Second cancer risk after surviving Hodgkin's lymphoma in people with HIV

• A California study found a second new cancer occurred in almost 10% of people with HIV who survived Hodgkin’s lymphoma
• The second new cancer usually appeared within five years after a lymphoma diagnosis
• Researchers recommend long-term cancer prevention and screening in this population

Hodgkin’s lymphoma is a form of cancer that affects the immune system. This lymphoma arises from a B-cell, a member of the immune system that has become abnormal. The abnormal B-cell subsequently transforms, becomes cancerous and forms more cells that multiply and become enlarged. The cancerous cells lodge inside a lymph node or within organs of the immune system such as the spleen or thymus gland.

Cancer promotion

The event that triggers the B-cell into an abnormal development pathway is not always clear. In some cases, scientists think that the cell may have become infected with a common member of the herpes virus family—Epstein-Barr virus (EBV). Emerging research suggests that proteins from HIV have the potential to push cells into developing abnormally. Another consideration is that chronic HIV infection causes excess inflammation and immune activation, issues that are only partially suppressed by ART. It is possible that chronic activation can prematurely age the immune system. Excess inflammation may contribute to an increased risk for the development of abnormal and pre-cancerous cells.

Lymphoma then and now

In the era before potent combination HIV treatment (ART), life-threatening cancers, including several forms of lymphoma, were relatively common among people with HIV. Back then, prospects for survival among people with HIV who developed serious cancers was poor.

However, after ART became available, such cancers became much less common. Furthermore, when they did occur, the chances of a person with HIV recovering from cancer were better. This benefit arises because when ART is taken as directed it suppresses levels of HIV in the blood, allowing the immune system to mostly recover. The power of ART is so tremendous that researchers expect many ART users to have near-normal life expectancy.

However, ART cannot solve every issue, and subtle defects within the immune system remain. Furthermore, some people with HIV are also co-infected with cancer-causing viruses such as EBV, human papillomavirus, and hepatitis B and C viruses. Some people with HIV also smoke.

Putting all of this information together, some people with HIV have a heightened risk for cancer. This does not mean that most people with HIV will get cancer. But it does mean that, as a group, people with HIV are at an elevated risk for cancer compared to people without HIV. It also means that people with HIV need help to take steps to improve or maintain their overall health and reduce their risk for cancer.

A second cancer

Researchers at the University of California, Davis reviewed health-related information that was collected between 1990 and 2015 on people who were diagnosed with Hodgkin’s lymphoma in California. The researchers focused on people who had survived Hodgkin’s lymphoma and subsequently developed a second new and different form of cancer.

Over the course of the period studied, researchers analyzed data from almost 20,000 people who survived Hodgkin’s lymphoma, distributed as follows:

• HIV positive – 735 survivors
• HIV negative – 18,932 survivors

A total of 1,772 of people developed a second new cancer, distributed as follows:

• HIV positive – 67 people
• HIV negative – 1,705 people

On average, people with HIV developed a second cancer in less time than people without HIV:

• HIV-positive people – developed a new cancer within five years after being diagnosed with Hodgkin’s lymphoma
• HIV-negative people – developed a new cancer within eight years after being diagnosed with Hodgkin’s lymphoma

The researchers stated that, overall, the risk for developing a second cancer was almost 40% greater among people with HIV than among the average person without HIV in California during the same period of time.

They suggested that people with HIV who have survived Hodgkin’s lymphoma be given long-term cancer screening and prevention interventions. This last point is important given that 27% of HIV-negative and 43% of HIV-positive people who survived Hodgkin’s lymphoma subsequently died during the period studied.

Study details

A brief average profile of participants with HIV when they sought care for Hodgkin’s lymphoma was as follows:

• 90% men, 10% women
• 42% were between the ages of 15 and 39; 58% were 40 and older
• 99% had what oncologists called “classic Hodgkin lymphoma”
• 64% had tumours in different parts of their immune system

Results

The main types of second new cancers in order of decreasing risk were distributed as follows:

People with HIV

• Kaposi’s sarcoma
• anorectal cancer
• head and neck cancers
• non-Hodgkin’s lymphoma
• lung cancer
• non-melanoma skin cancer

People without HIV

• non-Hodgkin’s lymphoma
• lung cancer
• leukemia
• gastrointestinal cancer
• skin melanoma
• thyroid cancer
• head and neck cancer
• kidney cancer

Trends in time

Overall, researchers found that the period of greatest risk for a second new cancer differed as follows:

• people with HIV – within two years after their Hodgkin’s lymphoma diagnosis
• people without HIV – 20 years or more after their Hodgkin’s lymphoma diagnosis

Bear in mind

In analyzing the data from about 20,000 people who survived Hodgkin’s lymphoma in California, researchers found that these people (regardless of their HIV status) had a two-fold increased risk for subsequently developing a second new cancer compared to the average person in California.

