Treatment and prognosis in sinonasal mucosal melanoma: A retrospective analysis of 65 patients from a single cancer center

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1 ORIGINAL ARTICLE Treatment and prognosis in sinonasal mucosal melanoma: A retrospective analysis of 65 patients from a single cancer center Chuan-Zheng Sun, MD, PhD, 1 Qiu-Li Li, MD, PhD, 2,3 Ze-Dong Hu, MD, 1 Yu-E Jiang, MD, 1 Ming Song, MD, PhD, 2,3 An-Kui Yang, MD 2,3* 1 Department of Head and Neck Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, People s Republic of China, 2 State Key Laboratory of Oncology in South China, Guangzhou, People s Republic of China, 3 Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People s Republic of China. Accepted 9 April 2013 Published online 22 April 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to evaluate the outcome in sinonasal mucosal melanoma (SMM). Methods. A retrospective analysis of clinicopathological data from January 1976 to December 2005 was performed. Survival curve, univariate, and multivariate analyses were undertaken. Results. Sixty-eight patients with SMM were enrolled; 3 patients refused treatment. The 3-year and 5-year overall survival (OS) rates in the remaining 65 cases of SMM were 36.5% and 29.7%, respectively. Patients who underwent surgery had better 3-year and 5-year OS rates than those treated without surgery (40.7% and 34.1% vs 21.4% and 14.3%, respectively), and the same was true for patients treated with and without biotherapy (58.2% and 50.9% vs 30.0% and 23.4%, respectively). Distant metastasis at presentation was associated with a worse prognosis. Those patients managed with multimodality treatment had better OS rates. Conclusion. The prognosis in SMM is poor, particularly for those with distant metastasis or without surgery. Multimodality treatment may improve survival. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: mucosal melanoma, sinonasal, treatment, prognosis, biotherapy INTRODUCTION Malignant melanomas develop from melanocytes derived from neural crest cells. Although cutaneous melanoma is by far the most common type, they can arise in any organ that has melanin-containing cells. Overall, mucosal melanomas are rare and account for only 0.8% to 3.7% of all melanomas. 1 However, the incidence is increasing in western countries by 6% to 7% every year. 2 Mucosal melanomas of the head and neck (MMHN) account for 0.72% of all melanoma cases, and for 50% to 55% of all mucosal melanomas. 3,4 The nasal cavity, paranasal sinuses, and oral cavity are the most common primary sites of MMHN 1,5 ; other sites less frequently affected include the oropharynx, nasopharynx, and larynx. 1,3 Sinonasal mucosal melanoma (SMM) accounts for 4% to 13% of all sinonasal malignant tumors. 6 The 5-year overall survival (OS) rate ranges from 17.1% to 35.1%. 3,6 *Corresponding author: A.-K. Yang, Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, , People s Republic of China. lql2206@126.com or yangak@sysucc.org.cn Contract grant sponsor: This work was supported by grants from the National Natural Science Foundation of China (Nos and ), the Special Combined Foundation of Technology Gallery of Yunnan Province and Kunming Medical University (No. 2009CD186), and Special Foundation of High Levels of Health Technical Personnel Training in Yunnan Province (D ). Chuan-Zheng Sun and Qiu-Li Li contributed equally to this work. The seventh edition of the American Joint Committee on Cancer Staging Manual (2010) classifies staging as follows: primary tumor (T); T3: mucosal disease; T4a: moderately advanced disease (tumor involving the deep soft tissue, cartilage, bone, or overlying skin); T4b: very advanced disease (tumor involving the brain, dura, skull base, lower cranial nerves, including IX, X, XI, XII, masticator space, carotid artery, prevertebral space, or mediastinal structures); regional lymph nodes (N); Nx: regional lymph nodes cannot be assessed; N0: no regional lymph node metastasis; and N1: regional lymph node metastasis present. The clinical stage is classified as follows: stage III: T3N0M0; stage IVa: T4aN0M0 or T3 to T4aN1M0; stage IVb: T4bNanyM0; and stage IVc: TanyNanyM1. 7 As well as being rare, SMM is also an aggressive tumor. In order to increase the number of samples in retrospective clinical studies, many have included MMHN as an entirety, yet the clinical features and prognosis of SMM are different to those of oral mucosal melanomas. 3 There have been few large sample reports on SMM, and no firm conclusions have been reached in terms of treatment. Thus, there is a need to summarize the clinical characteristics and the effects of multimodality treatment in SMM, and to provide practical and constructive information for clinicians. In the present study, we collected and reviewed clinical and survival data on 68 patients with SMM treated between January 1976 and December 2005, in order to investigate the clinical features, efficacy of treatment, as well as the factors that influence prognosis. HEAD & NECK DOI /HED MAY

