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Melanoma in Singapore: A 20-year review of disease and treatment outcomes

Introduction: Melanomas in Asians have different clinicopathological characteristics and prognosis from melanomas in Caucasians. This study reviewed the epidemiology and treatment outcomes of cutaneous melanoma diagnosed at a tertiary referral dermatology centre in Singapore, which has a multiracial population. The study also determined whether Asians had comparable relapse-free and overall survival periods to Caucasians in Singapore. Method: This is a retrospective review of cutaneous melanoma cases in our centre between 1996 and 2015. Results: Sixty-two cases of melanoma were diagnosed in 61 patients: 72.6% occurred in Chinese, 19.4% in Caucasians and 3.2% in Indians, with an over-representation of Caucasians. Superficial spreading melanoma, acral lentiginous melanoma and nodular melanoma comprised 37.1%, 35.5% and 22.6% of the cases, respectively. The median time interval to diagnosis was longer in Asians than Caucasians; median Breslow’s thickness in Asians were significantly thicker than in Caucasians (2.6mm versus 0.9mm, P=0.018) and Asians tend to present at a later stage. The mortality rates for Asians and Caucasians were 52% and 0%, respectively. Conclusion: More physician and patient education on skin cancer awareness is needed in our Asian-predominant population for better outcomes. Ann Acad Med Singap 2021;50:456-66


INTRODUCTION
Melanoma is rare in Asians. 1 Asian studies of melanoma have reported a larger proportion of patients diagnosed with advanced melanoma (stage III or IV), and overall five-year survival rates ranging from 41.6% to 45.6%. 2 This is in contrast to the 2019 statistics from the American Cancer Society where the 5-year survival rate for all surveillance, epidemiology, and end results (SEER) stages combined was 92% for melanoma in the US. In addition, melanoma presents differently in Asian patients, with clear distinctions in the prevalent subtype, site of presentation, risk factors and tumour mutations. Our study aims to describe the clinical presentation, treatment and outcomes of cutaneous melanoma in Singapore over the last 20 years.

METHODS
We conducted a retrospective single-centre review of cutaneous invasive melanoma diagnosed at the National Skin Centre, the only tertiary referral dermatology centre in Singapore, from January 1996 to December 2015. Epidemiologic, disease, treatment and outcome data were extracted from patients' medical records from the institute. Histopathology slides of all cases of melanoma were retrieved from the institution's data bank and reviewed. For patients referred to a tertiary referral cancer centre for further management, treatment records and outcome were retrieved from that institute. Clinical or pathological staging was determined according to the 7th edition of the American Joint Committee on Cancer. 3 Prophylactic lymph node dissection (PLND) was defined as lymph node removal without any clinical, radiological or histological evidence of lymph node involvement. Complete lymph node dissection (CLND) was defined as lymph node removal following sentinel lymph node positivity. In our institution, therapeutic lymph node dissection (TLND) involves lymph node

What is New
• The incidence of melanoma in Singapore has steadily increased in recent years.
• Asians have a thicker Breslow's thickness and tend to present later compared with Caucasians.

Clinical Implications
• Melanomas in Asians confer a worse prognosis than in Caucasians.
• Primary care providers should examine their patients for early lesions in the soles, palms and nails for unexplained pigmented lesions.
removal in the presence of clinical and/or histological confirmed lymph node involvement by melanoma. Locoregional relapse was defined as clinically recognisable lymph node metastases or histological relapse in the regional lymph node, satellite or in-transit lesions. Distant relapse was defined as visceral relapse.
Melanoma BRAF and c-KIT mutational analysis by Sanger sequencing started to be performed in Singapore from the year 2012. BRAF mutational analysis detects the V600E in exon 15 of BRAF gene while c-KIT 9 and 11 mutational analysis detects gene mutations in exons 9 and 11. If additional c-KIT rare mutations are requested for, they are performed for gene mutations in exons 13 and 17. NRAS mutational analysis is not routinely performed.
Median values were reported for non-normal continuous variables, and the Wilcoxon signed-rank test and Kruskal-Wallis test were performed to test for differences between 2 groups and among more than 2 groups, respectively. Counts and percentages were reported for categorical variables, and Fisher's exact test was used to test for differences in proportions between groups. Median survival time was analysed by the Kaplan-Meier method and compared using the Logrank test between groups. Univariate analysis of the association between the prognostic factors and survival was performed using the Cox proportional hazard model. To avoid missing potential significant factors, variables with a P value<0.15 by univariate analysis were further analysed by multivariable analysis. Hazard ratios (HR) with 95% confidence intervals (CI) obtained from the multivariable Cox proportional hazard model were reported. Significance was assessed at a level of 0.05. The Stata 15 software was used for all statistical analyses. 4 This study was approved by the institutional ethics review board.

