Revealing Insights and Outcomes in HIV/AIDS-Associated Lymphoma: A Comprehensive Review

Background¹

HIV infection continues to be a major health issue worldwide. According to 2022 data, 37.7 million people were living with HIV, and 1.5 million new infections were reported globally. Sadly, nearly 680,000 people lost their lives due to AIDS-related causes. HIV-positive individuals are more susceptible to various diseases, including cancer, particularly when they have advanced HIV infection and severe immunosuppression.

In the era of highly active antiretroviral therapy (HAART), malignancies have become a leading cause of morbidity and mortality in people with HIV/AIDS. Approximately 25% to 40% of people with HIV/AIDS develop malignancies, and more than 28% of HIV-related deaths are attributed to malignant tumors, with lymphomas being a significant portion.

HIV/AIDS-Associated Lymphoma ¹

HIV/AIDS-associated lymphoma are aggressive and invasive cancers that can spread quickly and lead to death within weeks or months if left untreated. Initially, these lymphomas were classified based on appearance and location. Still, the World Health Organization (WHO) has categorized them as distinct diseases based on their appearance, characteristics, and molecular changes. These lymphomas are a major complication of HIV infection and can be either AIDS-defining or non-AIDS-defining cancers. In HIV-positive individuals, lymphomas account for more than 50% of all AIDS-defining cancers.

Subtypes of HIV/AIDS-Associated Lymphoma

Lymphomas in HIV-infected individuals are heterogeneous and include (HL) and (NHL). NHL is formed in the lymph system which is part of the immune system and is the most common and aggressive type, particularly in advanced HIV infection. Common subtypes include Burkitt’s lymphoma (BL), diffuse large B cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), plasmablastic lymphoma (PBL), and primary effusion lymphoma (PEL). HL is another common lymphoma in HIV-infected patients, with an increased incidence since the introduction of HAART.²

Specific Subtypes²

1. Diffuse Large B-Cell Lymphoma (DLBCL): An aggressive B-cell lymphoma occurring in HIV-infected and non-infected individuals. It has subtypes based on cell morphology and gene expression profiling.

2. Burkitt’s Lymphoma (BL):  A fast-growing tumor often found in the oral cavity. It’s sub-classified into endemic, sporadic, and immunodeficiency-related variants.
   

3. Primary Central Nervous System Lymphoma (PCNSL): A subtype affecting the central nervous system, typically with EBV infection and multiple brain lesions in HIV-positive patients.

4. Primary Effusion Lymphoma (PEL): Caused by Human Herpesvirus-8 (HHV8), with effusion in serous cavities or masses in other organs. Typically expressed proteins LANA-1, v-cyclin, v-FLIP, and Kaposi. High expression of vascular endothelial growth factor.

5. Plasmablastic Lymphoma (PBL):  A rare subtype with giant neoplastic cells, occurring mainly in the oral cavity, associated with HIV infection.

6. Hodgkin Lymphoma (HL):  More common in HIV-infected individuals, especially those with mild immune compromise. Divided into classical Hodgkin lymphoma (CHL) and nodular lymphocyte-predominant HL (NLPH).

Pathophysiology

The pathogenesis of NHL development in the setting of HIV infection is not well elucidated. However, the following factors are thought to play an important role:

• Chronic B-cell stimulation³
• Cytokine dysregulation
• Co-infection with oncogenic viruses (Epstein-Barr virus [EBV], human herpesvirus 8 [HHV-8], hepatitis B and C viruses) in the setting of immune dysregulation, resulting in decreased surveillance for tumor antigens ^4,5
• Genetic abnormalities (decreased BCL-2 activation and increased BCL-6 and MYC expression)^6,7

Different clinicopathologic categories of AIDS-related lymphomas arise from distinct B-cell subtypes, and the factors mentioned above interplay in varying proportions to give rise to other varieties of NHL.

Epidemiology

It is estimated that 25% to 40% of patients with HIV infection will develop a malignancy and approximately 10% will develop NHL.⁸  HIV/AIDS-associated lymphoma is more common in males than in females.⁹  With the advent of antiretroviral therapy (ART), the incidence rate of HIV/AIDS-associated lymphoma has substantially declined; however, it remains substantially higher than the general population. ¹⁰ A meta-analysis of over 400,000 patients showed the observed rate of lymphoma development in the HIV population to be 11.03 times that of the general population. ¹¹

Up to 85% of AIDS-related lymphomas, including DLBCL, immunoblastic variant, and Burkitt lymphoma are highly aggressive. Incidences and relative risks of AIDS-related lymphomas are shown in Table 1 below.

Table 1: Incidence and relative risk of HIV/AIDS-associated lymphoma subtypes ^{12,13,14,15,16}

Examining HIV-Associated Lymphomas: Retrospective Insights¹⁷

The relentless risk of lymphomas persists among those living with HIV, even in the HAART era. A retrospective analysis of cases spanning January 2012 to October 2022, with a minimum 6-month follow-up, sheds light on patient outcomes. Parameters such as the overall response rate (ORR), overall survival (OS), and event-free survival (EFS) were meticulously assessed. Statistical tools were wielded for comprehensive analysis, including the Kaplan-Meier test and chi-square tests, were wielded for comprehensive analysis.

During this period, 23 patients with HIV-associated lymphoma were identified. Four were excluded due to data insufficiency. Among the remainder, 12 (63.15%) were male, and 07 (36.85%) were female, resulting in a male-to-female ratio of 1.7:1. The median age at diagnosis was 42 years, spanning 21 to 66 years. Notably, 11 (57.9%) presented with stage-4 disease. Median CD4 counts at diagnosis ranged from 130 to 1100/µl, with the majority facing diffuse large B cell lymphoma (DLBCL), and 60% achieving complete remission (CR) following first-line chemotherapy. At the latest follow-up, 04 (21.05%) patients regrettably passed away, while 15 (78.95%) persevered.

