With increasing incidence rates and severe morbidity and death, cutaneous squamous cell carcinoma (cSCC) has become a major global public health problem (1). Despite its prevalence, cSCC has often been overshadowed by research on melanoma, leaving considerable gaps in our understanding of its global burden, temporal trends, and regional disparities (2). As the second most common form of skin cancer, cSCC accounts for a growing number of healthcare encounters, which places a significant strain on healthcare systems, especially in regions with high ultraviolet (UV) exposure (1, 3). cSCC has been extensively studied at national and regional levels; however, the global burden and socio-demographic determinants remain underexplored. The prevalence of cSCC varies significantly by region, with higher incidence rates in countries like Australia, the United States, and New Zealand, where UV radiation exposure is particularly intense and a large proportion of the population is Caucasian (4, 5). However, these regional studies lack a comprehensive global perspective, and many focus solely on descriptive statistics without delving into the more nuanced aspects of disease burden or temporal trends. Moreover, while previous studies have identified risk factors such as UV exposure, immunosuppression, and older age, the research is often fragmented, lacking the integration necessary to reveal patterns over time and across populations and failing to examine disparities in healthcare access, early detection programs, and treatment availability (6, 7).

Building upon this foundation, our study employs innovative methodologies, including decomposition and frontier analyses, to assess the interplay between socio-demographic development and cSCC burden. The disease burden of cSCC includes not only clinical outcomes but also psychological and economic impacts, placing significant strain on healthcare systems (8). While mortality rates are relatively low, the rising incidence contributes to substantial disability-adjusted life years (DALYs) worldwide. However, many studies overlook the burden in lower- Sociodemographic Index (SDI) regions, and longitudinal data on changing trends remain scarce (9). Inequities in healthcare access and exposure to environmental risk factors further complicate efforts to understand cSCC globally (10).

This study leverages data from the Global Burden of Disease (GBD) framework to address these gaps, offering a robust longitudinal perspective on cSCC trends from 1990 to 2021. Key innovations include the use of frontier analysis to evaluate healthcare performance relative to economic resources, decomposition analysis to disentangle contributions of demographic factors to disease trends, and inequality analysis to explore disparities across regions and socio-economic groups (11, 12). Through these approaches, the study aims to answer critical questions about global cSCC trends, regional variations, and the factors driving temporal changes.

Cutaneous squamous cell carcinoma (cSCC) has become a prominent global health issue, increasingly recognized in the context of public health research. Historically, most studies have focused on melanoma, leaving a significant gap in our understanding of non-melanoma skin cancers like cSCC (4). The development of SCC has been associated with a number of risk factors. The main risk factors for SCC include aging, exposure to UV light, and occupation hazards (32). Recent research indicates a rising incidence of cSCC, particularly in regions with UV exposure (33). The majority of mutations discovered in cSCC have a “UV signature,” and epidemiological and clinical data support cumulative lifetime exposure to ultraviolet radiation as the primary environmental carcinogen responsible for cSCC (34). In addition to UV, exposure to polycyclic aromatic hydrocarbons, arsenic, and ionizing radiation at work and in the environment are other major risk factors for cSCC (35). Additionally, due to innate flaws in the immune system or DNA repair pathways, some hereditary disorders, like xeroderma pigmentosum and epidermodysplasia verruciformis, enhance vulnerability to cSCC (36).This study builds on existing literature by employing data from the 2021 GBD survey, providing a comprehensive analysis of cSCC prevalence, mortality, and DALYs across 204 countries. Importantly, our study employs a variety of innovative analytical techniques, including decomposition analysis to disentangle the contributions of demographic changes, frontier analysis to assess healthcare performance relative to socio-economic factors, and Bayesian age-period-cohort modeling to clarify temporal trends and project future burdens of cSCC (30, 37, 38).

