Characteristics and variations in young adults with cutaneous melanoma: A national cancer database analysis

Many cancers in young adulthood differ in terms of biology, histologic variation, and prognosis compared to cancer in other older age groups. Differences in cutaneous melanoma among young adults compared to other older age groups, as well as between sexes in young adults are not well studied.

Cutaneous melanoma is a commonly diagnosed primary cutaneous malignancy that accounts for 0.7% of all annual cancer deaths worldwide. 1,2Incidence rates for cutaneous melanoma have been continuously increasing by approximately 3% annually worldwide amongst the adult and pediatric populations. 1,3Melanoma is considered the second most common type of cancer in young adults aged 18-39 years old. 3,46][17][18][19] However, there have been few studies examining the differences specifically between young males and young females with melanoma. 20rly adult cancer is an underestimated challenge that merits specific resources, solutions, and a national focus. 5This study utilized a large national cancer database to evaluate patients with cutaneous melanoma.The primary aim of the study was to compare patient characteristics, disease factors, and management in young adults compared with other older age groups.The study's hypothesis is that young adults with melanoma have different patient and disease characteristics compared to other older age groups.
Further, there is a need to study differences between males and females in this age group, to better optimize diagnostic and therapeutic interventions for this population.Therefore, our secondary aim is to compare disease and treatment factors between young adult males compared to young adult females.We hypothesize that sex-specific differences will exist with variations in disease characteristics, treatment factors, and overall survival.

| Data source
Data for this retrospective cohort study was from the National Cancer Database (NCDB), a large hospital-based cancer collaboration sponsored by the American Cancer Society and the American College of Surgeons.The NCDB captures over 70% of all new cancer diagnoses from 1500 Commission on Cancer (CoC) accredited facilities, making it one of the most comprehensive sources of public health data on cancer in the United States. 21,22The NCDB contains a consistent set of data including demographic information, pathology, treatment modalities, and survival of individual patients who received some element of their cancer care at a CoC-accredited facility.This study was deemed to be exempt from institutional review board approval.

| Case selection criteria
The NCDB was queried for patients 18-90 years of age diagnosed with clinical stages I-IV cutaneous melanoma between 2004 and 2017.Staging was determined based on the American Joint Committee on Cancer (AJCC) Staging Manual, seventh edition.
International Classification of Diseases (ICD-O-3) primary site codes C440-C449 were used (Supporting Information S1: Appendix 1A).A subgroup of patients 18-39 years of age defined as young adults was further studied in subgroup analyses.Patients with missing data on clinical staging were excluded.Patients who had unknown surgical resection status or melanoma involving the eye were excluded (Supporting Information S1: Appendix 1B).

| Factors considered
Patient demographics and characteristics included age, sex, race, insurance status, median income status within the area of residence, urban/rural status of home zip code, and Charlson-Deyo Comorbidity Index (CDCI).Age groups included 18-39 years of age, 40-64 years of age, and 65 years of age and older.We defined the age range of 18-39 years as young adults based on previously published literature on melanoma in this demographic and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program, which categorizes adolescents and young adults as those aged 15-39 years. 3,5,10,14,23Furthermore, within the 18-39-year-old cohort, we conducted further analysis by stratifying individuals into two age groups: 18-25 years old and 26-39 years old.Urban/rural status was divided into metropolitan, rural adjacent to metropolitan area, and rural.Facility-related data included the distance traveled to the treatment facility.Variables such as facility location and facility type are suppressed in NCDB for patients less than 40 years of age and therefore not included in this study.The characteristics of melanoma included primary site location, histology, and clinical stage.Treatment variables included surgical status, surgical margins, radiation, chemotherapy, and immunotherapy.Overall survival and median follow-up time were also captured in the database.

| Statistical analysis
Chi-square tests were used to analyze differences between patient characteristics, tumor characteristics, and treatment options in the overall cohort and in the young adult subgroup, which was further stratified by the clinical stage of disease.Overall survival (OS) rates were examined using the Kaplan-Meier method and compared among age-based cohorts and sexes after stratifying by stage using log-rank tests.All statistical tests were two-sided, and alpha was set at a significance of 0.05.All analyses were performed using SAS statistical software, version 9.4 (SAS Institute Inc.).

