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Egyptian Journal of Pathology:
doi: 10.1097/01.XEJ.0000416072.56771.58
Original Articles

Mucoepidermoid carcinoma: a reappraisal of the influence of tumor grading on prognosis

Salama, Asmaaa; Magdy, Nesreen M.a; Salem, Mostafa M.a; Ramzy, Nevine I.a; Mahmoud, Mohammadb

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Author Information

Departments of aPathology

bRadiation Oncology & Nuclear Medicine, National Cancer Institute, Cairo University, Cairo, Egypt

Correspondence to Asmaa Salama, MD, Department of Pathology, National Cancer Institute, Cairo University, 11441 Cairo, Egypt Tel: +20 111 886 4044; fax: +23644720; e-mail: almadina.salama@gmail.com

Received January 9, 2012

Accepted January 24, 2012

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Abstract

Background: Mucoepidermoid carcinoma is the most common malignant salivary gland tumor. The histopathologic grade of this tumor is the most important predictor of prognosis, which has a huge impact on the treatment protocols. Tumor behavior is worse with an aggressive outcome in high-grade than in low-grade mucoepidermoid carcinoma, leading to a need for more intensive treatment.

Patients and methods: A retrospective clinical study and review of histopathologic grading were carried out, using the two most well-known grading systems, of 60 patients with mucoepidermoid carcinoma diagnosed at the Pathology Department, National Cancer Institute, Cairo University, from 2005 to 2010.

Results: The recurrence rate was strongly correlated with high tumor grade according to Armed Forces Institute of Pathology and Brandwein grading systems (P=0.003 and 0.03, respectively). Male sex was significantly correlated with a high tumor grade (P=0.01). Lymph node status was significantly correlated with the overall survival (P=0.026). Using the Brandwein grading system, it was found that as the histologic grade increased from low and intermediate to high, disease-free survival (P=0.029) was significantly decreased.

Conclusion: The outcome of the cases with intermediate-grade mucoepidermoid carcinoma is less clear and may be categorized as low or high grade according to the grading system used. The Brandwein grading system may have a better predictive value than the Armed Forces Institute of Pathology systems as it identifies the low-grade cases very well.

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Introduction

Mucoepidermoid carcinoma is the most frequently diagnosed malignancy in the salivary gland. Among the major salivary glands, the parotid is the most commonly involved (Boahene et al., 2004). It comprises ∼10–15% of all salivary gland neoplasms and about 30% of salivary malignancies (Rapidis et al., 2006).

Mucoepidermoid carcinoma is the histologic subtype of salivary gland tumors for which grading is the most prognostically and therapeutically relevant factor (Seethala, 2011). The overall 5-year survival rates vary from 92 to 100% in low-grade tumors, 62 to 92% in intermediate-grade tumors, and 0 to 43% in high-grade tumors (Pires et al., 2004).

The morphologic features of mucoepidermoid carcinoma have been incorporated into many different grading systems that were correlated with prognosis and therefore play an important role in treatment decisions (Nance et al., 2008).

Many grading schemes have been proposed depending on the subjective evaluation of the relative proportions of the different cell components, the degree of cellular atypia, mitotic frequency, the presence of necrosis, and invasiveness (Thompson, 2006). However, controversy still remains in terms of the grading of mucoepidermoid carcinoma, and there is no uniformly accepted grading system (Chenevert et al., 2011).

Initially, Stewart et al. (1945) had described two subtypes of mucoepidermoid tumor, namely, ‘benign’ and ‘malignant’ versions, which, today, are equivalent to low and high grade, respectively. Then, Foote and Frazell (1954) observed that some of the tumors originally classified as benign had metastasized. They then reported that all these tumors should be classified as carcinoma, some of them being ‘low grade’ and others being ‘high grade’.

Subsequently, Healey et al. (1970) replaced this old two-tiered system with a new three-tiered grading scheme to include a third, intermediate grade. This scheme was based on certain criteria including the predominant cell type, whether epidermoid or mucin-secreting cells, cystic and solid formations as well as the degree of cellularity, pleomorphism, atypia, nuclear hyperchromasia and prominent nucleoli as well as mitotic activity, and invasion into the surrounding structures.

