What cancers explain the growing rural‐urban gap in human papillomavirus‐associated cancer incidence?

Abstract

Purpose

Human papillomavirus (HPV) can cause cancers of the genital system, anus/rectum, and oropharynx. Prior research showed that HPV‐associated cancer incidence was rising faster in nonmetro than in metro populations. Our study identified which cancers contributed to the widening disparity.

Methods

Representing ∼93% of all cancers in the United States, we analyzed data from the North American Association of Central Cancer Registries (2000‐2019). Restricting the analysis to HPV‐associated cancers, we compared 5‐year average age‐adjusted incidence rates (per 100,000 population) for nonmetropolitan (Rural‐Urban Continuum Codes 4‐9) and metropolitan populations, by sex and cancer site. To quantify the rural‐urban gap, we calculated rate ratios and absolute differences of incidence trends.

Results

Although incidence was similar in 2000‐2004 (nonmetropolitan = 9.9; metropolitan = 9.9), incidence in 2015‐2019 was significantly higher in nonmetropolitan (12.3) than metropolitan (11.1) populations. The gap was widest for cervical cancers (females) in 2015‐2019 (1.0 case per 100,000) but grew the most since 2000‐2004 in oropharyngeal cancers among males (+1.1 cases per 100,000). The nonmetropolitan rate ratios for females (RR = 1.15, 95% C.I. = 1.13, 1.17) and males (RR = 1.07, 95% C.I. = 1.05, 1.09) in 2015‐2019 were higher than the respective RRs for all other years. Since 2000, the nonmetropolitan disparity has significantly grown for anal and cervical cancers in females, and oropharyngeal cancers in both sexes.

Discussion

Although preventable, nonmetropolitan Americans have shouldered a growing burden of HPV‐associated cancers. To address these cervical, anal, and oropharyngeal cancer disparities, it is imperative that HPV vaccination programs are effectively implemented at scale.

INTRODUCTION

In the United States, human papillomavirus (HPV) is extremely prevalent and is the most common sexually transmitted infection. ¹ Fourteen million new cases of HPV are reported each year, with an estimated lifetime prevalence exceeding 80% of all sexually active people. ¹ , ² Some subtypes of HPV can cancers of the genital system in females (cervical, vagina, vulvar) and males (penile), as well as some types of oropharyngeal, anal, and rectum cancers in both sexes. ³ HPV, and, therefore, at least 90% of these HPV‐associated (HPVa) cancers, can be prevented with on‐time HPV vaccination. ⁴ Still, contrary to the trends of cancer incidence overall in the United States, the incidence of HPVa cancers have been rising. ⁵ , ⁶ A growing body of evidence shows that the burden of HPVa cancer is rising faster in rural compared to urban populations. ⁷ , ⁸ , ⁹ , ¹⁰

Before we can explain and address the causes and respond to the consequences of, the widening rural‐urban disparity of HPVa cancer incidence, we must first understand which cancers contribute to the widening gap. Prior work shows the disparate and growing burden of HPVa cancers for rural Americans over the past 20 years. ⁹ Other work has highlighted the dynamic incidence trends within these heterogenous groups of cancers, specifically that as HPVa cervical cancer incidence rates are declining in females, oropharyngeal incidence rates are rising across the population. ⁷ , ⁸ , ¹¹ Yet, no research has systematically analyzed the differential trends in HPVa cancer incidence to quantify how the rural‐urban gap is changing over time and pinpoint the specific cancers driving this growing disparity.

METHODS

Data

We analyzed data from the North American Association of Central Cancer Registries (NAACCR) public use dataset. ¹² NAACCR data comprises over 93% of all cancers diagnosed within the United States. ¹³ Using SEER*Stat software, we extracted age‐adjusted incidence rates of HPVa cancers diagnosed between 2000 and 2019. We excluded the year 2020 to avoid issues with the onset of the COVID‐19 pandemic. ¹⁴ , ¹⁵ Using the 2013 Rural‐Urban Classification Code (RUCC) variable within NAACCR, all analyses were stratified by metropolitan (RUCC 1‐3) and nonmetropolitan (RUCC 4‐9).