2 SUN ET AL. TABLE 1. A comparison of survival rates between those with different clinical features and those who received different therapies. Clinical parameters MATERIALS AND METHODS Clinical data Case number OS (%) 3-y 5-y Chi-square p value Sex Male Female Age <55 y y Primary tumor site Nasal cavity Paranasal sinus Pathological LNM Yes No Distant metastasis Yes No ctnm classification III IV Biotherapy Yes No Chemotherapy Yes No Multimodality treatment Yes No Surgery Yes No Radiotherapy Yes No Residual/recurrent disease Yes No Abbreviations: OS, overall survival; LNM, lymph node metastasis, ctnm classification, clinical TNM classification. Sixty-eight patients with SMM were admitted to the Sun Yat-sen University Cancer Center between January 1976 and December The duration of the medical history ranged from 0.5 to 24 months. A summary of all clinical data from the included patients can be seen in Table 1. All cases were restaged according to the staging paradigm for MMHN. 7 Clinical TNM (ctnm) classification was determined by clinical and radiological examinations, including CT, MRI, and ultrasound. The possible presence of distant metastasis was assessed using chest radiography, ultrasound, bone scintigraphy, CT, and/or positron emission tomography/ct scans. Follow-up and statistical analysis Follow-up information was collected by letter, telephone, and face-to-face outpatient interviews, and continued to December The follow-up period was calculated from the date of the definitive diagnosis to the final visit. All data was analyzed using SPSS 18.0 software (SPSS, Chicago, IL). Survival curves were generated using the Kaplan Meier method and the log-rank test was used for univariate analysis. A Cox model was applied for multivariate analysis. The cutoff for statistical significance was In order to compare the value of different treatment modalities and investigate the factors that affect prognosis, the 3 patients who refused treatment were excluded from the survival analysis. RESULTS Clinical features Forty-seven patients were men and 21 were women, with a male:female ratio of 2.2:1. Age at first diagnosis ranged from 2 to 79 years, with a median of 55 years. The time from the appearance of symptoms to diagnosis ranged from 0.5 to 24 months, with a median of 3 months. The primary sites for SMM included the lateral wall of the nasal cavity (35 cases; 51.5%), the nasal septum (6 cases; 8.8%), the entire nasal cavity (14 cases; 20.6%), and the paranasal sinuses (13 cases; 19.1%; maxillary sinus, n 5 10; ethmoidal sinus, n 5 2; and frontal sinus, n 5 1). Forty-five cases were pigmented and 23 were nonpigmented (33.8%). Most patients had nasal obstruction or hemorrhage at initial diagnosis. Clinically lymph node metastases had occurred in 5 cases and distant metastases in 4 cases by the time of the initial consultation (liver metastases in 2 patients and multiple distant metastases in another 2 patients). Thirty-six patients were stage III, 24 were stage IVa, 4 were stage IVb, and 4 were stage IVc. Among the 5 patients with pathological lymph node metastases at the time of diagnosis, 2 patients were confirmed to have metastases by neck dissection. The other 3 cases were identified by lymph node biopsy or ultrasound-guided fine needle biopsy. Rates of cervical lymph node metastasis in patients with a primary site in the nasal cavity and the paranasal sinus were 7.3% (4 of 55 patients) and 7.7% (1 of 13 patients), respectively. Imaging studies and pathological examination revealed that 2 patients had level Ib lymph node metastasis; 1 had level II; 1 had level Ib, level II, and level III; and 1 had bilateral level Ib and unilateral level II. In our study, there was no significant difference in the incidence of pathological lymph node metastasis (7.3% vs 7.7%; chi-square ; p 5.959) and distant metastasis (3.6% vs 15.3%; chi-square ; p 5.108) between those with nasal cavity mucosal melanoma and those with paranasal sinus mucosal melanoma. Therapeutic regimen While undertaking our retrospective research for this article, it seemed that changes in treatment regimens were mainly indicated for biological therapies: skin punctures with the bacillus Calmette Guerin (BCG) vaccine from 1980 to 1998, and hypodermic injection of interleukin (IL)-2 or interferon (IFN)-a-2b from 1999 to Three patients refused treatment, due either to the advanced stage of their tumor or to the presence of other 676 HEAD & NECK DOI /HED MAY 2014