| Patient and disease characteristics
We identified 329 765 patients from the NCDB diagnosed with stages I-IV cutaneous melanoma between 2004 and 2017.Table 1 summarizes patient and disease characteristics for the overall cohort stratified by age group.In the overall cohort, a larger proportion of the patients were male, White non-Hispanic, insured, and from a metropolitan area.Regardless of age, most patients had stage I melanoma and received surgery for their disease.Of the 18-39-yearold patients, 63.5% (n = 21 987) were female, which was the opposite of the proportions in the 65-year-old and greater age group, where 34.1% (n = 51 256) of the patients were female (p < 0.001).The proportion of patients with insurance increased as patients aged, with 93.4% (n = 32 347) insured at ages 18-39 years old and 97.9% (n = 146 996) insured at age 65 and older (p < 0.001).There was a higher proportion of White Hispanic and Asian Pacific Islander patients in the younger age group compared to the older patients (p < 0.001).
The primary site of the tumor differed by age group in that tumors of the head, neck, upper extremities, and back were more prevalent in other older age groups and tumors of the trunk and lower extremities were more common in younger adults (p < 0.001).
Tumor histology also revealed similar transitions; younger adults were more likely to have superficial spreading melanoma while other older age groups were more likely to have nodular or lentigo maligna melanoma compared to the opposing age group (p < 0.001).Overall, younger adults had higher proportions of stage I tumors and lower proportions of stage IV tumors compared to other older age groups (p < 0.001).A higher percentage of patients in the younger adult age group lived more than 6 months compared to the oldest age group (91.3% vs. 57.3%,p < 0.001).The median follow-up time for patients alive after 6 months was 78.2 with an interquartile range (IQR) of 48.0-118.7 months from diagnosis for those 18-39 years old, which was the longest compared to 77.7 (IQR: 49.5-115.9)months for those 40-64 years old and 65.5 (IQR: 43.9-97.1)months for those 65 years and older (p < 0.001).
In the young adult subgroup summarized in Table 2, there was a higher percentage of male patients without insurance compared to female patients (5.3% vs. 3.8%, p < 0.001).Male young adults were more likely to have melanoma of the head, neck, and back, while female young adults were more likely to have melanoma of the upper and lower extremities (p < 0.001).Male patients also had a greater likelihood of having nodular melanoma, while female patients were more likely to have superficial spreading disease (p < 0.001).After stratifying by stage, the differences in the primary site of the melanoma between young males and females persisted across all stages (all p < 0.05), while histology was only significantly different between sexes for stage I and stage II patients (p < 0.05) (Table 3).
A higher proportion of male young adults had stage II or greater melanoma compared to female young adults (30.6% vs. 17.5%, p < 0.001).With male patients having higher tumor stages, they had an increased percentage of patients who received immunotherapy, radiation, and chemotherapy compared to female patients (p < 0.001).
Male young adults subsequently had decreased percentages of patients that lived more than 6 months compared to female young adults (86.3% vs. 94.2%,p < 0.001).The median follow-up time for young females alive after 6 months was 79.4 (IQR: 48.6-119.9)months from diagnosis which was longer than young males who had a median follow-up of 75.7 (IQR: 46.9-116.1)months from diagnosis (p < 0.001).

| Kaplan-Meier analysis of overall survival
In the overall cohort, patients in the young adult subgroup had improved 5-year OS compared to patients 40-64 years and greater than 65 years of age across all stages (all p < 0.001) (Figure 1).In the young adult subgroup, an increased 5-year OS was seen in female patients compared to male patients for all stages of disease (all p < 0.001) (Figure 2).Once further stratified, a decreased 5-year OS was seen in the 26-39-year-old cohort compared to the 18-25-yearold cohort (all p < 0.05) (Figure 3).

