|Year : 2019 | Volume
| Issue : 4 | Page : 187-193
Cutaneous malignant melanoma in Eastern Taiwan: Clinicopathologic analysis of 56 cases
Kai-Chi Tsai1, Sung-Jen Hung2, Jen-Hung Wang3, Shyh-Jer Huang1, Chien-Hsing Wang4, Jiunn-Tat Lee4, Chia-Yi Lee5, Chung-Hsing Chang6
1 Skin Institute, Department of Dermatology, Hualien Tzu Chi Hospital, Hualien, Taiwan
2 Skin Institute, Department of Dermatology, Hualien Tzu Chi Hospital; Department of Dermatology, Tzu Chi University, Hualien, Taiwan
3 Department of Medical Research, Hualien Tzu-Chi Hospital; Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
4 Department of Plastic Surgery, Hualien Tzu-Chi Hospital, Hualien, Taiwan
5 Department of Medicine, Tzu Chi University, Hualien, Taiwan
6 Skin Institute, Department of Dermatology, Hualien Tzu Chi Hospital; Department of Dermatology, Tzu Chi University; Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
|Date of Submission||13-Aug-2018|
|Date of Decision||12-Mar-2019|
|Date of Acceptance||12-Mar-2019|
|Date of Web Publication||31-Oct-2019|
Dr. Chung-Hsing Chang
707, Sec. 3, Chung-Yang Rd., Hualien 970
Source of Support: None, Conflict of Interest: None
Background: The incidence, histological subtypes, and tumor behaviors of cutaneous malignant melanoma are quite different in Asian and Western countries. Objectives: Our purpose was to define the epidemiology, tumor behaviors, and possible prognostic predictors of cutaneous melanomas based on an Eastern Taiwanese population. Methods: We conducted a retrospective study to collect cases of cutaneous melanoma at Buddhist Tzu-Chi General Hospital, Hualien, Taiwan, from May 1, 2003, to August 31, 2017. We analyzed mean age at onset, gender, primary tumor locations, histological subtypes, Breslow's thickness, Clark's level, ulceration, lymph nodes, and distant metastatic status. Univariate and multivariate analyses for survival were performed by means of Cox proportional hazard model. Survival curves were plotted by Kaplan–Meier method. Results: A total of 56 cases of cutaneous melanoma were recorded. The male-to-female ratio was 3.67:1. The median survival was 2.82 years (0.63–5.00 years). Acral melanoma (AM) accounts for 69.6% of cases, and feet are the most common location (62.5%). Acral lentiginous melanoma (ALM) is the most common histological type (44.6%), followed by nodular melanoma (33.9%). Poor prognostic factors include older age (≧65 years), male gender, Breslow's thickness >4 mm, distant metastasis, and head-and-neck location. Conclusion: AM is the most common location, and ALM is the most common histological type of cutaneous melanoma in Eastern Taiwan. Melanoma in Eastern Taiwan tends to be delay diagnosed with advanced stage and thicker tumors than Western Taiwan. Prudent palm and sole examinations, improved medical accessibility, and more public educational programs may help encourage the early detection of melanoma.