Batsakis and Luna (1990) modified the previous Healey system using more precise criteria including macrocystic and microcystic formations, the ratio between mucous and epidermoid cells, pleomorphism, and tumor borders, whether well circumscribed or invasive.

The WHO approved the established Armed Forces Institute of Pathology (AFIP) grading system proposed by Auclair et al. (1992), which has been shown to be reproducible and to be predictive of the patient’s outcome by defining low-grade, intermediate-grade, and high-grade tumors using five histopathologic features including the intracystic component, mitotic figures per 10 high-power fields, neural invasion, necrosis, and cellular anaplasia (Eveson et al., 2005).

Brandwein et al. (2001) reported that the AFIP system tended to downgrade mucoepidermoid carcinoma, which could lead to undertreatment. Then this grading system was modified to place more importance on the histological impact of invasion, assigning points including the pattern of infiltration, vascular invasion, and bony invasion.

Although the AFIP system downgrades the tumors, the Brandwein system upgrades them and, accordingly, the AFIP system can categorize some biologically aggressive tumors as low grade, leading to higher recurrence rates than expected. In contrast, the Brandwein system may categorize some indolent tumors as high grade, resulting in unnecessary radiation or additional surgery (Seethala, 2011). However, recent reviews of the pathology literature have established that the Brandwein grading scheme is the best classification system available, given its reproducibility and predictability (Nance et al., 2008).

The surgical treatment varies with the tumor grade. Low-grade parotid mucoepidermoid carcinoma can be adequately treated by conservative parotidectomy. For high-grade mucoepidermoid carcinoma, radical parotidectomy is the treatment of choice (Nagarkar et al., 2004), to be followed by radiotherapy (Chummun et al., 2008).

The aim of the study is to reassess the tumor grade according to the AFIP grading system and the Brandwein grading system in order to determine which system is more useful in the precise prediction of the prognosis.

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Patients and methods

This is a retrospective study that was carried on 60 patients diagnosed with mucoepidermoid carcinoma at the Pathology Department, National Cancer Institute (NCI), Cairo University, during the period from January 2005 to June 2010. Data were collected from patients’ files at the Radiotherapy Department and Department of Statistics and Epidemiology, NCI, for personal data (age and sex) and clinical data (stage, type of surgery, date of surgery, presence of local recurrence and its date, nodal or distant metastases, date of metastasis, and radiotherapy). Pathological data were retrieved from the database of the pathology department for topography, tumor size, nodal metastases, state of resection margins and pathological diagnosis.

Hematoxylin and eosin-stained paraffin sections were prepared from all available blocks. Retrieval of all available referred hematoxylin and eosin slides was carried out for patients who had undergone biopsies or surgical intervention outside NCI. Histopathological examination was performed for revision and confirmation of the diagnosis. Tumors were classified according to the criteria described by the WHO system (Eveson et al., 2005). Alcian-blue, pH 2.5, staining was performed to highlight mucin-secreting cells. Tumors were graded according to the AFIP system, the Brandwein system, and the modified Healey system as detailed in Table 1. Immunostaining using S-100 for the detection and confirmation of perineural invasion was carried out in unclear cases. Patients were assigned a clinical stage according to the Union Internationale Contre le Cancer (UICC) system and the TNM system (Yousem and Nicholson, 2004; Eveson et al., 2005; Edge et al., 2010).

Table 1
Table 1
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Patients were followed from the date of diagnosis until the date of the last visit to determine disease-free survival (DFS; duration from surgical excision until date of recurrence) as well as overall survival (duration from the date of diagnosis until the date of the last visit).

Data management and analysis were carried out using SigmaStat program, version 3.5 (SPSS package system, IBM, Chicago, Illinois, USA). The graphs were prepared using Microsoft Excel 2007. The numerical data were statistically presented in terms of range, mean, SD, median, and interquartile range. Categorical data were summarized as percentages. Comparisons between the numerical variables of two groups were carried out using unpaired Student’s t-test for parametric data or the Mann–Whitney Rank Sum test for nonparametric data. Comparison of categorical variables was carried out using the χ2-test or the Fisher exact test for a small sample size. The duration of overall survival was calculated from the date of diagnosis until loss of follow-up or death, whatever the cause. The duration of DFS was calculated from the date of surgery until the date of first relapse or death or loss of follow-up. The survival curves were computed using the Kaplan–Meier technique. The significance of the difference between the different subgroups was estimated using the log-rank test. All P-values were considered significant when P-values were less than 0.05.

