O R I G I N A L A R T I C L E

Sinonasal melanoma: survival and prognostic implications based on site ofinvolvement

Mohemmed N. Khan, MD1,2, Vivek V. Kanumuri, BS1, Milap D. Raikundalia, BS1, Alejandro Vazquez, MD1,Satish Govindaraj, MD, FACS2, Soly Baredes, MD, FACS1,3 and Jean Anderson Eloy, MD, FACS1,3,4

Background: Sinonasal melanoma (SNM) is a rare malig-nancy that commonly presents at an advanced age and hasa slight male predominance. Local recurrence has been im-plicated as a major reason for treatment failure, and thereare poor reported 5-year survival rates. We analyzed theimpact of specific location within the sinonasal region onthe survival of this rare malignancy.

Methods: The U.S. National Cancer Institute’s Surveillance,Epidemiology, and End Results (SEER) registry was usedto extract data on SNM between 1973 and 2009. Survivaltrends and hazard ratios (HRs) were calculated to comparethe prognostic implications of involvement of varying areasof the sinonasal tract.

Results: A total of 567 cases were identified. Females con-stituted 56.44% patient. Disease-specific survival (DSS) at5 years was 36.66% for patients diagnosed with nasal cav-ity disease, 23.80% for patients with maxillary sinus tumors,and 18.20% for patients with ethmoid sinus disease. Pa-tients showing evidence of overlapping sinus involvementhad approximate 1-year survival of 54.45% and none sur-

vived beyond 49 months. HRs for maxillary sinus, ethmoidsinus, and overlapping sinus disease were 1.34, 1.60, and2.30, respectively. All DSSs and HRs were statistically signif-icant (p < 0.05). There was a higher proportion of earlier-stage disease in the nasal cavity compared to the most com-mon paranasal sinus region (p < 0.05).

Conclusion: Prognosis in SNM is dependent on theanatomic subsite. Paranasal sinus involvement indicatesa poorer prognosis when compared to nasal cavity dis-ease. Patients presenting with overlapping sinus involve-ment have the poorest prognosis. C© 2013 ARS-AAOA, LLC.

Key Words:melanoma; nasal mucosa; nose neoplasms; paranasal sinusneoplasms; maxillary sinus neoplasms; nasal cavity

How to Cite this Article:Khan MN, Kanumuri VV, Raikundalia MD, et al. Sinonasalmelanoma: survival and prognostic implications basedon site of involvement. Int Forum Allergy Rhinol. 2014;4:151–155.

M elanomas are malignancies of neural crest cell–derived melanocytes. Sinonasal melanoma (SNM)

in particular can have a poor prognosis due to its diffi-

1Department of Otolaryngology–Head and Neck Surgery, Rutgers NewJersey Medical School, Newark, NJ; 2Department ofOtolaryngology–Head and Neck Surgery, Mount Sinai School ofMedicine, New York, NY; 3Center for Skull Base and Pituitary Surgery,Neurological Institute of New Jersey, Rutgers New Jersey MedicalSchool, Newark, NJ; 4Department of Neurological Surgery, RutgersNew Jersey Medical School, Newark, NJ

Correspondence to: Jean Anderson Eloy, MD, FACS, Department ofOtolaryngology–Head and Neck Surgery, Rutgers New Jersey MedicalSchool, 90 Bergen St., Suite 8100, Newark, NJ 07103; e-mail:jean.anderson.eloy@gmail.com

Potential conflict of interest: None provided.Presented orally at the 59th Annual ARS Meeting on September 28, 2013,Vancouver, BC, Canada.

Received: 2 July 2013; Revised: 4 September 2013; Accepted:24 September 2013DOI: 10.1002/alr.21243View this article online at wileyonlinelibrary.com.

cult anatomic location and nonspecific symptomatology,with overall 5-year survival reported as low as 24%.1

This poor life expectancy can be attributed to delayeddiagnosis due to asymptomatic early stages and lack ofovert visibility, compounded by the aggressive nature ofthe disease and proximity to vital anatomy.1,2 SNM orig-inates from the sinus/nasal mucosa and may be asso-ciated with benign melanosis of the area.3,4 Mucosalmelanomas may develop in any noncutaneous tissue con-taining melanocytes, including anorectal, vulvovaginal,sinonasal cavity, and oral cavity.2,5,6 Each of these sub-types may vary in expression of c-kit, molecular markers,and other gene-specific mutations, further suggesting thatprognosis and treatment may not always be generalizedbetween melanomas of separate origin.2,5,7–9 Unlike 75%of cutaneous melanomas that express the BRAF oncogene,mucosal melanomas are rarely associated with this mu-tation, and thus have poor response to BRAF mutation–targeted therapies. This may result in worse prognosis forSNM.2,9