Keywords: Acral lentiginous melanoma, cutaneous melanoma, malignant melanoma
|How to cite this article:|
Tsai KC, Hung SJ, Wang JH, Huang SJ, Wang CH, Lee JT, Lee CY, Chang CH. Cutaneous malignant melanoma in Eastern Taiwan: Clinicopathologic analysis of 56 cases. Dermatol Sin 2019;37:187-93
|How to cite this URL:|
Tsai KC, Hung SJ, Wang JH, Huang SJ, Wang CH, Lee JT, Lee CY, Chang CH. Cutaneous malignant melanoma in Eastern Taiwan: Clinicopathologic analysis of 56 cases. Dermatol Sin [serial online] 2019 [cited 2020 Mar 31];37:187-93. Available from: http://www.dermsinica.org/text.asp?2019/37/4/187/270159
| Introduction|| |
Cutaneous malignant melanoma represents 4% of skin cancers but is responsible for 80% of skin cancer deaths, corresponding to approximately 1%–2% of all cancer deaths., In the United States, the incidence rate of melanoma doubled from 1982 to 2011. The melanoma incidence rates are also expected to continue rising in most European countries. Factors that may have contributed to the continued increase in melanoma incidence rates in populations with light-colored skin include increases in natural (sun) and artificial (sunbed) ultraviolet (UV) radiation exposure, skin cancer awareness, and early detection. Malignant melanoma is a rare disease in Taiwan, but its incidence rate is increasing. In 2015, 266 cases of cutaneous malignant melanoma were diagnosed in Taiwan, accounting for 0.25% of all cases of malignancy. In the same year, 152 patients died of cutaneous melanoma, accounting for 0.25% of overall cancer deaths. Between 1996 and 2015, age-adjusted incidence rates increased by 57% and 44% for men and women in Taiwan, respectively.,
Several studies have analyzed the clinical and pathological features of cutaneous melanoma in Taiwan.,, Acral lentiginous melanoma (ALM) is the most common type, accounting for more than half of all the analyzed cases.,, Soong et al. studied 22 cases of malignant melanoma at Tri-Service General Hospital in Northern Taiwan and revealed that the 5-year survival rate was 39%. Chang et al. studied 181 cases of cutaneous malignant melanoma at Chang Gung Memorial Hospital (CGMH) in Northern Taiwan and revealed that the 5-year survival rate was 45.63%. Chen et al. reported 51 patients of cutaneous melanoma at Veterans General Hospital, Taichung (VGHTC), in Middle Taiwan. Factors associated with a poor prognosis include being at an older age (≧55), having a Breslow's thickness of >4 mm, having a Clark's level of IV or V, being male, and undergoing tumor staging., However, data from Eastern Taiwan are still lacking. Here, we present the epidemiology and prognostic factors of primary cutaneous melanoma in the Eastern Taiwanese population.
| Patients and Methods|| |
We reviewed all cases of malignant melanoma from the cancer registry at Buddhist Tzu-Chi General Hospital, Hualien, Taiwan, from May 1, 2003, to August 31, 2017. Mucosal melanoma, ocular melanoma, and melanoma of unknown origin were excluded from the study. We reviewed the characteristics of the remaining cases of cutaneous malignant melanoma, namely age, sex, primary location of tumor, stage of cancer, lymph nodes and distant metastasis, and survival status. The histological features of each specimen, such as histological subtypes, maximum tumor thickness, level of invasion, and ulceration, were reviewed. Staging was performed according to the sixth edition of the American Joint Committee on Cancer staging system published in 2002. The prognostic factors were analyzed using the Cox proportional hazard model. The statistically significant factors in the univariate analysis were further analyzed using multivariate analysis. Survival status was analyzed using the Kaplan–Meier method. The treatments which they received were also reviewed in this article. The proposal was approved by the Institutional Review Board in Research Ethics Committee, Hualien Tzu-Chi Hospital, Buddhist Tzu-Chi Medical Foundation. (IRB no. IRB106-166-A obatined on Feb. 12nd, 2018) with the requirement of obtaining informed consents from the study participants.
| Results|| |
From May 1, 2003, to August 31, 2017, 82 cases of malignant melanoma were recorded. A total of 26 cases with mucosal (3 cases), ocular (11 cases), or melanoma of unknown origin (12 cases) were excluded from the study. The age of the patients ranged from 27 to 91 years. The mean age was 64.79 ± 14.04 years. There were 44 males and 12 females, with a male-to-female ratio of 3.67:1 [Table 1]. The mean follow-up time was 2.80 ± 2.38 years. Males had a higher mortality rate than females (P = 0.045). No significant gender differences were observed regarding age, histology, Clark's level, Breslow's thickness, tumor location, lymph nodes metastasis, distant metastasis, or cancer stage.