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Results

Clinical characteristics

During the period from January 2005 to June 2010, a total number of 302 specimens and biopsies of major and minor salivary gland lesions were received at the Pathology Department, NCI, Cairo University. The distribution of these cases in different salivary glands was as follows: 235 cases for the parotid gland (78%), 56 cases for the submandibular gland (18%), eight cases for the minor salivary gland (3%), and three cases for the salivary gland (NOS). The majority were of a neoplastic nature (278 cases), where malignant and benign neoplasms constituted 47.4 and 44.7% of the total cases, respectively.

Of the benign salivary gland tumors, the highest frequency was for pleomorphic adenoma, followed by Warthin’s tumor, representing 62 and 33% of benign, and 30 and 16% of all salivary tumors, respectively. In terms of malignant tumors, mucoepidermoid carcinoma was the most frequent neoplasm (47 cases), representing 32.8 and 16.9% of malignant and all salivary tumors, respectively (Table 2). In terms of the total malignant tumors presented to NCI during this time period, mucoepidermoid carcinoma constituted 0.49% of cases. In terms of lung and bronchial tumors, a total of 683 specimens and biopsies were presented during the same time interval. Of these cases, mucoepidermoid carcinoma represented only 1% (seven cases) of all lung tumors.

Table 2
Table 2
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The current study was carried on the 60 cases of mucoepidermoid carcinoma with available slides, blocks, and clinical files. Forty patients had tumors involving the major salivary glands, distributed as follows: 34 parotid and six submandibular. Twelve patients had tumors affecting the minor salivary glands (eight at intraoral sites and four at extraoral sites). In six cases, the lung and bronchus had been affected and one case was metastatic to cervical lymph nodes with an unknown primary origin. Only one case showed lacrimal gland affection (Table 3).

Table 3
Table 3
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The study included 32 male and 28 female patients, with a slightly higher number of male patients; the male to female ratio was 1.14 : 1. The patients’ age ranged from 7 to 90 years, mean age 49.6 (±21.1) years. The median age was 51 years. Age distribution was equal to, above, and below the median age, 30 cases each. Seven patients were 18 years of age or younger.

The prevalence was almost the same for stages T1, T2, and T4, representing 26.6, 25, and 23.3%, respectively. T3 was found in 11.6% of the cases. About half of the patients (53.3%) did not have lymph node metastases, whereas only 28.3% presented with nodal metastases (N1; six cases, N2; 11 cases, and none with N3 disease). Only two patients had M1 disease, metastatic to the lung at initial presentation. According to the UICC system, stages I, II, III, and IV were present in 22, 23, 8, and 34% of the cases, respectively.

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Pathological features

The tumors varied in size from 1 to 12 cm (mean 3.8±2.2 cm, median 3 cm). Cystic component (i.e. occupying >25% of the histologic sections examined) was present in 27 specimens (45%). Thirteen specimens (22%) showed no nuclear pleomorphism, whereas 47 (78%) had moderate to marked nuclear pleomorphism. Seventeen specimens (28.3%) had four or more mitoses in 10 high-power fields. An infiltrative tumor border was found in 47 specimens (78%) and neural invasion in 16 (27%). Twenty-five (42%) cases showed vascular invasion. Tumor necrosis was noted in 18 (30%) cases. Alcian blue stain was useful in high-grade cases with wide areas of solid growth, as it highlighted the mucin content (Fig. 1). Of all 60 patients, according to the AFIP grading system, 26 patients had high-grade, 15 had intermediate-grade, and 19 had low-grade tumors. According to Brandwein grading, 44 patients had high-grade, five had intermediate-grade, and 11 had low-grade tumors (Figs 2 and 3).

Fig. 1
Fig. 1
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Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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The status of lymph nodes could be assessed in 49 out of the 60 patients. Seventeen patients had positive nodes and 32 patients had negative nodes. The surgical margin could be assessed in 45 cases and was positive in 16 tumors, close (<0.2 cm) in seven cases, and negative in 22 cases.

