Circles are placed on the prominent nodule, ulceration, or center of the darkest point within the lesion. Weight-bearing areas are the more predominant sites, and melanoma lesions are distributed mainly at the periphery and borders (A). The thumb and great toe, when subjected to long-term physical stress and trauma, are the most common sites of nail apparatus melanomas (B).
Melanomas on the sole develop adjacent to the border of each area and spread along the naturally occurring deep and semi-deep creases or fine wrinkles in the inner area (A), on the borderline of the center and outer areas of the forefoot (B), in the outer area of the midfoot (C), on the borderline of the midfoot and the heel (D), in the inner (E) and outer (F) areas of the midfoot, and in the heel (G and H).
Survival curve stratified by TNM stage shows a more rapid decrease in survival rate at the early phase in stages III and IV than in stages 0, I, and II (A). There are no significant differences in the survival rate between patients with weight-bearing (n = 75) and non–weight-bearing (n = 13) melanomas of the sole (B) (P = .63) and between patients with volar (n = 105) and nail apparatus (n = 43) melanomas (C) (P = .66).
eTable 1. Histopathologic Characteristics and TNM Stage of 149 Patients
eTable 2. Multivariate Analysis of the Prognostic Factors
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Jung HJ, Kweon S, Lee J, Lee S, Yun SJ. A Clinicopathologic Analysis of 177 Acral Melanomas in Koreans: Relevance of Spreading Pattern and Physical Stress. JAMA Dermatol. 2013;149(11):1281–1288. doi:10.1001/jamadermatol.2013.5853
The pathogenesis of acral melanoma remains unclear, even though trauma may be a predisposing factor. A study about the association of long-term physical stress with the incidence and spreading patterns through detailed anatomic mapping may be important to understand the unique features of acral melanoma.
To analyze the epidemiologic and clinicopathologic characteristics of acral melanoma and evaluate how long-term physical stress or pressure strength influences acral melanoma based on the analysis of differences in incidence, prognosis of the distinct site (weight or non–weight-bearing portion of sole, volar, or subungual location), and the spreading pattern of melanoma on the soles.
Design, Setting, and Patients
Cross-sectional, retrospective study of 177 Korean patients with acral melanoma from January 1, 1994, through October 31, 2012.
Main Outcomes and Measures
Anatomic mapping and histopathologic examination of acral melanoma.
The male to female ratio was 1:1.03, and the mean age at first admission was 55.3 years. Acral lentiginous melanoma was the most common histopathologic subtype (85.9%), followed by nodular melanoma (12.8%). There was a high incidence of acral melanoma at more physically stressed sites, such as the center of the heels and inner forefoot. In addition, a peculiar spreading pattern with the long axis of melanoma, typically along naturally occurring creases due to long-term pressure on the soles, was often observed. The prognostic index and survival rate showed no significant difference between volar and subungual locations or between weight and non–weight-bearing portions of the soles.
Conclusions and Relevance
Clinicopathologic characteristics of acral melanoma diagnosed at an advanced stage and resulting in a low survival rate are not significantly different between Koreans and other Asians. Interestingly, based on our study, long-term physical stress or pressure strength can influence the incidence and spreading pattern of acral melanoma in a particular manner. Acral melanoma occurs on more physically stressed sites with the long axis along natural creases on the sole. A further prospective investigation, especially of in situ lesions, regarding location-based differences in incidence, progress, and survival is necessary to better understand the pathophysiologic characteristics of acral melanoma.
