Human Papillomavirus–Attributable Cancers — United States, 2012–2016

Virginia Senkomago, PhD1; S. Jane Henley, MSPH1; Cheryll C. Thomas, MSPH1; Jacqueline M. Mix, PhD1; Lauri E. Markowitz, MD2; Mona Saraiya, MD1 (View author affiliations)

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Summary

What is already known about this topic?

Human papillomavirus (HPV) causes nearly all cervical cancers and some cancers of the vagina, vulva, penis, anus, and oropharynx. Cervical cancer screening and HPV vaccination can prevent many of these cancers.

What is added by this report?

An average of 34,800 cancers reported annually in the United States during 2012–2016 were attributable to HPV. Of these, 32,100 (92%) cancers were attributable to HPV types targeted by the 9-valent HPV vaccine, ranging by state from 40 to 3,270.

What are the implications for public health practice?

Ongoing surveillance for HPV-associated cancers can inform state-level and national-level HPV vaccination and cervical cancer screening efforts and monitor their long-term impact.

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Human papillomavirus (HPV) causes nearly all cervical cancers and some cancers of the vagina, vulva, penis, anus, and oropharynx (1).* Most HPV infections are asymptomatic and clear spontaneously within 1 to 2 years; however, persistent infection with oncogenic HPV types can lead to development of precancer or cancer (2). In the United States, the 9-valent HPV vaccine (9vHPV) is available to protect against oncogenic HPV types 16, 18, 31, 33, 45, 52, and 58 as well as nononcogenic types 6 and 11 that cause genital warts. CDC analyzed data from the U.S. Cancer Statistics (USCS) to assess the incidence of HPV-associated cancers and to estimate the annual number of cancers caused by HPV, overall and by state, during 2012–2016 (3,4). An average of 43,999 HPV-associated cancers were reported annually, and an estimated 34,800 (79%) of those cancers were attributable to HPV. Of these 34,800 cancers, an estimated 32,100 (92%) were attributable to the types targeted by 9vHPV, with 19,000 occurring among females and 13,100 among males. The most common were cervical (9,700) and oropharyngeal cancers (12,600). The number of cancers estimated to be attributable to the types targeted by 9vHPV ranged by state from 40 to 3,270 per year. HPV vaccination is an important strategy that could prevent these cancers, but during 2018, only half of adolescents were up to date on HPV vaccination (5). These surveillance data from population-based cancer registries can be used to inform the planning for, and monitor the long-term impact of, HPV vaccination and cancer screening efforts nationally and within states.

CDC analyzed cancer incidence data from USCS, which includes cancer registry data from CDC’s National Program of Cancer Registries and the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program. Data from the District of Columbia (DC) and all states met high-quality data criteria for 2012–2016, covering 100% of the U.S. population. Invasive cancer cases were classified by anatomic site using the International Classification of Diseases for Oncology, Third Edition (ICD-O–3)§ (Supplementary Table, https://stacks.cdc.gov/view/cdc/80649) and were histologically confirmed. Cancers are not tested for HPV in most cancer registries; therefore, HPV-associated cancers were defined as invasive cancers at anatomic sites with cell types in which HPV DNA frequently is found, including carcinomas of the cervix (i.e., squamous cell cancers [SCC], adenocarcinomas, and other carcinomas) and SCC of the vulva, vagina, penis, oropharynx, and anus (including rectal SCC) (4). Oropharyngeal SCC included squamous cell cancer types at the base of tongue, pharyngeal tonsils, anterior and posterior tonsillar pillars, glossotonsillar sulci, anterior surface of soft palate and uvula, and lateral and posterior pharyngeal walls. Anal SCC also included rectal SCCs because they are biologically similar and might be misclassified.

