Human papillomavirus–associated anal squamous cell carcinoma: sociodemographic, geographic, and county-level economic trends in incidence rates—United States, 2001-2019

Abstract

Background

Incidence of anal squamous cell carcinoma is increasing, but vaccination against human papillomavirus (HPV) and removal of precancerous anal lesions could prevent new cases. The overall HPV-associated cancer incidence is reported to be higher in rural populations and in counties with lower economic status. We assessed these differences specifically for HPV-associated anal squamous cell carcinoma and described the geographic, county-level economic, and sociodemographic variations in incidence rates and trends.

Methods

We analyzed data from the US Cancer Statistics to assess age-standardized incidence rates of HPV-associated squamous cell carcinomas among adults aged 18 years and older from 2001 to 2019. We calculated rate ratios and 95% confidence intervals to examine differences in incidence rates. We also quantified changes in incidence rates over time using joinpoint regression.

Results

From 2001 to 2019, 72 421 new cases of HPV-associated anal squamous cell carcinoma were diagnosed among women (2.8 per 100 000) and 37 147 among men (1.7 per 100 000). Age-standardized incidence rates were higher in the South compared with other census regions and in counties ranked in the bottom 25% and 25%-75% economically than in the top 25%. The overall incidence rate increased in women but remained stable in men during 2009-2019. Incidence rates increased in adults aged 50 years and older but decreased among those aged 40-44 years from 2001 to 2019 in women and from 2007 to 2019 in men.

Conclusions

There were inequities in HPV-associated anal squamous cell carcinoma incidence by geographic and county-level economic characteristics. Failure to improve vaccine and treatment equity may widen existing disparities.

Anal cancer is a rare malignancy accounting for an estimated 0.5% of all new cancer cases in the United States (1). Despite being relatively uncommon in the general US population, anal cancer incidence has increased steadily since the 1970s (2-5).

Infection with human papillomavirus (HPV) is an established risk factor for anal cancer (6,7). HPV causes approximately 91% of anal squamous cell carcinoma, the most common histologic subtype (8). In the United States, routine HPV vaccination has been recommended for females since 2006 and males since 2011 (9). The increase in HPV vaccination coverage among adolescents (10) and young adults (11) may prevent new cases of HPV-associated squamous cell carcinomas among vaccine-eligible persons, as observed for cervical cancer (12). Also, screening and removing high-grade squamous intraepithelial lesions could reduce the incidence of anal cancer among persons with HIV (PWH) (13).

As geography can influence cancer prevention and screening opportunities, we assessed if the incidence of HPV-associated anal squamous cell carcinoma differed between people living in metropolitan and nonmetropolitan areas. Previous studies have reported a higher incidence of HPV-associated cancers in rural populations (14,15). The rate of HPV-associated cancers has also increased in rural areas, reflecting rural–urban differences in cancer incidence and trends.

In addition, cancer rates vary by socioeconomic status (SES), with a strong association between lower SES and higher incidence (16-18). For instance, women with lower individual-level and census-based area-level SES measures had higher cervical cancer incidence than their more affluent counterparts (19). For HPV-associated anal squamous cell carcinomas, whether incidence differs by county-level economic status needs to be understood. To better understand these economic, sociodemographic, and geographical variations in incidence, we calculated and examined incidence rates, rate ratios, and trends over time for HPV-associated anal squamous cell carcinomas in the United States.

Methods

Data source

We analyzed population-based incidence data from the US Cancer Statistics. The US Cancer Statistics includes cancer registry data from the Centers for Disease Control and Prevention’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (20). Cancer registry data were collected using uniform data items and codes and met the US Cancer Statistics publication criteria (21), covering 98% of the US population from 2001 to 2019.

Case definition

We defined new cases of invasive HPV-associated anal squamous cell carcinoma according to the International Classification of Diseases for Oncology, Third Edition, site (C21.0-21.8, 20.9) and histology (8050-8084, 8120-8131) codes (22). HPV-associated anal squamous cell carcinoma also included rectal squamous cell carcinoma as they are biologically similar and might be misclassified (23); however, we also performed sensitivity analyses excluding rectal squamous cell carcinoma (C20.9). We restricted our analyses to microscopically confirmed cases (99.5% of cases).

