Recent research has shown that HIV-infected individuals have elevated rates of several cancers, and that an increasing proportion of these cancers are now non–AIDS-related malignancies.1–5 HIV-infected individuals have a higher incidence of both virus-related cancers and tobacco/alcohol-related cancers because of higher prevalence of HIV-induced inflammation, immunodeficiency, and tobacco use among HIV-infected compared with HIV-uninfected individuals (40%–60% vs. 17%).2,4,6–9 Malignancies with an infectious origin are also elevated among HIV-infected individuals, including malignancies related to Epstein–Barr virus (lymphoma, nasopharyngeal cancer), hepatitis B and C (hepatocellular carcinoma), human herpesvirus 8 (Kaposi sarcoma), and human papillomavirus (HPV) (oropharyngeal, cervical, and anal cancer).2–4
HPV infection causes a subset of oropharyngeal squamous cell cancers.10,11 Incidence of HPV-positive oropharyngeal cancers have increased over the past several decades, in contrast to the decreasing incidence of other head and neck cancer (HNC) sites over the same time period.10,12 The basic biology and prognosis associated with HPV-related oropharyngeal cancers seem distinct from tobacco-related HNC,13,14 but these characteristics are unknown for HIV-infected individuals.
HIV-infected individuals are known to have an increased prevalence of oral HPV infection (∼2-fold)15–18 and a higher incidence of HNC (∼2.3-fold).19–21 An increased risk of oropharyngeal cancer has been observed in AIDS–cancer registry studies,3,21,22 as well as 2 HIV-infected cohort studies that compared HIV cases to population controls,20,23 although 1 other cohort study found a more modest and not statistically significant increased risk.2 The AIDS–cancer registry studies suggested that HIV-infected individuals are at 1.6- to 6.0-fold increased risk of developing oropharyngeal cancer and 1.7- to 4.0-fold increased risk of developing HNC overall compared to the general population.3,21,22
Prevalence of oral HPV16 infection, the HPV type that accounts for the majority of HPV-related oropharynx cancers, is 2%–7% among HIV-infected individuals compared with ∼1.0% among healthy US adults.15,18,24,25 Because many treated HIV-infected individuals now have a near-normal life span because of the effectiveness of highly active antiretroviral therapy (HAART), they now have the “opportunity” to develop HPV-related cancers at higher rates than were observed in the pre-HAART era.20 Given the higher levels of both tobacco use and sexual risk factors among HIV-infected individuals, it is unclear how much of the increased cancer risk is explained by (1) increased tobacco use, (2) higher number of oral sexual partners (oral HPV exposure), (3) different oral health conditions in HIV-infected individuals, or (4) the effect of immunosuppression on the natural history of oral HPV infection.
In this study, we compare the epidemiology of HNC among HIV-infected individuals with available data on HNC cases in the United States. This is one of the first studies to characterize HNC and the role of HPV among HIV-infected HNC (HIV-HNC) cases.
This study is a case series of HIV-infected patients seen at 6 tertiary care referral centers between 1991 and 2011 across the United States. Cases were contributed from 5 HNC-SPORE sites including M. D. Anderson Cancer Center (n = 34), Emory University (n = 26), University of Pittsburgh (n = 12), University of Michigan (n = 5), and Johns Hopkins University (n = 5), as well as a sixth clinical site at Mount Sinai Medical Center (n = 12). HIV-infected patients diagnosed with incident HNC were retrospectively identified through medical record review at each center. To identify cases, pathology records were searched using the terms HIV and HNC to identify archived material and then cross-referenced with pathology databases to requisition appropriate tumor material. A second query was performed using the electronic HIV and oncology clinic databases at each institution, to identify those with a history of HIV and HNC. Demographic, risk factor, and clinical-pathologic data were abstracted from the medical record, and a sample of tumor tissue was obtained, when available, for biomarker testing. Institutional review board approval or exemption to share de-identified data was obtained at each study site.
Medical Record Abstraction
Each site abstracted demographic, biologic, and behavioral information from the medical record of each patient using a standardized survey form. De-identified information was then submitted to the study data center. Quality assurance was performed on abstracted data, including range and logic checks, with reverification or correction of all atypical data reported by the sites, through a second medical record review. Cases that had documentation of HIV infection and clinical cancer data were included in the study even if the clinical medical record at the cancer center did not include other HIV-related data (CD4, HIV viral load, HAART use) in the medical record; 25% of cases did not have these data. Data for cancer stage among our HIV-infected cases were limited to cases with known data on stage, including 63 HNC, 27 oropharyngeal, and 28 oral cavity cases.
