- Email: [email protected]
Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes
Accepted Manuscript Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes Robert J. Lee, BS, Elizabeth L. Tong, BS, Riki Patel, BS, Nihal Satyadev, BS, Russell E. Christensen, DDS, MS PII:
S2212-4403(15)01237-7
DOI:
10.1016/j.oooo.2015.09.019
Reference:
OOOO 1320
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 12 May 2015 Revised Date:
17 September 2015
Accepted Date: 24 September 2015
Please cite this article as: Lee RJ, Tong EL, Patel R, Satyadev N, Christensen RE, Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2015), doi: 10.1016/j.oooo.2015.09.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes Robert J. Lee BSa; Elizabeth L. Tong BSa, Riki Patel BSb; Nihal Satyadev BSc, Russell E. Christensen DDS, MSd a
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Conflict of Interest: None Financial Disclosures: None Funding for this work: None Abstract word count: 138 Manuscript word count: 2,314 Number of tables: 4 Number of figures: 2 Number of supplementary elements: None
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Dental student, UCLA School of Dentistry, Los Angeles, California. Master’s student, Department of Statistics, UCLA, Los Angeles, California. c Undergraduate student, Department of Life Sciences, UCLA, Los Angeles, California. d Associate professor, Department of Oral & Maxillofacial Pathology, UCLA School of Dentistry, Los Angeles, California. b
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Corresponding Author: Russell E. Christensen DDS, MS UCLA Department of Oral & Maxillofacial Pathology 10833 Le Conte Ave., CHS 53-058 Los Angeles, CA 90095 Phone: (310) 825-6140 E-mail: [email protected]
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Abstract Objective. To determine the demographics, prognostic factors, and optimal treatment modalities of patients diagnosed with malignant primary tumors of the sublingual gland.
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Materials and Methods. The Surveillance, Epidemiology, and End Results (SEER) registry contains 210 patients diagnosed with sublingual gland tumors in the SEER database. KaplanMeier and multivariate Cox regression analysis were performed on age, sex, race, histologic
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subtype, stage, and treatment modality.
Results. Kaplan-Meier analysis found an overall survival (OS) and disease-specific survival
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(DSS) at 5 years of 69% and 83% respectively. Multivariate analysis demonstrated that age, sex, stage, and surgery were predictors of OS, while stage was a predictor of DSS. Conclusions. Here we report, to our knowledge, the largest study to date investigating demographics, prognostic factors, and treatment modalities of patients diagnosed with primary
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malignant tumors of the sublingual gland. Increased age and stage correlated with decreased survival while female gender and surgical therapy correlated with increased survival in the overall population. Radiation therapy for patients diagnosed with adenoid cystic carcinoma in the
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sublingual gland was correlated with increased survival.
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Introduction Salivary gland tumors, which comprise 2.0-6.5% of all head and neck tumors, occur in the major salivary glands (parotid, submandibular, and sublingual) or in the minor salivary
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glands.1,2 Of all salivary gland tumors, sublingual gland tumors have been found to occur the least frequently, constituting only 0.3-1.0% of all epithelial salivary gland tumors.3–9 Sublingual gland tumors have a high frequency of malignancy of 70-90%. This is significantly higher than
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the frequency of malignancy of 15-32% for parotid gland tumors,41-45% for submandibular gland tumors, and 50% for minor salivary gland tumors.4,6–8,10,11
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Due to the low incidence of sublingual gland tumors, there is limited information in regards to treatment modalities, survival rates, and prognostic factors. The accepted treatment protocol is a wide surgical resection, with adjuvant radiation therapy for clinically advanced disease, high-grade tumors, or inadequate surgical margins.5,12,13 Although adjuvant radiotherapy
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has been shown to improve locoregional control, controversy still remains as to its benefit with regards to overall or disease-free survival.13,14
Much of the current existing literature for sublingual gland tumors consists of case
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reports and single institution studies, with large population data being limited to studies analyzing salivary gland tumors in general, rather than sublingual gland tumors specifically.1– The limited literature available presents challenges to understanding treatment,
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6,10,12–32
outcomes, and prognostic factors for sublingual gland tumors. The purpose of this study was to determine the demographics, prognostic factors, and optimal treatment outcomes of patients with primary malignant tumors of the sublingual gland in a larger population. Data from 210 patients diagnosed with a primary malignant sublingual gland tumor in the U.S. National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) cancer registry was used in order to analyze several patient demographics and disease characteristics to determine factors affecting
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both overall survival (OS) and disease-specific survival (DSS). The SEER database is a source of epidemiological information collected from a variety of diverse regions across the United States. The use of this database for clinical outcomes research has been previously validated for
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both salivary gland tumors and other malignancies of the head and neck.33–37
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Materials and Methods
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Data Source
In this study, data was collected from the SEER 18 Registries, which spans from 19732011 and is estimated to encompass 27.8% of the U.S. population, including 40% of Hispanics, 23% of African Americans, and 20 different U.S. geographic regions. This data was extracted in
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order to perform a population-based cohort analysis of patients diagnosed with a primary malignant tumor of the sublingual gland. Because the SEER database is publicly available and
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all patient data is de-identified, no institution review board approval was required for this study.
Study Participants
A total of 210 patients, diagnosed between 1973 and 2011 with primary epithelial
malignant tumor of the sublingual gland and confirmed by histological diagnosis, were identified in the SEER database by using the primary site cancer label C08.1 (sublingual gland). Patient
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demographic information obtained from the SEER databaseincluded age at diagnosis, sex, and race. The clinical variables obtained for this study were treatment with radiation therapy or surgical resection, overall survival (OS) in months, and disease-specific survival (DSS) in
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months. Pathologic variables obtained for this study included tumor grade, tumor histologic subtype (International Classification of Disease, Ninth Revision, Clinical Modification [ICD-9DM] code), tumor extent and size (from both extent of disease (EOD) and collaborative stage
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(CS) coding methods), and stage at presentation (American Joint Committee on Cancer (AJCC)). The SEER database records tumor grade as well-differentiated, moderately differentiated, poorly
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differentiated, and undifferentiated. We classified well-differentiated as low grade, moderately differentiated as intermediate grade, and grouped together poorly differentiated and undifferentiated into high grade. Additionally, in the SEER database, stage at presentation was recorded for patients diagnosed after 2003. For patients diagnosed in 2003 and earlier, stage at
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presentation was retroactively determined where possible using EOD and CS staging codes for tumor size, extent, and lymph node involvement according to AJCC protocol.
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Statistical Analysis
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Patient outcomes were quantified by 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 disease as reported in the SEER database. Median survival time was defined as the length of time, in years, in which half of the patients in the group with the disease were still alive. If at the end of the time period, there was an insufficient amount of deaths to reach this number, the median survival time was noted as undefined.