Study variables

We examined incidence rates and trends by sex, age, race and ethnicity, US census regions, rural-urban county classification, and county-level economic status. We grouped race and ethnicity into 5 mutually exclusive groups: non-Hispanic American Indian or Alaska Native, non-Hispanic Asian or Pacific Islander, Hispanic, non-Hispanic Black, and non-Hispanic White. We categorized geographic area by 4 US census regions: Northeast, Midwest, South, and West. Based on population size and proximity to metro areas, we used the rural–urban continuum code designations to classify counties into 3 categories: metropolitan counties (rural–urban continuum code 1-3), nonmetropolitan counties adjacent to a metro area (rural–urban continuum code 4, 6, 8), and nonmetropolitan counties not adjacent to a metro area (rural–urban continuum code 5, 7, 9). We used an index-based county economic classification based on 3 economic indicators, including a 3-year average unemployment rate, per capita market income, and poverty rate (24). Each county was ranked on its composite index value in the bottom 25% (distressed and at-risk counties), 25%-75% (transitional counties), and top 25% (competitive and attainment counties) economically. Data on county-level economic status was assessed from 2007 to 2019 only.

Statistical analyses

We calculated incidence rates expressed per 100 000 persons and age standardized the rates to the 2000 US standard population by the direct method (25). The corresponding 95% confidence intervals (CIs) were calculated as modified gamma intervals (26). We estimated rate ratios and 95% confidence intervals to assess relative differences in incidence rates by sex, race and ethnicity, census regions, rural-urban county classification, and county-level economic status.

We assessed trends in incidence rates using joinpoint regression, which involves fitting a series of joined straight lines on a logarithmic scale to the trends in the annual age-standardized rates (27). We quantified the change in rates through annual percent change and used the permutation test for model selection and the parametric method for 95% confidence intervals. For cases with fewer observations, as seen in younger age groups, we also used the Bayesian information criterion for model selection and the empirical quantile method for 95% confidence intervals as part of sensitivity analyses. If annual percent change differed from zero at an alpha of 0.05, we considered the rates to increase or decrease; otherwise, we reported the rates as stable. We calculated incidence rates using the Surveillance, Epidemiology, and End Results SEER*Stat software (version 8.4.0) and trends using the Joinpoint Regression Program (version 4.9.1.0).

Results

Incidence rates

From 2001 to 2019, a total of 72 421 new cases of HPV-associated anal squamous cell carcinoma were diagnosed among women (2.8 per 100 000) and 37 147 among men (1.7 per 100 000) (Table 1). Age-specific incidence was highest among women aged 60-69 years (7.1 per 100 000), followed by women aged 70 years and older (6.5 per 100 000). By race and ethnicity, age-standardized incidence rates among women were highest in non-Hispanic White (3.2 per 100 000) and non-Hispanic Black and Hispanic (2.2 per 100 000) women; among men, rates were highest in non-Hispanic Black men (2.3 per 100 000).

HPV-associated anal squamous cell carcinoma incidence rates were highest in the South census region for women (3.0 per 100 000) and in the South and Northeast census regions for men (1.8 per 100 000). By rural-urban county classification, incidence rates were higher among women from nonmetropolitan counties adjacent to a metro area than women from metropolitan counties (rate ratio = 1.1, 95% CI = 1.1 to 1.1). Conversely, incidence rates were lower among men from nonmetropolitan counties not adjacent to a metro area (rate ratio = 0.8, 95% CI = 0.7 to 0.8) and nonmetropolitan counties adjacent to a metro area (rate ratio = 0.9, 95% CI = 0.8 to 0.9) when compared with men from metropolitan counties.

