Mucosal melanoma of head and neck (MMHN) is an extremely rare disease entity, accounting for 1% to 3% of all malignant melanoma diagnoses and almost 6% of head and neck melanomas [1,2]. Common sites of involvement in the head and neck are the nasal cavity and the paranasal sinuses, accounting for up to 72% of patients [3,4]. Nonspecific symptoms and complex anatomic structures of the head and neck often delay early diagnosis of MMHN. Furthermore, due to high incidence of local recurrence and distant metastasis, MMHN is well known for poor prognosis with the 5-year overall survival (OS) ranging from 15% to 35% [5]. Although definitive guidelines for optimal management have not been established, proper surgical resection with a clear margin is accepted as the mainstay of treatment in operable MMHN [6,7].

Besides the recent revision of MMHN cancer staging in the 7th edition of the American Joint Committee on Cancer (AJCC) cancer staging manual, debatable issues regarding standard, oncologic care have been observed in localized MMHN, recently [8]. First, in light of advancements in optic technology, the incidence of endoscopic or endoscopy-assisted surgery, especially for sinonasal disease, is on the increase to ensure more precise resection as well as better cosmetic outcomes, compared to external approaches [4,8,9]. Second, the role of postsurgical, adjuvant treatment, such as postoperative radiotherapy (PORT) or systemic therapy, has been still controversial due to contradicting reports [1,10,11].

The purpose of this study is to investigate the prognostic impact of different, surgical approaches (external vs. endoscopic) and postoperative, adjuvant treatments (PORT and/or systemic therapy) on oncological outcomes, measured as treatment failure patterns, disease-free survival (DFS), and disease-specific survival (DSS) in patients with stage III/IVA MMHN, who underwent surgery-based treatment with curative intent.

Median age was 56.0 years old (interquartile range, 50.0 to 71.0 years old) and sex distribution (male:female) was 18:13. The most common primary site was sinonasal (81%, 25/31), followed by oral cavity (16%) and oropharyngeal (3%). No patient showed nodal disease at initial presentation, 77% of patients (24/31) were classified as T3N0 (stage III), and the remaining patients (7/31) were classified as T4aN0 (stage IVA). Sixteen patients (15 T3 and 1 T4a) were treated with the endoscopic approach only, and the other 15 patients (9 T3 and 6 T4a) received the external approach for curative surgery. As expected, the external approach was preferred for patients with stage IVA (6/7, 86%), compared to patients with stage III (9/24, 38%) with a statistical difference (P=0.03). By subgroup analyses according to the surgical approach, mean age, sex distribution, and primary sites were balanced between the two groups. Regardless of the surgical approach, operation followed by PORT was the treatment of choice for our cohort (42%). The number of patients treated with operation alone and with operation followed by systemic therapy only (chemotherapeutic agents or high-dose interferon) was similar (29% and 23%, respectively). With a median follow-up of 9.0 months, 45% of patients remained free of disease, 34% of patients died of disease, and 10% of patients were still alive with disease.

The present study aimed to investigate the impact of the surgical approach and adjuvant treatment modalities on oncologic outcomes in operable, stage III/IVA MMHN.

Because MMHN is known to aggressively invade adjacent tissue and occur frequently with skipped lesions, it is necessary to obtain wide surgical resection with clear margin, which is shown to be an important prognostic factor [12,13]. However, complex anatomic structures such as the nasal cavity and the paranasal sinuses, sites commonly involved in MMHN, could impede meticulous resection of tumor even with open, external approaches (eq., maxillectomy), often resulting in unsatisfactory aesthetic appearance and three dimensional defects, requiring reconstruction. That is why the endoscopic technique has been gaining popularity for dealing with various tumors in the sinonasal region with acceptable outcomes [12]. Among the sparse clinical studies conducted on endoscopic surgery for MMHN, it was reported that endoscopically resected patients (27%, 31 out of 115 with sinonasal malignant melanoma) had a significant OS advantage for up to 5 years (endoscopic 45.6% vs. open minor 24% vs. open major 10%) [3]. The results suggested that endoscopic techniques may be employed with at least similar outcomes and minimal morbidity. Another study involving large case series of sinonasal malignant melanoma demonstrated that among 70 out of 133 patients that underwent endoscopic or endoscopy-assisted surgery, 37.1% experienced recurrences, which was significantly lower than patients treated with the external approach only [4]. Also, it was shown that the endoscopic approach was associated with better survival, compared to the external approach group with statistical significance (HR, 1.702). The present study is different from previous reports in that pure endoscopic surgery, not endoscopy-assisted surgery, was performed to resect MMHN in all 16 cases, and clear information on the AJCC stage was described to avoid potential bias from a preference for endoscopic techniques in the early stages of cancer. Notably, the endoscopic approach was adopted more frequently in stage III (15/24, 62.5%), than in stage IVA (1/7, 14.2%). It is also interesting that endoscopic approaches replaced open approaches in the latter series of our cohort (13/16, 81.2% performed after the year 2012), reflecting the trend toward minimally invasive techniques.

