Lentigo maligna melanoma, UV light exposure associated, study finds

Key Points

Palo Alto, Calif. - A study shows for the first time prospectively that chronic ultraviolet (UV) light exposure raises the risk of lentigo maligna melanoma (LMM), a study co-author says.

"We know that melanoma has both genetic and environmental etiologies," says Eleni Linos, M.D., Ph.D., a second-year dermatology resident at Stanford University School of Medicine under the supervision of Abrar Qureshi, M.D., M.P.H., and Jiali Han, Ph.D. "However, to date large observational studies have not shown an effect of chronic sun exposure."

Intermittent sun exposure and sunburns, especially early in life, appear to predict later development of melanoma, Dr. Linos says, adding that she and her colleagues were interested in studying LMM specifically because this melanoma subtype occurs in chronically sun-exposed areas.

Study details

For their study, Dr. Linos and her colleagues analyzed the impact of lifetime UV exposure on incident LMM in a prospective cohort of patients. Assessing UV exposure is difficult, especially over long time periods, she says. To do this, "We used an objective measure - UV index - to stratify the United States into three sections: low-, medium- or high-exposure, based on sunlight, latitude and altitude," she says.

The researchers used data collected from large cohorts of women and men recruited in 1976 and 1984 for the Harvard-based Nurses' Health Study and the Health Professionals' Follow-Up Study. The former included 121,700 women, while the latter included 51,529 men. Both cohorts are followed up biennially and have long-term response rates of 90 percent, Dr. Linos says.

Researchers used subjects' state of residence at birth, age 15 and age 30 to estimate lifetime UV exposure. For subjects who lived in areas of similar UV exposure from birth through adulthood, investigators estimated a cumulative long-term UV index.

"Melanoma diagnoses were made from 1980 onward. However, we were interested in UV exposure early in life. This is a true prospective study in that the exposure occurred prior to the diagnosis of melanoma," Dr. Linos says.

All melanomas diagnosed in the study were confirmed by a dermatologist's histopathologic report, Dr. Linos says. "We adjusted for all the established and validated risk factors for melanoma, including number of blistering sunburns, family history, hair color, moles, age, gender and sun sensitivity."

Results

Ultimately, investigators found 1,798 cases of malignant melanoma, of which 274 were LMM (Linos E, Han J, Qureshi A. Poster 371. Society for Investigative Dermatology Annual Meeting, Atlanta, 5-8 May 2010). "The mean age of patients with LMM was 66 years - slightly older than for other melanomas, as expected based on prior literature," Dr. Linos says.

Regarding age-adjusted risk of non-LMM melanoma, "There appears to be no effect of UV exposure at any time point. However, for LMM, we saw an elevated risk" that was nearly double over a lifetime, she says. From birth to age 30, relative risk measured between approximately 1.5 and 1.6. "This effect is significant (p <0.05) at all time points," she says.

In multivariate analysis, Dr. Linos explains, "The male-to-female ratio was significantly higher for LMM compared to other melanomas." Men faced more than twice the relative risk of LMM versus women, she says, and a 26 percent increased risk of other melanomas subtypes (p trend <0.001 in both analyses).

Overall, women and men born in an area of high UV index faced a 37 percent higher risk of LMM and a much lower relative risk of other melanoma subtypes, Dr. Linos says. "The lifetime effect of high UV index infers about a 56 percent higher risk of LMM, but no real increase in other types of melanoma," she says.

In conclusion, "We saw that lifetime UV exposure is significantly associated with LMM, but not other melanoma subtypes. Associations appear strongest among those who stayed in an area of high UV residence from birth throughout adulthood. These findings imply that chronic UV exposure is an independent risk factor for LMM. Although this may be an intuitive fact for many clinicians, this has not been shown prospectively before," Dr. Linos says. These findings imply that LMM's etiology may differ from that of other melanomas, and that LMM may require different screening and prevention guidelines, she says.

High index vs. low

Investigators also found the magnitude of the UV:LMM association somewhat surprising, Dr. Linos says. Using the same cohorts, exposures and covariates, researchers compared the effect of high UV index versus low UV index on incidence of squamous cell carcinoma and found a relative risk of 2.07 for the high UV index. "However, for basal cell carcinoma, the risk is about 30 percent higher for patients in areas of high UV exposure," Dr. Linos says.

Lifetime risk of LMM for patients in high UV areas falls between these two extremes, she says, while relative risk of other types of melanoma has a null effect. "This confirms prior studies (Qureshi AA, Laden F, Colditz GA, Hunter DJ. Arch Intern Med. 2008 Mar 10;168(5):501-507), but gives us an interesting bit of additional information for LMM as a photosensitive tumor," she says.

Limitations

Study limitations include its observational nature and the fact that investigators had only three measurements of UV index until age 30. "We made some assumptions about where these subjects lived between these time points. Also, in this study we didn't analyze information about adult UV exposure after age 30. However, we know that the most critical period of sun exposure for melanoma development is early life," Dr. Linos says.

In the future, Dr. Linos says she and her colleagues plan to compare the differences in LMM versus non-LMM melanoma risk using more detailed and finite measurements of UV exposure. In the study population, "We have data on UV flux to do that, and some data on location after age 30. The key is to identify whether there is a critical time period, or a dose response effect" in the development of LMM, she explains.

Additionally, "We can explore differences in LMM compared to other melanomas using genome-wide association or microarray expression studies to see whether or not these tumors also differ in genetic etiology, since they differ so much in their environmental components," Dr. Linos says.