Elizabeth R. Unger

Prevalence of human papillomavirus genotypes in high‐grade cervical precancer and invasive cervical cancer from cancer registries before and after vaccine introduction in the United States

BackgroundUS population‐based cancer registries can be used for surveillance of human papillomavirus (HPV) types found in HPV‐associated cancers. Using this framework, HPV prevalence among high‐grade cervical precancers and invasive cervical cancers were compared before and after HPV vaccine availability.MethodsArchived tissue from 2 studies of cervical precancers and invasive cervical cancers diagnosed from 1993‐2005 (prevaccine) were identified from 7 central cancer registries in Florida; Hawaii; Iowa; Kentucky; Louisiana; Los Angeles County, California; and Michigan; from 2014 through 2015 (postvaccine) cases were identified from 3 registries in Iowa, Kentucky, and Louisiana. HPV testing was performed using L1 consensus polymerase chain reaction analysis. HPV‐type–specific prevalence was examined grouped by hierarchical attribution to vaccine types: HPV 16, 18, HPV 31, 33, 45, 52, 58, other oncogenic HPV types, and other types/HPV negative. Generalized logit models were used to compare HPV prevalence in the prevaccine study to the postvaccine study by patient age, adjusting for sampling factors.ResultsA total of 676 precancers (328 prevaccine and 348 postvaccine) and 1140 invasive cervical cancers (777 prevaccine and 363 postvaccine) were typed. No differences were observed in HPV‐type prevalence by patient age between the 2 studies among precancers or invasive cancers.ConclusionsThe lack of reduction in vaccine‐type prevalence between the 2 studies is likely explained by the low number of cases and low HPV vaccination coverage among women in the postvaccine study. Monitoring HPV‐type prevalence through population‐based strategies will continue to be important in evaluating the impact of the HPV vaccine.

Cervical adenocarcinoma in situ: Human papillomavirus types and incidence trends in five states, 2008–2015

Primary prevention through the use of human papillomavirus (HPV) vaccination is expected to impact both cervical intraepithelial neoplasia (CIN) and adenocarcinoma in situ (AIS). While CIN is well described, less is known about the epidemiology of AIS, a rare cervical precancer. We identified AIS and CIN grade 3 (CIN3) cases through population‐based surveillance, and analyzed data on HPV types and incidence trends overall, and among women screened for cervical cancer. From 2008 to 2015, 470 AIS and 6,587 CIN3 cases were identified. The median age of women with AIS was older than those with CIN3 (35 vs. 31 years; p < 0.01). HPV16 was the most frequently detected type in both AIS and CIN3 (57% in AIS; 58% in CIN3), whereas HPV18 was the second most common type in AIS and less common in CIN3 (38% vs. 5%; p < 0.01). AIS lesions were more likely than CIN3 lesions to be positive for high‐risk types targeted by the bivalent and quadrivalent vaccines (HPV16/18, 92% vs. 63%; p < 0.01), and 9‐valent vaccine (HPV16/18/31/33/45/52/58, 95% vs. 87%; p < 0.01). AIS incidence rates decreased significantly in the 21–24 year age group (annual percent change [APC] overall: −22.1%, 95% CI: −33.9 to −8.2; APC among screened: −16.1%, 95% CI: −28.8 to −1.2), but did not decrease significantly in any older age group. This report on the largest number of genotyped AIS cases to date suggests an important opportunity for vaccine prevention of AIS, and is the first to document a decline in AIS incidence rates among young women during the vaccine era.

HPV type‐specific trends in cervical precancers in the United States, 2008 to 2016

AbstractDeclines in cervical intraepithelial neoplasia grades 2 to 3 and adenocarcinoma in situ (CIN2+) observed among young women suggest impact from human papillomavirus (HPV) vaccination. To further evaluate vaccine impact including cross‐protection and type replacement, we described high‐risk (HR)‐HPV type‐specific cervical precancer incidence rates among women aged 20 to 39 years, 2008 to 2016. We analyzed cross‐sectional population‐based data on 18 344 cases of CIN2+ from a 5‐site surveillance system. Diagnostic specimens were tested for individual HPV types, including 14 HR‐HPV types (HPV16/18/31/33/35/39/45/51/52/56/58/59/66/68). We estimated age‐specific annual HR‐HPV type‐specific CIN2+ incidence per 100 000 screened women for individual types, vaccine HR‐HPV types (HPV16/18) and nonvaccine HR‐HPV types (non‐HPV16/18). We evaluated trends using average annual percent changes (AAPC) and 95% confidence intervals (CI), and estimated total declines by comparing 2015‐2016 to 2008‐2009 using incidence rate ratios. Among 20‐24‐year‐olds, HPV16/18‐CIN2+ declined from 2008 through 2016 (AAPC: −21.3%, 95% CI: −28.1%, −13.8%), whereas no trend was observed for non‐HPV16/18‐CIN2+ (AAPC: −1.8%, 95% CI: −8.1%, 4.9%). After 2010, CIN2+ among 20‐24‐year‐olds was more often caused by nonvaccine vs vaccine HR‐HPV types. No significant declining trends were observed in older age groups. In 2015‐2016 compared with 2008‐2009, HPV16‐CIN2+ declined 78%, HPV18‐CIN2+ 72% and HPV31‐CIN2+ 51% among 20‐24‐year‐olds; no increases were observed in type‐specific CIN2+ incidence. Among 25‐29‐year‐olds, HPV16‐CIN2+ declined 18%; CIN2+ attributed to seven nonvaccine types increased significantly. No significant declines were observed in older groups. Significant declines in HPV16/18‐CIN2+ in 20‐24‐year‐olds and HPV16‐CIN2+ in 25‐29‐year‐olds corroborate impact of HPV vaccination. A declining trend in HPV31‐CIN2+ is consistent with cross‐protection from vaccination.

Cervical Precancers and Cancers Attributed to HPV Types by Race and Ethnicity: Implications for Vaccination, Screening, and Management

AbstractBackgroundRacial and ethnic variations in attribution of cervical precancer and cancer to human papillomavirus (HPV) types may result in different HPV vaccine protection, screening test coverage, and clinical management.MethodsPooling data from 7 US studies, we calculated the proportional attribution of precancers and cancers to HPV types using HPV DNA typing from diagnosis. All statistical tests were 2-sided.ResultsFor all racial and ethnic groups, most cases of cervical intraepithelial neoplasia grade 3 (CIN3) (84.2%-90.8% of 5526) and squamous cell carcinoma (SCC) (90.4%-93.8% of 1138) were attributed to types targeted by the 9-valent vaccine. A higher proportion of CIN3s were attributed to nonvaccine HPV types among non-Hispanic Black women (15.8%) compared with non-Hispanic Asian or Pacific Islander (9.7%; P = .002), non-Hispanic White (9.2%; P < .001), and Hispanic (11.3%; P = .004) women. The proportion of SCCs attributed to 9-valent types was similar by race and ethnicity (P = .80). A higher proportion of CIN3s were attributed to nonvaccine HPV35 among non-Hispanic Black (9.0%) compared with non-Hispanic Asian or Pacific Islander (2.2%), non-Hispanic White (2.5%), and Hispanic (3.0%; all P < .001) women. Compared with CIN3, the proportion of SCCs attributed to HPV35 among non-Hispanic Black women (3.2%) was lower and closer to other groups (0.3%-2.1%; P = .70).ConclusionThe 9-valent HPV vaccine will prevent nearly all cervical precancers and invasive cancers among major racial and ethnic groups in the United States. Adding HPV35 to vaccines could prevent a small percentage of CIN3s and SCCs, with greater potential impact for CIN3s among Black women. HPV screening tests target high-risk HPV types, including HPV35. Future genotyping triage strategies could consider the importance of HPV35- and other HPV16-related types.

High-Grade Vulvar, Vaginal, and Anal Precancers Among U.S. Adolescents and Young Adults After Human Papillomavirus Vaccine Introduction

Since human papillomavirus vaccine introduction, incidence rates of cervical precancers have decreased; however, the vaccine's impact on noncervical anogenital precancers has not been shown. These precancers are identified opportunistically and are not collected routinely by most cancer registries. This study examined the incidence rates of high-grade (intraepithelial lesions grade 3) vulvar, vaginal, and anal precancers among persons aged 15-39 years using 2000-2017 data from select cancer registries covering 27.8% of the U.S. population that required reporting of these precancers. Trends in incidence rates were evaluated with Joinpoint regression. Analyses were conducted in 2020. High-grade vulvar precancer rates declined by 21.0% per year after human papillomavirus vaccine introduction among females aged 15-19 years. In addition, high-grade vaginal precancer rates declined by 19.1% per year among females aged 15-29 years after human papillomavirus vaccine introduction. Compared with that in the prevaccine period when high-grade anal precancer rates were increasing, anal precancer rates after human papillomavirus vaccine introduction were stable among females aged 15-29 years and among males aged 30-39 years. Among males aged 15-29 years, the rates increased over the entire period but less so after human papillomavirus vaccine introduction. Opportunistically-detected high-grade vulvar and vaginal precancers among females aged 15-29 years decreased and anal precancers stabilized in years after the introduction of the human papillomavirus vaccine, which is suggestive of the impact of the vaccine on noncervical human papillomavirus cancers.