Although the present study is consistent with previous reports in that the endoscopic approach was sufficient to provide adequate resection margins as well as minimal aesthetic morbidity, clear margins could not be obtained in 2 cases with endoscopic approaches. In one case, the melanoma lesion directly invaded the Eustachian tube, and complete resection was not feasible even under endoscopic view. In the other case of sinonasal melanoma, clear margin was obtained in frozen pathology during surgery, but melanocytic nests were revealed in permanent pathology.

Recurrence control rates in the present study showed similarities to previous studies, in which 5-year local control rates ranged from 40% to 79% (present study, 43%), regional control rates ranged from 71% to 83% (84%), and distant metastasis control rates ranged from 17% to 49% (59%) [6,14-18]. Five-year DFS and OS were also in close agreement with previous reports, where DFS ranged from 4% to 40% (present study, 25%), and OS ranged from 20% to 48% (48%). However, it is not in accord with previous reports in that endoscopic approaches were not associated with better recurrence rates or survival gain, when the stage and other variables were adjusted by the Cox proportional hazard model in our study. Compared with other studies, there was no difference in the prognosis of MMHN (recurrence rate and survival rate) [9,19,20].

The role of adjuvant treatment needs to be determined to improve the oncologic outcomes of MMHN. It has been shown by recent meta-analysis that postoperative radiotherapy improves loco-regional recurrence of MMHN (HR, 0.36; 95% CI, 0.22 to 0.60; P=0.000), independent of OS [11]. The present study coincided with previous study in that PORT showed a significant association with reduced risk of local recurrence compared to no adjuvant treatment (HR, 0.02; P=0.02). Interestingly, the preventive impact of PORT for local control was evident in stage III patients, not stage IV, as patients with PORT showed better local recurrence-free survival than patients without PORT in stage III by the log-rank test. However, PORT did not show any association with survival benefits in this study, as with other reports [1,10,11].

After recurrence, salvage was successful only in patients with local recurrence treated by reoperation followed by PORT, giving a total salvage success rate of 2% (4/19) in this study. Contrary to patients with local recurrence, every regionally recurred case (n=4) failed to be salvaged, which could be attributable partly to the patients’ refusal to accept further treatments (2/4), and more importantly, to combined sites of recurrences (local or distant sites). It is also disappointing that the initial stage for all salvaged patients was confined to stage III, and that distant metastasis was the most common pattern of failure in stage IVA patients, which could not be salvaged by any form of treatment in our cohort. Among patients with systemic therapy (n=9), high-dose interferon was the most preferred regimen combined with or without PORT, except for 1 case treated with a chemotherapeutic agent in the present study (8/9, 89%; 3 cases in stage III and 5 cases in stage IVA). During follow-up, loco-regional recurrence developed in 4 cases (3 local and 1 regional), all of whom did not take PORT, and distant metastasis occurred in 1 case. Although it is well known that efficient control of hematogenous spread in MMHN is critical to improve the high rates of distant failures, the application of systemic therapy did not show any efficacy in preventing failure of any type in this study. Therefore, outcomes with novel systemic therapies, such as tyrosine-kinase inhibitor or immunotherapeutic agents, need to be investigated in the form of multicenter, prospective studies [21,22].

Major limitations of the present study are (1) the retrospective nature of the study in a single institute and (2) the small number of enrolled patients. These problems may stem from the rarity of the disease, requiring a long period to accumulate a sufficient number of cases. It is appreciable that the period for the present study (from 1999 to 2015) was relatively shorter than for previous studies, supporting the idea that the treatment protocols and related outcomes of the current study are less likely to be biased by different phases of study [6,20,23].

In conclusion, adequate surgical resection must be implemented either with the open or endoscopic approach and combined to obtain wide and clear surgical margins in operable MMHN. PORT, also, should be incorporated with postsurgical, adjuvant modality because it has been proven to be effective in reducing the risk of local and/or loco-regional recurrences. Systemic therapy requires further investigations and trials to improve survival in MMHN.