Impact of different surgical and postoperative adjuvant treatment modalities on survival of sinonasal malignant melanoma

In general, there were 69 patients included (37 males and 32 females) in the study, and the mean age at diagnosis was 65.9 years (age ranging from 28–89 years). The two most common chief complaints at presentation were epistaxis in 43 cases (62%) and nasal obstruction in 23 cases (33%). Other symptom such as epiphora, noticeable mass and nasal dryness, each was found in 1 case. The mean duration of symptoms before diagnosis was 5 months (ranging from 0.5-60 months).The most common sites of tumor invasion is in the nasal cavity while the maxillary sinus is most common paranasal sinus invaded. Detailed information about predominant sites of tumor invasion is graphed in Figure 1.

According to AJCC cancer staging system, T classification was as follows: T3 37 cases (54%), T4a 27 cases (39%), T4b 5 cases (7%). Only 1 case suffered regional lymph node invasion at diagnosis. There were no cases associated with distant metastasis at diagnosis. Thus, 37 cases were classified as stage III, 27 as IVa, 5 as IVb. Clinical characteristics of 69 cases of sinonasal malignant melanoma are presented in Table 1.

Surgical approaches involved lateral rhinotomy, Caldwell-Luc, transpalatal, midfacial degloving procedure, and endoscopic approach. Forty one and 28 cases underwent open and endoscopic approaches, respectively. One patient underwent neck dissection because regional lymph nodal metastasis was identified. Surgical approach distribution per year was listed in Figure 2. Thirty percent of cases needed multiple surgeries during their course of disease, with a mean of 1.6 times (ranging from 1–7 times). Twenty seven patients required surgical treatments alone, 24 patients accepted postoperative radiotherapy, and 18 patients accepted triple treatment of surgery, radiotherapy plus chemotherapy. Commonly, patients were not positioned for adjuvant therapy because they either refused, were intolerant to adjuvant therapy or were considered to have a complete tumor resection based on the surgeon's assessment. Clinical data was summarized in Tables 2 and 3 for different surgical and adjuvant treatment modalities and approaches. Statistical difference was not found in age, gender or staging among different surgical treatment modalities and approaches except the gender between groups of surgery alone and surgery plus radiotherapy, more male patients underwent postoperative radiation treatment than female patients.The cut-off date for follow-up was December 31st, 2012. By that time, 53 patients had died and 16 patients had survived for their last follow-up. Seven patients had died of unassociated conditions, such as heart and liver diseases. The mean follow-up time was 34 months (ranging from 1–144 months). Generally, 42% patients (n = 29) were certain to develop local recurrence, 17% (n = 12) and 41% (n = 28) for nodal recurrence and distant metastasis, respectively. The median overall survival time of all patients was 24 months (standard error (SE) = 2.373, 95% confidence interval (CI) = 19.349-28.651). The estimated 3 and 5 year overall survival rates for all patients were 35.8% and 21.8%, respectively, as depicted in Figure 3. The median overall survival time was 24 months (SE = 4.204, CI = 15.760-32.240) for male patients; and 24 months (SE 6.364, CI = 11.527-36.473) for female patients. There was no statistical significance reached between genders (P = 0.706).The median overall survival time was 18 months (SE = 3.894, CI = 10.367-25.633) for surgery alone, 32 months (SE = 8.124, CI = 16.077-47.923) for surgery plus radiotherapy, and 42 months (SE = 14.749, CI = 13.092-70.908) for surgery, radiotherapy plus chemotherapy. The 3 and 5 year overall survival rates for the groups mentioned above were 14.8% and 5.6%, 45.1% and 31.6%, 55% and 32.1%, respectively. Significance was found not only between surgery alone vs. surgery plus radiotherapy treatment modality (P = 0.012), but also surgery alone vs. surgery, radiotherapy plus chemotherapy modality (P = 0.002). There was no statistical difference between groups of surgery plus radiotherapy and surgery, radiotherapy plus chemotherapy (P = 0.601). Associated survival was graphed in Figure 4.