The incidence of melanoma is lower in Asians, including Koreans, than in whites, although there is a definite upward trend.1,2 Although one main characteristic of melanoma in Koreans is the high proportion that occurs at acral sites (palmoplantar with the medial and lateral sides of the fingers, toes, hands, and feet, as well as parts of the wrists and heels), the clinicopathologic features of acral melanoma in Koreans rarely have been clarified.1,3Quiz Ref IDThe pathogenesis of acral melanoma remains unclear since classic risk factors, such as sun exposure, fair skin type, family or personal history of previous melanoma, and preexisting melanocytic nevi, for melanoma appear to be less relevant in acral lesions.4-8 The more intense and long-term trauma experienced in acral locations may be a predisposing factor due principally to the anatomic location of the weight-bearing area.9,10 This hypothesis raises the question as to how the acral site is affected by long-term physical stress or pressure strength. Therefore, we evaluated the epidemiologic and clinicopathologic characteristics of acral melanoma in Koreans by detailed anatomic mapping and elucidated correlations between acral melanoma and long-term physical stress or pressure strength by analyzing differences in the incidence, prognosis of the distinct site, and the melanoma spreading pattern on the soles.
From the database of patients diagnosed with melanoma between January 1, 1994, and October 31, 2012, at the Chonnam National University Medical School in Gwangju, Korea, 177 acral melanomas, based on clinical photographs and medical records, were included in the present study. The acral sites of the dorsal parts of the hands and feet were excluded to provide a more accurate analysis of acral melanoma based on strict histopathologic and physiologic criteria. Clinical data included the age and sex of the patients, the location of the lesion, method of biopsy, lymph node invasion, and distant metastasis. In addition, survival curves were calculated based on the medical records of patients who died of melanoma. The study protocol was approved by the institutional review board at Chonnam National University Hwasun Hospital; the need for consent was waived.
We evaluated the role of long-term physical stress and pressure strength in acral melanoma. The acral site was divided into various regions for anatomic mapping, forming 2 major groups based on the histophysiologic difference in the originating tissue, which included the volar (originating from the glabrous tissue) and subungual (originating from the nail matrix) locations. We divided the sole into 3 regions (forefoot, midfoot, and heel) and each region into various areas (center, inner, outer, medial, lateral, and posterior) based on the degree of physical stress, as shown in Figure 1A. The forefoot includes the metatarsal area of the sole and is a weight-bearing portion. The midfoot is composed of the medial arch and the cuboid bone, which are non–weight-bearing and weight-bearing portions, respectively. The heel, the most weight-bearing portion of the sole, is composed of the calcaneus and talus bones. The inner area is aligned from the midpoint of the web space of the first toe toward the heel and the outer area from the midpoint of the web spaces of the third and fourth toes toward the heel. The center area is between the inner and outer areas, and the medial and lateral areas make up the volar surface of the soles as seen from the medial and lateral views, respectively.
The biopsy slides of 149 patients with acral melanoma were reviewed again by one of us (S.J.Y.). The following data were recorded: histopathologic subtype, tumor Breslow thickness, ulceration, predominant cell type, mitotic rate (mitotic count per millimeters squared), and vertical growth phase. The stage of disease was determined based on the most recent classification of the American Joint Committee on Cancer.11
The evaluation of data was performed using the statistical package SPSS, version 20.0 (SPSS, Inc). The Kaplan-Meier method was used to calculate survival curves, and significant differences were determined by the log-rank test. To compare the baseline characteristics of subgroups, we used the Pearson χ2 test or Fisher exact test as appropriate for the categorical variable. Multivariate analysis was performed with a Cox proportional hazards regression model in which age, TNM stage, ulceration status, vertical growth phase, mitotic rate, weight-bearing area, and subungual area were used as covariates. P < .05 was considered to indicate statistical significance.
A total of 177 patients with acral melanoma were evaluated; 87 (49.2%) were male and 90 (50.8%) were female. The mean age at the first diagnosis was 55.3 years, and most patients (82.5%) were diagnosed after their sixth decade of life, as shown in Table 1. Only 52 (29.4%) of the 177 patients were available to provide information regarding trauma history, and 15 recalled their exact trauma history. Among 15 patients, 5 (33.3%) traumas were on a subungual site (2 thumbs, 1 third finger, 1 great toe, and 1 fifth toe), 5 (33.3%) were on the heel, 3 (20.0%) were on the sole, 1 (6.7%) was on the palm, and 1 (6.7%) was on the finger. Most trauma was caused by a mild injury, such as tearing on a stone, cutting with a knife, pricking on a thorn or spike, hitting by a sliding door or car door, or stepping on hot charcoal.