Tumor HPV Testing
There were 39 cases with available tumor sample for centralized HPV testing, including 22 oral cavity, 9 oropharyngeal, 6 laryngeal, 1 hypopharyngeal, and 1 multisite (base of tongue/hypopharynx) cancers. One of these cases only had p16 testing because of insufficient material. In addition to these 39 cases, there were 6 cases from Mount Sinai [4 oropharyngeal, 1 supraglottis (laryngeal), and 1 multisite pharyngeal wall/laryngeal case] that did not have tumor available for centralized testing but had been tested locally for p16; 4 of these had been tested locally for HPV. There was also 1 oropharyngeal case from the Pittsburgh, which had HPV but not p16 data in the medical record. The abstracted tumor test results for these 7 cases were included in this analysis, resulting in 46 total HIV-HNC cases with tumor HPV status: 45 with p16 and 43 with HPV testing. A composite HPV measure was made (using p16 to infer HPV status in those without HPV data). The 46 tumors with HPV data represented a similar distribution of calendar time as the data set overall, with 48% of tested tumors diagnosed 2006–2011, 35% diagnosed 2001–2005, and 17% diagnosed 1991–2000.
For the 39 tumors centrally tested, formalin-fixed paraffin-embedded tumor specimens were collected from each center, given a barcode, and tested in a single centralized laboratory. Tumors were tested for (1) oncogenic HPV by in situ hybridization (ISH), (2) oncogenic HPV DNA using PCR-MassArray, and (3) p16 expression by immunohistochemistry (IHC).26,27 Tissue microarrays (TMAs) were created from the tumor tissue when sufficient material was available, or tests were conducted on individual slides when the biopsy was too small. DNA was isolated from a single tumor tissue core or microdissected from tissue sections for small samples. Formalin-fixed paraffin-embedded blocks were evaluated by a board-certified head and neck pathologist in the University of Michigan Pathology Laboratory for the presence of sufficient tumor for construction of a TMA and for DNA isolation. Cases that were p16-positive but HPV-negative were reassessed with L1 consensus primers and sequenced to detect and identify other HPV types. ISH was also performed for HPV DNA using the INFORM HPV III assay (Ventana; Roche, Tucson, Arizona) to detect any of the 12 high-risk HPV types (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 66). Expression of p16INK4a was assessed by IHC using the CINtec p16INK4a Histology kit and protocol (MTM Laboratories, Westborough, MA, now part of Ventana, Tucson, AZ [a Subsidiary of Roche]). These tests were carried out on the TMA or on individual slides from tissue samples too small to be arrayed. The p16 staining was scored for proportion of stained tumor cells and for staining intensity; each on a 4-point scale: 1 = no staining, 2 = low, 3 = moderate, and 4 = high; proportion of tumor cells staining; and 1: <5%, 2: 5%–20%, 3: 21%–50%, 4: 51%–100%. IHC scores (proportion times intensity) from each 0.6 mm-diameter core or tissue section were averaged for each patient, and IHC scores of 12–16 were considered to be positive for p16. Both assays were scored at 400× magnification by another pathologist who was blinded to the origin of the individual samples.
Sample with adequate DNA that was positive by p16INK4a but negative by HPV16 ISH were reexamined by consensus PCR targeting the L1 region of the viral genome using PGMY primers28 and sequencing of the PCR product to identify the unknown type. All specimens that were found to contain an identifiable high-risk HPV type were scored as HPV positive. High-risk oncogenic HPV types were assessed in tumor DNA using PCR-MassArray designed to detect and identify 15 high-risk HPV subtypes (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 73), using type-specific, multiplex, competitive PCR, and single base extension followed by matrix-assisted, laser-desorption/ionization- time of flight mass spectrometry analysis, as previously described.27
HIV-HNC) cases in this study were stratified by tumor site. Sites were classified a priori as oropharynx (ICDO C01.9, C02.4, C09.0-10.9), oral cavity (ICDO C00.3-00.9, C02.0-02.3, C02.8-C6.9), larynx (ICDO C32.0-32.9, C10.1), and hypopharynx (ICDO C12.9, C13.0-13.9).
Characteristics of HIV-HNC cases were described using medians and interquartile range (IQR) for continuous variables and proportions for categorical variables. Demographic and behavioral characteristics were compared by tumor site using Fisher exact test for categorical and test of medians for continuous data. Characteristics of HIV-oropharynx cases were similarly compared by tumor HPV status. Survival was analyzed using Kaplan–Meier curves, with log-rank testing to assess for statistically significant differences between groups. Cox proportional hazards regression analysis was used to test the effect of multiple covariates on overall survival. Final models retained risk factors that were marginally or statistically significant (P < 0.10) and those variables known to be relevant from previous research.