|Table 1: Demographic data of cutaneous melanoma in Hualien Tzu-Chi Hospital (n=56)|
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Histology and location
Of the 56 cases, the ratio of ALM was 44.6% (25 cases), nodular melanoma (NM) was 33.9% (19 cases), superficial spreading melanoma (SSM) was 8.9% (5 cases), and lentigo maligna (LM) melanoma was 1.8% (1 case) [Table 1]. The histological subtypes of the remaining six cases (10.7%) were not recorded. ALM was the most common histological subtype. In 42 (75.0%) cases, the tumor was located on the extremities (including the hands and feet); in nine cases (16.1%), it was located on the trunk; and in five cases (8.9%), it was located on the head and neck [Table 1] and [Figure 1]a.
|Figure 1: Tumor location of cutaneous melanoma in Eastern Taiwan, (a) Tumor location of cutaneous melanoma in males and females, (b) Tumor location in 14 patients of acral melanoma with available clinical photography (the picture was modified from the original design by Sheen et al.)|
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The incidence rate is: In situ disease 6.3%, Stage I 6.3%, Stage II 31.3%, Stage III 27.1%, and Stage IV, respectively [Table 1].
In the present study, 92.9% (52/56) of the cases received wide excision. Cases of melanoma in situ and Stage I disease received wide excision only. Among patients of Stage II disease, 26.7% (4/15) of them received additional sentinel lymph node biopsy (SLNB), 60% (9/15) received additional regional lymph node dissection (LND), and the remaining two cases received wide excision only. All (13/13) patients of Stage III disease received wide excision following by regional LND. Patients of Stage IV disease received traditional chemotherapy or palliative treatment, and 28.6% (4/14) of them received regional LND. None of them received immune checkpoint inhibitor (ICB).
Age and gender
Being older than 65 years (hazard ratio [HR] = 7.87) was associated with a significantly increased risk of death (P = 0.023). Male gender was associated with a worse survival rate (HR = 7.07) than was the female gender [Table 2].
|Table 2: Univariate and multivariate analyses of prognostic factors in patients with cutaneous malignant melanoma (n=56)|
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Breslow's thickness and Clark's level
Of the 49 patients with complete tumor thickness data, the survival rates decreased significantly for thick lesions (Breslow's thickness >4 mm, HR = 2.61) and for Clark's Levels IV and V (HR = 3.76) [Table 2].
The 5-year survival rates of patients with overall, in situ, and Stage I, II, III, and IV diseases were 42%, 100%, 100%, 53%, 38%, and 7%, respectively. The median survival rate was 2.82 years (0.63–5.00 years) for all the 56 patients, 4.04 years (0.80–7.27 years) for Stage III disease patients, and 0.80 years (0.41–1.19 years) for Stage IV disease patients [Figure 2]. Stage IV disease was associated with a statistically significantly increased risk of death (HR = 5.71, P < 0.001).
Patients with ALM had a trend of better, but not significantly different, survival rates than NM patients. None of the patients with SSM or LM died during the follow-up period [Table 2].
Cases with the tumor location being in extremities had better survival rates than did cases with the tumor location being in the head and neck (P = 0.014). Compared with melanoma of the head and neck, the HRs for trunk and extremity were 0.20 (95% confidence interval [CI], 0.02–2.62) and 0.08 (95% CI, 0.01–0.60), respectively [Table 2].
In the univariate analysis, gender, Breslow's thickness, Clark's level, location, lymph node metastasis, distant metastasis, and tumor stage were significantly associated with prognosis [Table 2]. To avoid confounding the results, a multivariate analysis was also performed after adjusting for these factors [Table 2]. Being older than 65 years became a statistically significant factor (HR = 7.87, P = 0.023) in multivariate analysis. Male gender also became a more consequential factor (HR = 7.07, P = 0.012) in the multivariate analysis. The Breslow's thickness affected survival in both univariate (HR = 2.61, P = 0.022) and multivariate analyses (HR = 6.49, P = 0.022), but the Clark's level became less consequential after adjusting for other confounding factors. Metastasis remained consequential in both univariate (HR = 3.13, P = 0.001) and multivariate analyses (HR = 4.12, P = 0.012). The worst prognostic factors in the patients were age ≥65 years (HR = 7.87, P = 0.023), male gender (HR = 7.07, P = 0.012), and Breslow's thickness (HR = 6.49, P = 0.022).