The decadal overall survival [OS] and progression-free survival [PFS] rates stood at 78.95% ± 11, supported by a median follow-up period spanning 1.7 to 114.3 months. Despite numerous patients presenting with stage 4 disease, low median CD4 counts, concurrent ART, and intensive chemotherapy, HIV-associated lymphomas displayed a commendable prognosis.

Conclusion

Lymphoma is a condition that can affect individuals at risk of HIV/AIDS, and it presents with varying pathogenesis, morphology, and clinical manifestations. Despite the significant reduction in most types of NHL following the introduction of HAART, it remains a primary cause of morbidity and mortality in these patients compared to the general population. Conversely, HL has increased in the HAART era.¹

With the advent of HAART, the management of lymphoma has become more similar to that of the general population, thanks to the immune reconstitution of patients.^1,2 Most notably, these patients exhibit favorable responses to chemotherapy, albeit with some considerations related to potential drug interactions. However, it is essential to emphasize that further research is necessary to determine the optimal treatment strategies for lymphoma in this patient population.^10,11

In summary, this review highlights that while the incidence of HIV/AIDS-Associated Lymphoma has diminished since the introduction of HAART, it continues to significantly contribute to morbidity and mortality among individuals living with HIV/AIDS compared to the general population. Moreover, the incidence of HL has displayed an upward trend in the HAART era. Therefore, it is strongly recommended that additional research focused on understanding the pathogenesis and refining the treatment of lymphoma in HIV/AIDS patients is warranted. Routine screening for lymphoma in these individuals is also imperative to reduce its impact on morbidity and mortality in this vulnerable population.^{1,2,8,10,11,17}

References

1. Berhan A, Bayleyegn B, Getaneh Z. HIV/AIDS Associated Lymphoma: Review. Blood Lymphat Cancer. 2022 Apr 29;12:31-45. doi: 10.2147/BLCTT.S361320.
2. AIDS-Related Lymphoma Treatment (PDQ) – NCI [Internet]. www.cancer.gov. 2023 [cited 2023 Oct 9]. Available from: https://www.cancer.gov/types/lymphoma/hp/aids-related-treatment-pdq#section/all.
3. Yawetz S, Cumberland WG, van der Meyden M, et al. Elevated serum levels of soluble CD23 (sCD23) precede the appearance of acquired immunodeficiency syndrome-associated non-Hodgkin’s lymphoma. Blood. 1995 Apr 1. 85 (7):1843-9
4. Arvey A, Ojesina AI, Pedamallu CS, et al. The tumor virus landscape of AIDS-related lymphomas. Blood. 2015 May 14. 125 (20):e14-22.
5. Carbone A, Gloghini A, Bontempo D, et al. Proliferation in HHV-8-positive primary effusion lymphomas is associated with expression of HHV-8 cyclin but independent of p27(kip1). Am J Pathol. 2000 Apr. 156(4):1209-15.
6. Gaidano G, Carbone A. AIDS-related lymphomas: from pathogenesis to pathology. Br J Haematol. 1995 Jun. 90(2):235-43.
7. Gaidano G, Carbone A, Pastore C, et al. Frequent mutation of the 5′ noncoding region of the BCL-6 gene in acquired immunodeficiency syndrome-related non-Hodgkin’s lymphomas. Blood. 1997 May 15. 89(10):3755-62.
8. Rabkin CS. Epidemiology of AIDS-related malignancies. Curr Opin Oncol. 1994 Sep. 6 (5):492-6.
9. Dal Maso L, Franceschi S. Epidemiology of non-Hodgkin lymphomas and other haemolymphopoietic neoplasms in people with AIDS. Lancet Oncol. 2003 Feb. 4(2):110-9.
10. Yanik EL, Achenbach CJ, Gopal S, et al. Changes in Clinical Context for Kaposi’s Sarcoma and Non-Hodgkin Lymphoma Among People With HIV Infection in the United States. J Clin Oncol. 2016 Sep 20. 34 (27):3276-83.
11. Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007 Jul 7. 370 (9581):59-67.
12. Cote TR, Biggar RJ, Rosenberg PS, et al. Non-Hodgkin’s lymphoma among people with AIDS: incidence, presentation and public health burden. International Journal Cancer. 1997 Nov 27. 73(5):645-50.
13. Mantina H, Wiggill TM, Carmona S, et al. Characterization of Lymphomas in a high prevalence HIV setting. Journal of  Acquired Immune Deficiency Syndrome. 2010 Apr. 53 (5):656-60.
14. Biggar RJ, Engels EA, Frisch M, et al. AIDS Cancer Match Registry Study Group. Risk of T-cell lymphomas in persons with AIDS. Journal of Acquired Immune Deficiency Syndrome. 2001 Apr 1. 26 (4):371-6.
15. Carbone A. AIDS-related non-Hodgkin’s lymphomas: from pathology and molecular pathogenesis to treatment. Human Pathology. 2002 Apr. 33(4):392-404.
16. Flinn IW, Ambinder RF. AIDS primary central nervous system lymphoma. Current Opinion in Oncology. 1996 Sep. 8(5):373-6.
17. Singh, R., Kapoor, J., Panwar, N. et al. HIV Associated Lymphomas: A Double-Edged Sword. Indian J Hematol Blood Transfus (2023). https://doi.org/10.1007/s12288-023-01636-3

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