Kaplan-Meier survival analysis was used
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calculate OS and DSS curves, and the log-rank test was used to formally test differences in survival. Covariates were analyzed with univariate and multivariate Cox proportional hazards regression models using hazard ratios with 95% confidence intervals (CI) with regards to OS and
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DSS. Multivariate analysis covariates were chosen based on the variables identified in univariate analysis to be statistically significant. This minimizes the total number of covariates used in the multivariate analyses leading to improved generalizability of the findings and minimized
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instability in the model. Treatment modalities were included in all multivariate models as a default. Statistical significance was set at the p<0.05 threshold. Statistical analysis was
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performed using SPSS software (version 21.0; SPSS, Chicago, IL). This method has been previously validated.38,39
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Results
210 patients were diagnosed with primary epithelial sublingual gland tumors from 19732011 in the SEER database. The mean age was 58.7 years, ranging from 25-96 years old (Table
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1). 53.3% of the patients were female and 46.7% were male. 76.7% of the patients were Caucasian, 9.0% were African American, 7.1% were Asian, 2.9% were Pacific Islander, 1.0%
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were Native American, and 0.5% were other races or unknown. The most common histologic subtypes of sublingual gland tumors were mucoepidermoid carcinomas (38.6%) and adenoid cystic carcinomas (34.8%). Other notable histologic subtypes were squamous cell carcinomas (13.3%), adenocarcinomas (9.5%), and other or unknown (3.8%). The adenocarcinoma subtype consisted of papillary adenocarcinoma (0.5%), clear cell adenocarcinoma (0.9%) , mucinous adenocarcinoma (0.5%), polymorphous low-grade adenocarcinoma (0.9%), and adenocarcinoma,
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NOS (6.7%). 11.0% of the tumors were low grade, 32.4% intermediate grade, 16.7% high grade, and 40.0% were unknown grade. The stage at presentation for the entire population was 17.1% for stage I, 14.8% for stage II, 17.6% for stage III, 11.4% for stage IV, and 39.0% were
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unknown. For cases after 2003, 25.6% were stage I, 21.1% were stage II, 24.4% were stage III, 13.3% were stage IV, and 15.6% were unknown. For cases that were diagnosed 2003 and earlier, stage at presentation was retroactively determined and 10.8% were stage I, 10.0% were stage II,
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12.5% were stage III, 10.0% were stage IV, and 43.3% were unknown. The majority of patients, 93.8%, had surgery, whereas 6.2% had no surgery. 51.0% had radiation therapy, 45.2% had no
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radiation therapy, and it was unknown for 3.8% of the patients. The mean tumor size at presentation was 2.6 cm.
Kaplan-Meier Analysis
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Using Kaplan-Meier analysis, the OS was determined at 2 years (81%), 5 years (69%), and 10 years (57%). The DSS was also determined at 2 years (91%), 5 years (83%), and 10 years (76%). Kaplan-Meier analysis was also used to determine OS and DSS for grade, stage at
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presentation, and notable histologic subtypes (Figure 1, Table 2).
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Univariate and Multivariate Analysis
Univariate analysis showed that age (p<0.001 OS and p<0.001 DSS), sex (P<0.001 OS
and p=0.001 DSS), histologic subtype (p<0.001 OS and p<0.001 DSS), tumor grade (p=0.002 OS and p=0.019 DSS), stage at presentation (p<0.001 OS and p<0.001 DSS), and surgery performed (p<0.001 OS and p<0.001 DSS) were significant predictive factors in OS and DSS
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(Table 3). Univariate analysis was also performed on the adenoid cystic carcinoma and mucoepidermoid carcinoma populations. In the adenoid cystic carcinoma population, radiation therapy (p=0.004 OS and p=0.078 DSS) was a significant predictive factor for OS (Figure 2).
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Using the Cox proportional hazards model for multivariate analysis, stage at presentation (Hazard ratio (HR) 1.49 [95% Confidence interval (CI), 1.00-2.20]; p=0.048) and (HR 2.42 [95% CI, 1.14-5.14]; p=0.021) was the only significant predictive indicator for OS and DSS
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respectively. Other significant predictive factors for OS were age (HR 1.06 [95% CI, 1.03-1.09];
CI, 0.04-0.71); p=0.016) (Table 4).
Discussion
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p<0.001), sex (HR 0.36 [95% CI, 0.17-0.74]; p=0.006), and surgery performed (HR 0.16 [95%
Sublingual gland carcinomas account for only 0.3-1.0% of all salivary gland tumors.3–6
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As a result of their rarity, ambiguity remains as to the prognostic factors and optimal treatment options for patients diagnosed with sublingual gland carcinomas. The SEER database has the capability to help elucidate this ambiguity through allowing for the analysis of prognostic factors
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in survival with greater statistical power than previous studies, due to the larger sample size. However the SEER database does contain inherent limitations. The database lacks information
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regarding extent of surgical resection, margin status, patient comorbidities, and administration of chemotherapy as a treatment regimen. Additionally, lack of centralized review by a head and neck pathologist can lead to some misclassification. The limitation of missing chemotherapy data is not particularly problematic because chemotherapy is generally only used palliatively and there has been no demonstrated benefit in the induction or adjuvant setting.14 Nevertheless, this
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study represents, to our knowledge, the largest population based analysis of prognostic factors for survival in patients diagnosed with a sublingual gland tumor. Analysis of the demographics from the SEER database showed that the mean age for
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sublingual gland tumors was 58.7 years which is consistent with what has been reported in the literature.12,13 Previous studies have shown a slight female predominance for overall salivary gland tumors.18,23 However, in prior sublingual gland tumor studies there is controversy as to
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whether there is no sex predilection9 or a female predominance.4,5 This study found a slight female predominance for sublingual gland tumors, 1.14:1 female to male ratio. Consistent with
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the literature, mucoepidermoid carcinoma and adenoid cystic carcinoma were the most common histologic subtypes.1,4–6,10,13 However, squamous cell carcinoma presented with a higher than expected frequency. It is likely that some of the squamous cell carcinomas identified in this study may have mucosal origins rather than sublingual gland origins.9 Past studies have shown that
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most patients presented with an advanced stage at presentation (stage III or IV) because most sublingual tumors are asymptomatic.10,12,13 Surprisingly, in this study, only 29% of the tumors presented at stage III or IV, while 32% of tumors presented at stage I or II. This discrepancy
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from past studies may be due to the small sample sizes of past studies or the 39% of the tumors with unknown stage.12
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Female gender was considered a significant prognostic factor for OS and DSS in
univariate analysis and for OS in multivariate analysis. Sex did not correlate with survival in some past studies that analyzed salivary glands tumors as a whole.14,31 However, other studies of salivary gland tumors have shown that sex may be associated with increased survival.40–42 In this study, female gender was consistently a beneficial indicator of OS. Female gender has also been found to significantly improve survival in other forms of cancer such as non-small-cell lung
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cancer.43 However, for these other cancer types, there are currently conflicting reports on whether female gender significantly improves survival for all stages of cancer or just more treatable low-staged cancers.44–47 Lifestyle differences rather than an inherent biological
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advantage may play a role since sex has a greater impact on OS rather than DSS. Age at
presentation was also a prognostic indicator for OS and DSS in univariate analysis and OS in multivariate analysis. A possible explanation for this is that increased age may result in greater
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T-lymphocyte depletion, increased chance of developing metastasis, differences in disease management, or intolerance to the cytotoxic effects of chemotherapy.48,49
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Lower stage at presentation was found to significantly increase survival for both OS and DSS in univariate and multivariate analysis. This is consistent with past studies that analyzed salivary gland tumors as a whole and sublingual gland tumors.4,12,30 Stage at presentation impacts the course of treatment, and a higher stage indicates a wider excision, neck dissection, and
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adjuvant radiotherapy or chemotherapy.4,5,12,13 More aggressive treatment increases the chances of complications. Furthermore, a higher stage has been shown to be a predictive factor for recurrence in salivary gland carcinomas.32 Tumor recurrence has been shown to significantly
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decrease survival in sublingual gland tumors.12 In previous literature, sublingual gland tumors have been reported to typically present at an advanced stage because they generally manifest as
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asymptomatic swellings in the floor of the mouth and are often clinically misdiagnosed as a cyst or benign tumor.4,10,12,13 Thus, strict screening and early detection of sublingual gland tumors may lead to improved prognosis for patients diagnosed with a sublingual gland tumor. In regards to treatment options, surgical therapy was found to significantly improve
survival for both OS and DSS in univariate analysis and for OS in multivariate analysis. This is consistent with previous literature which has also shown surgical therapy improves patient
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prognoses.5,6,10 In addition, for adenoid cystic carcinomas, radiation therapy was found to improve survival. The use of adjuvant radiation therapy has been shown to be a positive prognostic factor in previous studies since it has been shown to improve locoregional control, but
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controversy still remains as to its benefit with regards to overall or disease-free survival.12–14 Thus, this study demonstrated that surgical resection improves survival for sublingual gland tumors while the radiation therapy improves survival for patients diagnosed with adenoid cystic
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carcinoma in the sublingual gland.
