Exposure to Agent Orange in U.S. veterans was associated with an increased odds of developing acral melanoma compared with controls with and without cutaneous melanoma, according to findings published in JAMA Dermatology.
The study authors suggested that there is a need for continued investigation of this association to better inform diagnostic strategies in veteran populations that may be at higher risk for developing acral melanoma.
“Acral melanoma is often diagnosed later and can be harder to treat, which makes research like this especially urgent,” said team principal investigator Marc Hurlbert, PhD, Chief Executive Officer of the Melanoma Research Alliance. “For veterans who may have been exposed [to Agent Orange] decades ago, this study provides important insight and reinforces the need to keep investing in research that can translate into earlier diagnosis and better outcomes."
“Our results support the need for continued studies of acral melanoma as a distinct entity from cutaneous melanoma,” said senior author Rebecca I. Hartman, MD, MPH, Director of Melanoma Epidemiology at Brigham and Women’s Hospital in the Mass General Brigham Department of Dermatology. “We should also consider additional investigations of Agent Orange as a risk factor for acral melanoma and evaluate whether a similar link might exist with other herbicides.”
Study Methods
Researchers aimed to determine risk factors for developing acral melanoma in U.S. veterans. They conducted a nested case-control study of the Veterans Affairs health-care system, including data of patients diagnosed with acral melanoma from 2000 to 2024. A validated natural language processing pipeline was also used on pathology reports to find additional cases of veterans with acral melanoma.
“Acral melanoma appears on the palms, soles of feet, or under fingernails or toenails and has a poorer prognosis than the more common cutaneous melanoma, because it is often diagnosed at later stages and doesn’t respond as well to current therapies,” said Dr. Hartman. “We need more information on risk factors to help us identify high-risk patients, which may lead to earlier detection, when treatments are most effective.”
Each case of a patient with acral melanoma was matched to four cases of patients with nonacral cutaneous melanoma and four controls of individuals without a melanoma diagnosis (ie, acral, mucosal, or ocular melanoma).
Key Findings
A total of 1,292 participants with acral melanoma were matched to 5,168 controls without melanoma, and 1,286 individuals with acral melanoma were matched to 5,144 controls with cutaneous melanoma. Due to a lack of matches, six patients with acral melanoma were excluded from the cutaneous melanoma comparison.
Agent Orange exposure had a significant association with increased odds of developing acral vs cutaneous melanoma (adjusted odds ratio [aOR] = 1.31; 95% confidence interval [CI] = 1.06–1.62) as well as for acral melanoma vs controls without melanoma (aOR = 1.27; 95% CI = 1.04–1.56).
Current smokers had the lowest odds of developing acral vs cutaneous melanoma (aOR = 0.65; 95% CI = 0.52–0.81) and vs controls without melanoma (aOR = 0.50; 95% CI = 0.40–0.62).
Higher odds for developing acral melanoma were also seen in those with prior keratinocyte carcinoma or actinic keratosis as compared with controls without melanoma, but the odds were lower in comparison with those cutaneous melanoma. A similar trend was also seen in patients with prior nevus.
DISCLOSURE: This work was supported by the Department of Defense and by the Department of Veterans Affairs Cooperative Studies Program. Dr. Hartman reported receiving grants from the Department of Defense and grants from Veterans Affairs during the conduct of this study. For full disclosures of the other study authors, visit jamanetwork.com.
