eFigure. Overall and Disease-Specific Survival Stratified by Tumor Size
Lee RJ, Tan AP, Tong EL, Satyadev N, Christensen RE. Epidemiology, Prognostic Factors, and Treatment of Malignant Submandibular Gland TumorsA Population-Based Cohort Analysis. JAMA Otolaryngol Head Neck Surg. 2015;141(10):905-912. doi:10.1001/jamaoto.2015.1745
Malignant tumors of the submandibular gland are uncommon, leading to limited information regarding prognostic factors and difficulty in evaluating treatment modalities.
To investigate the correlates of survival in patients with primary malignant tumors of the submandibular gland.
Design, Setting, and Participants
Data from 2626 patients with a diagnosis of primary tumors of the submandibular gland between 1973 and 2011 in the Surveillance, Epidemiology, and End Results database were used in a retrospective population-based cohort analysis. Kaplan-Meier analysis along with multivariate Cox regression analysis was performed to determine prognostic factors in overall survival (OS) and disease-specific survival (DSS).
Patients were treated with surgery, radiation therapy, both, or neither.
Main Outcomes and Measures
Overall and disease-specific survival.
We identified 2626 patients with a diagnosis of primary malignant tumors of the submandibular gland, 52.9% male and 47.1% female, with a mean (range) age of 61.3 (7-101) years. Adenoid cystic carcinoma (36.0%) was the most prevalent histologic subtype, followed by squamous cell carcinoma (18.1%), mucoepidermoid carcinoma (16.9%), and adenocarcinoma (13.7%). Kaplan-Meier analysis demonstrated an OS and DSS of 65% and 74% at 2 years, 54% and 67% at 5 years, and 40% and 60% at 10 years, respectively. Multivariate Cox regression analysis revealed independent predictors of OS and DSS to be age (HR, 1.04 [95% CI, 1.03-1.04], P < .001; HR, 1.02 [95% CI, 1.01-1.03], P < .001), sex (HR, 0.69 [95% CI, 0.57-0.84], P < .001; HR, 0.73 [95% CI, 0.56-0.96], P = .02), tumor grade (HR, 1.47 [95% CI, 1.19-1.81], P < .001; HR, 1.67 [95% CI, 1.25-2.25], P = .001), stage at presentation (HR, 1.56 [95% CI, 1.41-1.72], P < .001; HR, 1.96 [95% CI, 1.69-2.28], P < .001), and surgical resection (HR, 0.55 [95% CI, 0.41-0.74], P < .001; HR, 0.51 [95% CI, 0.35-0.75], P = .001).
Conclusions and Relevance
We report, to our knowledge, the largest study to date focused on correlates of survival in submandibular gland malignant neoplasms. Multivariate analysis found that older age at diagnosis, high tumor grade, and later stage at presentation were correlated with decreased survival whereas female sex and surgical resection were correlated with increased survival. In addition, a 3-cm tumor cutoff size was demonstrated above which was associated with a significantly less favorable prognosis. Radiation therapy had mixed association with survival, dependent on tumor size and subtype.
Malignant primary tumors of the salivary glands account for less than 5% of all cancers of the head and neck.1 The most common tumor location in the salivary glands is in the parotid gland, whereas tumors in the submandibular gland are less common; only 5% to 15% of all salivary gland neoplasms occur in the submandibular gland.2- 7 Submandibular gland tumors have a frequency of malignancy of roughly 43%, almost double that of the parotid gland.8,9 In general, tumors of the submandibular gland are associated with higher rates of malignancy and less favorable prognoses when compared with other primary tumors of the salivary glands.2,5,10- 12
Because of the relatively low incidence of submandibular gland tumors, it has been difficult to evaluate treatment modalities, and limited information is available in the literature regarding survival and prognostic factors. In almost all cases of primary tumors of all salivary glands, surgery is the primary treatment modality.6 Patients with submandibular gland carcinoma are more likely to undergo radical resection of the affected gland in comparison with patients with other forms of salivary gland cancers; such procedures are more extensive and include the removal of the adjacent muscles and nerves.6,13- 15 However, the role of radiation therapy to provide enhanced locoregional control for the treatment of submandibular gland malignant neoplasms is still unclear.1,2,7,13,15- 17
This study focused on determining the incidence and survival of, to our knowledge, the largest population of patients to date with a diagnosis of primary malignant tumors of the submandibular gland. Data from 2626 patients with a diagnosis of submandibular gland cancer from 1973 through 2011 in the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer registry were used to analyze several patient and disease characteristics to determine possible factors affecting both overall survival (OS) and disease-specific survival (DSS). Much of the existing literature consists of small case series and reports from single- and multicenter studies, with limited large-population data.4,14,15,18- 24 A previous SEER database analysis on submandibular gland cancer was performed in 2004 on data from 370 patients who received a diagnosis from 1988 through 1998.2 Our study expands on the previous SEER database analysis through increasing the sample size, analyzing DSS, and performing statistical analysis on patient populations stratified by histologic subtype, stage, and tumor size. Use of this database for clinical outcomes research has been validated in previous studies investigating several types of cancers of the head and neck.25- 30
Data were gathered from the SEER 18 Registries, estimated to encompass 27.8% of the US population, including 40% of Hispanics, 23% of blacks, and 20 different US geographic regions. Because the SEER database is publicly available and all patient data are deidentified, no institutional review board approval or informed consent was required for this study.
