Global incidence, risk factors and trends of vulvar cancer: A country‐based analysis of cancer registries

Vulvar cancer is an uncommon malignancy. Vulvar cancer alarmed the public health problem in terms of the cost of diagnostic and medical treatments and psychical health of females. Our study aims to provide a thorough analysis of the global disease burden, related risk factors and temporal incidence trends of vulvar cancer in population subgroups. Data from Global Cancer Observatory and the Cancer Incidence in Five Continents Plus were used for the vulvar cancer incidence. Age‐standardized rates (ASR) were used to depict the incidence of vulvar cancer. The 10‐year trend of incidence was assessed using joinpoint regression with average annual percentage change and 95% confidence intervals in various age groups, while its correlations with risk factors were investigated using linear regression. Higher ASR were found in Western Europe (2.4), Northern America (1.9), Northern Europe (1.9), Australia and New Zealand (1.8) and Eastern Africa (1.4). The associated risk factors of higher vulvar cancer incidence were gross domestic product per capita, Human Development Index, higher prevalence of smoking, alcohol drinking, unsafe sex and human immunodeficiency virus infection. The overall trend of vulvar cancer incidence was increasing. An increasing trend was found in older females while a mixed trend was observed in younger females. The disease burden of vulvar cancer follows a bimodal pattern according to its two histologic pathways, affecting women in both developed and developing regions. Smoking cessation, sex education and human papillomavirus vaccination programs should be promoted among the general population. Subsequent studies can be done to explore the reasons behind the increasing trend of vulvar cancer.

The associated risk factors of higher vulvar cancer incidence were gross domestic product per capita, Human Development Index, higher prevalence of smoking, alcohol drinking, unsafe sex and human immunodeficiency virus infection.The overall trend of vulvar cancer incidence was increasing.An increasing trend was found in older females while a mixed trend was observed in younger females.The disease burden of vulvar cancer follows a bimodal pattern according to its two histologic pathways, affecting women in both developed and developing regions.Smoking cessation, sex education and human papillomavirus vaccination programs should be promoted among the general population.Subsequent studies can be done to explore the reasons behind the increasing trend of vulvar cancer.
incidence, risk factors, temporal trend, vulvar cancer What's new?
Vulvar cancer is rare, and despite increased awareness of potential risk factors, evidence for demographic and lifestyle factors associated with vulvar cancer is limited.Here, using information from global cancer databases, the authors examined disease burden, risk factors and global incidence trends for vulvar cancer.Analyses uncovered a bimodal pattern in disease burden, which followed two histologic pathways, including vulvar high-grade squamous intraepithelial lesion or differentiated vulvar intraepithelial neoplasia, and which affected women in developed and developing regions.Factors linked to elevated incidence included alcohol consumption, gross domestic product per capita, HIV infection, human development incidence, smoking and unsafe sex.

| INTRODUCTION
Vulvar cancer is an uncommon malignancy.Vulvar carcinoma makes up 5% of all cancers of the female genital tract and is the fourth most common gynecologic malignancy. 1 Vulvar cancer can be categorized into various types of histology, with squamous cell carcinoma being the most common subtype, followed by basal cell carcinoma, extramammary Paget's disease and vulvar melanoma. 2,3The diagnosis of vulvar cancer is frequently delayed due to various reasons.First, it can remain asymptomatic for an extended period, 3 making it difficult to detect.Additionally, there is insufficient awareness among women regarding the disease and its symptoms, which further contributes to the delay in diagnosis.The delay in diagnosis led to poorer prognosis, and limited choice of medical treatment, which in turn affects females psychosexually and psychosocially. 3man papillomavirus (HPV) was indicated for 40% of all vulvar malignancies. 4Meanwhile, several potential risk factors were also identified in various studies, including smoking, 5 alcohol consumption 6 and sexual behavior. 7However, there has been limited evidence linking factors such as Human Development Index (HDI) and gross domestic product (GDP) per capita to vulvar cancer.By analyzing the demographic and lifestyle factors on a population level and vulvar cancer incidence in different age groups, the current study would provide a better understanding of the association between vulvar cancer and various risk factors, both previously identified and not fully explored.
Several studies have been conducted on the disease burden of vulvar cancer in specific countries, such as Denmark, 8 Korea 9 , and the United States. 4However, there is a lack of research focusing on the global temporal incidence trends of vulvar cancer across different age groups.To address this gap, our study aims to conduct a comprehensive analysis of the global disease burden, risk factors, and incidence trends of vulvar cancer.By utilizing data from international cancer registries and risk factor databases, our study can contribute to the development of effective screening policies for the early detection of vulvar cancer and provide insights into primary prevention strategies, including lifestyle modification and education.

