Susan M. Swetter, MD
Professor of Dermatology
Director, Pigmented Lesion and Melanoma Program
Stanford University Medical Center and Cancer Institute
VA Palo Alto Health Care System
Christina A. Clarke, PhD, MPH
Research Scientist, Cancer Prevention Institute of California
Consulting Associate Professor
Dept. of Health Research & Policy
Stanford University School of Medicine
Theresa H. M. Keegan, PhD, MS
Research Scientist, Cancer Prevention Institute of California
Consulting Assistant Professor
Dept. of Health Research & Policy
Stanford University School of Medicine
In 1969, melanoma pioneer Dr. Wallace Clark and colleagues proposed that melanoma behaves in a “somewhat less malignant” manner in women than in men.1 Over the ensuing four decades, worldwide data have confirmed higher melanoma mortality in men compared with women, particularly in older white males.2-4 However, it remains unclear whether these survival disparities are due to diagnostic delay, other related health behaviors in men, or gender differences in tumor biology. Recent published data support the notion that gender differences in melanoma biology may play a larger role in patient outcome than previously thought.
Mortality by Gender
In 2013, an estimated 9,480 persons died from melanoma in the US, nearly two-thirds men.5Almost 60 percent of melanoma deaths occur in white men aged 50 years and older,6 and the American Association for Cancer Research (AACR) Cancer Progress Report in 2013 noted that melanoma is one of only three malignancies in men whose death rates from 1990 to 2009 increased (by 10.5 percent).7 In contrast, melanoma death rates in women declined by 9.6 percent over the same period. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry data similarly show that white men >age 65 have the highest melanoma mortality (Figure 1),8 and this has mainly been attributed to health behaviors and practices in men that result in reduced skin screening and later detection of thicker, more lethal melanoma.
Role of Health Behaviors and Practices
In a study of 227 men older than or equal to age 40 with newly diagnosed melanoma, factors related to thicker melanoma at diagnosis included nodular histologic subtype, lack of atypical nevi, education level below high school, and patient (vs. physician) detection of melanoma.9 Physician-detected melanomas on the back of the body were significantly thinner compared to patient-detected tumors.10 Nearly one-third of melanomas in men occur on the back, are likely to be thicker, and are often missed by patients. Therefore, promoting regular examination of the back by older men, their spouses, and their health providers may prove beneficial in reducing melanoma mortality in this age group.
Female partners may play a critical role in increasing melanoma awareness in the older male population by encouraging routine skin checks during primary medical care exams and assisting with skin self-examination practices.11 Multiple studies have demonstrated that thinner lesions are found by health providers during routine professional examination (i.e., opportunistic screening) than lesions found when patients notice a symptomatic or bleeding pigmented lesion then bring it to medical attention.12,13 In a survey study of 566 recently diagnosed adults with cutaneous melanoma, the odds of older men (>60 years) presenting with a thin (T1, ≤1mm) melanoma were four times higher if they had received a physician skin examination for skin cancer in the year before diagnosis (OR 4.09, 95 percent confidence interval (CI) 1.88-8.89), even though most melanomas (81 percent) were not reported to be physician-detected.14 It was also demonstrated in the study that use of a melanoma picture aid and routine self-examination of some/all of the body prior to diagnosis were more beneficial for older men than younger men in detecting thinner tumors.
Role of Biological Differences
These studies show that delays in diagnosis due to health behaviors may account for gender disparities in melanoma survival. However, several recent publications suggest that biologic differences may play an equally, if not more important, role. In 2011, Joosse et al15 assessed gender differences in survival and disease progression in the Munich Cancer Registry (Germany) between 1978 and 2007, finding that in over 11,000 melanoma cases, women had a 38 percent survival advantage compared to men (adjusted Hazard Ratio (HR) 0.62; 95% CI 0.56-0.70), and were significantly less likely to progress to lymph node and visceral metastasis (42 percent and 44 percent less likely, respectively). In addition, women retained an approximate 20 percent survival advantage even after disease progression, including in-transit and lymph node but not visceral metastasis. Cutaneous melanomas in women appeared to have a lower propensity to metastasize, and the authors postulated that differences in tumor-host interaction were evident by gender.