| Discussion|| |
Compared with patients in other studies and cancer registries in Taiwan, our patients had a much higher male-to-female ratio (3.67:1)., In cancer registries in Taiwan, the 2015 age-adjusted incidence rates for invasive melanoma were 0.85/100,000 for males and 0.65/100,000 for females, with the age-adjusted male-to-female ratio of 1.31:1. The male-to-female ratio of melanoma in a previous study at CGMH was 1:1.13. Our results were closer to those of data from VGHTC (male:female = 2.92:1), and the author explained male predominance at VGHTC. In Eastern Taiwan, we also observed a slight male predominance. The mean male-to-female ratio was 1.05 in I-lan (from 2001 to 2017), 1.07 in Hualien (from 2002 to 2018), and 1.09 in Taitung (from 2008 to 2017), compared with 0.99 in the general Taiwanese population. We speculated that the gender difference in our study may have been attributed to the population structure, the fact that more males are farmers, and that elderly men have more of a habit of walking bare foot in Eastern Taiwan. Further, epidemiology studies are warranted.
Acral melanoma (AM) is defined as a malignant melanoma located on nonhair-bearing skin of the palms and soles or under the nail bed. AM is rare in Caucasians but common in Asians. In our study, AM accounted for 69.6% of the cases, and feet are the most common location (62.5% of all cases). The known risk factors for melanoma in Western countries include UV radiation exposure, Fitzpatrick skin phenotypes I and II, blistering sunburn before the age of 14 years, having red hair or freckles, atypical nevus, numerous nevus, and a past history or family history of melanoma. AM occurrence is not associated with UV exposure. Instead, mechanical stress has been reported to increase the formation of melanomas. Sheen et al. reported that stress-bearing areas (the rear and front of the foot) were statistically significantly more conducive to the generation of AM than nonstress-bearing areas (P < 0.0001). We reviewed 14 AM patients with available clinical photography in our study. The front and the rear of the foot accounted for 28.6% and 21.4% of cases, respectively [Figure 1]b. However, nonstress-bearing areas, such as the subungual area, arch of foot, and the lateral aspects of foot, also accounted for 21.4%, 14.3%, and 14.3% of cases, respectively. Further studies of the association of stress-bearing areas and generation of AM are warranted. In a study of AM from Australia, an increased risk was associated with penetrating injury of the feet or hands (relative risk [RR]: 5.0) and heavy exposure to agrichemicals (RR: 3.6). Chang et al. reviewed Taiwanese melanoma cases from the National Health Insurance Research Database between 2005 and 2011. They observed that approximately 29% of Taiwanese patients with melanoma were farmers. The mortality rate of farmers (36.5%) was slightly higher than that of nonfarmers (22.4%) (HR: 1.136). The age of diagnosis of farmers (82% above age 65) was also much higher than that of nonfarmers (34% above age 65). Therefore, mechanical stress, penetrating injury, and direct agrochemical contact may be associated with developing AM in Taiwan, and further studies are warranted. Prudent palm and sole examinations would be helpful in the early detection of melanoma in AM-prevalent areas.
ALM is the most common (44.6%) histological subtype in our studies, followed by NM (33.9%). Compared with patients in other studies, our patients had a lower ratio of ALM and a slightly higher ratio of NM (ALM: 54.9% and NM: 29.4% in VGHTC; ALM: 58% and NM: 30.4% in CGMH). The difference may be attributed to no recorded histological type in 10.7% of our cases. In our patients, none of the SSM and LM cases died during the follow-up period. None of the histological subtypes achieved significantly different survival rates than did the other subtypes. Patients with ALM had a trend of better, but not significantly different, survival rates than did NM patients. This result is similar to that of a previous study in CGMH. However, another study in VGHTC demonstrated a better prognosis for melanoma patients with ALM than melanoma patients with non-ALM in Taiwan. In addition, a better survival rate for patients with SSM than for patients with ALM and NM was also reported. Patients with NM have a higher death rate than patients with SSM because patients with NM tend to have a vertical growth pattern. In our data series, tumor thickness, lymph nodes, and distant metastasis were more consequential than the histological subtype itself.