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Treatment modalities

A multidisciplinary approach was adopted for most patients with mucoepidermoid carcinoma. Most of them underwent surgical excision, followed by radiotherapy with or without chemotherapy. For the parotid gland, total parotidectomy, defined as the total removal of the parotid gland with preservation of the facial nerve, was the most common operation that was performed (13 patients, 21.6%). The second most common operation, superficial parotidectomy, was performed in 12 patients (20%). For the submandibular salivary gland, four patients underwent wide excision of the tumor; one of them was accompanied by radical neck dissection. Maxillectomy was performed in three patients, two with a hard palate tumor and one with maxillary sinus affection. Mandibulectomy was performed in one patient with a tumor in the lower gum. Wide excision was performed for five patients (one case of hard palate, one case of cheek mucosa, two cases of nasal cavity, and one case of the lacrimal gland). Surgical intervention was performed in only two patients with lung mucoepidermoid carcinoma; one patient underwent lobectomy and the other underwent pneumonectomy.

The total number of patients who received radiotherapy was 30; some received adjuvant radiotherapy (preceded by surgery), some received palliative and radical regimens, whereas others received radiotherapy for the treatment of recurrence. Twenty-five patients received postoperative radiotherapy, with doses ranging from 30 to 66 Gy. Fourteen of these patients had a positive surgical margin, three had a close margin, and seven had a negative margin. Four out of those with negative margins had high-grade tumors, one with perineural invasion and one with positive lymph nodes. Of those patients who received adjuvant irradiation, 21 patients had no residual disease, three had residual tumors, and one patient developed distant lung metastases. One patient had an advanced parotid tumor, clinical stage IV, and received palliative radiotherapy. Four patients received only radiotherapy not followed by surgery (radical radiotherapy), two with a hard palate tumor (achieved complete remission) and one with a lung tumor (lost to follow-up). The last one had nasopharyngeal mucoepidermoid carcinoma (this patient developed locoregional recurrence and received further radiotherapy). One year later, he developed lung metastases together with locoregional recurrence, for which he received further radiotherapy.

Eleven patients received chemotherapy. Three of these patients had a distant metastatic disease and the remaining eight had an irresectable tumor. Of these patients, two received concomitant radiotherapy and four had previously received radiotherapy.

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Patients’ outcome

Locoregional recurrence occurred in 20 (33%) patients, with DFS periods ranging from 3 to 37 months. Local recurrence occurred in 13 patients (65%), regional lymph node recurrence in four patients (20%), and both local and nodal recurrence in three patients (15%). Of these, twelve patients with only local recurrence were treated by resurgery, whereas only one patient received radiotherapy without surgery. Three patients with nodal recurrence were treated with nodal dissection, whereas one patient with both local and nodal recurrence underwent excision with node dissection. Three patients were lost to follow-up, and management of their recurrence is not known.

The second recurrence occurred in 13 out of those 20 patients, which was local in five cases, local and nodal in one case, nodal in three cases, local and distant in three cases, and distant in one case. Patients with local second recurrence were treated by resurgery (four patients) and radiotherapy (one patient). Two out of those patients with second nodal recurrence were treated with neck dissection and the last one was lost to follow-up. The patient with local and nodal was treated with excision and node dissection and those with distant metastases were lost to follow-up.

The mean duration from the first treatment or complete remission (complete eradication of the tumor by surgery, radiotherapy, or both) to the last follow-up was 25 months (median, 24 months; range, 1–65 months). Twenty-eight out of the 60 patients were alive without disease, 17 patients died because of the disease, and 15 were lost to follow-up.

The Kaplan–Meier method was used to estimate the overall survival rate of all 60 patients treated. The Kaplan–Meier-estimated probability of the 1-, 3-, and 5-year overall survival of the patients studied was 65.2, 55.5, and 41.0%, respectively (Fig. 4). On comparing all the variables and their association with 1- and 2-year overall survival as shown in Table 4, there was a significant association between lymph node status and overall survival (P=0.026). Figure 5 shows that the 1-year overall survival was higher in cases with no nodal metastases than cases with positive lymph nodes (80.8 and 53.8% vs. 75 and 41.7%, respectively).

Fig. 4
Fig. 4
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Table 4
Table 4
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Fig. 5
Fig. 5
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There was a significant association between 1-year DFS and tumor grades according to the Brandwein grading system (P=0.029). Table 5 and Fig. 6 show that 1-year DFS was significantly higher in low-grade tumors than intermediate-grade and high-grade ones (57.1 vs. 25 and 16.7%, respectively).

Table 5
Table 5
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Fig. 6
Fig. 6
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Analysis of grading systems

According to the AFIP grading system, male sex was significantly associated with high-grade mucoepidermoid carcinoma as the prevalence of high-grade tumors was higher in men than women (P=0.01). However, female predominance was found for low-grade and intermediate-grade tumor grades (Fig. 7). Recurrence was significantly higher in patients with high-grade mucoepidermoid carcinoma (P=0.003). It was observed that the mean age of the patients with high-grade mucoepidermoid carcinoma was higher than patients with low-grade and intermediate-grade tumors (55 vs. 47.7 years, respectively), but the difference was not statistically significant (P=0.2). Advanced tumor stage (III and IV) was more prevalent in patients with high-grade mucoepidermoid carcinoma than patients with low-grade and intermediate-grade tumors (13 vs. six and six cases, respectively); yet, there was no statistically significant difference (P=0.3). Lymph node metastases were reported more in patients with high-grade tumors than patients with low-grade and intermediate-grade tumors (10 cases vs. two and three cases, respectively); unfortunately, the difference was not significant (P=0.09) as shown in Table 6.

Fig. 7
Fig. 7
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Table 6
Table 6
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However, according to the Brandwein grading system, recurrence was significantly higher among patients with high-grade mucoepidermoid carcinoma (P=0.03). Age, sex, clinical stage, and positive surgical margin were comparable among the three grade categories (P> 0.05) (Table 7).

Table 7
Table 7
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Discussion

Mucoepidermoid carcinoma is the most common primary major and minor salivary gland malignancy (Williams and El-Naggar, 2010) both in adults and in children (Eveson et al., 2005), and this was also reported by the AFIP(Boukheris et al., 2009). Despite being so common, the current study is considered one of the few studies carried out on mucoepidermoid carcinoma.

During the period from January 2005 until June 2010, mucoepidermoid carcinoma constituted 0.49% of the total malignancies presented to the Surgical Pathology Unit, NCI, which was exactly the same as that documented in the NCI Cancer Pathology Registry, which included all cases presented during the years 2003–2004 (Mokhtar et al., 2007). This is similar to a Nigerian population-based study (Ochicha et al., 2009) in which salivary tumors represented 0.4% of all malignancies.

This study showed that malignant salivary gland tumors comprise 51.5% of all salivary tumors in both major and minor glands. This is considered a high incidence when compared with other reported incidence rates, such as 35.1% in the UK (Jones et al., 2008) and 32% in China (Tian et al., 2010). This higher frequency in NCI may be attributed to the fact that NCI is an oncology referral center that receives patients from all over the country. Also, this higher frequency illustrates the magnitude of carcinogenic environment and pollution in Egypt.

In the current study, mucoepidermoid carcinoma was the most common primary major and minor salivary gland malignancy, accounting for 32.8% of all malignant salivary tumors. This was slightly higher than that reported at the Iraqi Cancer Registry (Muzahim et al., 2005), a Brazilian population-based study (Junior et al., 2009), a Nigerian population-based study (Ochicha et al., 2009), and a study in Eastern China (Tian et al., 2010), in which mucoepidermoid carcinoma represented 28.5, 29, 23.1, and 30%, respectively, of all salivary malignancy. However, our result is similar to that documented in a European population-based study (32.7%) (Jones et al., 2008).

The age of the patients included in the current study ranged from 7 to 90 years. The mean age was 49.6±21.1 years. This is almost similar to that reported in a UK population, which is 48.9±17.9 years (Jones et al., 2008). The median age in our study was 51 years, which is close to that reported by Brandwein et al. (2001) and Nance et al. (2008), who reported a median age of 49 and 54 years, respectively.