3 SINONASAL MUCOSAL MELANOMA medical problems. Chemotherapy alone was administered to 6 patients, and radiotherapy alone to 4 patients. Surgical resection alone was performed in 18 patients. Thirtyseven patients received combined treatment: surgery combined with radiotherapy, n 5 13; surgery combined with radiotherapy and biotherapy, n 5 1; surgery combined with biotherapy and chemotherapy, n 5 10; surgery combined with chemotherapy, n 5 9; radiotherapy combined with chemotherapy and biotherapy, n 5 2; and chemotherapy combined with biotherapy, n 5 2. Depending on the extent of the involved primary site, the surgical approach included primary tumor resection in 47 cases and primary tumor resection combined with neck dissection in 4 cases (selective neck dissection in 2 cases, and radical neck dissection in 2 cases). Twenty patients received radiotherapy, with conventional fractionation in 15 patients and hypofractionation in 5 patients. The median radiation dose was 56 Gy (range, Gy). Chemotherapy regimens included the following: a combination of dacarbazine, cisplatin, and Me-CCNU in 4 cases; a combination of dacarbazine, vindesine, and cisplatin in 5 cases; a combination of dacarbazine and vindesine in 4 cases; a combination of dacarbazine, cyclophosphamide, and vincristine in 2 cases; and dacarbazine alone in 14 cases. The median duration of chemotherapy was 3 courses, with a range of 1 to 4 courses. Biotherapy included the following: skin punctures with BCG vaccine weekly (7 times) in 10 cases (from 1980 to 1998); hypodermic injection of IL-2 (3,000,000 units) 10 times in 3 cases; and hypodermic injection of IFN-a-2b (3,000,000 units) 7 times in 2 cases (from 1999 to 2005). Prognosis Three patients refused treatment. The 3-year and 5-year OS rates of the remaining 65 patients with SMM were 36.5% and 29.7%, respectively. A comparison of OS rates between those with different clinical features and those who received different treatments can be seen in Table 1. In patients <55 years at initial diagnosis, the 3-year and 5-year OS rates were 46.9% and 39.9%, respectively, compared with 27.3% and 20.5% in patients >55 years (p 5.058). In patients with distant metastases at the time of the initial diagnosis, the 3-year and 5-year OS rates were both 0, compared to 39.0% and 31.7%, respectively, in patients without distant metastasis (p <.05; Figure 1A). Patients who had undergone surgery had better survival rates (3-year and 5-year OS rates of 40.7% and 34.1%, respectively) than those who did not have surgery (23.7% and 15.9%, respectively; p 5.008; Figure 1B). Patients who received biotherapy had better survival rates (3-year and 5-year OS rates of 58.2% and 50.9%, respectively) than those who did not receive biotherapy (30.0% and 23.4%, respectively; p 5.076; Figure 1C). Similarly, 13 patients who received surgery with postoperative radiotherapy had a better survival rate and a lower incidence of residual/recurrent disease than those who did not have postoperative radiotherapy, but the difference was not significant (Table 2; Figure 1F). Univariate analysis showed that factors such as sex, primary tumor site, ctnm classification, chemotherapy, and radiotherapy, were not significantly associated with prognosis. In patients with nasal cavity SMM, the survival rates when the primary tumor was located in the lateral wall of the nasal cavity (3-year and 5-year OS rates of 44.9% and 35.3%, respectively; chi-square ; p 5.048) and in the nasal septum (33.3% and 33.3%, respectively; chi-square ; p 5.120) were both better than when the tumor occupied the entire nasal cavity (15.4% and 7.7%, respectively). For multivariate analysis, variables such as age, ctnm classification, multimodality treatment, chemotherapy, surgery, radiotherapy, biotherapy, pathological lymph node metastasis, distant metastasis, and residual/recurrent disease, were entered into a Cox model. Distant metastasis, surgery, and biotherapy (p <.05) were identified as independent prognostic factors in patients with SMM (Table 3). Follow-up Twelve patients had residual tumor after their first treatment. Twenty-four patients relapsed 6 to 114 months after definitive treatment (median time to relapse, 16 months) and 3 patients were lost to follow-up. Fifty-seven patients died: 3 from uncertain causes; 1 from a nasal hemorrhage during treatment; 14 from distant metastasis (present at initial diagnosis, 4 patients; occurred during or after treatment, 10 patients); and 39 as a result of locoregional disease progression. The remaining 8 living patients were followed until December The median survival time was 24 months (range, months). DISCUSSION Prognosis and influencing factors The former MMHN ctnm staging method introduced by Ballatyne et al 8 in 1970 is easy to use and requires little information; however, most clinical results show that stage is not related to prognosis. 