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  Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 55  |  Issue : 1  |  Page : 98-104
 

Prognostic factors in parotid cancers: Clinicopathological and treatment factors influencing outcomes


1 Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Radiotherapy, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication23-Aug-2018

Correspondence Address:
Dr. Deepa Nair
Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_503_17

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 » Abstract 


Background: Parotid cancers are uncommon and have a relatively long natural history. Determination of prognostic factors affecting the outcome is difficult. Materials and Methods: The primary objective was to determine the demographic, clinical, histopathology and treatment-related factors affecting overall survival (OS) in parotid cancers. The secondary objective was to study the impact of these factors on disease-free survival (DFS) and patterns of failure. Data of consecutive patients who underwent parotidectomy for primary parotid malignancy between July 2006 and April 2015 with at least 6 months of posttreatment follow-up were retrospectively retrieved. Patients whose follow-up status was known at the time of analysis were included. One hundred and sixty-five patients met the inclusion criteria. Results: The median follow-up was 38 months. The mean OS and DFS were 141.03 and 124.38 months, respectively. Age > 45 years affected both OS and DFS (P = 0.00 and 0.002 respectively) adversely. Advanced T stage affected adversely OS in univariate (P = 0.00) but not in multivariate analysis (P = 0.91) and DFS in both univariate (P = 0.00) and multivariate analysis (P = 0.005). Nodal positivity adversely affected survival adversely in univariate (P = 0.00 for OS and DFS) and multivariate analysis (P = 0.022 for OS and P = 0.001 for DFS). Resection margin of < 5mm affected OS as compared to a margin of ≥5mm (P = 0.03). Conclusions: Nodal positivity is the single most important factor affecting survival in parotid cancers. A histopathological resection margin of at least 5 mm is desirable. Advanced age along with high grade, advanced T and N stages need to be considered for adjuvant treatment.


Keywords: Lymphatic metastasis, parotid cancers, parotid neoplasms, prognostic factors, retrospective studies, risk assessment, survival analysis


How to cite this article:
Chakrabarti S, Nair D, Malik A, Qayyumi B, Nair S, Agrawal JP, Chaturvedi P. Prognostic factors in parotid cancers: Clinicopathological and treatment factors influencing outcomes. Indian J Cancer 2018;55:98-104

How to cite this URL:
Chakrabarti S, Nair D, Malik A, Qayyumi B, Nair S, Agrawal JP, Chaturvedi P. Prognostic factors in parotid cancers: Clinicopathological and treatment factors influencing outcomes. Indian J Cancer [serial online] 2018 [cited 2018 Dec 11];55:98-104. Available from: http://www.indianjcancer.com/text.asp?2018/55/1/98/239601





 » Introduction Top


Parotid cancers are uncommon and constitute <1%–3% of all head and neck malignancies.[1] Due to the rarity, treatment of these malignancies varies considerably depending on individual and institutional preferences. To help formulate a uniform treatment guideline, we conducted a retrospective analysis on the prognostic significance of various factors affecting the outcome in malignant parotid neoplasms treated in a tertiary cancer center. The primary objective of our study was to determine the demographic, clinical, histopathology, and treatment-related factors that affected overall survival (OS). Our secondary objective was to study the impact of these factors on disease-free survival (DFS) and the pattern of failure in these patients.


 » Materials and Methods Top


We performed a retrospective study on all patients who underwent parotidectomy between July 2006 and April 2015 at our institution. Of the 224 consecutive patients operated for primary parotid malignancies, we included only those with at least 6 months posttreatment completion whose follow-up status was known at the time of analysis (February 2016). One hundred and sixty-five patients met the inclusion criteria [Figure 1]. Data were retrieved from case record files and electronic medical records. All the eligible patients were staged according to the preoperative clinical examination and radiological imaging. All patients underwent parotidectomy, the extent of which was decided by operating surgeon, depending on the clinical and intraoperative findings. The extent of neck dissection was determined by clinical staging and grading as well as an intraoperative frozen section of nodes when required. Patients received adjuvant therapy as per histopathology report and prior treatment received.
Figure 1: Study design