Epidemiological data
Sixty-two cases of invasive cutaneous melanoma were diagnosed in 61 patients at our centre (1 patient had 2 melanomas on different anatomical regions diagnosed at different time points). Cases of melanoma in situ (MIS) were excluded from the analysis. Table 1 summarises the clinical characteristics of patients with cutaneous melanoma.
There was a predominance of Chinese (72.6%), followed by Caucasians (19.4%) and Indians (3.2%), with an over-representation of Caucasians. Bangladeshi, Filipino and Nepalese constitute the other ethnicities (4.8%). There were no Malays diagnosed with cutaneous melanoma although Malays constitute the second largest group in the racial composition of the population in Singapore.
There were 39 male patients (62.9%), with a male to female ratio of 1.7 to 1, in keeping with an earlier melanoma study in Singapore. 5 The most common age of onset was in both the 6th and 7th decade and the median age at diagnosis was 64.0 years (range 27-99). Overall, there was a decreasing trend in age at the time of initial diagnosis, contributed by the After adjusting for population census, the incidence of cutaneous melanoma diagnosed at our centre between 2011 and 2015 was 0.13 patient per 100,000 patient-years, representing an approximately 3-fold increase compared to the period from 1996 to 2010.

Pathologic data
The most common histological subtype of cutaneous melanoma diagnosed were superficial spreading melanoma (SSM) at 37.1% and acral lentiginous melanoma (ALM) at 35.5%, followed by nodular melanoma (NM) at 22.6%. The following subtypes had one patient each: lentigo maligna melanoma, melanoma arising from a congenital melanocytic nevus, and spitzoid melanoma ( Table 2). This is in contrast to earlier Singapore studies in which ALM 5 and NM 6 were the most common histological subtypes. Among Asians in our study, the most common subtype of melanoma was ALM (44.0%) followed by SSM (32.0%) and NM (20.0%); and among Caucasians, the most common subtype of melanoma was SSM (58.3%) followed by NM (33.3%) (P=0.005).
There was no significant change in the proportion of melanoma subtypes in 2009-2015 compared to 1995-2008. The most common site of presentation in Asians was the sole of the foot (46.0%) versus the back (33.3%) and lower limb (33.3%) in Caucasians. There were no cases of melanoma on the foot in Caucasians ( Table 3).
Only 13 (21.0%) and 6 (9.7%) patients were tested for BRAF and c-KIT mutation, respectively. Four patients had BRAF and 1 had c-KIT mutation detected.

Staging data
Nineteen (30.6%), 25 (40.3%), 15 (24.2%) and 1 (1.6%) cases were diagnosed with stages I to IV disease, respectively. Two cases (3.2%) did not undergo staging procedure-1 patient opted to explore alternative medicine while the other patient declined in view of advanced age. Twenty eight percent of Asians were diagnosed with advanced melanoma (stage III or IV) at presentation, while 16.7% of Caucasians were diagnosed with advanced melanoma (P=0.046). Stratified by histological subtype of melanoma, only 27.3% and 13.0% of patients with ALM and SSM, respectively had advanced melanoma at presentation, while 50.0% of patients with nodular melanoma had advanced melanoma at presentation (P=0.04).
The median time interval to diagnosis (defined as the duration between the onset of a new pigmented lesion, change in an existing mole or previous normal surveillance and the diagnosis of melanoma) for the total study cohort was 24 months (range 1-240 months).
When stratified against ethnicity, the delay was longer for Asians (24±50.3 months) than in Caucasians (12±6.9 months) although this did not reach statistical significance (P=0.23). Time interval to diagnosis in the last 5 years (2011-2015) compared to the preceding 5-year interval was not significantly shorter (P=0.65).