Among 177 patients, 124 (70.1%) melanomas were on the volar area and 53 (29.9%) were on the subungual site. In the volar area, the heel was the most common region, with the fingernail being a more frequent site than the toenail. Interestingly, acral melanoma was more common on the left side, but when focused on the phalanges, the right side was more susceptible, especially the fingers, including the nail (Table 1). The precise anatomic mapping of the site distribution is shown in Figure 1. Quiz Ref IDNotably, the more weight-bearing areas, such as the inner forefoot, outer midfoot, and center of the heel, within each region of the sole were the predominant sites. Melanoma lesions on soles were distributed mainly at the periphery and borders of each area.Quiz Ref IDIn addition, the thumb and great toe were most commonly affected by long-term physical stress and trauma among the subungal melanomas, as predicted.
Melanoma on the sole appeared to develop adjacent to the border of each area, spreading with the long axis along the spontaneous deep and semi-deep creases or fine wrinkles. Deep and semi-deep creases are folding lines of separated tissue on the soles, caused by long-term pressure on the fibrous septa or anatomic demarcation of bone shape. A deep crease is a depression that can be seen easily, and a semi-deep crease can be noted on folding or flexing the soles slightly. Fine wrinkles are similar to “dermatoglyphics” (ie, a naturally occurring surface skin marking that has a linear or semicircular pattern). These lines are affected by long-term physical stress when the soles contact a surface. For example, most melanoma in the inner area of the forefoot developed adjacent to the inner borderline and spread longitudinally, curving along the deep crease demarcated from the first web space to the medial arch (Figure 2A). Some melanoma in the center or outer areas of the forefoot developed around the borderline between the areas and spread longitudinally along the semi-deep crease shaped from the third web space outward (Figure 2B). Melanoma in the outer area of the midfoot tended to be distributed along the semi-deep crease, extending from the middle area to the lateral side of the sole (Figure 2C), and melanoma on the borderline of the midfoot and the heel showed a similar tendency (Figure 2D). Some melanomas developed at the outer or inner area of the forefoot and midfoot, spreading along the semi-deep creases and fine wrinkles demarcated from each side to the sole (Figure 2E and F). Most melanomas in the heel developed horizontally along the fine wrinkles, regardless of the area of the heel involved (Figure 2G and H).
Histopathologic examination was performed on 149 acral melanomas by punch (47.0%) or excisional (53%) biopsy. Melanoma subtype was classified into 129 acral lentiginous melanomas (ALMs; 86.6%), 19 nodular melanomas (12.8%), and 1 superficial spreading melanoma (SSM; 0.7%). The SSM originated on the medial side of the heel adjacent to the dorsal part of the foot. Of the 19 nodular melanomas, 7 (36.8%) were on the heel, 5 (26.3%) on the forefoot, 3 (15.8%) on the toes, 2 (10.5%) on the subungual location, 1 on the palm, and 1 on the midfoot. Ulceration was identified in 63 (42.3%) acral melanomas. The prognostic indexes, including Breslow thickness, mitotic rate, vertical growth phase, and TNM stage (according to the American Joint Committee on Cancer11), are shown in eTable 1 in the Supplement.
The mean survival time of the 172 patients whose survival status was identified was 95.5 months, and the median disease-free survival time was 56.1 months. The 5-year survival rate was 49.3%, and the survival curve stratified by TNM stage showed a rapid decrease in the survival rate at the early phase in stages III and IV (Figure 3A). The mean survival time of the 149 patients according to stage was 144.3, 72.2, 30.3, and 16.5 months for stages I to IV, respectively.
We evaluated the prognostic influence and survival rate of long-term physical stress in acral melanoma. The sole is a good site for analysis because it can be divided into 2 portions based on the degree of long-term physical stress (weight-bearing and non–weight-bearing portions). A statistical comparison of prognostic indexes between the weight-bearing and non–weight-bearing portions is shown in Table 2. There were no significant differences in prognostic indexes and survival rate between the 2 groups (Figure 3B).