Characteristics of HNC cases in this study, stratified by tumor site and HPV status, are also presented alongside national HNC data from the Surveillance Epidemiology and End Results (SEER), referred to as US-HNC, using SEER cases between 1991 and 2009 (analysis performed using SEER 18, from SEER-STAT 8.02; Surveillance, Epidemiology, and End Results Program, Bethesda, MD).
HIV-infected individuals diagnosed with incident HNC between 1991 and 2011 (n = 94) were identified across 6 participating US sites. Demographic information was available for all 94 cases, HIV-related clinical data were available for 71 (76%) cases, and tumor samples were available for centralized testing or had local testing result for 46 (49%) cases.
HIV-HNC cases included 38 oral cavity and 31 oropharyngeal cancers, as well as 17 laryngeal, 5 hypopharyngeal, and 3 multisite cancers with either a laryngeal or hypopharyngeal site of involvement (which were grouped together). As described in Table S1 (see Supplemental Digital Content,http://links.lww.com/QAI/A496), oropharynx and oral cavity cases were more likely than larynx/hypopharynx cases to be male (97% vs. 72%, P = 0.002). Median age was 50 years, and most cases were current tobacco (59%) and alcohol (55%) users, and half were diagnosed at stage IV (49%). Only 11% of cases were never-smokers, and 15% had never used alcohol. Although the majority of oral cavity cases were white (61%), a significantly smaller proportion of oropharynx and larynx/hypopharynx cases were white (36%, P = 0.014). Age, gender, and CD4 cell count of cases at diagnosis were similar across study sites. However, tumor site differed by study site, with a higher proportion of oral cavity cases at M. D. Anderson Cancer Center and a higher proportion of oropharyngeal cases at Mount Sinai Medical Center and Johns Hopkins University (see Table S1, Supplemental Digital Content,http://links.lww.com/QAI/A496).
Survival information was available for 86 cases (median = 49 months). Survival varied considerably by tumor site, with higher survival among oropharyngeal (82 months) and oral cavity (63 months) cases than the larynx/hypopharynx (14 months) cases, P = 0.001 (Fig. 1A; see Table S1, Supplemental Digital Content,http://links.lww.com/QAI/A496). Survival was especially poor among those with CD4 <100 at diagnosis (median, 15 months; IQR = 10–38) and increased among those with CD4 of 100–199 (33 months), 200–349 (63 months), and ≥350 (73 months) cells per microliter at diagnosis. Survival was significantly poorer among those with CD4 counts <200 vs. ≥200 cells per microliter at diagnosis (median, 16.1 vs. 72.8 months; P < 0.001).
Of the 46 HIV-HNC cases with tumor HPV testing, 7 (17%) contained HPV16 DNA, including 6 of 11 (55%) oropharyngeal cancers (see Table S1, Supplemental Digital Content,http://links.lww.com/QAI/A496; P < 0.001). Four other HPV types were identified, all in oral cavity tumors, including HPV26 (hard palate), HPV33 (tongue), HPV69 (alveolar ridge), and HPV82 (mandible). HPV16 was also detected in 1 pyriform sinus (hypopharyngeal) case. Using our composite HPV-positive status (which included any oncogenic HPV and p16 status for those without HPV data), 30% of HIV-HNC and 64% of HIV-oropharyngeal cancers were considered HPV related. High p16 expression was detected in 42% of the 45 HIV-HNC cases tested, including 93% of HPV-positive cases but only 23% of HPV-negative cases. Considering only oropharyngeal cases, a marginally higher proportion of white than black cases were HPV16-positive [100% (5/5) vs. 38% (3/8); P = 0.051]. Cases with and without HPV tumor data were similar regarding, gender, race, age, subsite, and CD4 at diagnosis, but varied by study site including the following proportion of cases with known tumor status at each site: University of Pittsburgh (11/12), Emory University (20/27), Johns Hopkins University (3/5), Mount Sinai Medical Center (6/12), Michigan University (2/6), and M. D. Anderson Cancer Center (4/34).
