Acral Melanoma Following Trauma: A Systematic Review and Meta-Analysis

Abstract

Anecdotal evidence suggests an association between trauma and the subsequent development of acral melanoma. However, good-quality supporting evidence has been lacking, prompting this review which aimed to address the uncertainty by compiling and analyzing the frequency of trauma, tumor features, disease progression, and death due to melanoma for acral site melanomas associated with trauma and cases without a trauma history. A systematic review was performed with searches of Medline, Embase and the Cochrane CENTRAL register of trials to May 15, 2025. Included studies were those that reported cases of acral melanoma and a history or absence of preceding trauma. Data were pooled using a random-effects model. The frequency of trauma with acral site melanomas, tumor features at presentation and death from melanoma were collated and analyzed. From 1448 titles, 97 studies reported cases of acral melanoma with trauma status. Two case–control studies compared the frequency of a trauma history in patients with and without acral melanomas, both reporting that a trauma history was more frequent in patients with acral melanoma (odds ratios 5.2, 95% CI 3.0-8.8 and 8.1, 95% CI 4.3-15.5). Fifty case reports and 45 multicase studies reported acral melanoma features along with trauma history. The extensive evidence analyzed in this review confirmed with considerable confidence that acral melanomas may develop after trauma. The important practical implication of the study findings is that early biopsy of any unusual acral lesion that develops or persists after prior trauma should be considered. This will allow treatment to be undertaken expeditiously if melanoma is diagnosed.

Introduction

Cutaneous melanomas at acral sites develop in hairless skin on the soles of the feet, the palms of the hands, and in the nail apparatus. ¹ Their frequency is reported to be similar in light and darker skinned people^1,2 but they represent very different proportions of melanomas within different populations. In Caucasians, acral melanomas are estimated to comprise 2% to 7% of all melanomas,^3-7 with the acral lentiginous melanoma (ALM) subtype accounting for around 60% to 74% of acral melanomas.^4-6,8 However, in darker-skinned people from Africa, Asia, and Latin America, in whom cutaneous melanomas are uncommon, acral site melanomas are relatively more frequent, making up 60% to 75% of melanomas in African Americans,^9,10 57% to 69% of melanomas in Asian populations^11,12 and 23% to 49% in Hispanic populations.^7,13

Acral site melanomas can be of several histopathological subtypes; superficial spreading melanoma (SSM), nodular melanoma, desmoplastic melanoma and ALM. The most frequent of these subtypes is ALM, ¹ but its frequency at acral sites varies depending on the population studied and possibly the method of patient selection. For example, in 2 of 3 studies from China, quite consistent findings of 42% and 46% of acral site melanomas being ALM were reported^14,15 but the third study reported that 86% of acral melanoma were of the ALM subtype. ¹⁶ Studies from Germany and Australia reported ALM making up 60% to 70% of acral melanomas.^17-19

The mutational burden of acral melanomas is much lower than that of nonacral cutaneous melanomas and is dominated by large-scale structural variants ²⁰ and gene amplifications and deletions rather than the C-to-T nucleotide transitions associated with ultraviolet (UV) radiation exposure.^21-23 However, there is some evidence that subungual acral melanomas, arising in the nail apparatus, have a greater likelihood of UV signature mutations compared to nonsubungual acral melanomas arising on the sole and palm. ²⁴

Trauma leading to the subsequent development of cutaneous melanoma was noted as early as 1880 according to an article published by Coley and Hoguet. ²⁵ Since then many cases and case series have been reported.^26-30 Many studies have reported cases of acral melanoma following penetrating trauma but these have generally been single case reports or small case series without the requisite power to analyze lesion features or to document clinical outcomes with reasonable precision.

The aim of this review was to identify studies reporting acral site melanomas and a history of trauma or a stated absence of a trauma history to estimate the strength of the association with trauma and to report clinical features and patterns of disease progression.

Materials and Methods

Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) reporting guidelines were followed. ³¹ A registered protocol for the study is available through the INPLASY platform which accepts noninterventional systematic review protocols (INPLASY202590121). Medline, Embase, and the Cochrane CENTRAL register of trials were searched up to May 15, 2025. Medline and Embase searches used the Medical Subject Heading melanoma and text words acral and acral melanoma. Full details are provided in Supplementary Table 1. Studies selected included patients with acral site melanomas and a history of trauma prior to the diagnosis or stated an absence of preceding trauma. Studies that used the words trauma or injury, including burns, were eligible while those that reported only chronic pressure or irritation such as due to barefoot walking were not included. Studies without primary data (reviews, editorials, guidelines) were excluded, as were laboratory studies without patient data. No study design or language restrictions were used. Titles were assessed by 1 author (G.J.W.) with studies of likely or uncertain eligibility obtained for full-text review. Reference lists of included studies and review articles were checked to identify additional studies. Eligible studies in non-English languages were translated using Google Translate.

