Demographics and Treatment Trends in Sinonasal Mucosal Melanoma

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1 The Laryngoscope VC 2011 The American Laryngological, Rhinological and Otological Society, Inc. Demographics and Treatment Trends in Sinonasal Mucosal Melanoma Thomas J. Gal, MD, MPH; Natalie Silver, MD, MS; Bin Huang, DrPH, MS Objectives/Hypothesis: To evaluate the population characteristics of mucosal melanoma of the nasal cavity and paranasal sinuses and determine the impact of the new staging classification. Study Design: Analysis of a national database. Methods: Patients were identified from the Surveillance, Epidemiology, and End Results tumor registry data with mucosal melanoma of the nasal cavity and paranasal sinuses between 2000 and Tumors were classified using the American Joint Committee on Cancer (AJCC) 6th edition site-specific staging as well as 7th edition staging for head and neck mucosal melanoma (HNMM). Incidence rates and descriptive statistics were calculated, and multivariate analysis was performed to examine the impact of demographic factors and staging on survival. Results: A total of 304 patients were identified. The incidence rate was 0.05 per 100,000. Fifty-six percent were female, 92% were >50 years old, and more than 90% were Caucasian; 81.6% of patients were treated with surgery, and 38.5% of patients received postoperative radiation. Overall, the 5-year survival rate was 24.2%. Significant differences in survival were observed for surgery with radiation (P ¼.005) and surgery alone (P ¼.04) compared with radiation alone. TNM staging using the AJCC 6th and 7th edition classification schemes yielded similar survival curves. However, the new classification for HNMM allows for better delineation of stage IV disease, revealing slightly improved survival for stage IVA disease. Conclusions: HNMM is a rare disease with a poor prognosis. Surgery remains the treatment of choice, with some role for adjuvant therapy. The new staging classification for HNMM appears to more efficiently stage this disease. Demographics and therapeutic findings are discussed. Key Words: Mucosal melanoma, nasal cavity, paranasal sinuses, staging, epidemiology, demographics. Level of Evidence: 2c. Laryngoscope, 121: , 2011 INTRODUCTION Mucosal melanoma is an exceedingly uncommon condition. 1 3 National Cancer Database statistics report that melanomas of mucosal origin comprise only 1.3% of all melanomas. 4 However, more than half of all mucosal melanomas arise in the head and neck region. The most common sites for the development of mucosal melanoma are the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma comprises roughly 4% of all head and neck melanomas and approximately 3.5% of all sinonasal malignancies. 1 Given the rarity of mucosal melanoma, much of the existing literature on mucosal melanoma of the head and neck relies on case reports and single-institution retrospective series. Frequently, cases from the oral cavity are combined with cases from the nasal cavity and paranasal sinuses to increase reported numbers. There is no evidence to suggest that the etiology and behavior of melanomas differ at these respective sites. 2,3,5 It is From the Division of Otolaryngology Head and Neck Surgery (T.J.G., N.S.); and Kentucky Cancer Registry (B.H.), University of Kentucky, Lexington, Kentucky, U.S.A.. Editor s Note: This Manuscript was accepted for publication May 2, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Thomas J. Gal, MD, MPH, Division of Otolaryngology, Department of Surgery, University of Kentucky Medical Center, 800 Rose St, Rm C236, Lexington, KY tjgal2@uky.edu DOI: /lary also uniformly accepted that surgery with clear margins is critical in the management of the disease. However, the ability to achieve clear margins surgically differs greatly between the oral cavity and paranasal sinuses, regardless of tumor type. The ability to discern survival differences across tumor sites therefore becomes difficult in smaller case series. Despite the rarity of mucosal melanoma, the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual contains an entirely new chapter focusing on the staging of mucosal melanoma of the head and neck. 6 The utility of this primarily arises from the difficulty of staging melanoma, essentially a cutaneous disease, using the classification schemes for mucosal head and neck cancer. The difficulty arises from the fact that the former is almost exclusively tumor thickness specific, and the latter is a combination of tumor size and tumor site. What is less clear is whether the changes in the classification of head and neck mucosal melanoma allow for the useful delineation of survival by staging group. The goal of this investigation was to determine whether the changes in staging of mucosal melanoma of the head and neck have resulted in a more effective means of profiling survival or simply a more efficient way to stage the disease. For the purposes of this investigation, we have limited our study to tumors of the nasal cavity and paranasal sinuses. Although the pathology of the tumor itself does not differ from those seen in the oral cavity, both the nature of the staging

