Cancer is a major global public health problem. In 2022, cancers of the lip, oral cavity, salivary glands, and oropharynx (LOC-SG-OP) constituted a substantial global health burden, with an estimated 551,200 new cases and 264,650 deaths worldwide. These malignancies not only severely impair critical functions such as speech, mastication, and swallowing but also adversely affect facial aesthetics and mental health, leading to a profound deterioration in patients' quality of life and survival [1, 2].

Anatomically and physiologically, the LOC-SG-OP region constitutes the initial segment of the upper digestive tract, wherein these structures function in a highly coordinated manner. Etiologically, they may share multiple risk factors such as tobacco use, alcohol consumption, betel quid chewing, poor oral hygiene, and human papillomavirus (HPV) infection [3, 4]. Clinically, malignancies arising in these sites are predominantly epithelial in origin, often preceded by comparable precancerous lesions and presenting with overlapping symptomatology [5]. Unlike the nasopharynx and hypopharynx, the anatomical accessibility of these regions further facilitates visual and physical examination, allowing for preliminary screening and early lesion detection. Given these anatomical, etiological, and clinical commonalities, we analyzed cancers of the lip and oral cavity, salivary glands, and oropharynx as a unified entity, designated as LOC-SG-OP cancers.

In previous research, LOC-SG-OP cancers have been either included in the broader category of head and neck cancers or analyzed as components of lip, oral cavity, and pharyngeal (LOCP) cancers. Their incidence, mortality, risk factors, and socioeconomic disparities across the entire age spectrum have been extensively documented [6, 7, 18, 26]. However, studies specifically focusing on the unified LOC-SG-OP cancers and conducting comparative analyses across different age groups remain scarce. To address this gap, our study focuses on the 15−74-year-old population with LOC-SG-OP cancers and categorizes them into four age groups. This age restriction helps minimize confounding effects from rare genetic predispositions in very young individuals [8] and from age-related comorbidities or heterogeneous treatment approaches in older populations [9].

The primary objective of this study is to elucidate age-specific epidemiological variations in LOC-SG-OP cancers using population-based data, with the aim of informing targeted resource allocation, tailored intervention strategies, and enhanced preventive measures, thereby advancing comprehensive cancer control efforts.

Study design

This study focused on individuals aged 15 to 74 years, stratified into age groups of 15–29, 30–44, 45–59, and 60–74 years. Based on the International Classification of Diseases, 10th Revision (ICD-10), we analyzed three types of malignant cancer from the GLOBOCAN 2022 database: cancers of the lip and oral cavity (C00-C06), salivary glands (C07-C08), and oropharynx (C09-C10). As the study utilized publicly available anonymized data, it was exempt from institutional ethical review and patient informed consent.

Data source

Data were extracted from the GLOBOCAN 2022 estimates by the International Agency for Research on Cancer (IARC). https://gco.iarc.fr/today/en/dataviz/tables. Accessed 2 July 2025. Six countries/regions were selected via a two-step process to represent the high burden of LOC-SG-OP cancers. First, the top three countries/regions ranked by age-standardized incidence rate (ASIR) were identified. Second, the top three countries/regions ranked by age-standardized mortality rate (ASMR) were selected. Where overlaps occurred between the ASIR and ASMR lists, duplicates were sequentially replaced with the next highest-ranked non-overlapping countries from the ASMR rankings until six unique targets were established per age group. Substitution was based on ASMR rankings rather than ASIR rankings because ASMR more effectively reflects the disease burden and health loss. The Human Development Index (HDI) data for each country were obtained from the United Nations [10]. As a comprehensive indicator, it measures the overall development level of a country or territory. Given the vast population sizes and unique socio-developmental contexts of China and India, we opted to utilize the HDI (excl. China & India) classification from the GLOBOCAN database for subsequent data analysis. This categorizes the 185 countries and territories into six groups: Very High HDI, High HDI (but China), China, Medium HDI (but India), India, and Low HDI.

The Global Landscape of LOC-SG-OP cancers among 15–74 year-olds, 2022.

In 2022, among the global population aged 15–74, there were 454,807 new cases and 210,802 deaths from cancers of LOC-SG-OP. The Age-Standardized Rate was 7.50 per 100,000 person-years for incidence and 3.50 per 100,000 person-years for mortality. Among this population, lip and oral cavity (LOC) cancer was the most diagnosed type in terms of both incidence and mortality, accounting for approximately 70% of the cases. Moreover, the burden of LOC-SG-OP cancers was markedly higher in men, with male-to-female ratios of 2.78 (11.10 vs. 4.00 per 100,000 person-years) for ASIR and 3.12 (5.30 vs. 1.70 per 100,000 person-years) for ASMR (Table S1, S2).