| Data sources
The Global Cancer Observatory (GLOBOCAN) database, which is a public and global online database that gathered the incidences and mortality statistics of 26 cancer types, was accessed to retrieve the vulvar cancer incidence in 185 countries. 10GLOBOCAN was established by the International Association of Cancer Registries, partnering with the World Health Organization and other publicly available online data.The cancer figures in GLOBOCAN were estimated from global or regional cancer registries using incidence-to-mortality ratio, prediction from trend analysis, and approximation from surrounding countries if data are not available. 11To determine the proportions of vulvar cancer incidences by cancer sites, the Cancer Incidence in Five Continents Plus (CI5 Plus) was used.It is a database with yearly cancer incidences from different countries and offers the most recent and historical cancer statistics, broken down by year, population subgroup and geographic region. 12o analyze the risk factors of vulvar cancer, the Global Burden of Disease (GBD) database was accessed to generate country-specific data including the prevalence of smoking, alcohol drinking, hypertension, diabetes, lipid disorders and unhealthy dietary. 13GBD aims to improve the healthcare system and health equity by collecting and measuring data on heath loss resulting from specific illnesses, accidents and risk factors.
Early death and disability data of 350 diseases and traumas were obtained and evaluated by over 7000 researchers from 156 countries and regions.The HDI and the GDP of each country were retrieved from the United Nations and the World Bank, respectively. 14,15Agestandardized rates (ASR) per 100 000 population according to the World standard population (Segi 1960) were used to depict the all figures to facilitate comparisons between different countries.

| Statistical analysis
The association of vulvar cancer by age with different risk variables (HDI, GDP per capita, lifestyle and metabolic risk factors) was evaluated by adopting both univariate and multivariate linear regression analysis.Corresponding beta coefficients (β) and 95% confidence intervals (CI) for the regression analysis were generated.The ratio of the change in an outcome variable (ASR of incidence) for every unit increase in a predictor variable (risk factor) is expressed as the β estimates, it is determined as statistically significant when the P-value is less than .05. 95% CI was used to ensure the accuracy of trend estimations.For example, if there is a range overlap with 0, it represents a stable trend without a significant increase or decrease.Moreover, the incidence rate of vulvar cancer was also investigated in relation to age (all population: 0-85+, young population: 15-49, old population: 50-74) and geographical regions (Asia, Oceania, America, Europe and Africa).As a common practice in cancer research, 50 years old is considered the cut-off for early onset, 16 while individuals under 14 are excluded due to the rarity of vulvar cancer in this age group, and those over 74 are excluded due to the potential confounding effects of comorbidities and complications. 17| RESULTS

