Abstract
Background
Men who have sex with men (MSM) without HIV are known to be at elevated relative risk for Human papillomavirus (HPV)-associated anal cancer in comparison to men who have sex with women (MSW), but are poorly characterized in terms of anal cancer incidence due to absence of reporting of sexual behavior/identity at a population-level.
Methods
By combining age-specific statistics from multiple data sources (anal cancer incidence among all males; anal cancer incidence among MSM and MSW with HIV; population size of men with HIV by sexual orientation), we developed a mathematical model to estimate anal cancer incidence, annual number of cases, and proportion by (a) sexual orientation (MSM versus MSW), (b) HIV status, and (c) age (<30, 30–44, 45–59, and ≥60 years).
Results
Anal cancer incidence (per 100 000) among MSM without HIV was 1.4 (95% uncertainty interval [UI], 0.6 to 2.3), 17.6 (95% UI = 13.8–23.5), and 33.9 (95% UI = 28.3–42.3), at ages 30–44, 45–59 and ≥60 years, respectively. 19.1% of all male anal cancer occurred in MSM without HIV, increasing from 4% of anal cancer diagnosed at 30–44 years to 24% at ≥60 years; 54.3% occurred in MSW without HIV (increasing from 13% at age 30–44 to 67% at >60 years), and the remaining 26.6% in men (MSM and MSW combined) with HIV (decreasing from 83% at age 30–44 to 9% at >60 years).
Conclusions
These findings should inform anal cancer prevention recommendations in male risk groups, including, for the first time, for the important group of MSM without HIV.
Keywords: anal cancer, men who have sex with men, HIV, squamous cell carcinoma of the anus, incidence
The present study is the first to characterize anal cancer incidence and burden among US men by sexual orientation, human immunodeficiency virus (HIV) status, and age. The findings provide critical data necessary to define screening-eligible population (based on risk threshold).
Nearly 11 000 human papillomavirus (HPV)-attributable anal cancer cases were diagnosed worldwide among men in 2020, and incidence continues to rise in high- and middle-income countries [1–6]. Given the established mode of anal HPV transmission through anal sexual intercourse, men who have sex with men (MSM) are recognized as having elevated anal cancer risk and are an important group for anal cancer prevention [7,8]. MSM with human immunodeficiency virus (HIV), due to a combination of both greater anal HPV acquisition and HIV-related immunosuppression, have the highest anal cancer incidence, which increases with age to reach ≥100 per 100 000 among persons aged ≥45 years [9, 10].
Understanding anal cancer incidence by age is essential to inform potential anal cancer screening programs, which are fast evolving from local research initiatives to recommended public health programs, particularly following the proof of principle that treating anal precancer can prevent cancer [11]. In particular, several health professional organizations are steering towards generating anal cancer screening recommendations, with anal cancer incidence thresholds (eg, > 25 or >50 cases per 100 000 persons) under consideration as potential benchmarks to define the age to start anal cancer screening in different high-risk groups [12].
MSM without HIV, however, despite being one of the largest risk groups in terms of population size (eg, an estimated 6 million MSM are estimated to be living in the United States, the large majority in the absence of HIV) [13, 14], remain poorly characterized in terms of anal cancer incidence, given that sexual characteristics and identity are not reported at the population level in the absence of disease (eg, HIV). Best current estimates of anal cancer incidence for MSM without HIV derive from the US Multicenter AIDS Cohort Study (MACS) [15], which, given the <10 observed anal cancers among MSM without HIV, precludes the ability to estimate age-specific incidence. Thus, there is an important knowledge gap for informing age-based screening recommendations for this risk group.
Therefore, by combining data from multiple US-based databases into a mathematical model, our objective was to estimate and validate anal cancer incidence by age among MSM without HIV. We further described anal cancer burden (annual number of cases and proportion) among men in the United States according to sexual orientation, HIV status, and age.
METHODS
Data Sources
Anal Cancer Cases in U.S. Males (Irrespective of Sexual Orientation and HIV Status)
Annual number of anal cancer cases diagnosed in US men during 2011–2016, as well as male population size, were obtained according to age (<30, 30–44, 45–59, and ≥60 years) from US Cancer registry data sets, composed of the National Program of Cancer Registries (NPCR) from the Centers for Disease Control and Prevention (CDC), and the National Cancer Institute's (NCI) Surveillance, Epidemiology, and End Results (SEER) Program, using SEER*Stat v4.8.0 (Supplementary Table 1). The data set covers nearly 100% of the US population. We focused on HPV-associated anal cancers only, defined hereafter as squamous cell carcinoma of the anus (SCCA), using the International Classification of Diseases for Oncology, Third Edition codes (ICD-O-3) C21.0–21.8 and 20.9, and histology codes 8050–8084 and 8120–8131 [1,2].