The parotid gland was the most commonly affected site in our study, constituting 56.7% of all studied cases and 85% of major salivary gland mucoepidermoid carcinoma. This is similar to other studies reporting the parotid gland as the site most commonly affected by mucoepidermoid carcinoma, accounting for 40% (Nance et al., 2008), 42% (Brandwein et al., 2001), 65% (Ozawa et al., 2008), and 35.3% (Pires et al., 2004) of head and neck mucoepidermoid carcinoma and 85.3% of major salivary gland mucoepidermoid carcinoma (Boukheris et al., 2009).

In our study, 53% of the patients were men and 47% were women. The male to female ratio was 1.14 : 1. These results are in agreement with other studies, 1.2 : 1 in an American study (Pires et al., 2004) and 1.5 : 1 in a Japanese one (Ozawa et al., 2008), thus indicating a lower incidence in women than in men. This was in contrast to what was reported in WHO (Eveson et al., 2005), which reported a 3 : 2 female predilection. Our result can be attributed to the fact that most of our patients had high-grade tumors, which showed a significant correlation with male sex. This was proved by our finding that female predominance was observed in both low-grade and intermediate-grade mucoepidermoid carcinoma (using the AFIP grading system), in which the male to female ratio was 0.9 : 1 and 0.4 : 1, respectively. This finding is similar to that reported in a recent US study (Nance et al., 2008) in which the male to female ratio was 0.3 : 1 and 0.8 : 1 in low and intermediate grades, but was 1.9 : 1 in high-grade mucoepidermoid carcinoma.

Most of our patients (51.6%) had a T1/T2 tumor, which is in agreement with that reported in other studies (Pires et al., 2004; Ozawa et al., 2008), in which 50.3 and 48% of the patients, respectively, had a T1/T2 tumor. However, this was lower than that reported in the Mayo clinic study (Boahene et al., 2004), in which 87.6% of the patients had a T1/T2 tumor. In our study, 35% of patients had a T3/T4 tumor. The latter constituted only 17.9% of all cases in the Mayo clinic study. Fifty-four percent of our patients showed no nodal metastases, which is lesser than that Ozawa et al. (2008) reported, 62.7%, and much less than that reported in other studies: 95.5% (Boahene et al., 2004), 81.2% (Pires et al., 2004), and 64% (Nance et al., 2008). This is attributed to late presentation of patients in our country due to diminution of medical services in our country.

In the current study, there was a significant correlation between lymph node status and 1- and 2-year overall survival (P=0.026). This is in agreement with that reported in other studies (Pires et al., 2004; Nance et al., 2008; Ozawa et al., 2008).

Final stage grouping indicated that 45% of our patients had stage I/II cancer, which is not very different from a Japanese study (Ozawa et al., 2008) that reported that 48% of patients had stage I/II cancer. Other studies have reported a higher incidence of stage I/II cancer: 75% (Brandwein et al., 2001), 50.3% (Pires et al., 2004), and 77% (Boahene et al., 2004). However, 34% of our patients had stage IV tumors, lesser than that reported in the previously mentioned Japanese study in which 44% of the patients had stage IV tumors , but higher than that reported by Brandwein et al. (2001), who reported stage III/IV in 25% of patients. The late clinical presentation observed in our studied cases can be attributed to negligence and lack of health education in our patients.

Most of our patients (83.3%) underwent surgical intervention, including all patients who had parotid gland affection. This is in agreement with other studies reporting surgical intervention in the treatment of salivary mucoepidermoid carcinoma, in 100% (Nance et al., 2008), 87.3% (Pires et al., 2004), 88.2% (Boahene et al., 2004), and 72% of patients (Ozawa et al., 2008).

At the time of initial surgery, positive/close margins were present in 46% of all operated patients; most of them were of the high-grade category. This is much higher than the results of Nance et al. (2008), who reported that only 22% of operated patients had positive surgical margins, and also with the predominance of high-grade mucoepidermoid carcinoma. Our high incidence of positive/close surgical margins can be attributed to the high number of T3/T4 (advanced local stage) with invasion of the surrounding vital structures, making it more difficult to perform complete tumor resection.

Half of our patients received adjuvant radiotherapy; most of them (56.6%) had positive/close surgical margins and the rest had high-grade tumors. Compared with other studies, high-grade tumor was the most common indication for radiotherapy (Boahene et al., 2004; Nance et al., 2008).

