Abstract
Background
Male sex appears to be associated with more advanced melanoma stage and inferior prognosis, but population‐based data on sex disparities in stage‐specific recurrence and mortality remain limited.
Objectives
The objective of this study was to examine sex disparities in (1) melanoma stage at diagnosis and (2) stage‐specific recurrence and long‐term melanoma‐specific mortality.
Methods
This population‐based cohort study included all Danes with melanoma from 2004 to 2022 identified in the Danish Cancer Register. The impact of sex on melanoma stage diagnosis (Breslow thickness, presence of ulceration, presence of lymph node metastases and presence of distant metastases) was investigated using multivariable logistic regression models. Furthermore, we examined melanoma recurrence, melanoma‐specific and overall mortality for stage I + II (localized), stage III (locoregional) and stage IV (metastatic) melanoma in a competing risk model, adjusting for stage at diagnosis, comorbidity, age and calendar year.
Results
This study included 30,497 individuals diagnosed with melanoma; the median follow‐up time was 8 years, and 14,409 (47%) were male. Males had, compared to females, an increased adjusted odds ratio (aOR) of Breslow thickness >4 mm (aOR 1.45, 95% CI: 1.31–1.59), presence of ulceration (aOR 1.28, 1.18–1.39), >1 lymph node metastases (aOR: 1.58, 1.38–1.80) and distant metastases (aOR: 1.69, 1.48–1.94). In stage‐adjusted analyses, males with localized melanoma had an increased adjusted hazard ratio (aHR) of melanoma recurrence (aHR: 1.38, 1.27–1.51) and melanoma‐specific mortality (aHR: 1.51, 1.34–1.71). In patients with locoregional and metastatic melanoma, males had an inferior prognosis, but it was less pronounced.
Conclusions
This nationwide cohort study found that males were more likely to be diagnosed with more advanced stages of melanoma. Analyses stratified by stage at diagnosis, showed that males had a 20%–50% higher risk of melanoma recurrence, melanoma‐specific and overall mortality across localized, locoregional and metastatic melanoma.
Keywords: melanoma, mortality, neoplasm recurrence, neoplasm staging, prognosis, sex
Plain Language Summary
What is the disease?
Melanoma is a form of skin cancer that develops from pigment‐producing cells in the skin. The number of people diagnosed with melanoma has been increasing worldwide.
Location of the study
This study was carried out in Denmark using nationwide health registers.
Aim of the study
We wanted to find out if men and women differ in how advanced their melanoma is at diagnosis—such as if it has grown deeper into the skin or spread—and if their risks of recurrence or death vary by stage of the disease.
Methodology
We included 30,497 people diagnosed with melanoma in Denmark between 2004 and 2022, with a median follow‐up of 8 years. We compared stage at diagnosis (tumour thickness, ulceration, spread to lymph nodes or distant metastases) as well as the risk of recurrence and death from melanoma between men and women.
Key findings
Men were more likely than women to be diagnosed with thicker tumours, ulceration, lymph node spread and distant metastases. Even when comparing men and women at the same melanoma stage, men had a 20%–50% higher risk of recurrence and death from melanoma.
Conclusions and practical implications
This study shows that men are at higher risk of advanced melanoma at diagnosis and worse outcomes across all stages. These findings highlight the need for sex‐specific approaches in early detection, follow‐up and treatment strategies, to improve prognosis and reduce the gap between men and women.
In this nationwide Danish cohort of 30,497 melanoma patients, males were more often diagnosed with advanced disease and had a 20%–50% higher risk of recurrence and melanoma‐specific mortality than females, underscoring the need for sex‐specific detection strategies and improved risk stratification.
Why was the study undertaken?
Male sex appears to be associated with a more advanced melanoma stage and worse prognosis. Still, population‐based data on sex disparities in stage‐specific recurrence and long‐term melanoma‐specific mortality are limited.
What does this study add?
In a nationwide Danish cohort of 30,497 patients with individual‐level data and long‐term follow‐up, males were more likely than females to present with thicker melanomas, ulceration, lymph node involvement and distant metastases. Stage‐stratified analyses showed males had a 20%–50% higher risk of melanoma recurrence and melanoma‐specific mortality across localized, locoregional and metastatic melanoma.