The median cause-specific survival time was 21 months (SE = 3.450, CI = 14.238-27.762) for surgery alone, 35 months (SE = 10.055, CI = 15.291-54.709) for surgery plus radiotherapy, and 42 months (SE = 14.749, CI = 13.092-70.908) for surgery, radiotherapy plus chemotherapy. The same statistical significance was found as the overall survival comparison among these groups: (sa vs. sr, P = 0.041; sa vs. src P = 0.011; sr vs. src, P = 0.593).The estimated 3 year local control rate was 25.3% for surgery alone, 48.7% for surgery plus radiotherapy, and 42.9% for surgery, radiotherapy plus chemotherapy. The estimated 3 year nodal control rate was 51% for surgery alone, 71.6% surgery plus radiotherapy, and 56.3% for surgery, radiotherapy plus chemotherapy. The estimated 3 year distant metastasis-free rate was 38.6%, 53.6% and 55% for groups mentioned above respectively. The median disease-free survival time was 11 months (SE = 2.077, CI = 6.929-15.071) for surgery alone, 16 months (SE = 4.882, CI = 6.431-25.569) for surgery plus radiotherapy, and 16 months (SE = 2.121, CI = 11.842-20.158) for surgery, radiotherapy plus chemotherapy. There was no statistical significance reached for above survival comparisons among these groups. In regards to different surgical approaches, median overall survival time was 24 months (SE = 2.554, CI = 18.993-29.007) for open approach and 27 months (SE = 5.170, CI = 16.866-37.134) for endoscopic approach. The 3 and 5 year overall survival rate were 36.6% and 20.9% vs. 34% and 23.8% for each group mentioned above respectively. There was no survival statistical difference between the two groups (P = 0.687). Associated survival was graphed in Figure 5.

The median cause-specific survival time was 25 months (SE = 8.147, CI = 9.031-40.969) for open approach and 27 months (SE = 4.712, CI = 17.764-36.236) for endoscopic approach. The median disease-free survival time was 14 months (SE = 2.680, CI = 8.748-19.252) for open approach and 15 months (SE = 2.639, CI = 9.828-20.172) for endoscopic approach. There was no statistical significance reached for cause-specific survival (P = 0.989) and disease-free survival (P = 0.899) comparion between these two groups.

From our study, we found that the 3 and 5 year overall survival rates of all patients were 35.8% and 21.8% respectively. This is similar to most other studies [6, 13‐18]. Poor prognosis may be due to the frequent recurrence and distant metastasis at an early stage, despite radical surgeries performed. It was reported that the postoperative time for local recurrence presentation was 19.8 months and even 12.3 months for distant metastasis [19]. The local recurrence and distant metastasis rate was 31-85% and 25-50%, respectively [20‐23]. In our cohort, 42% patients were certain to develop local recurrence, 17% and 41% for nodal recurrence and distant metastasis, respectively. Though surgical resection is considered the mainstay therapy, tumor resections with clear negative surgical margins were frequently impossible due to the anatomical complexity and the adjacent vital structures of the sinonasal region. Thus, adjuvant therapy was frequently given following surgery. In localized patients, surgery alone or surgery in combination with radiotherapy has been advocated as definitive therapy. Despite the fact that malignant melanoma is considered as radioresistant, radiation therapy would be planed if complete surgical excision is not possible due to the extent of disease at presentation [2, 24].

The role of adjuvant therapy like radiotherapy and chemotherapy is still controversial. Gore did a meta-analysis on the survival of sinonasal melanoma, and demonstrated that multimodality therapy, particularly the addition of chemotherapy or immunotherapy to surgery, might increase survival in a subset of patients; while radiation therapy did not appear to increase survival. There may be a significant increase in the overall survival rate with combined modality therapy including surgery and chemotherapy or immunotherapy versus single modality therapy [9]. Kanetaka found immunotherapy using LAK cell treatment may contribute to the improvement of the prognosis in patients with malignant melanoma in the head and neck [25].