A clear age-dependent increase in case numbers for both incidence and mortality from LOC-SG-OP cancers was observed across all age subgroups, with cases mainly concentrated in males (Fig. 1A). Regarding cancer types, LOC cancer accounted for the majority of incident cases, death cases, ASIR, and ASMR across all age groups (Fig. 1B, C). Furthermore, apart from the notable exception of salivary gland (SG) cancers in the 15–29 and 30–44 age groups, which exhibited a comparable sex burden, the disease burden for all three cancer types was consistently higher in males across all other age subgroups, with male-to-female ratios for incident cases and deaths ranging from 1.26 to 4.88 and 1.46 to 5.54, respectively (Table S1, S2).

Figure 1 Global burden of LOC-SG-OP cancers by age group, 2022. A. Global age-specific counts of incident cases and deaths by sex. B. Global age-specific counts and proportions of incident cases and deaths by cancer type. C. Global age-specific counts of incident cases and deaths for LOC-SG-OP cancers.

The geographic differences in burden of LOC-SG-OP cancers by age group, 2022.

National-level data reveal distinct geographical clustering of LOC-SG-OP cancers by age group. Among the 15–29 years age group, Chad and Burkina Faso in Sub-Saharan Africa showed the highest ASIR (both 1.3 per 100,000 person-years) (Fig. 2A and Table S3). In the 30–44 years age group, the highest ASIR shifted to India and Pakistan in South Asia (9.9 and 9.1 per 100,000 person-years, respectively) (Fig. 2B and Table S4). For older adults aged 45–59 and 60–74 years, Papua New Guinea in Melanesia recorded the highest ASIR, demonstrating a commanding lead (62.3 and 82.3 per 100,000 person-years, respectively) (Fig. 2C, D and Table S5, 6).

A similar regional pattern was observed for mortality (Fig. 2E-H and Table S3-6). The highest ASMR was identified in Chad (0.87 per 100,000 person-years) among the 15–29 years age group. For the 30–44 years age group, Pakistan and India in South Asia showed the highest ASMR (5.1 and 4.6 per 100,000 person-years, respectively). In the 45–59 years age group, the highest ASMR was reported in Bangladesh, Pakistan, India in South Asia, and Papua New Guinea in Melanesia (20.9, 17.8, 17.1, and 17.1 per 100,000 person-years, respectively). Finally, among those aged 60–74 years, Bangladesh in South Asia and Papua New Guinea in Melanesia had the highest ASMR (39.4 and 38.5 per 100,000 person-years, respectively). Across the four age groups, a clear geographical overlap exists between high-incidence and high-mortality regions of LOC-SG-OP cancers, accompanied by a marked increase in both rates with advancing age.

Based on the geographical distribution patterns of LOC-SG-OP cancers, six high-burden countries/regions were selected to analyze the proportional distribution of ASIR and ASMR. In the 15–29 years age group, Solomon Islands exhibited exclusive attribution of both ASIR and ASMR to SG cancers, whereas Mozambique showed predominant contributions from SG cancers to both ASIR (60%) and ASMR (72.88%) (Fig. 3A). In the 30–44 years age group, LOC cancers constituted the major proportion of both ASIR and ASMR in most countries, with SG cancer proportions declining substantially. Solomon Islands represented an exception, maintaining SG cancers as the predominant component in both ASIR and ASMR (73.96% each) (Fig. 3B). In the 45–59 years age group, LOC cancers dominated ASIR and ASMR profiles across all six countries (ASIR: 49.58–90.85%; ASMR: 55.85–90.91%). Slovakia had notably higher oropharynx (OP) cancer proportions than other countries (ASIR: 47.31%; ASMR: 41.89%) (Fig. 3C). In the 60–74 years age group, LOC cancers remained the principal component in both ASIR (71.22–90.75%) and ASMR (64.91–90.39%) across all included countries (Fig. 3D).

HDI-related disparities in the burden of LOC-SG-OP cancers by age group, 2022.

