Melanoma thickness and long-term mortality

Depth of invasion by melanoma was reported as a prognostic factor by the pathologist Alexander Breslow at George Washington University in 1970. Many studies have confirmed the role of depth of invasion (or Breslow thickness) in the prognosis of this tumor. The Breslow thickness of melanoma remains the single most important predictor of outcome, followed by patient age and ulceration, and it is included in the American Joint Committee on Cancer staging guidelines. The Breslow thickness, Age, Ulceration, Subtype, Sex and Site biomarker provides an accurate method to determine mortality risk compared with other approaches including sentinel lymph node biopsy (1).

There are several reasons why the brief communication by Serigne Lo and colleagues (2) in this issue of JNCI is important. First, the study has a long follow-up (30 years) and is methodologically sound, being based on nationwide registry data instead of clinical series (ie, it has a population base). The results show a strikingly larger risk of death in patients with higher Breslow thickness (ie, a 6 times higher risk in thickness category T4 compared with T1). In the meantime, total nonmelanoma mortality is approximately the same in the different stages, which reassures that the differences observed for melanoma deaths cannot be explained by other factors like socioeconomic status (SES). The relationship with SES is particularly interesting because it sheds light on different and even contrasting aspects of cancer incidence and mortality. A large investigation on more than 600 000 cutaneous melanomas in 17 Surveillance, Epidemiology, and End Results Program registries in the United States was published (3) to try to explain why melanoma incidence has increased in the last 4 decades with no increase in mortality [see also (4)]. The authors found that increasing melanoma incidence was predominantly driven by melanoma in situ and the thinnest invasive tumors (0.01-0.8 mm), which accounted for 82% of the increase in total patients between 2000 and 2019. They also found a strong positive correlation between a SES index and melanoma incidence (higher SES corresponding to higher incidence) and a clear inverse relationship between higher SES and Breslow thickness. In a study in New South Wales, Australia, patients from the most disadvantaged areas had lower survival rates (5). The conclusions of the authors of the American study by Maghfour et al (3) are that “together, these findings highlight the need for large prospective studies with extended follow-up to assess the effect of screenings on the incidence of cutaneous melanoma with poor outcomes and associated healthcare costs while considering appropriate timing, frequency, and target population of screenings to reduce overdiagnosis” (3). I will return to the issue of screening later.

The observation of increasing incidence and stable or declining mortality trends, together with other specific epidemiological features, applies to some cancer types, particularly those that typically develop slowly, remain asymptomatic for long periods, or never progress to cause harm during a person’s lifetime. These are also tumors for which readily available early diagnosis tests exist, like prostate or thyroid cancers (6,7). Such observations are interpreted as suggesting overdiagnosis, defined as the diagnosis of cancers that would be clinically silent forever (ie, they would not lead to clinical signs or symptoms or would even regress).

Other reflections can be made on the paper by Lo and colleagues (2), including the distribution of known risk factors in the population and by SES, for example, vitamin D deficiency; a study in Australia has found that serum 25(OH)D less than 50 nmol/L (vs ≥50 nmol/L) was associated with a nearly fourfold increase in risk of having a thicker tumor (8). Vitamin D deficiency is associated with lower SES. However, Lo and colleagues do not have data on Vitamin D. An interesting feature of the paper by Lo et al. (2) is that T1 was more common on the trunk, while T4 was more common on the head and neck. This looks counterintuitive, because the trunk has more intermittent sun exposure and is less visible than head and neck surfaces. It is not clear whether this is attributable to less accessible areas of the head covered by hair (9).

Based on the observations by Lo and colleagues (2), which confirm and strengthen previous results from cohort studies with shorter follow-up, one might think that they could support screening for melanoma. There could be some justifications for such a proposal, including that melanoma is the most common cancer in Australian individuals aged 15-39 years and accounts for nearly two-thirds of all skin cancer deaths. Skin cancer is one of the most expensive cancers for Australia’s health-care system, costing an estimated $1.7 billion each year (including diagnosis, treatment, and pathology). However, the evidence to support screening is not enough. I remind the reader that early diagnosis per se is not sufficient (though it is necessary) to propose screening. Usually the following criteria must apply (see the World Health Organization Short Guide to Cancer Screening) (10): the condition should have a presymptomatic stage that can be detected by screening, and a suitable test is available; facilities are in place for testing and for diagnostic follow-up assessment and management of individuals with a positive screening test; and treatment is effective, available, accessible, and acceptable for people who are diagnosed through screening. Usually, screening is approved if there are randomized controlled trials that show a decrease in mortality in those who are screened, which is not the case for melanoma. In 2023, the US Preventive Services Task Force released updated skin cancer screening recommendations and concluded that “the current evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adolescents and adults” (11). The same conclusion was reached by the Australasian College of Dermatologists in January 2024 (12).

So, although screening seems intuitively logical for melanoma, there is no evidence to suggest that screening would save lives.

Data availability

No new data were generated or analyzed for this editorial.

Author contributions

Paolo Vineis, MD (Conceptualization; Writing—original draft; Writing—review & editing).

Funding

No funding was used for this editorial.

Conflicts of interest

Paolo Vineis has no disclosures.

Acknowledgements

I am grateful to Marianne Berwick and Salvatore Vaccarella for thoughtful suggestions.