A groundbreaking study conducted by researchers at Mass General Brigham has shed new light on the environmental factors contributing to acral melanoma, a rare and aggressive subtype of melanoma. This investigation focuses on the potential connection between exposure to the herbicide Agent Orange and an increased risk of developing acral melanoma, a form of skin cancer that manifests in areas typically not associated with sun exposure such as the palms of the hands, soles of the feet, and beneath the fingernails or toenails.
Acral melanoma distinguishes itself from more common cutaneous melanomas not just by its location, but also in its clinical behavior and prognosis. Unlike predominant forms of melanoma that develop on sun-exposed skin, acral melanoma’s etiology remains elusive, complicated by its lower incidence and less apparent risk factors. Crucially, this subtype often escapes early diagnosis, resulting in poorer outcomes as treatment options tend to be less effective once the disease advances.
The research team, led by Dr. Rebecca I. Hartman, Director of Melanoma Epidemiology at Brigham and Women’s Hospital, undertook an extensive analysis of medical data spanning nearly a quarter-century from the U.S. Veterans Health Administration. This dataset is uniquely valuable due to the veterans’ distinctive environmental and occupational exposures, as well as documented elevated melanoma rates compared to the general population. It represents a rich resource for elucidating associations that may otherwise be obscured in broader demographic groups.
In a comparative framework, 1,292 veterans diagnosed with acral melanoma were matched against 5,168 veterans without melanoma, as well as a cohort diagnosed with conventional cutaneous melanoma. This methodology enabled the researchers to isolate factors particularly correlated with acral melanoma risk. Among these, the history of Agent Orange exposure emerged as a significant variable, linked with approximately a 30 percent increased likelihood of acral melanoma diagnosis in veterans.
Agent Orange, infamous for its widespread use during the Vietnam War as a defoliant, has long been associated with several malignancies, including various blood cancers and solid tumors. Nonetheless, its connection to melanoma has been contentious, with regulatory bodies historically lacking sufficient evidence to confirm a definitive link. This new finding challenges existing paradigms and implies that chemical exposures outside of ultraviolet radiation may play a more critical role in melanoma pathogenesis than previously appreciated.
Apart from Agent Orange exposure, the study examined demographic and clinical variables traditionally considered in melanoma risk assessment. Female sex, specific racial and ethnic backgrounds, and histories of prior skin lesions were identified as potential risk factors; however, their associations were comparatively weaker. This nuance reinforces the distinct biological and environmental context in which acral melanoma arises, differentiating it from melanomas primarily driven by sun damage.
The implications of this study extend into clinical practice and public health policy. Early detection of acral melanoma remains a formidable challenge due to its atypical presentation and frequent misdiagnosis. Dr. Hartman highlights the necessity of refining diagnostic strategies, particularly for populations with high-risk exposures such as military veterans. Enhanced screening protocols, informed by environmental exposure histories, could revolutionize how clinicians identify and manage this lethal cancer subtype.
Moreover, the findings prompt urgent calls for further research into the mechanistic pathways by which Agent Orange and potentially similar herbicides might induce acral melanoma. Understanding the molecular and cellular interactions implicated could foster the development of targeted therapies and interventions. Additionally, exploring whether comparable associations exist with other chemical agents used in agricultural or military contexts may broaden our comprehension of carcinogenic risks beyond ultraviolet radiation.
The study’s observational design, leveraging the extensive Veterans Health Administration database, underscores the value of longitudinal, real-world data in uncovering rare disease patterns. However, the authors caution that while the association between Agent Orange and acral melanoma is compelling, it remains correlative and necessitates more rigorous, prospective investigations. Such future research should integrate genetic, biochemical, and environmental data to provide definitive causal insights.
Notably, acral melanoma’s poor response to existing treatments—including immunotherapies effective against cutaneous melanoma—emphasizes a pressing need for novel therapeutic approaches. Identifying risk factors tied to chemical exposures may lead to personalized treatment paradigms and preventive measures tailored to the unique etiological features of this melanoma subtype.
As the veteran population continues to age and medical records become increasingly digitized, there is unprecedented potential to harness big data analytics in cancer epidemiology. The present study exemplifies how integrating clinical data with environmental exposure assessments can uncover hidden cancer risks, ultimately informing more precise and equitable healthcare delivery.
The research, funded by the U.S. Department of Defense and the Department of Veterans Affairs, embodies a collaborative effort across multiple institutions and disciplines, with contributions from epidemiologists, oncologists, dermatologists, and biostatisticians. This interdisciplinary approach is crucial for addressing the multifaceted challenges posed by acral melanoma and translating findings into impactful clinical strategies.
In sum, this pioneering research challenges existing assumptions about melanoma causation by highlighting a significant association between Agent Orange exposure and acral melanoma risk. It calls for renewed investigative focus on environmental carcinogens beyond ultraviolet radiation and underscores the vital importance of tailored surveillance and intervention efforts for vulnerable populations such as U.S. veterans. Continued exploration in this direction promises to deepen our understanding of melanoma biology and improve outcomes for those afflicted by this devastating disease.
Subject of Research: People
Article Title: Identification of Risk Factors for Acral Melanoma in US Veterans
News Publication Date: 4-Feb-2026
Web References:
https://jamanetwork.com/journals/jamadermatology/fullarticle/10.1001/jamadermatol.2025.5827
References:
Hwang JC et al. “Identification of Risk Factors for Acral Melanoma in US Veterans” JAMA Dermatology DOI: 10.1001/jamadermatol.2025.5827
Keywords: Melanoma, Skin cancer, Melanoma cells, Cancer risk, Oncology, Dermatology
