Update of HPV-Associated Female Genital Cancers in the United States,1999

Abstract

In 2008, CDC published a supplement to the journal Cancer describing incidence patterns of human papillomavirus (HPV)-associated cancers prior to availability of an HPV vaccine. This report updates the information on HPV-associated female genital cancer incidence with more recent data, adds information on trends, and includes American Indian/Alaska Native (AI/AN) populations. We used combined data from two federal cancer surveillance programs, CDC's National Program of Cancer Registries (NPCR) and NCI's Surveillance, Epidemiology, and End Results (SEER) Program, covering 92% of the U.S. population from 1999 to 2004, to examine recent trends and incidence of invasive cervical carcinoma and vaginal and vulvar squamous cell carcinoma (SCC). Incidence of in situ vaginal and vulvar SCC are also presented. The average annual age-adjusted rate of cervical cancer among women of all races/ethnicities was 8.5/100,000. Annual cervical cancer incidence rates were highest but declined more rapidly among Hispanic and black women compared with non-Hispanic and white women. The rate of vulvar cancer among all women was 1.7/100,000 and was higher among white women than other racial groups. Vulvar cancer rates rose among black women (+2.9% per year) and were relatively stable among all other racial and ethnic groups over the 6-year period. Vaginal cancer was rare (rate 0.5/100,000); the rate was higher among black women than other racial groups and higher among Hispanic women than among non-Hispanic women. A significant decline of vaginal cancer was observed only among black women (−6.2% per year). This article confirms previous findings on racial disparities in HPV-associated female genital cancers. Any post-HPV vaccine declines in these cancers should be interpreted in light of current declines. Enhancing current cancer surveillance systems, combined with special studies to collect data on in situ or precancerous lesions of these cancers, will provide important information in determining the potential impact of the HPV vaccine.

Introduction

Almost all cervical cancers and many vulvar and vaginal cancers are caused by the human papillomavirus (HPV).^1,2 HPV types 16 and 18 have been found in about 70%–80% of cervical cancers studied; a recent meta-analysis of U.S. studies estimated that HPV 16 can be found in about 50% of vulvar squamous cell carcinomas (SCCs) and 60% of vaginal SCCs.^3,4 A vaccine protecting against HPV types 16, 18, 6, and 11 was approved and recommended for use among 11–12-year-old girls in the United States in 2006 and has been shown to effectively prevent precancerous lesions of the cervix, vulva, and vagina associated with HPV types 16 and 18.⁵ In 2008, CDC led the development of a supplement to the journal Cancer describing the burden of HPV-associated cancers prior to the vaccine, using cancer registry data mostly from 1998–2003, covering 83% of the U.S. population.⁶ With more recent data covering 92% of the U.S. population, the current report updates information on the burden of female genital HPV-associated cancers published in the Cancer supplement, describes trends of these cancers by race and ethnicity, and adds information on American Indian/Alaska Native (AI/AN) populations.

Materials and Methods

The 1999–2004 data from two federal cancer surveillance programs, CDC's National Program of Cancer Registries (NPCR) and NCI's Surveillance, Epidemiology, and End Results (SEER) Program, were used in this study. The data from 45 registries (Alaska, Alabama, Arkansas, Arizona, California, Colorado, Connecticut, District of Columbia, Delaware, Florida, Georgia, Hawaii, Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Massachusetts, Maine, Michigan, Minnesota, Missouri, Montana, North Carolina, Nebraska, New Hampshire, New Jersey, New Mexico, Nevada, New York, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, South Carolina, Texas, Utah, Vermont, Washington, Wisconsin, West Virginia, and Wyoming) met the publication criteria for the United States Cancer Statistics (USCS) report and covered 92% of the U.S. population for those years.⁷ More information on the data sources in this article can be found in Watson et al.⁶

We examined invasive cervical carcinomas and invasive and in situ vulvar and vaginal SCCs, diagnosed during 1999–2004. In situ cervical cancers are not collected by NPCR and SEER. Cervical carcinomas and vulvar and vaginal SCCs are more likely than other cell types to be HPV associated; the case selection criteria in this report are the same as those of the Cancer supplement⁶ and are listed in Table 1. All analyses were limited to microscopically confirmed lesions.

