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The global burden of thyroid cancer (TC) is rising, with significant economic and clinical impacts (1, 2). In the United States, out-of-pocket costs for TC diagnosis and treatment range from $1,425 to $17,000, with 16 to 50 per cent of patients facing financial hardship (3). The cost of papillary TC in the United States alone is projected to reach $21 billion by 2019, yet research funding remains low (4). Thyroid cancer patients have the highest rate of bankruptcy after diagnosis, at 9.3 cases per 1,000 person-years (5). In China, new cases have increased from 10,030 in 1990 to 39,080 in 2019 and are expected to reach 47,820 by 2039 (6). The rapid rise in incidence, especially in low- and middle-income countries, coupled with high diagnostic costs, exacerbates economic pressures (2). Globally, thyroid cancer survivors face both economic and psychological hardship, highlighting the urgent need for more cost-effective management and increased research funding.

TC is influenced by multiple risk factors, including genetic predisposition, exposure to radiation, and endocrine disruption, and is therefore a multifactorial disease with a significant impact on morbidity, mortality, and disability-adjusted life years (DALYs) (7). Genetic factors such as BRAF and RET/PTC mutations are associated with more aggressive forms of TC, often resulting in higher morbidity due to the need for extensive treatments and prolonged care (8, 9). Environmental factors, particularly radiation exposure during childhood, are linked to more invasive and potentially lethal types of TC, thereby increasing the risk of mortality (10). Additionally, elevated thyroid-stimulating hormone (TSH) levels have been correlated with a heightened risk of papillary thyroid carcinoma, further contributing to the disease burden (11). These risk factors cumulatively impact DALYs by increasing the years lived with disability, as patients often require lifelong monitoring and treatment for complications such as hypothyroidism, significantly affecting both their quality of life and long-term health outcomes (12).

In 2021, the global incidence, mortality, and DALYs for TC were 249,538, 44,799, and 646,741, respectively, showing an increase from 233,846 new cases and 45,575 deaths in 2019 (1, 13). This highlights the growing burden of TC worldwide. Several studies have identified long-term trends in cancer incidence and mortality at both global and regional levels. Given the significant changes in risk factors, understanding future trends is essential for adapting health systems to meet these evolving challenges. However, much of the previous research has been retrospective, focusing on overall populations rather than specific age groups. Studying TC in adolescents and young adults (AYA), aged 15-39, is particularly crucial because this group exhibits distinct patterns of disease presentation and outcomes compared to other age groups (14). The incidence of TC in AYA patients is significantly higher than in children, with a 10-fold increase observed in adolescents (15). In fact, TC is among the top five cancers diagnosed in individuals aged 15-39, emphasizing the importance of focused research on this specific age group (16).

Our study will use the Global Burden of Disease (GBD) database to explore male-female differences in TC incidence and mortality in this age group, revealing gender-specific risk factors and outcomes. In addition, we will use autoregressive integrated moving average (ARIMA) models to predict future trends in TC up to 2050.

TC has emerged as a significant global health concern, with its age-standardised incidence rate (ASIR) rising consistently between 1990 and 2019 (23). This increase was particularly pronounced among women, who faced a higher overall burden of disease compared to men at both time points. The male-to-female ASIR ratio grew from 0.41 in 1990 to 0.51 in 2019, while the age-standardised mortality rate (ASDR) also increased, rising from 0.60 to 0.82 (23). Over recent decades, thyroid cancer has become one of the most prevalent malignancies of the endocrine system. AYA, aged 15 to 3, is especially common, with a 5-year survival rate as high as 98% (24). However, treatments such as radioactive iodine therapy and thyroid hormone suppression can lead to long-term adverse effects. Notably, AYA patients who developed synchronous or early secondary thyroid cancer faced a higher risk of death compared to those whose secondary cancers developed years later (25). In response to these trends, we conducted a comprehensive analysis of gender and temporal trends in TC in young adults and used an ARIMA model to predict the prevalence, incidence, and mortality DALYs of thyroid cancer globally and under different characteristic stratifications for the next 20 years.