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Parotid tumors are characterized by a lot of heterogeneity in relation to histopathologic subtypes.[11] Owing to the relatively small number of patients in each subtype, the analysis was done using tumor grade and not specific histology. Different tumor histologies were classified into low grade (low-grade mucoepidermoid carcinoma, acinic cell carcinoma, and low-grade myoepithelial carcinoma) and high-grade tumors (intermediate and high grade mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary duct carcinoma, pleomorphic adenoma ex carcinoma, high-grade myoepithelial carcinoma, adenocarcinoma, and squamous cell carcinoma [SCC]).[3] As only 35 patients in the series had intermediate-grade mucoepidermoid carcinoma, they were included in high-grade tumors and not as a separate group. Histopathological margin status was divided into 3 categories-tumor at the resection margin or <2 mm of any resection margin, 2 mm to ≤5 from any resection margin, and ≥5mm away from all resection margins.

Statistical methods

OS, disease-free survival DFS, locoregional failure, and distant metastasis (DM) rates were calculated using Kaplan–Meier method. The differences in survival rates were assessed by the log-rank test. OS was calculated from the date of registration to the date of death from any cause or last follow-up whichever was earlier. DFS was calculated from the date of registration to date of recurrence (local, regional, locoregional, or distant) or date of the last follow-up whichever was earlier. To identify predictors of outcome, we performed a univariate analysis for each of the following variables-age (≤45 years vs. >45 years, based on the median age being 46 years), gender, clinical tumor stage (T1+T2 vs. T3+T4), nodal status (N0 vs. N+), resection margin status, tumor grade (low vs. high), perineural invasion (PNI), and lymphovascular spread (LVS), previous surgery (completion surgery following incomplete resection vs. treatment naïve patients) and adjuvant treatment (no adjuvant vs. adjuvant radiotherapy with/without chemotherapy) [Figure 1].

The variables that had prognostic potential as suggested by the univariate analysis were subjected to multivariate analysis with the Cox proportional hazards regression model. As the numbers of events occurred were few, only those factors most significant on univariate analysis were assessed on multivariate analysis. All statistical tests were two-sided, and a P = 0.05 or less was considered statistically significant. Analysis was performed using IBM SPSS Statistics for Windows, Version 21.0. (Armonk, NY: IBM Corp). Released 2012.


 » Results Top


We found 165 eligible patients who were operated for primary parotid malignancy with a minimum follow-up of 6 months after completion of treatment. The patient demographics are depicted in [Table 1]. There was a slight male preponderance (male-female ratio 1.5:1). The median age of presentation was 46 years (range: 12–87 years). Patients with early and advanced T stage were equally distributed in the study. Node-negative patients (N0) dominated our study population (73.9%). Most patients (67.27%) had high-grade tumors. PNI was present in 22.42% tumors and 12% harbored LVS.
Table 1: Patient demographics (n=165)

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The most common surgery performed was radical parotidectomy (42.4%) followed by superficial parotidectomy (41.2%) and total conservative parotidectomy (16.4%). Sixty-three percent patients were treatment naïve whereas 37% had undergone some form of surgical procedure previously. The previous surgical treatment most commonly included incisional/excisional biopsy or inappropriate extirpation.

About 64% patients received adjuvant treatment. Of these, 18% received concomitant chemotherapy along with radiotherapy. There were various indications of radiotherapy which included high-grade tumors, advanced stage tumors, positive resection margin, PNI, LVS, metastatic neck nodes, or a combination of these. Chemotherapy was most commonly given to patients with extracapsular nodal spread.

The mean and median follow-up was 43.5 months and 38 months, respectively (6 months-163 months]. The estimated mean OS was 141.03 (±5.24) months, 95% confidence interval (CI) (130.75–151.32). The estimated mean DFS was 124.38 (±6.07) months, 95% CI (112.48–136.29). Locoregional failure was present in 22 patients (isolated in 18 and along with DM in 4 patients) while DM was present in 14 patients (isolated in 10 patients).

