Contemporary Patterns in HPV-Associated Cancer Incidence Among Young US Men

INTRODUCTION

Human papillomavirus (HPV)–associated oropharyngeal and anal cancer incidence has increased markedly among men over the last several decades in the United States (US).¹ Recent studies reported decreased cervical cancer incidence among young women, attributable to HPV vaccination.² However, contemporary patterns in cancer incidence among young men during the HPV vaccination era remain unclear. We evaluated trends in HPV-associated cancer incidence (all, oropharyngeal, and anal) among men aged 15–39 years and by year of birth.

METHODS

We analyzed the 2001–2018 US Cancer Statistics dataset from the Centers for Disease Control and Prevention’s National Program of Cancer Registries and the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. The dataset represents nearly 100% of the US population. The HPV-associated cancers were identified using CDC-recommended International Classification of Diseases for Oncology, Third Edition codes, and histology codes. SEER*Stat v8.4.0 was used to calculate incidence rates. Joinpoint Regression Program software v4.8.0.1 (Division of Cancer Control & Population Sciences) was used to estimate piecewise–log-linear trends and derive annual percentage changes (APCs). We used weighted Bayesian Information Criteria to determine the number of joinpoints. Finally, we conducted age-period-cohort models to simultaneously evaluate the effect of age, period, and birth cohort on cancer incidence utilizing the NCI’s Age-Period-Cohort web tool. Cohort effects are presented graphically as incidence rate ratios (IRRs) adjusted for age and calendar period effects.

RESULTS

Between 2001 and 2018, 2842 oropharyngeal, 1738 anal, and 670 penile (a total of 5250 HPV-associated) cancers were reported among men aged 15–39 years. Of those, 61% (3200) occurred among NH White men and 21% (1094) among NH Black men. Among NH White men, HPV-associated cancer incidence decreased by 1.9%/year (95%CI, −2.6 to −1.3%). Particularly, oropharyngeal cancer incidence started to decline 2.9%/year (95%CI, −4.6 to −1.2%) since 2008 after an initial 1.8%/year increase (95%CI, −1.0 to 4.6%). Anal cancer incidence decreased 4.1%/year (95%CI, −5.4 to −2.7%). Among young NH Black men, no significant change in the collective incidence of HPV-associated cancers occurred. Oropharyngeal cancer incidence declined 2.4%/year (95%CI, −4.5 to −0.3%). In contrast, a marked 3.8%/year (95%CI, 1.2 to 6.4%) increase in anal cancer incidence occurred during 2007–2018 (Fig. 1).

Figure 1.

Trends in annual incidence rates of HPV-associated all, oropharyngeal, and anal cancer among young (15–39 years old) NH White and NH Black men: National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program (2001–2018). HPV-associated all, oropharyngeal, and anal cancer incidence rates among NH White and NH Black young men aged 39 years old or younger. Malignant and microscopically confirmed anal, oropharyngeal, and penile cancer cases were identified using International Classification of Diseases for Oncology, Third Edition code (ICD-O-3) C21.0–21.8 and 20.9 for anal cancer; C01.9, 02.4, 02.8, 05.1–05.2, 09.0–09.1, 09.8–09.9, 10.0–10.4, 10.8–10.9, 14.0, 14.2, and 14.8 for oropharyngeal cancer; and C60.0–60.9 for penile. Histology codes 8050–8084 and 8120–8131 were used to confirm squamous cell histology that is generally HPV-attributable. *Statistically significant change. A two-sided t-test was used to test whether the annual percent change (APC) was statistically different from zero (p <.05). To determine the statistical significance of average APC (AAPC) (p <.05), a two-sided t-test was used for 0 joinpoints, and a two-sided z-test was used for 1 or more joinpoints.

Age-period-cohort modeling revealed a steep decrease in HPV-associated cancer risk among the 1970s and 1980s birth cohorts (compared to men born circa 1969). Notably, oropharyngeal cancer risk lowered 38% (IRR=0.62; 95%CI, 0.38 to 0.99) and anal cancer risk lowered 41% (IRR=0.59; 95%CI, 0.40 to 0.86) in the most recent birth cohorts. Among NH Black men, in the 1984 birth cohort, anal cancer risk RR was 1.46 (95%CI, 0.98 to 2.16) and oropharyngeal cancer risk RR was 0.54 (95%CI, 0.29 to 1.02) compared to the 1969 birth cohort (Fig. 2).

Figure 2.

Incidence rate ratios (IRRs) by birth cohort for overall HPV-associated cancers (referent cohort = 1969), oropharyngeal cancer (referent cohort = 1969) and anal cancer (referent cohort = 1969) among young NH White and NH Black men: National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program (2001–2018). Shaded bands indicate 95% confidence interval. IRRs for some specific birth cohorts are suppressed due to the small number of cancer cases (less than 16). Note that the choice of referent cohort does not affect result interpretation.

DISCUSSION

Our study reports a reduction in the HPV-associated cancer risk among contemporary birth cohorts (born after the 1970s) of NH White men, largely due to the recent reduction in oropharyngeal and anal cancer incidence. Among young NH Black men, while oropharyngeal cancer incidence steadily decreased, anal cancer incidence has risen in recent years. While the reason for the continued decline in oropharyngeal cancer incidence among NH Black men has been previously speculated,³ the reversal in incidence among young NH White men may be partly due to direct and herd immunity benefits from the HPV vaccination (despite suboptimal [only 21.5%] coverage among young adults). The decline in incidence may also be likely due to the decreasing prevalence of risky sexual behaviors in the US.⁴

The troubling rise in anal cancer incidence among young NH Black men may be HIV-attributable (HIV prevalence [per 100,000 persons] is nearly 10 times greater among NH Black men [1907] compared to NH White men [198]) given disproportionally elevated anal cancer risk among persons living with HIV.⁵ Consistent with this finding, a recent study showed nearly 73% anal cancer cases among young NH Black men were HIV-infected compared to 43% among NH White men.⁶ The limitation of this analysis is that due to the unavailability of information regarding risk factors (HIV, sexual behavior) and prevention measures (i.e., HPV vaccination), our explanation for changes in trends is speculative. Future studies that incorporate etiologic information are needed to understand overall trends and differences across racial/ethnic groups.

In summary, our study documents contemporary patterns in HPV-associated cancer incidence among young men and highlights growing racial disparities that could be potentially minimized by improving HPV vaccination coverage.

Abbreviations

HPV

Human papillomavirus

RR

Rate ratio

APC

Age-period-cohort

IRR

Incidence rate ratio

SEER

Surveillance, Epidemiology, and End Results

Funding

The research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers R01CA232888, U54CA096300, and 2U54CA096297-18, and the National Institute on Minority Health and Health Disparities under Award Number K01MD016440. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declarations

Conflict of Interest

Dr. Ortiz reported receiving consulting fees from Merck & Co, outside the submitted work. Dr. Sonawane reported receiving personal fees from Value Analytics Lab, outside the submitted work. The other authors have no relevant conflicts to disclose.