Abstract
Background:
Non-AIDS–defining cancers in HIV-infected patients in the highly active antiretroviral therapy era have increased. To our knowledge a comprehensive review of non-AIDS–related malignancies in New Orleans has not yet been conducted.
Methods:
Databases from main institutions in New Orleans were queried retrospectively for the years 2001 to 2011. The International Classification of Diseases, Ninth Revision codes were used to search for HIV infection and cancer comorbidity.
Results:
A total of 16 patients were diagnosed with lung cancer (mean age 50 years) with 81% of the patients presenting with advanced stages. In all, 20 (mean age 47 years) were diagnosed with anal cancer, and 35% presented in late stages. In all, 14 patients (mean age 42 years) were diagnosed with Hodgkin Lymphoma, and 64% were diagnosed at late stage. A total of 5 women (mean age 44 years) were diagnosed with breast cancer with 40% of them presenting at late stage.
Conclusion:
Malignancies were diagnosed at late stages in the majority of the cases, presented with worse outcomes, and had higher recurrence rates. The role of HIV and other viruses (Epstein Barr virus, human papillomavirus) and the potential mechanisms or pathways of oncogene activation also need to be clarified.
Keywords
Introduction
Non-AIDS–defining cancers (NADCs) in HIV-infected patients in the highly active antiretroviral therapy (HAART) era have increased, 1–5 as has the mortality of patients with these non-AIDS–defining malignancies. 6 With a prevalence of 7% to 15%, NADCs have become a major cause of morbidity and mortality in the HIV population. 7 Retrospective analyses have shown that malignancies have an earlier onset and worse prognosis in HIV-infected patients than in the general cancer population. 6 Initial data reports from Interim Louisiana Public Hospital HIV Outpatient Program clinic in New Orleans indicate the frequency of these conditions to be at around 10% of the total HIV population (Marco Ruiz, unpublished data, 2011). This correlates with the data from a very recent 20-year cohort study where it was found that 10% of the HIV-infected population developed cancer. 8
Frequent solid tumor NADCs include anal carcinoma, liver cancer, lung cancer, melanoma, oropharyngeal carcinoma, colorectal cancer, and renal cancer. Hematologic malignancies found to be more prevalent in HIV-infected patients compared with the general population 9 include Hodgkin lymphoma (HL) and leukemia. Studies have looked at the influence of T-cell count and T-cell nadir in regard to the risk of developing NADCs. Neither T-cell count at the time of diagnosis nor viral load seems to be a risk factor for developing non-AIDS cancers. 6 Controversy remains concerning the role of the T-cell count nadir. 8 ,10
HAART therapy appears to be a protective factor against the appearance of certain NADCs (other than Kaposi sarcoma, non-HL, and invasive cervical carcinoma). 6 ,8,11 Some authors have suggested that, in view of the fact that newer antiretroviral (ARV) regimens have more favorable toxicity and better resistance profiles than prior regimens, initiating therapy at higher CD4 counts may be a better option for adjuvant treatment in HIV-infected patients with NADCs. 10
According to recent reports, New Orleans is the fifth city in the country in terms of new cases of HIV infection. 12 To our knowledge a comprehensive review of non-AIDS–related malignancies in New Orleans has not yet been conducted and published. Since the incidence of new HIV cases is high compared with other cities, a relative increase in the diagnosis of these conditions is expected. A better characterization of this population is therefore needed. This retrospective study aims to characterize the NADCs population in New Orleans.
Methods
Database from main institutions that are responsible for taking care of the majority of HIV-infected patients in New Orleans were queried retrospectively for the years 2001 to 2011. International Classification of Diseases, Ninth Revision codes were used to search for HIV infection and cancer comorbidity. The information collected included demographics, type of malignancy, ARV treatment, cancer treatment (chemotherapy, radiotherapy, and surgery), opportunistic infections, CD4 count, HIV viral load, comorbidities, and T-cell nadir. A multivariate analysis was performed to determine the relationships among variables.
Patients were considered regular attendees if they had at least 2 visits per year during the study period. Incidence rates were calculated. The mean of CD4 count and HIV polymerase chain reaction (PCR) viral load were also taken into account. Comorbidities were also included in the analysis. Smoking, alcohol, and drug use were also studied.
Because of the retrospective nature of the study and the fact that a biorepository has not been established in the city, viral PCRs for Epstein Barr virus (EBV), human papillomavirus (HPV), and other viruses were not performed in tissue specimens.
Results
We studied approximately 3400 patients at the Louisiana State University HIV outpatient clinic, NO/AIDS Task Force, and Ochsner Medical Center in New Orleans. Two of these institutions are privately funded and one is a university-affiliated institution. Although there may be differences in the age, sex, and race of the patients seen in these institutions, more than 90% of the patients with cancer came from the university-affiliated institution.
