Sinonasal mucosal melanomas: The prognostic value of tumor classifications

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1 ORIGINAL ARTICLE Sinonasal mucosal melanomas: The prognostic value of tumor classifications Justin Michel, MD, MSc, 1 * Audrey Perret Court, MD, 2 Nicolas Fakhry, MD, PhD, 1 David Braustein, MD, 3 Sandrine Monestier, MD, 2 Marie-Aleth Richard, MD, PhD, 2 Jean-Jacques Grob, MD, PhD, 2 Antoine Giovanni, MD, PhD, 1 Patrick Dessi, MD, MSc 1 1 Department of Otorhinolaryngology Head and Neck Surgery, La Timone Universitary Hospital Center, Aix-Marseille University, 264 rue St. Pierre, 13385, Marseille cedex, France, 2 Department of Dermatology, La Timone Universitary Hospital Center, Aix-Marseille University, 264 rue St. Pierre, 13385, Marseille cedex, France, 3 Department of Public Health and Medical Information, La Timone Universitary Hospital Center, Aix-Marseille University, 264 rue St. Pierre, 13385, Marseille cedex, France. Accepted 29 January 2013 Published online 1 June 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. The purpose of this study was to assess the prognostic value of the 3 staging systems found in the literature for sinonasal mucosal melanomas tumors: the Ballantyne staging system modified by Prasad (Ballantyne/Prasad staging system), the American Joint Committee on Cancer (AJCC) TNM classification for mucosal melanomas (mmtnm), and the 2009 AJCC TNM classification for carcinomas of the nasal cavity and sinuses (cartnm). Methods. A retrospective study of 35 patients treated between 1995 and 2010 was conducted for this study. Each patient was retrospectively staged using the Ballantyne/Prasad staging system, mmtnm, and cartnm. Results. There were 20 women (57.1%) and 15 men (42.9%). Only cartnm was significantly correlated with overall survival (p ¼.012) and disease-free survival (p ¼.041). The other 2 classifications were not correlated with survival except for metastatic patients whose overall survival was lower (p ¼.032). Conclusion. On the basis of these findings, we believe that cartnm should be the primary staging system for patients with mucosal melanomas of the sinonasal tract. VC 2013 Wiley Periodicals, Inc. Head Neck 36: , 2014 KEY WORDS: sinonasal cancer, staging system, melanoma, survival, TNM INTRODUCTION Sinonasal mucosal melanomas are rare tumors that represent less than 1% of all melanomas and about 5% of nasal cavity tumors. 1 Despite limited tumor extension at diagnosis, published studies report rates of overall survival at 5 years between 0 and 55%. 2,3 The high frequency of recurrence and metastatic dissemination explains these very low survival rates. The prognostic factors for cutaneous melanoma, such as the Breslow score or the Clark index, are of no value in mucosal melanomas. 4 Tumor staging for sinonasal mucosal melanoma remains problematic. The Ballantyne staging system, the most commonly used, distinguishes 3 stages depending on the local, regional, or disseminated nature of the disease. 5 However, it takes into account neither the depth of invasion nor local extension. 6 This staging system was modified in 2004 by Prasad who proposed microstaging of stage I into 3 levels depending on the degree of tumor *Corresponding author: J. Michel, Department of Otolaryngology Head and Neck Surgery, La Timone Universitary Hospital Center, Aix-Marseille Univ, 264, rue St-Pierre, Marseille cedex, France. justin.michel@ap-hm.fr This work was presented at the 1st Congress of the European Confederation of Otorhinolaryngology and Head and Neck Surgery and the Spanish Society of ENT- HN, Barcelona, Spain, July 2 6, 2011, the 118th Congress of the French ENT Society, Paris, France, October 13 15, 2011, and the 24th Congress of the European Rhinologic Society and the 31th International Symposium of infection and allergy of the nose, Toulouse, France, June 17 21, invasion 2 (Table 1). In 2009, the American Joint Committee on Cancer (AJCC) proposed a TNM staging system for upper aerodigestive tract mucosal melanomas (mmtnm). It is infrequently used, probably because of its newness (Table 1). 