The researchers stated that the “greatest overall risk” for a second cancer in people with HIV occurred less than two years after a diagnosis of Hodgkin’s lymphoma. In contrast, in people without HIV, the period of greatest risk for a second cancer was extended to 20 or more years after their diagnosis of Hodgkin’s lymphoma.

Based on these findings, the researchers stated: “Earlier or more intensive [cancer screening] strategies should be implemented to help address the higher incidence of early [second new cancers] in survivors of Hodgkin’s lymphoma who live with HIV.”

Managing risk

The researchers noted that compared to the average person living in California, “people living with HIV have a higher incidence of both first and second primary cancers. Careful assessment of the efficacy, potential harms and benefits of various screening strategies are needed, especially for high-risk HIV-positive cancer survivors in whom there are no specific post-treatment recommendations.”

Timing of a second new cancer in people with HIV

The study was not designed to uncover issues that increased the risk of a second cancer. However, the researchers made several points about such risk. They stated that people with HIV who survived Hodgkin’s lymphoma “were likely to develop a second [new cancer] relatively soon after Hodgkin’s lymphoma therapy.”

They added that “it was plausible that chemotherapy administered during Hodgkin’s lymphoma treatment further suppressed the immune system and contributed to the development of these tumors.”

The researchers also cited other possible factors that could have played a role in cancer susceptibility, such as:

• smoking
• alcohol
• sun exposure
• viral co-infections

In addition to modifying the above risk factors (where possible), they also raised the following points:

Screening for lung cancer

The researchers underscored results from other studies in Europe and the U.S. that used computer simulations to model the potential impact of using low-dose CT (computed tomography) scans of the lungs to screen for lung cancer. They stated that the simulations “suggested a reduction in lung cancer mortality and higher lung cancer detection, particularly when CT screening was done at earlier ages and/or a lower smoking threshold criterion was applied. Despite potential benefits, careful consideration of the individualized risk, life expectancy, ART adherence, and possible harms of CT screening should guide clinicians in the decision-making process on whether to recommend lung cancer screening for Hodgkin’s lymphoma survivors with HIV.”

Screening for HPV-related disease

Strains of human papillomavirus (HPV) can cause cancers of the anus, cervix, back of the tongue, throat and vulva. The researchers recommended screening HIV-positive survivors of Hodgkin’s lymphoma for HPV-related cancer, particularly anal cancer. They also encouraged the use of HPV vaccines in eligible people.

The importance of a cancer specialist

The researchers suggested that HIV-positive cancer survivors should be referred to an oncologist for “long-term cancer survivorship care.”

—Sean R. Hosein

Resources

Can the CD4/CD8 ratio be used to predict the risk of anal cancer in HIV-positive people? – CATIE News

Changes in CD4+ cell count after cancer treatment linked to survival among HIV-positive people – CATIE News

Canadian Cancer Society

Hodgkin lymphoma – Canadian Cancer Society

Cancer – Government of Canada

Cancer – Government of Quebec

REFERENCES:

1. Abrahão R, Brunson AM, Kahn JM, et al. Second primary malignancy risk after Hodgkin lymphoma treatment among HIV-uninfected and HIV-infected survivors. Leukemia and Lymphoma. 2022; in press.
2. Jacobson CA and Longo DL. Hodgkin’s lymphoma. In: Jameson L, Kasper DL, Longo DL, Fauci AS, Hauser SL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York: McGraw-Hill; 2018.
3. Poizot-Martin I, Lions C, Allavena C, et al. Determinants of second primary cancer type in survivors of virus-related and non-virus-related cancer living with HIV in the French Dat’AIDS Cohort. Cancer Control. 2021;28:1-7.
4. Poizot-Martin I, Lions C, Delpierre C, et al. Prevalence and spectrum of second primary malignancies among people living with HIV in the French Dat’AIDS cohort. Cancers. 2022; in press.
5. Centers for Disease Control (CDC). Diffuse, undifferentiated non-Hodgkins lymphoma among homosexual males—United States. MMWR Morbidity and Mortality Weekly Report. 1982 Jun 4;31(21):277-9. PMID: 6808345.
6. Reichert CM, O’Leary TJ, Levens DL, et al. Autopsy pathology in the acquired immune deficiency syndrome. American Journal of Pathology. 1983 Sep;112(3):357-82.
7. Brynes RK, Chan WC, Spira TJ, et al. Value of lymph node biopsy in unexplained lymphadenopathy in homosexual men. JAMA. 1983 Sep 9;250(10):1313-7. PMID: 6224029.
8. Global Burden of Disease 2019 Cancer Collaboration, Kocarnik JM, Compton K, Dean FE, et al. Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: A systematic analysis for the Global Burden of Disease Study 2019. JAMA Oncology. 2022; in press.
9. Chavez-Dominguez R, Perez-Medina M, Aguilar-Cazares D, et al. Old and new players of inflammation and their relationship with cancer development. Frontiers in Oncology. 2021 Nov 22;11:722999. 
10. Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nature Medicine. 2019 Dec;25(12):1822-1832. 
11. Medzhitov R. The spectrum of inflammatory responses. Science. 2021 Nov 26;374(6571):1070-1075.
12. Frasca D, Pallikkuth S, Pahwa S. Effects of aging on metabolic characteristics of human B cells. JAIDS. 2022 Feb 1;89(Suppl 1):S23-S28. 
13. Isaguliants M, Bayurova E, Avdoshina D, et al. Oncogenic effects of HIV-1 proteins, mechanisms behind. Cancers (Basel). 2021 Jan 15;13(2):305.
14. Heath JJ, Fudge NJ, Gallant ME, et al. Proximity of cytomegalovirus-specific CD8+ T cells to replicative senescence in human immunodeficiency virus-infected individuals. Frontiers in Immunology. 2018 Feb 15;9:201.
15. Royston L, Isnard S, Lin J, et al. Cytomegalovirus as an uninvited guest in the response to vaccines in people living with HIV. Viruses. 2021 Jun 29;13(7):1266. 
16. Isnard S, Ramendra R, Lin J, et al. Anti-cytomegalovirus immunoglobulin G is linked to CD4 T-cell count decay in human immunodeficiency virus (HIV) elite controllers. Clinical Infectious Diseases. 2021 Jul 1;73(1):144-147.
17. Ramendra R, Isnard S, Lin J, et al. Cytomegalovirus seropositivity is associated with increased microbial translocation in people living with human immunodeficiency virus and uninfected controls. Clinical Infectious Diseases. 2020 Sep 12;71(6):1438-1446.
18. de Vries S, Schaapveld M, Janus CPM, et al. Long-term cause-specific mortality in Hodgkin lymphoma patients. Journal of the National Cancer Institute. 2021 Jun 1;113(6):760-769. 
19. Schaapveld M, Aleman BM, van Eggermond AM, et al. Second cancer risk up to 40 years after treatment for Hodgkin’s lymphoma. New England Journal of Medicine. 2015 Dec 24;373(26):2499-511.
20. Díaz-Álvarez J, Roiz P, Gorospe L, et al. Implementation of a lung cancer screening initiative in HIV-infected subjects. PLoS One. 2021 Dec 10;16(12):e0260069. 
21. Molina-Montes E, Ubago-Guisado E, Petrova D, et al. The role of diet, alcohol, BMI, and physical activity in cancer mortality: Summary findings of the EPIC Study. Nutrients. 2021 Nov 28;13(12):4293.
22. Connolly EL, Sim M, Travica N, et al. Glucosinolates from cruciferous vegetables and their potential role in chronic disease: Investigating the preclinical and clinical evidence. Frontiers in Pharmacology. 2021 Oct 26;12:767975.
23. Verdu-Bou M, Tapia G, Hernandez-Rodriguez A, et al. Clinical and therapeutic implications of Epstein–Barr virus in HIV-related lymphomas. Cancers. 2021; 13(21):5534.
24. Díaz-Álvarez J, Roiz P, Gorospe L, et al. Implementation of a lung cancer screening initiative in HIV-infected subjects. PLoS One. 2021 Dec 10;16(12):e0260069.
25. Makinson A, Tron L, Grabar S, et al. Potential lung cancer screening outcomes using different age and smoking thresholds in the ANRS-CO4 French Hospital Database on HIV cohort. HIV Medicine. 2020 Mar;21(3):180-188.