| Vulvar cancer incidence by age group in 2020
The estimated number of new cases for younger females aged between 15 and 49 is 7085 with an ASR of 0.35.Southern Africa is the region with the highest incidence (1.5), followed by Eastern Africa (1.3) and Western Europe (1.1).Meanwhile, Western Asia records the lowest incidence with an ASR of 0.11, followed by Northern Africa (0.12) and South-Central Asia (0.14).Furthermore, countries with the higher vulvar cancer ASRs are Eswatini (6.2), Lesotho (4.3) and Botswana (3.1), while the countries with the lower vulvar cancer ASRs are Ecuador (0.2), Nepal (0.2) and Egypt (0.3).In terms of HDI, younger females in low HDI (0.90) regions have the highest ASR, while the regions with very high HDI (0.54) and high HDI (0.23) rank second and third highest.
As for the older population aged between 50 and 74, the incidence rate is higher than the young population, with an estimated 22 561 new cases (2.7).Western Europe (7.8) is reported to have the highest ASR, followed by Northern America (6.4), and Australia and New Zealand (6.2).
Regions with the lower ASRs are Melanesia (0.88), Eastern Asia (0.99) and Western Asia (1.7).Germany (11.3) is the country with the highest ASR.
The Netherlands (9.7) and Romania (7.4) are the countries with the second and third highest ASRs.Countries with the lower ASRs are Haiti (0.27), Islamic Republic of Iran (0.33) and the Dominican Republic (0.33).Region with very high HDI (4.9) reports the highest ASR, followed by low HDI (3.0) and medium HDI (2.0) are the second and third highest, respectively.

F I G U R E 3 Associations between risk factors and vulvar cancer by ages.
As for the older population, GDP per capita (β = 0.354, CI 0.211-0.496,P < .001),HDI (β = 0.358, CI 0.211-0.496,P < .001),higher prevalence of smoking (β = 0.187, CI 0.148-0.227,P < .001)and alcohol drinking (β = 0.326, CI 0.265-0.388,P < .001)are found to have a significant positive association with the vulvar cancer incidence.Physical inactivity and obesity are found to have no significant linear associations with higher vulvar cancer incidence.In contrast to the findings for the younger population, unsafe sex and HIV infection do not appear to be risk for vulvar cancer.Multivariate regression analysis shows similar results, with smoking (β = 0.127, CI 0.077-0.178,P < .001)and alcohol drinking (β = 0.227, CI 0.140-0.314,P < .001)being the only risk factors associated among the older population after adjusted for confounders.

| Variation in the disease burden
Overall, there is a substantial geographical variation in the disease burden of vulvar cancer.A high burden of disease is observed in regions with higher HDI including Western Europe, Northern America and Northern Europe, which is in line with findings in previous studies regarding the higher burden disease found in higher-income countries. 18One possible explanation is the disparity in the availability of screening and public awareness of the disease.The detection of vulvar cancer is mostly through cervical cancer screening programs as there is no known screening recommendation for vulvar cancer. 19wever, there have been limited screening strategies in low-and middle-income countries (LMICs), 19 and the participation rate in cervical screening is low owing to the lack of knowledge, socioreligious and cultural barriers. 20Furthermore, the lack of national databases and suboptimal quality of cancer registries may have also contributed to the lower disease burden. 21ere is a remarkable discrepancy in the age pattern of the disease burden.In our study, we identify a higher disease burden in  [22][23][24][25] The difference could possibly ascribe to the difference in the type of vulvar cancer.It is suggested that vulvar squamous cell carcinomas (the majority of vulvar malignancies) may develop following two pathways, leading to a heterogeneous etiology, based on histopathologic characteristics. 26,27[30]

