Infectious Diseases in Clinical Practice:
Cancers Among HIV-infected Persons
Crum-Cianflone, Nancy F. MD, MPH; Burgi, Alina MPH
TriService AIDS Clinical Consortium, Rockville, MD and Naval Medical Center San Diego, San Diego, CA.
The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.
Address correspondence and reprint requests to Nancy Crum-Cianflone, MD, MPH, Clinical Investigation Department (KCA), Naval Medical Center San Diego, Ste 5, 34800 Bob Wilson Dr., San Diego, CA 92134-1005. E-mail: firstname.lastname@example.org.
Abstract: Before the advent of highly active antiretroviral therapy (HAART), persons infected with HIV typically died of opportunistic infections; malignancies accounted for less than 10% of all deaths. In the pre-HAART era, 3 cancers were classified as AIDS-defining conditions, including Kaposi sarcoma, non-Hodgkin lymphoma, and invasive cervical cancer. Since the introduction of HAART, the incidence of Kaposi sarcoma and non-Hodgkin lymphoma has decreased, but certain non-AIDS-defining cancers are occurring at increased rates and accounting for greater numbers of deaths. We review the trends in the incidence and the proportion of deaths due to malignancies among adult HIV-infected persons.
In the pre-highly active antiretroviral therapy (HAART) era, the Centers for Disease Control and Prevention established clinical criteria for the diagnosis of AIDS, which included Kaposi sarcoma (KS); this was followed by modifications adding non-Hodgkin lymphoma (NHL) and invasive cervical cancer.1,2 Early reports suggested that other unusual malignant tumors occurred within this population but were largely overshadowed by AIDS-defining cancers and opportunistic infections.3
The use of HAART led to a dramatic decline in the mortality rate for HIV patients,4 with a shift in the causes of death from AIDS-defining conditions to liver disease, cardiovascular events, and non-AIDS-defining cancers (NADCs).5-8 An early report from the 1980s suggested that virus-associated malignancies might emerge as a secondary epidemic; this has been realized,3 as 28% of deaths among HIV-infected persons are now due to cancer.9
Rates of AIDS-defining malignancies such as KS and some subtypes of NHL have declined,10 whereas the proportion of deaths due to NADCs has increased. For instance, NADCs accounted for less than 1% of all causes of death in the pre-HAART era, but a recent study showed a rate of 13% in the post-HAART era.9,11 Whether the actual incidence of NADCs has increased is debated because some studies show a stable incidence rate, whereas others show a rising rate with standard incidence ratios (SIRs) ranging between 1.9 and 2.8.10,14-19 Different study designs and populations of geographic areas, risk factors, and behaviors may account for the varying results between studies.15
The reasons that the proportion of deaths due to NADCs has increased are likely multifactorial. One of the most important factors is the increasing life expectancy among HIV-infected patients, which allows for more time for the development of malignancies. In addition, the loss of competitive risks from other causes of death is contributory. Patients with HIV are also frequently coinfected with oncogenic viruses, which may have increased viral replication in the setting of HIV immunosuppression. These viruses include human herpesvirus 8 (HHV-8) associated with KS and primary effusion lymphoma; human papillomavirus (HPV) with cervical, anal, and possibly skin cancer; and Epstein-Barr virus (EBV) with Hodgkin disease (HD), primary central nervous system lymphoma and pediatric malignancies.20 Genetics and behavioral factors may also play a role in the development of malignancies among HIV-infected persons; for instance, tobacco use is more common among HIV-infected persons.21 Whether HIV itself contributes to oncogenesis is unclear; the Tat gene may modulate the expression of proto-oncogenes (p53, c-myc) and oncosuppressor proteins (pRb2/p130), as well as induce angiogenesis in cancers.22
Despite these potential explanations of the high rates of cancers, it remains troubling that HAART has not diminished the rates of NADCs.12,23,24 Explanations for this lack of response to HAART include lack of adequate virologic suppression among HAART users and continued viral replication within tissues reservoirs, despite adequate virologic control as assessed by currently available techniques.24,25 A persistent state of mild to moderate immunosuppression that remains despite HAART may contribute to NADC development; a longer duration of HIV infection is a risk factor for NADCs.26 Maintenance of a high CD4 count by the use of HAART does not prevent NADCs, with most studies finding no association between these cancers and a low current or nadir CD4 count26; the 2 exceptions may include HD and anal carcinoma.13,15,18 In a recent study, 75% of NADCs had a CD4 count at cancer diagnosis of more than 200 cells/μL.26 Despite these findings, a single study showed that HAART may be protective for the development of some NADCs, but this finding requires validation by other studies.26 In summary, unlike the protective effect of HAART on the development of AIDS-defining cancers such as KS and NHL, antiretroviral medications seem to have little or no effect on NADCs.
