Squamous Cell Carcinoma of the Maxillary Sinus: A Population- Based Analysis

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1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. Squamous Cell Carcinoma of the Maxillary Sinus: A Population- Based Analysis Pariket M. Dubal, BA; Amit Bhojwani, DO; Tapan D. Patel, MD; Omry Zuckerman, BA; Soly Baredes, MD, FACS; James K. Liu, MD, FACS; Jean Anderson Eloy, MD, FACS Objectives/Hypothesis: Squamous cell carcinoma (SCC) accounts for > 90% of head and neck cancers and 60% to 75% of malignancies of the paranasal sinuses. The most commonly affected paranasal sinus is the maxillary. Epidemiologic, incidence, and survival trends have been studied for maxillary sinus SCC (MSSCC), but far less is known about its metastatic potential. Study Design: Retrospective database analysis. Methods: The Surveillance, Epidemiology, and End Results database was used to extract frequency, incidence, and survival data for MSSCC between 2004 and The resultant cases were stratified according to patient demographics and collaborative stage information, including extent of disease, lymph node involvement, TNM staging, and regional and distant metastasis. Results: A total of 854 cases of MSSCC were identified. The mean age at diagnosis was 66.6 years, with 87.4% presenting at > 50 years. Most patients (65.1%) were male. Whites accounted for 74.6% of cases. A majority (64.3%) of cases presented with stage IV disease. Overall 5-year disease-specific survival was 23.4%. Neck involvement was seen in 7.6% of T1 tumors, 22.2% of T2 tumors, 18.5% of T3 tumors, and 12.2% of T4 tumors. Distant metastasis was not seen in T1 T3 tumors, but was present in 6.8% of T4 tumors. Conclusions: MSSCC is a rare entity with poor overall prognosis. The majority of patients included in this study were white males aged 50 years, with most tumors presenting at advanced stages. Nodal involvement and distant metastasis are poor prognostic indicators. T1 T3 tumors did not metastasize to distant sites. Key Words: Squamous cell carcinoma, paranasal sinus neoplasm, SEER, sinonasal malignancies, maxillary sinus, population-based, metastasis. Level of Evidence: 4 Laryngoscope, 126: , 2016 Additional supporting information can be found in the online version of this article. From the Department of Otolaryngology Head and Neck Surgery, Rutgers New Jersey Medical School, Newark (P.M.D., T.D.P., S.B., J.K.L., J.A.E.); Department of Otolaryngology and Facial Plastic Surgery, Rowan University School of Osteopathic Medicine, Stratford (A.B.); Rowan University School of Osteopathic Medicine, Stratford (O.Z.); Center for Skull Base and Pituitary Surgery, Neurological Institute of New Jersey, Rutgers New Jersey Medical School, Newark (S.B., J.K.L., J.A.E.); Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark (J.K.L., J.A.E.); and Department of Ophthalmology and Visual Science, Rutgers New Jersey Medical School, Newark, New Jersey, U.S.A. (J.A.E.). Editor s Note: This Manuscript was accepted for publication July 30, Presented in part at the American Rhinologic Society Meeting, Combined Otolaryngology Spring Meetings, Boston, Massachusetts, U.S.A., April 23, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jean Anderson Eloy, MD, FACS, Neurological Institute of New Jersey, Rutgers New Jersey Medical School, 90 Bergen St., Suite 8100, Newark, NJ jean.anderson.eloy@gmail.com DOI: /lary INTRODUCTION Sinonasal cancers are rare, comprising approximately 3 5% of head and neck cancers, and <1% of all malignancies. 1,2 Of these, squamous cell carcinoma (SCC) is the most common, accounting for 80% to 90% of head and neck cancers and 60% to 75% of malignancies of the paranasal sinuses. 3,4 The most commonly affected paranasal sinus is the maxillary sinus. 5 Exposure to asbestos; occupational exposures to arsenic, textile dusts, and welding fumes; inhalation of nickel compounds; and smoking have all been implicated in an increased risk for sinonasal SCC. 6,7 Although epidemiologic, incidence, and survival trends have been studied for maxillary sinus SCC (MSSCC), 4,5 far less is known about its metastatic potential. Diagnosis of MSSCC most often occurs at an advanced stage due to nonspecific symptoms early in the disease, with >80% of patients reportedly presenting with at least stage T3 disease. 8 Local recurrence has proven to be the primary challenge in the treatment of MSSCC, highlighting the importance of local control. 9,10 Traditionally, lymph node involvement at the time of diagnosis of maxillary sinus malignancies has been considered rare due to limited lymphatic drainage. 8 However, MSSCC can present with nodal involvement at initial diagnosis. 11,12 In the present analysis, the authors utilize the Surveillance, Epidemiology, and End Results (SEER) database, a nationally representative resource that has 399