2 classification as well as the technical considerations of surgery for tumors of the paranasal sinuses and skull base make for significant differences in the approach and management of the disease. In the study of uncommon disease, such as mucosal melanoma, data from the Surveillance, Epidemiology, and End Results (SEER) program have proven to be a useful tool. Using the SEER data, we have applied the current staging system (7th edition) to a retrospective cohort of patients and compared it to the classification derived from the 6th edition. 7 In addition, examination of this cohort will allow for the evaluation of the epidemiology of mucosal melanoma and the assessment of the overall frequency of the disease, demographics of the patient population, and survival across general treatment trends using a sizable database. MATERIALS AND METHODS A retrospective cohort study was performed using data from the SEER tumor registry, which includes 17 SEER registries and covers about 26% the U.S. population ( seer.cancer.gov/). Utilization of the deidentified data set does not require institutional review board approval. The public use database was used to extract index cases occurring between 2000 and Given a survival rate that was anticipated to be poor, cases prior to 2000 were not used in order to optimize available staging information. Data were extracted from the SEER database via the SEER*Stat software (version 6.4.3) registry using a series of codes for histologic tumor type, primary site, and extent of disease. Using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), the code 8720/3 was used to designate malignant melanoma. Site-specific coding was utilized to designate tumors specific to the sinonasal tract. To capture the greatest number of cases, site-specific codes for the maxillary sinus, ethmoid sinus, and accessory sinuses were used. Utilizing a combination of SEER extent of disease codes and SEER collaborative staging codes, tumors were staged according to AJCC stage based on the primary site of origin. Second primary tumors and patients with multiple tumors identified within the registry were excluded. Tumors determined to represent metastatic disease from a cutaneous primary site were also excluded. For comparison purposes, tumors were staged using both the 6th and 7th editions of the AJCC staging manual. The TNM classification from the 6th edition is summarized in Table I. The 7th edition staging is summarized in Table II. Changes in stage as a result of the classification changes are tabulated and discussed. Kaplan-Meier calculations with log rank test by stage for each system were performed. All data were extracted from the SEER*Stat software program, from which case level demographic data as well as data for survival analysis were obtained. Additional descriptive and multivariate Cox regression statistical analysis incorporating race, stage, sex, age at diagnosis, and treatment modality, as well as Kaplan-Meier statistics and log rank tests were performed using SAS (version 9.1; SAS Institute, Cary, NC). RESULTS A total of 304 patients with mucosal melanoma of the nasal cavity, nasopharynx, and paranasal sinuses between 2000 and 2007 were identified; 56.3% (n ¼ 133) were female, and the majority of patients (90.8%) were Caucasian. The overall incidence rate was 0.05 per 100,000. Mean age at diagnosis was 71.2 years. The nasal cavity was the most common tumor site of origin, representing 65.5% of cases, followed by the maxillary sinus (15.1%), the accessory sinus (10.5%), and ethmoid sinus (8.9%). A summary of patient demographics is listed in Table III. As seen in Table III, the majority of patients were more than 75 years old. A comparison of TNM staging for the 6th and 7th edition AJCC staging for mucosal melanoma of the paranasal sinuses is shown in Table IV. Specific differences in T, N, and M stage for the 6th and 7th editions are listed in Table V. Table VI demonstrates the distribution of regional and distant metastatic disease by T stage using the 7th edition staging classification. Of the 103 T3 tumors, 101 would have been staged as T1 tumors using the 6th edition. Of the 71 T4a tumors, 22 (30.9%) would have been staged as T2, 41 (57.7%) would