Head and Neck Cancer among American Indian and Alaska Native Populations in California, 2009–2018

Simple Summary In the United States, it is estimated there will be 54,000 new cases of oral cavity and pharyngeal cancer in 2021. Tobacco exposure and drinking alcohol are the main causes of head and neck cancer (HNC). Human Papilloma Virus (HPV) is now increasing in prevalence and is the most common cause of oropharyngeal cancer in the United States. This study assessed the incidence of HNC and HPV status in American Indian/Alaska Native (AI/AN) populations in California and determined if incidence was higher among AI/ANs compared to other ethnicities. We found that AI/AN and White patients had the highest burden of late-stage HNC and HPV+ lip, oral cavity, and pharynx cancer compared to other ethnicities. In addition, AI/ANs had a decreased survival rate compared to White patients. These findings reveal ethnic or racial differences in incidence, presentation, and survival, and should inform future preventative care measures for the AI/AN population. Abstract The purpose of this study was to determine the incidence of HPV-positive (HPV+) and HPV-negative (HPV-) head and neck cancer (HNC) in the American Indian/Alaska Native (AI/AN) population in California to assess whether incidence is higher among AI/ANs compared to other ethnicities. We analyzed data from the California Cancer Registry, which contains data reported to the Cancer Surveillance Section of the Department of Public Health. A total of 51,289 HNC patients were identified for the years 2009–2018. Outcomes of interest included sex, stage at presentation, 5-year survival rate, tobacco use, and HPV status. AI/AN and White patients had the highest burden of late stage HNC (AI/AN 6.3:100,000; 95% CI 5.3–7.4, White 5.8:100,000; 95% CI 5.7–5.9) compared to all ethnicities or races (Black: 5.2; 95% CI 4.9–5.5; Asian/Pacific Islander: 3.2; 95% CI 3–3.3; and Hispanic: 3.1; 95% CI 3–3.2 per 100,000). Additionally, AI/AN and White patients had the highest burden of HPV+ lip, oral cavity, and pharynx HNC (AI/AN 0.9:100,000; 95% CI 0.6–1.4, White 1.1:100,000; 95% CI 1–1.1) compared to all ethnicities or races (Black: 0.8:100,000; 95% CI 0.7–0.9; Asian/Pacific Islander: 0.4; 95% CI 0.4–0.5; and Hispanic: 0.6; 95% CI 0.5–0.6). AI/ANs had a decreased 5-year survival rate compared to White patients (AI/AN 59.9%; 95% CI 51.9–67.0% and White 67.7%; 95% CI 67.00–68.50%) and a higher incidence of HNC in former and current tobacco users. These findings underscore the disparities that exist in HNC for California AI/AN populations. Future studies should aim to elucidate why the unequal burden of HNC outcomes exists, how to address increased tobacco usage, and HPV vaccination patterns to create culturally and community-based interventions.


Introduction
Cancer is the second leading cause of death for American Indian/Alaska Natives (AI/ANs) in the United States [1]. Cancer incidence rates vary by geographic region for AI/AN populations. The incidence rates of lung and colorectal cancers were reported to be three times higher in AI/AN males and females compared with White patients in the Great Plains, Pacific Coast, and Alaskan regions of the US. In all regions, cancers of the liver, kidney, and stomach were significantly higher in AI/ANs than White patients [2,3].
The incidence of head and neck cancer (HNC) among AI/AN populations is less well studied. It is estimated that in 2021, 54,000 new cases of oral cavity and pharyngeal cancer will occur in the United States, with 10,000 cancer-related deaths and a 5-year survival rate of 66% [4]. HNC has historically been linked to tobacco exposure, most commonly cigarette smoking, in conjunction with drinking alcohol. Persistent infection with high-risk strains of Human Papilloma Virus (HPV) is the most common cause of oropharyngeal cancers in the United States and there has been a continuous increase in the prevalence and incidence of HPV-positive (HPV+) HNC for the past 2-3 decades [5], with males being the most affected. Thus, HNCs not associated with HPV are now known as HPV-negative HNC.
While many studies have assessed the disparities in HNC rates in African American and Latinx populations compared to White populations [6,7], little is known regarding comparative HNC epidemiology in AI/ANs. In the Center for Disease Control's (CDC) most recent national data from 2018, 265 new cases of oral cavity and pharynx cancer were reported among the AI/AN population as well as 50 AI/AN deaths from this cancer [8]. Two studies reported that the incidence rate of late-stage HNC increased 75.3% from 2004 to 2015 in AI/AN and Asian/Pacific Islanders [9,10]. The Institute of Population Health at the University of California Davis released data from the period of [2000][2001][2002][2003][2004][2005][2006][2007][2008][2009][2010][2011][2012][2013][2014][2015][2016] showing that AI/ANs (aged 20-44 years) in California similarly had increased incidence of late-stage oral cancer diagnosis compared to White patients. This report also found that AI/ANs had a lower 5-year survival rate for patients with oropharynx cancers [11]. According to the Indian Health Service cancer registry, oropharyngeal cancers were the most common HPV+ cancer among AI/AN males in all regions of the United States (from 2013 to 2017) [1, 11,12].
Few studies have examined HNC in the AI/AN population in California [13,14], the most populated state in the United States with 39.5 million people and 631,000 people identifying as American Indian [15]. Investigation of the HNC burden among AI/ANs will identify opportunities to improve prevention and treatment for this population. To this end, we determined the incidence of HNC and HPV status of patients in California according to sex and race or ethnic group to assess whether the incidence of HPV+ and HPV− HNC is higher among AI/AN compared to other ethnicities in this large, diverse state.