Demographic prognostic factors

Age >45 years was a significant prognostic factor with older patients having worse OS (P = 0.000), DFS (P = 0.002), increased chances of locoregional failure (P = 0.027), and DM (P = 0.039) as compared to younger (age ≤45 years) patients [Figure 2].
Figure 2: Kaplan–Meier estimates of effect of age on overall survival

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There was no significant difference in survival or failure pattern between males and females [Table 2].
Table 2: Univariate analysis of outcomes

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Clinical prognostic factors

Tumor and nodal stages were found to be major prognostic determinants. Patients with advanced T stage had worse OS as compared to those with early disease in univariate analysis (P = 0.00), but the difference was not significant in multivariate analysis (P = 0.91). DFS was significantly worse in advanced T stage in univariate (P = 0.00) as well as in multivariate analysis (P = 0.005, hazard ratio [HR] 4.66 95% CI [1.58–13.72]). Locoregional failure and DM were also significantly worse in advanced T stage (P = 0.00 in univariate and P = 0.02, HR 4.41 95% CI [1.25–15.51] in multivariate analysis for locoregional failure and P = 0.001 in univariate P = 0.039, HR 8.82 95% CI [1.11–70.02] in multivariate analysis for DM).

Patients with nodal positivity (N+) had worse survival as compared to node negative (N0) patients in both univariate [Figure 3] and [Figure 4] and multivariate analysis (P = 0.00 in univariate and P = 0.02, HR 3.41 95% CI [1.19–9.73] in multivariate analysis for OS and P = 0.00 on univariate and P = 0.001HR 3.45; 95% CI [1.63–7.28] in multivariate analysis for DFS). Locoregional failure and DM were significantly more in node-positive patients (P = 0.00 in univariate and 0.013, HR 3.06 95% CI [1.26–7.43] in multivariate analysis for locoregional failure and P = 0.00 in univariate and 0.026 HR 3.58 95% CI [1.16–11.03] in multivariate analysis for DM).
Figure 3: Kaplan–Meier estimates of effect of nodal metastasis on overall survival

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Figure 4: Kaplan–Meier estimates of effect of nodal metastasis on disease-free survival

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Histopathological prognostic factors

Margin of resection was found to be a significant prognostic determinant. Patients who had a resection margin of <5mm had worse survival outcomes as compared to those with a resection margin ≥5 mm (P = 0.03 for OS and 0.004 for DFS) [Figure 5]. There was no difference in OS (P = 0.135) whether the margins were ≥2mm or <2 mm, however, a worse DFS (P = 0.001) was observed in the latter group.
Figure 5: Kaplan–Meier estimates of effect of margins on overall survival

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In univariate analysis, tumor grade was found to be of prognostic significance with high-grade tumors having worse survival outcomes as compared to low-grade ones (P = 0.001 for OS and 0.003 for DFS). Locoregional failure was also more common in high-grade tumors (P = 0.019); however, no significant difference in DM was observed (P = 0.06) In multivariate analysis, grade did not significantly affect OS (P = 0.92), however, high-grade tumors had a trend toward worse DFS (P = 0.05, HR 2.79, 95% CI [0.96–8.15]). The presence of PNI and LVS significantly affected survival although only 22% and 12% patients in our series had PNI and LVS, respectively [Table 2] and [Table 3].
Table 3: Multivariate analysis

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Treatment-related prognostic factors

Completion parotid surgery following previous incomplete resection did not impact any of the outcomes assessed when compared to treatment naïve patients.

In our study, adjuvant treatment improved both OS and DFS (P = 0.004 for both OS and DFS). There were reduced instances of both locoregional failure (P = 0.011) and DM (P = 0.041) in patients who received adjuvant treatment. This benefit was seen in older patients >45 years with increased OS (P = 0.032), DFS (P = 0.014), and reduced chances of locoregional failure (P = 0.007). No benefit was seen in patients ≤45 years [Table 2].

