Racial disparities in cervical cancer incidence and mortality have persisted for decades in the United States, representing one of the largest Black-White mortality gaps for any cancer.24,25 To date, few studies have evaluated these disparities by histologic subtype, particularly with respect to mortality. In line with our current findings, studies have suggested that although cervical SCC incidence rates are highest among Black women, ADC incidence rates are lowest compared with all racial/ethnic groups.1,3,5,6 A limitation of some of these previous studies is that they only looked at individual metrics, like incidence, which may result in misleading conclusions. By performing an integrated population-based analysis of subtype-specific incidence, survival, and incidence-based mortality, we have, to our knowledge, for the first time, demonstrated that although incidence rates of ADC may be lowest in Black women, there are profound racial disparities in ADC survival, leading to Black women having the highest ADC mortality rates compared with all other groups. Notably, although Black women also had the highest SCC incidence and mortality rates, survival disparities were much less pronounced for this subtype, suggesting subtype-specific differences that may be related to both systemic inequities that influence receipt of high-quality care as well as potential biological factors distinctive of ADC.
Some,3,26 but not all, studies4 have previously suggested that ADC has worse prognosis than SCC. Our findings suggest that at the population level, ADC has better stage-specific survival compared with SCC among all groups except Black women. Most understanding of cervical cancer, including optimal treatment, has resulted from studies in predominantly White patients with SCC.27–29 Currently, there are no explicit differences in treatment recommendations for cervical cancer by histologic subtype, despite important histologic differences with respect to clinical behavior,30 recurrence risk,28 response to therapy,31,32 and prognosis.32–36 For example, studies have shown a greater benefit of posthysterectomy adjuvant radiation among patients diagnosed with ADC compared with those with SCC.31 Others have shown that addition of cisplatin-based chemotherapy to radiation versus radiation alone confers a greater benefit among patients with locally advanced ADC compared with SCC.32 Furthermore, in this study, chemoradiation mitigated survival disparities observed among Black patients treated with radiation alone who had worse overall survival compared with White women. Subtype-specific differences in response to therapy may point to the contribution of treatment-related factors, such as receipt of guideline-concordant care and/or differential access to skilled gynecologic oncologists, to the subtype-specific racial survival disparities observed in our study. Another possible explanation could be that some cases diagnosed as cervical ADC are of endometrial origin. Although immunohistochemical markers (eg, p16 and hormone receptors) can differentiate endocervical adenocarcinomas from low-grade endometrioid adenocarcinomas, these markers are less helpful for distinguishing cervical ADC from endometrial serous adenocarcinomas, which are more common in Black women.37,38 This distinction is critical for optimizing management and could lead to disparities if misclassification occurs more often in Black women.
It is not clear why Black women have the lowest incidence of ADC despite having the highest incidence of SCC. We hypothesized that racial differences by subtype could be partially explained by social determinants of health associated with access to care and screening. However, whereas SCC incidence rates decreased with increasing county-level socioeconomic status (SES) measures, ADC incidence rates were less affected. Notably, disparities in SCC incidence rates persisted in all strata (ie, Black women from high SES counties still had much higher incidence rates than White women). It is possible that differences in the distribution of HPV genotypes and variants39 contribute to subtype-specific differences in incidence. For example, Black women have a lower prevalence of HPV16 compared with White women, and HPV16 is more likely to cause ADC compared with other HPV types.7,40–42 It is unlikely that proposed risk factors for ADC such as nonsmoking43 and obesity44 contribute to racial differences in incidence, as obesity is more prevalent and smoking is less prevalent in Black women compared with White women.45,46
Interestingly, although Hispanic women had high incidence of SCC and the highest incidence of ADC and ADSC, they also had the highest 5-year relative survival compared with all other racial and ethnic groups. A recent population-based study also found Hispanic women have higher incidence of cervical cancer overall, but similar 5-year relative survival compared with non-Hispanic Whites47; however, differences in survival appear to vary by factors such as nativity.48,49 Although incidence and mortality rates were generally lowest among API women in our study, we noted relatively worse survival for those diagnosed with regional and distant ADC compared with their White and Hispanic counterparts. More research is needed to better understand these differences, particularly by country of origin and ancestry.
We observed important racial and ethnic differences with respect to age-specific incidence rates. For example, in White women, incidence rates of SCC and ADC peaked at age 35-44 years and remained stable thereafter, whereas incidence rates continued to increase with age among Black women, peaking at age 65-74 years for both subtypes. Incidence rates of SCC also peaked at age 65-74 years among Hispanic women. High incidence rates of cervical cancer in Black and Hispanic women older than 65 years are concerning and may reflect inadequate screening in the preceding decade. Our findings underscore the need for more research in clinical populations age 65+ years to ensure the safety of screening cessation recommendations for all individuals.50
Our study has many strengths as the first and largest nationally representative population-based study, to our knowledge, of hysterectomy-corrected cervical cancer incidence and mortality rates by histologic subtype and race/ethnicity. Furthermore, we conducted expert pathology review of all histologic diagnosis categories coded by SEER to reduce misclassification, although we were unable to evaluate individual cases for accurate designation of histologic cell type and HPV status. Other limitations are also worth noting. Although we evaluated differences in incidence by county-level SES and accounted for SES when matching individuals in the survival cohort analysis, we were unable to evaluate individual-level SES; furthermore, numbers were limited to assess mortality differences by county-level SES measures. Misclassification of race/ethnicity is possible despite SEER registries using standardized codes and procedures.51 Additionally, SEER categorizes sex as male or female52; therefore, transgender individuals with a cervix could have been unknowingly excluded from our analysis. Furthermore, SEER stage categories do not directly correspond to clinical FIGO staging, and we lacked access to imaging data that are increasingly important for tumor staging; however, most cases in our cohort were diagnosed before 2018, before FIGO staging guidelines were updated to emphasize the importance of imaging.53 Finally, we do not have reliable data on treatment variables in SEER. There are many nonbiological and biological factors that could explain the racial/ethnic differences in survival that we observed in our study, and these factors need to be comprehensively studied in diverse clinical populations with high-quality individual-level data.
In conclusion, despite Black women having the lowest incidence of ADC, we show dramatic and profound disparities in cervical cancer survival affecting Black women with regional and distant ADC, resulting in higher ADC mortality rates among Black women compared with all other racial and ethnic groups. Although racial and ethnic differences in incidence rates of SCC are likely due to disparities in access to care and screening, the reasons underlying the observed racial and ethnic differences in incidence rates of ADC are less clear. More research is needed to better understand the influence of factors such as differences in detection (screening; including later ages at diagnosis), treatment, and management, as well as potential biological differences, on these disparities.
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