An “alarming difference” in survival outcomes between young, non-Hispanic white males and females with primary invasive melanoma “highlights the urgent need for both behavioral interventions to promote early detection strategies in young men and further investigation of the biological basis for the sex disparity in melanoma survival,” investigators from Stanford University Medical Center and Cancer Institute and the Cancer Prevention Institute of California concluded in a study published in JAMA Dermatology.¹ Among 26,107 non-Hispanic white adolescents and young adults (AYAs), males accounted for 39.8% of overall cases of melanoma but 63.6% of melanoma-specific deaths.

Surveillance, Epidemiology, and End Results (SEER) data from 18 population-based registries across the United States were used to identify 10,378 males and 15,729 females between the ages of 15 and 39 with primary invasive melanoma of the skin diagnosed between 1989 and 2009. “Because approximately 95% of cutaneous melanoma cases occur in whites, the analysis was limited to non-Hispanic white patients,” the investigators explained.

A total of 1,561 deaths (993 among the males and 568 among the females) occurred during a mean follow-up of 7.5 years. “Adolescent and young adult males were 55% more likely to die of melanoma than age-matched females after adjustment for tumor thickness, histologic subtype, anatomic location, presence and extent of metastasis, and anatomical location (hazard ratio = 1.55; 95% confidence interval [CI] = 1.39–1.73),” the researchers reported. “Males were also more likely to die within each age range assessed (eg, 15–24, 25–29, 30–34, and 35–39 years), and even those with thin melanomas (≤ 1.00 mm) were twice as likely to die as age-matched females (hazard ratio = 1.95; 95% CI = 1.57–2.42).”

“The findings are so consistent that they imply a fundamental biological difference in ‘male’ vs ‘female’ melanoma, at least for a significant fraction of patients,” according to an editorial² accompanying the study report.

Tumor Thickness, Histology, Location

Looking at tumor thickness, “which is the most important determinant of how patients do, we found across the board that the young men did worse than the young women, regardless of the thickness,” the study’s corresponding author, Susan M. Swetter, MD, said in an interview with The ASCO Post. Dr. Swetter is Professor of Dermatology and Director of the Pigmented Lesion & Melanoma Program at Stanford University Medical Center and Cancer Institute in Palo Alto, California.

Although tumors of the lower extremity are generally associated with better outcomes than those of the head or neck or trunk, a persistent survival disadvantage was observed in men with lower extremity tumors, Dr. Swetter added. Even after adjusting for tumor thickness, males were 67% more likely than the females to die of lower extremity melanomas.

In males and females, the most common histologic subtype was superficial spreading subtype, but males were more likely to be diagnosed with nodular melanoma, 6.8% vs 4.1% in females. “Although males presented with more [nodular melanomas], which have been associated with rapid growth, the male survival disadvantage was not limited to this subtype. In fact, AYA males with [superficial spreading subtype]…had a 73% higher risk of melanoma death compared with females. This study provides evidence that the AYA male survival disadvantage is not explained simply by health screening differences, because one would then expect the sex disparity to be limited to thicker primary melanomas or to tumors located on the head and neck and trunk,” according to the study report.

“One thing that we would emphasize in our study.” Dr. Swetter said, “is that despite the fact that men are doing worse with all tumor thicknesses, it is still critical to enhance early detection strategies, because patients do better with a thinner melanoma than a thicker melanoma. So even though we are seeing men twice as likely to die with a very thin T1 melanoma (less or equal to a millimeter in depth), the chance of surviving those tumors is so great that we want to promote detection of these thin tumors in general in both young men and women.”

Biology vs Behavior

The researchers proposed several possible biologic mechanisms for the higher male melanoma mortality, including differences in sex hormones, immune homeostasis, vitamin D metabolism, and oxidative stress, but firm evidence for these and other possible mechanisms is lacking. “There is not substantial evidence or understanding of what is driving this from a biologic standpoint,” Dr. Swetter stated. “The bottom line is we don’t really understand what is causing this biologic difference.”