The prognosis of in situ and Stage I melanoma was extremely good. The survival rate declined rapidly after Stage II disease. Therefore, early detection of suspicious lesions is strongly recommended. However, diagnosis of cutaneous melanoma in Eastern Taiwan tends to be delayed. Our cases tended to have a thicker tumor (Breslow's thickness ≥4 mm: 41.7%) than those in VGHTC (33.3%) and CGMH (30.4%)., A lower ratio of Stage I disease was also found in our patients. In our data series, in situ/Stage I accounted for 12.6% of cases, Stage II accounted for 31.3% of cases, Stages III accounted for 27.1%, and Stage IV accounted for 29.2% of cases. In one study of patients in CGMH, Stages I, II, III, and IV accounted for 27.5%, 13.5%, 33.9%, and 25.1%, respectively. Several factors may contribute to delayed diagnosis. First, more than half of the Taiwanese melanoma patients had ALM, which is difficult to detect in its early stages. Second, in Eastern Taiwan, the relative deficiency of medical accessibility and public educational programs further impair the early detection of melanoma.
Our data demonstrated a worse prognosis in patients of an older age, of male gender, with a thicker tumor, with distant metastasis, and at the advanced stage; the results were similar to previous studies., Cases with the tumor location being in the head and neck also had worse survival rates than did cases with the tumor location being in extremities (P = 0.014), and the finding was not shown in previous studies. We speculated that the survival difference may be attributed to different lymphatic drainage, and further studies are warranted.
According to the National Comprehensive Cancer Network guideline, wide excision is suitable for Stage I–III melanoma. In our study, all the patients of Stage I–III melanoma received wide excision. SLNB is associated with improvement in distant metastasis-free survival among patients with melanomas 1.2–3.5 mm thick. Among the patients of Stage II disease in our study, 26.7% (4/15) of them received SLNB and 60% (9/15) of them received LND. Complete LND should be performed in the setting of Stage III disease (sentinel node positive or clinical positive node). All the patients of Stage III disease in our series received LND. Most of the Stage IV disease patients in our study received conventional chemotherapy or palliative treatment; none of them received ICB. Interestingly, although our cases had a thicker tumor and a lower ratio of Stage I disease, the overall 5-year survival rate of 42% in our study was similar to the rate of 45.6% in CGMH and 39% in Tri-Service General Hospital. This result may indicate that the overall treatment outcome of malignant melanoma was unsatisfactory under the currently used standard treatment strategies regardless of tumor staging. Recent advances in treatment with adjuvant ICB have demonstrated survival benefits, substantiating the Food and Drug Administration approval of single-agent ipilimumab (cytotoxic T lymphocyte antigen-4 blockade) and nivolumab (programmed cell death 1 blockade) treatments in patients with high-risk resected disease, with recent data also showing benefits with adjuvant pembrolizumab. A study also described the feasibility of neoadjuvant ICB in high-risk resectable melanoma (Stage III resectable melanoma or oligometastatic Stage IV melanoma). Additional studies are needed to optimize treatment regimens.
| Conclusion|| |
Patients in Eastern Taiwan had a much higher male-to-female ratio (3.67:1) than patients in Western Taiwan and cancer registries in Taiwan. AM accounts for 69.6% of cutaneous melanoma in Eastern Taiwan, and feet are the most common location (62.5%). ALM is the most common histological type (44.6%), followed by NM (33.9%). Older age (≥65 years), male gender, Breslow's thickness >4 mm, head-and-neck location, and distant metastasis are the independent risk factors for poor prognosis. Melanoma in Taiwan, especially ALM, is often overlooked until the advanced stages. Our cases tended to have a thicker tumor (Breslow's thickness ≥4 mm) and a lower ratio of Stage I disease than those in CGMH. The overall 5-year survival rate of 42% in our study is similar to that of previous studies. Prudent palm and sole examinations, improved medical accessibility, and more public educational programs in Eastern Taiwan may help encourage the early detection of melanoma.