Addition of adjuvant treatment improved survival outcomes in high-grade tumors (P = 0.023 for OS and 0.005 for DFS) but had no additional advantage in low-grade tumors.


 » Discussion Top


Parotid malignancies are relatively uncommon, and apart from a few aggressive variants, they are relatively indolent with a long natural history. Acquiring sufficient patients for analysis as well as following them up is difficult and time-consuming. A prospective study in this scenario seems impractical. Therefore, unlike SCCs of the head and neck, data on prognostic factors of parotid malignancies are limited to retrospective studies.

Heterogeneity exists in the survival data of parotid malignancies. In our series, 2- and 5-year-OS were 96.9% and 93.3% and DFS 93.8% and 88.7%, respectively. In a series of 2807 patients of salivary gland neoplasms, the 2- and 5-year OS were 85% and 72% and DFS 93% and 89%, respectively.[2] In another series of 903 patients with parotid cancers, the mean 5- and 10-year actuarial survival were 66.6% and 49.7%, respectively.[5] The improved survival in our series may be related to the selection bias where 59 patients were excluded from analysis due to lack of proper follow-up. Further, a relatively young patient population in our series (median age 46 years) can result in such discrepancy.

In our study, advanced age was found to be a poor prognostic factor for survival as well as locoregional and distant failure. Bhattacharyya and Fried found increasing age to adversely affect survival.[12] Similarly, in another study from Brazil, age was found to be a poor prognostic factor.[13] In a large series of 2465 patients from the Swedish Cancer registry, Wahlberg et al. found advancing age to have a negative impact on survival for mucoepidermoid carcinoma, adenocarcinoma, and undifferentiated cancers of the parotid.[7] Although the reason for age being a poor prognostic factor is unclear, this may be explained by the increased incidence of high-grade tumors with advancing age. In our study, high-grade tumors were more commonly seen in the older patients (78.31% in patients > 45 years and 56.09% in patients ≤ 45 years) (P = 0.002). Similarly, in another study from our institution analyzing the prognostic factors on outcome of mucoepidermoid carcinoma of the parotid, the median age for high-grade tumors was a decade higher as compared to that for low-grade tumors (mean age 47 years for high-grade tumors and 35 years for low-grade tumors).[14] In another study form the west, Renehan et al. found that younger patients tended to have low-grade histology.[5]

In concordance to Bhattacharyya et al,[12] we did not find gender to significantly affect survival or failure pattern.

Advanced T stage negatively affected OS, DFS, and increase chances of locoregional failure and DM in univariate analysis. This finding was consistent with multiple studies where advanced T stage, extraglandular extension and tumor size >4 cm have been found to adversely affect survival.[12],[13],[5],[6] However, on multivariate analysis, T stage did not affect OS although DFS, locoregional failure and DM were significantly affected. Owing to the relatively indolent course and long natural history of most parotid cancers, even patients with locoregional or distant failure may have a prolonged OS similar to those free of disease.

A little more than one fourth patients in our series had neck nodal metastasis. Nodal metastasis was found to be a poor prognostic factor for survival as well as locoregional failure and DM in both univariate and multivariate analysis; despite the fact that all patients with nodal metastasis received adjuvant treatment. Literature review on the effect of nodal metastasis on survival in parotid malignancies is fairly consistent. In a study of 121 patients, Kelley and Spiro found neck nodal metastasis to be a significant prognostic factor for OS.[4] Renehan et al. in a study assessing clinicopathological factors affecting survival in parotid cancers, found nodal metastasis to be a significant factor affecting survival on multivariate analysis.[5] Similar results were shown in another retrospective study of 1268 patients from the SEER database.[8] The Dutch Oncology Group in a multiinstitutional study of 565 patients of malignant salivary gland tumors found nodal stage to be a significant prognostic factor and advocated complete nodal clearance and adjuvant treatment for patients with neck nodal metastasis.[9],[10]

High-grade tumors were found to be a poor prognostic factor for survival in univariate analysis. In multivariate analysis, OS was not affected, but there was a trend toward worse DFS in high-grade tumors (P = 0.05) Multiple studies have confirmed tumor grade to be a poor prognostic factor for survival.[12],[13],[5],[16] We did not find a significant effect on OS in multivariate analysis may be due to the incorporation of intermediate grade histology into high-grade tumors.