Studies showing higher melanoma mortality among older men than women have reported that men “tend to be more resistant to screening practices—skin self-exams, seeing the doctor, navigating the health-care system effectively—than women,” Dr. Swetter noted, and that older men “may have a huge benefit” from physician intervention and skin exams. “But we are talking here about a younger population that doesn’t see the doctor as much, other than women because of reproductive health issues in the childbearing years. This is also a population in whom the melanomas tend to be more self-detected, rather than physician detected,” Dr. Swetter said.

“In general, the patients in this age group are healthier compared to older individuals. They are seeing physicians less regularly, and just a very small percentage of melanomas in this young, less than 40 age group are discovered by physicians. So we don’t think it is just a matter of improved physician detection in young women compared to young men.” Behavioral factors or different health surveillance patterns can’t be entirely ruled out, Dr. Swetter said, “but I think that our data more strongly suggest that biology is at play.”

Youth May Feel Impervious to Effects of UV Exposure

The mean age at diagnosis was 31.9 years in males and 31.2 years in females, but 34.2% of the melanomas occurred before age 30. Dr. Swetter said that she didn’t think young people “are sufficiently aware” of their risk of melanoma. “I think it is analogous to the smoking argument. Younger individuals feel impervious to the long-term effects of ultraviolet [UV] exposure and assume, ‘Well I’ll get my skin cancer in my 50s, and it is curable,’” Dr. Swetter commented. 

“I do think that we need to raise awareness of the dangers of excessive sun exposure, promote avoidance of tanning—particularly artificial tanning through tanning bed use—and enhance sun protection through regular sunscreen use and sun protection practices,” Dr. Swetter said. “A large, population-based study from Australia first published online in 2010³ suggested that regular sunscreen use could reduce the incidence of melanoma by 50% compared to those who used it on a discretionary or optional fashion,” she noted.

The Food and Drug Administration (FDA) “is providing a great benefit to consumers,” Dr. Swetter said, through its efforts to relabel sunscreens so that the labels are easy to understand and make it clear that sunscreens do not provide a total sunblock but are instead sun protective agents that should provide broad-spectrum UV filtration of both UVB and UVA. “Traditionally UVA filtration has been less effective in the U.S. sunscreens compared to other sunscreens worldwide. Hopefully, the FDA will expedite the approval of better UV filters that have been studied worldwide and are in widespread use in Australia and the European Union,” Dr. Swetter said. “We really do need better sunscreens to be readily available in the United States.”

The ‘Ugly Duckling’

“We also need to promote awareness of changing lesions on the skin, whether they look like a classic melanoma, which tends to be the superficial spreading subtype with the ABCDE clinical warning signs, or an ‘ugly duckling’ lesion that just doesn’t look like a person’s other skin lesions,” Dr. Swetter told The ASCO Post. The ABCDE acronym, introduced in 1985 as ABCD and with the E added in 2004, stands for some key features of melanoma: Asymmetry, Border irregularity, Color variability, Diameter greater than 6 mm, and Evolution or change.

Named after the Hans Christen Anderson fairy tale, the ugly duckling concept is based on the premise that nevi in the same individual tend to look alike, but a melanoma looks different. “Some of the nodular melanomas that we see, which tend to grow more rapidly and elude early detection, don’t have those typical ABCDE warning signs,” Dr. Swetter noted. “They tend to grow upward and may bleed. There may be no color variation, and the lesion may not have a large diameter.”

“Despite our study’s alarming findings in young men, we still tell both men and women of all ages, that they should see a health provider promptly for any changing mole or skin lesion that doesn’t match the others,” Dr. Swetter said. “It could be a harmless finding, but it could also be early detection of melanoma, which could save their life.” ■

Disclosure: Dr. Swetter reported no potential conflicts of interest.

References

1. Gamba CS, Clarke CA, Keegan THM, et al: Melanoma survival disadvantage in young non-Hispanic white males compared with females. JAMA Dermatol. June 26, 2013 (early release online).

2. Fisher DE, Geller AC: Disproportionate burden of melanoma mortality in young U.S. men: JAMA Dermatol. June 26, 2013 (early release online).

3. Green AC, Williams GM, Logan V, et al: Reduced melanoma after regular sunscreen use: Randomized trial follow-up. J Clin Oncol 29:257-263, 2010.