SCCA Incidence Among MSM and MSW With HIV
Anal cancer incidence estimates for men with HIV according to age (similar age groups) were obtained separately for MSM and for men who have sex with women (MSW), from the US HIV Cancer match study and were assumed to be all HPV-associated SCCA (Supplementary Table 2).
Population Size of Persons With HIV According to Age and Sexual Orientation
The population size of MSM and MSW with HIV for similar age groups was obtained from an individual-level open cohort microsimulation model of persons with HIV, informed by the CDC's HIV/AIDS surveillance system (Supplementary Methods 1, Supplementary Table 3).
Population Size of MSM in the U.S. General Population (Irrespective of HIV Status)
We estimated the population size of MSM according to age using the National Health and Nutrition Examination Survey (NHANES) (Supplementary Table 4), a nationally representative survey of non-institutionalized US individuals. NHANES identifies participants using a complex clustered multi-stage probability sample and collects information on sociodemographic, health, and sexual behaviors by trained interviewers during the home interview or in mobile examination centers. Sexual orientation was identified based on self-reported data on the lifetime number of male sex partners and sexual identity. We determined MSM prevalence using SAS PROC SURVEY procedures in SAS software v9.4 (SAS Institute), which take weight, cluster, and strata statements into account to incorporate sampling weights and adjust for the complex survey design.
Analytic Approach
Number of SCCA Among MSM and MSW With HIV
We applied SCCA incidence estimates for MSM and MSW with HIV to respective population size, to derive number of SCCA among MSM and MSW with HIV for each age group.
Number of SCCA Among All Men Without HIV
Anal cancer cases occurring in men without HIV were then obtained by subtracting all anal cancer cases diagnosed in men with HIV from SCCA among the US general population.
Population Size of MSM and MSW Without HIV
Population size of MSM without HIV was derived as: (US male population size × MSM prevalence)—population size of MSM with HIV. Similarly, the population size of MSW without HIV was derived as: (US male population size × [1—MSM prevalence])—MSW with HIV.
SCCA Incidence Among MSM and MSW Without HIV
The mathematical model was parameterized to consider known variables (population sizes of MSM and MSW with and without HIV, and SCCA incidence among MSM and MSW with HIV) and 2 unknowns (incidence of SCCA among MSM without HIV and MSW without HIV). We calculated the age-specific incidence rates by solving the analytic model (described in Supplementary Methods 2) for each age group. We solved the model 5000 times to incorporate the uncertainty in the SCCA incidence among the HIV population and MSM population size. The uncertainty intervals for the incidence rates were calculated as 2.5% and 97.5% quantiles among the best 50 solutions by assigning a goodness of fit value to each of the 5000 solutions to determine the best parameter set (technical details are presented in the supplement). The model was coded in MATLAB 2020b and was run biennially. Technical and formulaic modeling details are presented in Supplementary Methods 2.
Number of SCCA Cases Among MSM and MSW Without HIV
We applied age-specific SCCA incidence rates for MSM and MSW without HIV to the population size for the respective groups to estimate number of SCCA cases that are MSM and MSW without HIV.
Validation of SCCA Incidence for MSM Without HIV
We compared above estimates of age-specific SCCA incidence in MSM without HIV with those obtained by an alternative model by first calculating age-specific IRRR calculated for MSW with HIV versus the general US male population (as a surrogate of the effect of HIV on SCCA risk in men), then multiplying age-specific SCCA incidence among MSM with HIV by 1/IRR [9, 15].
We also calculated age-standardized incidence from ≥30 years, first because SCCA incidence is very low in all risk groups below 30 years, and also to be able to compare with observed SCCA incidence from the MACS study [15] that recruited MSM without HIV from >30 years.
RESULTS
Overall, during 2011–2016, estimated age-standardized (to 2000 US population) SCCA incidence for adult MSM without HIV aged 15 years or older was 11.7 per 100 000 (crude rate based on US population structure was 13.6 per 100 000). Incidence rates were very low (<1 per 100 000) for MSM without HIV aged <30 years. Age-standardized incidence for MSM without HIV aged ≥30 years was 15.8 per 100 000 (crude rate 18.8 per 100 000) and was integrated with a previously published unified scale of anal cancer incidence across risk groups (Figure 1). Age-specific SCCA incidence rates (per 100 000) for MSM without HIV aged 30–44, 45–59, and ≥60 years were 1.4 (95% uncertainty interval [UI] = 0.6–2.3), 17.6 (95% UI = 13.8–23.5), and 33.9 (95% UI =28.3–42.3), respectively (Figure 1). Age-specific estimates for MSM without HIV were similar when estimated by an alternative approach based on back calculation from SCCA incidence for MSM with HIV using relative risk for women living with HIV (2.9, 14.9, and 30.2, respectively; see Supplementary Table 5).