Based on EAPC trends from 1990 to 2021, the EAPC for the AYA population (15-39 years) decreases with increasing age group, but the EAPC for disease, morbidity, and DALYs peaks for the 20-24 age group. This peak can be attributed to several key factors. Enhanced diagnostic sensitivity and the potential for overdiagnosis have likely played a significant role, as improved medical technologies and increased health screenings during early adulthood have led to the detection of subclinical thyroid cancers, which may not have caused symptoms or mortality otherwise (26). Additionally, exposure to environmental endocrine-disrupting chemicals (EDCs), found in everyday products like plastics and personal care items, may interfere with thyroid function, increasing cancer risk in younger populations (27). The heightened sensitivity of the thyroid gland to these external factors during early adulthood likely contributes to the rapid rise in TC incidence (28). Lifestyle factors, including rising rates of obesity and altered dietary habits, further exacerbate this trend by promoting metabolic changes that can increase cancer susceptibility (29, 30). As the AYA population ages beyond 24 years, EAPC begins to decline. This may be due to a decrease in the number of new cases diagnosed, changes in diagnostic methods, or the natural aging process that may alter risk factors. However, the overall burden in the 25-39 age group remains high, even though the relative growth rate (EAPC) becomes less steep as individuals approach their 30s, suggesting that while the incidence of new cases stabilizes, the long-term effects and health burden persist.

The substantial regional variations in the incidence and prevalence of TC among AYA populations, as revealed by the GBD database, can be attributed to several factors (27). Environmental and lifestyle differences, such as higher exposure to carcinogens, tobacco use, and dietary patterns in regions like the MENA, likely contribute to the higher rates observed. Genetic predispositions in these populations could also play a significant role in their susceptibility to TC (31). In contrast, the lower incidence in Western Sub-Saharan Africa might stem from a combination of underreporting due to limited healthcare access and fewer environmental risk factors. Additionally, different challenges, such as economic problems, armed conflicts, and political instability, alongside the uneven distribution of equipped or experienced healthcare staff, have led to unfavourable figures in some countries (32). Stigmatization of and mistrust in the healthcare system further exacerbate these challenges, limiting access to early diagnosis and treatment, thus impacting the overall disease burden. Addressing these socio-political factors could significantly improve cancer care and reporting in affected regions.

Mortality and DALY patterns also show stark contrasts across regions (33). Mortality and disability-adjusted life year (DALY) patterns also show contrasts across regions, with a downward trend in Europe (especially Central and Western Europe), which is largely attributed to improved healthcare, early diagnosis, advanced treatment options, and strong public health interventions, such as the finding of the Westland Cancer Screening Programme in Sweden that the European Thyroid Imaging Reporting and Data System (EU-TIRADS) that the selective use of fine needle aspiration cytology (FNAC) in thyroid cancer management has reduced unnecessary surgery (34). Regions such as Eastern Sub-Saharan Africa, which have the highest mortality rates and DALYs from TC, face significant challenges due to insufficient medical resources, delayed diagnoses, and a lack of effective treatment programs (35). Non-communicable diseases like cancer have now emerged as the leading cause of death in this region, exacerbating the healthcare crisis. The disproportionate burden of cancer may also be tied to rapid urbanization, coupled with unhealthy lifestyles often associated with poverty and inequality (36). These factors highlight the urgent need for targeted interventions and a more equitable allocation of resources to reduce disparities in cancer outcomes, particularly in regions with rising mortality rates and high DALY burdens.

Libya reports the highest global DALY rate, underscoring the significant disease burden in North Africa. Furthermore, Libya also exhibits one of the highest morbidity rates, with a prevalence exceeding 40 per 100,000. Despite these figures, there is a relative scarcity of reports specifically addressing thyroid-related diseases in the country, suggesting a gap in focused research or reporting on this condition (37). Despite the relatively low incidence of thyroid cancer in India, the burden of morbidity and mortality remains significant. The country recorded 815 deaths, highlighting a substantial disease impact, which is likely amplified by its large population and healthcare disparities. A key factor contributing to this burden is the stark contrast between urban and rural healthcare systems. In urban areas, access to diagnostic facilities and treatment protocols allows for more effective disease management. Conversely, rural areas suffer from limited healthcare infrastructure, leading to delayed diagnoses and inadequate treatment, which results in higher mortality rates and poorer outcomes (38). Notably, between 2006 and 2012, the incidence of thyroid cancer in Trivandrum, Kerala, surged by 93%, reaching 13.3 per 100,000 in 2012. This sharp increase is likely driven by overdiagnosis, particularly among those under 40, exacerbating the apparent disease burden (39, 40).