What are the implications of this study for disease understanding and/or clinical care?
These findings support the need for sex‐specific detection strategies and improved risk stratification, as early detection alone may be insufficient to address the worse prognosis observed in males.
INTRODUCTION
During the past decade, male sex has been suggested to be associated with more advanced melanoma stage at diagnosis and inferior survival. 1 , 2 Both biological and behavioural factors are proposed to contribute to these disparities between the sexes. 3 , 4 , 5 , 6 However, the underlying mechanisms are not fully understood.
Most studies have focused on a single outcome, reporting an association between male sex and increased tumour thickness and ulceration at diagnosis, 7 decreased melanoma‐specific survival 8 , 9 and decreased overall survival. 10 , 11 , 12
However, there is limited knowledge of the impact of sex on melanoma stage at diagnosis and melanoma progression within the same population. One study from Germany found more advanced tumour stages and increased risk of recurrence in males compared with females among 11,744 patients with melanoma diagnosed between 1978 and 2007. 1
As melanoma treatment continues to evolve, accurate risk stratification is essential to ensure that patients are allocated to relevant treatment and follow‐up regimens. Understanding sex differences in melanoma progression and prognosis is therefore crucial for optimizing clinical decision‐making and treatment strategies. To improve our understanding of sex disparities in melanoma and their clinical implications, population‐based studies assessing multiple relevant outcomes in the same population are needed.
To address this gap, we conducted a nationwide population‐based study to assess the impact of sex on melanoma stage at diagnosis and long‐term outcomes, including melanoma recurrence, melanoma‐specific mortality and overall mortality. By performing stage‐specific analyses, we aim to enhance risk stratification and guide treatment strategies for patients with melanoma.
MATERIALS AND METHODS
Study design and population
This population‐based cohort study included all individuals aged 18 years or older diagnosed with invasive melanoma in the Danish Cancer Register from January 1, 2004, to December 31, 2022. The included individuals were followed until Dec 31, 2024. Individuals with a history of cancer and individuals with melanoma in situ were excluded.
Description of melanoma treatment regimes in Denmark
In Denmark, T1 melanomas are treated surgically with a 1 cm resection margin. For stage II melanomas and higher, a 2 cm resection margin is used. Patients with ulcerating T1b melanomas or higher are offered sentinel node biopsy. Until 2018, the standard treatment for sentinel node metastasis was complete lymph node dissection; hereafter, this was only performed for macro metastases. Systemic treatments for metastatic melanoma include immune checkpoint inhibitors, introduced in 2010 and BRAF inhibitors, introduced in 2012. Adjuvant treatment with nivolumab for stage III melanoma was introduced in 2018. A comprehensive analysis of medical treatment of melanoma could not be conducted, due to unavailability of data.
Data sources
This study was conducted using population‐based data from the Danish health registries. These registries contain information on all contacts with the tax‐funded universal health care system and can be linked with a unique personal identification number assigned to all Danish residents. The validity and completeness of the Danish registries are generally of high quality and are widely used in epidemiological research. 13 The Danish Cancer Registry 14 was used to identify individuals diagnosed with melanoma and to determine melanoma stage at diagnosis. The Danish Civil Registration System 15 was used to obtain the age and sex of the patients. Cause and date of death were identified in the Danish Register of Causes of Death. 16 The Danish National Patient Registry 17 was used to determine comorbidity at the time of diagnosis and was combined with the Danish National Pathology Registry 18 to determine melanoma recurrence.
Exposure and covariates
The main exposure in this study was sex. The biological sex is registered at birth as part of the unique personal identification number. Individuals who undergo legal gender change are assigned a new personal identification number corresponding to their gender identity. Legal sex change was made possible in Denmark in 2014. Since then, 2691 individuals (0.05% of the total Danish population) have undergone legal sex change during the study period. 19 It is not possible to identify these individuals; however, we assume that such few cases will not impact our results.
Comorbidity at the time of melanoma diagnosis was obtained from diagnoses related to hospital admissions as per the Charlson Comorbidity Index (CCI) 20 and categorized as a score of 0, 1–2 and >2. Furthermore, the American Joint Committee on Cancer (AJCC) clinical stage, age and year of diagnosis were recorded at baseline.