In agreement with most other studies (Boahene et al., 2004; Pires et al., 2004; Cheung et al., 2011), male sex was significantly associated with occurrence of high-grade mucoepidermoid carcinoma. This was evident with the use of the AFIP grading system (P=0.01). Moreover, in the current study, high-grade mucoepidermoid carcinoma, graded using either the AFIP or the Brandwein grading system, was significantly associated with tumor recurrence (P=0.003 and 0.03, respectively). Accordingly, our results indicate that mucoepidermoid carcinoma is the histologic subtype of salivary gland tumors for which grading is the most prognostically and therapeutically relevant factor (Seethala, 2011).

Locoregional recurrence occurred in 33% of our patients. A similar result was reported by Nance et al. (2008). However, this is higher than the results of other studies carried out by Brandwein et al. (2001), Pires et al. (2004), and Ozawa et al. (2008), who reported 20, 23.3, and 22.5% recurrences, respectively. Our higher rate of recurrence can be attributed to the fact that our patients had high-grade tumors, high tumor stage (T3/T4), as well as a high incidence of positive/close margins.

The current study showed that high-grade cases according to both grading systems are more prevalent than low-grade and intermediate-grade ones (high-grade AFIP 43.3% and Brandwein 73.4%). This prevalence of high-grade mucoepidermoid carcinoma was also reported in two American studies in which high-grade tumors constituted 46 and 55.4% of cases, respectively. However, other studies have reported a prevalence of low-grade tumors, constituting 48, 45.2, and 39.5% of all cases studied by Boahene et al. (2004), Pires et al. (2004), and Ozawa et al. (2008), respectively. This shows that no uniformly accepted grading system exists and that the current grading systems still lack interobserver reproducibility.

Our study showed that high-grade cases according to the Brandwein grading system are more prevalent than high-grade cases according to the AFIP grading system (44 vs. 26, respectively). This is in agreement with Seethala (2011), who reported that the AFIP grading system may downgrade the tumors and the Brandwein grading system may upgrade them. Here, the AFIP system may potentially place biologically more aggressive tumors into a low-grade category, increasing the possibility of a high recurrence rate and treatment failure among low-grade tumors. Conversely, high-grade mucoepidermoid carcinomas are aggressive tumors and require more intensive postoperative adjuvant treatment (adjuvant radiotherapy).

Our study found a significant association between tumor grade according to the Brandwein grading system and the 1-year DFS (P=0.029). One-year DFS was significantly higher in low-grade tumors than intermediate-grade and high-grade ones. The results of the current study are in agreement with the results obtained by Brandwein et al. (2001) and Nance et al. (2008); all confirmed the efficacy of the Brandwein grading system. This system delineates very well patients with an expected better prognosis (low-grade tumors) from those with an expected poorer prognosis (intermediate-grade and high-grade tumors) on the basis of the fact that this system could successfully classify patients in terms of their susceptibility to cancer recurrence: high-grade patients have a high rate of disease recurrence and low-grade patients have a significantly lower recurrence rate.

Our study showed that the probability of 1-, 3-, and 5-year overall survival as 65.2, 55.5, and 41.0%, respectively. This is much lower than that reported in other studies; Nance et al. (2008) reported 1-, 3-, and 5-year overall survival of 90, 80, and 75, respectively, and Ozawa et al. (2008) reported 1-, 3-, and 5-year overall survival of 80, 85, and 62.3%, respectively. The 5-year survival rates reported by Boahene et al. (2004) and Pires et al. (2004) were 98.9 and 70.2%, respectively. Our low survival results can be attributed again to the predominance of high-grade tumors, the high incidence of positive/close margins, and the high tumor stage in our patients; moreover, the current study was limited by the relatively small sample size.

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Conclusion

Histopathologic grading of mucoepidermoid carcinoma is the most important prognostic factor that also governs postoperative management. Precise histopathological grading requires extensive sampling of the tumor in order to check accurately each factor that determines the grade. The Brandwein grading system seems to be more useful for the prediction of a patient’s prognosis; however, approval of this system requires extensive studies on large sample sizes.

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Acknowledgements
Conflicts of interest

There are no conflicts of interest.

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