Table 1 describes HIV-related variables of interest among the 71 cases (76% of all HNC) for whom HIV clinical information could be found in the medical record. Cases with and without HIV-related variables were similar regarding, gender, race, age, and subsite but were more likely to come from M. D. Anderson Cancer Center, Michigan University, and University of Pittsburgh (data not shown). Most patients were on HAART at cancer diagnosis (77%). Interestingly, only 1 case had an undetectable HIV viral load at cancer diagnosis, suggesting HIV might be inadequately controlled in many of these cases (Table 1). Median time from HIV diagnosis to cancer was 6 years (IQR = 2–10 years). Median CD4 counts at cancer diagnosis varied by tumor site (Table 1), with a higher proportion of immunosuppressed (CD4 <200 cells per microliter) patients among laryngeal/hypopharyngeal (53%) than oropharyngeal (12%, P = 0.004) or oral cavity (26%, P = 0.07) cases. Among the 39 cases with available nadir CD4 cell counts, 28 (72%) had nadir CD4 cell counts <200 cells per microliter, including 13 individuals with CD4 counts <50 cells per microliter.
Among 42 individuals with tumor HPV status and follow-up, median survival was longer, but not statistically different among HPV-positive than HPV-negative (62.9 vs. 37.8 months, P = 0.90, Fig. 1B) and p16-positive compared with p16-negative (62.9 vs. 37.8 months, P = 0.84) HIV-HNC cases. When restricted to oropharyngeal cancers, there was also a longer median survival of 9 HPV-positive compared with 5 HPV-negative cases, although this was not statistically significant (81 vs. 16 months, P = 0.74).
Multivariate risk factors for survival are shown in Table 2. Risk factors associated with poorer overall survival included CD4 <100 cells per microliter [adjusted hazard ratio (aHR) = 2.52, 95% confidence interval (CI): 1.06 to 6.0], larynx/hypopharynx site (aHR = 3.12, 95% CI: 1.35 to 7.23), current tobacco use (aHR = 1.92, 95% CI: 0.92 to 4.03), and minority race (aHR = 2.73, 95% CI: 1.30 to 5.76). Age, gender, tumor HPV status, and tumor stage were not significant predictors of survival.
Among the subset of oropharyngeal cases with tumor available for testing, characteristics of HIV-infected oropharyngeal cases (HIV-OP) with HPV-positive (n = 9) and HPV-negative (n = 5) tumors were contrasted (see Table S2, Supplemental Digital Content,http://links.lww.com/QAI/A496). Compared with HPV-negative cases, HPV-positive OP cases appear to have higher CD4 cell counts at diagnosis (668 vs. 266, P = 0.54) and to be more likely to be younger (52 vs. 58 years, P = 0.27) and white (56% vs. 0%, P = 0.054), although the number of these cases was limited and none of these differences were statistically significant (see Table S2, Supplemental Digital Content,http://links.lww.com/QAI/A496). When compared to results from 2 recent large US general population OP studies (US-OP), HIV-OP cases in this study were more likely than US-OP cases to be nonwhite, to be current smokers, and to be detected at a later stage. HIV-OP cases appeared to have poorer survival than US-OP: (81 vs. 131 months for HPV-positive OP; 16 vs. 20–58 months for HPV-negative); see Table S2, Supplemental Digital Content,http://links.lww.com/QAI/A496.10,14
Next, we compared characteristics of all HIV-HNC to national HNC cases (US-HNC). Because laryngeal cases are excluded from these US-HNC numbers, laryngeal cases were similarly excluded from the HIV-HNC results in this table, leaving 77 cases (Table 3). HIV-HNC cases were more likely than US-HNC to be male (91% vs. 68%), younger (median age, 50 vs. 62 years), nonwhite (49% vs. 18%), and current smokers (61% vs. 18%29), as expected given the different distribution in age, race, and tobacco use in the HIV-infected US population than the general US population. HIV-HNC cases were also more likely than US-HNC to be an advanced stage (60% vs. 20%). Survival was not notably different between HIV-HNC and US-HNC (Table 3).
This study is, to our knowledge, the largest case series of HIV-HNC to date and these findings help to characterize the epidemiology of HIV-infected individuals with HNC. HIV-infected individuals have increased exposure to tobacco, alcohol, and HPV infection, the 3 primary HNC risk factors. This study suggests that a subset of HIV-HNC is HPV-positive, and that as in the general population, these HPV-HNC are primarily oropharyngeal cancers. Tobacco use was common in this population, however HNC were detected in some HIV-infected individuals without the traditional HNC risk factors of tobacco and alcohol use. Thus, this research suggests that HNC cases among HIV-infected individuals include both HPV-related and tobacco/alcohol-related HNC.