Outcomes
Melanoma TNM stage at the time of diagnosis was defined based on tumour thickness (T), lymph node involvement (N) and the presence of distant metastasis (M), following the AJCC staging system. 21 The T‐stage in melanoma is determined by the tumour thickness and the presence of ulceration. Breslow thickness was categorized into 0–1, >1–2, >2–4 and >4 mm. Ulceration was categorized as the absence/presence of ulceration. The N‐stage was determined by the presence of lymph node metastases. The N‐stage was categorized as the absence of lymph node metastases, 1 lymph node involved and >1 lymph node involved. The M‐stage is defined by the presence of distant metastases and was categorized as the absence/presence of distant metastases.
Melanoma recurrence was defined using a validated algorithm as described by Rasmussen et al., 22 based on the following criteria: (1) a diagnosis code of melanoma recurrence or melanoma metastasis, (2) a procedure code for radiotherapy, immunotherapy or chemotherapy related to melanoma, (3) a procedure code for surgical excision of melanoma recurrence of metastasis or (4) a SNOMED morphology code of melanoma recurrence of metastasis.
Melanoma‐specific mortality was defined as an ICD‐10 code of C43 (0–9) registered in the Danish Register of Causes of Death. 16
Ethics approval
The study was approved by the central region Denmark (file no. 1‐16‐02‐304‐19). Ethical approval is not required for register‐based studies under Danish law.
Statistical analysis
For the primary outcome, we performed a cross‐sectional analysis using univariable and multivariable logistic regression to estimate odds ratios (OR) of having an advanced stage of melanoma at diagnosis between males and females. The models were adjusted for age, comorbidity and year of diagnosis. OR for tumour thickness in categories >1–2, >2–4 and >4 mm was estimated with the thickness of 0–1 mm as reference. The presence of ulceration, 1 lymph node metastasis, >1 lymph node metastasis and distant metastases was estimated, with the absence of the outcomes as reference. Individuals with missing information were excluded from the respective analyses.
Cumulative incidence proportions of melanoma recurrence, melanoma‐specific mortality and overall mortality were estimated using the Aalen–Johansen estimator in a competing risk setting. 23 To examine the impact of sex on melanoma recurrence and melanoma‐specific mortality, we performed univariable and multivariable proportional subdistribution hazards regression analyses in a competing risk setting. 24 To examine overall mortality, we conducted univariable and multivariable Cox proportional hazards regression analyses. The patients were followed from melanoma diagnosis until emigration (censored), death (event) or end of follow‐up (December 31, 2024). In the analysis of melanoma‐specific mortality, non‐melanoma deaths were treated as competing risks, while in the recurrence analysis, mortality was treated as a competing risk. Two different models of the adjusted analyses were conducted, one adjusted for age, comorbidity and year of diagnosis, and another additionally adjusted for stage at diagnosis. The regression analyses were stratified by localized melanoma (stage I + II), locoregional melanoma (stage III) and metastatic melanoma (stage IV). Individuals with unknown melanoma stage were excluded. All analyses were conducted in R. The results were presented with 95% confidence intervals (CI). A p‐value of <0.05 was considered statistically significant.
RESULTS
Baseline characteristics
We identified 42,268 individuals diagnosed with melanoma between 2004 and 2022 in Denmark. A total of 11,771 were excluded (Figure 1). A total population of 30,497 individuals was included with a median follow‐up time of 8.0 years. Of the patients, 14,409 (47%) were males and 16,088 (53%) were females. Compared to females, males were older at the time of diagnosis (median of 61 years vs. 54 years), more likely to be diagnosed with stage III + IV melanoma (14% vs. 9.2%) (Table 1 and Table S1) and diagnosed with more pre‐existing comorbidities (CCI score >0: 27% vs. 21%) (Table 1).
FIGURE 1.
Number of patients included in the study after applying the exclusion criteria.
TABLE 1.