Conclusions
The rarity of sublingual gland tumors has led to limited understanding and controversy over its determinants of survival. Here we report, to our knowledge, the largest study to date of
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patients diagnosed with a malignant sublingual gland tumor in which we have shown that increased age and stage at presentation are correlated with decreased survival while female gender and surgical resection were correlated with increased survival. In addition, radiation
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therapy for patients diagnosed with adenoid cystic carcinoma in the sublingual gland was
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correlated with increased survival.
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References
Lukšić I, Virag M, Manojlović S, Macan D. Salivary gland tumours: 25 years of experience from a single institution in Croatia. J Craniomaxillofac Surg. 2012;40:e75-e81.
2.
Mariano F V, da Silva SD, Chulan TC, de Almeida OP, Kowalski LP. Clinicopathological factors are predictors of distant metastasis from major salivary gland carcinomas. Int J Oral Maxillofac Surg. 2011;40:504-509.
3.
Kumar VS, Prathi VS, Manne RK, Beeraka S, Natarajan K. Adenoid cystic carcinoma of sublingual salivary gland obstructing the submandibular salivary gland duct. J Clin Imaging Sci. 2013;3:10.
4.
Kumar AN, Nair PP, Thomas S, Raman PS, Bhambal A. Mucoepidermoid carcinoma of sublingual gland: a malignant neoplasm in an uncommon region. BMJ Case Rep. 2011.
5.
Sun G, Yang X, Tang E, Wen J, Lu M, Hu Q. The treatment of sublingual gland tumours. Int J Oral Maxillofac Surg. 2010;39:863-868.
6.
Rinaldo A, Shaha AR, Pellitteri PK, Bradley PJ, Ferlito A. Management of malignant sublingual salivary gland tumors. Oral Oncol. 2004;40:2-5.
7.
Barnes L, Eveson JW, Reichart P, Sidransky D. Pathology and Genetics of Head and Neck Tumours. WHO Classif Tumour. 2005;163-175.
8.
Andersen LJ, Therkildsen MH, Ockelmann HH, Bentzen JD, Schiødt T, Hansen HS. Malignant epithelial tumors in the minor salivary glands, the submandibular gland, and the sublingual gland. Prognostic factors and treatment results. Cancer. 1991;68:2431-2437.
9.
Ostman J, Anneroth G, Gustafsson H, Tavelin B. Malignant salivary gland tumours in Sweden 1960-1989--an epidemiological study. Oral Oncol. 1997;33:169-176.
10.
Ariyoshi Y, Shimahara M, Konda T, Tsuji M. Carcinoma ex pleomorphic adenoma of the sublingual gland: a case report. Int J Oral Sci. 2012;4:50-53.
12.
13.
SC
M AN U
TE D
EP
AC C
11.
RI PT
1.
Batsakis JG. Carcinomas of the submandibular and sublingual glands. Ann Otol Rhinol Laryngol. 1986; 95:211-212.
Yu T, Gao Q-H, Wang X-Y, Wen Y-M, Li L-J. Malignant sublingual gland tumors: a retrospective clinicopathologic study of 28 cases. Oncology. 2007;72:39-44. Zdanowski R, Dias FL, Barbosa MM, et al. Sublingual gland tumors: clinical, pathologic, and therapeutic analysis of 13 patients treated in a single institution. Head Neck. 2011;33:476-481.
ACCEPTED MANUSCRIPT
Bell RB, Dierks EJ, Homer L, Potter BE. Management and Outcome of Patients With Malignant Salivary Gland Tumors. J Oral Maxillofac Surg. 2005;63:917-928.
15.
Maruse Y, Kawano S, Kiyoshima T, et al. Case of mucoepidermoid carcinoma of the sublingual gland accompanied with extensive dystrophic calcification and intratumoral bone formation. Head Neck. March 2015.
16.
Luo C, Zhang Q, Chen L, Wang Y, Tan W. Carcinoma ex pleomorphic adenoma occurring in the sublingual gland: a case report. Hua Xi Kou Qiang Yi Xue Za Zhi. 2014;32:418-419.
17.
Leiser Y, Peled M, Wolff A, El-Naaj IA. Lymphoepithelial carcinoma--review of the treatment modalities and report of a rare case in the sublingual gland. J Oral Maxillofac Surg. 2014;72:823-828.
18.
Lawal AO, Adisa AO, Kolude B, Adeyemi BF, Olajide MA. A review of 413 salivary gland tumours in the head and neck region. J Clin Exp Dent. 2013;5:e218-e222.
19.
Eichhorn W, Precht C, Wehrmann M, et al. First description of a hybrid tumor of the sublingual gland. Anticancer Res. 2013;33:4567-4571.
20.
Nag D, Biswas PK, Mandal PK, Bhattacharyya NK, Gautam D, Mukhopadhyay S. Tumours of minor salivary glands--a clinicopathologic study. J Indian Med Assoc. 2012;110:567-569,
21.
Bombeccari GP, Guzzi GP, Pallotti F, Spadari F. Mucoepidermoid carcinoma of the sublingual gland associated with Sjögren’s syndrome. Indian J Cancer. 48:381-383.
22.
Papadogeorgakis N, Kalfarentzos EF, Vourlakou C, Malta F, Exarhos D. Simultaneous pleomorphic adenoma of the left parotid gland and adenoid cystic carcinoma of the contralateral sublingual salivary gland: a case report. Oral Maxillofac Surg. 2009;13:221224.
23.
Sirohi D, Sharma R, Sinha R, Suresh Menon P. Salivary gland neoplasms: an analysis of 74 cases. J Maxillofac Oral Surg. 2009;8:164-166.
25.
SC
M AN U
TE D
EP
AC C
24.
RI PT
14.
Weinreb I, Seethala RR, Perez-Ordoñez B, Chetty R, Hoschar AP, Hunt JL. Oncocytic mucoepidermoid carcinoma: clinicopathologic description in a series of 12 cases. Am J Surg Pathol. 2009;33:409-416. Bhatt V, Evans M, Malins TJ. Squamous cell carcinoma arising in the lining of an epidermoid cyst within the sublingual gland--a case report. Br J Oral Maxillofac Surg. 2008;46:683-685.
ACCEPTED MANUSCRIPT
Kwon Y-D, Biesterfeld S, Hansen T, Schwerdtfeger A, Kunkel M. Lymphadenomatous carcinoma of the sublingual gland: report of a first case in an unusual localization. Head Neck. 2008;30:1394-1398.
27.
Saito M, Nishiyama H, Maruyama S, Oda Y, Saku T, Hayashi T. Adenoid cystic carcinoma of sublingual gland involving the submandibular duct. Dentomaxillofac Radiol. 2008;37:421-424.
28.
Yu T, Gao Q, Wang X, Wen Y, Wang C, Zhang Y. A retrospective clinicopathologic study of 30 cases of sublingual gland malignant tumors. Hua Xi Kou Qiang Yi Xue Za Zhi. 2007;25:64-66.
29.
Sartorius C, Gille F, Bédrossian-Pfingsten J, Kempf H-G. Salivary duct carcinoma of the sublingual gland--a case report. Laryngorhinootologie. 2006;85:517-519.
30.
Da Cruz Perez DE, Pires FR, de Abreu Alves F, de Almeida OP, Kowalski LP. Sublingual salivary gland tumors: Clinicopathologic study of six cases. Oral Surgery, Oral Med Oral Pathol Oral Radiol Endodontology. 2005;100:449-453.
31.
Gurney TA, Eisele DW, Weinberg V, Shin E, Lee N. Adenoid cystic carcinoma of the major salivary glands treated with surgery and radiation. Laryngoscope. 2005;115:12781282.
32.
