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Melanoma Article from NEJM

By Janice Nelson - Posted on September 13th, 2010
From the New England Journal of Medicine - September, 2010:
An
estimated 1 million times per day, someone in the United States uses
ultraviolet (UV) radiation for skin tanning. According to the indoor
tanning industry, tanning beds are used by 30 million Americans, or
about 10% of the U.S. population, each year (www.theita.com/indoor).
These users include minors, who often have ready access to tanning beds.
In response to considerable grassroots and political opposition to
indoor tanning, in late March the Food and Drug Administration (FDA)
convened an advisory panel to review the safety of the procedure. The
FDA is expected to announce a decision soon on whether and how to
reclassify tanning lamps and possibly to address minors' access to them. The
concern arises from increases in the incidence of melanoma and its
related mortality. In the United States, the incidence of melanoma is
increasing more rapidly than that of any other cancer. From 1992 through
2004, there was a particularly alarming trend in new melanoma diagnoses
among girls and women between the ages of 15 and 39. Data from the
National Cancer Institute's Surveillance, Epidemiology, and End Results
registry show an estimated annual increase of 2.7% in this group.1
Researchers suspect that the increase results at least partially from
the expanded use of tanning beds. The possibility that changes in
diagnostic criteria may have contributed to the increased incidence is
lessened by the fact that the trend is specific to a certain age range
and sex. The incidence of thicker cutaneous melanomas (>1 mm) has
also increased, and the incidence of regional and distant tumors has
increased at an estimated annual rate of 9.2% — a change that could
portend a surge in advanced melanomas in young women. Although
substantial advances have been made in melanoma therapies, the risk of
death from advanced disease remains high. Abundant epidemiologic
data have been examined to assess potential connections between indoor
tanning and both melanoma and non-melanoma cutaneous cancers. According
to a 2006 meta-analysis by the International Agency for Research on
Cancer (IARC), among people who first used indoor tanning before 35
years of age, the relative risk of melanoma was 1.75 — a finding that
prompted the World Health Organization to classify tanning beds as a
group I carcinogen. Similarly, a recent case–control study in Minnesota
showed an adjusted odds ratio of 1.74; the risk of melanoma increased as
the number of years of tanning and hours of tanning sessions increased.2 An
even more dramatic association has been found between exposure to UV
radiation and non-melanoma skin cancers. In the IARC study, history of
any indoor tanning was associated with a relative risk of 2.25 for
squamous-cell carcinoma. Although most of these lesions are successfully
treated at an early stage, metastasis persistently occurs in a small
minority of such lesions, at which point cure is rare. Although the
overall rate of death from squamous-cell carcinoma is low, the high
incidence of this form of cancer means that it accounts for 25 to 35% of
skin-cancer–related deaths. In response to such data, numerous
countries have tightened their restrictions on indoor tanning; France,
Germany, Austria, Finland, and Britain, for instance, ban indoor tanning
for people under the age of 18. Some U.S. states have also enacted
restrictions on access for minors, but many have not. The FDA classifies
tanning beds as medical devices and designates them as class I, the
same class as tongue depressors and adhesive bandages — in contrast to
tampons, for example, which are considered class II devices. Although no
formal vote was reported at the March meeting of the FDA advisory
committee, its members appeared to be unanimous in suggesting a change
of classification. Advances in the molecular understanding of
signaling pathways in skin have yielded insights into the relationship
between tanning and cancer, showing that the common molecular
intermediate for both is DNA damage, which activates melanin synthesis,
even when triggered by the singular, precise activity of restriction
endonucleases.3
Studies have also revealed the involvement of p53 and
proopiomelanocortin in the processing and secretion of
melanocyte-stimulating hormone (MSH), which activates pigment production
in epidermal melanocytes4 (see diagramMolecular Mechanism of Skin Pigmentation Induced by UV Radiation.).
The tanning response is thus an offshoot of the p53 tumor-suppressor
pathway. A striking example of the carcinogenic activity of UV radiation
is also seen in xeroderma pigmentosum, a condition involving a
DNA-repair deficiency. The tanning industry argues that indoor
tanners avoid sunburn better than outdoor tanners. This difference could
arise from increased use of UVA, rather than UVB, wavelengths, but UVA
radiation also damages DNA and induces discrete mutations. Moreover, UV
radiation may be carcinogenic without causing sunburn. The precise roles
of specific UV wavelengths in both tanning and carcinogenesis remain to
be fully elucidated, but since DNA damage appears to be the key
intermediate for both, tanning induced by UV radiation that is devoid of
carcinogenic risk may be scientifically impossible. Some
evidence suggests that repeated UV irradiation, and the use of indoor
tanning beds specifically, may have important systemic and behavioral
consequences, including mood changes, pain, and physical dependency. In a
series of studies, Feldman and colleagues identified the ability of
frequent tanners to perceive the difference between UV-radiating and
sham devices, suggesting the presence of a reinforcing stimulus, and
found that the administration of an opiate-receptor blocker induced
withdrawal-like symptoms among frequent tanners, suggesting the presence
of opiate-like addiction. More recent data have shown addictive
features of indoor tanning in a large cohort of college-age tanning-bed
users.5
A mechanistic explanation may lie in the fact that MSH production in
the UV-tanning response is accompanied by the release of β-endorphin,
which shares the same precursor peptide (proopiomelanocortin)4 (see diagram). One
plausible model for the evolution of such behavioral sun-seeking
effects involves the participation of UV radiation in the cutaneous
production of vitamin D. In settings such as high latitudes, where
exposure to such radiation is limited, a behavioral inclination toward
sun exposure might have historically provided a survival advantage by
averting lethal vitamin D deficiency at prereproductive ages. Is
cutaneous vitamin D synthesis a justifiable defense of indoor tanning in
2010? In addition to the tight overlap between UV radiation's action
spectra for DNA damage and vitamin D synthesis, a key reason why such
radiation is a poor choice for vitamin D replacement is the many
(sometimes uncontrollable) variables involved in its use, including the
quantity of skin exposed, the darkness or pigmentation of that skin, the
wavelength or energy of the source (which varies with the time of year
and latitude), and the degree of one's vitamin D deficiency. It is
difficult to consume sufficient vitamin D from typical diets, but oral
supplements and intermittent testing of blood levels would appear to be
significantly more effective than tanning, without carcinogenic risk. An
estimated six of every seven melanomas are now being cured, thanks to
early detection, but the U.S. Preventive Services Task Force does not
recommend skin-cancer screening, since the evidence for its benefit has
not been validated in large, prospective, randomized trials. Meanwhile, a
number of promising new drugs for metastatic melanoma are progressing
slowly through clinical trials to satisfy the FDA's stringent safety and
efficacy criteria — requirements that, remarkably, have not been
applied to indoor tanning devices. Relatively few human cancers are
tightly linked to a known environmental carcinogen. Given the
mechanistic and epidemiologic data, we believe that regulation of this
industry may offer one of the most profound cancer-prevention
opportunities of our time. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.Source InformationFrom
the Department of Dermatology and Cancer Center, Massachusetts General
Hospital and Harvard Medical School, Boston (D.E.F.); and the Department
of Dermatology, University of Pennsylvania School of Medicine,
Philadelphia (W.D.J.).
For the full article, click here.