Baseline characteristics of study cohort.
| Baseline characteristics | |||
|---|---|---|---|
| Characteristic | Males; N = 14,409 (47%) | Females; N = 16,088 (53%) | Total; N = 30,497 |
| Age a , Median (IQR) b | 61 (49, 71) | 54 (42, 68) | 58 (45, 70) |
| Follow‐up time, median (IQR) b | 7.3 (3.8, 12.1) | 8.6 (4.7, 13.6) | 8.0 (4.2, 12.9) |
| Melanoma stage at diagnosis | |||
| Localized melanoma c | 11,630 (81%) | 13,830 (86%) | 25,460 (83%) |
| Locoregional melanoma d | 1,334 (9.9%) | 1,046 (6.9%) | 2,380 (8.3%) |
| Metastatic melanoma e | 573 (4.2%) | 345 (2.3%) | 918 (3.2%) |
| Unknown | 872 (6%) | 867 (5%) | 1,739 (6%) |
| Breslow tumour thickness | |||
| 0–1 mm | 7,890 (54.8%) | 10,203 (63.4%) | 18,093 (59.3%) |
| >1–2 mm | 2,582 (17.9%) | 2,695 (16.8%) | 5,277 (17.3%) |
| >2–4 mm | 1,466 (10.2%) | 1,162 (7.2%) | 2,628 (8.6%) |
| >4 mm | 1,123 (7.8%) | 843 (5.2%) | 1,966 (6.4%) |
| Unknown | 1,348 (9.4%) | 1,185 (7.4%) | 2,533 (8.3%) |
| Presence of ulceration | |||
| Absent | 11,637 (80.8%) | 13,737 (85.4%) | 25,374 (83.2%) |
| Present | 1,468 (10.2%) | 1,180 (7.3%) | 2,648 (8.7%) |
| Unknown | 1,304 (9.0%) | 1,171 (7.3%) | 2,475 (8.1%) |
| Presence of lymph node metastases | |||
| Absent | 10,625 (73.7%) | 12,591 (78.3%) | 23,216 (76.1%) |
| 1 lymph node involved | 1,016 (7.1%) | 777 (4.8%) | 1,793 (5.9%) |
| >1 lymph node involved | 567 (3.9%) | 404 (2.5%) | 971 (3.2%) |
| Unknown | 2,201 (15.3%) | 2,316 (14.4%) | 4,517 (14.8%) |
| Presence of distant metastases | |||
| Absent | 12,421 (86.2%) | 14,121 (87.8%) | 26,542 (87.0%) |
| Present | 573 (4.0%) | 345 (2.1%) | 918 (3.0%) |
| Unknown | 1,415 (9.8%) | 1,622 (10.1%) | 3,037 (10.0%) |
| Charlson comorbidity index score | |||
| 0 | 10,461 (72.6%) | 12,676 (78.8%) | 23,137 (75.9%) |
| 1–2 | 2,868 (19.9%) | 2,718 (16.9%) | 5,586 (18.3%) |
| >2 | 1,080 (7.5%) | 694 (4.3%) | 1,774 (5.8%) |
Age at melanoma diagnosis.
Interquartile range.
American Joint Committee on Cancer (AJCC) clinical stage I + II.
AJCC clinical stage III.
AJCC clinical stage IV.
Melanoma stage (TNM) at diagnosis
Males were more likely than females to be diagnosed with advanced melanoma (thickness, ulceration, lymph node and distant metastases) (Figure 2 and Table S1), and they had an increased adjusted OR (aOR) of being diagnosed with melanoma thickness of >1–2 mm (aOR 1.18, 95% CI: 1.11–1.26), >2–4 mm (aOR 1.43, 95% CI: 1.32–1.56), >4 mm (aOR 1.45, 95% CI: 1.31–1.59) and the presence of ulceration (aOR 1.28, 95% CI: 1.18–1.39) (Table 2). Furthermore, males had an increased risk of having 1 lymph node metastasis (aOR 1.51, 95% CI: 1.37–1.66), >1 lymph node metastasis (aOR 1.58, 95% CI: 1.38–1.80) and distant metastases (OR 1.69, 95% CI: 1.48–1.94) at the time of diagnosis.
FIGURE 2.
Barplot of the proportional distribution of melanoma stage at diagnosis between males and females.
TABLE 2.