The worldwide burden of cSCC is still increasing in ASPR and ASDR, despite the fact that primary and secondary preventive strategies for the disease, such as UVR protection and early self-detection, have the potential to significantly lower morbidity and medical expenses of cSCC in particular areas and nations (39, 40). Our analysis reveals that, as of 2021, there were over 2.27 million cases of cSCC worldwide, reflecting a 345% increase since 1990. The ASPR rose from 14.69 to 26.85 per 100,000 individuals, while the ASMR experienced a modest increase from 0.67 to 0.69 per 100,000. In terms of DALYs, there was a striking 122% increase, rising from approximately 545,000 to over 1.21 million. The primary cause of the rise in ASPR of cSCC globally is most likely the worsening effects of population aging (41). Additionally, cSCC-related ASPR increased abruptly and dramatically in East Asia in the past three decades, where cSCC preventive and monitoring initiatives should be implemented to save healthcare expenditures and morbidity (42). The SCC mortality and DALYs in Central Asia increased at a disproportionately high rate from 1990 to 2021 compared to other parts of the world. It is believed that a large number of patients with SCC and other cancers in Central Asia who present with late-stage disease have restricted resources, a lower socioeconomic status, and a lack of accessibility to early identification and prompt therapy (14, 43). High-income North America recorded the highest ASPR in 2021, yet it also has a relatively low ASMR. Our analysis highlights that regions with high UV exposure, such as High-Income North America and Australasia, exhibit the highest prevalence rates of cSCC. This aligns with previous studies showing that UV radiation is the primary environmental carcinogen for cSCC (33, 34). This discrepancy can be attributed to several factors. First, individuals in North America generally have lighter skin, which increases their susceptibility to UV light. Darker-skinned populations demonstrate lower prevalence rates due to higher melanin levels, which provide enhanced protection against UV-induced damage. Additionally, a cultural tendency to seek sunbathing contributes to this increased exposure, resulting in a higher detection rate of skin tumors. Furthermore, this trend reflects the significant efforts made in high-income regions to promote early screening and treatment of these tumors (44, 45). Public health strategies aimed at reducing UV exposure, such as promoting sun protection measures and regulating indoor tanning, could significantly mitigate cSCC prevalence in these regions. While resource-poor regions must make up for their lack of medical resources through early screening(such as dermatoscopy), resource-rich regions (like North America) have reduced mortality rates through effective care management and individualized approaches, such as immunotherapy and photodynamic therapy (46–48). Australia ranked first in the world for both ASDR and ASMR of cSCC in 2021. However, due to its national emphasis on lifelong outdoor activity, coupled with inadequate sun protection measures and a population with fair skin, Australia could benefit from North America’s approach. Specifically, Australia should focus on educating the public about effective sun protection, reducing outdoor exercise time during peak UV hours, and improving early diagnosis and treatment of skin lesions (49–51). By reducing the prevalence of indoor tanning in North America and Europe, prohibiting indoor tanning for the next generation of people between the ages of 12 and 35 might prevent 9.7 million keratinocyte carcinomas and 448,000 melanomas, as well as save US $5.7 billion in medical expenses (44).

Our findings reveal notable differences in cSCC prevalence and outcomes across ethnic groups. Darker-skinned populations (such as Africans and People of African Descent) demonstrate lower prevalence rates due to higher melanin levels, which provide enhanced protection against UV-induced damage. Conversely, lighter-skinned individuals (like Caucasoid), particularly in high-SDI regions, face higher risks due to their lower natural UV protection (52). This disparity underscores the need for targeted prevention strategies that account for genetic and environmental factors. For example, early screening and public education campaigns could help bridge the gap in outcomes between different ethnic groups and regions.

Our data also indicated that males had higher ASPR, ASMR, and ASDR compared to females, with the most pronounced disparities occurring in older age groups. This aligns with existing literature that highlights the male gender as a risk factor for cSCC due to greater UV exposure from outdoor activities, less sun protection, and occupational hazards (53, 54). The aging population intensifies these trends as older individuals experience heightened vulnerability to skin cancers. This is largely due to cumulative UV exposure over the years and a decline in immune function associated with aging, which compromises the body’s ability to detect and respond to malignancies (55, 56).

Between 1990 and 2021, the ASMR and ASPR of cSCC gradually increased globally. High SDI areas and affluent nations like America, Australasia, and New Zealand, where a significant section of the population is light-skinned, continue to have high prevalence and significant ASDR burdens from skin malignancies (57, 58). A major contributing factor to cSCC, aside from UVR exposure, is the correlation between skin color and skin cancer (59, 60). Dark-pigmented individuals have a lower incidence of skin cancer than light-colored Caucasians because their complexion has more epidermal melanin to defend it from UVR ray damage (52). Furthermore, using the global heat map, we were able to see regional differences in the incidence of cSCC, with larger incidence trends reported distant from the equator. However, it is important to note that the growth rate of ASMR is smaller than that of ASPR. This trend reflects the global efforts in recent years to enhance early screening, diagnosis, and treatment of skin cancer. Australia’s “Slip, Slop, Slap, Seek, and Slide” campaign has significantly reduced UV-related skin cancer by promoting sunscreen use, protective clothing, and limited sun exposure during peak hours (49). Similar programs in high-risk regions could mitigate rising cSCC cases. Outdoor workers, such as farmers and construction workers, are highly exposed to UV radiation. Preventative measures like workplace regulations, UV-protective gear, and sunscreen distribution have proven effective and should be implemented more broadly. Community-based screenings, like those by the American Academy of Dermatology, improve early cSCC detection, reducing morbidity and mortality (39). Expanding these programs to low- and middle-SDI regions is essential. Advances in teledermatology and AI (artificial intelligence)-powered diagnostic tools offer promising solutions for improving access to early detection in underserved populations. Advancements in machine learning (ML) have revolutionized skin cancer detection (61). Deep learning models, such as convolutional neural networks (CNNs), achieve high accuracy in classifying dermoscopic images, sometimes surpassing dermatologists (62, 63). Combined with imaging modalities like high-resolution dermoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT), ML enables non-invasive, accurate cSCC detection, reducing unnecessary biopsies and supporting early intervention (61, 64). Expanding these tools to resource-limited regions could significantly reduce the global cSCC burden. These technologies facilitate remote evaluation of skin lesions and reduce the burden on specialized healthcare facilities. Pilot programs in regions with limited dermatology services have demonstrated their effectiveness (65, 66). Moreover, initiatives such as themed skincare days offering free diagnosis, increased patient awareness about outdoor exercise and sun protection, and public education on skin tumors can also have contributed to these improvements (67–70).