Table 1.

Histology Categories and International Classification of Diseases (ICD-O-3) Site Codes Used to Define Cases Included in Analysis

Histology definitions	ICD-O-3 histology Codes	Sites and ICD-O-3 site codes
Squamous cell and transitional cell carcinomas	8050–8084, 8120–8131^a	Cervix (C53) Vulva (C51) Vagina (C52)
Adenocarcinomas	8140–8149, 8160–8162, 8190–8221, 8260–8337, 8350–8551, 8570–8576, 8940–8941	Cervix only (C53)
Adenosquamous and glassy cell	8560, 8015
Small cell/neuroendocrine	8013, 8041–8045, 8240–8246
Other specified carcinomas	8014, 8030–8040, 8046, 8090–8110, 8150–8157, 8170–8180, 8230–8239, 8247–8255, 8340–8347, 8561–8562, 8580–8671
Unspecified carcinomas	8010–8012, 8020–8022

Vulvar and vaginal intraepithelial neoplasias, code 8077/2, are not collected consistently from all registries. Thus, this code has been excluded from analyses examining in situ tumors.

We examined cancers by race, including white, black, Asian/Pacific Islander (API), and AI/AN; “All races” also includes other and unknown categories. AI/AN data were enhanced by linkage with the Indian Health Service (IHS) administrative records database.⁸ Hispanic ethnicity includes women from all race categories identified as being Hispanic in the medical record or by use of an algorithm to increase Hispanic identification.⁹ Whites were used as the referent group for race comparisons and rate ratios (RRs); non-Hispanics were used as the referent group for Hispanic ethnicity.

Age-adjusted incidence rates per 100,000 females were calculated by age, race, and ethnicity in SEER*Stat and standardized to the 2000 U.S. Standard Population; limits of confidence intervals (CIs) were 95% and were based on the Gamma method using the Tiwari modification.¹⁰ In describing rate comparisons, the term “higher” or “lower” was used when the RR differed significantly from 1.0 (p < 0.05) unless otherwise specified. Annual percent change (APC) was calculated using the weighted least squares method.¹¹ APC was not presented when based on <16 cases for any single year within 1999–2004.

Results

Invasive cancers

There were an average of 11,657 invasive cervical carcinomas, 2,522 invasive vulvar SCCs, and 670 invasive vaginal SCCs diagnosed per year during 1999–2004, with respective rates of 8.5, 1.7, and 0.5/100,000 women (Table 2). The rate of cervical cancer was highest among women aged 40–44. Rates of vulvar and vaginal cancer increased with advancing age and were highest among women ≥80 years.

Table 2.

Annual Counts, Age-Adjusted Incidence Rates and Median Age at Diagnosis of Invasive HPV-Associated Female Genital Cancers by Selected Variables, United States, 1999–2004^† ^‡

Median age at diagnosis	Cervix 48				Vulva 69				Vagina 69
Median age at diagnosis	Average Annual Incidence Count	Incidence Rate (95% C.I.)			Average Annual Incidence Count	Incidence Rate (95% C.I.)			Average Annual Incidence Count	Incidence Rate (95% C.I.)
All ages	11657	8.53	8.46	8.59	2,522	1.71	1.68	1.74	670	0.45	0.44	0.47
Age in years
0–14	^	^	^	^	^	0	0	0	^	0	0	0
15–19	14	0.15	0.12	0.19	^	0.01	0	0.02	^	0	0	0.01
20–24	133	1.48	1.38	1.59	3	0.04	0.02	0.06	^	0.01	0	0.02
25–29	558	6.40	6.18	6.62	12	0.14	0.11	0.18	^	0.03	0.01	0.04
30–34	1124	11.93	11.65	12.22	40	0.43	0.38	0.49	6	0.06	0.04	0.08
35–39	1436	14.20	13.91	14.51	99	0.98	0.90	1.06	17	0.17	0.14	0.2
40–44	1658	15.75	15.44	16.06	174	1.65	1.55	1.75	33	0.31	0.27	0.36
45–49	1425	14.60	14.29	14.91	201	2.06	1.94	2.18	40	0.40	0.35	0.46
50–59	2157	13.85	13.61	14.09	388	2.49	2.39	2.59	111	0.71	0.66	0.77
60–69	1464	14.23	13.93	14.53	380	3.70	3.55	3.86	129	1.26	1.17	1.35
70–79	1053	12.38	12.08	12.69	578	6.76	6.53	6.98	166	1.94	1.82	2.07
80+	636	10.76	10.42	11.10	647	10.86	10.52	11.20	166	2.79	2.62	2.97
Race
White	9151	8.08	8.01	8.14	2,273	1.78	1.75	1.81	546	0.42	0.41	0.44
Black	1764	11.88^*	11.65	12.11	187	1.30^*	1.23	1.38	99	0.73^*	0.67	0.79
AI/AN	78	6.5^*	5.9	7.14	8	0.81^*	0.58	1.08	3	0.34	0.2	0.54
API	448	7.97	7.67	8.29	19	0.41^*	0.33	0.49	14	0.29^*	0.23	0.36
Ethnicity^§
Non-Hispanic	9834	8.04	7.97	8.1	2400	1.76	1.73	1.79	614	0.45	0.43	0.46
Hispanic	1823	13.55^*	13.29	13.82	123	1.25^*	1.16	1.35	57	0.56^*	0.50	0.62