It is intriguing that NHL and KS, rather than other cancers, were sentinel signs of the HIV epidemic in the early 1980s. Equally interesting is that only certain types of NADCs occur at an increased rate among HIV-infected persons. We review AIDS-defining and non-AIDS-defining malignancies (Tables 1 and 2) that occur at increased rates among HIV-infected persons.9,10,12-15,17-19,23,26-29
Before the advent of HAART, KS was the most common malignancy among HIV-infected persons with a more than 1000-fold increased risk; each decrement in the CD4 count of 100 cells/μL was associated with a higher risk.14,16,18,24,28 The introduction of HAART led to a decline in the incidence of KS from 15.2/1000 × person-years in 1992 to 1996 to 4.9 in 1997 to 1999 (rate ratio of 0.32, P < 0.001).10 Despite these beneficial findings in the developed world, KS remains a significant problem in Africa, where access to HAART remains limited and the rate of endemic HHV-8 infection is high.27
In the US, KS occurs most commonly among homosexual men, mirroring their higher rate of HHV-8 coinfection; however, HIV-infected persons who are drug users also have an elevated rate. One study showed a 2000-fold increased rate among men who have sex with men (MSM) and a 150-fold increase in drug users.17 Among women, the highest rates are found in those infected by bisexual men.15
Disease involvement ranges from minimal to fulminant.30 Treatment is with antiretroviral therapy-both protease and nonnucleoside agents in combination with 2 nucleosides are equally effective in KS prevention; hence, both are likely beneficial for active disease.31 Depending on the extent of involvement, local or systemic chemotherapy is used in addition to HAART.
The incidence of NHL is 200-fold higher among HIV-infected individuals than the general population.32 AIDS-defining NHL tumors include small noncleaved lymphoma, large cell lymphoma, immunoblastic lymphoma, and primary central nervous system lymphoma.33 Risk factors for NHL include age, low current CD4 count, longer duration of HIV infection, and chronic B-cell stimulation.28,30,34 Oncogenic viruses such as EBV and HHV-8 also play a role.30,32,35
The rates of NHL have decreased more slowly than KS, perhaps because the pathogenesis of NHL begins early in the course of HIV infection, requiring early administration of HAART for its prevention.36 With declining numbers of AIDS-defining events overall, NHL has increased proportionally as an AIDS diagnosis and remains an important cause of death in the HAART era.8 Most studies have demonstrated a fall from the pre-HAART to the post-HAART eras in the number of primary central nervous system cases (27.8/10,000 to 9.7/10,000 person-years); however, the rate of systemic NHL has been less affected (86/10,000 to 42/10,000 person-years).10,25,36-39 Of note, there has been a decrease in high-grade histology of the cancers.38
The overall prognosis for NHL has improved in the post-HAART versus pre-HAART eras, which is likely due to higher CD4 counts at diagnosis and the increased use of chemotherapy.38 Despite this, survival remains poor, with most studies reporting a median survival of 9 months at most.38 Treatment consists of standard dose chemotherapy and HAART.30,40
Cervical cancer has been classified as an AIDS-defining malignancy, and it occurs at a 5-fold higher rate among HIV-infected women when compared with the general population.15,23,41 However, its occurrence is not consistently associated with a low CD4 count,18,23 and its incidence rate does not appreciably change with CD4 count reduction.18,23 Furthermore, the rate of cervical cancer has not declined in the post-HAART era,13,23,42 and there are some suggestions of an increased rate.10 Behavioral risk factors, coinfection with high-risk HPV types due to shared routes of transmission, and tobacco use may play a larger role than immunosuppression in the development of cervical cancer among this population.
HPV infection and anal squamous intraepithelial lesions (SILs) are more common among HIV-positive compared with HIV-negative men.43 Furthermore, MSM are at higher rate of SILs and anal cancer than intravenous drug users, which is likely due to the increased carriage of HPV strains related to malignancy (e.g., HPV types 16 and 18).44,45 A study by Piketty et al44 showed that HPV infection and SILs may be found among drug users in the absence of anal intercourse among HIV-infected persons; risk factors for abnormal histological findings among drug users include a low CD4 count (<250 cells/μL) and high viral load.