A total of 2626 patients who received a diagnosis between 1973 and 2011 of a primary epithelial malignant tumor of the submandibular gland, confirmed by histological diagnosis, were identified within the SEER database by using the primary site cancer label C8.0 (submandibular gland). Patient data within the SEER database included demographic variables for age at diagnosis, sex, and race. Pathologic variables for this study included tumor histologic subtype (International Classification of Diseases, Ninth Revision, Clinical Modification code), tumor grade (categorized into 2 groups: low grade and high grade), tumor extent, lymph node involvement, tumor size (from both extent of disease and collaborative stage coding methods, divided into 2 groups: tumors ≤3 and >3 cm), and tumor stage at presentation (American Joint Committee on Cancer [AJCC]). The clinical variables used in our analysis were treatment with radiation (yes or no), treatment with surgery (yes or no), OS in months, and DSS in months. For the purposes of this study, well-differentiated and moderately differentiated histological subtypes were grouped together and classified as low grade, and poorly differentiated and undifferentiated histological subtypes were grouped together and classified as high grade. The AJCC stages are recorded in the SEER database for patients who received a diagnosis after 2003; for cases diagnosed before 2003, AJCC stages were retroactively determined where possible using extent of disease and collaborative stage staging codes for tumor size, extent, and lymph node involvement according to AJCC protocol.
Patient outcomes were measured on the basis of OS, the time in months between diagnosis and death from any cause, and DSS, the time in months between diagnosis and death directly caused by the primary tumor as reported in the SEER database. Median survival time was defined as the smallest length of time, in years, in which half the patients in the group with a diagnosis of the disease are still alive; if at the end of the period there were not sufficient deaths to reach this number, the median survival time is listed as undefined. Kaplan-Meier survival analysis was used to evaluate differences between survival curves. The log-rank test was used to determine statistical differences using the threshold P < .05. Covariates were chosen for multivariate Cox proportional hazards regression models with 95% confidence intervals with regards to OS and DSS. Multivariate analysis was conducted for the following groups of patients: overall patients with submandibular gland tumors, patients grouped by tumor stage (stage I or II and stage III or IV), tumor size (primary tumors ≤3 and >3 cm), and tumor histologic subtype (squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma). Tumor size, extent, and lymph node involvement were not used in the multivariate analysis because these were each used to determine tumor stage at presentation, so using these variables in addition to stage at presentation would violate the principle of excluding linearly codependent variables. Using this methodology, there were no less than 10 events per covariate for each model.31 Statistical analysis was performed using SPSS software, version 21.0 (SPSS).
Data on 2626 patients with a diagnosis of primary epithelial tumor of the submandibular gland from 1973 through 2011 were extracted from the SEER database. Quiz Ref IDA total of 52.9% of patients were male and 47.1% were female (Table 1). Mean (range) age of diagnosis was 61.3 (7-101) years. A total of 81.9% of patients were white, 8.7% were black, and 9.4% were other races. Quiz Ref IDPatients presented with various histological subtypes of submandibular gland tumor, with the most common being adenoid cystic carcinoma (36.0%), followed by squamous cell carcinoma (18.1%), mucoepidermoid carcinoma (16.9%), and adenocarcinoma (13.7%). A total of 24.8% of tumors were classified as low-grade malignancy and 28.8% as high-grade malignancy, whereas for 46.4% of tumors the grade was unknown at the time of presentation. At presentation, 16.6% of tumors were classified as stage I, 11.2% as stage II, 16.0% as stage III, 20.1% as stage IV, and 36.0% had unknown stage. A total of 87.4% of patients were treated with surgery, whereas 57.8% of patients received radiation therapy as part of treatment. Mean (SD) tumor size at presentation was 3.0 (2.0) cm, while median tumor size at presentation was 2.5 cm.