Compared to prior epidemiological studies, our analysis offers new insights by employing advanced methodologies. Earlier studies primarily reported rising cSCC prevalence but lacked global data or advanced modeling. For example, Zhang et al (2). demonstrated increasing cSCC incidence globally but relied heavily on descriptive statistics without exploring the contributions of demographic or epidemiological factors. Our analysis of cSCC trends using BAPC models, we projected the ASPR of cSCC to increase from 42.89 per 100,000 in 2021 to 64.66 per 100,000 by 2045, primarily due to demographic shifts, especially in aging populations. Unlike prior studies, the BAPC model allowed us to disentangle the specific impacts of age, period, and cohort on prevalence trends. Our analysis also revealed significant regional disparities, with high-SDI regions such as North America and Australasia experiencing the highest prevalence, likely due to UV exposure and higher rates of early detection. Conversely, ASMR and ASDR are projected to decline slightly, reflecting possible improvements in healthcare access and interventions aimed at early diagnosis and treatment (71). The anticipated rise in ASPR across most age groups, particularly among those over 95, underscores the need for targeted healthcare strategies to address the demands of an aging population (72).

Mortality trends in cSCC have been underreported in the literature, with most studies attributing rising death rates to late diagnoses or healthcare inequalities. For example, Gordon et al (52). noted a correlation between advanced age and higher cSCC mortality but lacked data on how demographic changes contributed to this increase. The decomposition analysis reveals that population growth and aging were primary contributors to increased ASMR across all SDI regions from 1990 to 2021, especially in low to middle-SDI region, where resource constraints may exacerbate the burden. This nuanced analysis showed that population aging was the dominant factor driving increased mortality, especially in low- and middle-SDI regions. Effective strategies, such as increasing awareness and screening in high-risk demographics, should be prioritized in these regions to mitigate further mortality increases (38).

Few studies have focused on the DALYs associated with cSCC. Studies such as Huang et al. (2024) emphasized DALYs for melanoma but offered limited data on cSCC (4). Frontier analysis in ASDR highlights significant effective disparities among countries, with regions like Georgia, Tonga, and Cuba experiencing higher-than-expected ASDR relative to their development levels. Conversely, countries like the Syrian Arab Republic and Sudan demonstrated lower ASDR rates, indicating potential resilience factors or effective healthcare strategies that could be emulated (73, 74). The use of frontier analysis allowed us to identify regions with disproportionate d healthcare system performance and resource allocation. Addressing these disparities by optimizing resource allocation and increasing preventive measures could narrow the “effective difference” in DALY rates globally.

Our findings from the cross-country inequality analysis underscore persistent health disparities in cSCC burden associated with SDI levels, which remained substantial from 1990 to 2021. The concentration and slope indexes indicate that higher SDI nations continue to face disproportionately higher ASMR and ASDR, likely due to differences in healthcare infrastructure and access. Policymakers should prioritize equitable access to healthcare resources, especially for under-resourced regions, to reduce these disparities and improve outcomes.

Several limitations of our study should be acknowledged. First, the GBD 2021 assessment lacks detailed information on skin cancer histology subtypes, risk factors, and specific mortality data for cSCC. This absence restricts our ability to analyze spatial and temporal trends in prevalence, DALYs, and mortality rates, which are crucial for understanding the disease. Second, the quality of the GBD data on cSCC raises concerns, particularly regarding underreporting. Variations in data sources and differing definitions of skin cancers can lead to inconsistencies that compromise the reliability of our findings. Lastly, our predictions did not account for external influences, such as changes in healthcare policy or public health initiatives, which could significantly impact the burden of skin cancer. Future research should address these limitations by incorporating more comprehensive data and considering these external factors to achieve a clearer understanding of skin cancer epidemiology.

In conclusion, the significant rise in cSCC prevalence and mortality reflects broader public health challenges linked to demographic shifts, environmental factors, and disparities in healthcare access. Addressing these issues requires a multifaceted approach focused on prevention, early detection, and equitable healthcare access. The findings underscore the urgent need for comprehensive strategies to manage and mitigate the burden of cSCC globally.