have been T3, and 10 (14.1%) would have been staged as T4 tumors using the 6th edition classification. Of the 36 T4 tumors (6th edition), 26 (72.2%) were staged as T4b tumors using the 7th edition classification, and 10 would have been downstaged to T4a. The vast majority (n ¼ 205, 67.4%) of patients were N0. Of the 15 patients with Nþ disease, 13 were N1, two were N2, and none were N3 by 6th edition staging; 233 (76.6%) were M0, and 58 patients (19.1%) did not have sufficient data for staging. A total of 248 patients underwent surgery as part of the treatment regimen (81.6%), and 117 patients received postoperative radiation (38.5%), with three patients receiving radiation before surgery. Only 23 patients were treated with radiation alone (7.6%). Treatment distribution by TNM 7th edition stage is listed in Table VII. General observed trends suggest surgery, with or without postoperative radiation, as the primary treatment modality. Overall 5-year survival rate was 24.2%. Median survival for the cohort was 18 months. Kaplan-Meier survival curve for the entire cohort is seen in Figure 1. Survival by stage using the 6th and 7th AJCC staging editions is demonstrated in Figures 2 and 3, respectively. It appears that 6th edition stage I and II correspond relatively closely with 7th edition stage III disease. Although 6th edition stage II and IV disease appear to have poor survival that would seem to parallel 7th edition stage IVB and IVC disease, it would seem that a slightly better prognosis becomes apparent with 7th edition stage IVA disease (Fig. 3) (P ¼.0001). Survival by treatment is shown in Figure 4. A statistically significant increase in survival was observed with treatment with surgery in conjunction with radiation compared to radiation alone (P ¼.005). A statistically significant increase in survival was observed when comparing surgery alone to radiation alone (P ¼.04). However, no significant differences in survival were observed between treatment with surgery with or without radiation (P ¼.37). Multivariate analysis, however, demonstrated no significant associations between treatment and survival. TNM stage using either the 6th or 7th editions was significantly associated with survival (P ¼.001). Statistically significant differences in survival were also observed by T stage (P <.0001), N stage (P <.0001), and 2027

3 TABLE I. American Joint Committee on Cancer Staging Nasal Cavity and Paranasal Sinuses, 6th Edition. Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ Maxillary Sinus T1 Tumor limited to maxillary sinus mucosa with no erosion or destruction of bone T2 Tumor causing bone erosion or destruction including extension into hard palate and/or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates T3 Tumor invades any of the following: bone of the posterior wall of maxillary sinus, subcutaneous tissues, floor or medial wall of orbit, pterygoid fossa, ethmoid sinuses T4a Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid or frontal sinuses T4b Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx, or clivus Nasal cavity and ethmoid sinus T1 Tumor restricted to any one subsite, with or without bony invasion T2 Tumor involving two subsites in a single region or extending to involve an adjacent region within the nasoethmoidal complex, with or without bony invasion T3 Tumor extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate T4a Tumor invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid or frontal sinuses T4b Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than V2, nasopharynx, or clivus Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastasis in a single, ipsilateral lymph node, 3 cm in greatest dimension N2 N2a Metastasis in a single, ipsilateral lymph node, >3 cm and <6 cm N2b Metastasis in multiple ipsilateral lymph nodes, none >6 cm N2c Metastasis in bilateral or contralateral lymph nodes, none >6 cm N3 Metastasis in a lymph node >6 cm Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Staging Stage 0 Tis, N0, M0 Stage I T1, N0, M0 Stage II T2, N0, M0 Stage III T3, N0, M0 T1 T2, N1, M0 Stage IVA T4a, N0/N1, M0 T1 T4a, N2, M0 Stage IVB T4b, any N, M0 Any T, N3, M0 Stage IVC Any T, Any N, M1 M stage (P <.0001), respectively. Age at diagnosis was also significantly associated with survival, with a 20% increased risk of death per 10 years of age (P ¼.02). Race and sex were not significantly associated with survival. DISCUSSION Because of the rarity of mucosal melanoma, most of the data on this disease are derived from published case series. To generate reasonable numbers for analysis, 2028