HPV-associated cancer incidence rates were calculated using reported cases as the numerator and modification of annual county population estimates as the denominator,** standardized to the 2000 U.S. standard population and expressed as cases per 100,000 persons. The USCS data, including the numbers and rates of HPV-associated cancers, are available to the public through the USCS Data Visualizations Tool.†† To estimate the number of HPV-attributable cancers (cancers that are probably caused by HPV), the average annual number of HPV-associated cancers was multiplied by the percentage of each cancer type found to be attributable to HPV in a large U.S. study using HPV genotyping (3). Estimates of HPV-attributable cancers were rounded to the nearest 100 for national data and to the nearest 10 for state-level data. Cancers were grouped as those attributable to the types targeted by 9vHPV, to other HPV types, and HPV-negative cancers (those that occur at anatomic sites in which HPV-associated cancers are often found but do not have detectable HPV DNA). The percentage of HPV-negative cancers was calculated as the difference between the total HPV-associated cancers and the HPV-attributable estimates.

During 2012–2016, an average of 43,999 HPV-associated cancers (12.2 per 100,000 persons) were reported annually, and an estimated 79% (34,800) of these cancers were attributable to HPV (Table 1). Of these cancers, an estimated 32,100 (92%) were attributable to the types targeted by 9vHPV. The largest number were oropharyngeal cancer (12,600), followed by cervical (9,700), anal (6,000), vulvar (2,500), penile (700), and vaginal cancers (600). Among cancers estimated to be attributable to the types targeted by 9vHPV, 19,000 (59%) occurred among females, and 13,100 (41%) occurred among males.

The annual number of cancers estimated to be attributable to the types targeted by 9vHPV ranged by state from 40 (Wyoming) to 3,270 (California) (Table 2). Oropharyngeal cancer was the most common cancer estimated to be attributable to types targeted by 9vHPV in most states, except in Texas, where cervical cancer was most common and in Alaska, DC, New Mexico, and New York, where estimates of oropharyngeal and cervical cancers attributable to the types targeted by 9vHPV were the same.

Discussion

Each year during 2012–2016, an estimated average of 34,800 HPV-attributable cancers were diagnosed in the United States, and 92% (32,100) were attributable to the HPV types targeted by 9vHPV. Previous annual estimates of cancers attributable to the types targeted by 9vHPV were 28,500 for 2008–2012 (4), 30,000 for 2010–2014,§§ and 31,200 for 2011–2015.¶¶ The higher estimates in more recent years are, in part, due to an aging and growing population and increases in oropharyngeal, anal, and vulvar cancers (6).

HPV vaccination is an important component of cancer prevention, yet only about half of adolescents are up to date on this vaccine (5). The Advisory Committee on Immunization Practices recommends routine HPV vaccination at age 11–12 years and catch-up HPV vaccination for all persons through age 26 years. Catch-up vaccination is not recommended for all adults aged >26 years because the benefit of HPV vaccination decreases in older age groups; however, vaccination based on shared clinical decision-making can be considered for some persons aged 27–45 years who are not adequately vaccinated (7). In 2018, HPV vaccination coverage varied by state, and no state met the Healthy People 2020 objective for HPV vaccination (receipt of 2 or 3 doses of HPV vaccine by 80% of adolescents aged 13–15 years).*** State efforts to meet the Healthy People 2020 objective for HPV vaccination could reduce geographic disparities in HPV-associated cancer incidence in the future.

Cervical cancer is the only HPV-associated cancer for which screening is routinely recommended. Recommendations state that women aged 21–65 years be screened regularly for cervical precancers and cancers. Women aged 21–29 years should be screened with the Papanicolaou (Pap) test every 3 years. Women aged 30–65 years can be screened with one of three strategies: the Pap test every 3 years, an HPV test every 5 years, or both a Pap and HPV test every 5 years. Regardless of screening strategy, all abnormal test results require follow-up of abnormal results and appropriate treatment (8). The Healthy People 2020 target for cervical cancer screening coverage is 93%; however, in 2015 only 81% of women aged 21–65 years reported receiving a Pap test within the past 3 years; coverage was lower among Asians, Hispanics, non–U.S. born, and uninsured women.†††

Progression from persistent HPV infection to precancers and eventually invasive cancer occurs over many years, so it might be too soon to see the effects of HPV vaccination on invasive cancers (2). However, several studies have demonstrated the population-level impact of HPV vaccination in the United States, including a reduction in the prevalence of vaccine-type HPV infection (9) and rates of high-grade cervical precancers in women aged <25 years (10). Cervical cancer rates declined 1.6% per year during 1999–2015, largely because of screening, although decreases among the youngest age group of women might be due in part to HPV vaccination (6).

