Highlights
- Agent Orange exposure (AOE) is significantly associated with an increased risk of acral melanoma (AM), with adjusted odds ratios ranging from 1.27 to 1.31.
- Current smoking exhibits a paradoxical inverse association with AM risk, similar to patterns seen in some other non-UV-related cancers.
- Acral melanoma risk factors differ substantially from nonacral cutaneous melanoma (CM), particularly regarding the prevalence of UV-related precursors like actinic keratosis and keratinocyte carcinoma.
- The study utilizes a robust natural language processing (NLP) pipeline to identify AM cases within the massive Veterans Affairs (VA) health care system, providing a high level of statistical power.
Background: The Unique Challenge of Acral Melanoma
Acral melanoma (AM) represents a distinct clinical and biological entity within the spectrum of melanocytic malignancies. Unlike the more common nonacral cutaneous melanomas (CM), which are primarily driven by ultraviolet (UV) radiation-induced DNA damage, AM occurs on non-hair-bearing skin—specifically the palms, soles, and nail units (subungual sites). Because these areas are often shielded from direct sunlight, the pathogenesis of AM has long been suspected to involve distinct genetic alterations and environmental triggers.
Epidemiologically, while AM accounts for a small percentage of melanomas in light-skinned populations, it represents a disproportionately high percentage of melanoma cases in individuals with darker skin phototypes. Despite its clinical importance and often late-stage presentation, the specific risk factors for AM remain poorly understood compared to those for CM. For US veterans, a population with unique environmental and occupational exposures, understanding these risks is a matter of significant clinical and policy concern.
Study Design: A Comprehensive Nested Case-Control Analysis
To address the knowledge gap regarding AM risk factors, researchers conducted a large-scale nested case-control study within the Veterans Affairs (VA) health care system, spanning the years 2000 to 2024. The study population was primarily composed of male veterans, reflecting the historical demographics of the military.
Case Identification and Matching
Individuals with histologically confirmed AM were identified using a combination of the VA Cancer Registry and a validated natural language processing (NLP) pipeline applied to electronic pathology reports. This sophisticated approach allowed for the accurate extraction of anatomical site data, which is often missing or poorly coded in standard registries.
Each AM case was matched to two distinct control groups in a 1:4 ratio:
- Nonacral Cutaneous Melanoma (CM) controls: To identify factors specific to the acral subtype.
- Controls with no melanoma diagnoses: To identify general risk factors for developing AM.
The matching criteria included diagnosis year and outpatient visit frequency to control for healthcare utilization bias. Participants with mucosal or ocular melanoma were excluded to maintain the focus on cutaneous and acral subtypes.
Exposures and Variables
The researchers evaluated a wide array of potential risk factors, including demographic data (age, sex, race/ethnicity, rurality), military-specific exposures (military branch, Agent Orange exposure), comorbidities (NCI Comorbidity Index), lifestyle factors (smoking, alcohol use, BMI), and dermatological history (nevi, keratinocyte carcinoma, actinic keratosis, and dermatology visit frequency).
Key Findings: Agent Orange, Smoking, and Clinical Precursors
The study included 1,292 individuals with AM, with a median age of approximately 70 years. The vast majority (94%) were male. The results provide several groundbreaking insights into the etiology of this melanoma subtype.
The Role of Agent Orange
One of the most significant findings was the association between Agent Orange exposure (AOE) and acral melanoma. AOE was associated with a 31% increase in the odds of AM when compared to CM controls (AOR, 1.31; 95% CI, 1.06-1.62) and a 27% increase when compared to controls without any melanoma (AOR, 1.27; 95% CI, 1.04-1.56). This finding is particularly salient for Vietnam-era veterans and suggests that the chemical components of Agent Orange, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), may play a role in the oncogenesis of non-UV-related melanomas.
The Smoking Paradox
The study observed a statistically significant inverse association between current smoking and AM. Current smokers had 35% lower odds of AM compared to CM controls and 50% lower odds compared to healthy controls. While this may seem counterintuitive, similar inverse associations have been noted in other dermatological and non-dermatological conditions. However, the researchers emphasize that this does not imply a protective benefit of smoking, but rather points toward a complex biological interaction, possibly involving the aryl hydrocarbon receptor (AhR) pathway or nicotine’s effect on melanocyte signaling.
Dermatological Precursors and UV Markers
When comparing AM to healthy controls, prior diagnoses of keratinocyte carcinoma (KC) and actinic keratosis (AK) were associated with higher odds of AM. However, when AM was compared to CM, patients with AM were significantly less likely to have a history of AK or KC. This reinforces the theory that while AM patients may share some general susceptibility to skin cancer, they lack the heavy cumulative UV damage profile characteristic of patients with traditional cutaneous melanoma.
Expert Commentary: Mechanistic Insights and Clinical Implications
The association between Agent Orange and acral melanoma provides a new lens through which to view veteran health. TCDD, the primary contaminant in Agent Orange, is a known potent activator of the aryl hydrocarbon receptor (AhR). The AhR pathway is involved in cellular proliferation, differentiation, and immune response. In the context of the skin, dysregulation of this pathway could theoretically contribute to the development of melanocytic lesions in areas not typically exposed to the sun.
From a clinical perspective, these findings suggest that clinicians treating Vietnam-era veterans should be particularly vigilant during skin examinations. While routine screening for melanoma often focuses on sun-exposed areas, this data underscores the necessity of a comprehensive skin check that includes the palms, soles, and nail beds, especially in those with a history of herbicide exposure.
Furthermore, the data regarding smoking and BMI (which showed varied associations) suggests that the metabolic and systemic environment of the patient plays a role in AM development that is distinct from the localized DNA damage caused by sunlight. The lower prevalence of AK and KC in the AM group compared to the CM group serves as a clinical marker; a patient with an acral lesion but otherwise “clean” (non-sun-damaged) skin should still be treated with a high index of suspicion for AM.
Conclusion: A Call for Targeted Vigilance
This study represents one of the largest investigations into acral melanoma risk factors within a veteran population. By identifying Agent Orange exposure as a significant risk factor, the research provides a basis for potentially expanding the list of service-connected conditions and improving screening protocols for at-risk veterans.
The findings also highlight the biological divergence between acral and nonacral melanomas. As we move toward more personalized medicine, recognizing AM as a distinct entity with unique environmental triggers—rather than simply a variation of cutaneous melanoma—will be essential for developing effective prevention and early detection strategies. Future research should focus on the molecular mechanisms by which chemical exposures like TCDD influence acral melanocyte transformation and whether these insights can lead to targeted therapies for this aggressive melanoma subtype.
References
1. 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
2. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353(20):2135-2147.
3. Bradford PT, Goldstein AM, McMaster ML, Tucker MA. Acral lentiginous melanoma: incidence and survival patterns in the United States, 1986-2005. Arch Dermatol. 2009;145(4):427-434.
