    Martin-Carbonero, L. et al. Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with Kaposi's sarcoma. AIDS 18, 1737–1740 (2004).

    CAS  Google Scholar 

  164. 164

    Lichterfeld, M. et al. Treatment of HIV-1-associated Kaposi's sarcoma with pegylated liposomal doxorubicin and HAART simultaneously induces effective tumor remission and CD4+ T cell recovery. Infection 33, 140–147 (2005).

    CAS  Google Scholar 

  165. 165

    Esdaile, B. et al. The immunological effects of concomitant highly active antiretroviral therapy and liposomal anthracycline treatment of HIV-1-associated Kaposi's sarcoma. AIDS 16, 2344–2347 (2002).

    CAS  Google Scholar 

  166. 166

    Tulpule, A. et al. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 95, 147–154 (2002).

    CAS  Google Scholar 

  167. 167

    French, M. A. HIV/AIDS: immune reconstitution inflammatory syndrome: a reappraisal. Clin. Infect. Dis. 48, 101–107 (2009).

    Google Scholar 

  168. 168

    Letang, E. et al. Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK. AIDS 27, 1603–1613 (2013).

    CAS  Google Scholar 

  169. 169

    Crum-Cianflone, N. F. et al. Is Kaposi's sarcoma occurring at higher CD4 cell counts over the course of the HIV epidemic? AIDS 24, 2881–2883 (2010).

    PubMed Central  PubMed  Google Scholar 

  170. 170

    Silverberg, M. J. et al. HIV infection, immunodeficiency, viral replication, and the risk of cancer. Cancer Epidemiol. Biomarkers Prev. 20, 2551–2559 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  171. 171

    Smith, R. A., Brooks, D., Cokkinides, V., Saslow, D. & Brawley, O. W. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. CA Cancer J. Clin. 63, 88–105 (2013).

    Google Scholar 

  172. 172

    Sigel, K. et al. Cancer screening in patients infected with HIV. Curr. HIV/AIDS Rep. 8, 142–152 (2011).

    PubMed Central  PubMed  Google Scholar 

  173. 173

    Tyerman, Z. & Aboulafia, D. M. Review of screening guidelines for non-AIDS-defining malignancies: evolving issues in the era of highly active antiretroviral therapy. AIDS Rev. 14, 3–16 (2012).

    Google Scholar 

  174. 174

    HIV clinical resources [online], (2014)

  175. 175

    AIDSinfo. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents [online], (2014).

  176. 176

    Denny, L. A. et al. Human papillomavirus, human immunodeficiency virus and immunosuppression. Vaccine 30 (Suppl. 5), F168–F174 (2012).

    CAS  PubMed  Google Scholar 

  177. 177

    Ramogola-Masire, D. et al. Cervical cancer prevention in HIV-infected women using the “see and treat” approach in Botswana. J. Acquir. Immune Defic. Syndr. 59, 308–313 (2012).

    Google Scholar 

  178. 178

    Palefsky, J. M. Anal cancer prevention in HIV-positive men and women. Curr. Opin. Oncol. 21, 433–438 (2009).

    PubMed Central  PubMed  Google Scholar 

  179. 179

    Palefsky, J. M. Practising high-resolution anoscopy. Sex Health 9, 580–586 (2012).

    Google Scholar 

  180. 180

    Rockstroh, J. K. et al. European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults. HIV Med. 9, 82–88 (2008).

    CAS  Google Scholar 

  181. 181

    Aberle, D. R. et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365, 395–409 (2011).

    PubMed  Google Scholar 

  182. 182

    Crum-Cianflone, N. et al. Cutaneous malignancies among HIV-infected persons. Arch. Intern. Med. 169, 1130–1138 (2009).

    PubMed Central  PubMed  Google Scholar 

  183. 183

    Lam, J. M. et al. Cost-effectiveness of screening for anal precancers in HIV-positive men. AIDS 25, 635–642 (2011).

    Google Scholar 

Download references

Acknowledgements

A.C. and S.F. are Members of WHO IARC Monograph Working Group on Biological Agents, Lyon, 2009. This work was supported in part by an Institutional grant from Centro di Riferimento Oncologico Aviano for an intramural project “Infectious agents and cancer” (A.C.), by an Institutional grant from the Fondazione IRCSS Istituto Nazionale Tumori Milano “Validation of a new algorithm for HPV status assessment in head and neck carcinoma” (A.G.).

Author information

Affiliations

Authors

Contributions

A.C. and S.F. researched data for the article. A.C., E.V., A.G., L.P., A.A., P.d.P. and S.F. all equally contributed to discussion of the content and to the writing of the manuscript.

Corresponding author

Correspondence to Antonino Carbone.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Carbone, A., Vaccher, E., Gloghini, A. et al. Diagnosis and management of lymphomas and other cancers in HIV-infected patients. Nat Rev Clin Oncol 11, 223–238 (2014). https://doi.org/10.1038/nrclinonc.2014.31

Download citation

Further reading

Search

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing