FormalPara Key Points

  • The high-risk genotype for human papillomavirus (HPV), which causes cervical cancer, is higher among American Indian/Alaska Native (AI/AN) women than non-Hispanic White (NHW) women.

  • The uptake of HPV screening among AI/AN women is below the US national average.

  • The incidence of cervical cancer is subject to Tribal variation and is higher among some groups of AI/AN women.

  • Cervical cancer mortality is higher among AI/AN women than NHW women.

  • Self-sampling for HPV testing offers advantages and is preferred by women. Primary HPV testing is likely to be presented for approval in the USA, allowing this method to become available to AI/AN women.

The United States is home to over 570 federally recognized Tribes who speak about 150 Tribal languages. The majority (54%) of the American Indian/Alaska Native (AI/AN) population live in rural and small-town areas, while 30% live in suburban and exurban areas and 16% in urban areas [1]. Approximately 68% of the AI/AN population live on or near reservations or Tribal lands. In the context of AI/AN healthcare access, purchased/referred care delivery areas (PRCDAs) are counties that contain federally recognized Tribal lands or are adjacent to Tribal lands and to the Indian Health Service. Figure 42.1 shows the geographic distribution of PRCDAs [2]. A great deal of AI/AN healthcare is centered in community and Tribal centers, with a focus on healthy food and water sources and on creating local health awareness for disease prevention [3].

Fig. 42.1
A U S map highlights P R C D A majorly in the states in the north, north-west, and west. The legends for P D C R A county and state are given at the bottom.

Indian Health Service Purchased/Referred Care Delivery Area counties, by region—United States 2013–2017 [2]

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Primary Prevention of Cervical Cancer: HPV Vaccination

Cervical cancer prevention begins with human papillomavirus (HPV) vaccination uptake. A Cherokee Nation Health Services survey indicates that 71% of adolescents in the PRCDA have received at least one dose of the HPV vaccine [4]. However, the predominant high-risk HPV genotype across two separate AI communities was HPV 51, which is not included in the current HPV vaccine [5]. Likewise, prevalent HPV infection rates for women over 30 years old are higher among Great Plains Native American Tribal women than the general US population, with 35% of the Great Plains population testing positive for at least one high-risk HPV type [6]. In 2011, South Dakota AI/AN were reported to have a 42% HPV prevalent infection rate, with 32% of the HPV infections not vaccine-preventable types. This is significantly higher than the non-Hispanic White (NHW) comparison population [7]. The risk of cervical cancer may or may not be inherently higher for AI women as the HPV vaccination does not protect them from their most common forms of HPV infection. As such, AIs rely on screening as the next step in early detection and treatment.

HPV in the general population does not reflect HPV genotype distribution in the cervical cancer population [8]. Many common infections do not progress to the cancer stage. While HPV 16, 18, and 31 are relatively uncommon in general infections, they are the dominant types in cancers. HPV genotypes taken from the cervical cancer population among AN women between 1980 and 2007 (prevaccination) indicated the presence of HPV 16, 18, 31, 33, 39, 45, 58, 59, 73, and 82 with no HPV detected in 8% (5/62) of specimens [9]. This set of cervical cancers did not detect HPV 51.

Secondary Prevention: Historical Cytology Screening Results

In the past, cervical cancer screening was cytology dominated, with only recent advances that base the risk of cervical intraepithelial neoplasia grade 3 or worse (CIN 3+) on persistent high-risk HPV infection. Cytologic changes visually represent biochemical changes within the host, and viral DNA post-HPV infection and are necessarily subjective. Screening studies, to date, are based predominantly on women attending screening events and do not report the distribution of cytologic abnormalities for the AI/AN population.

The National Breast and Cervical Cancer Early Detection Program (NBCCEDP) was formally extended to AI/AN in 1993 [10, 11], with funding for 11 Tribal programs. In the 20 years between 1991 and 2012, almost 160,000 AI/AN women were screened with cytology, resulting in 2301 cases of CIN 2+ (1.4% of screened women) and 98 invasive cancers (0.06% of screened women). Between 1991 and 2012, cytology was used as the primary screen, using HPV triage for women with a cytology result of atypical squamous cells of undetermined significance (ASCUS). In the NBCCEDP between 2009 and 2011, AI/AN women with an ASCUS cytology result had the highest rate (56%) of HPV-positive ASCUS results of any race, 15 points higher than other races/ethnicities. Most importantly, 25% did not return for any follow-up, which was almost double the rate of no-follow-up for other races/ethnicities [12]. The lack of follow-up among AI/AN women was 14% when the level of cytologic abnormality extended to low-grade squamous intraepithelial lesions (LSIL), with a higher attendance at colposcopy [13].

Uptake of Screening Remains Low

Screening rates, including HPV testing in some programs, from 2011 to 2019 for Pacific Northwest AI/AN women reveal a nonimproving rate of between 57% and 62%, which is below the US national average of 73.5%. In addition, AI/AN women aged 50–64 years have the lowest cervical cancer screening rate [14]. Tribal variations show the lowest screening rates among AI/AN women in the Northern Plains (46%), followed by the Pacific Coast (49%) and the Southwest (52%) [15]. Screening result data are not available.

Cervical Cancer Incidence Remains High

PRCDA county data from over 10 years of cytology-based screening from 1999 to 2009 revealed a 1.5-fold increase in the incidence of cervical cancer (11/100,000 among AI/AN vs. 7.1/100,000 among NHW), with Tribal variation: women from the Northern Plains have the highest increased relative incidence (1.97) compared to NHW, followed by AN women from Alaska (1.94) and from Southern Plains (1.64), Southwest (1.19), and Pacific Northwest (1.36) Tribes [16, 17]. No cervical cancer incidence inequities were found among East Coast Tribes. Between 2001 and 2008, a similar proportion of AI/AN (22%) and NHW (21%) women on Medicaid were diagnosed with late-stage cervical cancer [18].