Although oral HPV prevalence has been associated with HIV-infection and current CD4 cell count in several studies, this is one of the first studies to test for HPV in HIV-HNC tumors. Half of the HIV-oropharyngeal cancers and one quarter of all HIV-HNC were HPV-positive, consistent with some population studies,30 but lower than others.11,14 These results are also consistent with 1 smaller case series of HIV-HNC that reported HPV tumor detection in 6 of 25 (24%) cases.31 As 42% of oropharyngeal cases and 72% of HNC overall were HPV-negative, it suggests that although HPV is a causal factor in a notable number of cases, tobacco use and other factors remain important contributors in the majority of HIV-HNC.
Survival was not notably different between HPV-positive and HPV-negative HNC in this study; however, there were a limited number of cases with tumor HPV data and differences in cancer therapy or cause of death were not accounted for. Current tobacco use was associated with poorer survival, consistent with the poorer prognosis seen among HNC smokers in the general population.14
Although almost all of HIV-HNC cases had been on HAART therapy at some point in time, and a large proportion were on HAART at diagnosis, current CD4 cell count was <350 cells per microliter in 60% of cases, and many participants had a history of low nadir CD4 cell counts. This is consistent with the possibility that immunosuppression may increase oral HPV persistence and/or progression to cancer, similar to that observed for cervical HPV infection and immunosuppression.32 However, the higher median CD4 of HPV16-positive than HPV16-negative oropharyngeal cases argues against a strong role of current CD4 on the final stages of HPV-transformation. Cases with lower CD4 cell count at diagnosis had significantly poorer survival, which might be because of poorer cancer-related outcomes and/or to mortality from other HIV-related comorbidities. The relatively high current CD4 count among some HPV-positive oropharyngeal cases in our study contrasts with several previous studies, where lower current CD4 count was associated with increased risk of HNC, as well as other HPV-related cancers.2,3,23,33 However, many of the HIV-positive oropharyngeal cases in this study had a history of low nadir CD4 cell counts, suggesting that immunosuppression, if it had an effect on HPV progression, may have acted earlier in the cancer process. Although median CD4 was 300 cells per microliter among HIV-HNC cases at diagnosis, all but 1 case had detectable HIV viremia.
HIV-HNC cases in this study differed from HNC cases in the general US population in terms of demographic (gender, age, race) and behavioral (smoking, drinking) characteristics, although it is unclear whether these differences are entirely explained by differences in the characteristics of the HIV-infected population. Indeed, the median age of HIV-infected individuals in the US is younger than the general US population (∼30 vs. ∼37 years).34 Similarly, a greater proportion of HIV-infected individuals in the US are smokers (50%–70%) compared to <20% of individuals in the general population.35 Therefore, it is of note that there were some cases in our study that were nonsmokers/nondrinkers.
This study has several limitations and strengths. Behavioral data were retrospectively abstracted from the medical record and not available for all cases. Because clinical information was not collected prospectively, data on sexual behavior were not available, although we did have data on tobacco and alcohol use for most cases. Tumor tissue was not available for all cases; however, the tumor HPV results that are presented are one of the first explorations of HPV in HIV-HNC tumors. Cases were not systematically sampled but represent a convenience sample of all HIV-HNC cases identified at participating centers. Treatment of cases across sites was not standardized and likely varied, impacting overall survival. Finally, although this is the largest non-registry study of HIV-HNC to date, sample sizes remained limited when stratified by tumor site. Strengths of this study included centralized validated tumor testing, analysis stratification by tumor site and tumor HPV status, inclusion of several US clinical centers, restriction to cases diagnosed between 1991 and 2011, inclusion of survival data, and a larger sample size than any previous non-registry study.
This multiple institution study describes the epidemiology of HNC among a case series of HIV-infected individuals in the HAART era in the US. It suggests that a subset of HIV-HNC is HPV-positive, and many of these cancers occurred among individuals who were not currently immunosuppressed, but had been immunosuppressed in the past. Many of the HIV-HNC cases were on HAART therapy, but had detectable viremia indicating they were either poorly adherent to HAART, were failing their regimen, or had only recently started therapy. Because this study included cases occurring over the past 20 years, the current role of HPV might currently be larger than that captured in this study. Because HIV-infected individuals live longer due to HAART, they now have the “opportunity” to develop non–AIDS-related cancers including HPV-HNC. Given the higher prevalence of oral HPV16 among HIV-infected individuals, and the suggestion that HPV persistence is increased among immunosuppressed individuals, HIV-infected individuals remain at increased risk for developing HPV-HNC. Earlier diagnosis and treatment of HIV infection with HAART leading to full suppression of viremia and immune reconstitution may reduce cancer risk and improve outcomes overall.
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