Using Kaplan-Meier analysis, 2-year OS and DSS for tumors of the submandibular gland were determined to be 65% and 74%, 5-year survival was 54% and 67%, and 10-year survival was 40% and 60%, respectively, with median (SE) survival being 7.1 (0.4) years for OS and 23.0 (2.5) years for DSS (Table 2). Kaplan-Meier analysis was also performed for notable histologic subtypes, stage at presentation, and tumor size (Figure, Table 2, and eFigure in the Supplement).
The results of the multivariate Cox regression analysis of OS and DSS for the overall population, as well as stratified by tumor stage and size, are reported in Table 3. Table 4 contains multivariate Cox regression analysis of OS and DSS broken down by histologic subtype. Independent correlates of OS and DSS for these different populations included age at diagnosis, sex, grade, stage at presentation, and surgery. Quiz Ref IDOlder age at diagnosis, higher grade, and later stage at presentation were found to have a negative impact on survival whereas female sex and surgical resection had a positive impact on survival.
Tumors presenting in the submandibular gland are uncommon, making up only 5% to 15% of all salivary gland neoplasms.2- 7 Because of the relatively low incidence of this malignant neoplasm, the majority of studies on submandibular gland tumors have been limited to case reports and small single- or multi-institution studies. In addition, they are often conducted within larger studies on tumors of other major salivary gland tumors, leading to uncertainty of the prognostic factors and optimal treatment for submandibular gland malignant neoplasms.4,12,14,15,20,32 The SEER database allows for analysis of prognostic factors in survival with greater statistical power than previous studies. The SEER database has been previously validated to have the capability to find correlates of survival in many types of head and neck cancer.25,33- 36 However, fundamental limitations exist in such a study design. Quiz Ref IDThe database lacks information on patient comorbidities, extent of surgical resection, margin status, and administration of chemotherapy as a treatment regimen. This limitation of missing chemotherapy data is likely not problematic for this study on submandibular gland tumors because chemotherapy has not been shown to be effective in the treatment of salivary gland cancer and has been recommended for use only in recurrence, palliative care, and rapidly progressive disease.16 Furthermore, there are concerns of tumor misclassification because there is a lack of centralized review by a head and neck pathologist.
This study represents, to our knowledge, the largest population-based analysis of prognostic factors for survival in patients with tumors of the submandibular gland, including analysis based on tumor stage, size, and type. The large sample size of this study allowed for the comparison of survival among several primary histologic tumor subtypes within the submandibular gland. However, because of the rarity of some of these histologic subtypes leading to an inadequate number of cases for sufficient statistical power, median survival and multivariate analysis were calculated only for primary adenoid cystic carcinoma, adenocarcinoma, mucoepidermoid carcinoma, and squamous cell carcinoma. The most common malignant histologic tumor subtype reported in this study was adenoid cystic carcinoma (36.0%) (Table 1), which matches what has been reported in previous studies.32,37,38 Primary squamous cell carcinoma was reported in this database at a higher frequency than expected. This may be due to the difficulty in distinguishing between metastatic squamous cell carcinoma to the submandibular gland, primary mucoepidermoid tumors, and true primary squamous cell carcinoma, which may have led to some misclassification of tumor types.2 We also report the incidence of mucoepidermoid carcinoma to be 16.9%, which is similar to what has been reported in other studies.5,12,32,38,39 The incidence of adenocarcinoma in the patients whom we reviewed (13.7%) matches what has been reported in some studies but is higher compared with other studies.32,38,39Quiz Ref ID Adenoid cystic carcinoma demonstrated the best median OS (12.1 years), whereas squamous cell carcinoma exhibited the lowest (1.9 years), matching what has been reported in the literature.2
Analysis of survival data from the SEER database showed that larger tumor size and advanced tumor stage at presentation were associated with a decrease in median OS. Kaplan-Meier survival curves also demonstrated a tumor size cutoff of 3 cm, above which the prognosis significantly decreases. Overall survival of the entire population was found to be 65%, 54%, and 40% for 2, 5, and 10 years, respectively, which is consistent with what has been reported in the literature (50% 5-year OS, 36% 10-year OS).7 Disease-specific survival of the entire population was found to be 67% at 5 years and 60% at 10 years, compared with 60% for 5 years and 50% for 10 years in other studies.7,40
This study found, through multivariate analysis of the overall population as well as stage at presentation, tumor size, and histologic subtype subcategories, that independent correlates of OS and DSS generally included age at diagnosis, sex, grade, stage at presentation, and receipt of surgery. Mean age at diagnosis was 61.3 years for patients in this study, which is similar to what has previously been reported in the literature.7,21 Older age was associated with significantly worse OS and DSS, which is largely in accordance with other published studies.2,7,15,32,38 The hazard ratio for older age demonstrates a larger impact on OS than on DSS because older patients with submandibular cancer may have poorer survival as a result of the presence of comorbidities or intolerance for cytotoxic effects of chemotherapy.41