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There is a general consensus that primary treatment ofSNM (as for other mucosal melanomas of the head andneck [MMHNs]) is complete surgical resection.2,10 Postop-erative adjuvant radiation therapy remains controversial,as it has been shown to improve regional control of thedisease, but not to improve survival rates.2,5,7,11 The ex-tent of surgical resection and feasibility of additional treat-ment is highly dependent on the anatomic location of thetumor. Eventual prognosis may depend highly on whichsinuses are involved and the extent of involvement. Thiswas originally described for carcinoma by the Swedish oto-laryngologist Dr. Ohngren in 1933 with the developmentof “Ohngren’s line.” This theoretical line, starting fromthe medial canthus and passing through the angle of themandible, divides the facial skeleton into a suprastructureand infrastructure component, and the maxillary sinus intoa posterosuperior portion and an anteroinferior portion. Itwas developed taking into consideration the possibility oftumor resection and the possible structures involved withposterosuperior positioned tumors.12,13

Here we use data from the Surveillance, Epidemiology,and End Results (SEER) program from 1973 to 2009 toperform a comparative study on prognosis of treatmentoutcomes of SNM based on anatomic subsite.

Materials and methodsThe SEER database was used to extract survival data. SEERconsists of cancer registries from 18 states and metropoli-tan areas in the United States. Institutional review boardapproval was not required, as SEER does not uncover sen-sitive patient information. Using the International Clas-sification of Diseases for Oncology, 3rd edition (ICD-O-3) codes, we extracted data for the histologic category ofmelanoma (8720/3–8780/3). Next, we restricted our resultsto the nasal cavity (C30.0) and paranasal sinuses (C31.0,C31.1, C31.2, C31.3, C31.8, and C31.9). Staging data wasretrieved using SEER collaborative staging codes and up-dating them to reflect the American Joint Committee onCancer Staging (AJCC) for Mucosal Melanoma of the Headand Neck (ie, MMNH), 7th edition.14

The SEER*Stat 8.0.4 software (National Cancer In-stitute, Bethesda, MD) was used to extract and ana-lyze data for melanoma of the sinonasal tract. Com-parison of proportions was done using the 2-proportionZ test (VassarStats, Richard Lowry, Vassar College;http://www.vassarstats.net/).15 Kaplan-Meier analysis wascarried out with JMP Statistical Discovery 10 (SAS Insti-tute, Cary, NC); survival curves were compared using thelog-rank test. Relative survival (RS) data was derived withSEER*Stat 8.0.4 and analyzed with multivariate Cox pro-portional hazards regression using CanSurv 1.1 (NationalCancer Institute, Bethesda, MD). Microsoft Office Excel2007 (Microsoft Corporation, Redmond, WA) was usedfor additional data processing. A probability value (p value)of <0.05 was considered statistically significant for all tests.

FIGURE 1. Kaplan-Meier survival curve for sinonasal melanoma. Marksabove line represent censoring, marks below line represent failures (deaths).

ResultsIn total, 567 patients with SNM were identified in the 18registries of the SEER database from 1973 to 2009. Themost common primary site for SNM was the nasal cav-ity, accounting for 67.55% of cases. The maxillary sinuswas the next most common location (16.93%), followedby the ethmoid sinus (7.23%), the sphenoid sinus (1.59%),and the frontal sinus (0.35%). Overlapping lesions of theaccessory sinuses (indicating multiple sinus involvement)accounted for 1.94% of cases, while accessory sinus nototherwise specified accounted for the remaining 4.41% ofcases. Overall 1-year and 5-year disease-specific survival(DSS; also known as cause-specific survival) for SNM was76.09% and 31.49%, respectively (Fig. 1). Overall relativesurvival (the ratio of the observed survival rate to the ex-pected age-adjusted background survival rate) was 75.00%at 1 year and 31.40% at 5 years.