Extracted data included first author, year of publication, country, study design, setting, patient characteristics, lesion features, investigations and treatments, follow-up duration, node status, recurrences and deaths. Data were extracted by 1 author (G.J.W.). The number of patients with features of interest were recorded within trauma and no-trauma groups and risk estimates were generated using Review Manager 5 (RevMan 5) [Computer program]. Version 5.4. Copenhagen: The Cochrane Collaboration, 2020. ³² Data were pooled when 3 or more studies reported the same outcome. A random-effects model was used for all risk analyses and heterogeneity assessments used the I² measure. ³³ Summary risks were reported only when the I² value was ≤65%, indicating low-to-moderate heterogeneity. Sensitivity analyses were performed when any single study contributed a weighting of 25% or greater. A funnel plot of the risk of death from melanoma was generated to assess publication bias. Risk of bias was assessed using the Newcastle-Ottawa scale for cohort, cross sectional, and case–control studies and a tool developed for case reports. ³⁴

Results

From 1501 titles, 97 studies that included patients with acral melanomas and reported the presence or absence of a history of trauma were identified (Supplementary Figure 1 and Supplementary Tables 2 and 3). Nine studies were translated into English.

Study designs included 50 case reports, 29 cohort studies, 16 case series without follow-up after diagnosis (cross-sectional studies) and 2 case–control studies that compared the frequency of a history of trauma in patients with acral melanomas compared to people without acral melanomas.

Risk of Bias

Summarized risk of bias assessments within study design groups are shown in Supplementary Figure 2. The 2 case–control studies included cases of acral melanoma that likely represented the full spectrum of disease; one used electoral roll candidates for the healthy controls (low bias) and the other used hospital-based controls that did not have acral melanoma but had other reasons for admission (high bias). The 2 studies were both likely to have had a differential recall bias for trauma, as injuries are much more likely to be remembered when a malignant lesion develops following that trauma as opposed to injuries that healed uneventfully. This effect would result in an exaggerated risk of associating the acral melanoma with prior trauma relative to people without acral melanoma.

The 50 case reports were reported largely for their unusual presentation and often-delayed diagnosis, therefore representing a highly selected case, although most had a histopathologically verified diagnosis. Lesions had been present for <2 years in 32 studies (64%) suggesting the recall of trauma or absence of trauma was at low risk of bias, while for 7 studies the interval was 3 to 5 years (moderate risk of bias) and in a further 6 studies >5 years had elapsed (high risk of bias). Five studies did not report how long the lesion had been present. Reporting was considered complete if age, sex, Breslow thickness, treatment, and follow-up duration were reported; this was so in 24 case reports, but 19 studies were missing either treatment or follow-up information and 7 studies were missing both treatment and follow-up details.

Cohort studies were a mix of highly selected and representative cases of acral melanoma, and the length of time between trauma and the diagnosis of lesions was also variable, with 4 studies reporting trauma events that were more than 5 years in the past (high risk of bias). A major limitation in 27 of the 29 cohort studies was the absence of a comparison of tumor characteristics, treatments or outcomes between trauma-associated cases and cases without a history of trauma.

Cross-sectional studies (ie, case series without follow-up) also had very mixed biases; only 1 of the 15 studies compared patients with trauma-associated acral melanoma to patients without trauma, and completeness of reporting was poor in 6 studies (high bias).

The absence of details in the cohort studies and case series prevented calculation of risk estimates and the data reported are thus based on very few studies, leaving these vulnerable to chance differences.

A funnel plot of the outcome death from melanoma did not show good evidence of asymmetry and therefore publication bias, but was very limited because there were so few studies (Supplementary Figure 3).

Trauma Frequency and Type

Two case–control studies reported data allowing completion of a 2 × 2 table of acral melanoma or not and preceding trauma or not. The odds ratios (ORs) showed a much higher likelihood of a trauma history in patients with acral melanomas than in people without acral melanomas (healthy controls or patients admitted for other diagnoses); OR 5.2 (95% CI 3.03-8.81) ³⁵ and OR 8.1 (95% CI 4.29-15.45). ³⁶ Combining the data and expressing the findings as frequencies, trauma occurred in 28% of cases of acral melanoma compared with 7% of people without acral melanoma.

In 42 studies with 5 or more cases of acral melanoma, the median frequency of trauma was 20.2% (Interquartile range (IQR) 10.5%-37.8%), range 4.7% to 87.5%.

