Cancers are a range of diseases caused by uncontrolled cell division.

A number of cancers occur more frequently among people with HIV than in the general population. Some of these cancers are AIDS-defining illnesses, such as Kaposi's sarcoma (KS), non-Hodgkin's lymphoma (NHL), and and cervical cancer.

Other cancers are not identified as AIDS-defining illnesses despite a higher incidence among HIV-infected people. These non-AIDS-defining cancers include Hodgkin's disease, anal cancer, squamous cell carcinoma of the eye (conjunctival), skin, lip and anogenital region, testicular cancer, lung cancer, multiple myeloma (a type of leukaemia) and leiomyosarcoma (a type of connective tissue cancer). These cancers are not regarded as AIDS defining because the increased incidence has not been definitively linked to immune deficiency. Other factors such as high smoking rates or sexual activity may account for the high incidence.

Separate entries for KS, NHL, cervical and anal cancer (see Human papilloma virus), Hodgkin's disease, testicular cancer, and lung cancer can be found in Symptoms and illnesses: A to Z of illnesses. For information about liver cancer see Hepatitis C - key research in Symptoms and illnesses: A to Z of illnesses.

The role of viruses

Failure to control normally harmless viruses may lead to cancer in HIV-infected people. The following viruses are thought to contribute to malignant disease in immune suppressed individuals:

• Human herpes virus 8 (HHV-8) - causal role in Kaposi's sarcoma.

• Human papilloma virus (HPV) - causal role in anal and cervical cancer.

• Epstein-Barr virus (EPV) - possible causal role in lymphoma.

• Hepatitis B virus (HBV) and hepatitis C virus (HCV) - causal role in liver cancer.

Epidemiology

Studies have compared rates of cancer in people with and without HIV. This has led researchers to identify which cancers are more common among people with HIV. For example, the National Cancer Institute in the United States analysed data on nearly 100,000 people with AIDS and over one million people with cancer. People with AIDS had a greater risk of particular cancers: a 310-fold risk of KS; a 113-fold risk for NHL; a 36.7-fold risk of blood vessel cancer; a 7.6-fold risk of Hodgkin's disease; a 4.5-fold risk of multiple myeloma; a 3.5-risk of brain cancer and a 2.9-fold risk of testicular cancer (Goedert 1998).

Research conducted by the Medical Research Council in the United Kingdom has also found that people with HIV are at greater risk of non-AIDS-defining cancers. Data from over two thousand HIV-infected people in the United Kingdom was compared with the Thames Cancer Registry for south-east England. The risk of anal cancer was greater for HIV-infected, non-African men and women. The incidence of Hodgkin's disease was also higher among people with HIV.

Two more recent studies have also found that people with HIV have a greater risk of non-AIDS-defining cancers than non-infected people. For example, an Italian study of over 5000 HIV-infected men and 2000 HIV-infected women has found that HIV-infected individuals have a greater risk of liver cancer (19-fold risk), Hodgkin's disease (11-fold risk) and lung cancer (fourfold risk). When comparing the incidence of cancers among several cohorts of HIV-infected men in southern Europe, Hodgkins disease, liver cancer and cancer of the salivary glands were more common in the HIV-infected men. HIV-infected women were more likely to have cervical cancer (17-fold risk). When considering all non-AIDS-defining cancers, HIV-infected had twice the risk of cancer when compared to non-infected individuals (Serraino 2000).

An American study compared cancers in 871 HIV-infected women and 439 uninfected women. Among the HIV-infected women there were eight cases of non-Hodgkin's lymphoma, five cases of invasive cervical cancer, one case of KS and twelve non-AIDS defining cancers, including four cases of lung cancer. In comparison, there were only four cases of cancer among the HIV-uninfected women, including one case of lung cancer. Statistical analysis showed that women with HIV were at a significantly greater risk of cancer than HIV-negative women.

An Australian analysis of cancer registries found a significant trend of increasing relative risk of cancer with increasing time since HIV diagnosis for connective tissue cancer, Hodgkin's disease and multiple myeloma (Grulich 2002).