Univariable and multivariable logistic regression analyses of the melanoma stage (TNM) at the time of diagnosis in males compared with females.
| TNM stage at the time of diagnosis for males compared to females | ||||
|---|---|---|---|---|
| Characteristic | Crude OR a | 95% CI b | Adjusted OR c | 95% CI b |
| Tumour thickness | ||||
| Tumour thickness 0–1 mm | Ref. | Ref. | Ref. | Ref. |
| Tumour thickness >1–2 mm | 1.24 | 1.17–1.32*** | 1.18 | 1.11–1.26*** |
| Tumour thickness >2–4 mm | 1.63 | 1.50–1.77*** | 1.43 | 1.32–1.56*** |
| Tumour thickness >4 mm | 1.72 | 1.57–1.89*** | 1.45 | 1.31–1.59*** |
| Presence of ulceration | ||||
| No | Ref. | Ref. | Ref. | Ref. |
| Yes | 1.47 | 1.36–1.59*** | 1.28 | 1.18–1.39*** |
| Presence of lymph node metastases | ||||
| No | Ref. | Ref. | Ref. | Ref. |
| 1 lymph node involved | 1.55 | 1.41–1.71*** | 1.51 | 1.37–1.66*** |
| >1 lymph node involved | 1.66 | 1.46–1.90*** | 1.58 | 1.38–1.80*** |
| Presence of distant metastases | ||||
| No | Ref. | Ref. | Ref. | Ref. |
| Yes | 1.89 | 1.65–2.16*** | 1.69 | 1.48–1.94*** |
Odds ratio.
Confidence interval.
Adjusted for age, comorbidity and year of diagnosis.
p‐value ≤0.001.
Melanoma recurrence, melanoma‐specific mortality and overall mortality
During a median follow‐up period of 8.0 [interquartile range (IQR): 4.2, 12.9] years after melanoma diagnosis, 4181 individuals with melanoma developed recurrence, 6222 died, and 2493 (40%) of the cases were caused by melanoma. For localized melanoma, estimated 5‐year melanoma recurrence was 9.0% for males and 5.2% for females [risk difference (RD): 3.8% (CI: 3.1%–4.5%)], melanoma‐specific mortality was 4.6% for males and 2.5% for females [RD: 2.1% (CI: 1.7%–2.5%)], and overall mortality was 13% for males and 7.8% for females [RD: 4.7% (CI: 4.0%–5.4%)] (Figure 3 and Table S2). For locoregional melanoma, estimated 5‐year melanoma recurrence was 49% for males and 42% for females [RD: 6.6% (CI: 2.4%–10.8%)], melanoma‐specific mortality was 24% for males and 19% for females [RD: 5.8% (CI: 2.4%–9.1%)]. For metastasized melanoma, estimated 5‐year melanoma‐specific mortality was 61% for males and 52% for females [RD: 8.5% (CI: 1.6%–15.4%)]. Stage‐specific incidence rates of melanoma recurrence, melanoma‐specific mortality, and overall mortality for stage IA to IIC showed similar results with a favourable prognosis among females (Tables S3–S5).
FIGURE 3.
Cumulative incidence proportions of melanoma recurrence, melanoma‐specific mortality and overall mortality for males and females.
Both unadjusted and adjusted regression analyses, across all cancer stages, found males to have an increased risk of melanoma recurrence, melanoma‐specific mortality and overall mortality, when compared with females (Table 3). The first adjusted model showed that in patients with stage I + II melanoma, males had an increased adjusted hazard ratio (aHR) of melanoma recurrence (aHR: 1.49, 95% CI: 1.37–1.62), melanoma‐specific mortality (aHR: 1.63, 95% CI: 1.44–1.84) and overall mortality (aHR: 1.45, 95% CI: 1.37–1.55). The fully adjusted model incorporating stage at diagnosis showed only slightly weaker associations (Table 3). Among patients with locoregional melanoma, the adjusted model 1 showed that males had an increased HR of melanoma recurrence (aHR: 1.20, 95% CI: 1.07–1.35), melanoma‐specific mortality (aHR: 1.33, 95% CI: 1.12–1.58) and overall mortality (aHR: 1.32, 95% CI: 1.19–1.46) compared with females. Adjusting additionally for stage at diagnosis showed similar results (Table 3). Similarly, for metastasized melanoma, males had an increased adjusted HR of melanoma‐specific mortality (aHR: 1.28, 95% CI: 1.07–1.52), when compared with females.
TABLE 3.