Analysis of survival by anatomic siteDSSs and relative survivals (RS) were calculated for 4 of themost common primary sites for SNM (Table 1). The nasalcavity had a much higher DSS at 1 year (81.06%) and5 years (36.66%) than any other site. Kaplan-Meier analy-sis of the survival curves for these sites (Fig. 2) and the log-rank test showed this difference to be significant (p < 0.05).RS was also highest for the nasal cavity, with 1-year RS of80.06% and 5-year RS of 36.30%. Survival was lowest forlesions with multiple sinus involvement, with 1-year DSSof 54.55% and RS of 55.58%, with no patients survivingbeyond 49 months (or lost to follow-up), although therewere only 11 cases with this kind of tumor involvement.While only 2 cases of frontal sinus disease were extractedfrom the database, both of these patients died of diseasewithin a year of diagnosis.

Hazard ratios (HRs) were also generated using RSs andthe Cox proportional hazards regression model. Relativeto the nasal cavity, involvement of the maxillary sinus

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TABLE 1. Analysis of survival in SNM by site

Cases DSS (%) Relative survival (%)

Site n (%) 1 year 5 years p 1 year 5 years

Total 567 76.09 31.49 75.00 31.40

Nasal cavity 383 67.55 81.06 36.66 <0.001a 80.06 36.30

Maxillary sinus 96 16.93 73.73 23.80 73.85 25.61

Ethmoid sinus 41 7.23 62.58 18.20 57.46 17.02

Overlapping lesion of accessory sinuses 11 1.94 54.55 b 55.58 b

aValue of p using log-rank test to compare DSS for 4 listed sites is significantbThere were no cases remaining after 49 months for overlapping lesion of accessory sinuses.DSS = disease-specific survival; SNM = sinonasal melanoma.

FIGURE 2. Kaplan-Meier survival curve for 4 of the most common anatomicsites for sinonasal melanoma. Log rank test for statistical difference(p < 0.001).

(HR = 1.34), ethmoid sinus (HR = 1.60), and overlap-ping sinuses (HR = 2.30) were significant poor prognosticindicators (Table 2). Frontal sinus and sphenoid sinus HRsare not shown due to small sample sizes for these primarysites.

Demographics and stagingThe 2 most common primary sites for SNMs were com-pared with respect to their demographics and staging char-

TABLE 2. Cox proportion hazards regression of SNM bysite

Characteristic HR 95% CI p

Nasal cavity Reference

Maxillary sinus 1.34 1.12–1.60 <0.01

Ethmoid sinus 1.60 1.23–2.09 <0.001

Overlapping lesion of accessory sinuses 2.30 1.42–3.74 <0.001

CI = confidence interval; HR = hazard ratio; SNM = sinonasal melanoma.

acteristics (Table 3). Subgroup analysis was not conductedfor other sites due to small sample sizes. Both sites showeda higher percentage of females; there was no significant dif-ference in gender ratio between the sites. The AJCC forMMHN, 7th edition14 classifies T3 disease as limited tomucosal disease and T4 (there is no T1-T2) as moderateto advanced disease involving deep tissues and/or adjacentstructures. Among those with sufficient staging informa-tion, there was a significant difference between the propor-tion of T4 disease in the nasal cavity (44.13%) and theproportion of T4 disease in the maxillary sinus (80.56%,p < 0.001). When classified as stage III or IV with thecomplete tumor-node-metastasis (TNM) criteria, there wasalso a significant difference in the proportion of stage IVdisease in the nasal cavity (51.05%) and the maxillary sinus(82.86%, p < 0.05).

TherapyA greater proportion of patients with maxillary sinus in-volvement (76.34%) received radiation therapy at somepoint during the duration of their disease than those withprimarily nasal cavity involvement (52.28%, p < 0.05).Analysis of individual sinus DSS when comparing the useof radiation alone, surgery alone, and combination ther-apy with surgical resection and radiation therapy was alsoconducted. Patients with nasal cavity disease treated withsurgery alone and combination therapy had very similar 5-year survivals, at 37.50% and 34.45%, respectively. How-ever, patients receiving radiation therapy alone had a sig-nificantly lower 5-year survival, at 22.97% (p < 0.05).Patients with maxillary sinus disease also had the greatestsurvival when treated with surgical resection alone, witha 5-year survival of 46.75%. However, patients receiv-ing combination therapy had a significantly lower survival,with a 5-year survival of 19.63% (p < 0.05). Patients withmaxillary sinus disease receiving radiation therapy alonehad a 1-year survival of approximately 41.14% and nonesurvived to 5 years. Treatment for other individual areas ofthe sinonasal tract was not analyzed due to lack of sufficientcases.

