Frequency of Trauma, Physical Stress, and Occupation in Acral Melanoma: Analysis of 313 Acral Melanoma Patients in Korea

There are racial differences in the prevalence of the subtypes of cutaneous melanoma, and acral melanoma is the most common subtype in Asian, Hispanic, and African populations1. Acral melanoma occurs on the palms, soles of the feet, and nails. Unlike cutaneous melanomas in Caucasian populations, ultraviolet (UV) exposure is not a major etiological factor in acral melanoma2. In addition, the number of melanocytic or dysplastic nevi is not a significant risk factor for acral melanoma3. A recent molecular classification of cutaneous melanoma found distinct subsets of genetic alterations in acral melanoma compared with other subtypes4, 5, 6. However, the pathogenesis of acral melanomas is still not clear. Recent Asian studies have shown that acral melanomas frequently occur on the heel and forefoot of the plantar surface, unlike benign acral melanocytic lesions such as acral nevi and lentigines, suggesting a role of trauma or physical or mechanical stress in the development of acral melanomas7, 8, 9. Therefore, we conducted a retrospective study to investigate the frequency of trauma, physical stress, and occupation in patients with acral melanoma.

We found that acral melanomas are common on the sole, especially the borders of the foot, and that more than half of patients have a history of trauma or physical stress. Farmers and fishermen were the occupations most commonly affected.

Acral melanoma occurs on acral sites, such as the hands, feet, and nails. Analysis of the site details revealed that only 15 of 313 (4.8%) patients had melanomas of the hands, whereas 212 patients (67.8%) had them on the feet and 86 patients (27.5%) on the nails. Therefore, acral melanomas occur predominantly on the feet, rather than the hands. Interestingly, we found that border areas of the feet (the medial, lateral, and posterior parts of the sole, the toe webspaces, and the anterior parts of the toes) are commonly involved. Previously, we reported that melanoma lesions on the soles were distributed mainly at the periphery7. There have also been reports of melanomas on the plantar surfaces of the forefoot and heels, suggesting that mechanical stresses such as plantar pressure and shear stress increase the formation of acral melanomas9. In the present study, the heel was the dominant site of plantar melanomas, and the edges of the foot were commonly involved; these areas are readily traumatized or irritated by chronic physical stresses.

The role of trauma in melanoma development has long been controversial10, 11. In 1965, Lea10 performed a statistical analysis of the incidence of trauma in melanoma, using basal cell carcinoma as a control. A history of trauma was present in 38% of 193 melanomas but in only 12% of 530 basal cell carcinomas, and the relationship between trauma and the development of melanoma was regarded as established beyond reasonable doubt. However, Briggs11 could not find statistical evidence to support this relationship. The role of trauma is especially important in acral melanoma because acral sites are more exposed to traumatic events than other body sites. But a study conducted in Durban, South Africa found no evidence of traumatic acral melanoma in the deeply pigmented skin of Zulus12. In Europe, single or recurrent traumatic events were more often associated with acral melanoma or melanoma located on the extremities than melanoma on other sites13. In China, a study of 685 cutaneous melanomas revealed a possible association between traumatic events and melanoma of the lower limbs14. In case-control studies, two major risk factors for hand and foot melanoma were previous trauma and nevi on the sole15.

In the present study, 26.8% of the patients recalled traumatic events. There was a significant difference in the frequency of trauma at the lesion sites (p=0.002). Although melanoma development on burn scars has been reported, penetrating injuries and contusions are more common at acral sites16, 17, 18, 19. There is a higher incidence of trauma in subungual melanoma compared with melanoma on the volar surfaces of hands and feet14, 20. Subungual melanoma was associated with a high incidence of traumatic events (40.5%, n=34). The frequency of subungual melanomas located on the thumb and the nails of the big toe also suggests a role of trauma7, 21. In our study, fingernails (42.0%, 21 of 50) were the most frequently affected by trauma, followed by toenails (36.1%, 13 of 36). Trauma-associated subungual melanomas often presented with ulcerated or nodular lesions and nail dystrophy. Based on this finding, we postulate that patients with nail dystrophy, nodular lesions, or non-healing wounds after trauma to nails should watch for the development of acral melanoma. These patients should be followed up by a dermatologist and monitored for the development of skin cancer from chronic wounds or long-lasting ulcers. Border areas of the foot were less closely associated with trauma (17.6%, 24 of 136) than non-border areas (31.6%, 24 of 76). From this finding, we conclude that traumatic injuries can affect any part of the foot and not merely border areas.

Physical stress has not been well studied in melanoma. Anatomical mapping suggests that mechanical stress and chronic physical stress are associated with acral melanoma7, 9. However, the exact kind of physical stress is not known. In our study, physical stresses were found in 29.1% of acral melanoma patients, including abrading or rubbing keratoderma or thick scales on the foot, maceration resulting from wet conditions, chronic friction caused by using farming tools, counting paper money with the fingers, and climbing mountains frequently wearing tight hiking boots. These physical stresses are not caused simply by body weight pressure.