2 TABLE I. Patient Characteristics for MSSCC ( ) Characteristic No. % Total MSSCC Mean age at diagnosis, yr ( 6 SD) 66.6 ( ) Age groups 0 19 years years years years years years years years Gender Male Female Race White Black Asian or Pacific Islander American Indian or Alaska Native Unknown 5 MSSCC 5 maxillary sinus squamous cell carcinomas; SD 5 standard deviation. proven useful in describing rare clinical entities, to characterize the malignant behavior of MSSCC, including rates and patterns of metastasis. MATERIALS AND METHODS The SEER 18 database was utilized to extract frequency, incidence, and survival data. The SEER 18 data set contains population data for patients diagnosed with malignancies between 1973 and It is maintained by the National Cancer Institute (Bethesda, MD) and contains extensive information regarding patient demographics, tumor histology and behavior, extent of disease, treatment, and long-term follow-up. Data are updated periodically, and the database is estimated to represent approximately 28% of the United States population. SEER omits patient identifiers and, therefore, institutional review board (IRB) approval was not required per the standing policy of the IRB of Rutgers New Jersey Medical School (Newark, NJ). All statistical analysis was carried out at a significance level of a Patient Characteristics The SEER 18 database was searched for malignancies diagnosed between 2004 and The results were subsequently filtered by histology using the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) codes for traditional squamous cell carcinoma: 8070/3 (squamous cell carcinoma, NOS), 8071/3 (squamous cell carcinoma, keratinizing, NOS), 8072/3 (squamous cell carcinoma, large cell, nonkeratinizing), and 8073/3 (squamous cell carcinoma, small cell, nonkeratinizing). The results were then limited to include cases arising in the maxillary sinus using the corresponding ICD-O-3 site code (C31.0). The remaining cases were stratified by patient characteristics, including gender, race, and age at diagnosis. Tumor Characteristics We stratified the identified MSSCC cases by clinicopathologic behavior. Cases were analyzed for American Joint Committee on Cancer (AJCC), 7th Edition staging, AJCC TNM classification, histologic grade, tumor size, regional lymph node involvement, and distant metastasis. We included all unknown values in the results, but excluded them from distribution percentage calculations. This was based on the assumption that the expected distribution of unknown values should follow the observed distribution for the known values. Incidence and Survival Incidence rates and trends were calculated for MSSCC diagnosed between 2000 and All incidence data were adjusted to the standard 2000 United States population per Census P The annual percentage change (APC) in incidence was calculated using 1-year endpoints, and significance testing was carried out using weighted least squares analysis. Disease-specific survival (DSS) was calculated using individual case listings extracted from the SEER 18 database. The list of patients diagnosed with MSSCC between 2004 and 2012 TABLE II. Clinicopathologic Characteristics of Maxillary Sinus Squamous Cell Carcinoma ( ) Characteristic No. % Histologic grade Well differentiated, grade I Moderately differentiated, grade II Poorly differentiated, grade III Undifferentiated, grade IV Unknown/not recorded 178 AJCC stage I II III IV Unknown 70 T classification T T T T TX 49 N classification N N N N NX 92 M classification M M MX 71 Average tumor size, cm ( 6 SD), n ( 6 2.0) AJCC 5 American Joint Committee on Cancer; SD 5 standard deviation. 400

3 TABLE III. Neck Involvement and Distant Metastasis for Maxillary Sinus Squamous Cell Carcinoma ( ) Characteristic No. % Maxillary sinus squamous cell carcinoma 854 Neck involvement No neck involvement Unspecified LN involvement Unknown 92 Distant metastasis No distant metastasis Unknown 71 LN 5 lymph node. who had 5-year follow-up information was extracted from SEER 18 and imported into Excel 2013 (Microsoft, Redmond, WA). Each patient on the list was assigned the standard binary code according to end vital status ( 1 for patients who were alive or died of other causes at the end of the study period, and 0 for disease-specific deaths within the study period). Data were subsequently imported into JMP Statistical Discovery 11 (SAS Institute, Cary, NC) for Kaplan-Meier analysis, which provided DSS rates. Kaplan-Meier analysis was carried out for multiple parameters, including nodal involvement, distant metastasis, and TNM stage. Significance testing for survival analysis was performed via the log-rank test. RESULTS Patient Characteristics Eight hundred fifty-four cases of MSSCC were identified. Demographic data for this set of patients are available in Table I. The mean age at diagnosis was 66.6 years, with a standard deviation of 14.6 years. Most patients (87.4%) were aged > 50 years at the time of diagnosis. Males comprised 65.1% of cases, whereas females represented 34.9%. Whites were most commonly affected (74.6%), followed by blacks (13.3%) and Asians/ Pacific Islanders (11.4%). TABLE IV. Metastasis in Maxillary Sinus Squamous Cell Carcinoma by T Stage ( ) T Stage Neck Involvement