A 2004 analysis of all HIV-positive deaths from cancer in France in 2000, found that cancer accounted for 28% of the 964 deaths recorded. AIDS-related cancers represented 17% of total causes of death, most of which were non-Hodgkin's lymphoma (11%), KS (5%), and cervical cancer (1%). Non-AIDS-related malignancies represented 13% of total causes of death, most of which were tumours in the lungs, liver, stomach and anus. Systematic cancers accounted for just 17 cases, the majority of which were Hodgkin's lymphoma and myeloid leukaemias. Those who died from non-AIDS tumours were significantly more often men, smokers, and had a higher CD4 count than those dying from others causes (Bonnet 2004).

But is the excess of particular cancers among HIV-infected individuals directly attributable to HIV, or are other factors at play?

The United States AIDS-Cancer Match Registry Study Group has conducted a large and comprehensive analysis of cancers among people with HIV / AIDS to identify which cancers are influenced by immune suppression. By comparing risk ratios for particular cancers from pre- and post-AIDS, the team discovered which non-AIDS defining cancers became more common as immune deficiency progressed. Hodgkin's disease was clearly linked to immune suppression, as were lip cancer and testicular seminoma. The authors explained the excess of other cancers in terms of lifestyle factors or incorrect diagnosis of KS. Interestingly, the risk of breast cancer among women fell as the immune system weakened but increased among male injecting drug users (Frisch 2001). These findings have been supported by more recent studies, showing that lung, head / neck and anorectal cancers, Hodgkin's lymphoma and melanoma are more common in HIV-positive patients, and that the lowest-ever CD4 cell count is strongly associated with their incidence (Patel 2004).

Rapid progression, development and spread of cancerous lesions or tumours have been reported in patients responding to antiretroviral therapy. It is postulated that these growths are an immune reconstitution response to the viruses that trigger these cancers.

Despite the elevated incidence of many types of cancers in HIV-positive people, a number of studies have reported that survival rates have increased since the introduction of highly active antiretroviral therapy (HAART) in 1996. For example, a comprehensive analysis of survival rates in AIDS patients with cancer in New York City between 1980 and 2000 has shown significant improvements in survival for the AIDS-related cancer non-Hodgkin's lymphoma, as well as the non-AIDS-related cancers colorectal, anal and breast cancer. Although survival rates were similar between patients with and without AIDS for the period 1996 to 2000 for some cancers, such as Kaposi's sarcoma and cervical cancer, survival rates for others continued to lag behind patients without AIDS. These cancers included lung cancer and large cell diffuse lymphoma, a type of non-Hodgkin's lymphoma (Biggar 2005).

Other recently published studies support the findings of the New York study, showing links between the use of HAART and lymphoma survival. A French study, looking at 28 AIDS patients with the rare non-Hodgkins primary effusion lymphoma found two factors that were linked to poorer outcome: poor performance status (a measure of the ability to carry out normal daily activities) and the absence of effective HAART (Boulanger 2005).

Similarly, a larger study of 363 patients with AIDS-related lymphoma found that survival of patients with diffuse large cell lymphoma increased in the HAART era. In contrast, however, survival of Burkitts lymphoma patients with AIDS remains poor, and that poor survival is related to low CD4 cell counts (Lim 2005). This was in agreement with a sub-study of the PETHEMA-LAL3/97 study, showing significantly better two-year survival in Burkitts lymphoma patients with a successful virological response to HAART, compared with those who did not reach viral loads below 80 copies/ml (Oriol 2005).

UK guidelines on cancer treatment in people with HIV

Multiple myeloma

Multiple myeloma is a type of bone marrow cancer or leukaemia that affects white blood cells called myeloma or plasma. Symptoms of multiple myeloma include bone weakness and damage, and anaemia. Despite an elevated risk of multiple myeloma among people with HIV, this cancer may not be influenced by immune deficiency (Frisch 2001).

Chemotherapy is the most common treatment for leukaemia, although some people may have radiation therapy or a bone marrow transplant.