Incidence rates were higher among women from counties ranked in the bottom 25% (rate ratio = 1.1, 95% CI = 1.1 to 1.1) and 25%-75% (rate ratio = 1.1, 95% CI = 1.1 to 1.1) economically when compared with counties ranked in the top 25% in the nation economically. Similarly, incidence rates were higher among men from counties ranked in the 25%-75% (rate ratio = 1.2, 95% CI = 1.1 to 1.2) and bottom 25% (rate ratio = 1.1, 95% CI = 1.1 to 1.2) economically when compared with the top 25%. Of all HPV-associated cancers from 2001 to 2019, 13.7% of new cases among women and 11.9% among men were rectal squamous cell carcinoma. Age-standardized incidence rates and trends for HPV-associated anal squamous cell carcinoma, excluding rectal squamous cell carcinoma cases, are presented in Supplementary Tables 1 and 2 (available online), respectively.

Incidence rate trends

The overall incidence rate for HPV-associated anal squamous cell carcinoma was stable among men during 2009-2019 but increased among women by 2.1% annually during the same period (Table 2). Among adults aged 18-39 years, rates were stable among women during 2001-2019 and men during 2011-2019 (Figure 1). The incidence rate among adults aged 40-44 years decreased by 1.2% in women annually during 2001-2019 and by 6.3% in men annually during 2007-2019. Rates also decreased annually among women aged 45-49 years during 2007-2019 and men aged 45-49 years during 2010-2019; however, incidence rates increased in adults aged 50 years and older. These incidence rate trends for age groups followed the same pattern when we excluded rectal squamous cell carcinoma cases from the analyses (Supplementary Figure 1, available online).

For all ages combined, incidence rates increased in persons from all racial and ethnic groups, with some exceptions. Rates did not increase among non-Hispanic White men during 2009-2019 or non-Hispanic Asian or Pacific Islander men and women during 2001-2019. Incidence rates increased in the Northeast, Midwest, and South census regions for both sexes but remained stable in the West region among men during 2001-2019 and women during 2010-2019.

Incidence rates increased for metropolitan counties, nonmetropolitan counties adjacent to a metro area, and nonmetropolitan counties not adjacent to a metro area, except for men in metropolitan counties from 2009 to 2019. Rates also increased in counties of all economic status designations from 2007 to 2019, except for men residing in counties ranked in the top 25% economically.

Discussion

Like other HPV-associated cancers (15,28), HPV-associated anal squamous cell carcinoma is a cancer of health inequity with higher incidence rates observed among persons living in the South region and in economically deprived and transitional counties. Incidence rates were also higher among non-Hispanic Black men compared with other race and ethnicity groups, but not for non-Hispanic Black women. In the last decade, rates declined among men aged 40-44 years and stabilized among men aged younger than 40 years. From 2001, these trends were mirrored among women in the same age groups.

The stabilization of incidence among vaccine-eligible adults aged younger than 40 years is encouraging and is consistent with the stable incidence trends of anal precancers reported after HPV vaccine introduction (29). Similar to vaginal and vulvar precancers, anal precancers are detected opportunistically in the absence of a screening program, making it difficult to quantify the true vaccine-associated reduction in disease. A previous study reported that the decline in the incidence of anal squamous cell carcinomas among adults aged 20-44 years was likely because of the HPV vaccination (30). However, our analysis of disaggregated age groups shows that the decrease in this age group is largely driven by the decline in incidence among adults aged 40-44 years who were not eligible for vaccination and may not have accounted for the latency period of the disease. As HPV vaccination coverage increases and HPV prevalence decreases in the United States, the incidence of HPV-associated anal squamous cell carcinoma is expected to decline among vaccinated persons. The reasons for the recent decline in incidence among adults aged 40-44 and 45-49 years and stabilization among men overall warrant further investigation. However, these findings correspond to the declining trend in anal cancer incidence reported among men with HIV (31). Approximately one-third of new anal squamous cell carcinoma cases in men were among persons with HIV, and 56% of cases among men younger than 49 years occurred among persons with HIV (31).