4 TABLE II. American Joint Committee on Cancer Staging Mucosal Melanoma of the Head and Neck, 7th Edition. Primary tumor (T) T3 Mucosal disease T4a Moderately advanced disease; tumor involving deep soft tissue, cartilage, bone, or overlying skin T4b Very advanced disease; tumor involving brain, dura, skull base, lower cranial nerves (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 metastases N1 Regional lymph node metastases present Distant metastasis (M) M0 No distant metastasis M1 Distant metastasis present Staging Stage III T3, N0, M0 Stage IVA T4a, N0, M0 T3 T4a, N1, M0 Stage IVB T4B, any N, M0 Stage IVC Any T, any N, M1 most published series include mucosal melanoma from any and all sites within the head and neck. The use of SEER data allows one to focus specifically on tumors of the nasal cavity and paranasal sinuses. Although the biologic behavior of melanoma is unlikely to be different from that of tumors occurring in other mucosal sites within the head and neck, the unique anatomic considerations of this area as it relates to a disease that is best treated surgically merits further study. As these data are derived from population-based data, incidence rates can be determined. The incidence rate for mucosal melanoma is 0.05 per 100,000 population. These are rare tumors with incidence rates comparable to those of other rare nasal cavity tumors such as esthesioneuroblastoma or sinonasal undifferentiated carcinoma. 8 Overall, rates for cutaneous melanoma approach 16 per 100,000. In comparison, oral cavity squamous cell carcinoma has an incidence rate of 11.3 per 100,000, and breast cancer has a rate of 122 per 100, Mucosal melanoma is thought to be a disease occurring in the fifth to eighth decade of life. In this cohort, 92.1% of patients diagnosed were older than 50 years; 90.8% of patients were Caucasian. We observed a slightly higher proportion of females (56%) in this cohort. Unlike age and race, it would appear that sex is less significant with regard to the development of the disease. Tumor stage has no impact on the overall poor prognosis of this disease. Regardless of staging system utilized, overall 5-year survival was 24.2%. For early stage disease, 5-year survival is around 40%. The question is whether the AJCC 7th edition classification scheme for mucosal melanoma of the head and neck provides any advantage to previous classification methods. Clearly the new classification provides a more efficient means of staging the disease. It is not as heavily dependent on site-specific data that are required for classification of other tumors of the nasal cavity and paranasal sinuses. It respects the oncologic premise that the behavior of mucosal melanoma, unlike other tumors of the nasal cavity and paranasal sinuses, behaves the same regardless of the site of origin. For example, a squamous cell carcinoma of the maxillary sinus that invades the palate is relatively resectable with a TABLE III. Patient Demographics for Mucosal Melanoma of the Head and Neck. Characteristic No. % Sex Male Female Race White Black American Indian/Alaska Native Asian or Pacific Islander Age, yr þ Site Nasal cavity Maxillary sinus Ethmoid sinus Accessory sinuses

5 TABLE IV. TNM Stage as Staged by American Joint Committee on Cancer 6th Edition for Paranasal Sinuses Compared With 7th Edition for Mucosal Melanoma of the Head and Neck. TNM Stage 6th Edition vs. TNM Stage 7th Edition Stage 7th Edition Stage III Stage IVA Stage IVB Stage IVC Unknown/NA Stage 6th Edition No. % No. % No. % No. % No. % Stage I Stage II Stage III Stage IV Unknown NA ¼ not applicable. maxillectomy and would be staged as a T2 lesion. The prognosis of a comparable mucosal melanoma with this degree of invasion carries a much different prognosis and would be staged as a T4a tumor. In this regard, in simple terms the new classification for mucosal melanoma of the head and neck is similar to staging of cutaneous melanoma, where extent or depth of invasion is more important than invasion of anatomically specific sites. The most obvious difference with the AJCC 7th edition staging of mucosal melanoma of the head and neck is that there is no stage I or II. Using this cohort, the vast majority of tumors that would presently be classified as stage III disease would have been classified as stage I disease using the AJCC 6th edition staging system (Table IV). A total of 85.7% of stage II tumors using the 6th edition were upstaged to stage IVA using TABLE V. Changes in T, N, and M Stage From the American Joint Committee on Cancer 6th Edition Staging of Paranasal Sinus Tumors to the 7th Edition Staging of Mucosal Melanoma of the Head and Neck. 6th Edition 7th Edition Stage No. % No. (%) TX T T T T T4a T4b NX N N N n/a 0 N3 0 0 n/a 0 MX M M the 7th edition. All tumors classified as stage III using the 