1,9 Prasad et al 10 proposed a microstaging system based on the extent of tumor in the invaded mucosa among the patients with stage I disease. Because of the lack of microstage data, its prognostic value was not discussed in the present study. Even though all cases were restaged according to the staging paradigm for mucosal melanomas of the head and neck (the 7th edition of American Joint Committee on Cancer Staging Manual, 2010), 7 we did not find that the prognosis of the patients with stage III disease was better than that of patients with stage IV disease (chi-square ; p 5.444). However, we found that there was a significant difference between patients with stage IVC (with distant metastasis, M1) and stage III plus stage IVA/B disease (without distant metastasis, M0; chi-square ; p 5.006; Table 1; Figure 1A). These results were similar to those in the report by Shiga et al 10 published in Their study included 94 patients with MMHN, 75.5% patients (71 of 94 cases) with SMM diseases. They found that there were significant differences in terms of survival rates between the patients with stage IVC (M1) and stages I, II, III, IVA, or IVB (M0) disease (TNM classification, Union Internationale Contre le Cancer sixth edition, 2002). They did not report the difference between any other 2 groups. Furthermore, they evaluated the survival rates of patients according to their HEAD & NECK DOI /HED MAY

4 SUN ET AL. FIGURE 1. (A) Survival curves of patients with and without distant metastasis (p 5.006). (B) Survival curves of patients who underwent surgery and those who did not (p 5.008). (C) Survival curves of patients who received biotherapy and those who did not (p 5.076). (D) Survival curves of patients who received multimodality treatment and those who did not (p 5.046). (E) Survival curves of patients with and without residual/recurrent disease (p 5.005). (F) Effect of postoperative radiotherapy in patients with SMM (p 5.308) 678 HEAD & NECK DOI /HED MAY 2014

5 SINONASAL MUCOSAL MELANOMA TABLE 2. Effect of postoperative radiotherapy in patients with sinonasal mucosal melanoma. Chi-square p value ctnm classification Residual/ recurrent disease rate OS (%) III IV No. (%) Chi-square p value 3-y 5-y No. of patients Item S (61.1) S1R (46.1) Abbreviations: ctnm classification, clinical TNM classification; OS, overall survival; S, surgery; R, postoperative radiotherapy. Note: There were 3 patients with postoperative residual disease and 8 patients with recurrence in the S group. There were 2 cases of postoperative residual disease and 4 of recurrence in the S1R group; no significant difference in the rate of residual disease before radiotherapy was found between the 2 groups (16.7% vs 15.4%; chi-square ; p 5.925). TABLE 3. Results of multivariate analysis using Cox regression in patients with sinonasal mucosal melanoma. Factors Hazard ratio 95% CI p value Distant metastasis Surgery Biotherapy Abbreviation: CI, confidence interval. T classification, and no significant differences were observed. However, they found that nodal status was related to prognosis, which was in accordance with our results (Table 1). Thus, the prognostic predictive value of this new staging system needs confirmation in future studies. Jethanamest et al, 3 in their study on MMHN, found that the prognosis for primary tumors in the nasal cavity was better than that observed for primary tumors of the paranasal sinus. However, in our study, we did not find a significant difference in OS rates between these tumor sites (chi-square ; p 5.517). This discrepancy may be related to the fact that the 2 groups have similar rates of lymph node and distant metastasis, or to the fact that the number of samples was small. In those with nasal cavity mucosal melanomas, we found that patients with primary tumors of the entire cavity had a worse prognosis than those with tumors in the lateral cavity wall (p 5.048) or in the nasal septum (p 5.120). This indicated that patients with more extensive nasal mucosal melanoma lesions had a worse prognosis. Similar to those with head and neck squamous cell carcinomas, patients with SMM with lymph node or distant metastases had a worse prognosis than those without metastases. In our study, patients who were >55 years of age at presentation had a worse 3-year and 5-year OS rates (27.3% and 20.5%, respectively) than those aged <55 years (46.9% and 39.9%, respectively; chi-square ; p 5.058). Jethanamest et al 3 reported similar results: patients with MMHN aged >70 years had a worse prognosis than those <70 years. In the present study, the residual/recurrent disease rate was 55.3% (36 of 65 cases), and patients with residual/recurrent tumor had worse 3-year and 5-year OS rates (26.3% and 21.1%, respectively) than those without (51.1% and 42.1%, respectively; chi-square ; p 5.005; Figure 1E). Thus, it is important that residual and recurrent disease rates be reduced so that survival rates may improve. Clinical features Previous studies have shown that the male:female ratio in SMM is 1:1 to 2:1, and the median age is 64 to 69 years. 