Generally, the global burden of LOC-SG-OP cancers exhibits a distinct age-dependent pattern, characterized by consistently rising incidence and mortality across all HDI country groups with advancing age (Fig. 4A and Table S7, 8). In the 15–29 and 30–44 years groups, India had a substantially higher LOC-SG-OP cancer burden, with incident cases (3,139 and 30,265, respectively) and deaths (1,706 and 13,970, respectively) far exceeding those in all other HDI country groups. This trend continued in the 45–59 and 60–74 years groups in mortality, where India maintained notably higher death counts (37,315 and 36,862, respectively). Meanwhile, the number of new cancer cases in very high HDI countries increased significantly from age 45 onward (49,808 and 81,306 cases, respectively), reaching the highest level among all country groups in the 60–74 age group. Notably, unlike the sharp increase in incident cases, deaths in very high HDI countries rise only moderately from the 45 years age group onward (13,871 and 25,833, respectively). Consistent with the trend in case numbers, ASIR and ASMR both increased progressively with advancing age. Across all age groups, India demonstrated the highest ASIR and ASMR for LOC-SG-OP cancers (ranging from 0.85 to 50.70 and from 0.46 to 31.10 per 100,000 person-years, respectively). In contrast, China consistently showed the lowest levels for both ASIR and ASMR across all groups except the 15–29 years age group (ranging from 1.30 to 10.90 and from 0.32 to 5.60 per 100,000 person-years, respectively) (Table S7, 8).

When examining cancer type composition by age and HDI group, distinct profiles emerge, starting with the 15–29 years age group (Fig. 4B). Unlike India and the Low HDI countries, Very High HDI, High HDI (but China), China, and Medium HDI (but India) all displayed relatively high proportions of SG cancers in ASIR (45.45%, 44.19%, 54.05%, and 44.83%, respectively). Regarding ASMR, LOC cancers dominated across most groups, with the exception of High HDI countries where SG cancers accounted for a considerable share (44.44%). In the 30–44 years age group, the proportion of SG cancers decreased substantially, with LOC cancers becoming the dominant component of ASIR. Notably, OP cancers accounted for significantly increased proportions in ASMR for Very High HDI, High HDI (but China), and China (53.93%, 48.89%, and 60.87%, respectively). Finally, the 45–59 and 60–74 years age groups exhibit similar patterns: across all HDI groups, LOC cancers constitute the predominant proportion (all above 55%) in both ASIR and ASMR. The detailed data are available in Additional Tables S9 and S10.

The relationship between national-level MIR of LOC-SG-OP cancers and HDI is illustrated in Fig. 5. Across all age groups, MIR exhibited a linear decrease with increasing HDI (Spearman’s ρ = -0.65, -0.61, -0.69, and − 0.79, respectively; all p < 0.001). This significant negative correlation persisted in both sexes after stratification (all p < 0.001; Table S11). In line with this trend, the concentration curve further confirmed that populations with low HDI bear a disproportionately high MIR, revealing significant health inequalities across all age groups and for both sexes. (Fig. 5 and Table S12) Unexpectedly, both the Absolute Concentration Index (ACI) and Relative Concentration Index (RCI) revealed variations in HDI-related inequalities by age group and sex (Table S13). The 15–29 years age group displayed the largest absolute values of ACI and RCI (0.24 and 0.63, respectively), while the other three age groups (30–44, 45–59, and 60–74 years) showed relatively comparable absolute values of ACI (ranging from 0.11 to 0.17) and RCI (ranging from 0.27 to 0.36). Across all age groups, females had larger absolute ACI and RCI values than males, with this gender difference being most striking in the 15–29 years group (ACI: 0.31 vs. 0.17; RCI: 0.95 vs. 0.41). Collectively, these findings demonstrate that the distribution of MIR is characterized by significant HDI-related inequalities, which are most pronounced among younger populations (15–29 years) and females.

Figure 4 HDI-related disparities in the burden of LOC-SG-OP cancers by age group, 2022. A. HDI-specific counts of incident cases and deaths by age groups. LH denotes Low HDI; IND denotes India; MH denotes Medium HDI (but India); CHN denotes China; HH denotes High HDI (but China); and VHH denotes Very High HDI. B. HDI-specific proportion and age-standardized rates of incidence and mortality by cancer type and age group.

Figure 5 HDI-related inequalities in burden of LOC-SG-OP cancers by age group, 2022. (A-D) Associations between the incidence-mortality ratio and the HDI for age groups 15–29, 30–44, 45–59, and 60–74 years. Each dot represents a country, with its size proportional to to the number of incident cases. (E-H) Concentration curves of the incidence-mortality ratio for the same age groups.