Distant Metastasis T1 7.6% 0.0% T2 22.2% 0.0% T3 18.5% 0.0% T4 12.2% 6.8% TABLE V. Five-year Disease-Specific Survival for MSSCC Stratified by TNM and AJCC Stage ( ) Parameter No. DSS, % P* MSSCC overall T stage.0063 T T T T TX N stage <.0001 N N N N NX M stage.0183 M M MX AJCC stage <.0001 I II III IV UNK *Probability values do not take into account TX, NX, MX, or UNK cases. AJCC 5 American Joint Committee on Cancer; DSS 5 diseasespecific survival; MSSCC 5 maxillary sinus squamous cell carcinoma; UNK 5 unknown. Tumor Characteristics Clinicopathologic characteristics of MSSCC are available in Table II. The average tumor size was 4.7 cm, with a standard deviation of 2.0 cm. Histologic grade was available for 676 patients, of which most were moderately differentiated, grade II (43.3%), and poorly differentiated, grade III (42.0%). The next most common were well-differentiated (grade I) tumors at 12.4%. Undifferentiated (grade IV) tumors represented 2.2% of known cases. AJCC stage was known for 784 cases. Of these, stage IV was the most common (64.3%), followed by stage III (21.8%), stage I (8.5%), and stage II (5.4%). By T classification, T4 tumors were the most common (56.9%), followed by T3 (25.5%), T1 (9.8%), and T2 (7.8%). A majority (77.4%) of cases had no nodal involvement, whereas 8.1% were N1, 13.3% were N2, and 1.2% were N3. Distant metastasis was rare, with 96.0% of tumors classified as M0 and 4.0% as M1 (Table III). In terms of metastasis by T stage (Table IV), neck involvement was demonstrated in 7.6% of T1 tumors, 22.2% of T2 tumors, 18.5% of T3 tumors, and 12.2% of T4 tumors. Distant metastasis was not seen in T1 T3 tumors, but was present in 6.8% of T4 tumors. Incidence and Survival The incidence of MSSCC was per 100,000 people from 2000 to The calculated APC was 21.34% (P 5.070). In the same time interval, incidence by race was highest for blacks at per 100,000. This was significantly greater than for whites (0.106 per 100,000; P <.0001). There was no statistically significant difference between incidence in blacks compared to Asians/ 401

4 Fig. 1. Five-year Kaplan-Meier survival analysis of maxillary sinus squamous cell carcinoma stratified by T stage, n ( ); P < Pacific Islanders (0.140 per 100,000; P ) or American Indians/Alaska Natives (0.090 per 100,000; P ). The overall 5-year DSS for MSSCC (n 5 479) was 23.4%. Five-year DSS rates stratified by TNM classification and AJCC stage are available in Table V. By T stage (Fig. 1), 5-year DSS was 42.3% for T1 tumors, 17.2% for T2 tumors, 28.8% for T3 tumors, and 18.9% for T4 tumors (P , Table V). TX tumors had a 23.8% 5- year DSS. By N stage, N0 cases had a 5-year DSS of 26.1%, N1 had 12.2%, N2 had 6.3%, and N3 had 14.3% (P <.0001). NX tumors had a 5-year DSS of 33.1%. When comparing cases with no nodal involvement (N0) to cases with any nodal involvement (N1 N3), 5-year DSS for the former was 26.1% compared to 9.8% for the latter (P <.0001, Fig. 2). By distant metastasis, M1 cases had an 8.5% 5-year DSS whereas M0 cases had a 23.4% 5-year DSS (P , Fig. 3). Looking at AJCC stage (see Supporting Fig. 1 in the online version of this article), the highest 5-year DSS was for stage I tumors (49.5%), followed by stage III (32.3%), stage II (23.6%), and stage IV (17.4%; P <.0001). DISCUSSION Although our armamentarium of diagnostic and therapeutic tools for managing sinonasal cancers has expanded in recent years, the behavior of SCC at specific subsites in the sinonasal region has not been extensively studied. Previous SEER-based studies have focused on general epidemiologic, incidence, and survival trends for patients with sinonasal SCC. 4,5 As a result, there are no robust studies that specifically analyze the clinical behavior and metastatic potential of SCC based on specific sinonasal subsites. The goals of this study were to characterize the clinical behavior of, and delineate prognostic indicators for SCC for the maxillary sinus subsite. Approximately 3 5% of head and neck malignancies reportedly occur in the paranasal sinuses, of which roughly three-quarters involve the maxillary sinus. 5,8 In the current analysis, MSSCC was demonstrated to have an incidence of per 100,000, which is very low in 402 Fig. 2. Five-year Kaplan-Meier survival analysis of maxillary sinus squamous cell carcinoma comparing cases with no nodal involvement (N0) with cases with nodal involvement (N1 N3), n ( ); P < comparison to the approximate incidence of 30 per 100,000 for all head and neck cancers. 20 However, this rate is in accordance with previous studies that report an overall incidence of maxillary sinus cancer of <1 per 100, ,22 Although the APC for MSSCC in the current study was 21.34% from 2000 to 2012, this trend was not statistically significant. The present analysis is in accordance with a population-based study of paranasal sinus malignancies by Ansa et al. that demonstrated that whites (75.7%) and males (63.6%) and patients in the 7th decade of life were most often affected. 23 Although a majority of patients in this study were white, the incidence per 100,000 in blacks was significantly higher than in whites. Overall 5-year survival for paranasal sinus carcinoma has been reported to be 30.2%. 23 Our data suggest that the 5-year DSS for MSSCC is 23.4%. Nodal involvement and distant metastasis were both poor prognostic indicators. Patients with nodal involvement had a 5-year DSS of 9.8%, whereas those without nodal involvement had a 5-year DSS of 26.1% (Fig. 1). Likewise, distant Fig. 3. Five-year Kaplan-Meier survival analysis of maxillary sinus squamous cell carcinoma stratified by absence (M0) and presence (M1) of distant metastasis, n ( ); P