In addition, we evaluated the differences in prognostic indexes and survival rate between the volar and subungual locations because of innate histopathologic differences between the 2 groups, although nail apparatus melanoma has been categorized as a form of ALM. Melanoma at the subungual location showed a significantly increased ulcerative rate and a higher proportion of the mitotic rate (>6/mm2) than did melanoma in the volar area, but the Breslow thickness, vertical growth phase, TNM stage, and survival rate did not differ significantly between the 2 groups (Table 2 and Figure 3C). Multivariate analysis assessed the prognostic factors using a Cox proportional hazards regression model in which age, TNM stage, ulceration status, vertical growth phase, mitotic rate, weight-bearing area, and subungal location were used as covariates. Of these, only TNM stage and ulceration were independently poor prognostic factors (eTable 2 in the Supplement).
Most palmoplantar and nail apparatus melanomas are described as ALMs on the basis of clinical and histologic similarities.7 The predictive histopathologic subtype of palmoplantar and nail apparatus melanoma is considered to differ from those melanoma on the dorsal part. Thus, various studies have been conducted on the histopathologic differences between these 2 parts and the resulting prognosis. Kuchelmeister et al4 reported that all melanomas originating in palmoplantar and subungual regions were of the ALM histopathologic type, but all melanomas originating at dorsal parts of the hands and feet were of the SSM type. A survival rate comparison of 34 SSMs at the dorsal site and 67 ALMs at the palmoplantar and subungual sites showed a significantly better prognosis for SSM. However, other studies12-15 generally reported that although ALM was a distinct histopathologic type on the palmoplantar and subungual sites, other subtypes can also occur, with the survival rate not differing significantly between ALM and other histopathologic types at acral sites. Thus, we divided the acral site into palmoplantar and subungual areas to obtain maximal histopathologic consistency and to facilitate a more precise analysis of epidemiologic and prognostic differences according to location within the acral site. The major histopathologic subtype was ALM (85.9%), and only 1 SSM was identified among 149 patients.
There was no significant sex predominance, and the mean age was 55.3 years, which is similar to the results (male to female ratio, 1:1.22; mean age, 55.9 years) in another study on acral melanomas in Korean patients.3 In previous studies,4,12,13,15-18 the mean age was 55 to 63 years, and no significant sex predominance in acral melanoma or ALM was detected. However, a few studies5,14 of whites reported a clear ALM predominance in females (1:1.86-1.89).
Quiz Ref IDClinicopathologic characteristics of acral melanoma in Koreans indicated a high ulcerative rate (42.3%) and high proportion of Breslow thickness of 4 mm or more (32.9%; T stage 4), which might explain the lower 5-year survival rate (49.3%). The overall survival rate among all racial groups did not show statistically significant variation when controlling for Breslow thickness and tumor stage at diagnosis.19,20 However, in Asians (including Koreans), acral melanoma was generally at a more advanced stage, and they had a lower survival rate than did whites.4,5 Five-year survival rates of acral melanoma reported from China and Japan and cutaneous melanoma from Hong Kong and Singapore, where ALM is the main type, were less than 50%.16,19,21-23 Because of a lack of awareness of melanoma, lesions are often misdiagnosed as benign, contributing to the delay in diagnosis.
Both the volar and subungual areas are hairless, which supports their histopathologic similarity with ALM as the most common subtype in both regions. However, studies of the prognostic difference between the 2 groups have been conducted due to the histologically distinctive property of the nail matrix and unique features of the anatomic position. Most of these studies13,15,24,25 reported that the overall survival rates of volar and subungual melanoma did not differ significantly, as we report here, although in our study, some prognostic indexes were more severe in nail apparatus melanoma.