7 In the recent literature, the AJCC TNM classification for carcinoma of the nasal cavity and sinuses (cartnm; 2002) is increasingly used to characterize the extension of mucosal melanomas 7 (Table 2). This recent approach has not demonstrated its effectiveness in terms of prognostic value. The purpose of this study was to statistically analyze our series of sinonasal mucosal melanoma to assess the prognostic value in terms of overall and disease-free survival of the 3 staging systems found in the literature for these tumors: the Ballantyne staging system modified by Prasad (Ballantyne/Prasad staging system), mmtnm, and cartnm. MATERIALS AND METHODS This is a retrospective study of all patients treated in our institution for sinonasal mucosal melanoma between January 1995 and January Cases of endonasal metastasis of primary melanoma from other sites were excluded. Data were reviewed using a standardized reading grid. The database was created with FileMaker Pro software (version 5). To compare the classifications, tumors were all staged using the Ballantyne/Prasad staging system, the mmtnm, and the cartnm after reading through the histopathologic and radiologic records. The prognostic value HEAD & NECK DOI /HED MARCH

2 MICHEL ET AL. TABLE 1. Ballantyne, Ballantyne/Prasad and American Joint Committee on Cancer Staging Mucosal Melanoma of the Head and Neck (TNM classification for mucosal melanomas) staging systems. Stage Ballantyne 1970 Ballantyne / Prasad 2004 Mucosal melanoma TNM 2009 Stage I Any T N0M0 Level 1: in situ T3: epithelium/submucosal III Level 2: invasion up to lamina propria T3N0 Level 3: deep tissue invasion T4a: deep soft tissue, cartilage, bone IVa T4b: brain, dura, skull base T4aN0 T3/T4a N1 II Any T NþM0 IVb T4b III Any T any N M1 IVc M1 of these classifications was evaluated in terms of overall survival and disease-free survival. Survival rates (overall and disease-free) were calculated using the Kaplan Meier method. The log-rank test was used to compare survival curves. All analyses were performed using SPSS for Windows (version 17.0). For all tests used, a p significance value of <.05 was considered statistically significant. RESULTS Patients There were 35 patients: 20 women (57.1%) and 15 men (42.9%; sex ratio, 0.58). The average age at diagnosis was 64.8 years (range, years; median, 67 years). Only 1 patient had an occupational exposure risk for sinonasal neoplasia (carpentry). Mean follow-up was 49 months (range, months; median, 27.4 months). The initial clinical signs were epistaxis in 20 of 35 cases (57.1%) and nasal obstruction in 16 of 35 cases (45.1%). Other signs found were an endonasal or maxillary mass and pain. In all cases, the initial assessment included a contrastenhanced CT scan of the facial region for local staging and a contrast-enhanced chest CT for regional and remote staging. MRI of the facial region completed this assessment in 22 patients (63.1%). Radiologic analysis was used to define original tumor sites, modes of extension, and stages. In 27 of 35 cases (77%), tumor origin was the nasal cavity mucosa. The exact locations were as follows: lateral nasal wall (inferior turbinate and middle turbinate) 48.1% (n ¼ 13) and nasal septum 18.5% (n ¼ 5). There were 11 cases (40.7%) showing diffuse involvement of the entire nasal cavity mucosa. The maxillary sinus was affected in 5 of 35 cases (35%), the ethmoid in 2 of 35 cases, (5.7%) and the nasopharynx in 1 of 35 cases (2.9%). The tumor was lateralized to the right in 15 cases (42.8%), to the left in 18 cases (51.4%), and centrally in 2 cases (5.8%). All diagnostic and therapeutic decisions concerning patients in this study were taken at multidisciplinary meetings attended by teams representing head and neck surgery, medical oncology, radiation therapy, pneumology, pathology, radiology, nuclear medicine, and dermatology. Extension Using the Ballantyne/Prasad staging system, 33 tumors were classified as stage I (91.4%) including 2 level I, 2 level II, and 29 level III. No patient had metastatic lymph node at diagnosis (no stage II) and 2 were classified as stage III (5.7%; liver metastases). According to the mmtnm, 4 cases were staged T3 (11.4%), 30 cases T4a (85.7%), and 1 case T4b (2.8%). There were 4 stage III, 28 stage IVa, 1 stage IVb, and 2 stage IVc. According to the cartnm, tumors were classified T1 in 19 cases (all T1N0M0; 54.3%), T2 in 8 cases (all T2N0M0; 22.9%), T3 in 5 cases (3 T3N0M0 and 2 T3N0M1; 14.3%), and T4a in 3 cases (all N0M0; 8.5%). TABLE 2. American Joint Committee on Cancer sinonasal tracts carcinoma TNM. cartnm Maxillary Sinus (MS) Nasal cavity and ethmoid sinus T1 Limited to maxillary sinus One subsite T2 Hard palate, middle nasal meatus except posterior wall of MS Two subsites in a single region or extending to involve an adjacent region T3 Bone of posterior wall of MS, subcutaneous tissues, orbit, Medial floor of the orbit, maxillary sinus, palate, cribriform plate pterygoid fossa, ethmoid sinus T4a Orbital content, skin, pterygoid plates, cribriform plate Anterior orbital content, skin, minimal extension to cranial fossa, pterygoid, plates, sphenoid, or frontal sinus T4b Orbital apex, dura, brain... Orbital apex, dura, brain... 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. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, HEAD & NECK DOI /HED MARCH 2014