| DISCUSSION
Our retrospective study used a multicenter national database to evaluate the differences in patient characteristics, disease features, and management in young adults compared with other older age groups with stages I-IV cutaneous melanoma.7][8] While some studies have analyzed the differences between age groups, few studies have evaluated the characteristics and outcomes of young male compared to young female patients with cutaneous melanoma in the United States. 3,20,24Results from this study demonstrate that there are significant differences among young adult males and females, with young males having a higher likelihood of being uninsured, higher stage, and decreased overall 5-year OS compared to young adult females.While there were statistically significant differences in 5-year OS for each stage of disease between young males and young females, the difference was more pronounced in later stages of disease.Specifically, for stage I, the 5-year OS rates were 0.987 for young females compared to 0.973 for young males.For stages II, III, and IV, the survival rates were 0.889 versus 0.818, 0.807 versus 0.680, and 0.295 versus 0.240, respectively.This suggests that the clinically meaningful differences are potentially confined to patients in the later stages of disease.In stage I disease the 5-year OS difference is likely not clinically significant.
T A B L E 1 Description and univariate analysis for cutaneous melanoma patients comparing age groups.| 1557 Our study found that there is an inverse relationship between the proportion of melanoma between sexes in younger adults (36.5% male) compared to adults over 65 years of age (65.9% male).Similar trends have been reported in the literature utilizing institutional data, regional collaboratives, and the SEER program. 3,7,8,10,14,24Factors that have been attributed to this inverse relationship include an increased risk of melanoma in young females secondary to increased female sex hormones, the use of oral contraceptives, and hormonal replacement therapy. 12Others have postulated that young women are more likely to partake in tanning behaviors and the use of sunbeds, while older men are less likely to examine their skin and seek attention from dermatologists for skin examinations. 15A B L E 2 Description and univariate analysis of cutaneous melanoma young adult patients comparing gender.We also determined a significant difference in the distribution of tumor location and histological subtype between the age groups of interest.There is a higher proportion of young adults with tumors of the trunk and lower extremity and a lower proportion of tumors of the head, neck, upper extremity, and back compared to other older age groups.Plym et al. completed a retrospective review of patient data from the Uppsala/Örebro Health Care Region in Sweden and discovered comparable trends. 10Del Fiore et al. used the Veneto Cancer Registry in Italy and found parallel trends with the exception of no difference in the proportion of melanoma affecting the lower extremities. 36][27] Moreover, we found that young adults were more likely to present with a clinically lower or less advanced stage of disease compared to older adult patients, which was also associated with a better 5-year OS in the younger adult cohort.
Following stratification into two age groups, a significant decrease in 5-year OS emerged among patients aged 26-39 as opposed to those 18-25 within the young adult cohort.The Kaplan-Meier curve for this cohort suggests that the diminished survival is predominantly influenced by the older subgroup of patients.We then investigated the differences between males and females in the young adult cohort.We found that male patients were more likely to be uninsured compared to female patients.Callahan et al. completed a cross-sectional study examining young adults in Massachusetts and discovered that young males were twice as likely to be uninsured compared to young females. 28They also found young men had significantly higher odds of not having routine health checks and both males and females in the young adult population had significantly higher odds of reporting the inability to afford needed care. 28Similar trends were also seen in a larger analysis using the National Health Interview Survey. 29r study finds that young male patients are more likely to present with advanced clinical stages of melanoma compared to females.Males subsequently had decreased 5-year OS compared to their female counterparts for all stages of melanoma.One study theorizes that young males have a higher likelihood of having nodular melanoma and melanoma of the head/neck, both of which have been associated with a worse prognosis. 15Our study modeled these trends, as young adult males had a greater proportion of nodular melanoma and head/neck tumors in all clinical stages compared to young adult females.Enninga et al. completed a study using the SEER program and found the risk of death due to localized melanoma, regardless of Breslow depth, histology, or anatomic location, was greater in men compared to women after adjusting for age, with the most increased risk in the 18-45-year-old age group (hazard ratio [HR]: 2.05, confidence interval [CI]: 1.79-2.35,p < 0.001). 16These findings have been supported in more recent literature.Hieken et al.   found that females less than 45 years old with cutaneous melanoma had better cancer-specific survival within each stage compared to all other sex and age groups (p < 0.001). 30Bhutada et al. observed comparable sex-related distinctions among adolescents and young adults, noting that the presence of metastatic melanoma was independently correlated with male gender (adjusted OR = 3.11). 31tably, this disparity emerged as the most pronounced among the 12 cancers studied in terms of gender differences, underscoring the importance of understanding the gender-specific dynamics of melanoma in this population. 31r findings underscore the need for targeted interventions and heightened awareness in addressing the unique challenges faced by young adults.There is a need for actionable strategies to improve the outcomes in this population.Specifically, interventions with practical steps should be directed toward young males and patients 26-39 years old to address this need.Initiatives such as enhancing public health campaigns to educate young adults about melanoma risks and promoting sun-safe behaviors can contribute to prevention efforts.
