Melonoma is originated from melanocytes, located in skin epidermis, eye, and epithelia of the nasal cavity, oropharynx, anus, and genitourinary tract. Melanoma comprises about 4.3% of all new cancer diagnosed in United States according to the National Center for Health Statistics database report1. Compared to the cutaneous melanoma which consists of majority of disease, noncutaneous melanomas are relatively rare, which are comprised of ocular and various mucosal sites such as anorectal, vaginal, nasal, and gastrointestinal tract2 According to the National Cancer Data Base (NCDB) in the United States, the incidence of ocular, and mucosal melanoma were 5.5% and 1.3%, respectively. Intriguingly, the reported incidence of mucosal melanoma varies from 0.2% to 10.0% depending on the ethnic and geographic differences 345. In previous studies comparing melanoma patient cohort cohort, age-adjusted incidence of cutaneous melanoma was highest in non-hispanic whites, and visceral/cutaneous melanoma ratio was much higher for black individuals67. The proportion of mucosal melanoma seems to be higher in Asian ethnicity when compared with that in Caucasians 8910. Moreover, Asian groups showed the lower age-adjusted incidence rate of ocular melanoma compare to caucasian patients 1112. Such variations in ethnicity may reflect distinctive pathophysiology or tumorigenesis for each subtypes of melanoma.

The differential distribution of genetic alterations in BRAF, NRAS and KIT among melanoma subtypes according to anatomic sites and sun exposure strongly implicated different molecular pathways involved in tumorigenesis for each subtype (Antonescu et al, 2007). KIT mutations were detected in 21% of mucosal melanomas, 11% of acral melanomas, and 16.7% of melanomas arising in chronically sun-damaged skin as indicated by the presence of solar elastosis (Antonescu et al, 2007). In another recent study, KIT mutations were identified in 23% of acral melanomas, 15.6% of mucosal melanomas, 1.7% of cutaneous melanomas, and none in choroidal melanomas13. Mucosal melanomas pursued more aggressive natural course and poorer prognosis than other subsets of melanomas14. Nevertheless, owing to the rarity and heterogeneity of the disease entity, clinical characteristics and optimal therapeutic strategies have not been extensively defined yet. Given the distinct genetic aberrations for mucosal melanoma, there is an urgent need to redefine the clinical features and prognosis of this subtype of melanoma. Most of the previous reports on mucosal melanomas are focused on head and neck melanomas rather than melanomas arising from mucosal membrane at various anatomic sites3141516. Hence, we undertook this multicenter retrospective analysis to define clinical characteristics of mucosal melanomas and to devise a prognostic model which can effectively identify different risk groups based on initial clinical variables.

One-hundred twenty nine patients were included in the analysis. The clinical characteristics are provided in Table 1. After that, we further analyzed survival outcome for those who had received curative resection (R0 and R1 resection) as shown in Table 2. The median age was 61 years with a range of 26 to 95 years and male proportion was 40.3%. The median longest diameter of the primary tumor was 25 mm with a range from 2 to 135 mm. Noncutaneous melanoma cases were further divided into ocular melanoma (n = 14) and mucosal melanoma (n = 115).

To provide a more complete clinical picture of this uncommon disease entity and ultimately deduce the risk-adapted therapeutic strategies, we analyzed the largest series of noncutaneous melanomas in terms of clinical features and prognosis. In this study, we depicted distinctive clinical features of the rare disease entity and categorized heterogeneous subsets of noncutaneous melanoma into two groups: ocular and nonocular mucosal melanoma. Moreover, systemic analyses of prognostic factors reflecting poor survival have not been reported in noncutaneous melanoma patients. Hence, we attempted to devise a prognostic model incorporating readily available clinical variables which may assist clinicians for risk stratification.