A subsequent study by Joosse, et al16 suggested an even stronger role for gender differences in tumor biology. In a pooled analysis of 2,672 patients with cutaneous melanoma (stage I/II) enrolled in four European Organisation for Research and Treatment of Cancer (EORTC) prospective clinical trials, women demonstrated a 30 percent overall and melanoma-specific survival advantage, as well as a longer time before developing lymph node and distant metastasis. As in other studies,12,14,15 men were more likely than women to have thicker, ulcerated melanomas and tumors on the head, neck, and trunk – all well-established adverse prognostic factors. Men and women were matched for age (mean 52.5 years for men, 50.1 years for women), tumor characteristics (thickness, ulceration, histologic subtype), anatomic location of the primary, and trial-associated treatment and surveillance, so these confounding variables (including differences in patient follow-up or compliance with therapy) were unlikely to explain the findings. Female melanoma patients demonstrated not only a longer delay before relapse but a higher cure rate compared with males, and this was true across individual trials, prognostic parameters, and countries.16
Survival Differences in Younger Men and Women
As most of the published data demonstrating a survival difference between men and women pertain to middle-aged and older study populations, our team examined survival differences and prognostic factors among male and female adolescents and young adults (AYAs), aged 15-39 years at melanoma diagnosis (Figure 2).17 This collaboration involved investigators from the Stanford Cancer Institute and the Cancer Prevention Institute of California (CPIC), which is responsible for SEER cancer reporting in the Greater San Francisco Bay Area. From 1989-2009, there were 26,107 invasive melanoma cases among non-Hispanic white AYAs in the SEER analysis of 18 cancer registries nationwide, and 1,561 melanoma-specific deaths, with an overall mean follow-up of 7.5 years over the 20-year study period assessed.
Males accounted for only 40 percent of melanoma cases but comprised over 63 percent of melanoma-specific deaths. AYA males were 55 percent more likely to die from melanoma compared with women (HR 1.55; 95% CI 1.39-1.73), even after adjusting for age at diagnosis, other primary cancers, body site, tumor thickness, regional lymph node metastasis, distant metastasis, and histologic subtype. Males had significantly poorer survival across all age ranges <40 years, across all thickness ranges (with the exception of T2 melanoma, 1.01-2 mm), irrespective of superficial spreading or nodular melanoma subtype, and regardless of the presence or extent of metastasis. Men with cutaneous melanoma were 52 percent more likely to die than women, and those with regional nodal disease were 74 percent more likely to die than women (Figure 3). As in other studies, there were no significant survival differences between men and women with distant metastasis. Surprisingly, even men with the thinnest (T1) melanoma were nearly twice as likely to die as women (HR 1.95; 95% CI 1.57-2.42), although it should be emphasized that both men and women with thin melanoma have a high overall likelihood of cure.
Because younger men and women are more likely to self-detect their melanomas and less likely to rely on physician detection,18 our study suggests that biology may play a larger role in the observed gender disparity in survival in the AYA population. While we cannot exclude the possibility that increased health provider visits by AYA females during
their reproductive years may contribute to survival differences, physician discovery and skin self-examination practices are less likely to play a role in thinner melanoma detection in this age group compared with older individuals. Furthermore, we performed a subset analysis of patients diagnosed in California to adjust for health insurance and socioeconomic status (factors that correlate with skin examination), and found no difference in the gender survival disparity among AYAs.
Male Biologic Factors Potentially Behind Lower Survival
Differences in melanoma biology and/or immune surveillance between men and women have been proposed, including a possible “protective factor” in females or a “stimulating factor” in males.15,16 Theories include gender differences in sex hormones, vitamin D metabolism, immune homeostasis and regulation, oxidative stress, epigenetic factors such as methylation, and ultraviolet radiation-induced gene mutations and exposure patterns.17,19 Differences in sex hormones, especially estrogens, would appear to be the most plausible explanation. However, in the EORTC analysis,16 sex differences in survival were similar in pre- and post-menopausal-aged women, and other studies have reported a persistent female advantage in older, post-menopausal groups.15,20,21 Furthermore, no gender differences in the expression of estrogen receptor beta (associated with increased melanoma mortality) have been noted in melanocytic nevi or melanoma. Nor has a gender difference been seen in the incidence of BRAF, NRAS, or KIT mutations.
Perhaps a more compelling argument can be made for the potential deleterious effect of androgen expression, based on the elevated risks of melanoma among prostate cancer survivors and prostate cancer as a second primary malignancy in cutaneous melanoma patients. In a prior CPIC/Stanford Cancer Institute collaboration,22 we demonstrated an increased risk of prostate cancer following cutaneous melanoma diagnosis (between 1973 and 2003), which was not explained by surveillance bias or shared risk factors in older men. This risk was bidirectional, with a greater risk of cutaneous melanoma also observed following the diagnosis of prostate cancer.
Similar findings were reported in a recent study by Li, et al,23 which tracked over 42,000 male participants in the Health Professional Follow-Up Study from 1986 to 2010. During this time frame, 5,091 prostate cancers were documented in white male health professionals, along with 539 melanomas. Personal history of prostate cancer was significantly associated with an increased risk of subsequent melanoma (HR 1.83, 95% CI 1.32-2.54), even after adjusting for mole counts, sun exposure, and other characteristics in the study population. While both cancers tend to occur in older males and while chronic sun exposure could be a confounder, nonmelanoma skin cancer risk was only weakly associated with personal history of prostate cancer. The authors postulated a potential link between testosterone and increased melanoma cell proliferation or an androgenic effect on suppression of host immune response.
Evidence of sexual dimorphism in immune responses to melanoma is yet another competitive hypothesis. Mouse models have shown functional differences in regulatory T cells by gender in the absence of PD-L1, as well as differential responses to anti-PD-L1 therapy in males vs. females with murine B16 melanomas.24 Potential gender differences in immune cell subset profiles and function in humans have yet to be explored. Given the published data in the last few years suggesting a biological basis for gender disparities in melanoma survival, further research is warranted.
