Survival rates for invasive cutaneous malignant melanoma in South Korea in accordance with the Eighth edition AJCC Cancer Staging Manual: A retrospective single center study

Plain Language Summary

This study investigates the survival of patients with invasive cutaneous malignant melanoma (a type of skin cancer) in South Korea. A review of the medical records of 202 patients with melanoma found that the survival rate was lower in South Korea compared to Caucasians. Factors influencing survival included the thickness of the cancer, the presence of ulceration and the stage of the melanoma. The authors suggest that more attention should be given to the depth of the cancer invasion and its condition (whether it had ulcerated or not), rather than where the cancer is located and whether it has spread to lymph nodes to better understand the prognosis of invasive cutaneous malignant melanoma in South Korea. However, this study only looked at a small number of patients in one hospital, so more research is needed.

Introduction

Cutaneous malignant melanoma is an uncommon, but lethal, form of skin cancer. Its incidence is steadily rising, resulting in a significant increase in disease burden. The age-standardised worldwide incidence rate of cutaneous malignant melanoma increased 13% between 2012 and 2020 (from 3.0 to 3.4/100,000/year).^1,2 In South Korea the incidence increased from 2.6 to 3.0/100,000/year between 2004 and 2017.³

Asian patients with cutaneous malignant melanoma typically exhibit a more prominent acral distribution, advanced disease at diagnosis, and poorer prognosis compared to Caucasians.⁴ The poorer prognosis has been noted even in Asian–American patients living in the USA: among 49,772 patients with invasive cutaneous malignant melanoma in the US reported by Cormier et al., the 5-year overall survival rate (OS) was 80.2% in Asian-American patients compared to 89.6% in Caucasian patients.⁵ This suggests that ethnic and genetic factors may be more important than environmental factors (geographical location, ultraviolet radiation exposure) in influencing the prognosis of cutaneous malignant melanoma.^4,5

The American Cancer Society reported melanoma-specific survival rates (MSS) in accordance with the staging criteria of the 8th edition of the American Joint Committee on Center (AJCC) staging system in 2017. Among 43,792 patients from 10 institutions in the USA, Europe, and Australia from 1998, the 5-year MSS in patients with stages I, II and III of the diseases were 98%, 90%, and 77%, respectively.⁶ However, a recent retrospective study in patients with melanoma from South Korea using a customised research database from the National Health Insurance Sharing Service in 2002–2017 reported a much lower 5- and 10-year OS of 62.3 and 48.8%, respectively .⁷

Although an accurate understanding of survival rates is important for patient counselling, only a few studies have analysed the OS and MSS of cutaneous malignant melanoma patients in South Korea. Thus, we aimed to analyse the OS, the MSS, and prognostic factors in patients with invasive cutaneous malignant melanoma in South Korea.

Methods

This study was conducted at Kyungpook National University Hospital, a tertiary centre in South Korea and was approved by the institutional review board (KNUH 2021-07-024). Medical records from the hospital database between July 2006 and June 2016 were retrospectively reviewed and a total of 301 patients histologically diagnosed with malignant melanoma were retrieved.

The study only included patients diagnosed with primary invasive cutaneous malignant melanoma. Patients whose medical records were insufficient for clinical or pathological staging, those with a histological diagnosis of cutaneous malignant melanoma in situ or atypical melanocytic proliferation and those who presented with mucosal malignant melanoma or metastatic melanoma with unknown primary were excluded.

Thus, only 202 patients with invasive cutaneous malignant melanoma were included in the final analysis. The stages of all invasive cutaneous malignant melanomas were revised according to the 8th edition of the AJCC staging system.

The following data were collected:

1. Clinical characteristics: age at diagnosis, gender, duration from disease onset to the first visit, and anatomic location

2. Histopathological characteristics: including Breslow thickness, ulceration, presence of microsatellites, satellites, locally recurrent or in-transit metastasis, presence of tumour in sentinel lymph node, BRAF mutation status and clinicopathological stage

3. Follow-up data: date of mortality, OS, MSS, and follow-up period

The date of mortality was identified by checking the date of expiration from the National Health Insurance Sharing Service. Although other potential prognostic factors, such as family or personal history of melanoma were noted, they were not included in this study owing to their rarity among the patient population. The data were analysed and 3- and 5-year OS/MSS were calculated.

The Kaplan–Meier method was used to draw survival curves to estimate the OS and MSS of invasive cutaneous malignant melanoma patients. The difference between survival curves was determined by a log-rank test calculating the corresponding p values. The Cox proportional hazard model was used for both univariate and multivariate analyses to estimate prognostic factors associated with MSS. The statistically significant factors in the univariate analysis were consecutively tested using multivariate analysis. All statistical analyses were performed using PASW Statistics 18 (Release Version 18.0.0, SPSS, Inc., 2009, Chicago, IL, www.spss.com) and P < 0.05 was considered significant.