Univariable and multivariable hazard ratios comparing melanoma recurrence, melanoma‐specific mortality and overall mortality between males and females.
| Melanoma stage I + II | ||||||
|---|---|---|---|---|---|---|
| Characteristic | Crude HR a | 95% CI b | HR model 1 c | 95% CI b | HR model 2 d | 95% CI b |
| Melanoma recurrence | ||||||
| Female | Ref. | Ref. | Ref. | Ref. | Ref. | Ref. |
| Male | 1.65 | 1.52–1.80*** | 1.49 | 1.37–1.62*** | 1.39 | 1.28–1.52*** |
| Melanoma‐specific mortality | ||||||
| Female | Ref. | Ref. | Ref. | Ref. | Ref. | Ref. |
| Male | 1.83 | 1.62–2.06*** | 1.63 | 1.44–1.84*** | 1.52 | 1.34–1.71*** |
| Overall mortality | ||||||
| Female | Ref. | Ref. | Ref. | Ref. | Ref. | Ref. |
| Male | 1.71 | 1.60–1.81*** | 1.45 | 1.37–1.55*** | 1.43 | 1.34–1.52*** |
| Melanoma stage III | ||||||
| Characteristic | Crude HR a | 95% CI b | HR model 1 c | 95% CI b | HR model 2 d | 95% CI b |
| Melanoma recurrence | ||||||
| Female | Ref. | Ref. | Ref. | Ref. | Ref. | Ref. |
| Male | 1.23 | 1.09–1.38*** | 1.20 | 1.07–1.35** | 1.21 | 1.08–1.36** |
| Melanoma‐specific mortality | ||||||
| Female | Ref. | Ref. | Ref. | Ref. | Ref. | Ref. |
| Male | 1.40 | 1.18–1.65*** | 1.33 | 1.12–1.58*** | 1.35 | 1.14–1.60*** |
| Overall mortality | ||||||
| Female | Ref. | Ref. | Ref. | Ref. | Ref. | Ref. |
| Male | 1.40 | 1.22–1.61*** | 1.29 | 1.13–1.48*** | 1.32 | 1.15–1.51*** |
| Melanoma stage IV | ||||||
| Characteristic | Crude HR a | 95% CI b | HR model 1 c | 95% CI b | ||
| Melanoma‐specific mortality | ||||||
| Female | Ref. | Ref. | Ref. | Ref. | ||
| Male | 1.26 | 1.05–1.50* | 1.28 | 1.07–1.52** | ||
| Overall mortality | ||||||
| Female | Ref. | Ref. | Ref. | Ref. | ||
| Male | 1.31 | 1.12–1.53*** | 1.30 | 1.11–1.52*** | ||
Hazard ratio.
Confidence interval.
Model 1: Adjusted for age, comorbidity, year of diagnosis.
Model 2: Adjusted as model 1 and additionally for AJCC8 stage at diagnosis.
p‐value ≤ 0.01.
p‐value ≤ 0.001.
DISCUSSION
In this nationwide cohort study, we found substantial disparities between the sexes regarding melanoma stage at diagnosis and prognosis. Males were more likely to be diagnosed with increased tumour thickness and the presence of ulceration, as well as a higher likelihood of lymph node involvement and distant metastases compared with females. Furthermore, prognosis following a melanoma diagnosis was influenced by sex. Male sex was associated with a 20%–40% increased risk of melanoma recurrence and a 30%–50% increased risk of melanoma‐specific and overall mortality, even after adjusting for melanoma stage at diagnosis and comorbidity.
The higher risk of advanced melanoma T‐stage (characterized by thicker and ulcerated tumours) at diagnosis in males aligns with findings from three large studies primarily based on data collected before 2010; a population‐based study in the Netherlands (N = 54,645, year: 2000–2014), 7 as well as two large cohort studies from the U.S. (N = 106,511, 1992–2011) 9 and Germany (N = 11,734, 1978–2007). 1 Similar to our findings, the U.S. and German studies reported higher proportions of lymph node involvement (U.S.: 11% vs. 8.5%; Germany: 5.2% vs. 3.0%) and distant metastases (U.S.: 4.2% vs. 3.4%; Germany: 1.7% vs. 1.1%) at the time of melanoma diagnosis in males compared to females. 1 , 9 However, these studies did not provide adjusted analyses.