Figure 1.
Anal cancer incidence among MSM without HIV according to age, integrated into the Anal cancer risk scale. Abbreviations: HIV, human immunodeficiency virus; MSM, men who have sex with men; MSW, men who have sex with women; yrs, years old.
Incidence rates among MSW without HIV aged 30–44, 45–59 years and ≥60 years were estimated to be 0.1 (95% UI = 0.0–0.1) for 30–44 years old, 1.4 (95% UI = 1.3–1.5) for 45–59 years old, and 2.3 (95% UI = 2.1–2.5) for 60 years old and older (data not shown).
Overall, 26.6% of 1999 annual male SCCA cases in the United States were estimated to occur among men with HIV (23.9% MSM and 2.7% MSW) and 73.4% among men without HIV (19.1% MSM, 54.3% MSW). Annual number of male SCCA cases according to sexual orientation (MSM, MSW) and HIV status for men aged <30, 30–44, 45–59, and ≥60 years are illustrated in Figure 2A , with proportion distribution presented in Figure 2B . With increasing age, the proportions of SCCA that were diagnosed in men with HIV decreased, both for MSM (from 76.0% among 30–44 years to 7.5% among >60 years) and MSW (from 6.5% among 30–44 years to 1.3% among >60 years), whereas the proportion of SCCA that were diagnosed among men without HIV increased, both MSM (from 4.2% among 30–44 years to 23.9% among >60 years) and MSW (from 13.1% among 30–44 years to 67.3% among >60 years).
Figure 2.
Annual number of male SCCA cases according to sexual orientation (MSM, MSW) and HIV status for men aged <30, 30–44, 45–59, and ≥60 y. Abbreviations: HIV, human immunodeficiency virus; MSM, men who have sex with men; MSW, men who have sex with women; SCCA, squamous cell carcinoma of the anus; yrs, years old.
DISCUSSION
We report that similar to MSM with HIV and other well-characterized groups at elevated SCCA risk [9], SCCA incidence increases with age among MSM without HIV, reaching 34 per 100 000 among those aged ≥60 years. Of note, among MSW without HIV, incidence remains below 3 per 100 000 in all age groups. Our findings for MSM without HIV, particularly when integrated into a previously developed unified risk scale for anal cancer, enriches the understanding of anal cancer incidence for 1 of the largest but understudied risk groups for SCCA.
Our findings have important implications to inform cancer prevention recommendations. Health professional organizations in high-resource settings (eg, International Anal Neoplasia Society [IANS], CDC in the US; French National Society of Colo-Proctologists) are steering toward generating evidence-based cancer screening recommendations for anal cancer [12]. Incidence thresholds of ≥25 cases per 100 000, or >50 cases per 100 000, for example, are among those under consideration as potential benchmarks to define the burden of disease threshold for at-risk individuals for anal cancer screening programs. Our estimates suggest that anal cancer incidence among MSM without HIV aged ≥60 years would meet the criteria of >25 cases per 100 000 for screening but not that of >50 cases per 100 000. Whereas age groups of MSM without HIV below age 60 years do not attain either potential risk threshold. Although our findings can provide supporting evidence for screening recommendations to at least be based on a concept of similar management for similar SCCA risk, future evaluation of risk-benefit ratios and cost-effectiveness analyses associated with screening initiation at different age thresholds among MSM without HIV (and indeed also in risk groups with HIV) would be crucial to define the optimal age to initiate screening [16].
Our first ever description of the proportional and absolute male anal cancer burden in the United States according to HIV, sexual orientation (MSM and MSW), and age can help raise awareness, drive investment cases, and inform recommendations, for prevention. Both for secondary prevention by screening and early detection (as mentioned above) but also for prophylactic HPV vaccination. Furthermore, assuming that all SCCA diagnosed in men with HIV are attributable to HIV infection, the proportion of SCCA occurring among men with HIV also provides an estimate of the SCCA burden that can be potentially prevented by HIV control. Of note, we found that the proportion of SCCA occurring among men with HIV was lower at higher age. This finding is consistent with another recent study from the United States [17] and is expected to be partly due to the lower average age of men with HIV in comparison to men without HIV in the United States. However, these proportions may evolve with the aging of persons with HIV [18].