Oral cancer

Cancer of the mouth, or oral cancer, may appear as a persistent mouth sore. There is evidence that risk of lip cancer increases among HIV-infected individuals as immune deficiency progresses (Frisch 2001). Many different infections may cause chronic mouth problems in people with HIV and a biopsy is the way to determine whether or not a sore is cancer. Cancerous tumours may be surgically removed. Oral cancer is associated with alcohol and tobacco use in non-HIV-infected individuals.

Cancer of the eye or eye lid

The conjunctiva is the clear membrane that coats the inside of the eye lids and the outer surface of the eye. Cancer in this region is a type of squamous cell cancer called conjunctival cancer. As with multiple myeloma, despite suggestive evidence of increased incidence among people with HIV, research indicates that risk of conjunctival cancer does not risk with increasing immune damage (Frisch 2001).

Skin cancer

Melanoma is a type of skin cancer that affects cells called melanocytes. These cells may grow into harmless moles but a change in size, shape, or colour may be a sign of melanoma. Squamous cell cancer is another type of skin cancer characterised by raised, red, scaly or crusted plaques.

Skin cancers may be removed via freezing with liquid nitrogen, or surgery.

Exposure to the sun's ultraviolet light increases the risk of developing skin cancer.

Prostate cancer

Cancer of the prostate gland is a common disease in older men. A recent study has shown that it is more common in HIV-positive men, and that the risk is unrelated to CD4 cell count or the use of highly active antiretroviral therapy (HAART). The study also found that the risk of prostate cancer was associated with the patient's age and duration of HIV infection (Crum 2004). However, the small size of this study limits the strength of this study's conclusions, which will require verification in future studies.

Prostate cancer can be treated by surgery, radiotherapy or hormone therapy.

Key research

Crum (2004) conducted a prospective study to establish the incidence and risk factors for prostate cancer in men aged over 35. 3% of 216 men undergoing prostate-specific antigen (PSA) testing had elevated levels, although none had an abnormal prostate on digital rectal examination. In a retrospective analysis of medical records, 5 cases of prostate neoplasia were found, and 4/11 men aged over 60 had a diagnosis of prostate cancer, but with no association with CD4 cell count. African American ethnicity (p = 0.020) and duration of HIV infection (p = 0.047) were associated with the risk of prostate cancer.

Patel (2004) compared the incidence of lung, head / neck and anorectal cancers, Hodgkin's disease and melanoma between 12,100 HIV-positive patients and the general population between 1992 and 2002. The rates of all 5 cancers were increased in the HIV-positive population, and were associated with the lowest-ever CD4 cell count. Lung and head / neck cancers were associated with smoking.

Frisch analysed population-based and cancer registry data on 302,834 people in the US collected between 1978-1996. The relative risk (RR) of particular cancers was assessed by dividing the number of cancers among people with HIV by the number of cancer cases in the general population. Cancers were deemed to be influenced by immune deficiency if relative risk rose over three time periods: 60-27 months before AIDS, 4-27 months before AIDS, and 4 months before AIDS to 27 months post-AIDS. Hodgkin disease (particularly mixed cellularity and lymphocytic depletion subtypes), lung cancer, penile cancer, soft tissue cancer, lip cancer and testicular cancer all met this criteria. Other cancers (lymphatic/bone marrow cancer, brain, central nervous system etc) met the criteria but were deemed to be manifestations of AIDS-defining cancers. For Hodgkin disease, the RR went from 2.6 distant pre-AIDS to 6.7 early post-AIDS (p<0.001). The overall increase in lung cancer rose from RR 1.2 to 2.8 post AIDS but this was only significant in men, subgroups of whites and gay men, despite large numbers of cases in women. Rates of anogential cancers (cervix, vulva/vagina and penis) were high but only penile cancer showed a greater risk over time, with African Americans, Hispanics and IDU at particular risk. Lip cancer rates rose from 1.6 to 5.8 post AIDS (p<0.04). Testicular seminoma cancer RR rose from 0.7 distant pre-AIDS to 2 recent pre-AIDS and 1.8 post AIDS (p=0.003). Cancers with high incidence rates but no increasing trend over time were: leukaemia, multiple myeloma, cancer of the oral cavity, salivary glands, pharynx, oesophagus, stomach, anus, liver and intrahepatic bile ducts, pancreas, larynx, heart, mediastinum and pleura, vulva/vagina, kidney, some types of brain/CNS cancer, melanoma, testicular non-seminoma and conjunctival carcinoma. Subsequent statistical analysis showed anal cancer and tongue cancer coming into significance while lip cancer lost significance. Risk of breast cancer fell over time in women but increased in IDU men. The high rates of soft tissue cancers were attributed to failure to diagnose KS. Rates of leiomyosarcoma were elevated among 15-24 year-old but not significantly elevated among adults.