12 Lymph node metastasis occurs in 6% to 22% of patients. Distant metastases of MMHN at the time of presentation are relatively uncommon (4% to 10%), with no clear difference between oral and sinonasal mucosal melanomas; the most common sites of metastasis are the lungs (33%) and the brain (14%), with multiple sites involved in 33% of cases. 5,6,13 Our data is similar to that reported from other studies, although the male:female ratio and the rate of lymph node metastasis was higher than that what has been previously published. The rate of HEAD & NECK DOI /HED MAY

6 SUN ET AL. distant metastasis was lower than that observed in other studies. An explanation for the association between the incidence of SMM and ethnicity was not determined. Further research is needed to explore this issue. Primary tumor treatment: surgery and postoperative radiotherapy Because of the low incidence of MMHN, as yet, no definitive conclusions have been reached regarding the treatment of MMHN, and SMM has been studied even more rarely. Although multimodality treatment, including radical surgery, postoperative radiotherapy, chemotherapy, and biotherapy, is considered effective, the extent of its value requires further clarification. 1,4,6,14 19 Radical resection of the primary tumor with negative margins may provide to be the best therapeutic results for MMHN. However, negative margins may be difficult to achieve. 1 Furthermore, there is no consensus on the optimal extent of resection margins. It is generally accepted that complete resection involves the inclusion of at least 1.5 cm of normal tissue, as well as cervical lymph node treatment. However, the proximity of vital structures can make this difficult. Therefore, careful surgical planning is required to avoid both the higher morbidity and the negative impact on quality of life that can be associated with aggressive surgery, and a wide surgical resection with a higher morbidity does not necessarily decrease the rate of distant metastasis and improve OS. 1,4,6 Apart from postoperative radiotherapy in patients with residual tumor, in a recent study of oral mucosal melanoma, 5% imiquimod cream was applied with a nonabsorbing swab 3 times per week, with surrounding margins of approximately 0.5 cm on all histologically confirmed involved sites. After 3 months, no evidence of melanoma was detected. 15 This result suggests that local application of imiquimod may be an effective treatment option for patients with positive margins. This may also be useful in the treatment of SMM. Melanoma is relatively insensitive to radiotherapy, which therefore tends to be used as a palliative treatment or as postoperative adjuvant therapy ,20,21 In recent years, postoperative radiotherapy has become more widely utilized as part of the treatment algorithm for MMHN. Several series have reported an improvement in locoregional control with the use of postoperative radiation. Meleti et al 13 found that rates of locoregional recurrence of MMHN were higher with surgery alone (19 cases) than with combined surgery with postoperative radiotherapy (19 patients; p <.05). However, the distant metastases and OS rates were not improved (p >.05). These results have been confirmed in other studies. 14,16,17 At the MD Anderson Cancer Center, Moreno et al 19 reviewed 58 consecutive patients treated for SMM between 1993 and Thirty-three of the 58 patients received adjuvant radiation therapy, with a total radiation dose ranging from 30 to 66 Gy. Conventional fractionation was used in 23 patients and hypofractionation in 10 patients. Postoperative radiotherapy significantly improved the 5-year local disease-free survival (p 5.02), but only when a dose greater than 54 Gy and standard fractionation were utilized. In our study, 13 patients who received postoperative radiation had a lower rate of residual/recurrent disease, and higher 3-year and 5-year OS rates than those observed in the 18 patients who received surgery alone (rate of residual/recurrent disease: 46.1% vs 61.1%; p 5.409; 3-year and 5-year OS rates: 53.8% and 44.9% vs 27.8% and 13.9%, respectively; p 5.308). The small sample size may explain the nonsignificant difference observed (Table 2; Figure 1F). In theory, improvements in locoregional control may also result in lower rates of distant metastasis and higher survival rates. However, to date, no series has demonstrated a clear benefit in OS with adjuvant radiation therapy. In most series, there is a clear selection bias toward its use only in advanced and recurrent cases. Both the selection bias and the retrospective nature of these studies may obscure survival benefits that result from the use of postoperative radiotherapy. Further investigation is warranted. 