Globally, head and neck cancer is more common in men than in women [3, 12]. A retrospective cohort study from South Korea showed that the incidence of head and neck cancer in men is approximately three times that in women, and the male-to-female ratio increases with age in populations under 70 years old [13], which largely parallels our findings from LOC-SG-OP cancers. However, in the 15–29 and 30–44 age groups, SG cancer exhibited a comparable sex burden. It is important to note that SG cancer encompasses various histological types, such as mucoepidermoid carcinomas, adenocarcinomas, not otherwise specified, adenoid cystic carcinomas, and squamous cell carcinomas [14]. The relationship between each histological type and sex may differ [15]. Furthermore, the 15–44 age group largely corresponds to adolescents and young adults (AYA, 15–39 years old), and cancer patients in this age group display distinct biological, epidemiological, and clinical features [16]. These distinctive features may further explain the differential sex distribution patterns observed in SG cancer across different age groups.

In South Asia and Pacific islands, such as India, Pakistan, and Melanesia, the high burden of LOC-SG-OP cancers is a well-established fact, particularly for oral cancer [17, 18]. Tobacco and betel quid consumption are highly prevalent in these regions [19]. Similar to tobacco, betel quid has been classified as a Group 1 carcinogen by the IARC [20]. Chewing betel quid can cause fibrosis of the oral mucosa through chemical irritation and mechanical damage, which is a precancerous lesion [21]. Research by Neela Guha et al. showed that betel quid chewing increases the risk of oral and oropharyngeal cancer in an exposure-dependent manner [22] .

The heightened burden of LOC-SG-OP cancers in individuals aged 15–29 may be driven by a youthful population demographic, high prevalence of human immunodeficiency virus (HIV) infections, and constrained healthcare infrastructure in Sub-Saharan Africa, such as Chad and Burkina Faso [23, 24]. A retrospective study found that HIV-infected individuals face significantly higher risks of developing squamous cell carcinoma in the oral tongue, oropharynx, and other oral cavity sites compared to the general population [25]. A potential mechanism is that the immunosuppressive state induced by HIV infection can amplify the carcinogenic effects of certain exposure factors, thereby further increasing the risk of cancer. Of note, three European countries (Hungary, Belarus and Slovakia) are unexpectedly represented in the age group aged 30 years and above. Unlike other countries in the chart, these three nations exhibit a higher proportion of OP cancers. Beyond the well-recognized risk factors of tobacco and alcohol consumption, the high incidence of OP cancers in these countries may be closely linked to HPV infection [26, 27]. It is reported that HPV-positive OP cancer patients are predominantly white males at younger age, with less exposure to tobacco and alcohol, but often a history of multiple unprotected sexual exposures [27]. Mechanistically, HPV infection in host cells can inactivate tumor suppressor proteins p53 and pRb while upregulating p16 protein expression [28]. The 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual explicitly identifies HPV status as a key element of the revised staging system for OP cancer [29]. Accordingly, based on the detection of p16 overexpression via immunohistochemistry, OP cancer is now classified into two distinct subtypes: HPV-associated (p16-positive) and non-HPV-associated (p16-negative), each with its own dedicated staging algorithm. Compared to OP cancer with other causes, patients with HPV-associated OP cancer have a significantly higher overall survival rate [30]. Currently, HPV testing has become a standard clinical diagnostic procedure for oropharyngeal malignancies [27, 29].

As a core metric of development, HDI provides a critical framework to analyze health disparities worldwide. According to the HDI (excl. China & India) classification from the GLOBOCAN database, it is clear that India bears a particularly prominent burden of LOC-SG-OP cancers across all four age groups. This is primarily attributed to the high number of LOC cases in India, which is likely associated with insufficient public awareness of the need to quit tobacco, betel nut, and alcohol use, as well as to undergo cancer screening [19, 31].