During this 10-year period, 16 patients were diagnosed with lung cancer. Most patients (n = 11; 68.75%) were men, and the mean age at diagnosis was 50 years. Most of the patients were smokers (n = 13; 81%), 2 patients denied ever smoking, and for 1 patient, history of smoking was never documented. In all, 14 (87.5%) of the patients with lung cancer had nonsmall cell lung cancer (NSCLC), while the other 2 patients did not have the histologic subtype documented. Of the patients with NSCLC, 7 had adenocarcinoma, 2 (14.3%) had squamous cell carcinoma, and 5 (35.7%) had a nonspecified NSCLC. The majority of the patients (n = 13; 81%) were at late stage (stage III or greater) during diagnosis. When comparing patients who were diagnosed with late stage cancer versus those with early stage cancer, there was no significant difference in age or smoking status. The patients diagnosed at an early stage did have a significantly higher mean CD4 count (353 cells/mm3) than the late stage patients (241 cells/mm3). Also, a larger percentage of patients with early stage cancer were on HAART therapy (n = 2; 66%) when compared to patients with late stage (n = 5; 5 of 16 = 31.25%; 38%). Only 6 (37.5%) patients were candidates for definitive treatment of their cancer; 9 (56.25%) received either palliative or no treatment; and 1 patient never followed up.
Twenty patients in the study were diagnosed with anal cancer. All but 1 were men (95%) with a mean age of 47 years. Most of the cases were rectal/anal squamous cell carcinoma (n = 13; 65%), while 6 cases were adenocarcinoma (n = 6; 30%), and 2 cases with unknown pathology confirmation. Most of the patients (n = 13; 65%) were also diagnosed in an early stage (stage 0, I, or II) with 5 (25%) diagnosed in late stage and 2 patients never staged. There was no significant difference in age, CD4 count, or pathology when comparing late versus early stage patient populations. Of all, 12 patients were compliant with their HAART therapy, 4 were not on HAART, and 4 patients did not have documentation of HIV medications; the average CD4 count at diagnosis was 350 cells/mm3.
In the study, 14 patients were diagnosed with HL between 2001 and 2011. Of the patients, 12 (86%) were men with the mean age at diagnosis being 42 years. Of these patients, 9 (64%) were diagnosed as late stage, 2 (14%) were early stage, and 3 (22%) of the patients did not have documented staging of their lymphoma. There was no significant difference in age or CD4 count when comparing early versus late stage disease. Of all, 8 (57%) patients were compliant with their HAART therapy, while 6 (43%) were not on HAART; the average CD4 count was 219 cells/mm3.
Five women from the study were diagnosed with breast cancer between 2001 and 2011. The average age at diagnosis was 44 years and the average CD4 count was 175 cells/mm3. In all, 1 patient was diagnosed as late stage, 3 were early stage, and 1 was never staged. The 3 early-staged patients had an average CD4 count of 167 cells/mm3, while the late stage patient had a CD4 count of 91 cells/mm3. Only 3 of the 5 women were compliant with their HAART therapy at diagnosis.
During the period of this study, we also found 1 patient from the clinic who was diagnosed with renal cell carcinoma and 1 patient with multiple myeloma. The patient with renal cell carcinoma was diagnosed as stage I, and he was compliant with HAART therapy, with a CD4 count of 434 cells/mm3 at diagnosis. The patient with multiple myeloma was not compliant with her HAART and had a CD4 count of 303 cells/mm3 at diagnosis. Table 1 represents a summary of our findings.
Most Common Non-AIDS–Defining Cancers in the New Orleans Area.
Incidence rates of malignancies in New Orleans were compared with the state of Louisiana incidence rates. Interestingly, incidences of lung cancer, anal carcinoma, and HL were higher (100 000 × patient-year). Breast cancer rates were similar between HIV-infected and noninfected populations. Table 2 shows incidence rates between New Orleans and the state of Louisiana.
Comparison of Incidence Rates of Malignancies between HIV-Infected and Noninfected Patients in Louisiana (100 000 per Year).
Discussion
The prevalence of NADCs in the area of New Orleans appears to be higher for certain malignancies (HL, anal carcinoma, and lung cancer) and lower for other neoplasms (breast, renal carcinoma, and multiple myeloma) when compared with other studies. 1–5 Equally interesting is the fact that these malignancies in general presented at advanced stages which is a similar finding when compared with other studies. Delay in seeking care, even though possible, does not appear to be a significant problem in our study.
Lung Cancer
We found factors such as younger age, male sex, and extensive smoking history to be important for lung cancer development. Adenocarcinoma was the most common type found in our study. The majority of patients were diagnosed at advanced stages of the disease (IIIB and IV). These 2 findings are in positive correlation with the findings from other reports. 13–19
The role of immunosuppression has not been clearly defined. The results of our study suggest that immunosuppression may not play a role in lung cancer development. A nadir in T-cell count and length of immunosuppression may be important to take into consideration. 19–23 The role of HIV-RNA viral load is still undefined. Our results, with the exception of few cases, did not show a correlation at all between HIV-RNA viral load and lung cancer.