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TABLE 3. Demographics and characteristics of SNMof 2 most common sites

Characteristic

Nasal cavity

n (%)

Maxillary sinus

n (%) p

Gender

Male 160 (41.78) 44 (45.83) 0.24

Female 223 (58.22) 52 (54.17)

Race

White 337 (87.99) 90 (93.75) a

Black 18 (4.70) 0 (0.00)

Other 28 (7.31) 6 (6.25)

Age at diagnosis, years (mean) 69.01 69.01

TNMb

TX 14 (8.81) 0 (0.00)

T3 81 (50.94) 7 (19.44) <0.001c

T4a-b 64 (40.25) 29 (80.56)

NX 22 (13.84) 5 (13.89)

N0 126 (79.25) 30 (83.33) a

N1 11 (6.92) 1 (2.78)

MX 15 (9.43) 2 (5.56)

M0 129 (81.13) 29 (80.56) 0.48c

M1 15 (9.43) 5 (13.89)

Stagingd

Stage III 70 (48.95) 6 (17.14) <0.001

Stage IV 73 (51.05) 29 (82.86)

aComparison not done due to small sample sizes.bTNM staging is based on AJCC 7th edition and only includes data 2004–2009.cComparison includes only cases with TNM information (no TX, NX, MX).dStaging is based on AJCC 7th edition for cases with complete TNM staging.AJCC = American Joint Committee on Cancer; SNM = sinonasal melanoma;TNM = tumor-node-metastasis.

DiscussionSNMs are less common than cutaneous melanomas, butare associated with poorer prognosis.1,8 The site of ori-gin and salient early stages of the disease make diagnosisdifficult. Recent studies have suggested varied molecularexpression of each site-specific tumor and altered respon-siveness to therapies.1,2,5,8 In addition, site of origin in-fluences ease of surgical intervention; vital anatomy juxta-posed to a malignant tumor may warrant alternatives tosurgery.11 Previous studies in the literature have exploredincidence and survival of SNM but have not explored im-pact of anatomic site on survival or have been limited tosmall, single-institutional studies. Here we present the firstlarge-scale population-based study on site-specific survivalof SNM patients using the SEER database.1,16

A retrospective chart review of 58 SNM cases between1994 and 2004 at M.D. Anderson Cancer Center revealeda 5-year survival rate of 38.7%.17 Gal et al.16 conductedan analysis of SNM reports between 2000 and 2007 usingthe SEER database and reported a 5-year survival rate of24.2%. Our study assessed SNM cases from 1973 to 2009and found that overall 5-year survival rate in these patientswas 31.49%. In addition to the time periods, this differencemay also be due to the slightly different search criteria usedbetween the studies, including our use of a wider range ofSEER histologic codes to capture a larger cohort of patients.

We analyzed the SEER data with a focus on the impactof anatomic subsite, an important factor in clinical and sur-gical management not addressed in previous analyses. Pre-vious studies showed that the most common location formucosal melanoma in the sinonasal region and MMHN atlarge is the nasal cavity.1,16 We also found that the mostcommon site is the nasal cavity (67.55%). A small, single-institutional study by Chan et al.1 assessed site-specificprognosis of MMHN in general and concluded that therewere no associations. Dauer et al.,18 in another institutionalstudy, reported that tumors located on the nasal septum andin the maxillary sinus confer a poor prognosis. Our analysisof a larger database revealed that SNM originating in thenasal cavity conferred a better prognosis when comparedto tumors in the ethmoid sinus, maxillary sinus, or overlap-ping regions of the accessory sinuses (HRs of 1.60, 1.34,and 2.30, respectively). We believe this can be explainedat least partially by accessibility and clinical intervention.Lesions of the nasal cavity are relatively easier to visual-ize and detect and may cause early symptoms, facilitatingearlier diagnosis and treatment. This disparity in survivalmay also be explained by “Ohngren’s line.” This line wasoriginally described to delineate the limits of resectabilityof a tumor in the maxillary sinus. Tumors that extendedinto the suprastructure (superoposterior to Ohngren’s line)were more likely to involve the orbit, ethmoids, and ptery-gopalatine fossa. Tumors originating below this line wereconsidered to have a greater possibility of resection andbetter prognosis.12,13,19 The path of this line has not al-ways been clearly defined in such areas as the lateral nasalwall, but most of the nasal cavity would be below Ohn-gren’s line, reflected in the better prognosis for nasal cavitytumors shown in this work.19 However, patients with eth-moid sinus disease and some tumors of the maxillary sinuswould be considered to be above Ohngren’s line and in anarea with a poorer prognosis. A prior study by Ren et al.13

also indicated that disease simultaneously above and belowOhngren’s line has a worse prognosis than disease isolatedbelow this line.