Study Population
We analyzed data from the California Cancer Registry (CCR) [16], a surveillance database containing cancer data from California medical centers reported to the Cancer Surveillance Section of the Department of Public Health. Patients were identified who were 18 years or older and had a diagnosis of HNC from 2009 to 2018. Cases diagnosed at VA hospitals were excluded due to VA restrictions with their submissions to central cancer registries. This study was approved by the University of California, San Francisco Institutional Review Board (IRB number: 21-33716).

Data Collection
We identified all cases of HNC (oral cavity, pharynx, larynx, lip, oropharynx, nasopharynx, hypopharynx, paranasal and accessory sinuses, and salivary glands) using the International Classification of Diseases for Oncology, 3rd edition [12]. The primary covariate of interest was AI/AN race as designated by the CCR database. Other races were classified as non-Hispanic White, non-Hispanic Black, Hispanic, and Asian or Pacific Islander. For conciseness, the term "non-Hispanic" was omitted when discussing groups in this study. The outcomes of interest were sex, age at cancer diagnosis, stage at presentation, cancer-specific mortality, 5-year survival rate, tobacco use, and HPV status. HPV status was collected as defined by the CS Collaborative Stage Data Collecting System, version 02.05 schemas [17]. HPV status was determined on pathologic specimens by immunohistochem-istry for p16 expression and in situ hybridization, polymerase chain reaction (PCR), real time-PCR for viral DNA or RNA detection [18]. Grouped HPV status of the lip, oral cavity, and pharynx was available for the years 2009-2018. HPV status for individual sites within the pharynx (oropharynx, nasopharynx, hypopharynx), larynx, paranasal and accessory sinuses, and salivary glands HNC sites was limited to 2016-2018. The year 2016 represents the first-year data on HPV status for oropharynx, nasopharynx, hypopharynx, larynx, paranasal and accessory sinuses, and salivary glands were listed for HNC in the CCR.

Statistical Analysis
Age-Adjusted Rates in this report were calculated using the Surveillance Research Program, National Cancer Institute SEER*Stat software version 8.3.9. The yearly incidence and mortality per 100,000 persons for each age group were age-adjusted to the 2000 United States standard population. Rates based on less than five cases (or deaths) in any given year were not calculated [19]. We then calculated the 95% confidence intervals for each category of race or ethnicity, sex, age at cancer diagnosis, tobacco use, stage at diagnosis, cancer-specific mortality, 5-year survival rate, and HPV status. For AI/ANs aged 40-49 and 80+, the incidence rate of HNC in these age groups (12.9:100,000; 95% CI 9.1-17.1 and 67.2:100,000; 95% CI 46.5-93.9) was highest compared to all ethnicities. Amongst current and former tobacco users, the incidence rate of HNC in AI/ANs was 5.0 per 100,000 compared to never used tobacco (2.2:100,000). In contrast, in White current and former tobacco users, the incidence rate of HNC was 4.4 per 100,000, and 2.4 per 100,000 for those who had never used tobacco.