One Japanese female developed a black patch on her thumb after working as a seamstress for more than ten years, and melanoma could not be excluded22. Such work-associated chronic physical stress might induce melanoma. Among our patients, melanoma developed on the left finger of a cashier who counted paper money continuously and in a farmer who handled tools for decades. A study conducted in 1941 found that trauma and chronic irritation were evident etiological factors in 25% of all cutaneous melanomas23. The authors suggested that lack of information about melanoma delayed the diagnosis. In our study, about 56.0% of the acral melanoma patients had experienced trauma or physical stress. This high frequency might be explained by the fact that acral sites are more prone to trauma or physical stress and patients lack medical information about acral melanomas.

The mean duration of the acral melanomas before presentation in our study was 46.6±80.2 months. Acral melanomas tend to be present for a long time before the first visit to the hospital. There are several reasons for this. First, acral lentiginous melanoma usually has a long radial growth phase and then subsequently invades. Another reason is the delay in diagnosing acral melanomas. Acral melanoma is less affected by genetics and UV exposure than other subtypes of melanoma; chronic stimulation is a more important factor in its development. Squamous cell carcinoma is known to arise in the setting of long-standing chronic inflammation, repeated injury, unrestrained fibroproliferative healing, and subsequent tissue stiffening. These alterations might change the biophysical performance of the mesenchyme and lead to carcinoma conversion of keratinocytes24. We believe that acral melanoma, like squamous cell carcinoma, could develop gradually from chronic inflammation. Patients with a history of physical stress have experienced this stress over a long period of time, and may delay a visit to the hospital if they mistake melanoma lesions for calluses or benign lesions caused by chronic stimulation. Conversely, in our series, trauma led to a shorter disease duration and progression of the pre-existing acral melanoma. Trauma to a clinically apparent melanoma is a significant independent negative predictor of overall survival25. Occupational risks for cutaneous melanoma have been reported. Cutaneous melanoma is more common in high socioeconomic groups than in low socioeconomic groups. However, low socioeconomic groups were diagnosed at more advanced stages and had lower survival rates26. In regard to UV exposure as a causal factor, male workers in Sweden who were exposed to artificial UV sources developed melanomas on the trunk, and females exposed to arsenic/mercury had increased risk27, 28. In Asia, acral melanoma is the most common form of melanoma and exposure to sunlight is not a risk factor29. Therefore, the type of occupation and degree of exposure to UV differ in between Asian and Caucasian populations. In China, a higher risk of trauma-associated melanomas on the feet was observed in those living in the south of China, who preferred to walk bare-footed more often than those living in the north, who always wore shoes. Barefoot persons have higher risks of both localized trauma and melanoma on their lower extremities, indicating that the relationship between trauma and acral melanoma was significant in this population14. In our study, agriculture and fishery industry workers were the most common occupation with acral melanoma. Although these individuals are exposed to UV while working, the acral sites are not directly exposed to the sun. Instead, the patients might be subjected to trauma while working bare-footed or to physical stress from work shoes. People in these occupations had more melanomas at border sites and were subjected to significantly more physical stress.

The mechanism of the trauma- or physical stress-induced pathogenesis of melanoma is unknown. Chronic wounds and trauma induce local inflammation, which alters the microenvironment of immune cells. The inflammasomes involved in tissue damage provoke the development of melanoma30, 31. In addition, trauma and cellular damage might activate the cell cycle. Recurrent activation could contribute to cells experiencing critical telomere shortening at an earlier stage and provoking tumor growth via increased TERT expression32. Therefore, trauma or physical stress might induce melanoma-associated genetic changes. In our previous study, BRAF mutations were infrequent in acral melanomas33, and there were no differences in anatomical site when analyzing melanomas by common mutation type34. However, further studies of the pathogenic roles of trauma and physical stress-induced genetic alterations are warranted.

This study had several limitations. First, detailed trauma and physical stress histories were not available in 30% of the patients. This is a retrospective study, and accurate medical records were not available for former patients. Therefore, it was difficult to obtain precise histories for some patients. Second, the anatomical sites were not determined exactly at locations where border and non-border areas overlap for large lesions on the sole. To reduce this error, we used the location where patients reported the acral melanoma first developed or the deepest area of the lesion. Third, our findings may not be generalizable to all Korean occupations because jobs differ in different areas. Our study was conducted in the southern part of Korea, where there are many farmers and fishermen. Fourth, the frequency of trauma and physical stress in our study should be compared to the frequency in patients without acral melanoma, or to the frequency in acral areas on patients' non-melanoma sides. However, even this approach could be subject to recall bias. Patients may preferentially remember injuries at sites that later develop melanoma.

Our study is the first to report a high frequency of history of trauma, physical stress, and certain occupations in patients with acral melanoma. Acral melanomas occurred primarily in the border areas of the foot and were associated with traumatic events or physical stress in more than half of the patients. Farmers and fishermen tend to develop melanomas more often than other occupation groups because of their working environment. However, further studies are needed to determine whether trauma, physical stress, and occupation are causal factors or risk factors for acral melanoma. These studies should compare the frequency of trauma, physical stress, and occupation of patients with acral melanoma and a matched control group. Studies of the molecular mechanism of the traumaor physical-stress-induced pathogenesis of melanoma development are also needed.