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Conflicts of interest
There are no conflicts of interest
| References|| |
Miller AJ, Mihm MC Jr. Melanoma. N
Engl J Med 2006;355:51-65.
Turkmen M, Turk BG, Karaarslan IK, Yaman B, Ozdemir F. Blue-white variant of pigmented basal cell carcinoma. Dermatol Sinica 2018;36:136-9.
Guy GP Jr., Thomas CC, Thompson T, Watson M, Massetti GM, Richardson LC. Vital signs: Melanoma incidence and mortality trends and projections – United States, 1982-2030. MMWR Morb Mortal Wkly Rep 2015;64:591-6.
Arnold M, Holterhues C, Hollestein LM, Coebergh JW, Nijsten T, Pukkala E, et al.
Trends in incidence and predictions of cutaneous melanoma across Europe up to 2015. J Eur Acad Dermatol Venereol 2014;28:1170-8.
Jemal A, Saraiya M, Patel P, Cherala SS, Barnholtz-Sloan J, Kim J, et al.
Recent trends in cutaneous melanoma incidence and death rates in the United States, 1992-2006. J Am Acad Dermatol 2011;65:S17-25.e1-3.
Cancer Registry Annual Report, 2015, Taiwan, Health Promotion Administration Ministry of Health and Welfare, Taiwan; 2017.
Cancer Registry Annual Report, 1996, Taiwan, Health Promotion Administration Ministry of Health and Welfare, Taiwan; December, 1999.
Soong CY, Liu HN, Ger LP, Chu TL, Syu HL, Tseng HH. Malignant melanoma: A clinicopathologic study of 22 cases. J Formos Med Assoc 1991;90:365-70.
Chang JW, Yeh KY, Wang CH, Yang TS, Chiang HF, Wei FC, et al.
Malignant melanoma in Taiwan: A prognostic study of 181 cases. Melanoma Res 2004;14:537-41.
Chen YJ, Wu CY, Chen JT, Shen JL, Chen CC, Wang HC. Clinicopathologic analysis of malignant melanoma in Taiwan. J Am Acad Dermatol 1999;41:945-9.
Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG. Final version of the American Joint Committee on cancer staging system for cutaneous melanoma. J Clin Oncol 2001;19:3635-48.
Sheen YS, Liao YH, Lin MH, Chen JS, Liau JY, Tseng YJ, et al.
Aclinicopathological analysis of 153 acral melanomas and the relevance of mechanical stress. Sci Rep 2017;7:5564.
Tokura Y, Bastian BC, Duncan L. World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumours. Lyon: IARC Press; 2006. p. 73-5.
Green A, McCredie M, MacKie R, Giles G, Young P, Morton C, et al.
Acase-control study of melanomas of the soles and palms (Australia and Scotland). Cancer Causes Control 1999;10:21-5.
Chang HY, Feng HL, Wang L, Chou P, Wang PF. The incidence, prevalence, and survival of malignant melanoma in Taiwan. Value Health 2014;17:A740.
Chang JW. Cutaneous melanoma: Taiwan experience and literature review. Chang Gung Med J 2010;33:602-12.
Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson WE 3rd
, et al.
Melanoma, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2016;14:450-73.
Ianiro G, Gasbarrini A, Cammarota G. Ipilimumab adjuvant therapy in melanoma. N
Engl J Med 2017;376:398.
Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N
Engl J Med 2017;377:1824-35.
Eggermont AM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, et al.
Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N
Engl J Med 2018;378:1789-801.
Amaria RN, Reddy SM, Tawbi HA, Davies MA, Ross MI, Glitza IC, et al.
Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med 2018;24:1649-54.
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[Table 1], [Table 2]