Treatment and outcomes data
Follow-up data were not available for 15 cases and they were excluded from treatment outcome analysis. Forty-one patients (87.2%) underwent wide excision (Table 1), while 2 (4.3%) had adjuvant chemotherapy or radiotherapy.
Twenty-one patients (44.7%), all with Breslow's thickness of 1mm or more, underwent sentinel lymph node biopsy (SLNB), of which 6 (28.6%) yielded positive SLNB necessitating subsequent CLND. Five patients (10.6%) had lymph node dissection (LND) without prior SNLB-1 patient had fluorodeoxyglucose avid nodes on positron emission tomography, 1 patient had enlarged nodes on computed tomography, 1 patient had fine needle aspiration cytology proven disease, and the reason for LND was not stated in 2 cases. Three of the patients who had LND had lymph node metastases. Of the 21 cases who had neither SLNB nor LND, 3 had pT1a or pT1b disease, 9 declined or were considered unfit for surgery, 2 defaulted follow-ups, and 7 had unclear reasons that were not documented. Follow-up duration was defined as the time from the date of diagnosis to the date of the most recent review. Median follow-up duration was 22 months (range 1-199 months). Eighteen (38.3%) cases had relapse, higher than that in earlier studies of 18.5% 6 to 20.8%. 5 Of the patients who experienced a relapse, 10 had stage III disease, 9 had stage II disease, and 1 had stage I disease. The median duration between the most recent treatment and date of relapse was 8 months (range 1-31 months). Of the 18 patients who relapsed, 50.0% had locoregional relapse, 27.8% had concurrent locoregional and distant relapse, and 22.2% had distant relapse. Seven patients (38.9%) declined further treatment, 7 patients (38.9%) underwent repeat surgery, 2 (11.1%) had palliative radiotherapy to distant metastases, and 1 (5.6%) had palliative chemotherapy. One patient with c-KIT mutation was treated with imatinib and is still alive at the time of writing.
The median overall survival (OS) was 68 months, the relapse-free survival (RFS) was 31 months and the 5-year OS rate was 55.3% (95% CI 41.2-74.1) (Fig. 1). The median OS time for ALM and non-ALM were 55 and 102 months, respectively (P=0.58). The median RFS time for ALM and non-ALM were 26  Multivariable analysis demonstrated that the subtype of melanoma was not an independent prognostic factor for OS and RFS, but an older age at diagnosis (HR=1.07 and 1.06, P=0.006 and 0.02, respectively) and thicker Breslow's measurements (HR=1.21 and 1.63, P=0.045 and 0.01, respectively) were independent adverse prognostic factors for OS and RFS, respectively (Table 4).
Twenty-three patients in our cohort died, of which the cause of death in 14 patients (60.9%) was unknown. Significantly, all 8 patients (34.8%) who died from melanoma were Asians. Of these, 46.2% had ALM, 30.8% had SSM and 23.1% had NM. In the study group, 88.4% had stage II or III disease at diagnosis, and 34.6% either declined salvage treatment or defaulted follow-up. The mortality rate for Asians versus Caucasians was 52% and 0%, respectively.