This report highlights regional differences in the incidence of HPV-associated anal squamous cell carcinoma, which may partially stem from the state variation in risk factors, such as HIV and smoking prevalence (32). For instance, the high incidence of anal squamous cell carcinoma in the South mirrors the high proportion of HIV infections (33), vaccine-type HPV (34), and individuals who currently smoke (35) in this region. Higher incidence rates were observed in economically deprived and transitional counties, revealing disparities that could reflect inequities in accessing and utilizing timely prevention, screening, and treatment opportunities in these counties. HPV-associated cancers, including anal cancer, are associated with high area-level poverty measures (36). The prevalence of HIV (37) and smoking (38,39) are also higher in areas of lower SES. Furthermore, a recent study reported a rapid increase in anal cancer incidence among men living in the lowest-income counties and a slower increase in the highest-income counties (40). Similarly, anal cancer incidence increased markedly in counties with high smoking prevalence compared with low smoking prevalence (40).

The findings in this report are subject to at least 3 limitations. First, cancer registries do not routinely collect or report information on HPV DNA status in cancer tissue. However, HPV DNA was detected in more than 90% of anal squamous cell carcinoma cases by genotyping studies in the United States (8). Second, small case counts in some groups, such as younger age groups, could lead to unstable trends. However, the results did not vary when using data-dependent methods for model selection. Third, incidence rates and trends among high-risk groups (41), such as persons with HIV or men who have sex with men (MSM), and by important anal squamous cell carcinoma risk factors, such as smoking status, could not be assessed as these data are not routinely collected by cancer registries.

Recent results from the Anal Cancer–HSIL Outcomes Research (ANCHOR) trial showed that treating anal precursor lesions in persons with HIV reduces the progression to anal cancer (13). The trial results also have implications for screening. At present, no national recommendations exist for routine screening for anal cancer in the United States (42). According to the Sexually Transmitted Infections Treatment Guidelines (2021) (43), data are insufficient to recommend routine anal cancer screening with anal cytology in persons with HIV, MSM without HIV infection, and the general population (43,44). These guidelines also state that an annual digital anorectal examination might be useful to detect masses on palpation in persons with HIV and in MSM without HIV with a history of receptive anal intercourse (43). In 2019, the International Anal Neoplasia Society developed guidelines for performing digital anorectal examination, an extension of digital rectal examination, in certain high-risk populations (45). The New York State Department of Health AIDS Institute has recommended anal screening for specific subpopulations of PWH since 2007, and in 2022, expanded the recommendation to include anal cytology screening for adults aged 35 years and older who have HIV and are MSM, cisgender women, transgender women, or transgender men (46). The committee also recommends referral to high-resolution anoscopy exam when indicated (46). Despite differences in clinical practice patterns regarding anal cytology screening, programs should only initiate screening when referrals to high-resolution anoscopy and biopsy are available (43). Efforts are ongoing to review the evidence for anal precursors and cancer screening among high-risk populations, including by the US Preventive Services Task Force (47), International Anal Neoplasia Society, and the panel on Opportunistic Infections in Adults and Adolescents with HIV (48).

Anal cancer is a highly stigmatized disease of inequity. Improvement of HPV vaccination coverage among eligible groups and treatment of precancerous lesions among high-risk populations can reduce cancer incidence, and these prevention efforts could be advanced by prioritizing and integrating measures that address health equity. Failure to increase vaccine and treatment equity may widen existing disparities.

Data availability

We analyzed de-identified cancer incidence data from USCS. Investigators can access USCS public use databases after completing data-use agreements (49).

Author contributions

Sameer Vali Gopalani, PhD, MPH (Conceptualization; Formal analysis; Methodology; Software; Writing—original draft), Virginia Senkomago, PhD, MPH (Methodology; Software; Supervision; Writing—review & editing), Sun Hee Rim, PhD, MPH (Methodology; Supervision; Writing—review & editing), and Mona Saraiya, MD, MPH (Conceptualization; Methodology; Supervision; Writing—review & editing).

Funding

Not applicable.

Conflicts of interest

The authors have no potential conflicts of interest to disclose.

Acknowledgements

This project was supported in part by an appointment (SVG) to the Research Participation Program at the Centers for Disease Control and Prevention administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the Centers for Disease Control and Prevention.

The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

The authors are grateful for the efforts of state and regional cancer registry coordinators.

Results in this manuscript have been presented in part as an oral presentation at the International Anal Neoplasia Society Scientific Meeting 2022.

References