Protection against ultraviolet (UV) radiation from infancy remains a keystone to prevention. 7Public health campaigns in Australia and Europe have been executed to promote awareness of the risk of sun exposure which has subsequently resulted in stabilizing or decreasing melanoma incidence rates in young adults in those countries. 12To specifically target individuals 26-39 years old, workplaces should collaborate with employees to implement sun safety programs, emphasizing the importance of sun protection, particularly during breaks and outdoor work. 32Given that the majority of outdoor work is commonly carried out by males, the implementation of sun safety programs in the workplace becomes especially crucial. 33Another method for targeting this age group is to establish skin check clinics at fitness centers or gyms, which are frequently attended by individuals of this age group.Furthermore, societies should leverage social media platforms with content addressing skin health, melanoma awareness, and prevention strategies tailored to the interests of individuals aged 26-29. 34ditionally, the establishment of networks between melanoma centers, the development of specific clinical management guidelines including the use of gene expression profiling, and the promotion of multidisciplinary collaboration are crucial steps toward standardizing and improving the care of young adults with melanoma. 7In the absence of specific treatment guidelines, young adults with melanoma are managed similarly to other older adults with generalized guidelines. 7The Children's Oncology Group has formed an Adolescent and Young Adult (AYA) Committee that aims to improve access to care for young adults through understanding barriers of participation, enhance adolescent treatment adherence, and develop a cancer resource network to provide information about clinical trials to patients, families, and providers. 5Moreover, supporting research on gene-environment interactions and advocating for policy changes to address insurance disparities will further contribute to a comprehensive approach to addressing the specific needs of young adults, particularly young males, in the context of cutaneous melanoma. 12While improvements in the array of therapeutic options and enrollment in clinical trials have been historically lower in adolescents and young adults, there has been a positive trend in the enrollment of young adults with melanoma in recent years, associated with a better 3-year OS in young adults with advanced disease compared to those that were not enrolled. 7,35e results of this study should be interpreted with the following limitations.This was a retrospective study utilizing the NCDB database, thus, the data are vulnerable to potential clerical and coding errors.The NCDB database receives its data from CoCapproved hospitals, therefore there can be an inherent risk of selection bias as patients treated at many outpatient treatment centers may be excluded.Additionally, the study is limited by the absence of disease-specific survival and information regarding recurrence. 9Due to the lack of disease-specific survival data, the overall survival difference by sex we observed may be affected by sex differences in other causes of death, such as unintentional injury.Also, while statistically significant, the disparity in the 5-year OS rate for stage I disease between young males and females was only 0.014 (0.987 vs. 0.973), suggesting limited clinical significance.Moreover, the 5-year OS for stage I disease in young adults is likely comparable to that of the general population, given the high rates of survival for both sexes.However, based on the US Social Security's period life table, 36 the discrepancy in 1-year death probability for individuals aged 18-39 is around 0.001, a margin considerably smaller than the survival differences we observed in our melanoma cohort, especially among stages II, III, and IV patients.Further, our findings of sex difference in survival align with the study by Joosse et al., which examined metrics including overall survival, disease-specific survival, relapse-free survival, and time to distant metastasis. 37Finally, the NCDB suppresses the variable for facility location and facility type for patients less than 40 years of age so we were unable to include these important variables in our analysis.Nonetheless, our study included a large national sample size and highlighted key differences between age groups and sexes of melanoma patients.

| CONCLUSIONS
In this comprehensive retrospective study, we found that there are significant differences in patient characteristics, disease features, and management for young adults compared to other older age groups with stage I-IV cutaneous melanoma.When young adults were stratified by sex, there were also significant differences between females and males, with males having a greater proportion of higher disease stages, histology with worse prognosis, and disparities such as no insurance.Furthermore, after adjusting for the same clinical stage, male young adults had a worse overall survival compared to female young adults.The difference in overall survival was most pronounced in later stages of the disease.This study supports the continued need for increased attention in bringing awareness to the differences that young adults with cutaneous melanoma face, with particular attention on young males and those 26-39 years old.

T A B L E 3
Description and univariate analysis of cutaneous melanoma young adult patients comparing gender, stratified by clinical stage.