In contrast to other HDI settings, very high HDI countries present a distinct epidemiological pattern for LOC-SG-OP cancers, particularly in the 45–59 and 60–74 years age groups: while the number of incident cases increases, the corresponding number of deaths does not rise as sharply. This discrepancy can be explained by three interconnected factors: although populations in these countries face higher exposure to risk factors such as smoking, alcohol consumption, and specific environmental chemicals or radiation, leading to increased incidence rates, their well-established healthcare systems ensure early cancer screening and effective treatment [32]. Simultaneously, HPV-associated oropharyngeal cancers may account for a higher proportion in such countriesin the 45–74 years age groups, and this cancer type has a relatively favorable prognosis. Furthermore, robust data statistical systems guarantee the accuracy of the observed results [33]. In summary, high-quality healthcare services, favorable prognosis of HPV-related cancers, and comprehensive data systems may contribute to the unique cancer epidemiological profile observed in very high HDI countries.

In 2022, China demonstrated a relatively low burden of LOC-SG-OP cancers across most age groups. This may indicate that China's control over risk factors such as tobacco use and poor oral hygiene has been effective. Furthermore, the implementation of the "Three-Year Action Plan for Cancer Prevention and Treatment in China (2015–2017)" and the "Management Measures for Urban Cancer Early Diagnosis and Early Treatment Projects (Trial)" has provided policy support for early cancer intervention, laying the foundation for maintaining low ASMR for some cancers including oral cancer. However, when examining longer-term trends, China still faces substantial challenges in LOC-SG-OP cancer prevention and control. From 1992 to 2021, China witnessed a significant increase in the incidence of LOC cancers, representing the most pronounced growth among BRICS nations, with rising disease risks observed across all age groups [34]. Additionally, a notable urban-rural disparity in the oral cancer disease burden remains. Since 2006, the standardized years of life lost rate has declined significantly in urban areas, whereas no significant change has been observed in rural regions [35].

The high ASR proportion of SG cancer in the 15–29 years age group may be associated with the greater exposure of young people in higher-HDI regions to risk factors, including smoking, alcohol intake, and exposure to specific radiation or chemicals [32]. Higher-HDI regions, characterized by higher pathological diagnosis levels, can achieve early detection and accurate diagnosis of SG cancer. However, lower-HDI regions may not only face difficulties in early diagnosis but also misclassify some SG cancer cases as LOC cancer or OP cancer [36], which further reduces their statistical proportion.

The MIR serves as a a reference indicator to assess cancer control and audit the outcomes of cancer screening and treatment programs [37]. A lower MIR generally indicates more effective early detection and/or superior treatment outcomes, underscoring the health system's comprehensive performance in cancer control. Our results demonstrate that populations with a lower HDI bear a disproportionately high MIR for LOC-SG-OP cancers, likely attributable to insufficient screening, diagnostic delays, and limited treatment options in low-HDI settings [38, 39]. Furthermore, HDI-related inequalities in MIR varied by age and sex for LOC-SG-OP cancers. The most pronounced disparities were observed in the 15–29 years group, as evidenced by the largest absolute values of ACI and RCI. This heightened inequality suggests that young people may be systematically overlooked; their cancers are relatively rare and prone to misdiagnosis [11], and public health resources, including screening programs, are often prioritized for middle-aged and older populations. While the disease burden of LOC-SG-OP cancers is significantly higher in males across all age groups, the HDI-related inequality indices (ACI and RCI) were consistently higher in females. This disparity was most extreme in the 15–29 years age group. We posit that in low-HDI countries, socioeconomic barriers disproportionately affecting women, such as greater economic dependence, lower educational attainment, and limited autonomy in healthcare decisions, hinder their timely access to high-quality medical services [40].

Undeniably, this study has several limitations. First, the LOC-SG-OP cancer burden in developing countries with limited healthcare resources and unreliable cancer registration systems may be underestimated [33, 39]. Second, while the two-step selection method adopted in this study is simple to operate and enables rapid identification of the core countries/regions with the highest incidence and mortality burdens in each age group, it may obscure the substantial impact of absolute number of incident cases and deaths, and the sample size of six is relatively small. Third, MIR indirectly reflects the accessibility of medical resources and the quality of diagnosis and treatment, but it cannot distinguish between the independent effects of delayed diagnosis and treatment efficacy. Finally, the findings have not been externally validated using an independent database.

Conclusion

In summary, age-stratified analysis confirms that LOC-SG-OP cancers impose a global burden on individuals aged 15–74 years, with marked disparities across sex, geography, and HDI. These findings clarify the global burden and epidemiological characteristics of LOC-SG-OP cancers. It is important to emphasize that policymakers should consider implementing targeted interventions for regions and populations with a high disease burden. Furthermore, attention should also be paid to young and female populations in low-HDI regions to ensure they have access to equitable and timely diagnostic and treatment services.