Shigeishi H, Ohta K, Okui G, et al. Clinicopathological analysis of salivary gland carcinomas and literature review. Mol Clin Oncol. 2015;3:202-206.
33.
Lee RJ, Arshi A, Schwartz HC, Christensen RE. Characteristics and prognostic factors of osteosarcoma of the jaws: a retrospective cohort study. JAMA Otolaryngol Head Neck Surg. 2015;141:470-477.
34.
Mallen-St Clair J, Arshi A, Tajudeen B, Abemayor E, St John M. Epidemiology and treatment of lacrimal gland tumors: a population-based cohort analysis. JAMA Otolaryngol Head Neck Surg. 2014;140:1110-1116.
35.
Tajudeen BA, Arshi A, Suh JD, St John M, Wang MB. Importance of tumor grade in esthesioneuroblastoma survival: a population-based analysis. JAMA Otolaryngol Head Neck Surg. 2014;140:1124-1129.
37.
SC
M AN U
TE D
EP
AC C
36.
RI PT
26.
Zeidan YH, Pekelis L, An Y, et al. Survival benefit for adjuvant radiation therapy in minor salivary gland cancers. Oral Oncol. 2015;51:438-445.
Patel NR, Sanghvi S, Khan MN, Husain Q, Baredes S, Eloy JA. Demographic trends and disease-specific survival in salivary acinic cell carcinoma: an analysis of 1129 cases. Laryngoscope. 2014;124:172-178.
ACCEPTED MANUSCRIPT
Mendelsohn AH, Elashoff DA, Abemayor E, St John MA. Surgery for papillary thyroid carcinoma: is lobectomy enough? Arch Otolaryngol Head Neck Surg. 2010;136:10551061.
39.
Miller ME, Elashoff DA, Abemayor E, St John M. Tonsillar squamous cell carcinoma: are we making a difference? Otolaryngol Head Neck Surg. 2011;145:236-241.
40.
Wahlberg P, Anderson H, Biörklund A, Möller T, Perfekt R. Carcinoma of the parotid and submandibular glands--a study of survival in 2465 patients. Oral Oncol. 2002;38:706-713.
41.
Terhaard CHJ, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head Neck. 2004;2:681-692;
42.
North CA, Lee DJ, Piantadosi S, Zahurak M, Johns ME. Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 1990;18:1319-1326.
43.
Nakamura H, Ando K, Shinmyo T, et al. Female Gender Is an Independent Prognostic Factor in Non-small-cell Lung Cancer: A Meta-analysis. Ann Thorac Cardiovasc Surg. 2011;17:469-480.
44.
Ringer G, Smith JM, Engel AM, Hendy MP, Lang J. Influence of sex on lung cancer histology, stage, and survival in a midwestern United States tumor registry. Clin Lung Cancer. 2005;7:180-182.
45.
Alexiou C, Onyeaka CVP, Beggs D, et al. Do women live longer following lung resection for carcinoma? Eur J Cardiothorac Surg. 2002;21:319-325.
46.
Martin LW, Correa AM, Hofstetter W, et al. The evolution of treatment outcomes for resected stage IIIA non-small cell lung cancer over 16 years at a single institution. J Thorac Cardiovasc Surg. 2005;130:1601-1610.
47.
Paesmans M, Sculier JP, Lecomte J, et al. Prognostic factors for patients with small cell lung carcinoma: analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer. 2000;89:523-533.
49.
SC
M AN U
TE D
EP
AC C
48.
RI PT
38.
Smith RB, Apostolakis LW, Karnell LH, et al. National Cancer Data Base report on osteosarcoma of the head and neck. Cancer. 2003;98:1670-1680. Argiris A, Li Y, Murphy BA, Langer CJ, Forastiere AA. Outcome of elderly patients with recurrent or metastatic head and neck cancer treated with cisplatin-based chemotherapy. J Clin Oncol. 2004;22:262-268.
SC
RI PT
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Figure Legends
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Figure 1. A. Kaplan-Meier estimates of overall survival (OS) for the entire cohort of patients. B.
Kaplan-Meier estimates for disease-specific survival (DSS) for the entire cohort of patients. C. Kaplan-Meier estimates of OS stratified by tumor grade. D. Kaplan-Meier estimates of DSS stratified by tumor grade. E. Kaplan-Meier estimates for OS stratified by stage at presentation.
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F.. Kaplan-Meier estimates of DSS stratified by stage at presentation. G. Kaplan-Meier estimates for OS stratified by histologic subtype. H. Kaplan-Meier estimates for DSS stratified by histologic subtype.
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Figure 2. A. Kaplan-Meier estimates of overall survival (OS) for the adenoid cystic carcinoma population stratified by application of radiation therapy. B. Kaplan-Meier estimates of disease-
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specific survival (DSS) for the adenoid cystic carcinoma population stratified by application of radiation therapy.
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76.7% 9.0% 7.1% 2.9% 1.0% 0.5%
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13.3% 9.5% 34.8% 38.6% 3.8%
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46.7% 53.3%
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Years 58.7 ± 13.7 58 25 96 Percentage (%)
11.0% 32.4% 16.7% 40.0% 17.1% 14.8% 17.6% 11.4% 39.0%
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Age Mean Median Min Max Characteristic Sex Male Female Race White Black Asian Pacific Islander Native American Other/Unknown Notable Histologic Subtypes Squamous Cell Carcinoma Adenocarcinoma Adenoid Cystic Carcinoma Mucoepidermoid Carcinoma Other/Unknown Tumor grade Low Intermediate High Unknown Stage at presentation Stage I Stage II Stage III Stage IV Unknown Surgery performed Yes No Unknown Radiation therapy Yes No Unknown Size (cm) Mean Median
93.8% 6.2% 0.0% 51.0% 45.2% 3.8%
2.6 ± 1.4 2.3
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Overall (OS) Disease-specific (DSS)
Overall
12.5
Undefined
Stage I/II
17.8
Undefined
Stage III/IV
6.3
Undefined
2.6
14.2
Squamous Cell Carcinoma
Adenocarcinoma
5.6
12.2
Adenoid Cystic Carcinoma
12.1
Undefined
Mucoepidermoid Carcinoma
21.2
Undefined
Low Grade
25.0
Undefined
Intermediate Grade
14.4
Undefined
High Grade
2.8
Undefined
Percent survival (%) 81%
at 5 years
69%
at 10 years
57%
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at 2 years
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Grade
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Histologic Subtype
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Stage at presentation
91%
83%
76%
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Characteristic
OS (log rank p) DSS (log rank p)
Age
<0.001
<0.001
Sex
<0.001
0.001
Race Histologic subtype
0.268
0.830
<0.001
<0.001
0.002
0.019
Stage at presentation
<0.001
<0.001
Surgery performed
<0.001
<0.001
Radiation therapy
0.839
0.665
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Grade
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Overall
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Characteristic
Overall survival (OS) HR (95% CI) p-value
Disease-specific survival (DSS) HR (95% CI) p-value
Overall Age Sex Histologic Subtype Stage at presentation Surgery Radiation therapy
1.06 (1.03-1.09) 0.36 (0.17-0.74) 0.75(0.47-1.12) 1.49 (1.00-2.20) 0.16 (0.04-0.71) 1.08 (0.48-2.44)
1.01 (0.96-1.06) 0.30 (0.08-1.09) 0.78 (0.33-1.83) 2.42 (1.14-5.14) 0.26 (0.03-2.24) 1.02 (0.23-4.60)
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0.722 0.068 0.782 0.021 0.221 0.983
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<0.001 0.006 0.218 0.048 0.016 0.858
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Statement of Clinical Relevance Surgical resection and detection of sublingual gland tumors at an early stage significantly improve patient prognosis. Radiation therapy for patients diagnosed with adenoid cystic
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carcinoma in the sublingual gland was correlated with increased survival.