In 42 studies involving 646 patients the type of trauma was at least partially documented; 27% reported experiencing a penetrating injury, 20% a cut, 20% a blow to the area, 4% a crush injury, 2% a burn, 1% simply described stepping on an object. In 26% the type of trauma was not specified.

Duration of Acral Lesion Prior to Diagnosis

Forty-three studies reported the length of time that an acral lesion had been present before it was diagnosed in patients with and without trauma (Supplementary Table 4). There was no consistent pattern of longer or shorter duration for cases of acral melanoma and trauma compared to patients with acral melanoma and no preceding trauma.

Features at Diagnosis

In 17 patients with acral melanoma and a trauma history, the median Breslow thickness was 3.2 mm (IQR 2.4-4.5 mm) and for 6 patients with acral melanoma who had not experienced prior trauma; 3.9 mm (IQR 2.3-5.1 mm). Two studies reported thicker melanomas in the trauma cases relative to those without trauma^37,38 (Supplementary Table 4).

Analysis of 33 studies specifying T-categories showed very high heterogeneity (I² 70%), so calculation of a pooled estimate was not appropriate. Pooling studies of exclusively subungual acral melanomas gave a significantly increased risk of lesions being >4 mm in thickness (T4); risk ratio (RR) 2.3 (95% CI 1.42-3.62, P = .0006) for subungual melanoma+trauma compared to subungual melanoma-no trauma, with no heterogeneity (I² 0%; Supplementary Table 5).

Pooled analysis of 31 studies indicated a significantly increased likelihood of ulceration for trauma-associated acral melanomas compared to those without trauma RR 1.2 (95% CI 1.05-1.31, P = .004) with no heterogeneity (I² 0%). Exclusion of the pooled case reports did not change this estimate. Analysis of only subungual melanoma produced a similar, but nonsignificant risk (RR 1.1 95% CI 0.85-1.52, P = .40; Supplementary Table 5).

Mitotic rate was reported in 11 case reports, 1 small case series ³⁷ and 1 cohort study. ³⁹ The cohort study provided a reasonable sample size for mitotic rate data separately for the 2 groups and showed there was a slightly higher number of patients with acral melanomas and trauma having ≥1 mitosis/mm² compared to acral melanomas without associated trauma (Supplementary Table 4).

The presence of disease in regional lymph nodes at the time of diagnosis was reported in 30 studies and pooled analysis suggested an increased risk; RR of 1.5 (95% CI 0.90-2.33, P = .12), for acral melanomas with trauma but this was not statistically significant. Heterogeneity was quite high at 65%, but exclusion of each of the high-weight studies did not greatly change the estimate, significantly reduce heterogeneity or change the P value to a significant result (Supplementary Table 6).

The presence of distant metastases at the time of diagnosis of an acral melanoma was reported in 34 studies and analysis gave a pooled RR of 1.5 (95% CI 0.96-2.23, P = .08) with no heterogeneity, suggesting a higher risk of distant metastasis at diagnosis in the acral+trauma group. Analysis after exclusion of the combined case reports or the highest-weight study did not greatly change the risk estimate or P value (Supplementary Tables 5 and 6). Analysis of exclusively subungual melanomas did not greatly change the risk estimate (Supplementary Table 5).

Disease Recurrence and Progression

Data on local or in transit recurrence, lymph node metastasis and distant metastasis during follow-up were too few for confident calculation of risk estimates (Supplementary Table 4).

Disease beyond the primary lesion was reported in 40 studies and analysis demonstrated a significantly increased risk of disease progression in acral melanomas with a trauma history compared to those without (RR 1.8, 95% CI 1.43-2.29, P < .00001). Heterogeneity was low (I² 21%). Exclusion of the case reports or the highest weight study did not greatly change the estimate, heterogeneity or P value (Supplementary Tables 5 and 6). Analysis of only subungual cases resulted in an increased risk (RR 2.2, 95% CI 1.10-4.56, P = .03) but with greater heterogeneity; I² 53%. The risk was not significantly increased for nonsubungual cases; RR 1.3 (95% CI 0.46-3.52, P = .64), with heterogeneity 48% (Supplementary Table 5).

Death from melanoma was reported in 37 studies, and pooled analysis showed a similar risk in patients with and without a trauma history (RR 1.1 95% CI 0.59-2.05, P = .76) with low heterogeneity (I² 19%; Supplementary Figure 4). Exclusion of the grouped case reports and the single highest weight study did not greatly change the risk or heterogeneity and P values remained nonsignificant (Supplementary Tables 5 and 6). The average follow-up period for these studies was 31.8 months (with medians ranging from 10.0 to 53.5 months).