| Risk factors associated with vulvar cancer incidence
Our study has identified several risk factors associated with a higher incidence of vulvar cancer.
The association between unsafe sex 18,31 and HIV infection, [32][33][34] and vulvar cancer incidence has been recognized in previous studies.
An earlier study found that the standardized incidence ratio (SIR) for vulvar cancer in HIV-infected people was 9.35 (95% CI: 7.91, 11.0). 34 our study, we also identify that alcohol consumption is one of the risk factors for vulvar cancer.However, previous findings on the association have been inconclusive. 35,36We suspect that the factors of alcohol consumption, unsafe sex, and the prevalence of HIV interact and form a causal link in which alcohol consumption indirectly elevates the risk of vulvar cancer through increasing the intentions to engage in unsafe sex by impairing decision making, 37 and thence the risk of HIV transmission.9][40][41] Current smoking status could be one of the major factors as current smokers (OR: 2.2, 95% CI: 1.2-4.2) have a significantly higher risk of vulvar cancer, but significant risk elevation was not found among former smokers (OR: 1.4, 95% CI: 0.7-2.8). 42ese results might be suggestive of the importance of smoking cessation programs.
Obesity has been reported as a significant risk factor in several studies. 6,41A study reported a 62% (95% CI: 6%-134%) increase in the risk of vulvar cancer among women with a BMI of 30 or more (compared to body mass index [BMI] < 25). 41However, no significant association between obesity and higher vulvar cancer incidence is found in our study.A possible reason behind the disparity in findings is that vulvar cancer incidence follows a bimodal pattern, with higher incidence found in both developing and highly developed regions for the two histologic pathways, it is likely that there is a nonlinear association.
The bimodal pattern has also contributed to the highly varying risk factors among the two age groups, supporting the early findings regarding the disparity in disease burden: HIV and unsafe sex are associated with higher vulvar cancer incidence among younger females, while HDI, GDP per capita, smoking and alcohol drinking are associated with higher vulvar cancer incidence among older females in developed regions.

| Temporal incidence trends of vulvar cancer
4][45][46] There are some common explanations to increasing incidence rate in cancer, including improved diagnostic procedures, increasing awareness of the disease and increasing prevalence of risk factors. 44For instance, a highly significant increasing trend is found in Germany, possibly led by a higher HPV prevalence owing to more permissive sexual behaviors in German female birth cohorts from 1940 onwards, 47 and the increase in smoking prevalence and the decline in the age of smoking initiation. 48,49In some other countries, despite the increase in HPV vaccination coverage and the decrease in HPV prevalence, significant decline in vulvar cancer incidence is not observed, possibly ascribed to the latency period and delays in diagnosis. 50Nevertheless, an analogous decline in the incidence of vulvar cancer among the younger female population in the future can be anticipated.

| Limitations
There are several limitations that should be noted.First, underreporting or incorrectly categorized cancer cases are possible, due to the poor quality of cancer data, registry coverage and analytical capabilities, particularly in LMICs.Second, an ecological study design is used in our study using data on a population level, cautions must be exercised during the interpretation of the results, especially when comparing with studies using data on the individual level.Third, direct comparisons across nations may not be appropriate since state cancer registries could change over time.However, it is comparably reliable to compare site-and country-specific results for the same time span.

| Implications
The disease burden of vulvar cancer follows a bimodal pattern according to its two histologic pathways, affecting women in both developed and developing regions.There are modifiable risk factors contributing to the two types of vulvar cancer, including smoking and HPV infection.The former can be ameliorated by smoking cessation programs, was used for trend analysis.It is software developed by the SEER Program of the National Cancer Institute of the United States.Average Annual Percentage Change (AAPC) was used to examine the temporal trend of vulvar cancer incidence.As a common practice, the most recent 10 years of data available (2003-2012) are used to conduct the analysis.Logarithmic transformation was adopted for the incidence data and the corresponding standard errors were produced.The results were used to calculate the AAPC and 95% CI for various demographic categories.The temporal trends of vulvar cancer were represented by the AAPC.A positive AAPC represents an increasing trend while a negative AAPC represents a decreasing trend.

A
mixed trend is observed in the incidence of vulvar cancer among younger females aged between 15 and 49, as significant increasing trends and decreasing trends are observed in 5 and 2 countries, F I G U R E 4 AAPC of vulvar cancer incidence, females, all ages.*P values less than .05.AAPC, annual percentage change.

F
I G U R E 6 AAPC of vulvar cancer incidence, females, 50 to 74 years.*P values less than .05.AAPC, annual percentage change.Southern Africa and populations with low HDI among younger females; and Western Europe and populations with very high HDI among older females, which accord with previous findings using data on a national level.A retrospective study conducted in South Africa found that women referred to a local hospital with vulvar cancer (mean age [SD]: 52.5 [15.5]) were on average 10-15 years younger than those in high-income countries (median age: 67, USA 2003-2007; 70.4, the Netherlands 1992-2005; 64, Australia 1988-2009).