Histopathologic grade of mucoepidermoid carcinoma (MEC) is an established predictor of prognosis and affects treatment protocol. Tumor behavior is more aggressive in high-grade than in low-grade MEC, leading to a more intensive treatment protocol. Outcomes for patients with intermediate-grade MEC are less clear; therefore, the optimal treatment protocol for this group is not well defined. The treatment protocol and survival outcomes of patients treated for MEC of the head and neck was investigated.
A retrospective clinical review and prospective review of histopathologic grading were undertaken using the most recently established grading system of 50 patients with MEC of the head and neck from 1983 through 2004.
As histologic grade increased from low to intermediate to high, overall survival (P < .0001) and disease-free survival (P < .001) were significantly decreased. Overall and disease-free survival were significantly better for patients with intermediate-grade MEC than those with high-grade disease. Overall and disease-free survival were similar for patients with low-grade and intermediate-grade MEC. There was a low rate of disease recurrence in patients with intermediate-grade MEC, but this did not lead to death from disease. Although no patients with low-grade or intermediate-grade MEC died of disease, 52% of patients with high-grade MEC died of disease. Multivariate analysis revealed that histologic grade, age, and surgical margin status significantly predicted prognosis.
Mucoepidermoid carcinoma (MEC) is the most common malignancy of the major and minor salivary glands, comprising 34% of salivary gland malignancies.1 It has a female preponderance, with a prevalence that is highest in the fifth decade of life.2 Its clinical behavior is highly variable and ranges from slow-growing and indolent to locally aggressive and highly metastatic. Histologically, MEC is comprised of 3 different cell types: mucinous cells, intermediate cells, and epidermoid cells. Growth patterns range from cystic to solid to infiltrative. These parameters have been incorporated into several different grading systems that have been correlated with prognosis and therefore play an important role in treatment decisions. Most grading systems for MEC are 3-tiered, classifying tumors into low, intermediate, and high grade. Low-grade tumors are well-demarcated, with pushing margins and dilated cystic areas containing mucinous material. The cysts are formed by mucinous and intermediate cells. Low-grade histopathology is defined by its lack of aggressive invasion pattern.
With increasing histologic grade, tumors are more infiltrative and clear demarcation is lost. In intermediate-grade MEC, tissue architecture is solid rather than cystic and more irregular, with intermediate cells predominating over mucinous cells. Intermediate-grade tumors still often retain a well-demarcated rounded border and may occasionally demonstrate perineural invasion. High-grade MEC are characterized by an infiltrative border, anaplasia, necrosis, atypical mitoses, perineural and angiolymphatic invasion. Epidermoid cells predominate, but intermediate and mucinous cells must also be present along with intracellular mucin, which distinguishes MEC from squamous cell carcinoma. Mucicarmine stain is often used because mucinous cells are sparse and difficult to find.
There have been several different 3-tiered grading systems for histologic evaluation of MEC reported within the last 15 years, which complicates the retrospective study of outcomes.3 Although low-grade and high-grade cancers have an established correlation with good and poor prognosis, respectively, the prognosis for intermediate-grade MEC is not well defined.2, 4, 5 Therefore, the treatment plan for patients with intermediate-grade MEC is not standardized.
A standardized grading system that is reproducible and easy to use is necessary for accurate and consistent grading of MEC. The 3 most well-known grading systems were compared by Luna in 2006.3 These included the Batsakis and Luna modification of the Healey system, the Brandwein system in 2001, and an established Armed Forces Institute of Pathology (AFIP) system.6–9 Brandwein et al7 found that the AFIP system tended to downgrade MEC, which could lead to undertreatment. Their grading schema assigned points to various histologic features, including pattern of infiltration, vascular invasion, and bony invasion. Low-grade tumors have a score of 0; intermediate grade, 2-3 points; and high grade, ≥4 points. Local disease failure rates at 75 months for each grade were 0% (low), 30% (intermediate), and 70% (high). In reviewing all 3 grading systems, Luna et al found more accurate grading and congruence between the Luna/Batsakis modification and the Brandwein system. However, the Brandwein system was easier to use and more reproducible, which would facilitate standardization and permit more accurate comparative analysis.
