Study in U.S. Veterans Identifies Agent Orange Exposure as a Risk Factor for Rare Skin Cancer

A study of U.S. veterans led by investigators at Mass General Brigham, VA Boston Healthcare System, and the Melanoma Research Alliance has identified a possible link between exposure to the Agent Orange herbicide and a rare melanoma subtype less likely to be related to sun exposure. The authors of the study, published in JAMA Dermatology, say this link warrants further examination to inform diagnostic strategies for people who may be at a greater risk for 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 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 need more information on risk factors to help us identify high-risk patients, which may lead to earlier detection, when treatments are most effective.”

"Acral melanoma is often diagnosed later and can be harder to treat, which makes research like this especially urgent," said MRA's chief executive officer, Marc Hurlbert, PhD, and team principal investigator. "For veterans who may have been exposed 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."

For their study, researchers analyzed 2000–2024 data from the Veterans Health Administration, which contains a wealth of medical information on U.S. veterans, who have unique environmental and occupational exposures and higher melanoma rates than the general population.

The investigators compared 1,292 veterans with acral melanoma with 5,168 veterans without melanoma. Veterans with acral melanoma were also compared to veterans with cutaneous melanoma.

Exposure to the herbicide Agent Orange, which was used extensively during the Vietnam War and was banned in the 1970s, was linked with an approximately 30% higher odds of having acral melanoma. This finding is especially noteworthy, according to the authors, because officials have stated that several cancers are related to Agent Orange exposure, but that current evidence is insufficient to determine a link with melanoma.

Other potential risk factors for acral melanoma—including female sex, certain races/ethnicities, and prior skin lesions—were also identified in this study, but without as strong of an association.

“Our results support the need for continued studies of acral melanoma as a distinct entity from cutaneous melanoma,” said Hartman. “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.”

Authorship: In addition to Hartman, Mass General Brigham authors include Jonathan C. Hwang, Kelly Cho, and John M. Gaziano. Additional authors include Linden B. Huhmann, Sergey D. Goryachev, Nicholas Starink, Martin A. Weinstock, Maryam M. Asgari, Christy Zheng, Charles Lu, Theodore C. Feldman, Nhan V. Do, Yevgeniy R. Semenov, Marc S. Hurlbert, and Nathanael R. Fillmore.

Disclosures: Hartman reported grants from DOD and grants from VA CSRD during the conduct of the study. Additional author disclosures can be found in the paper.

Funding: This work was supported by the Department of Defense (W81XWH2110820, W81XWH2110819), and by the Department of Veterans Affairs Cooperative Studies Program. Hartman is also supported by the Department of Veterans Affairs under award number VA CSR&D IK2 CX-002531.The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The contents of this publication do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Paper cited: Hwang JC et al. “Identification of Risk Factors for Acral Melanoma in US Veterans” JAMA Dermatology DOI: 10.1001/jamadermatol.2025.5827