6th edition were similarly upstaged to stage IVA in the 7th edition staging for mucosal melanoma. Another significant change is that nodal disease for mucosal melanoma of the head and neck is no longer classified using the relatively standard classification of regional lymph node metastases for head and neck cancer. All patients with nodal disease are automatically stage IV disease. In this cohort, the majority of patients (67.4%) were N0. Only two patients had N2 disease of any stage, and there were no N3 tumors. It would appear from this cohort that the presence of regional lymphatic metastases is uncommon and would appear to have little impact on survival. Previous reports have stated that lymph node metastases were present in less than 6% of reported cases of sinonasal melanoma. 9 It is important to note that 84 patients, or 27.6%, did not have sufficient information available within the SEER database to sufficiently stage the neck. In terms of prognostic significance, comparison of survival curves using staging classification from the 6th and 7th edition yields similar results (Fig. 2 and Fig. 3). It would appear that 6th edition stage I and II tumors roughly parallel 7th edition stage III disease. Similarly, 6th edition stage III and IV tumors have similarly poor survival compared to 7th edition stage IVB and IVC. It does appear in Figure 3 that a slightly improved survival profile is demonstrated for stage IVA tumors compared to more advanced tumors. Thus the new 7th edition staging system may allow for a more accurate delineation of advanced disease. TABLE VI. Distribution of N and M Stage by T Stage Using the 7th Edition American Joint Committee on Cancer for Mucosal Melanoma of the Head and Neck. T Stage N0 N1 Unknown M0 M1 Unknown Total T T4a T4b Unknown Total

6 TABLE VII. Treatment by 7th Edition TNM Stage. Stage III Stage IVA Stage IVB Stage IVC Unknown/NA Treatment No. % No. % No. % No. % No. % Surgery only Radiation only Surgery and radiation Unknown/refused Total A total of 65.5% of patients presented with tumors of the nasal cavity. The duration of symptoms and symptoms at presentation of sinonasal mucosal melanoma depend on the primary location of the lesion. 1 Patients with mucosal melanoma in the nasal cavity often present with epistaxis and nasal obstruction and may have unilateral polyposis. Melanomas of the nasal cavity are more likely to be diagnosed with clinically localized disease, and melanomas in the paranasal sinuses are usually diagnosed at a more advanced stage. Loree et al. found that survival was also affected by the site of the tumor, with the best 5- year survival rate for tumors in the nasal cavity compared to paranasal sinus and oral cavity. 10 Overall, 5-year survival in this cohort was 24.2%. This is consistent with published data, where survival rates do not exceed 33% in any series. 10 Significant associations were observed with TNM stage, as well as T, N, and M stages independently. Age at diagnosis, however, was also significantly associated with survival, with a 28% increased risk in death per 10 years of age. Given the more elderly population at risk for this disease, this may have as much to do with the patient s overall health and functional status as with the disease itself. Race and sex were not associated with survival. Because of the rarity of sinonasal mucosal melanoma, poor prognosis, and reliance on retrospective series reviews, there is no consensus on best treatment. Primary surgical resection of tumor with clear margins appears to be the treatment of choice with or without postoperative radiation treatment. 5 Most of patients in this cohort were treated with surgery as part of the treatment regimen (80.7%, n ¼ 171). Of those patients receiving surgery as part or all of their treatment, the majority underwent surgery only (n ¼ 92 patients). The extent and type of surgery for sinonasal mucosal melanoma naturally depends on the location and extent of the tumor. Given the complex anatomy of the nasal cavity and paranasal sinuses, complete resection of the primary tumor or resection with wide margins is not always possible. Unfortunately, the SEER database contains no information on surgical approach or margin status. The role of radiotherapy in the management of mucosal melanoma is unclear. 11 Prior reports have shown that there is no statistical difference in local control or survival between patients with sinonasal mucosal melanoma receiving surgery alone and those receiving surgery and radiotherapy. Temam et al. demonstrated that postoperative radiotherapy increases the rate of local control in mucosal melanoma of the head and neck. 9 Owens et al. also found that the addition of radiotherapy to surgical treatment leads to better locoregional control. 12 However, in both studies, improved locoregional control did not affect overall survival rates. Fig. 1. Overall survival for mucosal melanoma of the nasal cavity and paranasal sinuses. Fig. 2. Survival by stage for mucosal melanoma using the American Joint Committee on Cancer 6th edition classification for tumors of the nasal cavity and paranasal sinuses. 2031