Inclusion criteria

We restricted our analysis to cancers attributable to HPV, based on the guidance from the Centers for Disease Control and Prevention. ³ , ¹⁶ , ¹⁷ For both males and females, this restriction included microscopically confirmed oropharyngeal squamous cell carcinoma (ICD‐O‐3 codes: 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, 14.8; Histology: 8050–8086, 8120–8131), anal and rectal (ICD‐O‐3 codes: C21.0–21.8, 20.9; Histology: 8050–8084, 8120–8131). For females, we also included microscopically confirmed vulvar and vaginal squamous cell carcinoma (ICD‐O‐3 codes: C51.0–51.9, C52.9; Histology: 8050–8084, 8120–8131, 8050–8084, 8120–8131) and cervical carcinoma (ICD‐O‐3 codes: C53.0‐53.9; Histology: 8010–8671, 8940–8941). For males, we included microscopically confirmed penile squamous cell carcinoma (ICD‐O‐3 codes: C60.0‐60.9; Histology: 8050–8084, 8120–8131). See Supplementary Exhibits A & B for the complete SEER*Stat case restriction criteria and SEER*Stat NAACCR Incidence listing files.

Statistical analysis

First, we calculated age‐adjusted incidence rates (per 100,000 population) of HPVa cancer for metropolitan and nonmetropolitan populations, overall, by sex, and by cancer site, over 5‐year increments (2000‐2004, 2005‐2009, 2010‐2014, 2015‐2019). To quantify how the rural‐urban gap is changing in absolute terms, we compare the change in incidence from 2000‐2004 to 2015‐2019 in the metro population with the respective change in the nonmetropolitan population. Within each 5‐year rate, we then calculate a nonmetropolitan to metropolitan rate ratio. For statistical significance, we calculate a 95% confidence interval based on the Tiwari method. ¹⁸ To determine if the rural‐urban disparity is significantly changing over time, we compare the confidence intervals of the rate ratios across years.

RESULTS

Between 2000 and 2019, 690,705 people were diagnosed with HPVa cancer in the United States (Table S1). Despite comprising only 16% of NAACCR's sample, nonmetropolitan populations accounted for 18% of all HPVa cancer diagnoses. Females also had a disproportionally higher incidence of HPVa cancers, overall, comprising just 51% of cases in the NAACCR data but 57% of HPVa cancer diagnoses. Females represented 50% of the nonmetropolitan population and 56% of all nonmetropolitan HPVa cancer cases.

Table 1 reports the age‐adjusted incidence rates over 5‐year periods from 2000‐2004 to 2015‐2019. Overall, the incidence of HPVa cancers were similar in 2000‐2004 for nonmetropolitan and metropolitan (9.9 cases per 100,000 for both). However, in all subsequent 5‐year periods, the nonmetropolitan rate exceeded the metropolitan rate, culminating with the largest gap in 2015‐2019 (nonmetropolitan = 12.3 cases per 100,000; metropolitan = 11.1). Since 2000‐2004, nonmetropolitan incidence grew by 1.2 cases per 100,000 more than the metropolitan growth. In 2005‐2009, 2010‐2014, and 2015‐2019, the nonmetropolitan rate ratio was significantly different (Table 1). The rate ratio in 2015‐2019 was 1.11 (95% C.I. = 1.10, 1.12), a ratio which was significantly higher than all other rate ratios from prior years.

TABLE 1.

HPV‐associated cancer incidence rates and rate ratios by year, sex, and metropolitan status.