The German study was the only study to examine the impact of sex on disease progression, and similar to our findings, it reported a lower risk of melanoma recurrence in females. 1 In the present study, we stratified analyses by tumour stage and found that males had an increased risk of recurrence, both in individuals with localized melanoma (39% increased risk) and locoregional melanoma (21% increased risk), compared to females, accounting for ulceration status and comorbidity which was not included in the previous study.
Three studies have investigated the impact of sex on melanoma‐specific survival, all suggesting an inferior prognosis in males compared to females: a small institution‐based study (N = 1156, 2006–2016), 8 and the previously mentioned studies from the U.S. 9 and Germany. 1 The U.S. study stratified their analyses by tumour extent at diagnosis—categorizing cases as localized, locoregional or metastatic—though not based on the AJCC staging system used in the current study. 9 Similar to our findings, it observed an inferior survival for males, most pronounced in localized melanoma, followed by locoregional melanoma. 9
However, unlike our study, they did not find a sex difference in metastatic melanoma. These contradicting results among patients with metastatic melanoma call for further studies of sex disparities in the efficacy of medical treatment for melanoma. Males are generally older at diagnosis and have higher levels of comorbidity, which may contribute to worse prognosis. 25 Therefore, accounting for these factors is essential when assessing sex differences in melanoma outcomes. However, previous studies investigating melanoma‐specific survival have not systematically accounted for these factors. Furthermore, while overall survival has been explored in other studies, it has not been assessed alongside melanoma‐specific mortality in the same population, limiting direct comparisons.
Three other studies have examined the impact of sex on overall survival, and similar to our study, they found a significant increase in mortality among males compared with females. 10 , 11 , 12 The studies were conducted in the Netherlands (N = 10,538, 1993–2004), 12 Italy (N = 1279, 2015), 11 and the U.S. (N = 104,938, 2000–2017). 10 The study from the U.S further stratified analyses based on tumour stage and estimated life years lost. 10 They found females to have a better prognosis when compared to males and that this was less pronounced with increasing age at diagnosis. 10
While earlier diagnosis of melanoma in males may reduce the risk of advanced melanoma, our findings suggested that this alone is not enough. After adjusting for stage at diagnosis male sex was still an independent risk factor associated with increased risk of melanoma recurrence and mortality, as well as overall mortality. This underscores the need to investigate the underlying biological and treatment‐related factors contributing to poorer outcomes in males.
The observed differences in both melanoma stage and prognosis between males and females may be attributed to several biological factors, including the effects of sex hormones on tumour growth, immunological response profiles and variations in gene expression. Sex hormones, particularly testosterone, have been shown to influence melanoma growth. Recent studies have shown that testosterone stimulates melanoma growth in males through the ZIP9 receptor, a zinc transporter expressed in human melanoma. 5 Recent studies have also highlighted significant differences in immunological responses between sexes, with females generally exhibiting a more robust immune response against tumour growth compared to males. 6 Animal studies support these findings, showing increased tumour growth in male mice compared to female mice. 26 Female mice exhibited higher levels of CD4+ and CD8+ T cells, critical components of the anti‐tumour immune response potentially explaining the slower tumour growth and better outcomes observed in females. 26
Furthermore, differences in gene expression between males and females may play a role. Chrysanthou et al. 27 identified distinct disparities between the sexes in survival‐associated gene expression, with a favourable profile in females.
These biological factors underscore the complex interplay between sex and melanoma progression. Understanding these mechanisms is essential for developing more individualized prevention and treatment strategies for patients with melanoma.
Beyond biology, it is also necessary to take social and behavioural differences between genders into consideration. Gender differences in health‐seeking behaviour may play a role, as a Danish registry study found that men used primary healthcare services less frequently than women both before and after major illness. 28 Such factors may contribute to later diagnosis and poorer outcomes in men. Moreover, sun exposure is a well‐established risk factor for melanoma, 29 and differences in behavioural patterns, such as tanning bed use or recreational and occupational sun exposure, may also contribute to sex disparities in stage at diagnosis and survival, with women reporting higher use of tanning beds and men more cumulative sun exposure. 30
Strengths and limitations
Our study has several strengths. Using data from the Danish national health registries, we had prospectively collected, nationwide, population‐based data with a high coverage rate, ensuring that our findings are representative of the entire population. 13 The Danish national health care system is tax‐funded and follows standardized national guidelines. We employed a validated register‐based algorithm to identify melanoma recurrence minimizing the risk of misclassification. 22 Furthermore, the study benefits from a large patient population and an extended follow‐up period providing robust statistical power.