Female sex was found to be more commonly a beneficial factor in OS rather than DSS in most analyses. Examination of existing literature reveals that many studies of submandibular gland cancer do not report sex to be a significant prognostic indicator, including the previous SEER analysis on submandibular gland cancer.2,10,32 This discrepancy with the previous SEER analysis is likely due to the previous study removing late-stage tumors from their study. The present study found that female sex has a positive impact on survival for late-stage tumors but not early-stage tumors, so these findings are consistent with the previous SEER study finding that female sex is not a significant prognostic indicator for early-stage submandibular gland tumors. Also consistent with our study, broader studies on salivary gland cancer have reported that sex may be associated with increased survival in some instances.38,42,43 In other cancers, female survival advantage was found to be unrelated to tumor characteristics, which may explain why female sex has a more pronounced positive effect on OS than on DSS.44
High-grade tumors were demonstrated to significantly decrease both OS and DSS, which confirms what has already been reported in the literature.7,10,32,45 High-grade mucoepidermoid carcinomas have been reported to demonstrate an increased propensity for distant metastasis and are associated with poorer survival rates.2,6 Another study reported that higher-grade adenoid cystic carcinomas arising in the salivary glands were more likely to recur, in part due to difficulty of complete surgical excision of higher-grade tumors, which tended to be larger and more invasive.46
Tumor stage at presentation was also shown to be a prognostic factor in OS and DSS using multivariate analysis. Tumor stage has been reported as a significant factor affecting the recommended course of treatment in cases of submandibular gland cancer due to its function as a predictor of locoregional control, as well as disease-free survival. Patients with higher-stage tumors are more likely to undergo adjuvant radiation therapy in addition to surgical treatment in an attempt to achieve better locoregional control; however, the 5-year survival rates for stage III and IV tumors remain significantly worse than those for stage I and II tumors.6,7,15,18 Patients with higher-stage III and IV tumors also experienced a higher recurrence rate, which has been associated with decreased survival.7
In analyzing treatment options for submandibular gland cancer, it was found that surgical treatment is an independent predictor of improved OS and DSS, which is consistent with several previous reports.6,7,11,14,22 Multivariate analysis on cohorts, separated by the critical cutoff tumor size of 3 cm, found that surgery and radiation therapy were both significant independent and positive correlates of survival for tumors larger than 3 cm. Radiation therapy has only recently become part of conventional treatment for submandibular gland tumors, which may explain its mixed results in our multivariate analysis of different tumors; it was associated with decreased survival for stage I and II DSS and mucoepidermoid carcinoma OS and DSS. In the past, the recommended treatment consisted solely of surgery without radiation therapy, so the overall percentage of patients receiving radiation therapy was much lower than it is currently, which could affect our results.39,47 Furthermore, in many cases, patients who are selected to receive radiation therapy without surgery are chosen because of their poor chances of surviving surgery or because of the presence of nonresectable disease, which also may affect our results.7,48 Because of the retrospective nature of this study and changes in treatment trends, it is difficult to make treatment recommendations based on our results, so future studies are needed to further investigate the efficacy of combining adjuvant radiation therapy with surgical resection.
The rarity of primary malignant submandibular gland tumors has led to uncertainty over prognostic factors and optimal treatment modalities. Here we report the largest study to date, in which we found that the correlates of survival for both OS and DSS include age at diagnosis, sex, tumor grade, stage at presentation, and receipt of surgical therapy. In addition, we demonstrated a 3-cm critical tumor size cutoff above which was associated with significantly worsened prognosis, as well as demonstrating that receipt of radiation therapy has mixed association with survival dependent on tumor subtype and size.
Submitted for Publication: March 18, 2015; final revision received July 8, 2015; accepted July 17, 2015.
Corresponding Author: Russell E. Christensen, DDS, MS, Department of Oral and Maxillofacial Pathology, University of California–Los Angeles, 10833 Le Conte Ave, CHS 53-058, Los Angeles, CA 90095 (firstname.lastname@example.org).
Published Online: September 17, 2015. doi:10.1001/jamaoto.2015.1745.
Author Contributions: Mr Lee had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Mssrs Lee and Tan served as co–first authors and contributed equally to this work.
Study concept and design: Lee, Christensen.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Lee, Tan, Tong.
Critical revision of the manuscript for important intellectual content: Lee, Tan, Satyadev, Christensen.
Statistical analysis: Lee, Satyadev.
Administrative, technical, or material support: Satyadev, Christensen.
Study supervision: Christensen.
Conflict of Interest Disclosures: None reported.