Discussions on sex-based disparities in cancer incidence and mortality have spanned decades; however, the consideration of sex in treatment options and patient care remains insufficient (12, 14, 15). In this study, we provided evidence that sex-based differences in lymphoma incidence, mortality, and survival outcomes have persisted over the past two decades. To the best of our knowledge, this study is the most up-to-date and comprehensive investigation using the SEER database to evaluate epidemiological patterns of sex-based disparities among patients with lymphoma in the United States. Additionally, we not only focused on sex differences but also considered other independent factors related to incidence and mortality rates, such as age at diagnosis, race/ethnicity, year of diagnosis, and subtypes of lymphoma, and conducted stratified analyses for these factors(16–18). Regarding survival disparities, we explored the risks of all-cause, cancer-specific, and CVD-related deaths, thereby providing a refined perspective on the differences in survival outcomes between male and female patients with lymphoma.
Our findings indicated that the degree of sex-based differences in lymphoma incidence varies among lymphoma subtypes. For instance, sex-based differences were negligible in MZL, whereas they were pronounced in NLPHL, BL, and MCL. Additionally, the male predominance in the incidence rates across lymphoma subtypes appears consistent among populations from different countries, which was also noted in studies conducted a decade ago in Korean and Chinese populations(19, 20).Consistent with our results, a recent investigation by Radkiewicz et al. in the Swedish population also reported an equivalent prevalence of MZL in both male and female patients (13).Considering the inherent biological distinctions between males and females in a range of cancer-related processes, such as epigenetics, X chromosome fragility, metabolism, the immune system, angiogenesis, and senescence, it is plausible to conclude that these biological disparities contribute to sex-based differences in cancer resistance and susceptibility(21–23). Consequently, these underlying biological differences are reflected in the patterns of sex-based disparities in cancer incidence, as captured by epidemiological studies (24–26). For instance, studies have investigated the genetic basis of sex disparities in BL, positing that men may face an elevated risk of developing BL owing to genetic mutations or epigenetic alterations in tumor suppressor genes located on sex chromosomes(27–29). Overall, the mechanisms underlying the patterns of sex-based differences in lymphoma incidence are not fully understood and require further investigation.
In studies on cancer incidence and mortality, fundamental demographic factors, such as age, sex, and race/ethnicity, are considered key and independent influencing factors (7, 30, 31). While most existing studies have concentrated on analyzing the separate effects of these variables, our investigation aimed to explore the combined impact of these factors, with a particular focus on understanding how they interact to impact the pattern of sex-based disparities in lymphoma(32–34). Consistent with previous research, we also observed that NHW individuals have higher incidence rates, whereas NHB individuals have higher mortality rates across various lymphoma subtypes, which may be explained by underlying socioeconomic disparities and unequal access to healthcare services that vary across ethnicities(4). Additionally, we noted that the degree of sex-based differences in lymphoma incidence and mortality rates was relatively consistent across different racial/ethnic subgroups. Moreover, in most racial/ethnic subgroups, the IRR and MRR values were nearly equivalent, implying that a portion of the observed mortality rate disparities could be linked to variances in incidence rates. A notable exception is in BL, where NHB males demonstrated a marked increase in mortality rates compared with females, indicating that other yet-undefined factors may influence survival outcomes. Future research should focus on identifying and addressing the controllable factors to reduce sex-based disparities in mortality rates.
Age is another essential factor, with numerous studies demonstrating an age distribution significance in lymphoma incidence.(35, 36). The SEER database does not provide information on age at death; therefore, our analysis was confined to examining sex-based differences in the incidence rates across various age brackets. Among aggressive lymphomas, we observed that MCL, BL, and NLPHL exhibited more pronounced sex-based disparities in younger populations, with these diminished differences as age increased. In the case of DLBCL, a slight surge in sex-based differences in lymphoma incidence rates was observed in middle-aged patients. In contrast, sex-based differences in the incidence rates of indolent B-cell lymphomas remained relatively stable across various age groups. The observed variations in sex-based differences across age groups were hypothesized to be related to factors such as fluctuations in female hormone levels and the generally longer lifespan of women, which requires further investigation and empirical confirmation via future research(37, 38).
Although male patients with lymphoma tend to have higher mortality rates than female patients with lymphoma, there is still no consensus on whether sex is an independent prognostic factor. In several previous studies on lymphoma prognosis, sex was not included as an independent prognostic factor in the nomogram models(39, 40). In this study, we quantitatively assessed the disparities in all-cause, cancer-specific, and CVD-related death risks between male and female patients with lymphoma. Our results revealed several intriguing findings. Specifically, within the NLPHL group, we detected no significant sex-based differences in the three survival outcomes, which was consistent with the outcomes of a study using the SEER database from 2000 to 2014(41). Although our study indicates that male patients exhibit a higher mortality risk across other lymphoma subtypes, caution is warranted when interpreting these results. Our analysis was adjusted only for fundamental clinical characteristics available in the SEER database. The elevated mortality risk observed in male patients with lymphoma is not solely due to sex-related biological differences. It may also be associated with more prevalent unhealthy lifestyle choices among men, such as smoking and alcohol consumption, and a higher incidence of cardiovascular risk factors, including hypertension and hyperlipidemia-associated risk factors(5, 9). These factors may introduce confounding biases that cannot be corrected using existing data. In summary, personalized treatment strategies can be provided if the influence of sex-based disparities on the prognosis of patients with lymphoma is understood.
Our study had some limitations, as it was a retrospective study based on a public database. First, lymphoma encompasses over 60 subtypes; however, our study concentrated on nine subtypes because of the limited number of patients with rarer subtypes. Moreover, we were unable to analyze age-specific trends in the MRRs because the age and year of death information were not available in the SEER mortality data. Furthermore, while Williams et al. demonstrated a more sophisticated approach by analyzing sex-based differences using a single year of age in their research, our study categorized the data by 10-year intervals for ease of generalization(24). Additionally, our study noted the inadequate consideration of sex in treatment decisions. However, the lack of detailed treatment information in the SEER database, such as immunotherapy choices, restricts a thorough analysis of the impact of treatment choices on different sexes(15, 38, 42). In addition, the SEER database does not provide molecular-level data on sex differences in genetic mutations, transcriptomics, metabolomics, or epigenetics, which are essential for a deeper understanding of the underlying sex-based disparities (22, 43). Nevertheless, this study outlined the patterns of sex-based differences in lymphoma epidemiology, paving the way for thorough future research on underlying causes.
In conclusion, this large population-based study comprehensively reviewed the manifestations of sex-based disparities in lymphoma incidence, mortality, and survival over the past two decades. Our results underscore the fact that male patients face an increased risk of disease development and mortality for most lymphoma subtypes. Relevant research delving into how sex differences influence other prognostic outcomes, such as secondary cancers and sepsis-related deaths, and further exploring the underlying mechanisms that contribute to these differences will be conducted. Finally, we emphasized the importance of incorporating sex differences into clinical decision-making, patient care, clinical trials, and basic medical research designs.