Kingdom and Kaplan reported patients who received postoperative radiotherapy appeared to have an increase in disease-free intervals and prolonged survival [26]. Evidences have also shown that radiotherapy could improve local control [7, 8, 18], but had no effect on overall survival, while others found little effect from postoperative radiotherapy [6, 9, 11, 20, 27]. Given the rarity and poor prognosis of SMM, radiotherapy groups in most studies involved patients who had extensive and unresectable tumors and were at more advanced stages. The unfavorable results of combined surgery and radiotherapy regimen might be related to much earlier distant metastasis and thus more advanced staged patients in postoperative radiotherapy groups.

We intended to analyze the impact of different surgical and postoperative adjuvant therapeutic modalities on survival, therefore all patients in our study were selected from surgical treatment pool and inoperable cases had been excluded. In our series, we did not find any statistical difference in age or stage among different surgical treatment modalities selected. Those patients who underwent radiotherapy or radiotherapy plus chemotherapy after surgery had better overall and cause-specific survival outcomes than those who accepted surgical treatment alone. There was no statistical difference between the former two modalities. In our cohort, patients who underwent radiotherapy or radiotherapy plus chemotherapy after surgery were also found to have a better local (nodal) control rate as well as a distant metastasis free rate, than those accepted surgical treatment alone. Although comparison regarding local (nodal) control status as well as distant metastasis free status among groups above did not revealed any statistical significance, adjuvant therapy is necessary to achieve maximal tumor eradication, because often the complete tumor resection with clear margin is unobtainable. Reports have shown that despite adequate local control, there were patients who still suffered frequent distant metastasis. Sinonasal melanoma is difficult to control as distant spread is likely to occur even in the presence of mainstay locoregional control [9]. Thus, future, more rigous, multi-center studies should be performed to further investigate the effect of combined therapeutic strategies against this aggressive malignancy.

The optimal therapeutic results can be achieved with radical tumor resection with wide negative margins. Complete resection requires the inclusion of at least 1.5 cm of normal tissue margins, as well as cervical lymph node dissections [3].

With the assistance of nasal endoscopy, better surgical optical visualizations were obtained than an open approach and in many cases the open surgical approach can be replaced by the endoscopic one. The endoscopic approach allows for intraoperative navigation to determine the border and resection margins of tumor. Doppler ultrasound is also a useful technology to ascertain the location of the internal carotid artery in order to avoid disastrous complications. Suh et al. reported fewer major surgical and medical complications in endoscopic resection of sinonasal malignancies vs. open approaches [11]. Moreno et al. found a higher rate of survival for patients who underwent endoscopic tumor surgeries, which might reflect a selection bias as this approach was more commonly used for lesser volume and more localized disease [19]. Vandenhende et al. found no difference in local control of T4 maligant lesions, comparing external versus endoscopic approaches [20]. We also compared open and endoscopic approach for treatment of SMM, and endoscopic approach had similar survival status as open approach which is in accordance with most other studies, without any statistical difference between two groups. Endoscopic tumor resection has many advantages such as minimally invasiveness, direct tumor exposure, more optimal post-operative cosmetic appearance, fewer complications and shorter hospital stays [11, 12]. When prudently selected, endoscopic approach might be the first choice for SMM surgery.

Like many others in the literature on SMM, our study is also a retrospective study which would make the results less valuable comparing to those randomized prospective controlled trials. Also due to the retrospective nature, we were not able to acquire the quality of life data (before and after surgery) from patients, which may be meaningful to reflect the potential advantage of endoscopic approach over open ones. Furthermore, we were not able to retrieve complete pathological information about surgical margins. Thus, it was difficult to analyze the impact of surgical margins on prognosis. Data from a single center may contain selection bias on its acceptance criteria for surgical and adjuvant treatment. Further multi-center or even population-based series would be the better model for studies of rare malignant tumors such as sinonasal malignant melanoma.