	5‐Year incidence rate
	2000‐2004	2005‐2009	2010‐2014	2015‐2019
Overall
Nonmetropolitan	9.9	10.5	11.2	12.3
Metropolitan	9.9	10.2	10.5	11.1
RR	1.01	1.03 #	1.07 #	1.11 #
	[0.99, 1.02]	[1.02, 1.04]	[1.06, 1.08]	[1.10, 1.12]
Female
Nonmetropolitan	12.7	12.6	12.7	13.5
Metropolitan	12.0	11.7	11.5	11.7
RR	1.06 #	1.08 #	1.11 #	1.15 #
	[1.04, 1.08]	[1.06, 1.09]	[1.09, 1.13]	[1.13, 1.17]
Male
Nonmetropolitan	7.1	8.5	9.9	11.3
Metropolitan	7.6	8.7	9.6	10.6
RR	0.93 #	0.98 #	1.03 #	1.07 #
	[0.91, 0.95]	[0.96, 0.99]	[1.01, 1.05]	[1.05, 1.09]

Note: All rates are adjusted for age, with 95% confidence intervals reported in brackets and reported per 100,000 population. Rate ratio (RR) confidence interval calculated by Tiwari method. Metro status determined by Rural Urban Continuum Code (RUCC). Metropolitan = RUCC 1‐3, nonmetropolitan = RUCC 4‐9.

^# Rural‐Urban difference is statistically significant (P < .05).

Females

For all 5‐year periods in this study, nonmetropolitan incidence of HPVa cancers in females exceeded the metropolitan incidence (Table 1 and Figure 1). The 2015‐2019 incidence rate in nonmetropolitan females was 13.5 cases per 100,000, which was significantly higher than the corresponding rate in metro females (11.7 cases per 100,0000). Since 2000‐2004, the gap between nonmetropolitan and metro HPVa cancer grew by 0.9 cases per 100,000. Unlike the decline (−0.1 cases/100k) in HPVa cancers for metropolitan females since 2000‐2004, incidence increased by 0.8 cases/100k in nonmetropolitan females. For all HPVa cancer sites combined, the nonmetropolitan rate ratio has increased significantly from 2000‐2004 (RR = 1.06, C.I. = 1.04, 1.08) to 2015‐2019 (RR = 1.15, C.I. = 1.13, 1.17).

FIGURE 1.

Trends in HPVa cancers, by sex, site, and metropolitan status.

Figure 1 visualizes the age‐adjusted incidence rate of HPVa cancer by site and status for males and females. Rates are grouped by 5‐year increments. Metro status determined by Rural‐Urban Continuum Codes. OPC = oropharynx cancer. For males, Site = “Other” includes anal, rectal, and penile HPVa cancer. For females, Site = “Other” includes anal, rectal, and vulva HPVa cancer. Rates are reported per 100,000 population.

Disaggregating female rates by site, Figure 2a shows that the incidence of HPVa cancer is highest for cervical cancers. Figure 2a also shows that the gap between the incidence of HPVa cancers in nonmetropolitan females and metro females is the widest for cervical cancer. Although, the gap grew for both anal and oropharyngeal cancers. In 2000‐2004, the incidence of HPVa anal cancer was similar in nonmetropolitan (1.4) and metropolitan females (1.4; Table S2). However, in 2015‐2019, the nonmetropolitan rate grew faster to 2.4 cases per 100,000 compared to the 2.1 cases per 100,000 in metro females, resulting in a rate ratio of 1.17 (C.I. 1.13, 1.21). Similarly, in 2000‐2004, the incidence of HPVa oropharyngeal cancer was similar in nonmetropolitan (1.5) and metropolitan females (1.5; Table S2). However, in 2015‐2019, the nonmetropolitan rate grew faster to 1.9 cases per 100,000 compared to the 1.7 cases per 100,000 in metropolitan females, resulting in a rate ratio of 1.16 (C.I. 1.12, 1.20). In all 3 cancer sites among females (cervical, anal, oropharyngeal), the nonmetropolitan rate ratio was significantly higher in 2015‐2019 than in all prior years (Figure 2a).

FIGURE 2.