In this study, the median overall survival for all patients and mucosal melanoma patients were 24.4 months (95% CI 13.2-35.5) and 34.6 months (95% CI 24.5-44.7), which is in accordance with previous studies1819. Based on those findings, we analyzed significant prognostic factors of OS for mucosal melanoma patients who had received curative resection. The significant poor prognostic factors were microscopic residual disease (P = .001; RR, 2.93; 95% CI 1.58-6.26), and age > 50 years (P = .008; RR, 2.88; 95% CI, 132-5.39) (Table 3). These findings are very consistent with previous study for mucosal melanoma 15. In the multivariate analysis, age greater than 60 years was one of the poor prognostic factors for survival. Contrary to cutaneous melanoma, achieving extensive resection is very difficult due to anatomical location or cosmetic concerns, and performing radical lymphadenectomy is much more challenging. Based on those results, more attention is required for achieving R0 resection for mucosal melanoma patients. In addition, even after the curative intended resection, patients with microscopically residual resection should be offered of more aggressive therapeutic strategy such as postoperative chemotherapy ± radiotherapy. Due to the inherent bias for retrospective study in nature and the limited sample size, this result should be prospectively validated before clinical application.

Importantly, the survival outcome seems to differ according to the primary site of nonocular mucosal melanoma. For instance, 5 of 6 gastrointestinal melanomas presented with disseminated disease and pursued a rapidly deteriorating natural course with median survival time of 7.5 months. There are several anecdotal case reports on primary gastric or esophageal melanoma which reported poor survival following resection in accordance with our observation 202122. In contrast, ocular melanomas exceptionally pursued a favorable clinical course with median survival of 51.2 months. Most of the ocular melanoma patients (13 of 14, 93%) presented with localized disease of whom eight achieved R0 resection. One of the plausible explanations for such significant difference in prognosis would owe to the anatomic location. For instance, ocular melanoma may be more noticeable and symptomatic than gastric melanoma; thus, over 90% of the ocular melanoma patients are diagnosed at localized stage. As shown in Figure 1B, genitourinary, anorectal and head and neck melanomas demonstrated relatively similar survival pattern.

In all, of the 100 noncutaneous melanoma patients who underwent surgical resection with curative intent, 70 patients achieved complete R0 resection and 58 developed recurrence (43% local relapse, 57% systemic relapse). Of the 51 recurred patients, only 6 patients underwent re-resection and half of the patients did not receive palliative treatment. Considering the high rate of systemic relapse following curative resection observed in our study along with previous reports 1423, an effective postoperative systemic treatment is urgently needed. The role of adjuvant treatment in mucosal melanoma has not been extensively studied compared to cutaneous melanoma probably owing to the rarity of disease. Several studies on adjuvant treatment using chemotherapeutic or immunotherapeutic agents, the results have been disappointing424252627. In line with these studies, our retrospective analysis on 100 noncutaneous melanoma patients with surgical resection showed no significant difference in survival associated with adjuvant chemotherapy (median survival; 45.3 months vs 34.5 months, adjuvant therapy vs observation, respectively, P = .085). In subgroup analysis, however, there was a trend toward better survival in anorectal and genitourinary mucosal melanoma patients who received postoperative chemotherapy (median OS 45.3 months vs 26.1 months, respectively, P = .20). Therefore, the role of adjuvant chemotherapy or immunotherapy should be actively sought in noncutaneous melanoma in the context of clinical trial.

A potential breakthrough in the management of mucosal melanoma has been recently suggested by the observation of relatively high incidence of KIT mutations in mucosal melanomas 282930. Excitingly, a major response has been reported following imatinib treatment in primary anal melanoma patient harboring a seven-codon duplication in exon 11 of KIT 31. Other reports also support the use of specific kinase inhibitors such as imatinib or dasatinib in melanoma patients with activating KIT mutation 3032. Given the high incidence of KIT mutations in mucosal melanoma, we plan to conduct a phase II clinical trial with KIT targeting small molecule in this subset of patients.

This is the first study to comprehensively review and describe the clinical features and prognosis of noncutaneous melanoma. Nonocular mucosal melanoma pursued an aggressive clinical course and high rate of systemic relapse following curative resection and thus, more aggressive postoperative treatment should be considered for the patients with poor risk factors. Moreover, further validation and postoperative study with different strategy is warranted in the future.

The authors declare that they have no competing interests.

HSK drafted the manuscript. HSK, EKK, HJJ, SYO, DHL, KWP, JHK, KMK and SIL collected the data and performed the statistical analysis. HSK, SYO, DHL, KWP, JHK, SIL, DHL, and JL followed the patients. DHL and JL designed the study and helped with the manuscript. All authors read and approved the final manuscript.