In concert with prior studies, we found PNI and LVS to have a negative impact on survival.[5],[6],[9],[16] However, a strong conclusion cannot be made as only 22%, and 12% patients in our series had PNI and LVS, respectively.

Unlike SCC, what constitutes a safe margin of resection in parotid malignancies is not well defined. This is due to the complex anatomy of the parapharyngeal space, the presence of vital structures and relative indolent nature of the most parotid tumors. Many studies have highlighted the negative impact of positive margins of resection, but none have defined what constitutes an adequate margin. In our study, a resection margin of ≥5 mm had better OS when compared to margins <5 mm. However, no difference in OS was seen with resection margin of ≥2 mm compared to lesser margins. Ghosh-Laskar et al. found positive margins tended to have a poor survival outcome in a series of mucoepidermoid cancers treated in our institution.[14] Interestingly, in our study, re-resection after incomplete surgery (incisional or excisional biopsy or inappropriate extirpation) did not worsen survival. Based on our results and that from another study from the same institution,[14] we recommend a margin of at least 5 mm should be taken during parotidectomy done for malignant lesions. If this “adequate” margin is not obtained on final histopathology, a reresection of the positive margin is recommended (if possible taking into consideration the anatomical constraints) followed by adjuvant therapy rather than sending the patient directly for radiation treatment.

In our study, adjuvant treatment overall improved survival (P = 0.004 for OS and DFS), decreased locoregional failure (P = 0.011) and DM (P = 0.041). Literature is divided on the prognostic significance of adjuvant treatment in parotid malignancies. This discordance is mainly due to the inherent bias in patient selection with high-risk patients receiving adjuvant treatment. A previous study from our institute did not find any benefit of adjuvant radiation in OS and DFS in patient with mucoepidermoid carcinoma.[14] However, most of the patients in that study were low- to intermediate-grade tumors. In the study by Bhattacharyya and Fried, radiation conferred a survival benefit, although not statistically significant.[12] Renden found adjuvant radiation to decrease locoregional recurrence with a trend to improve survival in large tumors.[5] As more than half of our patients had advanced stage cancer and about two-thirds had high-grade tumors, adjuvant treatment may have improved survival outcome in our series.

A subgroup analysis showed a significant benefit of adjuvant treatment in patients above 45 years of age in relation to OS, DFS and locoregional failure which was not replicated in younger patients. In view of poorer prognosis, an increased incidence of high-grade tumors and a benefit of adjuvant treatment, the role of postoperative radiation to patients above 45 years of age need to be emphasized. In low-grade tumors, however, adjuvant treatment will increase treatment-related toxicity without having a significant impact on survival. Hence, adjuvant treatment in low-grade tumors must be advised judiciously only in the presence of other adverse factors.

Our study being a retrospective one had certain limitations. First, due to the limited number of patients in each histological subtype, survival was calculated classifying tumors only as low grade or high grade. This limits us from drawing conclusions in specific histologies. Second, the limited number of events occurring led us to club the local and regional recurrences together. Thirdly, we had to exclude 59 patients from analysis due to lack of proper follow-up.

Despite these shortcomings, our study is the first one from India and one of the largest single institutional studies worldwide with reasonable follow-up evaluating the prognostic significance of various factors affecting the survival and failure pattern of malignant neoplasms exclusively of the parotid gland.