Women infected with HIV also have an elevated risk; the AIDS/Cancer Match Registry Study41 demonstrated a relative risk of 6.8 for invasive anal cancer in women. These data suggest that in addition to a history of anal intercourse, immunosuppression may also be a risk for HPV dysplastic changes. On the other hand, recent studies have shown that HAART and higher CD4 counts may have little effect on the incidence or progression of ASILs or cancer; further studies are needed.23,46
HD is the NADC that is most strongly linked to HIV infection.12,15,17 The histological types most associated with HIV infection are the mixed cellularity and lymphocyte depletion.9,15,47 Male sex and advanced immunodeficiency with low CD4 counts are risk factors.15,19,29 The pathogenesis of HD involves coinfection with EBV, as nearly all tumors among HIV-infected persons are positive.33,48 HD among those with HIV infection frequently presents at an advanced stage. The response to chemotherapy is often poorer than responses seen among HIV-negative persons, with one study reporting a less than 30% complete response rate. Patients receiving HAART may have a better response.48
Lung malignancies may account for up to 15% of cancer-related deaths in HIV-infected persons.9 In some studies, it is the most common NADC with a 3-fold to 5-fold increased occurrence;15,18 it typically presents at a relatively young age (median, 38-45 years).49,50
The direct link between HIV and lung cancer has been questioned. One study showed a relative risk of 2.5, but there was no change in the rate from pre-AIDS to post-AIDS, suggesting that immunosuppression is not an important factor in the pathogenesis of lung cancer.16 Furthermore, most patients with lung cancer have asymptomatic, well-controlled HIV, with a median CD4 count of more than 200 cells/μL and no prior history of AIDS-defining conditions.50,51 Studies have shown that intravenous drug users have a higher risk of lung cancer despite their HIV status and have a higher rate than HIV-infected MSM.17,19 Finally, a recent report showed that lung cancer among HIV-infected persons only occurred among smokers.23 These data strongly suggest that the increased risk for lung cancer is not because of immunosuppression but is mainly due to the higher rate of tobacco use among HIV-infected persons.21,52
The histopathologic type is frequently adenocarcinoma; some have suggested that HIV-infected patients are at higher risk of this tumor type because of its relationship with scarring secondary to prior lung infections such as tuberculosis.51 Lung cancer among AIDS patients is often aggressive in nature, diagnosed at a late stage, and with few good treatment options; these factors contribute to the high death rate among these patients.49,50 The 24-month survival in the post-HAART era remains the lowest of any cancer at 10%.53 A recent study showed that the rates of lung cancer have increased from the pre-HAART to the post-HAART era;12 the most beneficial step in halting this trend is smoking cessation among HIV-infected persons.
Although studies do not suggest an increased incidence of breast cancer,14,18,28,29 some cases have occurred at a relatively young age with a more aggressive clinical course. This may suggest that HIV immunosuppression does not have a direct role in tumor pathogenesis, but it may have a permissive effect on tumor growth.54,55 More recent articles have questioned whether HIV-infected women are truly at risk for more aggressive disease.56
Testicular seminoma may occur at a slightly higher rate than in the general population.15 Of note, the age of most HIV-infected men in the US mirrors the peak occurrence for testicular tumors. The natural history or response to therapy seems to be unchanged among HIV-infected men.
There is no compelling evidence of higher rates of hepatocellular carcinoma (HCC) despite that many HIV patients are coinfected with hepatitis B and/or C. The lack of convincing data to show a higher rate of liver cancer is surprising, but it may be because of competing causes of death and the longer interval between hepatitis infection and complications such as HCC.19 A recent study showed an increased rate (SIR, 7.0) of liver cancer, but the total number of cancers was small.23 Perhaps with increasing life expectancy, liver cancer may seem as an important non-AIDS-defining malignancy, but this has not been evident to date.
HIV-infected patients with HCC are often younger (mean age, 42 years) and have a more aggressive clinical course. Furthermore, HIV infection is independently associated with a reduced survival rate.57 Prevention of hepatitis B and C infections as well as treatment of coinfected patients may be helpful in reducing HCC-related deaths.
Most registry or cohort studies do not show an increased rate of prostate cancer.12-14,18,19,28 Our experience has been that prostate cancer may occur at higher rates among HIV-infected men compared with the general population (258.8/100,000 vs. 150.5/100,000 person-years, P < 0.05);26 however, this increased rate was only seen in whites. Another study reported that 4 of 11 men older than the age of 60 years developed prostate cancer and determined that the duration of HIV infection was predictive.58 These findings may be because of a higher rate of screening for prostate cancer in certain groups and that the disease can be asymptomatic for several years.