The incidence, prevalence, mortality and peak DALYS of thyroid cancer in the AYA female population coincide with the time when women experience major hormonal fluctuations such as puberty and pregnancy. One potential causative factor is premature oestrogen exposure, and exposure to higher levels of oestrogen during the reproductive years may increase the risk of TC (41). The onset of menstruation (the first menstrual period) and subsequent hormonal cycles may lead to increased susceptibility, particularly through oestrogen stimulation of thyroid cells. Pregnancy may further increase the risk of thyroid cancer, which is the second most common malignancy during pregnancy, after breast cancer, with 14 out of every 100,000 pregnant women having thyroid cancer (42). Nearly 10 per cent of thyroid cancer cases in women of childbearing age are diagnosed during pregnancy or early in the postpartum period (43). Elevated human chorionic gonadotropin (hCG) during normal pregnancy stimulates TSH receptors and directly increases thyroid hormone production, leading to elevated serum free T4 and decreased serum TSH during pre-pregnancy (44). TSH is a driver of thyroid cancer growth, and therefore elevated hCG and TSH receptor stimulation is considered a factor that may promote thyroid cancer growth during pregnancy (45).

Many studies explored the seasonal variations in thyroid function among women of reproductive age, with a focus on thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and the TSH index (TSHI) (21, 46). They observed that TSH and TSHI peaked in winter and were lowest in summer, indicating a clear seasonal pattern influenced by external environmental factors such as temperature and photoperiod. These fluctuations in thyroid hormone levels may contribute to the risk of thyroid cancer, as elevated TSH during winter could stimulate thyroid cell proliferation, potentially increasing the risk of malignant transformation over time (11). The relationship between temperature and TSH levels, where colder weather leads to higher TSH, suggests that thyroid function is regulated by environmental changes, potentially causing oxidative stress and DNA damage in thyroid cells, which may contribute to cancer development (47, 48). Given the seasonality in thyroid function, clinicians should consider the timing of diagnostic evaluations and treatments for thyroid-related diseases, especially in high-risk populations. The use of ARIMA (autoregressive moving average) and exponential smoothing models in this study is justified due to their ability to effectively capture both short-term fluctuations and long-term trends in thyroid hormone levels. These models provide valuable insights into the seasonal dynamics of thyroid function and its potential impact on thyroid cancer risk, while also enabling predictions of future diabetes incidence. (49).

The rationale for using both Exponential Smoothing and ARIMA to forecast TC incidence lies in their complementary strengths for different forecasting horizons and data behaviours. Exponential Smoothing is ideal for short-term forecasts as it quickly adapts to recent trends, making it suitable for predicting incidence rates driven by current healthcare policies and detection practices (e.g., 2021 to 2025) (50). In contrast, ARIMA excels in capturing historical patterns and long-term trends, making it better suited for extended forecasts (e.g., 2026 to 2050), where broader factors such as demographic aging and healthcare improvements are more influential (51). Together, these models address both short-term fluctuations and long-term structural shifts in incidence rates. ARIMA’s ability to handle non-stationary data, common in healthcare time series, and its proven success in forecasting non-seasonal, annual datasets like the GBD data, supports its application (52). While Exponential Smoothing lacks substantial evidence in GBD contexts, its flexibility in adapting to recent changes makes it valuable for short-term forecasts, even without seasonality. Combining both models enhances predictive robustness by addressing both short-term variations and long-term trends, with convergences boosting confidence in forecasts and divergences highlighting areas for further investigation.

This study presents several strengths and limitations that warrant discussion. One of the main strengths is its focus on the adolescent and young adult (AYA) population, a group that is often underrepresented in cancer research despite having distinct patterns of thyroid cancer incidence and outcomes. This focus addresses a critical gap and provides valuable insights into thyroid cancer dynamics in this age group. Additionally, the use of advanced predictive modelling techniques, including ARIMA and Exponential Smoothing models, enhances the study by offering both short- and long-term forecasts, providing a nuanced understanding of future trends in thyroid cancer burden. However, the study also has limitations. For example, the ARIMA model generated negative predictions for the 20-24 age group, highlighting the model’s limitations in handling small and volatile datasets without non-negativity constraints. This suggests caution in interpreting predictions for this age group. Furthermore, the study did not account for lifestyle risk factors or exposure to environmental toxins, such as smoking or endocrine-disrupting chemicals, which are known to influence thyroid cancer risk. This omission may limit the comprehensiveness of the analysis, as these factors play a crucial role in shaping thyroid cancer outcomes in different populations.