Anal Carcinoma
The prevalence of this condition is high among HIV-infected patients. Multiple studies have shown that men who have sex with men represent a high-risk group. Some findings show that HIV-positive patients with squamous cell carcinoma are much younger, more likely to develop local tumor recurrence, and ultimately die from anal cancer when compared with immune competent patients. 24 Interestingly, in our study, the majority of the patients were diagnosed at earlier stages of the disease. In this population, this condition is an opportunistic disease resulting in patients with suboptimal immune function from persistent infection and prolonged exposition to oncogenic HPVs. Unfortunately, we do not have information related to the presence of HPV in our tissue samples. The role of antiretroviral therapy (ART) and its positive effect on HPV clearance and protection against anal carcinoma development has been reported. 25
Hodgkin Lymphoma
The average CD4 counts in our study were very similar to other studies. 26–29 Although some authors state that a range of 150 to 200 cells/mm3 is critical for a higher risk of HL, others have mentioned that it is the decrease in CD4 counts, while patients are on ART, that increases the risk of developing HL. 26–28 Another possibility may be that declining CD4 counts below 200 cells/mm3 at any time are a harbinger of HIV-HL, the same way that this decrease has been related to other cancers and opportunistic infections in HIV-infected patients. It is interesting to note that in our cohort the average CD4 count decreased after treatment of HL. This may reflect the effects of chemotherapy cycles, drug–drug interactions and less availability of ARVs, or noncompliance with medications. The same situation may apply for increased HIV viral load ranges before and after the treatment for HL. This increase is interesting and it may be related to noncompliance with ART, chemotherapy agents that may induce HIV replication, and chemotherapy interventions that may reactivate other viruses (such as EBV and other herpes viruses). 26 , 29–33
Although patients were on ARVs their viral loads were not under good control, which may be accountable for their less than optimal response to HL treatments. This may also affect survival, since some reports mention unfavorable survival outcomes in patients with uncontrolled viral loads. This issue has been previously mentioned in some reports. 34–37
The issue of average number of years with HIV infection before the initial diagnosis of HIV-HL deserves further attention. This might be a proxy for CD4 nadir counts, length of immune suppression, or longer time of interaction among HIV virus, oncogenic viruses, and HL. Some studies have looked into the impact of CD4 counts at the time of diagnosis of HL. Interestingly, some studies showed a higher incidence of HL with CD4 counts >200 cells/mm3. More interesting is the fact that this correlation is lost when there is profound immunesuppression (less cases of HL in patients with severe immunesuppression), 26 , 34 , 35 suggesting a supportive role for a partially existing immune system.
The role of comorbidities in this population has not been determined. In our study, 100% of our patients presented with other medical issues. The factoring of this and the presence of AIDS opportunistic infections in our cohort, which in turn may predispose our patients to have a worse clinical course of HIV infection, is unknown. At the same time, the relationship between comorbidities and chronic inflammation with resultant premalignant conditions in HIV-infected patients has not been elucidated.
The majority, but not all of our patients, were on ART. This may reflect noncompliance, drug interactions, or side effects. The implications for lack of treatment might be crucial in response to HL treatment and prognosis in our cohort. The survival might have also been affected by this lack of compliance in our cohort even though measures to assure it were undertaken.
Breast Cancer
Given that the incidence of breast cancer in Louisiana is 115.7 per 100 000 patients, 38 the frequency of breast cancer in our population is low (taking into account the fact that we retrospectively reviewed charts from 2001 to 2011), and this fact with some other reports from the literature. 39 Potential reasons to explain this finding could be underreporting, misclassification, and truly low frequency of breast cancer.
The average age of our cohort is similar to that of the other studies. The average CD4 counts and viral loads were consistent with other reports in the literature. As published elsewhere, we did not find any relationship between immunosuppression and development of breast cancer. Other reports suggested that immunosuppression might be a protective factor against the development of breast cancer in HIV-positive patients. 40 ,41 The average number of years with HIV infection we report here (8.8 years) warrants discussion about the potential relationship between long-standing HIV presence and the development of breast cancer.
Renal Carcinoma and Multiple Myeloma
These 2 malignancies are not commonly reported in HIV-infected patients. In our study, we did not find a high prevalence of these malignancies. Possible reasons include the lack of interaction between HIV virus and the pathogenesis of these malignancies. Further studies are needed to determine the prevalence of these 2 malignancies.
Conclusion
In the HAART era, malignancies in HIV-infected patients have become more prevalent and are responsible for a significant morbidity and mortality in this patient population. In our retrospective cohort study, anal carcinoma, lung cancer, HL, and breast cancer were the most prevalent cancers. As expected, CD4 counts were above 200 cells/mm3 in the majority of the patients. These malignancies were diagnosed at late stages in the majority of the cases, presented with worse outcomes, and had a higher recurrence rates.
The role of CD4 in the pathogenesis of these malignancies deserves further evaluation. The role of HIV virus and the potential mechanisms or pathways of oncogene activation also needs to be clarified. The role of other viruses (EBV and HPV) in the activation of oncogenic pathways needs to be elucidated.
Treatment alternatives in relation to simultaneous treatment with ART and chemotherapy interventions and its impact on CD4 counts, HIV viral loads, and HIV resistance need to be elucidated.
Finally, populations at risk need to be screened thoroughly. The role of early biomarkers for early detection of these conditions has not been explored. Aggressive screening strategies have to be developed to tackle this new epidemic in HIV-infected patients in order to lower the mortality and morbidity associated with them.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.