Discussion

It is well documented that cutaneous squamous cell carcinoma (SCC) can be initiated by trauma,^40-42 notably in burns scars when they are designated as Marjolin’s ulcers. These appear to have a worse prognosis than that of SCCs that are not trauma-related.^43,44 There are also reports of cutaneous melanomas initiated by trauma ²⁶ or burns,^27,45 and sunburn is a well-known risk factor for melanoma . Many of the reports of the association between melanoma and trauma have been of melanomas arising on acral sites, possibly because the likelihood of trauma to hands, feet, and nails is greater than at other body sites.

Against this background, we conducted a systematic review of all available evidence relating to the association between acral site melanomas and trauma to determine the features of disease and disease progression under these circumstances. The review focused on injury or acute trauma and did not include studies reporting only cases of chronic pressure and irritation such as walking barefoot or wearing poorly fitting shoes.

The review identified 97 studies that reported acral site melanomas with trauma status. Two case–control studies reported a significantly higher frequency of trauma in patients with acral-site melanomas compared to people without acral melanoma. While both studies are likely to have had considerable recall bias, it seems unlikely that this could completely account for the reported 5 and 8 times greater likelihood of a history of trauma in acral site melanomas.

Analysis of the histological features and the risk of distant metastasis at diagnosis of the acral melanomas suggested more severe disease in patients with a history of trauma compared to those without. This pattern might be explained by diagnosis being delayed in cases where an injury disguised the underlying disease, however, the studies did not support a consistent pattern of a greater duration of the lesion before diagnosis. It is also possible that the greater severity pattern represented an accelerated disease course associated with inflammation from an injury and the wound healing process. In contrast to the greater severity of disease, the risk of death from melanoma was not increased for the patients with preceding trauma relative to those without. A possible explanation is the relatively short follow-up duration for many of the studies (mean 32 months). An additional confounding factor is that acral site melanomas are more frequent in people with darker skin who are more likely to live in low resource countries where healthcare is less accessible. Even in first-world countries delayed presentation can occur. Our review identified 2 reports from the United States of very severe lesions at presentation where the patients’ lack of insurance was the reason for the delay in their seeking treatment ⁴⁶ or receiving treatment. ⁴⁷ Late presentation because of cost or access may impact cases of acral melanoma following trauma more than those without a history of trauma as people might assume the abnormality is simply part of a slow but normal healing process. Physicians too may consider delayed healing or infection as an explanation for the condition.

Based on the current analysis of available evidence, it is not possible to conclude that there is a causal relationship between trauma and the development of acral melanoma, but it remains a distinct possibility that some cases of acral site melanoma develop after a period of intense or sustained inflammation following trauma. While the current evidence for a causal link is insufficient, there is biological plausibility, consistency across a number of independent studies and a reasonable temporal relationship.

Several of the studies reported in this review discussed possible mechanisms for trauma-induced melanoma^14,38 through wound factors activating the cell cycle and impacting telomere length, or inflammatory by-products inducing tissue damage. Mechanisms discussed in laboratory studies include that trauma can lead to greater numbers of T helper 2 lymphocytes and T regulatory cells, in turn increasing concentrations of cytokines released by these cells ⁴⁸ or that mechanical stress can rupture nuclear membranes leading to increased DNA damage. ⁴⁹

Strengths and Limitations

This review compiled a large array of studies that reported acral melanoma and trauma history and provides an overview of case presentations and disease progression. However, the review is limited by the insufficient detail provided in the primary studies preventing a more rigorous exploration of differences between the trauma and no-trauma groups. Additionally, there were no studies that reported outcomes for the various subtypes of melanoma, for example, ALM compared to SSM. This review was unable to clarify the possible causal effect of trauma on acral melanoma development, but it should serve to increase awareness of a possible association. In this way the study may encourage early biopsy and thus earlier diagnosis of acral melanomas that may not have the typical features of a melanoma and may be disguised by the presence of inflammation, ulceration or scarring following trauma.

Conclusion

There is suggestive evidence of an association between acral melanoma and preceding trauma. This should encourage early biopsy of any unusual lesion at an acral site that develops or persists after an injury, so that the diagnosis of an acral melanoma is not delayed, and treatment is undertaken expeditiously.

Supplemental Material

sj-docx-1-cms-10.1177_12034754261431836 – Supplemental material for Acral Melanoma Following Trauma: A Systematic Review and Meta-Analysis

Supplemental material, sj-docx-1-cms-10.1177_12034754261431836 for Acral Melanoma Following Trauma: A Systematic Review and Meta-Analysis by Gabrielle J. Williams and John F. Thompson in Journal of Cutaneous Medicine and Surgery