S2212-4403(15)01237-7
DOI:
10.1016/j.oooo.2015.09.019
Reference:
OOOO 1320
To appear in:
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Received Date: 12 May 2015 Revised Date:
17 September 2015
Accepted Date: 24 September 2015
Please cite this article as: Lee RJ, Tong EL, Patel R, Satyadev N, Christensen RE, Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology (2015), doi: 10.1016/j.oooo.2015.09.019. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Malignant sublingual gland tumors: demographics, prognostic factors, and treatment outcomes Robert J. Lee BSa; Elizabeth L. Tong BSa, Riki Patel BSb; Nihal Satyadev BSc, Russell E. Christensen DDS, MSd a
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Conflict of Interest: None Financial Disclosures: None Funding for this work: None Abstract word count: 138 Manuscript word count: 2,314 Number of tables: 4 Number of figures: 2 Number of supplementary elements: None
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Dental student, UCLA School of Dentistry, Los Angeles, California. Master’s student, Department of Statistics, UCLA, Los Angeles, California. c Undergraduate student, Department of Life Sciences, UCLA, Los Angeles, California. d Associate professor, Department of Oral & Maxillofacial Pathology, UCLA School of Dentistry, Los Angeles, California. b
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Corresponding Author: Russell E. Christensen DDS, MS UCLA Department of Oral & Maxillofacial Pathology 10833 Le Conte Ave., CHS 53-058 Los Angeles, CA 90095 Phone: (310) 825-6140 E-mail: [email protected]
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Abstract Objective. To determine the demographics, prognostic factors, and optimal treatment modalities of patients diagnosed with malignant primary tumors of the sublingual gland.
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Materials and Methods. The Surveillance, Epidemiology, and End Results (SEER) registry contains 210 patients diagnosed with sublingual gland tumors in the SEER database. KaplanMeier and multivariate Cox regression analysis were performed on age, sex, race, histologic
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subtype, stage, and treatment modality.
Results. Kaplan-Meier analysis found an overall survival (OS) and disease-specific survival
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(DSS) at 5 years of 69% and 83% respectively. Multivariate analysis demonstrated that age, sex, stage, and surgery were predictors of OS, while stage was a predictor of DSS. Conclusions. Here we report, to our knowledge, the largest study to date investigating demographics, prognostic factors, and treatment modalities of patients diagnosed with primary
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malignant tumors of the sublingual gland. Increased age and stage correlated with decreased survival while female gender and surgical therapy correlated with increased survival in the overall population. Radiation therapy for patients diagnosed with adenoid cystic carcinoma in the
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sublingual gland was correlated with increased survival.
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Introduction Salivary gland tumors, which comprise 2.0-6.5% of all head and neck tumors, occur in the major salivary glands (parotid, submandibular, and sublingual) or in the minor salivary
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glands.1,2 Of all salivary gland tumors, sublingual gland tumors have been found to occur the least frequently, constituting only 0.3-1.0% of all epithelial salivary gland tumors.3–9 Sublingual gland tumors have a high frequency of malignancy of 70-90%. This is significantly higher than
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the frequency of malignancy of 15-32% for parotid gland tumors,41-45% for submandibular gland tumors, and 50% for minor salivary gland tumors.4,6–8,10,11
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Due to the low incidence of sublingual gland tumors, there is limited information in regards to treatment modalities, survival rates, and prognostic factors. The accepted treatment protocol is a wide surgical resection, with adjuvant radiation therapy for clinically advanced disease, high-grade tumors, or inadequate surgical margins.5,12,13 Although adjuvant radiotherapy
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has been shown to improve locoregional control, controversy still remains as to its benefit with regards to overall or disease-free survival.13,14
Much of the current existing literature for sublingual gland tumors consists of case
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reports and single institution studies, with large population data being limited to studies analyzing salivary gland tumors in general, rather than sublingual gland tumors specifically.1– The limited literature available presents challenges to understanding treatment,
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6,10,12–32
outcomes, and prognostic factors for sublingual gland tumors. The purpose of this study was to determine the demographics, prognostic factors, and optimal treatment outcomes of patients with primary malignant tumors of the sublingual gland in a larger population. Data from 210 patients diagnosed with a primary malignant sublingual gland tumor in the U.S. National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) cancer registry was used in order to analyze several patient demographics and disease characteristics to determine factors affecting
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both overall survival (OS) and disease-specific survival (DSS). The SEER database is a source of epidemiological information collected from a variety of diverse regions across the United States. The use of this database for clinical outcomes research has been previously validated for
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both salivary gland tumors and other malignancies of the head and neck.33–37
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Materials and Methods
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Data Source
In this study, data was collected from the SEER 18 Registries, which spans from 19732011 and is estimated to encompass 27.8% of the U.S. population, including 40% of Hispanics, 23% of African Americans, and 20 different U.S. geographic regions. This data was extracted in
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order to perform a population-based cohort analysis of patients diagnosed with a primary malignant tumor of the sublingual gland. Because the SEER database is publicly available and
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all patient data is de-identified, no institution review board approval was required for this study.
Study Participants
A total of 210 patients, diagnosed between 1973 and 2011 with primary epithelial
malignant tumor of the sublingual gland and confirmed by histological diagnosis, were identified in the SEER database by using the primary site cancer label C08.1 (sublingual gland). Patient
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demographic information obtained from the SEER databaseincluded age at diagnosis, sex, and race. The clinical variables obtained for this study were treatment with radiation therapy or surgical resection, overall survival (OS) in months, and disease-specific survival (DSS) in
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months. Pathologic variables obtained for this study included tumor grade, tumor histologic subtype (International Classification of Disease, Ninth Revision, Clinical Modification [ICD-9DM] code), tumor extent and size (from both extent of disease (EOD) and collaborative stage
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(CS) coding methods), and stage at presentation (American Joint Committee on Cancer (AJCC)). The SEER database records tumor grade as well-differentiated, moderately differentiated, poorly
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differentiated, and undifferentiated. We classified well-differentiated as low grade, moderately differentiated as intermediate grade, and grouped together poorly differentiated and undifferentiated into high grade. Additionally, in the SEER database, stage at presentation was recorded for patients diagnosed after 2003. For patients diagnosed in 2003 and earlier, stage at
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presentation was retroactively determined where possible using EOD and CS staging codes for tumor size, extent, and lymph node involvement according to AJCC protocol.
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Statistical Analysis
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Patient outcomes were quantified by 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 disease as reported in the SEER database. Median survival time was defined as the length of time, in years, in which half of the patients in the group with the disease were still alive. If at the end of the time period, there was an insufficient amount of deaths to reach this number, the median survival time was noted as undefined.
Kaplan-Meier survival analysis was used
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calculate OS and DSS curves, and the log-rank test was used to formally test differences in survival. Covariates were analyzed with univariate and multivariate Cox proportional hazards regression models using hazard ratios with 95% confidence intervals (CI) with regards to OS and
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DSS. Multivariate analysis covariates were chosen based on the variables identified in univariate analysis to be statistically significant. This minimizes the total number of covariates used in the multivariate analyses leading to improved generalizability of the findings and minimized
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instability in the model. Treatment modalities were included in all multivariate models as a default. Statistical significance was set at the p<0.05 threshold. Statistical analysis was
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performed using SPSS software (version 21.0; SPSS, Chicago, IL). This method has been previously validated.38,39
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Results
210 patients were diagnosed with primary epithelial sublingual gland tumors from 19732011 in the SEER database. The mean age was 58.7 years, ranging from 25-96 years old (Table
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1). 53.3% of the patients were female and 46.7% were male. 76.7% of the patients were Caucasian, 9.0% were African American, 7.1% were Asian, 2.9% were Pacific Islander, 1.0%
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were Native American, and 0.5% were other races or unknown. The most common histologic subtypes of sublingual gland tumors were mucoepidermoid carcinomas (38.6%) and adenoid cystic carcinomas (34.8%). Other notable histologic subtypes were squamous cell carcinomas (13.3%), adenocarcinomas (9.5%), and other or unknown (3.8%). The adenocarcinoma subtype consisted of papillary adenocarcinoma (0.5%), clear cell adenocarcinoma (0.9%) , mucinous adenocarcinoma (0.5%), polymorphous low-grade adenocarcinoma (0.9%), and adenocarcinoma,
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NOS (6.7%). 11.0% of the tumors were low grade, 32.4% intermediate grade, 16.7% high grade, and 40.0% were unknown grade. The stage at presentation for the entire population was 17.1% for stage I, 14.8% for stage II, 17.6% for stage III, 11.4% for stage IV, and 39.0% were
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unknown. For cases after 2003, 25.6% were stage I, 21.1% were stage II, 24.4% were stage III, 13.3% were stage IV, and 15.6% were unknown. For cases that were diagnosed 2003 and earlier, stage at presentation was retroactively determined and 10.8% were stage I, 10.0% were stage II,
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12.5% were stage III, 10.0% were stage IV, and 43.3% were unknown. The majority of patients, 93.8%, had surgery, whereas 6.2% had no surgery. 51.0% had radiation therapy, 45.2% had no
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radiation therapy, and it was unknown for 3.8% of the patients. The mean tumor size at presentation was 2.6 cm.