The findings in this report are subject to at least one limitation. Although population-based cancer registries provide a reliable system for counting invasive cancers, they do not routinely collect or report information on HPV genotype status in cancer tissue; actual counts of HPV-associated cancers can be provided, but for HPV-attributable cancers, only estimates are available. An important strength of this study, however, is the use of high-quality, population-based surveillance data with 100% coverage of the U.S. population, allowing for specific histologic definitions to monitor HPV-associated cancer incidence nationally and in each state.

Among the 43,999 HPV-associated cancers that occur each year in the United States, an estimated 34,800 are attributable to HPV, including 32,100 attributable to HPV types targeted by 9vHPV. During 2018, only half of adolescents were up to date on HPV vaccination (5). Surveillance for HPV-associated cancers using population-based cancer registries with high-quality data and the assessment of HPV-attributable cancers can be used to monitor the long-term impact of HPV vaccination and current cervical cancer screening strategies in the United States. The examination of state-level data enables states to plan for and monitor the impact of vaccination and cervical cancer screening.

Corresponding author: Virginia Senkomago, vsenkomago@cdc.gov, 404-718-6369.


1Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, CDC; 2Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, CDC.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.


References

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TABLE 1. Average annual number and rate of human papillomavirus (HPV)–associated cancers and estimated percentage and annual number of cancers attributable to HPV, by HPV type, cancer type, and sex — United States,* 2012–2016Return to your place in the text
Cancer type Reported HPV-associated cancers Estimated no.§ (%) of cancers attributable to HPV types
Total no.** Rate†† 9vHPV-targeted Other HPV HPV-negative
Cervix 12,015 7.2 9,700 (81) 1,200 (10) 1,100 (9)
Vagina 862 0.4 600 (73) 0 (2) 300 (25)
Vulva 4,009 2.1 2,500 (63) 300 (6) 1,200 (31)
Penis 1,303 0.8 700 (57) 100 (6) 500 (37)
Anus 6,810 1.8 6,000 (88) 200 (3) 600 (9)
Female 4,539 2.3 4,100 (90) 100 (2) 300 (8)
Male 2,270 1.3 1,900 (83) 100 (6) 300 (11)
Oropharynx 19,000 4.9 12,600 (66) 900 (5) 5,500 (29)
Female 3,460 1.7 2,100 (60) 100 (3) 1,300 (37)
Male 15,540 8.5 10,500 (68) 800 (5) 4,200 (28)
Total 43,999 12.2 32,100 (73) 2,700 (6) 9,200 (21)
Female 24,886 13.7 19,000 (76) 1,700 (7) 4,200 (17)
Male 19,113 10.6 13,100 (69) 1,000 (5) 5,000 (26)