 » Conclusions Top


Advancing age, advanced T and N stages, inadequate resection margins, high-grade tumors, PNI and LVS are poor prognostic factors in patients of parotid malignancy. Nodal stage is the single most important factor affecting survival. The presence of these factors should warrant aggressive treatment with wide resection and multimodality adjuvant treatment. At the same time, efforts should be made to reduce the long-term treatment-related toxicities considering the relatively good survival of these patients. Attempts should be made to formulate uniform guidelines for parotid cancers to help plan proper treatment of this uncommon disease.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Spitz MR, Batsakis JG. Major salivary gland carcinoma. Descriptive epidemiology and survival of 498 patients. Arch Otolaryngol 1984;110:45-9.  Back to cited text no. 1
    
2.
Spiro RH. Salivary neoplasms: Overview of a 35 year experience with 2,807 patients. Head Neck Surg 1986;8:177-84.  Back to cited text no. 2
    
3.
Ellis GL, Auclair PL, Gnepp DR. Surgical Pathology of the Salivary Glands. Philadelphia: W. B. Saunders; 1991.  Back to cited text no. 3
    
4.
Kelley DJ, Spiro RH. Management of the neck in parotid carcinoma. Am J Surg 1996;172:695-7.  Back to cited text no. 4
    
5.
Renehan AG, Gleave EN, Slevin NJ, McGurk M. Clinico pathological and treatment related factors influencing survival in parotid cancer. Br J Cancer 1999;80:1296-300.  Back to cited text no. 5
    
6.
Hocwald E, Korkmaz H, Yoo GH, Adsay V, Shibuya TY, Abrams J, et al. Prognostic factors in major salivary gland cancer. Laryngoscope 2001;111:1434-9.  Back to cited text no. 6
    
7.
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;38:706-13.  Back to cited text no. 7
    
8.
Bhattacharyya N, Fried MP. Nodal metastasis in major salivary gland cancer: Predictive factors and effects on survival. Arch Otolaryngol Head Neck Surg 2002;128:904-8.  Back to cited text no. 8
    
9.
Vander Poorten VL, Hart AA, van der Laan BF, Baatenburg de Jong RJ, Manni JJ, Marres HA, et al. Prognostic index for patients with parotid carcinoma: External validation using the nationwide 1985-1994 Dutch Head and Neck Oncology Cooperative Group Database. Cancer 2003;97:1453-63.  Back to cited text no. 9
    
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Terhaard CH, Lubsen H, Van der Tweel I, Hilgers FJ, Eijkenboom WM, Marres HA, 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;26:681-92.  Back to cited text no. 10
    
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Eveson JW, Auclair P, Gnepp DR, El Naggar AK. Tumors of the salivary glands. In: Barnes L, editor. Pathology and Genetics of Head and Neck Tumours. Ch. 5. IARC Press: Lyon 2005: International Agency for Research on Cancer, World Health Organization. 2005. p. 210.  Back to cited text no. 11
    
12.
Bhattacharyya N, Fried MP. Determinants of survival in parotid gland carcinoma: A population based study. Am J Otolaryngol 2005;26:39-44.  Back to cited text no. 12
    
13.
Lima RA, Tavares MR, Dias FL, Kligerman J, Nascimento MF, Barbosa MM, et al. Clinical prognostic factors in malignant parotid gland tumors. Otolaryngol Head Neck Surg 2005;133:702-8.  Back to cited text no. 13
    
14.
Ghosh Laskar S, Murthy V, Wadasadawala T, Agarwal J, Budrukkar A, Patil N, et al. Mucoepidermoid carcinoma of the parotid gland: Factors affecting outcome. Head Neck 2011;33:497-503.  Back to cited text no. 14
    
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Bussu F, Parrilla C, Rizzo D, Almadori G, Paludetti G, Galli J, et al. ClinicaJRl approach and treatment of benign and malignant parotid masses, personal experience. Acta Otorhinolaryngol Ital 2011;31:135-43  Back to cited text no. 15
    
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Erovic BM, Shah MD, Bruch G, Johnston M, Kim J, O'Sullivan B, et al. Outcome analysis of 215 patients with parotid gland tumors: A retrospective cohort analysis. J Otolaryngol Head Neck Surg 2015;44:43.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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