Targeting screening of MSM without HIV aged ≥60 years has the potential to reduce SCCA burden among men aged ≥60 years by one quarter. Whereas for MSW without HIV, although the incidence is lower, this group contributes to 66% burden in ≥60-year-old men because of sheer population size. In the absence of screening recommendations for the general male population, anal cancer prevention in this group solely relies on direct and/or herd immunity benefits from HPV vaccination programs. However, HPV-vaccination-driven anal cancer prevention among this group will not be seen until currently vaccinated birth cohorts or their partners enter these age groups.
Our study has certain limitations. First, SCCA incidence rates were estimated by a data-driven analytic model synthesizing multiple population-based databases. Nevertheless, in the absence of robust population-based estimates, this study provides the best possible current estimates of age-specific SCCA incidence and burden by male sexual orientation and HIV, most notably for MSM without HIV. To validate our findings, we compared them with the only study to report SCCA incidence among MSM without HIV to date: the MACS [15]. Our estimated age-standardized SCCA incidence among MSM without HIV >30 years was 18.8 per 100 000, comparable to 19 per 100 000 in the MACS study (that enrolled MSM aged >30 years) [15]. Second, the population size of MSM was estimated using the NHANES, in which sexual behavior was self-reported, which is likely underreported because of social stigma and recall bias. However, self-report is the only way to obtain these data and the use of NHANES to estimate population size of MSM in the U.S. is considered standard practice [19]. Furthermore, although additional anal cancer risk stratification is expected within any given age-specific strata of the MSM population, most notably according to more detailed sexual behavior (number of receptive anal sexual partners, etc.) and even smoking habits, this is beyond the scope of this work, which is focused on informing pragmatic and potentially actionable public health recommendations. Third, all anal cancer cases diagnosed among persons with HIV, were assumed to be SCCA [10]. This assumption is expected to be valid given that <10% of all anal cancer cases diagnosed in the United States are non-SCCA [2], and that this proportion is expected to be even lower among people with HIV (for whom anal cancer excess is expected to be driven by HPV-related SCCA). Finally, although our estimated incidence rates for MSM without HIV may be applicable to other settings in the world, the fraction of anal cancer burden specific to HIV, MSM, and MSW and according to age is expected to vary given the differences in population size of people with HIV and MSM in different world settings.
Anal cancer incidence increases with age among MSM without HIV, reaching ≥25 per 100 000 among those aged ≥60 years. The growing population size of this risk group in high-income countries means that the anal cancer burden among MSM is expected to increase in future years [20]. Given that the MSM population size is unlikely to benefit from herd immunity through female-only HPV vaccination programs, targeted prioritization and improvement in HPV vaccination coverage among MSM is important. However, age groups that are currently bearing much of the anal cancer burden among MSM without HIV have missed the opportunity for prophylactic HPV vaccination prior to sexual debut, increasing the importance of secondary prevention. Such programs could consider an age-based approach for screening (triage tests from anal swabs; eg, cytology, HPV16 infection, or other molecular markers, followed by high-resolution anoscopy for detection and treatment of anal precancer) or early detection (using digital anorectal examination, to detect early stage cancer) by taking into consideration age-specific incidence rates as well as local screening infrastructure and resources. When screening for precancer, careful consideration should also be given to prevent overdiagnosis and overtreatment, particularly among young MSM without HIV among whom anal cancer remains rare. Future cost-effectiveness analyses will be crucial to inform whether to initiate age-specific screening for anal cancer prevention among MSM without HIV.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Supplementary Material
Contributor Information
Ashish A Deshmukh, Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
Haluk Damgacioglu, Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
Damien Georges, Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
Kalyani Sonawane, Department of Public Health Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.
Gary M Clifford, Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer (IARC/WHO), Lyon, France.
Notes
Acknowledgments. Research reported in this publication was supported by the National Cancer Institute (NCI) award number R01CA232888 and the National Institute on Minority Health and Health Disparities (NIMHD) award number K01MD016440.
Data availability statement. Only publicly available data were used in this study, and data sources and handling of these data are described in the Methods section. Further information is available from the corresponding author upon request.
Ethics statement. Where authors are identified as personnel of the International Agency for Research on Cancer (IARC) or World Health Organization (WHO), the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the IARC or WHO. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health (NIH). This article is based on research funded in part by the National Cancer Institute (NCI) and National Institute on Minority Health and Health Disparities (NIMHD) of the NIH of the United States. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the NIH. The authors alone are responsible for the views expressed in this article, and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated.