Kaplan-Meier Analysis
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Using Kaplan-Meier analysis, the OS was determined at 2 years (81%), 5 years (69%), and 10 years (57%). The DSS was also determined at 2 years (91%), 5 years (83%), and 10 years (76%). Kaplan-Meier analysis was also used to determine OS and DSS for grade, stage at
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presentation, and notable histologic subtypes (Figure 1, Table 2).
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Univariate and Multivariate Analysis
Univariate analysis showed that age (p<0.001 OS and p<0.001 DSS), sex (P<0.001 OS
and p=0.001 DSS), histologic subtype (p<0.001 OS and p<0.001 DSS), tumor grade (p=0.002 OS and p=0.019 DSS), stage at presentation (p<0.001 OS and p<0.001 DSS), and surgery performed (p<0.001 OS and p<0.001 DSS) were significant predictive factors in OS and DSS
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(Table 3). Univariate analysis was also performed on the adenoid cystic carcinoma and mucoepidermoid carcinoma populations. In the adenoid cystic carcinoma population, radiation therapy (p=0.004 OS and p=0.078 DSS) was a significant predictive factor for OS (Figure 2).
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Using the Cox proportional hazards model for multivariate analysis, stage at presentation (Hazard ratio (HR) 1.49 [95% Confidence interval (CI), 1.00-2.20]; p=0.048) and (HR 2.42 [95% CI, 1.14-5.14]; p=0.021) was the only significant predictive indicator for OS and DSS
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respectively. Other significant predictive factors for OS were age (HR 1.06 [95% CI, 1.03-1.09];
CI, 0.04-0.71); p=0.016) (Table 4).
Discussion
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p<0.001), sex (HR 0.36 [95% CI, 0.17-0.74]; p=0.006), and surgery performed (HR 0.16 [95%
Sublingual gland carcinomas account for only 0.3-1.0% of all salivary gland tumors.3–6
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As a result of their rarity, ambiguity remains as to the prognostic factors and optimal treatment options for patients diagnosed with sublingual gland carcinomas. The SEER database has the capability to help elucidate this ambiguity through allowing for the analysis of prognostic factors
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in survival with greater statistical power than previous studies, due to the larger sample size. However the SEER database does contain inherent limitations. The database lacks information
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regarding extent of surgical resection, margin status, patient comorbidities, and administration of chemotherapy as a treatment regimen. Additionally, lack of centralized review by a head and neck pathologist can lead to some misclassification. The limitation of missing chemotherapy data is not particularly problematic because chemotherapy is generally only used palliatively and there has been no demonstrated benefit in the induction or adjuvant setting.14 Nevertheless, this
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study represents, to our knowledge, the largest population based analysis of prognostic factors for survival in patients diagnosed with a sublingual gland tumor. Analysis of the demographics from the SEER database showed that the mean age for
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sublingual gland tumors was 58.7 years which is consistent with what has been reported in the literature.12,13 Previous studies have shown a slight female predominance for overall salivary gland tumors.18,23 However, in prior sublingual gland tumor studies there is controversy as to
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whether there is no sex predilection9 or a female predominance.4,5 This study found a slight female predominance for sublingual gland tumors, 1.14:1 female to male ratio. Consistent with
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the literature, mucoepidermoid carcinoma and adenoid cystic carcinoma were the most common histologic subtypes.1,4–6,10,13 However, squamous cell carcinoma presented with a higher than expected frequency. It is likely that some of the squamous cell carcinomas identified in this study may have mucosal origins rather than sublingual gland origins.9 Past studies have shown that
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most patients presented with an advanced stage at presentation (stage III or IV) because most sublingual tumors are asymptomatic.10,12,13 Surprisingly, in this study, only 29% of the tumors presented at stage III or IV, while 32% of tumors presented at stage I or II. This discrepancy
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from past studies may be due to the small sample sizes of past studies or the 39% of the tumors with unknown stage.12
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Female gender was considered a significant prognostic factor for OS and DSS in
univariate analysis and for OS in multivariate analysis. Sex did not correlate with survival in some past studies that analyzed salivary glands tumors as a whole.14,31 However, other studies of salivary gland tumors have shown that sex may be associated with increased survival.40–42 In this study, female gender was consistently a beneficial indicator of OS. Female gender has also been found to significantly improve survival in other forms of cancer such as non-small-cell lung
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cancer.43 However, for these other cancer types, there are currently conflicting reports on whether female gender significantly improves survival for all stages of cancer or just more treatable low-staged cancers.44–47 Lifestyle differences rather than an inherent biological
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advantage may play a role since sex has a greater impact on OS rather than DSS. Age at
presentation was also a prognostic indicator for OS and DSS in univariate analysis and OS in multivariate analysis. A possible explanation for this is that increased age may result in greater
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T-lymphocyte depletion, increased chance of developing metastasis, differences in disease management, or intolerance to the cytotoxic effects of chemotherapy.48,49
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Lower stage at presentation was found to significantly increase survival for both OS and DSS in univariate and multivariate analysis. This is consistent with past studies that analyzed salivary gland tumors as a whole and sublingual gland tumors.4,12,30 Stage at presentation impacts the course of treatment, and a higher stage indicates a wider excision, neck dissection, and
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adjuvant radiotherapy or chemotherapy.4,5,12,13 More aggressive treatment increases the chances of complications. Furthermore, a higher stage has been shown to be a predictive factor for recurrence in salivary gland carcinomas.32 Tumor recurrence has been shown to significantly
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decrease survival in sublingual gland tumors.12 In previous literature, sublingual gland tumors have been reported to typically present at an advanced stage because they generally manifest as
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asymptomatic swellings in the floor of the mouth and are often clinically misdiagnosed as a cyst or benign tumor.4,10,12,13 Thus, strict screening and early detection of sublingual gland tumors may lead to improved prognosis for patients diagnosed with a sublingual gland tumor. In regards to treatment options, surgical therapy was found to significantly improve
survival for both OS and DSS in univariate analysis and for OS in multivariate analysis. This is consistent with previous literature which has also shown surgical therapy improves patient
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prognoses.5,6,10 In addition, for adenoid cystic carcinomas, radiation therapy was found to improve survival. The use of adjuvant radiation therapy has been shown to be a positive prognostic factor in previous studies since it has been shown to improve locoregional control, but
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controversy still remains as to its benefit with regards to overall or disease-free survival.12–14 Thus, this study demonstrated that surgical resection improves survival for sublingual gland tumors while the radiation therapy improves survival for patients diagnosed with adenoid cystic
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carcinoma in the sublingual gland.