What Does This Mean for Patients?
Regardless of whether the cause of observed differences in melanoma survival between men and women is predominantly behavioral, biological, or a combination of factors, several key public health messages can be gleaned. Young men must be educated regarding the dangers of skin cancer. Most of the recent public health messages regarding tanning bed and suntan avoidance have focused on women. A similar message to AYA men emphasizing their poorer survival with melanoma may help to promote early detection and enhance the likelihood of cure. Men of all ages should seek prompt medical attention for any changing moles or skin lesions that look different from the rest. While these may end up being harmless skin findings, early detection of melanoma can be lifesaving.
- Clark WH, Jr, From L, Bernardino EA, et al. The histogenesis and biologic behavior of primary human malignant melanoma of the skin. Cancer Res 1969; 29:705-27.
- Geller AC, Miller DR, Annas GD, et al. Melanoma incidence and mortality among US whites, 1969-1999. JAMA 2002; 288:1719-20.
- de Vries E, Houterman S, Janssen-Heijnen ML, et al. Up-to-date survival estimates and historical trends of cutaneous malignant melanoma in the south-east of The Netherlands. Ann Oncol 2007; 18:1110-6.
- Bidoli E, Fratino L, Bruzzone S, et al. Time trends of cancer mortality among elderly in Italy, 1970-2008: an observational study. BMC Cancer 2102;12:443-52.
- American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013.
- Centers for Disease Control and Prevention, National Center for Health Statistics. US Dept. of Health and Human Services, Public Health Service, 2007.
- American Association for Cancer Research. AACR Cancer Progress Report 2013. Clin Cancer Res 2013; 19 (Suppl 1):S1-S88.
- Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Mortality—All COD, Aggregated With State, Total U.S. (1990-2010) <Katrina/Rita Population Adjustment>, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2013.
- Swetter SM, Johnson TM, Miller DR, et al. Melanoma in middle-aged and older men: a multi-institutional survey study of factors related to tumor thickness. Arch Dermatol 2009; 145:397-404.
- Geller AC, Johnson TM, Miller DR, et al. Factors associated with physician discovery of early melanoma in middle-aged and older men. Arch Dermatol 2009; 145:409-14.
- Swetter SM, Layton CJ, Johnson TM, et al. Gender differences in melanoma awareness and detection practices between middle-aged and older men with melanoma and their female spouses. Arch Dermatol 2009; 145:488-90.
- Schwartz JL, Wang TS, Hamilton TA, et al. Thin primary melanomas: associated detection patterns, lesion characteristics, and patient characteristics. Cancer 2002; 95:1562-8.
- Terushkin V, Halpern AC. Melanoma early detection. Hematol Oncol Clin North Am 2009; 23:481-500.
- Swetter SM, Pollitt RA, Johnson TM, et al. Behavioral determinants of successful early melanoma detection: Role of self and physician skin examination. Cancer 2012; 118:3725-34.
- Joosse A, de Vries E, Eckel R, et al: Munich Melanoma Group. Gender differences in melanoma survival; female patients have a decreased risk of metastasis. J Invest Dermatol 2011; 131:719-26.
- Joosse A, Collette S, Suciu S, et al. Superior outcome of women with stage I/II cutaneous melanoma: Pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials. J Clin Oncol 2012; 30:2240-7.
- Gamba CS, Clarke CA, Keegan THM, Tao L, Swetter SM. Melanoma survival disadvantage in young, non-hispanic white males compared with females. JAMA Dermatol 2013; 149:912-20.
- Brady MS, Oliveria SA, Christos PA, et al. Patterns of detection in patients with cutaneous melanoma. Cancer 2000; 89:342-7.
- Fisher DE, Geller AC. Disproportionate burden of melanoma mortality in young U.S. men: the possible role of biology and behavior. JAMA Dermatol 2013; 149:903-4.
- deVries E, Nijsten TE, Visser O, et al. Superior survival of females among 10,358 Dutch melanoma patients is independent of Breslow thickness, histologic subtype and tumor site. Ann Oncol 2008; 19:583-9.
- Micheli A, Ciampichini R, Oberaigner W, et al. The advantage of women in cancer survival: an analysis of EUROCARE-4 data. Eur J Cancer 2009; 45(6):1017-27.
- Spanogle JP, Clarke CA, Aroner S, Swetter SM. Risk of second primary malignancies following cutaneous melanoma diagnosis: a population based study. J Am Acad Dermatol2010; 62:757-67.
- Li WQ, Qureshi AA, Ma J, et al. Personal history of prostate cancer and increased risk of incident melanoma in the United States. J Clin Oncol 2013; 31:4394-9.
- Lin PY, Sun L, Thibodeaux SR, et al. B7-H1-dependent sex-related differences in tumor immunity and immunotherapy responses. J Immunol 2010; 185:2747-53.