Results

Discussion

Studies have shown that Asians with cutaneous malignant melanoma have a poorer prognosis as compared with Caucasians.^4,6,8–13 In 2017, the American Cancer Society reported the 5-year MSS for stages I-III based on the 8th edition of the AJCC staging system. The survival rates were 99% for stage IA, 97% for stage IB, 94% for stage IIA, 87% for stage IIB, 82% for stage IIC, 93% for stage IIIA, 83% for stage IIIB, 69% for stage IIIC, and 32% for stage IIID [Table 5].⁶ According to the Cancer Statistics 2020 report, the 5-year relative survival rate for cutaneous malignant melanoma with distant metastasis (stage IV) was 25%.⁸ Previous reports on survival rates of cutaneous malignant melanoma patients in Asian countries such as Japan, China, Singapore, and Taiwan have consistently shown lower rates compared to those in Western countries [Table 5].^6,9–13 Our study confirms the poorer prognosis of Asian patients with cutaneous malignant melanoma.

Although both the Western report⁶ and our current study showed a decrease in 5-year MSS between stages IIA and IIB, from 94 to 87% and from 88.5 to 74.3%, the decrease (7% vs 14.2%) is much greater in our study [Table 5]. We feel that adjuvant cancer therapy should also be administered in Korean patients with stages IIB and IIC. Also, and careful monitoring of the prognosis of stages IIB and IIC patients is necessary.

Earlier studies have associated tumour thickness, ulceration and advanced stage as factors contributing to the poor prognosis in Asian cutaneous malignant melanoma patients.^6,14 and our study confirms these as independent prognostic factors.

The reasons why Asian patients tend to present with more advanced stages of the disease are a matter of controversy. Some reports emphasised the predominant acral distribution as a major difference in ethnicities and suggested that the acral melanoma itself carries a worse prognosis due to its natural aggressive histopathologic features.^15,16 However, a Japanese study reported no survival difference between acral and non-acral melanoma patients,¹⁷ and a recent Korean study noted a better prognosis in patients with acral melanoma than non-acral melanoma located on the trunk.¹⁸ The acral location was not a prognostic factor in our study and acral melanomas may have a similar prognosis to malignant melanomas at other cutaneous sites if properly treated.

The sentinel lymph node biopsy is a widely accepted diagnostic procedure to determine nodal staging for cutaneous malignant melanoma patients and presence of tumour in sentinel lymph nodes is one of the important predictors of relapse-free survival and OS.¹⁹ However, several recent reports have demonstrated that the presence of tumour in sentinel lymph nodes is not an independent predictive factor of relapse or survival,²⁰ and this was confirmed in our study too.

BRAF and NRAS mutations are anticancer targets in melanoma and may have prognostic value. BRAF and NRAS mutations are present in 80% of all sporadic melanomas in Caucasians. However, BRAF mutations were present in only 30.4%–41.8% in Japan, 25.5% in China, 14.3% in Taiwan, respectively and in 11.9–19.4% in Korea, and NRAS mutations were present in 12.3% in Japan, 7.2% in China, 10.1% in Taiwan and 12.6%in Korea.^4,18,21 Similarly in our study, the frequency of BRAF mutation was 11.7%. The lower frequency of BRAF and NRAS mutation in Asian patients with cutaneous malignant melanoma may result in a lower utility of immune checkpoint inhibitors (ICIs; vemurafenib, dabrafenib, or trametinib).^4,18

Mutations in BRAF genes did not influence the prognosis in our study and conflicting results have been reported in previous studies.²² Further studies with large number of patients will be needed to determine whether the BRAF mutation status, with or without ICI and BRAF/MEK inhibitor therapy, plays a significant role in prognosis of invasive cutaneous malignant melanoma.

In addition, the difference in the timing of the introduction of ICIs by each country could also be the other contributing prognostic factor. ICIs had started to gain approval from the Food and Drug Administration for metastatic melanoma treatment beginning 2011, ²³ but the aforementioned survival studies in China and Taiwan were conducted before 2011. In Japan, the Ministry of Health, Labour and Welfare has approved coverage for ICIs beginning 2014,²⁴ and ICIs had gained approval from the Ministry of Food and Drug Safety in Korea beginning 2014 and have been subject to insurance benefits from 2017.⁷ In this study, most of the stage IV patients did not receive ICI treatment, and the 5-year OS/MSS of stage IV was low like 0%/0% and this could be a factor responsible for the lower survival rate [Table 5].

Our study has several limitations. As it was a retrospective analysis conducted at a single institution in South Korea and involved a relatively small number of patients, it was not possible to estimate survival rates for patients with stage IIIA melanoma. Furthermore, the study only compared melanoma survival rates reported by different countries and failed to take into consideration crucial factors such as governmental insurance support and timing of the study, which could potentially influence the results. Lastly, the study identified a perplexing paradox where the MSS for stage IIIB was higher than that of stage II, and a similar pattern was observed in data from the American Cancer Society for IIC and IIIA in 2017 [Table 5]. The reason behind this survival paradox is not apparent and requires further investigation through future studies to determine a more realistic survival rate according to the AJCC staging system.

Conclusion

This study presents 5-year OS and MSS as reference values for estimating survival rates of invasive cutaneous malignant melanoma patients in South Korea and showed that the prognosis was worse than that of Caucasians. In addition to already well-verified Breslow thickness and ulceration, the impact of tumour location and sentinel nodal metastasis on MSS should be reconsidered to better understand the prognosis of invasive cutaneous malignant melanoma patients in South Korea.