From 2014 to 2018, the incidence of cervical cancer worsened to 11.5 vs. 7.4/100,000, with AI/AN women having a 56% higher rate of cervical cancer incidence in PRCDA counties than NHW women [15]. Specifically, AI/AN women 35–49 years had a 1.5-fold increase in cervical cancer incidence over NHW women, and AI/AN women 50–64 years had a 1.8-fold increase in incidence rate [19]. AI/AN Tribal disparities continue, with Northern Plains and Pacific Tribes having nearly twice the rate of cervical cancer incidence as Alaska and Southern Plains AI/AN and 1.6-fold higher incidence as NHW [20].

Between 1999 and 2018, at 3.7/100,000, cervical cancer was the third most common cancer among adolescent and young adult (AYA) AI/AN females aged 15–29 years, after thyroid cancer and lymphoma [21]. Among 30- to 39-year-old AI/AN women, cervical cancer incidence is 18.1/100,000, which is significantly higher than the general US population rate of 7.1/100,000. In contrast, among this same demographic of AI/AN women, breast cancer incidence is 40.2/100,000 and thyroid cancer is 23.7/100,000 [21]. Cervical cancer incidence rates per 100,000 AYA AI/AN women vary by Tribal affiliation, with Southern Plains women having the highest incidence (14.7), followed by Alaska (13.2), Northern Plains (10.6), Pacific Coast (10.6), East Coast (7.8), and Southwest (5.3). Incidence trends did not change over this 20-year period.

By 2018, the incidence of cervical cancer among AI/AN women had increased by 0.6%, at a rate higher than all cancers combined among the AI/AN population [15]. In addition, AI/AN women present with later-stage cervical cancer than NHW women, with a 1.8-fold increase at the regional stage and a 2.4 increase in the distant stage at diagnosis compared to NHW women [15, 19]. Urban Indian Health Organizations (UIHO) data from 2008 to 2017 reveal that AI/AN women living in UIHO service areas had a 1.5-fold increase in the risk of cervical cancer compared to NWH urban counterparts, with Tribal inequities showing Alaskan AI/AN women at the greatest relative risk over NHW (2.0), followed by AI/AN women in the Northern Plains (1.8), Pacific Coast (1.6), Southern Plains (1.5), and Southwest (1.3) [22]. The significantly elevated relative risk of cervical cancer among AI/AN in urban areas (1.7-fold higher than urban NHW) was lower than in four Tribal regions, where the relative risk in Tribe-specific urban AI/AN women vs. NHW urban women is Pacific Coast (2.2), Northern Plains (2.1), Alaska (1.7), and Southern Plains (1.7) [23]. Only the East and Southwest Tribes had lower incidence.

Cervical Cancer Mortality Remains High

In parallel, cervical cancer mortality from 1999 to 2009 was twice as high among AI/AN as NHW (4.2/100,000 vs. US national rate 2.1/100,000), with AI/AN women aged 65–84 years having a 10/100,000 mortality rate (2.8-fold higher than NHW). Those older than 84 had a 23.7/100,000 mortality rate (6.1-fold higher than NHW) [17]. Again, rates varied between Tribal communities, with the highest relative mortality rate in the Northern Plains (4.2), Southwest (2.1), and Southern Plains (1.6), compared to NHW women, while relative rates of cervical cancer among the Eastern and Pacific Northwest Tribes, and Alaska Natives did not differ to those of the NHW population [17]. Up to 2019, mortality from cervical cancer remained 64% higher among AI/AN than NHW women and 2.9-fold higher for AI/AN women aged 50–64 years than for NHW women in the same age category [15, 19].

Screening Now Relies on More Accurate HPV Biomarkers

HPV detection is now a fundamental necessity in cervical cancer screening. The HPV genotypes requiring immediate referral to colposcopy are HPV 16, 18, and 31 [24]. Among AI/AN studies, the most common HPV genotypes, in descending order, are HPV 51, 58, 18, 52, 31, 66, 16, 56, 68, 59, 45, 39, 35, and 33 [6, 25]. The three highest-risk HPV types are present among AI/AN women. Other than prevalent epidemiologic studies on high-risk HPV genotypes in AI/AN populations, there are no data describing the results of a cervical cancer screening process based on HPV testing in the AI/AN population [26].

The Last Mile Initiative is a US-based National Cancer Institute (NCI)-sponsored trial to bring self-screening with primary HPV testing to women, regardless of race/ethnicity, to remove the barriers of the speculum exam and physician appointments. Piloted work carried out among several underserved populations reveals specific narratives for both the lack of screening uptake and the advantages of self-screening.

Primary themes from women involved in the pilot include the ease of collecting a vaginal sample, preference for HPV self-testing over the speculum exam, and positive recommendations to friends/relatives to use self-sampling for cervical cancer screening [25]. Nine countries (Albania, Kenya, Guatemala, Honduras, Malaysia, Netherlands, Peru, Rwanda, and Uganda) have introduced self-screening with primary HPV testing for all women, while eight countries (Argentina, Australia, Denmark, Ecuador, Finland, France, Myanmar, and Sweden) have introduced self-screening with primary HPV testing for underscreened populations, in addition to an option for well-screened populations [27].

Within a short time, self-sampling for primary HPV testing is likely to be presented to the Food and Drug Administration (FDA) for approval in the United States, allowing this most popular method of cervical cancer screening to be available to AI/AN women.