AI/AN = American Indian/Alaska Native; API = Asian/Pacific Islander.

*Denotes rate ratio statistically significant (p < 0.05); top row is referent group.

†

Rates are per 100,000 population and are age-adjusted to the 2000 U.S. standard population (19 age groups-Census P25-1130). Analysis limited to microscopically confirmed cervical carcinomas and vaginal and vulvar SCCs as described in Table 1.

‡

Data are from 45 population-based cancer registries that participate in the National Program of Cancer Registries (NPCR) and the Surveillance Epidemiology and End Results(SEER) Program and meet high-quality data criteria.^6,76,76,76 These registries cover approximately 92% of the U.S. population.

Hispanic origin is not mutually exclusive from race categories (white, black, Asian/Pacific Islander).

^ = count <16 for 1999-2004 total.

Race/ethnicity

Compared with white women, the rate of invasive cervical carcinoma was higher among black women (RR 1.5) and lower among AI/AN women (RR 0.8); the rate among API women was not statistically different from that for white women. Hispanic women had a higher rate of cervical carcinoma than non-Hispanic women (RR 1.7).

White women had a higher rate of invasive vulvar SCC than women of all other races (compared to white: black RR 0.7; AI/AN RR 0.5; API RR 0.2). Likewise, the rate of invasive vulvar cancer was higher for non-Hispanic women than for Hispanic women (RR 0.7). Compared with white women, invasive vaginal SCC rates were higher among black women (RR 1.7) and lower among API women (RR 0.7). The rate of invasive vaginal SCC among AI/AN women was not significantly different from that for white women. Hispanic women had a higher rate of vaginal cancer than non-Hispanic women (RR 1.2).

Annual percent change (APC)

The rate of invasive cervical carcinoma declined significantly over the 6-year period, from 9.3 in 1999 to 7.7 in 2004 (Fig. 1). Declines in invasive vulvar SCC (from 1.74 in 1999 to 1.71 in 2004) and invasive vaginal SCC (from 0.47 to 0.44) were not statistically significant.

FIG. 1.

*Denotes APC statistically different from zero (p < 0.05). ^†Rates are per 100,000 females and are age-adjusted to the 2000 U.S. standard population (19 age groups–Census P25-1130). Analysis limited to microscopically confirmed cervical carcinomas with ICD-O-3 histology codes 8010–8671, 8940–8941 and microscopically confirmed vulvar and vaginal SCCs with ICD-O-3 histology codes 8050–8084, 8120–8131. ^‡Data are from 45 population-based cancer registries that participate in the NPCR and the SEER Program and meet high-quality data criteria (U.S. Cancer Statistics Working Group, 2007 594 /id). These registries cover approximately 92% of the U.S. population.

Figure 2 displays APC during 1999–2004 by race/ethnicity. Cervical carcinoma declined significantly among all women (−4.1%) and for each race group separately: white (−4.0 %), black (−5.1%), AI/AN (−7.1%), and API (−4.8%); by ethnicity, non-Hispanic (−4.0%) and Hispanic (−5.0%) also declined. Trends in invasive vulvar SCC were not statistically significant for women of all races or for any racial/ethnic group, with the exception of black women, for whom vulvar SCC increased significantly (+2.9%). Trends in invasive vaginal SCC were also stable for all women combined and for all racial/ethnic groups except black women, among whom the rate declined (−6.2%). Low case counts for invasive vulvar and vaginal SCC prevented trend analysis among AI/AN women.

FIG. 2.

Percent changes were calculated using 1 year for each end point; APCs were calculated using weighted least squares method. *Denotes APC statistically different from zero (p < 0.05). ^†Rates are per 100,000 females and are age-adjusted to the 2000 U.S. standard population (19 age groups–Census P25-1130). Analysis limited to microscopically confirmed cervical carcinomas with ICD-O-3 histology codes 8010–8671, 8940–8941 and microscopically confirmed vulvar and vaginal SCCs with ICD-O-3 histology codes 8050–8084, 8120–8131. ^‡Data are from 45 population-based cancer registries that participate in the NPCR and the SEER Program and meet high-quality data criteria.⁷ These registries cover approximately 92% of the U.S. population. Hispanic ethnicity is not mutually exclusive from race (white, black, AI/AN, API). AI/AN and API APC not presented for cancers with diagnosis years <16 cases.

In situ cancers

There were an average of 1,660 in situ vulvar SCCs and 176 in situ vaginal SCCs diagnosed per year during 1999–2004, with respective rates of 1.2 and 0.1/100,000 women (Table 3). Women diagnosed with in situ tumors were younger compared to the respective invasive tumors. In situ vulvar cancer peaked at age 45–49, and in situ vaginal cancer peaked at age 70–79.

Table 3.

Annual Counts, Age-Adjusted Incidence Rates, and Median Age at Diagnosis of In Situ Vaginal and Vulvar SCC by Selected Variables, United States, 1999–2004^a ^b

Median age at diagnosis	Vulva Median age = 49				Vagina Median age = 58
Median age at diagnosis	Average annual incidence count	Rate	Lower CI	Upper CI	Average annual incidence count	Rate	Lower CI	Upper CI
All ages	1660	1.21	1.19	1.24	176	0.13	0.12	0.13
Age in years
0–14	^c	^c	^c	^c	0	0.00	0.00	0.00
15–19	11	0.12	0.09	0.16	^c	^c	^c	^c
20–24	32	0.35	0.31	0.41	4	0.04	0.02	0.06
25–29	51	0.58	0.52	0.65	^c	^c	^c	^c
30–34	98	1.04	0.96	1.13	6	0.06	0.04	0.09
35–39	168	1.67	1.56	1.77	11	0.11	0.09	0.14
40–44	228	2.17	2.05	2.28	14	0.13	0.10	0.16
45–49	246	2.52	2.40	2.66	23	0.23	0.20	0.28
50–59	374	2.40	2.30	2.50	34	0.21	0.19	0.25
60–69	222	2.16	2.05	2.28	32	0.31	0.26	0.35
70–79	158	1.86	1.74	1.98	32	0.38	0.33	0.44
80+	71	1.21	1.09	1.33	19	0.32	0.26	0.38
Race
White	1435	1.26	1.23	1.28	147	0.12	0.12	0.13
Black	135	0.88^d	0.82	0.95	17	0.12	0.10	0.15
AI/AN^e	12	1.01	0.78	1.28	^c	^c	^c	^c
API	9	0.16^d	0.11	0.21	^c	^c	^c	^c
Ethnicity^f
Non-Hispanic	1584	1.29	1.26	1.32	163	0.13	0.12	0.14
Hispanic	77	0.60^d	0.54	0.66	14	0.12	0.09	0.15

Rates are per 100,000 females and are age-adjusted to the 2000 U.S. standard population (19 age groups–Census P25-1130). Analysis limited to microscopically confirmed vaginal and vulvar SCCs as described in Table 1. Vulvar and vaginal intraepiethelial neoplasia, coded as 8077/2, are not included in analysis of in situ lesions.

Data are from 45 population-based cancer registries that participate in the NPCR and the SEER Program and meet high-quality data criteria.⁷ These registries cover approximately 92% of the U.S. population.

Count <16 for 1999–2004 total.

Denotes RR statistically significant (p < 0.05); top row is referent group.

AI/AN, American Indian/Alaska Native; API, Asian/Pacific Islander.

Hispanic origin is not mutually exclusive from race categories (white, black, API, AI/AN).

Race/ethnicity

The rate of in situ vulvar SCC was lower among black women (RR 0.7) and among API women (RR 0.2) compared with white women; the rate for AI/AN women was not significantly different from that of white women. The rate of in situ vulvar SCC was lower among Hispanic compared with non-Hispanic women (RR 0.5). The rate of in situ vaginal SCC was about the same among white and black women and among Hispanic and non-Hispanic women; rates for API and AI/AN were suppressed because of low numbers.

Discussion

This report uses recent population-based cancer registry data covering 92% of the U.S. population to assess racial and ethnic disparities in the burden of HPV-associated cervical, vulvar, and vaginal cancers and their incidence trends in recent years, confirming findings from our previous report and increasing the population coverage by 9%. AI/AN data are included for the first time, allowing for expanded racial comparisons of these cancers.

Our data showed that cervical cancer incidence rates decreased more rapidly in Hispanic and black women than in non-Hispanic and white women, possibly reflecting continued effectiveness and out reach of screening programs.¹² Although cervical cancer incidence rates declined substantially over time among Hispanic and black women, they remain higher than rates for non-Hispanic and white women. AI/AN women had the lowest incidence rate of cervical cancer and the highest decline in its rates over time. However, recent research specifically examining cancers among AI/AN women has shown up to 2-fold differences in cervical cancer rates among regions with large AI/AN populations; many regions had higher rates of cervical cancer among AI/AN women than white women.¹³ Our national analysis does not account for such regional variations. Recent decreases in rates could be related to recent screening programs targeted to AI/AN women, such as the Native American Breast and Cervical Cancer Treatment Technical Amendment Act in 2001, which helps improve access for AI/AN women to the National Breast and Cervical Cancer Early Detection Program (NBCCEDP).¹⁴ This decrease, together with ongoing disparities among black and Hispanic women, underscores the need to continue and emphasize targeted prevention and screening efforts among high-risk groups.

Consistent with previous publications, we found that vulvar cancer incidence rates were higher among white women than among women in other racial and ethnic groups.¹⁵ Certain histological subtypes of vulvar cancer (for instance, basaloid and warty types) are very strongly associated with HPV; however, these subtypes are difficult to assess using cancer registry data.¹⁵ Thus, it is possible that racial differences in vulvar SCC incidence rates may not reflect real racial differences in HPV-associated vulvar cancers. The trends in vulvar SCC indicated that race differences narrowed over time because the rate significantly increased among black women and leveled among white women; reasons for the increase among black women were not clear.

We found that incidence rates of vaginal SCC were higher among black and Hispanic women. Rates of vaginal SCC significantly declined since 1999 among black women; decreases among other race groups were not statistically significant. Although vaginal cancer risk factors, especially HPV infection, are similar to those for cervical cancer, effective screening programs led to declines in cervical cancer, and there is no screening program for vaginal cancer.

Continued surveillance of HPV-associated cancers using cancer registry data and special studies will enable us to monitor any changes in the burden of HPV-associated cancers among women. Although population-based cancer registeries are currently the best way to determine the ultimate outcome of cancer prevention efforts, they collect data on invasive cervical cancers only; monitoring precancers will identify any impact of the vaccine more quickly. Information from our previous study has been made available to the general public on the CDC website, in an HPV-associated cancers section available at www.cdc.gov/cancer/hpv, and a web portal linking all of CDC's information on HPV is being developed.

Cancer registries serve an essential public health function through the collection and compilation of cancer incidence data.¹⁶ The infrastructure to conduct population-based surveillance for the HPV vaccine is already in place through the cancer registries, and they provide a unique opportunity to build on existing programs to conduct enhanced surveillance of HPV-associated cancers and precancers. These efforts will require a well-funded and carefully organized national effort¹⁷; however, using central cancer registries for surveillance of the impact of the HPV vaccine poses numerous challenges. First, there is no central vaccine registry in the United States, and the ability of state registries to link vaccine records with cancer registry data varies by state. Special studies could link information on HPV vaccine status with cancer cases, but this information would likely be subject to recall bias or self-report issues, as with all survey data. Additionally, changes in treatment of HPV-associated lesions may result in fewer of these lesions progressing to the invasive stage, making it difficult to determine whether potential decreases in invasive cervical cancer and other HPV-associated cancers result from the vaccine or from changing treatment guidelines (although special studies could potentially assess changes in treatment). Also, changes in additional risk factors for HPV-associated cancers could affect the rates of these cancers in the population independent of any impact of the vaccine; if, for example, smoking rates increase, HPV-associated cancers could also increase. The recommended age for vaccination is 11–12 years of age, so surveillance of younger women is important. Because of the long latency between HPV infection and development of cervical cancer, the effectiveness of HPV vaccination may not be notable for decades, particularly for invasive cancers, which take longer to develop than earlier lesions.

Cancer registry data have some limitations that impacted on our study. Although NPCR and SEER registries combined currently (since 1998) cover the entire U.S. population, only registries that met USCS publication criteria for data completeness, quality, and timeliness for all 6 years were included in this analysis. As the quality and timeliness of NPCR data improve, national analysis of central cancer registry data covering 100% of the United States will be possible. However, we believe that recent analyses covering a large proportion of the U.S. population are generally representative of the rates of HPV-associated cancers.

Population-based cancer registries provide an excellent system to measure invasive cancers, but the information collected on preinvasive tumors is less comprehensive. Data on in situ cervical cancer are not collected nationally. Data on vaginal and vulvar intraepithelial neoplasia are not collected consistently at the national level; these lesions are strongly associated with HPV.¹⁸ Data on these precancers could provide more accurate information on the potential impact of the HPV vaccine years earlier than studying invasive cancers alone. However, as in situ cervical cancers and vaginal and vulvar intraepithelial neoplasia are often diagnosed and treated in outpatient settings and pathological diagnosis is not always consistent, collection of these data can be difficult and costly for registries. Another limitation of cancer registry data is that individual risk factor information, such as HPV status or smoking, is not readily available on cancer cases. Reporting of race and Hispanic ethnicity uses data from medical records, which may or may not be accurate. However, application of the North American Association of Central Cancer Registries (NAACCR) Hispanic Identification Algorithm (NHIA) to incidence data increased identification of women likely to be Hispanic. Linkage with IHS records increased identification of AI/AN women, but this linkage is more effective in rural areas, where IHS utilization is more common, than in urban areas, where AI/AN persons may be more likely to use private health services.¹⁹

Another limitation to this analysis may be that population denominators include all women, not just those with an intact cervix and, therefore, at risk for cervical carcinoma. Merrill²⁰ estimated cervical cancer rates in SEER using data from the Behavioral Risk Surveillance System and the National Health Interview Survey and excluding women having had hysterectomies from the denominator; rates of cervical cancer and racial disparities were substantially increased. More research is needed to determine the applicability of that method or other methods to determine the population at risk for developing cervical cancer.

Conclusions

Enhancing current cancer registry surveillance systems to record information on HPV-associated female genital cancers and their precursors, combined with special studies, can be of great importance in determining the impact of the HPV vaccine. Any post-HPV vaccine declines in cervical cancer should be interpreted in light of previous declines before the vaccine was available. This study confirms findings from our previous studies using newer data covering a larger proportion of the population to examine the most recent estimate of the burden of HPV-associated female genital cancers in the United States, setting the stage for monitoring the impact of the HPV vaccine and other emerging technologies to detect potential changes in the burden of cervical cancer over time. Although this report covers a large proportion of the U.S. population, improved collection of cancer registry data will be essential to continued monitoring of the burden of HPV-associated female genital cancer in all areas of the United States.

Footnotes

Acknowledgments

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

Disclosure Statement

The authors have no conflicts of interest to report.

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Update of HPV-Associated Female Genital Cancers in the United States,1999–2004

Abstract

Introduction

Materials and Methods

Results

Invasive cancers

Race/ethnicity

Annual percent change (APC)

In situ cancers

Race/ethnicity

Discussion

Conclusions

Footnotes

Acknowledgments

Disclosure Statement

References