Abbreviations: 9vHPV = 9-valent HPV vaccine; ICD-O-3 = International Classification of Diseases for Oncology, Third Edition.
* Compiled from population-based cancer registries that participate in the CDC National Program of Cancer Registries, and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program and meet the criteria for high data quality for all years during 2012–2016, covering 100% of the U.S. population.
HPV-associated cancers were defined as invasive cancers at anatomic sites with cell types in which HPV DNA frequently is found. All cancers were histologically confirmed. Cervical cancers (ICD-O-3 site codes C53.0–C53.9) are limited to carcinomas (ICD-O-3 histology codes 8010–8671, 8940–8941). Vaginal (ICD-O-3 site code C52.9), vulvar (ICD-O-3 site codes C51.0–C51.9), penile (ICD-O-3 site codes C60.0–60.9), anal (ICD-O-3 site codes C20.9, C21.0–C21.9) and oropharyngeal (ICD-O-3 site codes C01.9, C02.4, C02.8, C05.1, C05.2, C09.0, C09.1, C09.8, C09.9, C10.0, C10.1, C10.2, C10.3, C10.4, C10.8, C10.9, C14.0, C14.2, and C14.8) cancer sites are limited to squamous cell carcinomas (ICD-O-3 histology codes 8050–8084, 8120–8131).
§ HPV-attributable cancers are cancers that are probably caused by HPV (https://academic.oup.com/jnci/article/107/6/djv086/872092external icon). Estimates for attributable fraction were based on studies that used population-based data from cancer tissue studies to estimate the percentage of those cancers probably caused by HPV. The estimated number of cancers attributable to HPV was calculated by multiplying the number of reported HPV-associated cancer cases by the percentage of each cancer type attributable to HPV. The total of HPV-attributable cancers is the sum of cancers attributable to types included in the 9vHPV and cancers attributable to other HPV types (e.g. 32,100 + 2,700 = 34,800). Estimated counts were rounded to the nearest 100 (counts <100 are not displayed) and might not sum to total because of rounding.
“9vHPV-targeted” types include oncogenic HPV types 16, 18, 31, 33, 45, 52, and 58. “Other HPV” includes other oncogenic HPV types. “HPV-negative” cancers are those that occur at anatomic sites in which HPV-associated cancers are often found, but HPV DNA was not detected.
** The total reported count is the annual count averaged over the 5-year period and might not sum to total because of rounding.
†† Rates are per 100,000 persons; age-adjusted to the 2000 U.S. standard population.

TABLE 2. Estimated annual number of human papillomavirus (HPV)–attributable cancers,* by cancer type, HPV type,§ and state — United States, 2012–2016Return to your place in the text
State Estimated no.**
All cancers Oropharynx (male and female) Cervix
9vHPV-targeted Other HPV HPV-negative 9vHPV-targeted Other HPV HPV-negative 9vHPV-targeted Other HPV HPV-negative
Alabama 540 40 160 220 10 100 170 20 20
Alaska 60 <10 20 20 <10 10 20 <10 <10
Arizona 530 40 150 220 10 100 160 20 20
Arkansas 360 30 100 140 <10 60 120 10 10
California 3,270 260 870 1,170 80 510 1,120 130 130
Colorado 460 40 130 190 10 80 130 20 20
Connecticut 370 30 110 150 <10 70 100 10 10
Delaware 110 <10 30 40 <10 20 30 <10 <10
District of Columbia 60 <10 10 20 <10 <10 20 <10 <10
Florida 2,690 210 780 1,170 80 520 730 90 90
Georgia 1,050 80 300 400 30 180 320 40 40
Hawaii 120 <10 30 50 <10 20 40 <10 <10
Idaho 150 10 40 60 <10 30 40 <10 <10
Illinois 1,310 100 380 500 30 220 400 50 50
Indiana 740 60 220 300 20 130 210 30 20
Iowa 330 30 100 120 <10 50 90 10 10
Kansas 280 20 80 110 <10 50 80 10 <10
Kentucky 590 50 180 230 10 100 170 20 20
Louisiana 520 40 150 200 10 90 160 20 20
Maine 170 10 60 70 <10 30 30 <10 <10
Maryland 550 40 160 220 10 90 160 20 20
Massachusetts 660 50 210 290 20 130 150 20 20
Michigan 1,000 80 300 410 30 180 260 30 30
Minnesota 470 40 150 200 10 90 120 10 10
Mississippi 350 30 100 130 <10 60 110 10 10
Missouri 710 60 200 290 20 130 200 20 20
Montana 100 <10 30 40 <10 20 30 <10 <10
Nebraska 170 10 50 60 <10 30 50 <10 <10
Nevada 270 20 70 100 <10 50 90 10 10
New Hampshire 140 10 40 70 <10 30 30 <10 <10
New Jersey 880 70 250 320 20 140 290 30 30
New Mexico 170 10 50 60 <10 30 60 <10 <10
New York 1,980 160 530 660 40 290 660 80 80
North Carolina 1,100 90 330 470 30 210 300 40 30
North Dakota 60 <10 20 30 <10 10 10 <10 <10
Ohio 1,260 100 370 500 30 220 360 40 40
Oklahoma 420 30 120 150 <10 70 130 20 20
Oregon 430 30 120 190 10 80 110 10 10
Pennsylvania 1,410 110 420 550 40 240 400 50 50
Rhode Island 110 <10 30 40 <10 20 30 <10 <10
South Carolina 550 40 170 240 20 100 150 20 20
South Dakota 80 <10 20 30 <10 10 20 <10 <10
Tennessee 780 60 220 310 20 130 230 30 30
Texas 2,310 200 620 830 50 360 890 110 100
Utah 160 10 40 60 <10 30 50 <10 <10
Vermont 60 <10 20 30 <10 10 10 <10 <10
Virginia 760 60 220 310 20 140 210 30 20
Washington 690 50 200 280 20 120 190 20 20
West Virginia 250 20 70 100 <10 40 70 <10 <10
Wisconsin 560 40 170 240 20 100 150 20 20
Wyoming 40 <10 10 20 <10 <10 10 <10 <10