DISCUSSION
In our study, the incidence rate of melanoma was 0.12 per 100,000 and 4.33 per 100,000 person-years for Asians and Caucasians, respectively, between 2011 and 2015. This is in contrast to 0.2 to 0.65 per 100,000 person-years in other Asian studies, 5-14 21.9 per 100,000 person-years in the US, and 1.3 to 35.8 per 100,000 person-years in Europe. 15 Worrisome features observed in our study included thicker Breslow's thickness, later stage at diagnosis and poorer overall prognosis for Asians. Despite a call for greater education efforts on early melanoma detection in Singapore since 2001, 6 the Breslow's thickness has not decreased significantly in the last  AJCC: American Joint Committee on Cancer; CI: confidence interval 5 years. In fact, compared with previous melanoma studies in Singapore, our study cohort has a higher proportion of advanced disease at presentation, and a longer time interval to diagnosis (Table 5). Moreover, the incidence rate of melanoma between 2011 and 2015 had risen. We postulate that this could be due to the lack of skin cancer awareness among the Singapore population. In our study, 75% of Caucasians who had no previous skin cancer self-referred for a mole check and had the melanoma detected during the routine skin check. In contrast, only 10% of Asians consulted a dermatologist for a total body skin examination or mole check. Education directed at both general practitioners (GPs) and the public should be tailored to our mainly Asian population 17 with a predominance of the ALM subtype of melanoma. 18 The public should be taught how to self-monitor moles on the palms and soles, and pigmented bands on nails. Opportunistic melanoma screening may be performed strategically during annual health screening to include screening for pigmented lesions on the body, soles and palms. GPs may use the acronym CUBED 19 which stands for Coloured lesion, Uncertain diagnosis, Bleeding lesion on the foot or under the nail, Enlargement of a lesion, and Delay in healing to identify ALM. With regards to nail unit melanoma, melanoma is suspected when the first finger or toe is involved, two-thirds of the nail plate is pigmented, black-grey pigmentation is present, irregularly-sized, coloured-band, and Hutchinson signs are present. 20 Cost-effectiveness analysis for melanoma screening had been conducted predominantly in Caucasian populations, in which the incidence rate of melanoma is significantly higher than in Singapore with a predominantly Asian population. [20][21][22] We did not find any cost-effectiveness analysis studies for melanoma screening in Asian countries. However, there are several reasons to support melanoma screening in Singapore. Firstly, the incidence of melanoma in recent years is rising. Secondly, visual examination is a relatively simple and inexpensive screening modality. Thirdly, melanoma is a potentially curable disease if identified early, and non-operable melanoma has a high mortality and systemic treatment is expensive.
The prognosis of patients in our series is poor with almost 40% of our patients treated with curative intent experiencing subsequent relapse. As we seek to raise awareness about ALM in the Singapore population, it is also critical to identify risk factors that may predispose patients to ALM. In the recent decade, immune checkpoint inhibitors such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors and programmed death (PD-1) inhibitors have shown promising results mainly for patients with non-acral cutaneous melanoma in Caucasian populations. [27][28][29] However, 2 recent studies suggest that Asian patients with advanced ALM are relatively unlikely to respond to PD-1 blockade monotherapy 30 or toripalimab 31 compared to Caucasians. In our study, no patients received immune checkpoint, precluding us from drawing meaningful conclusions about whether the introduction of these drugs has improved the survival of melanoma in our population. This was because PD-1 inhibitors were only approved to be used in Singapore in 2016, which was after our study period. Another postulated reason may be due to the high costs of checkpoint inhibitors. Among the various genetic markers, patients were only tested for BRAF and c-KIT perhaps due to the low incidence of NRAS mutation in melanomas occurring in the Asian population. 33 One of the limitations of this study was its retrospective nature and high dropout rates in the Caucasian and non-resident population, precluding a detailed assessment of treatment outcomes in these patients. This is not unusual as these patients may have left the country and continued follow-up back in their home countries. For Singapore patients who were lost to follow-up, we propose a closer working relationship between oncologists and dermatologists to ensure that these patients have dermatologic follow-up for assessment for melanoma recurrence and regular skin surveillance.
There is a partial overlap of our current study population and an earlier melanoma study in Singapore. 5 However our duration of data collection and cohort size is significantly larger than this previous study. We have tabulated a comparison of epidemiology, clinical features, staging and outcomes of patients in our study and 2 previous Singapore melanoma studies (Table 5).
Our centre sees a significantly lower proportion of Malay patients and a significantly higher proportion of other ethnic groups, especially Caucasian patients (P<0.0001) when compared to our country's population consensus. However, we believe that the lower incidence of melanoma in ethnic groups of higher skin phototypes may reflect more than only sampling bias as a similar melanoma study conducted by the National Cancer Centre Singapore 32 also had a significantly lower proportion of Malay and Indian patients compared proportionately to population consensus. People with higher skin phototypes rarely or never sunburn and tan easily, reducing the risk of many skin cancers including melanoma. In addition, ethnic groups with more conservative clothing styles may have less sun exposed areas, resulting in less ultraviolet-induced types of melanoma.

CONCLUSION
Given our study findings, we propose more thorough and targeted education for primary healthcare providers and integration of efforts to teach patients selfexamination of pigmented lesions on the soles, palms and nails alongside opportunistic screening efforts. Prognosis is stage-dependent with good OS seen in patients with early disease and worse outcomes in patients with advanced melanoma. With our population, we should strive to improve survival of melanoma with earlier detection. Further research is needed to identify modifiable risk factors for ALM to address this increasing trend in the incidence of melanoma. Affordability of and healthcare financing models for genetic testing and targeted therapy or immune checkpoint inhibitors should also be re-evaluated as they offer better disease control for patients with metastatic or inoperable melanoma, 34,35 yet their current high costs at present may deter uptake of their use.