Stage at Diagnosis, Mortality, and 5-Year Survival
In Table 2

Discussion
With this study, we examined the burden of HNC in the AI/AN population in California. We then explored the incidence of HPV+ lip, oral cavity, and pharynx cancers between 2009 and 2018 and other HNCs between 2016 and 2018. HPV status was not collected for the soft palate, pharyngeal tonsil, and tongue base until 2016. Pharyngeal cancers (oropharynx, nasopharynx, hypopharynx, and other pharyngeal sites) were grouped in oral cavity and pharynx until 2016. We found that AI/AN and White patients had the highest burden of late stage HNC (AI/AN 6.3:100,000; 95% CI 5.3-7.4, White 5.8:100,000; 95% CI 5.7-5.9) and HPV+ lip, oral cavity, and pharynx HNC (AI/AN 0.9:100,000; 95% CI 0.6-1.4, White 1.1:100,000; 95% CI 1-1.1) compared to all ethnicities or races. Additionally, AI/ANs had a decreased 5-year survival rate compared to White patients (AI/ANs 59.9%; 95% CI 51.9-67.0% and White 67.7%; 95% CI 67.00-68.50%). The incidence of HNC in former and current tobacco users was highest in AI/AN patients compared to other ethnicities. Finally, the rates of overall HPV+ HNC from 2016 to 2018 were 1.3 to 4.5 times higher in the AI/AN population than Black, Hispanic, and Asian/Pacific Islander patients.
For the years 2016 to 2018, the incidence of HPV+ oropharyngeal cancer in AI/ANs (1.1:100,000; 95% CI 0.5-2.2) was higher than observed in Asian/Pacific Islanders, Hispanic, and Black ethnicities in California. The CDC similarly found a high proportion of HPV+ oropharyngeal HNC from 2013 to 2017 in the AI/AN population in the Pacific Coast region; 81% of the total HPV-associated cancers in AI/AN males (12.7:100,000) was oropharyngeal cancer [1, 20,21]. This disparity underscores the importance of understanding why AI/AN patients in California have a higher incidence of HPV+ HNC. The difference in rates could be due to differences in sex practices such as oral sex, oro-anal contact, number of oral sexual partners, barrier contraceptive usage, age, and gender, all of which play a role in increased HPV transmission [22,23]. However, this information was not available in the CCR. The higher incidence should therefore serve as an immediate focus for healthcare vaccination policy, in congruence with increased education about HPV+ HNC, to impact future cancer diagnosis. FDA-approved HPV vaccines have been found to be successful at preventing HPV+ HNC when administered prior to HPV exposure [5,24]. As of 2019, in the United States, 56.8% of female and 51.8% of male adolescents, ages 13-17, completed the HPV vaccine series compared to 61.5% and 51.4% in California [25]. Interestingly, a study in Michigan found that from 2006 to 2015, HPV vaccination completion rates were higher in the AI/AN cohort compared to White patients [26]. From the Indian Health Service (IHS) clinics in California who submitted quarterly reports for 13-to 17-year-old males and females in 2021, there was a trend that HPV vaccination in California was lower than IHS national average with vaccine initiation 19-29% lower, second dose 26-29% lower, and third dose 7-26% lower [27][28][29]. AI/AN children are eligible for the Vaccines for Children Program (VFC) as defined by the Indian Health Care Improvement Act and can receive vaccines at no cost through VFC-enrolled doctors [30]. Future work should elucidate current yearly vaccination uptake patterns in vaccine-eligible AI/AN populations both at IHS and non-IHS facilities to help reduce oral HPV infection rates.
Our work also supports previous findings that revealed disparities in survival rates of AI/ANs diagnosed with HNC [10,11]. The survival rates may have been affected by higher tobacco use in AI/AN compared to other races and ethnicities. Tobacco usage can be attributed to the commercial tobacco industry's targeting of AI/AN communities, leading to increased smoking prevalence as well as smoking-related diseases compared to other ethnicities or races [31,32]. In addition to the promotional and industry policy interventions to address the disparities, public health efforts should continue to work with tribes to denormalize recreational tobacco use.
It has been reported that HNC amongst AI/AN populations is often not diagnosed until later stages of the disease [4,10,11,33,34]. Our findings confirm and extend these observations, showing increased presentation of advanced stage HNC in AI/ANs in California. It is known that early detection of HNC leads to better prognosis [35]. Earlier detection and treatment of HNC can be improved by increasing provider surveillance across all races and ethnicities. Engaging AI/AN communities in all data-related processes and assessment of biases inherent in cancer surveillance is crucial to ensure that interventions are effective and culturally sensitive [36]. This will help elucidate multifactorial conditions contributing to disparities in HNC incidence and prognosis, such as socioeconomic status, exposure to tobacco and alcohol products, geographic distance from a cancer center, and health insurance status.
To our knowledge, this is the first study in California to reveal the disparity of HNC in the AI/AN population. Although this study used the most accurate and current data for cancer incidence in AI/AN populations in California, it has limitations. First, the AI/AN population, our population of interest, diagnosed with HNC in California was small compared to other races and ethnicities. This limited our ability to detect significant differences in the incidence of HNCs and interpretability of HPV-related data. Second, the California Cancer Registry only started collecting information on HPV status for all HNC sites since 2016. Therefore, we are limited in the number of cases where HPV status was known. Third, traditionally, the Veteran's Health Administration (VA) hospitals have been a critical source of data for cancers diagnosed amongst veterans who are eligible to receive care from these facilities. Since 2007, the VA enacted new restrictions for the submission of cancer cases to central cancer registries. The missing VA cases may impact the incidence rates and trends as VA cancers account for 3 to 8 percent of national cancer statistics. Lastly, we were unable to include information on alcohol status, as it is not currently collected by the state registry. This is one of the most common risk factors of HNC.

Conclusions
In summary we found that AI/AN populations in California have a higher burden of late-stage HNC including HPV+ HNC compared to other populations. This underscores the racial disparities existing in the causes, presentation, and survival rate of HNC in AI/AN populations in California. Future studies should focus on identifying factors contributing to late-stage diagnosis and unequal burden of HNC outcomes. Efforts should be made to understand current HPV vaccination patterns for vaccine-eligible individuals and screening patterns in vaccine-ineligible individuals in the AI/AN population compared to other races and ethnicities in California. Additionally, future studies should elucidate how to best address increased tobacco use among California tribes. Creating culturally informed and community-based interventions will help reduce these disparities in HNC incidence in the population.  Informed Consent Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.