1,6,17 Cervical lymph node treatment Because of the low rate of lymph node metastasis in SMM, elective neck dissection is not routinely required. 1,6 In our study, the pathological lymph node metastasis rate at diagnosis was 7.4% (5 of 68 cases), which was lower than the rate for oral mucosal melanoma in our cancer center during the same period. 22 Our data revealed that the distribution of lymph node metastases was similar to that observed for oral mucosal melanoma and for squamous cell carcinoma, which has higher rates of metastasis, mainly level Ib to III. 22 During follow-up, 6 patients presented with lymph node metastases in level Ib or II disease. The cumulative neck lymph node metastasis rate was 16.2% (11 of 68 cases), confirming that elective neck dissection is not routinely necessary, and that selective neck dissection should be performed for patients with N1 disease, and functional or radical neck dissection for patients with N2 or N3 disease. Adjuvant therapy: chemotherapy, biotherapy, and molecular targeted therapy The results of radical surgery depend on the extent of the surgical resection and the patient s subsequent quality of life. 9 The site and size of the tumor can limit radical surgery, and adjuvant therapy then becomes important. Dacarbazine and other cytotoxic agents have a response rate of approximately 10% to 20% in MMHN, irrespective of the different regimens used. 6 Chemotherapy fails to prolong survival and is often used as palliative treatment for those with advanced disease. 6 Our results are consistent with others reports. 9 No significant differences were observed between patients who received chemotherapy and those who did not. Biotherapy improves survival in patients with cutaneous melanoma. 5 However, improved survival in SMM has not been confirmed. Cytotoxic drugs combined with IFN or IL-2 can improve survival in MMHN. 1,5 A phase II study of metastatic melanoma, 23 in which a combination of temozolomide and pegylated IFN-a-2b was used, was well tolerated and demonstrated antitumor activity, with a response rate of 31%. Its role in mucosal melanoma needs 680 HEAD & NECK DOI /HED MAY 2014

7 SINONASAL MUCOSAL MELANOMA to be explored. In the present study, 15 patients received various forms of biotherapy, including BCG skin puncture and subcutaneous injections of IL-2 and IFN-a-2b, and this cohort had a longer 3-year and 5-year OS compared with those who did not receive biotherapy (58.2% and 50.9% vs 30.0% and 23.4%, respectively; p 5.076). Multivariate analysis confirmed biotherapy as an independent prognostic factor (p 5.032). These results suggest that biotherapy may be an effective adjuvant treatment for SMM. There is currently no consensus on the number of cycles and time of administration of biotherapy. Recently, O Day et al 24 conducted a phase II trial in 10 melanoma centers. Overall, 133 patients with metastatic melanoma were enrolled, and the biochemotherapy induction regimen included cisplatin, vinblastine, dacarbazine, decrescendo IL-2, and INF-a-2b with granulocyte-macrophage colony-stimulating factor. The response rate to induction biochemotherapy was 44.0%, and maintenance biotherapy after induction biochemotherapy prolonged progression-free survival and improved OS compared with biochemotherapy alone. In comparison to cutaneous melanoma with the common BRAF mutation, tyrosine kinase c-kit is overexpressed and frequently mutated in mucosal melanomas, as opposed to rare c-kit alterations in cutaneous melanomas. Emerging evidence indicates that melanomas with Kit activation may also respond to Kit inhibitors, such as imatinib. The role of these therapeutic agents in mucosal melanoma needs to be further investigated. 1,4,25 CONCLUSION The prognosis for SMM is poor, especially for those with distant metastasis or those who do not undergo surgery. The standard treatment for SMM continues to be primarily surgical. As a result of a low rate of cervical lymph node metastasis, neck dissection is usually reserved for patients with regional metastatic disease. 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