Grulich reported on a cohort study involving nationwide linkage of HIV, AIDS and cancer registries in Australia, in order to describe the incidence of non-AIDS-defining cancers in people with HIV infection and to examine the association of cancer risk with immune deficiency. Linkage with the cancer registry identified 1355 cancers, including 196 cases of non-AIDS-defining cancer in 8351 people notified with HIV infection and 8118 registered with AIDS (total 13,067) in the periods 1985 to 1995/1998. Significantly increased rates were observed in cancer of the lip (10 cases, Standardised Incidence Ratios of 2.26), anus (10, 37.1, respectively), connective tissue (20, 9.71, respectively), Hodgkin's disease (15, 7.85, respectively), myeloma (5, 4.15, respectively) and leukaemia (13, 3.38, respectively). Rates of colon cancer (3, 0.33, respectively) were significantly decreased. A significant trend of increasing relative risk of cancer with increasing time since HIV diagnosis was found for connective tissue cancer, Hodgkin's disease and multiple myeloma. Only cancer of the anus occurred at increased rates in people with early HIV infection.

References

Biggar RJ et al. Survival after cancer diagnosis in persons with AIDS. J Acquir Immune Defic Syndr 39: 293-299, 2005.

Bonnet F et al. Malignancies-related Causes of Death of HIV-infected Patients in the Era of Highly Active Antiretroviral Therapy. Eleventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 875, 2004.

Boulanger E et al. Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS. J Clin Oncol 23: 4372-4280, 2005.

Crum NF et al. Prostate carcinoma among men with human immunodeficiency virus infection. Cancer 101: 294-299, 2004.

Frisch M et al. Association of cancer with AIDS-related immunosuppression in adults. JAMA 285: 1736-1745, 2001.

Goedert JJ et al. Spectrum of AIDS-associated malignant disorders. Lancet 351: 1833-1839, 1998.

Goplen AK et al. High incidence and aggressive growth of non-AIDS-defining cancers among AIDS patients in Oslo. APMIS 104(10): 729-733, 1996.

Grulich AE et al. Risk of cancer in people with AIDS. AIDS 13: 839-843, 1999.

Grulich AE et al. Rates of non-AIDS-defining cancers in people with HIV infection before and after AIDS diagnosis. AIDS 16: 1155-1161, 2002.

Gunthel CJ et al. Cancers not associated with immunodeficiency in HIV infected persons. Oncology 8: 59-64, 1994.

Lim ST et al. AIDS-related Burkitts 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.

Newton R et al. A case-control study of human immunodeficiency virus infection and cancer in adults and children residing in Kampala, Uganda. Int J Cancer 92: 622-627, 2001.

Oriol A et al. Highly active antiretroviral therapy and outcome of AIDS-related Burkitts lymphoma or leukemia. Results of the PETHEMA-LAL3/97 study. Haematologica 90: 990-992, 2005.

Petruckevitch A et al. Risk of cancer in patients with HIV disease. London African HIV/AIDS study group. Int J STD AIDS 10: 38-42, 1999.

Phelps R et al. Incidence of cancer in women with or at risk of HIV. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 9, 2000.

Serraino D et al. Cancer risk among men with, or at risk of, HIV infection in southern Europe. AIDS 14(5): 553-559, 2000.