Surgical resection is the mainstay of treatment for all grades of MEC. Local resection of the cancer is considered sufficient treatment for low-grade tumors. High-grade tumors are generally treated with surgical excision with wide margins followed by postoperative radiotherapy. Neck dissection is often used when regional metastasis is present. Elective neck dissection has been used at our institution for high-grade cancers. Intermediate-grade MEC treatment has varied from local excision to wide excision with lymphadenectomy and/or postoperative radiotherapy. The current study investigated the treatment protocols and survival outcomes of patients treated for head and neck MEC, with a focus on the comparison of outcomes for patients with low-grade, intermediate-grade, and high-grade cancer.
MATERIALS AND METHODS
The setting was a tertiary care medical center. Between 1983 and 2004, 87 patients were treated at our institution for MEC of the head and neck. Fifty of these patients were available for retrospective clinical review. Inclusion criteria were: 1) histologic diagnosis of MEC, 2) documented treatment of primary cancer at our institution, and 3) minimum 6-month follow-up information.
Our head and neck pathologists (R.R.S. and S.I.C.) prospectively reviewed all cases to classify these cancers histopathologically according to the protocol published by Brandwein in 2001.7 This algorithm was validated through comparison review by Luna and is recommended as the current standard because of its enhanced predictability and proven reproducibility.3
Fifty MEC patients, with a total of 14 low-grade, 13 intermediate-grade, and 23 high-grade tumors, were included in the statistical analysis. Using a 1-sided log-rank test at a significance level of .05 resulted in a power of 85% to detect an absolute increase of 30% in 2-year overall survival (OS), and a power of 95% to detect an absolute increase of 45% in 2-year disease-free survival (DFS) for the intermediate-grade or low-grade groups compared with the high-grade groups.
Patients' characteristics were summarized by descriptive statistics (number, mean, standard deviation, median and range for continuous variables, and frequency and percentage for categoric variables).
The OS was calculated as the time interval between the date of first treatment and date of death from any cause. OS was censored by the last follow-up date if a patient was still alive at that time. DFS was calculated as the time interval between the date of first treatment and the date of disease recurrence or death from disease. For patients still alive and cancer-free or patients who died of other causes, DFS was censored by the last follow-up date when the patient was known to be disease-free. OS and DFS curves were estimated by the Kaplan-Meier method.10 A log-rank test was used to assess the association between OS, DFS, and categoric covariates such as histologic grade, sex, and treatment with radiotherapy. A univariate Cox regression model was used to assess the association between OS, DFS, and age.11 A multivariate Cox regression model was used to assess the association between OS, DFS, and covariates found to be significant on univariate analysis.12 Likelihood ratio tests were used to remove nonsignificant covariates from the multivariate Cox regression model. A significance level of .05 was used for all statistical tests.
Fifty patients with MEC were investigated, including 14 low-grade, 13 intermediate-grade, and 23 high-grade tumors (Table 1). The mean ages were 49 years, 39 years, and 63 years, respectively, for patients with low-grade, intermediate-grade, and high-grade MEC. The male:female ratio overall was 24:26, with a predominance of males in the high-grade group at 15:8, which was not noted in the intermediate-grade (6:8) and low-grade (3:10) groups. All head and neck sites were included, with the parotid gland being the most common primary tumor site (40%) (Table 1). Tumor stage averaged 2.1 overall and 1.3, 1.4, and 2.7 for low, intermediate, and high grade, respectively. The majority of the patients (32; 64%) presented without regional neck metastases (N0), whereas 16 patients (32%) were N+ at the time of presentation.
Table 1. Patient Characteristics (N=50)
Nominal variables listed with percentage of total.
