Agent Orange Exposure Linked to Increased Risk of Acral Melanoma in US Veterans

An epidemiologic study published in JAMA Dermatology provides new evidence that exposure to Agent Orange is associated with an increased risk of acral melanoma among US veterans.¹ Drawing on more than 2 decades of data from the Veterans Affairs (VA) health care system, the analysis suggests that veterans with documented herbicide exposure face approximately 30% higher odds of developing acral melanoma compared with veterans without melanoma and those with nonacral cutaneous melanoma.²

Study Design

The research, supported by the Melanoma Research Alliance, the US Department of Defense, and the Department of Veterans Affairs Cooperative Studies Program, examined Veterans Health Administration records spanning 2000 to 2024. Investigators conducted a nested case-control study using the VA Cancer Registry in combination with a validated natural language processing pipeline applied to pathology reports.

In total, 1,292 veterans with histologically confirmed acral melanoma were identified and matched to 2 separate control groups: 5,168 veterans without any melanoma diagnosis and 1,286 veterans with nonacral cutaneous melanoma. Matching criteria included year of diagnosis and outpatient visit frequency to reduce surveillance bias. The acral melanoma cohort had a median age of just over 70 years, and more than 94% of patients were male.

Results

The study’s primary finding was a statistically significant association between Agent Orange exposure and acral melanoma. After adjustment for demographic factors, comorbidities, health behaviors, and dermatologic history, Agent Orange exposure was associated with higher odds of acral melanoma compared with both nonacral cutaneous melanoma controls (adjusted odds ratio [AOR], 1.31; 95% CI, 1.06–1.62) and controls without melanoma (AOR, 1.27; 95% CI, 1.04–1.56). Using national incidence estimates of 1.5 to 2.8 cases per million individuals annually, the authors calculated that this increased risk translates to approximately 0.4 to 0.8 additional acral melanoma cases per million veterans per year.

Secondary analyses limited to Vietnam-era veterans and to specific anatomic subtypes (palmoplantar and subungual melanoma) yielded similar trends, further supporting the robustness of the association. The findings build on prior observations that environmental and occupational exposures may contribute to acral melanoma risk, while highlighting herbicide exposure as a potential and previously underrecognized factor in US veterans.

Identifying Risk Factors

Acral melanoma is biologically and clinically distinct from the more common cutaneous melanoma. It arises on the palms, soles, or nail units and is less strongly associated with ultraviolet radiation exposure. As a result, lesions often develop in less visible areas and may not be recognized as melanoma by patients or clinicians, contributing to later-stage diagnosis and poorer outcomes. These characteristics underscore the importance of identifying non-UV-related risk factors that may guide targeted screening and earlier detection.

In a statement, senior author Rebecca I. Hartman, MD, MPH, Director of Melanoma Epidemiology at Brigham and Women's Hospital, said, “Acral melanoma 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. Identifying risk factors is critical to improving detection and outcomes."¹

Beyond Agent Orange, the study evaluated a broad range of potential risk factors. Prior keratinocyte carcinoma and actinic keratosis were associated with higher odds of acral melanoma compared with veterans without melanoma, but lower odds when compared with cutaneous melanoma controls, emphasizing etiologic differences between melanoma subtypes. A history of nevi was associated with increased odds of acral melanoma versus controls without melanoma. Interestingly, current smoking was associated with lower odds of acral melanoma in both comparator analyses, a finding that the authors caution should not be interpreted as protective and may reflect residual confounding or differences in health care utilization.

Conclusion

Collectively, these results support continued investigation of acral melanoma as a distinct disease entity and suggest that herbicide exposure history may warrant consideration in future risk stratification and screening strategies for veterans. For dermatology clinicians, the study reinforces the importance of thorough skin examinations—including palms, soles, and nail units—and heightened vigilance in patients with known Agent Orange exposure.

"This study highlights an important and potentially underrecognized risk factor for acral melanoma, particularly for US veterans," said Marc Hurlbert, PhD, chief executive officer of the Melanoma Research Alliance and a principal investigator on the research. "Identifying exposures that may increase risk can help inform earlier recognition and, ultimately, earlier diagnosis when treatment is most effective."¹

References

1. Agent Orange Exposure Linked to Higher Risk of Rare Melanoma in US Veterans, Study Finds. News release. PR Newswire. Published February 5, 2026. Accessed February 23, 2026. https://www.prnewswire.com/news-releases/agent-orange-exposure-linked-to-higher-risk-of-rare-melanoma-in-us-veterans-study-finds-302680679.html

2. Hwang JC, Huhmann LB, Cho K, et al. Identification of Risk Factors for Acral Melanoma in US Veterans. JAMA Dermatol. Published online February 4, 2026. doi:10.1001/jamadermatol.2025.5827