In our study, nail apparatus melanoma comprised 28.9% of acral melanoma, which is similar to other studies24,26 reporting that 30% to 35% of acral melanoma was subungual. Nail apparatus melanoma appears to be more common on fingernails than on toenails and occurs predominantly on the thumb and great toe rather than on other phalanges.24-27 Our data showed that among 53 nail apparatus melanomas, 32 (60.4%) occurred on fingernails and 21 (39.6%) on toenails. Of the 53, 21 (39.6%) were on the thumb and 11 (20.8%) on the great toe. In addition, we identified a clear right-side predominance on the fingers, where distinguishing the degree of physical stress between the sides was easier than on the toes and soles. On the basis of the predominance of nail apparatus melanoma on the fingernails rather than toenails, as well as on the right rather than left side for fingernails, thumbs, and great toes instead of other phalanges, which was also reported previously,16,24,28-30 we suggest that long-term physical stress and pressure strength affect the incidence of nail apparatus melanoma. Saida30 also focused on the correlation between mechanical trauma and predominant subsite of acral melanoma and strongly suggested that mechanical trauma plays an important role in the induction of melanoma in acral skin.
Studies of the effect of long-term physical stress and trauma on the incidence of acral melanoma have focused on the sole, divided into weight-bearing and non–weight-bearing portions. Our data indicate a high incidence of acral melanoma on the weight-bearing portion of the soles, as reported by Hosokawa et al9 and Dwyer et al.10 Those studies suggested that most plantar melanomas originate in the weight-bearing areas (heels and metatarsal regions). In addition, we suggest that the predisposition of acral melanoma to the more weighted areas of the weight-bearing portion, such as the center area of the heels and the inner forefoot area, also indicates the effect of long-term physical stress on the incidence of acral melanoma. However, the prognostic indexes and survival rate did not differ significantly between the weight- and non–weight-bearing portions.
Interestingly, we found peculiar plantar melanoma distribution and spreading patterns. Quiz Ref IDFirst, melanoma on the sole was distributed in the area adjacent to the borderlines between each area; these were demarcated similarly to the deep and semi-deep naturally occurring creases of the soles, caused by long-term pressure on the fibrous septa. In addition, the long axis of spreading direction in all areas of plantar melanoma was typically along naturally occurring creases, and thus the creases of the sole encompassed the major axis of each lesion. Regardless of their depth, creases are the vectors that transmit the pressure strength when the soles contact a surface; this suggests that long-term physical stress and pressure strength influence the occurrence and progression of acral melanoma in a particular manner. Based on the spreading patterns, a more informed decision can be made regarding the extent of surgical removal of the acral melanoma. However, further investigation of the location-based differences in incidence, progress, and survival is necessary to better understand the pathophysiologic characteristics of acral melanoma.
This study had several limitations. First, because of its retrospective design, important clinical information, such as trauma history, which is regarded as a risk factor for acral melanoma, was not reviewed completely. Second, use of different biopsy methods (punch vs excisional biopsy) could result in unclear or erroneous histopathologic results. Last, the original site of the lesion might be misleading for some large tumors with a similar degree of pigmentation, unaccompanied by a definite prominent nodule or ulceration. A further prospective investigation of early in situ lesions is needed to understand the original site and spreading pattern. However, our data represent an epidemiologic and clinical database of Koreans and an adequate analysis of the role of long-term physical stress and pressure strength in acral melanoma.
Accepted for Publication: May 31, 2013.
Corresponding Author: Sook Jung Yun, MD, PhD, Department of Dermatology, Chonnam National University Medical School, 5 Hak-Dong, Dong-Gu, Gwangju, 501-746, South Korea (firstname.lastname@example.org).
Published Online: September 25, 2013. doi:10.1001/jamadermatol.2013.5853.
Author Contributions: Drs Jung and Yun had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Jung, Yun.
Acquisition of data: Jung, J.-B. Lee, S.-C. Lee, Yun.
Analysis and interpretation of data: Jung, Kweon, Yun.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: Jung, J.-B. Lee, S.-C. Lee, Yun.
Statistical analysis: Kweon.
Administrative, technical, and material support: Jung, J.-B. Lee, S.-C. Lee.
Study supervision: Yun.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by grant CRI09040-1 from the Chonnam National University Hospital Research Institute of Clinical Medicine and by a 2012 3rdAMOREPACIFIC/KDF Research Award.
Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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