Limitations of this study include the risk of misclassification of the melanoma stage by clinicians. Additionally, the causes of death may also be misclassified, as autopsies are rarely performed in Denmark. 31 There are also several potential confounders that we were unable to adjust for, including sun exposure, 30 socioeconomic status 32 and specific cancer treatment and adherence. As many patients in our cohort were diagnosed before immunotherapy became standard, potential sex disparities in treatment response remain uncertain. The generalizability of our results may be limited by the demographics of our study population. Since the Danish population is predominantly Caucasian and resides in a high‐income country, our findings may not be directly applicable to populations with different racial and ethnic backgrounds.
CONCLUSIONS
This study demonstrates that sex plays a significant role for patients with melanoma, with males being at higher risk for advanced disease at diagnosis and having a 20%–40% increased risk of melanoma recurrence, and a 30%–50% increased risk of melanoma‐specific mortality and overall mortality compared to females. These findings support the need for sex‐specific detection strategies to reduce the risk of advanced melanoma at diagnosis in males. However, as our study highlights that males have worse outcomes even after adjusting for stage at diagnosis, early detection alone is insufficient. Improved treatment strategies are essential to enhance prognosis, particularly for males with localized melanoma. Further studies are warranted to investigate the underlying biological mechanisms and improve risk stratification in patients with melanoma to address these sex disparities.
AUTHOR CONTRIBUTIONS
Jens Ejrnæs Lyngstrand: Writing – review and editing, Writing – original draft, Methodology, Funding acquisition, Formal analysis, Conceptualization Eeva‐Liisa Røssell: Writing – review and editing, Supervision, Conceptualization. Marie Louise Bønnelykke‐Behrndtz: Writing – review and editing, Supervision, Conceptualization. Tinne Laurberg: Writing – review and editing, Supervision, Conceptualization.
FUNDING INFORMATION
This work was supported by P. Carl Petersen's Fond and ‘Slagtermester Max Wørzner og hustru Inger Wørzners mindelegat til fordel for forskning af kræft’. The funders were not involved in the study design, data collection, data analysis or manuscript preparation.
CONFLICT OF INTEREST STATEMENT
None to declare.
ETHICAL APPROVAL
The study was approved by the Central Region Denmark (file no.: 1–16–02‐304‐19).
ETHICS STATEMENT
Per Danish law, ethics approval from the Committee on Health Research Ethics in the Central Denmark Region or informed consent are not required for register‐based studies. All data for this study were anonymized and not identifiable at individual level before access.
Supporting information
Data S1.
Lyngstrand JE, Røssell EL, Bønnelykke‐Behrndtz ML, Laurberg T. Sex disparities in melanoma stage, recurrence and mortality: A Danish cohort study, 2004 to 2024. J Eur Acad Dermatol Venereol. 2026;40:1515–1524. 10.1111/jdv.70180
M. L. Bønnelykke‐Behrndtz and T. Laurberg have contributed equally to this work.
Linked Article: E. Janušonytė and M. Trakatelli. J Eur Acad Dermatol Venereol 2026;40:1445–1446. https://doi.org/10.1111/jdv.70431.
DATA AVAILABILITY STATEMENT
Due to restrictions related to Danish law and protecting patient privacy, the register data that support the findings of this study are only available from a trusted third party, The Danish Health Data Authority. Restrictions apply to the availability of these data, which were used under licence for this study. University‐based Danish scientific organizations can be authorized to work with data within The Danish Health Data Authority and such organizations can provide access to individual scientists inside and outside of Denmark. Requests for data may be sent to The Danish Health Data Authority.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1.
Data Availability Statement
Due to restrictions related to Danish law and protecting patient privacy, the register data that support the findings of this study are only available from a trusted third party, The Danish Health Data Authority. Restrictions apply to the availability of these data, which were used under licence for this study. University‐based Danish scientific organizations can be authorized to work with data within The Danish Health Data Authority and such organizations can provide access to individual scientists inside and outside of Denmark. Requests for data may be sent to The Danish Health Data Authority.