Nonmetropolitan rate ratios by HPVa cancer site and sex.

Figure 2 visualizes the nonmetropolitan incidence rate ratio (compared to metropolitan) of HPVa cancer by site for males and females. Rate ratios are grouped by 5‐year increments. Metro status determined by Rural‐Urban Continuum Codes. OPC = oropharynx cancer. Error bars represent the 95% confidence interval of the ratio, calculated by the Tiwari method. The dotted line at 1 indicates similar rates between nonmetropolitan and metropolitan groups.

Although the incidence of HPVa vaginal and rectal cancer is higher in nonmetropolitan females (Figure 2b), compared to metropolitan females, the nonmetropolitan rate ratio has not significantly differed by 5‐year period since 2000‐2004.

Males

Contrary to the historical trends in females, between 2000 and 2009, the 5‐year incidence rates of HPVa cancer in males were higher among metropolitan populations than nonmetropolitan (Table 1 and Figure 1). Beginning in the 2010‐2014 period, the incidence of HPVa cancer was higher in nonmetropolitan males than in metro males. This reversal widened the nonmetro incidence gap by 1.2 cases per 100,000. Again, contrary to the results of females, the incidence of HPVa cancer has increased in both nonmetropolitan and metro male populations. In 2000‐2004, incidence was 7.1 cases per 100,000 in nonmetropolitan males and 7.6 cases per 100,000 in metropolitan males. In 2015‐2019, the incidence was 11.3 cases per 100,000 in nonmetropolitan males and 10.6 cases per 100,000 in metropolitan males. In 2015‐2019, the nonmetropolitan rate ratio (RR = 1.07, 95% C.I. = 1.05, 1.09) was significantly higher than the rate ratio of all prior years.

Disaggregating male rates by site, Figure 2b shows that the incidence of HPVa cancer is highest for oropharyngeal cancers. Figure 2b also shows that the gap between the incidence of HPVa cancers in nonmetropolitan males and metro males is the widest for oropharyngeal cancer. In 2000‐2004, the incidence of HPVa oropharyngeal cancer was lower in nonmetropolitan (5.9) than in metropolitan males (6.2; Table S2). However, in 2015‐2019, the nonmetropolitan rate grew faster to 9.6 cases per 100,000 compared to the 8.8 cases per 100k in metropolitan males. This reversal widened the nonmetropolitan HPVa oropharyngeal cancer incidence gap by 1.1 cases per 100,000, resulting in a rate ratio of 1.09 (C.I. 1.07, 1.11). For males, only among oropharyngeal cancer did the nonmetropolitan rate ratio significantly increase in each of the 5‐year periods from 2000‐2004 to 2015‐2019 (Figure 2b).

Male incidence of HPVa anal cancer is higher in metropolitan, compared to nonmetropolitan and there is no difference in the incidence of HPVa rectal cancers (Table S2). Although the incidence of HPVa penile cancer is higher in nonmetro, compared to metro males, the nonmetropolitan rate ratio has remained steady since 2000‐2004.

DISCUSSION

We examined the rural‐urban differences in HPVa cancers and found that rural females continue to have higher rates of cervical cancer than their urban counterparts. Additionally, both rural males and females have higher rates of oropharyngeal cancers compared to those in urban areas. Since 2006, millions of children and adolescents have been recommended to receive and completed the HPV vaccination schedule. ¹⁹ In 2026, 20 years after the vaccine was produced, there will exist a cohort of people, between the ages of 10‐35, who have effectively eliminated their risk of HPVa cancer. ²⁰ In the coming decades, policymakers and public health professionals will observe the fruits of their labor: reversal of rising HPVa cancer incidence and the possibility of elimination of cervical cancer as a public health problem. ²¹ , ²²