3 PROGNOSTIC VALUE OF TUMOR CLASSIFICATIONS FIGURE 1. Disease-free survival of patients with sinonasal melanoma. FIGURE 2. Overall survival of patients with sinonasal melanoma. For patients classified as T4a, there was a breach of the skull base in 1 case, the orbit in 1 case, and the skin in 1 case. Treatment Patients had received 4 types of initial treatment: surgery alone ¼ 54.3% (14 cart1n0m0, 3 cart2n0m0, and 2 cart3n0m0), surgery followed by adjuvant radiotherapy ¼ 31.4% (5 cart1n0m0 and 6 cart2n0m0), chemotherapy alone ¼ 8.6% (2 cart4an0m0 and 1 cart3n0m1), and concomitant chemoradiotherapy ¼ 5.7% (2 cart4an0m0). In total, 30 patients (85.7%) underwent surgery: 11 by a transfacial approach, 7 by degloving, and 12 by endoscopic endonasal surgery. Resection margins were unclear in 4 cases. Three of them had (75%), 1 of whom died at 31 months, and 2 are alive but not controlled (50%) at 12 and 26 months. In all cases, chemotherapy alone was intravenous dacarbazine. Regarding radiotherapy, the protocol involved delivery to the tumor site of a dose ranging from 45 to 70 Gy. Two patients classified T1N0M0 with unclear margins after surgery were treated with interferon alpha. The doses were 3 million units subcutaneously 3 times a week for 18 months (low-dose protocol) in 1 case and 6 million units 3 times a week for a year in the other case. Overall and disease-free survival Disease-free survival rates at 1 year and 5 years were 42.4% and 18.9%, respectively (Figure 1). The overall survival rates at 1 year and 5 years were 87.9% and 26.9%, respectively (Figure 2). Of the 35 patients followed, 27 (81.8%) relapsed. The other 8 patients were classified with stage I grade III and had no evidence of recurrence. The average time between diagnosis and recurrence of melanoma was 20.2 months (range, months; median, 8 months). Local recurrence, regional or remote depending on tumor location, TNM classification, and initial treatment are shown in Table 3. Eighteen patients with recurrence (66.7%) were treated surgically. Radiotherapy to the tumor site was used in 5 cases, to the cervical lymph nodes region in 2 cases, and to bone metastasis in 1 case. Chemotherapy was initiated in 6 cases and was continued in 4 cases (dacarbazine or second line fotemustine). Immunotherapy with high-dose interferon was initiated in 2 cases after local surgery. In total, 25 patients (75.7%) died (23 of neoplasia and 2 from other causes) and 10 patients are in remission after a mean duration of 27.4 months (range, months). Prognostic value of the staging systems The Ballantyne/Prasad staging system was significantly correlated only with overall survival. Patients classified as stage III (metastatic carcinoma) had a decreased overall survival (p ¼.032) compared with patients with stage I and II carcinomas. There was no significant difference in overall survival between stage I and stage II. The 3 levels of depth of invasion in stage I described by Prasad had no prognostic value in terms of overall survival. The Ballantyne/Prasad staging system did not influence diseasefree survival (p ¼.10). Regarding mmtnm, overall survival was significantly decreased for stages IVc (p ¼.012) and IVb (p ¼.000). This classification did not seem to be significantly correlated with recurrence-free survival. Regarding cartnm, T1 to T2 had disease-free survival rates at 1 and 5 years, respectively, of 46.2% and 24.6% versus 28.6% and 0% for T3 to T4. These differences are statistically significant (p ¼.041; Figure 3). T1 to T2 had overall survival rates at 1 and 5 years of 96.2% and 29.6%, respectively, versus 57.1% and 14.3% for T3 to T4. Stages T1 to T2 is a better prognostic factor for overall survival (p ¼.012; Figure 4). DISCUSSION Our results tend to show that cartnm is a superior classification system for the prognosis of sinonasal mucosal melanomas. In this series, we applied only the T classification of the cartnm because of the absence of patients with negative nodes. In our series, there was a majority of T1 and HEAD & NECK DOI /HED MARCH