The AJCC changed the TNM staging protocol for mu-cosal melanomas in 2010. Notable changes in the 7thedition include the elimination of Stage I and II mucosalmelanomas, greater emphasis placed on depth of the ma-lignancy on a particular site rather than invasion of nearbyanatomy, and categorization of metastatic lymph nodes asStage IV regardless of tumor status.14,16 We found that a

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Sinonasal melanoma site implications on survival

higher proportion of nasal cavity melanomas were foundat Stage III (48.95%) compared to the maxillary sinus(17.14%). This supports our belief that the better prognosisof nasal cavity tumors relative to the maxillary sinus may bedue to diagnosis of nasal cavity lesions at an earlier stage.Our studies revealed that the proportion of T4 tumors wasalso higher in the maxillary sinus, suggesting that initiallygreater local invasion may account for this prognostic dif-ference. This finding is further supported by the review ofMoreno and Hanna,8 who found that tumor staging wasthe best predictor of SNM survival. Other reports have sug-gested it is hematogenous not lymphatic spread that leads tometastasis in SNM, further emphasizing the importance oflocal invasion indicated by the tumor staging.20 Some havealso found nodal and distant metastasis to be important inpredicting poor outcomes in MMHN.6

In a prior study, Mihajlovic et al.5 reported a signifi-cantly higher incidence of mucosal melanomas originatingfrom the genital tract in females, but no gender differencesin extragenital melanomas. We found that a slightly higherproportion of females (56.44%) are diagnosed with SNMs.This finding contrasts the male predisposition reported byChan et al.,1 a study limited to the Queen Mary Hospi-tal in Hong Kong. Although gender weakly contributes tothe MMHN predisposition, race has a substantial contri-bution. In accordance with other studies, we found thatthe Caucasian population is disproportionately affected bySNM compared to blacks or others (American Indian/AKnative) (Table 3).5,11,16 This relationship seems more intu-itive in cutaneous melanoma, in which the Caucasian biasis due to increased penetration of solar radiation.5

In terms of treatment, surgical resection with nega-tive margins has been shown to have the best prognosis,with no benefit of adjuvant radiation therapy in terms ofsurvival.1,2,7,8,11,16 Surgical treatment is not always pos-

sible due to spread of disease in late stages and possibleinvolvement of vital anatomy.1,11 In our study, we foundthat surgical intervention carried the best overall prognosisfor both nasal cavity and maxillary sinus disease. However,this may be due in part to the fact that radiation therapyis reserved for patients with difficult surgical approaches,refractory disease, or late-stage disease. Further study isneeded to explore this issue.

There are a number of limitations of this study. The SEERdatabase does not provide extensive details of the surgicalprocedures, so it is difficult to interpret surgical merit ofnegative margin resection. In addition, we identified over-lapping regions of the accessory sinus to have the worstprognosis, but the inference made by this finding shouldbe further evaluated based on the limited sample size. Ev-ery attempt to maintain fidelity to the 7th edition TMNstaging protocol was made; however, the information is in-complete prior to 2004 and prior staging algorithms wereused, and subsequently there was a smaller sample size forTMN staging analysis. There is also limited information inthe SEER database on chemotherapy, an important treat-ment modality that some studies show to be of benefit inSNM.21 Finally, retrospective population-based studies aredependent on accurate coding and consistent data collec-tion among numerous sites, which can be imperfect.

ConclusionMelanoma of the sinonasal tract carries a significantly dif-ferent prognosis when analyzing individual site involve-ment. Maxillary or ethmoid sinus disease has a worse prog-nosis than nasal cavity disease. This may be due in part todiagnosis at a later stage and difficult accessibility to dis-ease for surgical resection. Patients presenting with multiplesinus involvement carried the worst prognosis.

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