Nonmelanomatous skin cancers also occur at increased rates. The incidence of skin cancers among HIV patients increased from pre-HAART rates of 0.33 per 1000 person-years to post-HAART rates of 3.64/1000 person-years.13 The most common skin cancer type is basal cell followed by squamous cell,26 both of which occur at higher rates than in the general population.13,19,23,47,59,60 A relationship between skin cancers and the degree of immunosuppression is not apparent;23,60 risk factors are the same as those for the general population, and they include fair skin, family history, and exposure to sunlight.51,59,60 HPV may also play a role in the pathogenesis.61
An increased risk of multiple myeloma has been reported in some studies.14,16,19,29 Chronic antigenic stimulation by HIV may incite B-cell activation, leading to neoplastic transformation.30,62 Whether EBV plays a role in this malignancy, as it does for HD, requires further study. The clinical presentation often differs from non-HIV-infected patients in that it often affects patients younger than 40 years and can manifest with atypical and aggressive features.62 The prognosis of these tumors remains poor.
Although some studies have shown an increased risk of leukemia in HIV-infected patients (SIRs range, 3.4-8.2),14,28,29 some of these cases may have been leukemoid transformations of NHL. Recent evidence suggests that viruses implicated in HIV-related malignancies, including EBV, HBV, HCV, HHV-8 and human T-cell leukemia virus-1 may play a role in the development of certain types of leukemia.63 Further study is required to determine whether HIV-infected patients are at increased risk of developing leukemia and associated virus-related risk factors.
A variety of cancers have also been reported at higher-than-expected rates, including conjunctiva, lip, oral, pharynx, head/neck, thyroid, penile, and renal cancer.15,23,27 Although some studies have shown an increased risk of soft tissue malignancies, many of these tumors were inaccurately recorded cases of KS.15 Leiomyosarcomas are commonly reported in children with HIV, but not in adults.20
Because patients with HIV infection live longer, the causes of death in this population may mirror the general population, in which many deaths are because of cancer. Screening and counseling of HIV-infected patients regarding tobacco, alcohol, and illicit drug use should be implemented. In addition, counseling regarding the importance of safe sex practices should be stressed, as concurrent infections with HPV and hepatitis B may lead to an increased risk of malignancy. Vaccination against hepatitis B among HIV patients is advocated, as is the use of clean needles or the discontinuation of illicit drug use to reduce hepatitis C infections.
HIV-infected patients should undergo routine health screening, as advised for the general population by the US Preventive Services Task Force and the American Cancer Society, for breast, colon, and prostate cancer64,65 (Table 3). Cervical cancer screening using Papanicolaou test is recommended. For patients with cervical dysplasia, guidelines for further management have been published.68 One study suggests the addition of HPV DNA testing, but this requires further study.69 Strategies for HPV vaccination in the HIV-infected population are under consideration. Although screening for anal cancer is not routinely performed in many HIV clinics, the efficacy and cost effectiveness has been shown to be comparable to other accepted screening tests.70
Patients should be instructed on the signs and symptoms of the more common cancers that may occur. Self-examination for skin and testicular cancers should be encouraged. A study recommended annual chest radiographs for lung cancer;9 however, this cannot be suggested because it is not currently recommended for the general population,71 and no formal studies among HIV-infected persons have been performed. Treatment of concurrent hepatitis B and C infections is recommended to reduce long-term complications from these viruses. Finally, patients presenting with AIDS-defining or malignant tumors with unusual features should be considered for HIV testing (e.g., patients <40 years with multiple myeloma).3,62
Most studies advocate the use of standard therapy for each individual cancer. Of course, HIV providers and oncologists must weigh the risks and benefits of potentially immunosuppressive and toxic treatments. Many patients are concurrently treated with HAART, especially patients with KS and NHL. Hematopoietic growth factors are often useful in preventing chemotherapy-related complications. Improved survival rates for malignancies are evident in the post-HAART era as the gap in survival between HIV-negative and HIV-positive persons has narrowed; further progress is needed for survival rates to become equivalent among these groups.53 Most NADCs have a 2-year survival of more than 50%.53
HIV-infected patients in the HAART era have an increased risk of a limited set of cancers, many of which are linked to viral coinfections or behaviors such as tobacco use. As patients survive longer and competing causes of death are modified, the impact of malignancies on the morbidity and mortality of this population may increase. Unlike KS and NHL, non-AIDS-defining malignancies frequently develop among patients without profound immunosuppression. Development of cancer screening programs is advocated to facilitate early recognition and for improved treatment options for early diagnosed disease.
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