Abbreviations: 9vHPV = 9-valent HPV vaccine; ICD-O-3 = International Classification of Diseases for Oncology, Third Edition.
* HPV-attributable cancers are cancers that are probably caused by HPV (https://academic.oup.com/jnci/article/107/6/djv086/872092external icon). Estimates for attributable fraction were based on studies that used population-based data from cancer tissue studies to estimate the percentage of those cancers probably caused by HPV.
HPV-associated cancers were defined as invasive cancers at anatomic sites with cell types in which HPV DNA frequently is found. All cancers were histologically confirmed. Cervical cancers (ICD-O-3 site codes C53.0–C53.9) are limited to carcinomas (ICD-O-3 histology codes 8010–8671, 8940–8941). Vaginal (ICD-O-3 site code C52.9), vulvar (ICD-O-3 site codes C51.0–C51.9), penile (ICD-O-3 site codes C60.0–60.9), anal (ICD-O-3 site codes C20.9, C21.0–C21.9), and oropharyngeal (ICD-O-3 site codes C01.9, C02.4, C02.8, C05.1, C05.2, C09.0, C09.1, C09.8, C09.9, C10.0, C10.1, C10.2, C10.3, C10.4, C10.8, C10.9, C14.0, C14.2, and C14.8) cancer sites are limited to squamous cell carcinomas (ICD-O-3 histology codes 8050–8084, 8120–8131).
§ “9vHPV-targeted” includes oncogenic HPV types 16, 18, 31, 33, 45, 52, and 58. “Other HPV” includes other oncogenic HPV types. “HPV-negative” cancers are those that occur at anatomic sites in which HPV-associated cancers are often found, but HPV DNA was not detected.
Compiled from population-based cancer registries that participate in the CDC National Program of Cancer Registries, and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program and meet the criteria for high data quality for all years 2012–2016, covering 100% of the U.S. population.
** The estimated number of HPV-attributable cancers was calculated by multiplying the number of HPV-associated cancer cases by the percentage of each cancer type attributable to HPV. The total of HPV attributable cancers was the sum of cancers attributable to types targeted by 9vHPV and other HPV types. HPV-negative counts were the difference of the total count and the HPV-attributable counts. Estimates were rounded to the nearest 10; counts <10 are not displayed.


Suggested citation for this article: Senkomago V, Henley SJ, Thomas CC, Mix JM, Markowitz LE, Saraiya M. Human Papillomavirus–Attributable Cancers — United States, 2012–2016. MMWR Morb Mortal Wkly Rep 2019;68:724–728. DOI: http://dx.doi.org/10.15585/mmwr.mm6833a3external icon.

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