4 MICHEL ET AL. TABLE 3. Sinonasal tract melanomas local, locoregional, regional, and remote according to subsite of origin, TNM classification for carcinomas of the nasal cavity and sinuses classification and initial treatment. Subsite of origin cartnm classification Initial treatment No. of patients Local Locoregional Regional Remote Nasal fossa Maxillary sinus Ethmoid Cavum T1N0M0 Surgery Surgery þ radiotherapy T2N0M0 Surgery Surgery þ radiotherapy T3N0M0 Surgery T3N0M1 Chemotherapy T4aN0M0 Radiochemotherapy T1N0M0 Surgery Surgery þ radiotherapy T2N0M0 Surgery þ radiotherapy T4aN0M0 Radiochemotherapy Surgery T3N0M0 Surgery T3N0M1 Surgery T1N0M0 Surgery + radiotherapy Abbreviations: cartnm, TNM classification for carcinomas of the nasal cavity and sinuses. T2 tumors. Sinonasal mucosal melanomas are often reported to be macroscopically limited tumors at diagnosis. 8,9 Despite this inhomogeneous distribution in the literature, as in our series, the cartnm staging system had a significant prognostic value in terms of overall and disease-free survival. There was a statistically significant decrease in overall and recurrence-free survival at 1 year and 5 years, respectively, for tumors classified T3 to T4. Many authors define sinonasal mucosal melanoma by coupling Prasad s classification and the Union Internationale Contre le Cancer TNM classification of sinonasal carcinoma (cartnm), although few studies have evaluated this strategy. 1,3,6,10,11 In 2003, Thompson et al 10 proposed a classification inspired by cartnm in which they opposed T1 with T2, T3, and T4. In 2010, Moreno et al 1 also highlighted the good correlation between use of the cartnm classification and patient survival. The significant difference in survival in our series between T1/T2 and T3/T4 confirms these data. Thus, the cartnm can be used to stage mucosal melanomas of the nasal cavity and sinuses. According to the National Cancer Institute, the stage can be used to estimate the person s prognosis. Staging helps health care providers and researchers to exchange information about patients. It also gives them a common terminology for evaluating the results of clinical trials and comparing the results of different trials. A good staging must reflect prognosis, be shared, and used. In our view, the cartnm staging system meets these 3 criteria, thus offering a very useful option. FIGURE 3. Disease-free survival of patients with sinonasal melanoma by T classification (p ¼.041). FIGURE 4. Overall survival of patients with sinonasal melanoma by T classification (p ¼.012). 314 HEAD & NECK DOI /HED MARCH 2014

5 PROGNOSTIC VALUE OF TUMOR CLASSIFICATIONS TABLE 4. Head and neck mucosal melanomas: 5-year disease-free survival and 5-year overall survival reported in the literature and in our series. Authors No. of patients 5-year disease-free survival, % 5-year overall survival, % % of postoperative radiotherapy Prasad et al. 2 (2004) Patel et al. 3 (2001) Dauer et al. 4 (2008) Temam et al. 6 (2004) Bridger et al. 8 (2005) Cheng et al. 9 (2007) Manolidis et al. 13 (1997) Huang et al. 14 (2007) Narasimhan et al. 15 (2009) Jethanamest et al. 16 (2011) Our series Our results show that the Ballantyne/Prasad staging system was poorly correlated with sinonasal mucosal melanoma prognosis. The main criticism of Ballantyne s staging system is that it emphasizes lymph node involvement to which it devotes an entire stage (stage II). However, this type of involvement is seldom found at diagnosis for these tumors (5% to 10% of cases in the literature). 6,12 This is why the majority of authors do not recommend systematic neck dissection in patients whose clinical and radiological lymph node status is negative (N0). 6,12 None of our patients had lymph node involvement at diagnosis. We were therefore unable to demonstrate a prognostic value for lymph node involvement. Distant metastases at diagnosis are also infrequent (10.5% of our cases). 1 However, they are a significant factor of poor prognosis in terms of overall survival in our series and in the literature. The existence of a separate stage for patients with metastatic carcinoma at diagnosis seems to be a strong feature of the classification of mucosal melanomas. Because of the scarcity of Ballantyne stages II and III in many studies, 75% to 95% of patients were classified Ballantyne stage I, thus limiting the prognostic significance. Furthermore, Ballantyne s classification does not take into account either local tumor extension or tumor depth. To better characterize the infiltrative nature of these tumors, Prasad et al 2 proposed to distinguish 3 levels of infiltration in stage I (Table 1). However, as this classification is histological, the level can only be determined after surgery except when a deep massive tumor invasion is visible on imaging. In their study, Prasad et al 2 found a statistically significant difference in survival between these different levels. Stage I level 1 had a median survival rate of 138 months versus 69 months for stage I level 2 and 28 