Skin Cancer Isn’t a Presumptive Condition in That Situation
U.S. Army Huey helicopter spraying Agent Orange over agricultural land during the Vietnam War in its herbicidal warfare campaign Source: Wikipedia
BOSTON — A rare melanoma skin cancer subtype which is less likely to be associated with sun exposure has now been linked to contact with Agent Orange.
Primarily led by researchers from the VA Boston Healthcare System in Jamaica Plain, MA, the Brigham and Women’s Hospital in Boston and the Melanoma Research Alliance (MRA), the study of U.S. veterans identified a possible link between exposure to the Agent Orange herbicide and acral melanoma. The findings were published in JAMA Dermatology.
“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.”
The case-control study of including U.S. veterans with acral melanoma (AM,) determined that Agent Orange exposure was associated with increased odds compared with cutaneous melanoma controls and with controls without melanoma. That translates to an approximately 30% higher odds of having acral melanoma after AO exposure, the researchers advised.
Click to Enlarge: Multivariable Conditional Logistic Regression for Acral Melanoma Compared With Controls in the US Veteran Population Source: JAMA Network
Few previous studies have evaluated AM risk factors in a population of U.S. veterans. For this study, conducted between 2000-2024, AM patients were identified using the VA Cancer Registry and a validated natural language processing pipeline applied to pathology reports. Each AM case was matched to four nonacral cutaneous melanoma (CM) controls and four controls with no melanoma diagnoses at any time by diagnosis year and outpatient visit frequency. Participants were veterans with histologically confirmed AM, nonacral CM controls, and controls with no melanoma diagnoses at any time.
The researchers analyzed the effects of age, sex, race and ethnicity, rurality, region, military branch, comorbidities (National Cancer Institute Comorbidity Index), smoking status, unhealthy alcohol use as measured by the Alcohol Use Disorders Identification Test-Consumption, body mass index, Agent Orange exposure (AOE), prior photosensitizing medications, nevi, keratinocyte carcinoma (KC), actinic keratosis (AK), and number of dermatology visits in the 2 years before diagnosis.
Overall, 1,292 veterans with AM—median age 70.13 and 94% male—were matched to 5,168 controls without melanoma (median age, 73.97 [IQR, 65.53-82.08] years; 5044 [97.6%] male). In addition, 1,286 patients with AM (median age, 70.13 [IQR, 61.97-78.67] years; 1210 [94.1%] male) were matched to 5,144 CM controls (median age, 74.58 [IQR, 66.86-82.05] years; 5068 [98.5%] male).
The results indicated Agent Orange exposure was significantly associated with higher odds of AM vs. CM (AOR, 1.31; 95% CI, 1.06-1.62) and vs, controls without melanoma (AOR, 1.27; 95% CI, 1.04-1.56).
Other findings included that current smoking was associated with lower odds of AM (vs. CM: AOR, 0.65; 95% CI, 0.52-0.81; vs. controls without melanoma: AOR, 0.50; 95% CI, 0.40-0.62). The study team reported that prior KC and AK were associated with higher odds vs. controls without melanoma but lower odds vs. CM, and prior nevus was associated with higher odds of AM vs. controls without melanoma.
“Results of this study suggest that several factors were associated with AM in veterans and a need for continued investigation of AM as a distinct entity from CM and may inform future evaluations of the associations between AOE and AM in veteran populations,” the authors pointed out.
Melanoma is the fifth-most-common cancer in the United States and fourth among veterans, but most studies examining risk factors have focused on nonacral cutaneous melanoma (CM). While acral melanoma has been considered a rare subtype of melanoma arising on the palms, soles and nail unit, it comprises 50% to 58% of melanomas in Asian patients, 39% to 75% in Black patients, 49% to 61% in Hispanic patients and 1% to 7% in non-Hispanic white patients, according to background information in the article.
Because it is often diagnosed at later stages, has a distinct variant profile with fewer known targetable alterations and responds less favorably to current therapies, AM has a poorer prognosis than CM. The causes of AM are not well understood, and few risk factors have been defined. Unlike CM, AM is not strongly linked to UV radiation, the authors emphasized.
Veterans are considered an important population for investigating AM risk factors, according to the report, and the VHA, the largest integrated health system in the U.S., has national longitudinal data that enable evaluation of rare cancers such as AM.
In addition, the researchers advised, “Veterans have unique environmental and occupational exposures and a higher melanoma burden than the general population. Although Agent Orange (AO) and other herbicides containing dioxin are no longer used, concerns about modern pesticides and melanoma risk remain.”
This study, which identified several factors associated with AM, confirmed that the higher proportions of female, Black, and Hispanic veterans with AM are consistent with prior epidemiologic research. On the other hand, the higher proportions of prior KC, AK, nevi and dermatology visits before AM diagnosis in the AM group vs. controls without melanoma baseline comparison might suggest differences in dermatologic surveillance, according to the study team, which suggests that diagnosis might also be less likely to occur in the initial dermatologic visit for AM, “given the challenges associated with biopsying these anatomic regions.”
In adjusted analyses, NCI scores of 2 or higher were associated with lower odds of AM vs. CM, suggesting competing comorbidities could reduce the likelihood of AM diagnosis. “Female veterans had nearly twice the odds of AM vs. controls. Prior studies have reported similar or lower incidence in females compared with males, but our models estimated relative odds within a predominantly male VA population (88.6% male and 11.4% female in 2023),” according to the authors. “AM in female veterans could reflect competing risks and residual confounding, since male and female veterans differ in demographics and overall health.”
Other findings included:
- Prior AK and KC showed divergent associations: lower odds in the AM vs. CM comparison but higher odds in the AM vs controls without melanoma comparison. Prior nevus was associated with higher odds of AM vs. controls without melanoma, according to the researchers, who said their results might indicate an underlying predisposition among veterans who develop AM, although the cause of these associations cannot be determined from this study.
- AUDIT-C positivity was associated with lower odds of AM compared with CM. Prior studies have found alcohol consumption associated with increased CM risk, which might account for why AUDIT-C positivity corresponded with lower odds of AM relative to CM.
- Current smoking was associated with lower odds of AM compared with both controls. This inverse association aligns with multiple studies reporting reduced CM and AM risk in current smokers, the mechanism of which remains unknown.
Exposure to Agent Orange, a defoliant used by the U.S. Air Force during the Vietnam War’s Operation Ranch Hand, was significantly associated with higher odds of AM compared with both controls in the primary models, and the association also was found in sensitivity analyses restricted to Vietnam Era veterans and to individuals with palmoplantar and subungual AM. AO contained 2 main herbicides: 2,4-D (2,4-dichlorophenoxyacetic acid) and 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), according to the study, which added that 2,4,5-T was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a compound that the International Agency for Research on Cancer and the US National Toxicology Program classify as a human carcinogen.
TCDD has been shown to induce chromosomal instability and epigenetic dysregulation, processes recently implicated in AM pathogenesis,” the researchers wrote.
The VA recognizes several cancers as presumptively related to AOE, but skin cancers are not included. The National Academies of Sciences, Engineering, and Medicine has concluded that evidence was insufficient to determine whether AOE is associated with melanoma or KC, citing inconsistent and underpowered studies.
“Our results support the need for continued studies of acral melanoma as a distinct entity from cutaneous melanoma,” Hartman said. “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.”
- Hwang JC, Huhmann LB, Cho K, et al. Identification of Risk Factors for Acral Melanoma in US Veterans. JAMA Dermatol. Published online February 04, 2026. doi:10.1001/jamadermatol.2025.5827