Continuous variable listed with calculated descriptive statistics.
All patients were treated with surgical resection of the primary cancer. A majority of patients with high-grade tumors (16; 70%) underwent concurrent neck dissection, whereas fewer than half (3; 23%) of intermediate-grade patients and only 1 patient (1; 7%) in the low-grade group underwent concurrent neck dissection at time of primary resection. At the time of initial surgery, positive margins were found on pathologic examination in 1 low-grade tumor, 3 intermediate-grade tumors, and 7 high-grade tumors. Of the 20 patients who underwent neck dissection, 13 had confirmed N+ disease, and 7 were pathologically staged as N0. The majority of patients with N+ disease (12 of 13; 92%) had high-grade tumors, whereas 1 of 13 (8%) had an intermediate-grade tumor. A majority of patients with high-grade tumors (70%) received adjuvant radiotherapy, whereas 23% of patients with intermediate-grade disease and only 1 patient (7%) in the low-grade group received radiotherapy.
OS and DFS are depicted for all patients with 95% confidence intervals (95% CI) (Figs. 1 and 2). The median survival for patients with high-grade MEC was 49 months, with a lower 95% CI of 24 months. The median survival for patients with low-grade or intermediate-grade MEC was not reached. There was a significant difference noted between high-grade and intermediate-grade with respect to OS (P < .0001, log-rank test) and high-grade and low-grade OS (P < .001, log-rank test) (Fig. 3). There was no significant difference noted between the low-grade and intermediate-grade groups.
Analysis of DFS similarly displayed a significant difference between high-grade and intermediate-grade MEC, with no significant difference noted between low-grade and intermediate-grade MEC (Fig. 4). Locoregional recurrence was observed in 7 of 23 high-grade patients (30%) and 3 of 13 intermediate-grade patients (23%), but was not observed in patients with low-grade MEC. Distant metastases occurred only in the high-grade MEC group (3 of 23 patients; 13%). Incidence of new primary tumor was only observed in the high-grade MEC group in 4 of 23 patients (17%). No low-grade MEC patients were diagnosed with a new primary malignancy or distant metastases during the current study.
All 14 patients with low-grade MEC remained alive and free of disease throughout the study. Ten of 13 intermediate-grade MEC patients remained free of disease throughout the study. One intermediate-grade MEC patient died of other causes at 78 months of follow-up, but no intermediate-grade patients died of disease. Approximately 52% (12 of 23 patients) of high-grade MEC patients died of disease. Nine of the 23 high-grade MEC patients remained free of disease, although 3 died of other causes. Two patients in this group were alive with disease at 39 months and 96 months of follow-up, respectively.
Univariate analysis (Table 2) revealed a statistically significant association with both DFS and OS for the following variables: age, T classification, N classification, histologic grade, surgical margin status, and treatment with radiotherapy. Neck dissection and sex were found to be significantly associated with DFS only. Anatomic site of tumor was not found to be significantly associated with either.
OS indicates overall survival; DFS, disease-free survival.
The log-rank test was used for categoric variables and the univariate Cox regression model was used for continuous variables to calculate P values.
Gender (female vs male)
Disease site (parotid vs oral cavity vs other)
T classification (0-2 vs 3-4)
N classification (N0 vs N+)
Neck dissection (yes vs no)
Histologic grade (low vs intermediate vs high)
Histologic grade (low vs intermediate)
Histologic grade (intermediate vs high)
Positive surgical margin (yes vs no)
Radiotherapy (yes vs no)
By controlling for histologic stage, Table 3 shows that treatment with radiotherapy did not significantly influence DFS or OS in the high-grade group. However, surgical margin status was found to have a significant effect on both DFS and OS. For intermediate-grade patients, radiotherapy and surgical margin status were found to be significantly associated with DFS only. Further analysis revealed that intermediate-grade patients who received radiotherapy and/or had positive margins had lower DFS than those who did not.