months for stage I level 3 (p ¼.003). In our series, 74% of patients (n ¼ 14) were classified as stage I level 3 (level 3). We were unable to demonstrate a statistically significant difference in survival for this subsegmentation, probably because of the small number of patients in stage I levels 1 and 2. Moreover, the Prasad et al 2 study covered all mucosal melanomas of the head and neck, whereas our series included only sinonasal melanomas. Even coupled, these 2 classifications do not take into account local tumor extension. The AJCC mmtnm staging system is recent and has not been thoroughly evaluated. It associates data from the Ballantyne/Prasad system (degree of tumor infiltration at stages mmt3 and mmt4a) with data from cartnm (local expansion for mmt4b classification). Table 2 shows that classification mmt3 corresponds to stage I levels 1 and 2 in the Ballantyne/Prasad staging system; classification mmt4a corresponds to stage I level 3, and classification mmt4b to classification cart4a and cart4b. It is logical, therefore, that we found no difference in survival between stages III and IVA because we found none between stages I levels 1, 2, and 3 of the Ballantyne/Prasad staging system and we had no cases of patients with N1 disease at diagnosis. Stage IVB was associated with a significant decrease in survival. This result is consistent with our finding using the cartnm classification. We observed that this classification was only weakly correlated with the prognosis of patients in our series. Our results in terms of disease-free and overall survival at 5 years and those of major published studies are presented in Table ,6,8,9,13,15,16 Sinonasal mucosal melanomas are rare entities with a poor prognosis. 1,13 In order to recruit sufficient numbers, many studies sometimes include patients treated for sinonasal mucosal melanoma and oral cavity as long as several decades ago. 4,13 To ensure consistency, we limited ourselves to sinonasal mucosal melanoma treated within the last 15 years. CONCLUSION The cartnm classification can be used to stage mucosal melanoma of the nasal cavity and sinuses. This staging system has the advantage of being well known to surgical oncologists. On the basis of these findings, we believe that cartnm staging system could be the primary staging system for patients with mucosal melanomas of the sinonasal tract. These results have to be evaluated by larger prospective, multicentric studies. REFERENCES 1. Moreno MA, Roberts DB, Kupferman ME, et al. Mucosal melanoma of the nose and paranasal sinuses, a contemporary experience from the M. D. Anderson Cancer Center. Cancer 2010;116: Prasad ML, Patel SG, Huvos AG, Shah JP, Busam KJ. Primary mucosal melanoma of the head and neck: a proposal for microstaging localized, stage I (lymph node-negative) tumors. Cancer 2004;100: HEAD & NECK DOI /HED MARCH

6 MICHEL ET AL. 3. Patel SG, Prasad ML, Escrig M, et al. Primary mucosal malignant melanoma of the head and neck. Head Neck 2002;24: Dauer EH, Lewis JE, Rohlinger AL, Weaver AL, Olsen KD. Sinonasal melanoma: a clinicopathologic review of 61 cases. Otolaryngol Head Neck Surg 2008;138: Ballantyne AJ. Malignant melanoma of skin of head and neck. An analysis of 405 cases. Am J Surg 1970;120: Temam S, Mamelle G, Marandas P, et al. Postoperative radiotherapy for primary mucosal melanoma of the head and neck. Cancer 2005;103: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, Bridger AG, Smee D, Baldwin MA, Kwok B, Bridger GP. Experience with mucosal melanoma of the nose and paranasal sinuses. ANZ J Surg 2005;75: Cheng YF, Lai CC, Ho CY, Shu CH, Lin CZ. Toward a better understanding of sinonasal mucosal melanoma: clinical review of 23 cases. J Chin Med Assoc 2007;70: Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol 2003;27: Martin JM, Porceddu S, Weih L, Corry J, Peters LJ. Outcomes in sinonasal mucosal melanoma. ANZ J Surg 2004;74: Bachar G, Loh KS, O sullivan B, et al. Mucosal melanomas of the head and neck: experience of the Princess Margaret Hospital. Head Neck 2008; 30: Manolidis S, Donald PJ. Malignant mucosal melanoma of the head and neck: review of the literature and report of 14 patients. Cancer 1997;80: Huang SF, Liao CT, Kan CR, Chen IH. Primary mucosal melanoma of the nasal cavity and paranasal sinuses: 12 years of experience. J Otolaryngol 2007;36: Narasimhan K, Kucuk O, Lin HS, et al. Sinonasal mucosal melanoma: a 13-year experience at a single institution. Skull Base 2009;19: Jethanamest D, Vila PM, Sikora AG, Morris LG. Predictors of survival in mucosal melanoma of the head and neck. Ann Surg Oncol 2011;18: HEAD & NECK DOI /HED MARCH 2014