Conclusions
The rarity of sublingual gland tumors has led to limited understanding and controversy over its determinants of survival. Here we report, to our knowledge, the largest study to date of
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patients diagnosed with a malignant sublingual gland tumor in which we have shown that increased age and stage at presentation are correlated with decreased survival while female gender and surgical resection were correlated with increased survival. In addition, radiation
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therapy for patients diagnosed with adenoid cystic carcinoma in the sublingual gland was
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correlated with increased survival.
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References
Lukšić I, Virag M, Manojlović S, Macan D. Salivary gland tumours: 25 years of experience from a single institution in Croatia. J Craniomaxillofac Surg. 2012;40:e75-e81.
2.
Mariano F V, da Silva SD, Chulan TC, de Almeida OP, Kowalski LP. Clinicopathological factors are predictors of distant metastasis from major salivary gland carcinomas. Int J Oral Maxillofac Surg. 2011;40:504-509.
3.
Kumar VS, Prathi VS, Manne RK, Beeraka S, Natarajan K. Adenoid cystic carcinoma of sublingual salivary gland obstructing the submandibular salivary gland duct. J Clin Imaging Sci. 2013;3:10.
4.
Kumar AN, Nair PP, Thomas S, Raman PS, Bhambal A. Mucoepidermoid carcinoma of sublingual gland: a malignant neoplasm in an uncommon region. BMJ Case Rep. 2011.
5.
Sun G, Yang X, Tang E, Wen J, Lu M, Hu Q. The treatment of sublingual gland tumours. Int J Oral Maxillofac Surg. 2010;39:863-868.
6.
Rinaldo A, Shaha AR, Pellitteri PK, Bradley PJ, Ferlito A. Management of malignant sublingual salivary gland tumors. Oral Oncol. 2004;40:2-5.
7.
Barnes L, Eveson JW, Reichart P, Sidransky D. Pathology and Genetics of Head and Neck Tumours. WHO Classif Tumour. 2005;163-175.
8.
Andersen LJ, Therkildsen MH, Ockelmann HH, Bentzen JD, Schiødt T, Hansen HS. Malignant epithelial tumors in the minor salivary glands, the submandibular gland, and the sublingual gland. Prognostic factors and treatment results. Cancer. 1991;68:2431-2437.
9.
Ostman J, Anneroth G, Gustafsson H, Tavelin B. Malignant salivary gland tumours in Sweden 1960-1989--an epidemiological study. Oral Oncol. 1997;33:169-176.
10.
Ariyoshi Y, Shimahara M, Konda T, Tsuji M. Carcinoma ex pleomorphic adenoma of the sublingual gland: a case report. Int J Oral Sci. 2012;4:50-53.
12.
13.
SC
M AN U
TE D
EP
AC C
11.
RI PT
1.
Batsakis JG. Carcinomas of the submandibular and sublingual glands. Ann Otol Rhinol Laryngol. 1986; 95:211-212.
Yu T, Gao Q-H, Wang X-Y, Wen Y-M, Li L-J. Malignant sublingual gland tumors: a retrospective clinicopathologic study of 28 cases. Oncology. 2007;72:39-44. Zdanowski R, Dias FL, Barbosa MM, et al. Sublingual gland tumors: clinical, pathologic, and therapeutic analysis of 13 patients treated in a single institution. Head Neck. 2011;33:476-481.
ACCEPTED MANUSCRIPT
Bell RB, Dierks EJ, Homer L, Potter BE. Management and Outcome of Patients With Malignant Salivary Gland Tumors. J Oral Maxillofac Surg. 2005;63:917-928.
15.
Maruse Y, Kawano S, Kiyoshima T, et al. Case of mucoepidermoid carcinoma of the sublingual gland accompanied with extensive dystrophic calcification and intratumoral bone formation. Head Neck. March 2015.
16.
Luo C, Zhang Q, Chen L, Wang Y, Tan W. Carcinoma ex pleomorphic adenoma occurring in the sublingual gland: a case report. Hua Xi Kou Qiang Yi Xue Za Zhi. 2014;32:418-419.
17.
Leiser Y, Peled M, Wolff A, El-Naaj IA. Lymphoepithelial carcinoma--review of the treatment modalities and report of a rare case in the sublingual gland. J Oral Maxillofac Surg. 2014;72:823-828.
18.
Lawal AO, Adisa AO, Kolude B, Adeyemi BF, Olajide MA. A review of 413 salivary gland tumours in the head and neck region. J Clin Exp Dent. 2013;5:e218-e222.
19.
Eichhorn W, Precht C, Wehrmann M, et al. First description of a hybrid tumor of the sublingual gland. Anticancer Res. 2013;33:4567-4571.
20.
Nag D, Biswas PK, Mandal PK, Bhattacharyya NK, Gautam D, Mukhopadhyay S. Tumours of minor salivary glands--a clinicopathologic study. J Indian Med Assoc. 2012;110:567-569,
21.
Bombeccari GP, Guzzi GP, Pallotti F, Spadari F. Mucoepidermoid carcinoma of the sublingual gland associated with Sjögren’s syndrome. Indian J Cancer. 48:381-383.
22.
Papadogeorgakis N, Kalfarentzos EF, Vourlakou C, Malta F, Exarhos D. Simultaneous pleomorphic adenoma of the left parotid gland and adenoid cystic carcinoma of the contralateral sublingual salivary gland: a case report. Oral Maxillofac Surg. 2009;13:221224.
23.
Sirohi D, Sharma R, Sinha R, Suresh Menon P. Salivary gland neoplasms: an analysis of 74 cases. J Maxillofac Oral Surg. 2009;8:164-166.
25.
SC
M AN U
TE D
EP
AC C
24.
RI PT
14.
Weinreb I, Seethala RR, Perez-Ordoñez B, Chetty R, Hoschar AP, Hunt JL. Oncocytic mucoepidermoid carcinoma: clinicopathologic description in a series of 12 cases. Am J Surg Pathol. 2009;33:409-416. Bhatt V, Evans M, Malins TJ. Squamous cell carcinoma arising in the lining of an epidermoid cyst within the sublingual gland--a case report. Br J Oral Maxillofac Surg. 2008;46:683-685.
ACCEPTED MANUSCRIPT
Kwon Y-D, Biesterfeld S, Hansen T, Schwerdtfeger A, Kunkel M. Lymphadenomatous carcinoma of the sublingual gland: report of a first case in an unusual localization. Head Neck. 2008;30:1394-1398.
27.
Saito M, Nishiyama H, Maruyama S, Oda Y, Saku T, Hayashi T. Adenoid cystic carcinoma of sublingual gland involving the submandibular duct. Dentomaxillofac Radiol. 2008;37:421-424.
28.
Yu T, Gao Q, Wang X, Wen Y, Wang C, Zhang Y. A retrospective clinicopathologic study of 30 cases of sublingual gland malignant tumors. Hua Xi Kou Qiang Yi Xue Za Zhi. 2007;25:64-66.
29.
Sartorius C, Gille F, Bédrossian-Pfingsten J, Kempf H-G. Salivary duct carcinoma of the sublingual gland--a case report. Laryngorhinootologie. 2006;85:517-519.
30.
Da Cruz Perez DE, Pires FR, de Abreu Alves F, de Almeida OP, Kowalski LP. Sublingual salivary gland tumors: Clinicopathologic study of six cases. Oral Surgery, Oral Med Oral Pathol Oral Radiol Endodontology. 2005;100:449-453.
31.
Gurney TA, Eisele DW, Weinberg V, Shin E, Lee N. Adenoid cystic carcinoma of the major salivary glands treated with surgery and radiation. Laryngoscope. 2005;115:12781282.
32.
Shigeishi H, Ohta K, Okui G, et al. Clinicopathological analysis of salivary gland carcinomas and literature review. Mol Clin Oncol. 2015;3:202-206.
33.