7 Fig. 3. Survival by stage using the American Joint Committee on Cancer 7th edition classification for mucosal melanoma of the head and neck. All tumors arise in the nasal cavity and paranasal sinuses. In this study, 117 patients (38.5%) received postoperative radiation. A statistically significant increase in survival was observed for surgical treatment with postoperative radiation when compared to radiation alone. However, patients treated nonoperatively tended to have advanced, inoperable disease or were unable to tolerate surgery for other medical reasons. Thus, this observation may be the result of differences in primary tumor stage or patient functional status and not a function of the therapy itself. Only 23 patients (7.6%) were treated with radiation alone. A trend toward increased survival with surgery alone compared with radiation alone was also observed but was not statistically significant. Again, it is likely that this observation results from the fact that more advanced tumors were more likely to be treated with primary radiotherapy. Multivariate analysis, which adjusted for age and tumor stage, demonstrated no significant associations between treatment and survival. However, what is most important to note is that no survival differences were observed for surgery alone compared with surgery with postoperative radiotherapy. This suggests, as has been reported historically, mucosal melanoma is primarily a surgical disease. One of the major shortcomings of the SEER database is the lack of data on the use of chemotherapy. The role of chemotherapy in the management of mucosal melanoma is considered to be limited. Under most circumstances, it is considered to be palliative at best. There is some evidence to suggest prolonged survival with the addition of chemotherapy. Therapy may include dacarbazine, platinum analogues, nitrosureas, and microtubular toxins. 13 There is limited evidence to suggest that dacarbazine in combination with either tamoxifen or interferon-alpha 2 was more beneficial than dacarbazine alone. 14 Similarly, there is some promise in the use of taxols. 15 However, given the overall limited utility of chemotherapy in the management of the disease, the impact on this cohort is expected to be limited. Although SEER data do not allow for the evaluation of surgical approaches or surgical results, the data do allow for the compilation of the most extensive evaluation of the demographics of the disease and analysis of outcomes available. The efficacy of specific surgical approaches cannot be derived from these sorts of data. It can be inferred, however, that the best possible surgical margins were obtained through the most optimal approaches necessary. Radiation and even chemotherapy were used under conditions that were determined to be in the best interest of the patients in this cohort, given both the state of their disease and their coexisting morbidities. Under these conditions, it remains clear that mucosal melanoma of the nasal cavity and paranasal sinuses remains an infrequent but serious disease with a grave prognosis. Surgery, as deemed indicated, preferably with clear margins, remains the mainstay of therapy. Cases where radiation is indicated demonstrate unfavorable outcomes, regardless of therapy, compared to surgery alone. CONCLUSION Mucosal melanoma of the nasal cavity and paranasal sinuses remains a rare neoplasm of the head and neck, based on population-based estimates. Survival, regardless of therapy, remains poor. The new staging system for mucosal melanoma of the head and neck appears to be a more efficient means to classify the disease, with slightly increased precision in the staging of advanced tumors with regard to survival. Surgery remains the mainstay of therapy, with clear margins when possible. Given the challenges of complete extirpation in this anatomic region, little benefit is achieved with the addition of radiotherapy. Fig. 4. Survival by treatment for mucosal melanoma of the nasal cavity and paranasal sinuses BIBLIOGRAPHY 1. Conley JJ. Melanomas of the mucous membrane of the head and neck. Laryngoscope 1989;99: Panje WR, Moran WJ. Melanoma of the upper aerodigestive tract: a review of 21 cases. Head Neck Surg 1986;8:

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