Financial support. National Cancer Institute and the National Institute on Minority Health and Health Disparities.
References
- 1. Deshmukh AA, Damgacioglu H, Georges D, et al. Global burden of HPV-attributable squamous cell carcinoma of the anus in 2020, according to sex and HIV status: a worldwide analysis. Int J Cancer. 2023; 152:417–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Deshmukh AA, Suk R, Shiels MS, et al. Recent trends in squamous cell carcinoma of the anus incidence and mortality in the United States, 2001–2015. J Natl Cancer Inst 2020; 112:829–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Islami F, Ferlay J, Lortet-Tieulent J, Bray F, Jemal A. International trends in anal cancer incidence rates. Int J Epidemiol 2017; 46:924–38. [DOI] [PubMed] [Google Scholar]
- 4. Kang YJ, Smith M, Canfell K. Anal cancer in high-income countries: increasing burden of disease. PLoS One 2018; 13:e0205105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Nielsen A, Munk C, Kjaer SK. Trends in incidence of anal cancer and high-grade anal intraepithelial neoplasia in Denmark, 1978–2008. Int J Cancer 2012; 130:1168–73. [DOI] [PubMed] [Google Scholar]
- 6. Damgacioglu H, Lin YY, Ortiz AP, et al. State variation in squamous cell carcinoma of the anus incidence and mortality, and association with HIV/AIDS and smoking in the United States. J Clin Oncol 2022;41:1228–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Daling JR, Weiss NS, Klopfenstein LL, Cochran LE, Chow WH, Daifuku R. Correlates of homosexual behavior and the incidence of anal cancer. JAMA 1982; 247:1988–90. [PubMed] [Google Scholar]
- 8. Frisch M, Smith E, Grulich A, Johansen C. Cancer in a population-based cohort of men and women in registered homosexual partnerships. Am J Epidemiol 2003; 157:966–72. [DOI] [PubMed] [Google Scholar]
- 9. Clifford GM, Georges D, Shiels MS, et al. A meta-analysis of anal cancer incidence by risk group: toward a unified anal cancer risk scale. Int J Cancer 2021; 148:38–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Colon-Lopez V, Shiels MS, Machin M, et al. Anal cancer risk among people with HIV infection in the United States. J Clin Oncol 2018; 36:68–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Palefsky JM, Lee JY, Jay N, et al. Treatment of anal high-grade squamous intraepithelial lesions to prevent anal cancer. N Engl J Med 2022; 386:2273–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Abramowitz L, Etienney I, de Parades V, Pigot F, Talence BLS. Recommandations pour la Pratique Clinique: Lesions precancereuses anales liees aux papillomavirus humains : depistage et prise en charge. Société Nationale Française de Colo-Proctologie. Available at: https://www.snfcp.org/wp-content/uploads/2017/03/Recommandations-pour-la-pratique-clinique-2022-texte-court.pdf. Accessed 1 February 2023.
- 13. Mosher WD, Chandra A, Jones J. Sexual behavior and selected health measures: men and women 15–44 years of age, United States, 2002. Adv Data 2005; 15:1–55. [PubMed] [Google Scholar]
- 14. Mauck DE, Gebrezgi MT, Sheehan DM, et al. Population-based methods for estimating the number of men who have sex with men: a systematic review. Sex Health 2019; 16:527–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. D'Souza G, Wiley DJ, et al. Incidence and epidemiology of anal cancer in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr 2008; 48:491–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Deshmukh AA, Chiao EY, Cantor SB, et al. Management of precancerous anal intraepithelial lesions in human immunodeficiency virus-positive men who have sex with men: clinical effectiveness and cost-effectiveness. Cancer 2017; 123:4709–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Zhang ER, Pfeiffer RM, Austin A, et al. Impact of HIV on anal squamous cell carcinoma rates in the United States, 2001–2015. J Natl Cancer Inst 2022; 114:1246–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Althoff KN, Stewart CN, Humes E, et al. The shifting age distribution of people with HIV using antiretroviral therapy in the United States. AIDS 2022; 36:459–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Grey JA, Bernstein KT, Sullivan PS, et al. Estimating the population sizes of men who have sex with men in US states and counties using data from the American community survey. JMIR Public Health Surveill 2016; 2:e14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Jones J. LGBT identification in U.S. ticks up to 7.1%: Gallup Poll. Gallup Poll Social Series. Available at: https://news.gallup.com/poll/389792/lgbt-identification-ticks-up.aspx. Accessed January 2022.
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