Lee RJ, Arshi A, Schwartz HC, Christensen RE. Characteristics and prognostic factors of osteosarcoma of the jaws: a retrospective cohort study. JAMA Otolaryngol Head Neck Surg. 2015;141:470-477.
34.
Mallen-St Clair J, Arshi A, Tajudeen B, Abemayor E, St John M. Epidemiology and treatment of lacrimal gland tumors: a population-based cohort analysis. JAMA Otolaryngol Head Neck Surg. 2014;140:1110-1116.
35.
Tajudeen BA, Arshi A, Suh JD, St John M, Wang MB. Importance of tumor grade in esthesioneuroblastoma survival: a population-based analysis. JAMA Otolaryngol Head Neck Surg. 2014;140:1124-1129.
37.
SC
M AN U
TE D
EP
AC C
36.
RI PT
26.
Zeidan YH, Pekelis L, An Y, et al. Survival benefit for adjuvant radiation therapy in minor salivary gland cancers. Oral Oncol. 2015;51:438-445.
Patel NR, Sanghvi S, Khan MN, Husain Q, Baredes S, Eloy JA. Demographic trends and disease-specific survival in salivary acinic cell carcinoma: an analysis of 1129 cases. Laryngoscope. 2014;124:172-178.
ACCEPTED MANUSCRIPT
Mendelsohn AH, Elashoff DA, Abemayor E, St John MA. Surgery for papillary thyroid carcinoma: is lobectomy enough? Arch Otolaryngol Head Neck Surg. 2010;136:10551061.
39.
Miller ME, Elashoff DA, Abemayor E, St John M. Tonsillar squamous cell carcinoma: are we making a difference? Otolaryngol Head Neck Surg. 2011;145:236-241.
40.
Wahlberg P, Anderson H, Biörklund A, Möller T, Perfekt R. Carcinoma of the parotid and submandibular glands--a study of survival in 2465 patients. Oral Oncol. 2002;38:706-713.
41.
Terhaard CHJ, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head Neck. 2004;2:681-692;
42.
North CA, Lee DJ, Piantadosi S, Zahurak M, Johns ME. Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 1990;18:1319-1326.
43.
Nakamura H, Ando K, Shinmyo T, et al. Female Gender Is an Independent Prognostic Factor in Non-small-cell Lung Cancer: A Meta-analysis. Ann Thorac Cardiovasc Surg. 2011;17:469-480.
44.
Ringer G, Smith JM, Engel AM, Hendy MP, Lang J. Influence of sex on lung cancer histology, stage, and survival in a midwestern United States tumor registry. Clin Lung Cancer. 2005;7:180-182.
45.
Alexiou C, Onyeaka CVP, Beggs D, et al. Do women live longer following lung resection for carcinoma? Eur J Cardiothorac Surg. 2002;21:319-325.
46.
Martin LW, Correa AM, Hofstetter W, et al. The evolution of treatment outcomes for resected stage IIIA non-small cell lung cancer over 16 years at a single institution. J Thorac Cardiovasc Surg. 2005;130:1601-1610.
47.
Paesmans M, Sculier JP, Lecomte J, et al. Prognostic factors for patients with small cell lung carcinoma: analysis of a series of 763 patients included in 4 consecutive prospective trials with a minimum follow-up of 5 years. Cancer. 2000;89:523-533.
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Smith RB, Apostolakis LW, Karnell LH, et al. National Cancer Data Base report on osteosarcoma of the head and neck. Cancer. 2003;98:1670-1680. Argiris A, Li Y, Murphy BA, Langer CJ, Forastiere AA. Outcome of elderly patients with recurrent or metastatic head and neck cancer treated with cisplatin-based chemotherapy. J Clin Oncol. 2004;22:262-268.
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Figure Legends
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Figure 1. A. Kaplan-Meier estimates of overall survival (OS) for the entire cohort of patients. B.
Kaplan-Meier estimates for disease-specific survival (DSS) for the entire cohort of patients. C. Kaplan-Meier estimates of OS stratified by tumor grade. D. Kaplan-Meier estimates of DSS stratified by tumor grade. E. Kaplan-Meier estimates for OS stratified by stage at presentation.
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F.. Kaplan-Meier estimates of DSS stratified by stage at presentation. G. Kaplan-Meier estimates for OS stratified by histologic subtype. H. Kaplan-Meier estimates for DSS stratified by histologic subtype.
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Figure 2. A. Kaplan-Meier estimates of overall survival (OS) for the adenoid cystic carcinoma population stratified by application of radiation therapy. B. Kaplan-Meier estimates of disease-
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specific survival (DSS) for the adenoid cystic carcinoma population stratified by application of radiation therapy.
ACCEPTED MANUSCRIPT Table 1: Demographics
76.7% 9.0% 7.1% 2.9% 1.0% 0.5%
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13.3% 9.5% 34.8% 38.6% 3.8%
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Years 58.7 ± 13.7 58 25 96 Percentage (%)
11.0% 32.4% 16.7% 40.0% 17.1% 14.8% 17.6% 11.4% 39.0%
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Age Mean Median Min Max Characteristic Sex Male Female Race White Black Asian Pacific Islander Native American Other/Unknown Notable Histologic Subtypes Squamous Cell Carcinoma Adenocarcinoma Adenoid Cystic Carcinoma Mucoepidermoid Carcinoma Other/Unknown Tumor grade Low Intermediate High Unknown Stage at presentation Stage I Stage II Stage III Stage IV Unknown Surgery performed Yes No Unknown Radiation therapy Yes No Unknown Size (cm) Mean Median
93.8% 6.2% 0.0% 51.0% 45.2% 3.8%
2.6 ± 1.4 2.3
ACCEPTED MANUSCRIPT Table 2: Survival data Median survival (years)
Overall (OS) Disease-specific (DSS)
Overall
12.5
Undefined
Stage I/II
17.8
Undefined
Stage III/IV
6.3
Undefined
2.6
14.2
Squamous Cell Carcinoma
Adenocarcinoma
5.6
12.2
Adenoid Cystic Carcinoma
12.1
Undefined
Mucoepidermoid Carcinoma
21.2
Undefined
Low Grade
25.0
Undefined
Intermediate Grade
14.4
Undefined
High Grade
2.8
Undefined
Percent survival (%) 81%
at 5 years
69%
at 10 years
57%
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at 2 years
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Grade
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Histologic Subtype
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Stage at presentation
91%
83%
76%
ACCEPTED MANUSCRIPT Table 3: Univariate analysis of variables
Characteristic
OS (log rank p) DSS (log rank p)
Age
<0.001
<0.001
Sex
<0.001
0.001
Race Histologic subtype
0.268
0.830
<0.001
<0.001
0.002
0.019
Stage at presentation
<0.001
<0.001
Surgery performed
<0.001
<0.001
Radiation therapy
0.839
0.665
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Overall
ACCEPTED MANUSCRIPT Table 4: Cox proportional hazards model for multivariate analysis of overall sublingual gland tumors
Characteristic
Overall survival (OS) HR (95% CI) p-value
Disease-specific survival (DSS) HR (95% CI) p-value
Overall Age Sex Histologic Subtype Stage at presentation Surgery Radiation therapy
1.06 (1.03-1.09) 0.36 (0.17-0.74) 0.75(0.47-1.12) 1.49 (1.00-2.20) 0.16 (0.04-0.71) 1.08 (0.48-2.44)
1.01 (0.96-1.06) 0.30 (0.08-1.09) 0.78 (0.33-1.83) 2.42 (1.14-5.14) 0.26 (0.03-2.24) 1.02 (0.23-4.60)
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0.722 0.068 0.782 0.021 0.221 0.983
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<0.001 0.006 0.218 0.048 0.016 0.858
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Statement of Clinical Relevance Surgical resection and detection of sublingual gland tumors at an early stage significantly improve patient prognosis. Radiation therapy for patients diagnosed with adenoid cystic
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carcinoma in the sublingual gland was correlated with increased survival.