Still, HPV vaccination has been uneven, creating gaps and opportunities to advance health equity. ²³ , ²⁴ Among those gaps has been the limited success of wide‐scale adherence to the HPV vaccination schedule in rural communities. ²⁵ , ²⁶ , ²⁷ , ²⁸ These gaps, however, present an opportunity for rural public health and cancer control systems to make a strong impact reducing the burden of cancer in future generations. Today, children and adolescents are recommended to initiate the HPV vaccination schedule at 9 years old and complete it on time by age 13. ²⁹ Although slower than urban vaccination rate growth, rural HPV vaccination rates have improved over the last decade. To sustain the progress, evidence suggests leveraging existing rural health system resources and targeted intervention approaches. ³⁰ , ³¹ , ³² , ³³ This is especially important for raising vaccination rates for rural males, who bear the greatest burden of HPVa oropharyngeal cancer—now the most common HPVa cancer. ³⁴ , ³⁵

The growing disparity in HPVa cancer incidence warrants greater attention from policymakers, but fortunately, there are many opportunities to implement best practices and evidence‐based policies. ³⁶ Many rural and urban communities have yet to meet the Healthy People 2030 target of 80% vaccination coverage for the HPV vaccine. ³⁷ In addition to promoting greater vaccination coverage, HPVa cancer prevention and control systems can also promote adherence to screening recommendations. ³⁸ , ³⁹ While adolescent vaccination may be the most effective strategy for preventing adult‐onset HPVa cancer, screening can also be an effective preventive approach for older females. ⁴⁰ Additionally, the July 2024 FDA approval of HPV self‐collection in health care settings may facilitate future approval of home self‐collection that may circumvent rural access to care disparities. ⁴¹ , ⁴² Multifaceted primary and secondary prevention efforts will be needed to combat the rising burden of HPVa in the United States. ⁴³

Our study discovers that the widening rural‐urban disparity stems from differential trends with the heterogenous group of all HPVa cancers. Among all HPVa cancers, 3 cancers specifically explain the widening rural‐urban gap: cervical and anal cancer in females and oropharyngeal cancer in both males and females. This influx of patients and survivors increases the risk of straining rural cancer control systems. It is imperative to implement a range of multilevel policies and educational efforts (ie, at federal, state, local, and clinical levels) to improve rural HPV vaccination implementation and adherence, though few interventions have been tested in rural settings. ²⁷ , ³⁶ Until policymakers effectively implement vaccination and screening programs at scale, these HPVa cancers will plague rural communities for decades.

Limitations

This study is not without its limitations. First, this is purely a descriptive study, using secondary data. Our goal was to identify which cancer sites were driving male and female HPVa cancer disparities between metropolitan and nonmetropolitan counties in the United States. We made no attempts to identify mechanisms explaining the growing rural‐urban divide. Further, we did not attempt to explore the intersection of rurality and other socioeconomic factors. We leave such work for future research. Finally, we used data during a 20‐year time period, and may be missing important context regarding trends leading up to 2000 and dynamic incidence of HPVa cancer beyond 2020.

CONCLUSIONS

Although almost entirely preventable, rural Americans shoulder a growing burden of HPVa cancers. In the early 2000s, the incidence of HPVa cancers in urban populations was higher or similar to the incidence in rural populations. Over the last 2 decades, the rural incidence overtook the urban rate and the gap has since widened. Among all HPVa cancers, 3 cancers specifically explain the widening rural‐urban gap: cervical and anal cancer in females and oropharyngeal cancer in both males and females. As the United States observes a declining incidence of HPVa cancers in certain age cohorts receiving the HPV vaccine, more work is needed to treat a growing number of HPVa cancer survivors in rural communities, and to identify and overcome gaps in vaccination coverage.

CONFLICT OF INTEREST STATEMENT

The authors report no conflict of interest.

ETHICS STATEMENT

Not human subjects research.

Supporting information

Supporting Information

Supporting Information

Semprini J, Zahnd W, Brandt HM. What cancers explain the growing rural‐urban gap in human papillomavirus‐associated cancer incidence? J Rural Health. 2025;41:e12915. 10.1111/jrh.12915