5 metastasis dropped 5-year DSS rates from 23.4% (M0) to 8.6% (Fig. 2). This reinforces the concept that identifying tumors prior to lymphatic or hematogenous spread has significant implications in terms of survival. The most common presenting symptoms of MSSCC are nonspecific and include pain, edema, obstruction, and epistaxis. 24 Thus, MSSCC may masquerade as a more benign process, and when treating patients presenting with these symptoms, otolaryngologists should maintain clinical suspicion of a more aggressive process. Our analysis of the data demonstrated that histologic grade was most commonly moderately or poorly differentiated (Table II). The most common T classification was noted to be T4 (56.9%). It has been posited that these tumors commonly present at higher stages because the paranasal sinuses are hollow air-filled cavities, thus accommodating significant tumor growth before signs and symptoms are apparent. 23 Moreover, it has been argued that due to limited lymphatic drainage pathways for the maxillary sinus, maxillary tumors can grow insidiously before demonstrating lymphatic involvement. 8 In the current analysis, only 4.0% of cases had distant metastasis, with a higher proportion (22.2%) demonstrating nodal involvement in the neck. These results indicate that despite the accommodating anatomy and limited lymphatic drainage, MSSCC demonstrates a degree of nodal involvement. Nodal involvement varied, but most patients (77.4%) were found to be N0 at the time of presentation. Very few patients (1.2%) were found to have nodal disease with at least one lymph node greater than 6 cm in diameter (N3 disease). Given that nodal involvement was seen with all T stages, the neck should be carefully assessed in all patients presenting with known MSSCC. Interestingly, neck involvement was most common for T2 tumors (22.2%). This finding is consistent with the study by Cantu et al., who demonstrated that T2 tumors of the maxillary sinus have the highest incidence of nodal positivity. 12 Their study also showed that nodal involvement is a poor prognostic factor, a conclusion supported by the current analysis. In terms of distant metastasis, our study demonstrates an important point for clinicians managing and treating these patients: T1 T3 tumors showed no distant metastasis, whereas T4 tumors demonstrated distant metastasis in 6.8% of cases. Therefore, one could make an argument that extensive workup searching for distant disease may not always be necessary. Extensive workup in these patients may cause unnecessary distress for both the patient and the clinician and places additional burden on an already strained healthcare system. However, despite this trend, judgment regarding metastatic workup should ultimately be made in accordance with an otolaryngologist s clinical suspicions, while keeping in mind that all patients diagnosed with malignant tumors should be appropriately staged. Although this study is the first specifically analyzing population-based variables for patients with metastatic MSSCC, there are certain limitations to this analysis. SEER contains data from 18 geographic locations within the United States, which may not necessarily reflect the general national population. Furthermore, a portion of patients for whom epidemiologic trends and tumor characteristics were analyzed were lost to followup and thus excluded from subsequent survival analysis. Additionally, although MSSCC is known to occur in the setting of inverted papilloma, data regarding the coincidence of these pathologies was not readily available in the database. Lastly, when calculating DSS, we censored patients who died of other causes, but it is unclear how SEER made these determinations and how stringent the protocols were for ensuring their accuracy. Nevertheless, the SEER database provides us with robust longitudinal cross-institutional data with standardized reporting and high external validity. 16,28 42 As such, we hope physicians will consider this analysis in their decision-making process when managing patients with MSSCC. CONCLUSION Maxillary sinus squamous cell carcinoma is a rare entity with poor overall prognosis. The majority of patients in this study were white males aged >50 years. Tumors are most commonly moderately (grade II) or poorly (grade III) differentiated, with a majority of cases classified as AJCC stage IV. 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