Table 3. Univariate Analysis Stratified by Disease Grade
OS indicates overall survival; DFS, disease-free survival; NA, not applicable.
No event in patients with positive surgical margins.
Multivariate analysis included all variables that were found to be statistically significant on univariate analysis. This approach revealed that histologic grade was significantly associated with both OS (P = .04) and DFS (P = .003). Age was significantly associated with OS (P = .04) and surgical margin status (P = .0004) was significantly associated with DFS (Table 4).
OS indicates overall survival; DFS, disease-free survival; NS, not significant.
Multivariate Cox regression model was used to calculate P values.
Positive surgical margin
Traditionally, the distinct difference between the clinical behavior of low-grade MEC and high-grade MEC has directed therapeutic options.13–15 Low-grade MEC is known to behave less aggressively and is treated with surgical excision alone. High-grade MEC is treated with wide surgical excision of the primary lesion with lymphadenectomy when cervical metastases are present, and adjuvant external beam radiotherapy. The treatment protocol for intermediate-grade MEC is not well established and a variety of treatment protocols have been proposed.3, 16, 17 Several studies have examined cohorts of MEC patients over the years, but are subject to discrepancies related to MEC grading classification.14, 17–20 The pathologic classification of MEC has been modified several times to improve the correlation of tumor grade with clinical prognosis. Given the relatively rare nature of this disease, prior studies have spanned relatively long time periods to accumulate a reasonable number of patients. Thus, changes in pathologic grading could affect these retrospective analyses. Recently, reviews of the pathology literature have established the consensus that the Brandwein grading scheme is the best classification system available given its reproducibility and predictability. In addition, this system stratifies patients into 3 fairly uniform groups with different prognoses.3, 21 In light of the wide variability of prognosis in MEC and the findings of the current study, meticulous histopathologic grading is of utmost importance.
We set out to examine tumor behavior and patient outcomes in MEC, in light of this new consensus on the grading system. Our focus was on histologic grade and the effect on prognosis. We also attempted to elucidate further the optimal treatment protocol for intermediate-grade cases. We included MEC patients from all anatomic sites to capture both major and minor salivary gland tumors. All of the cases were re-evaluated to confirm the presence of MEC and the tumors were prospectively graded based on the Brandwein classification.
We found a significant trend of worsening OS and DFS from low-grade to intermediate-grade to high-grade MEC (Figs. 2 and 3). This trend has been demonstrated previously in the literature.3, 7 Despite this important trend, we found no significant difference in OS between low-grade and intermediate-grade MEC. However, the OS for patients with high-grade MEC was significantly worse than that for patients with intermediate-grade and low-grade MEC, resulting in an absolute increase of 30% in the 2-year OS rate. Similarly, there was no significant difference noted between low-grade and intermediate-grade disease DFS, whereas DFS for high-grade MEC was significantly worse. The result was an absolute increase of 45% in 2-year DFS rate for the intermediate-grade or low-grade group compared with high-grade MEC. These results demonstrate a considerable difference in survival and tumor recurrence outcomes between high-grade and intermediate-grade MEC. Using several forms of analysis, intermediate-grade MEC was found to be similar to low-grade MEC. Although some of the intermediate-grade MEC patients developed disease recurrence, this did not decrease the OS.
Demographic factors and tumor characteristics were assessed for effect on prognosis. Individually, age, sex, tumor size (T classification), regional metastasis (N classification), and histologic grade each significantly affected both OS and DFS, whereas anatomic site did not. In terms of age, older patients had worse OS and DFS. This may be related to comorbid conditions or other confounders related to age, perioperative issues, and/or tolerance of adjuvant therapy. Several studies have documented a female preponderance in salivary gland MEC patients, with as high as a 3:2 female-to-male ratio.2 In the current study, males had lower OS and DFS than females. The average age of males was higher than females, which may have contributed to this finding. Further study may be warranted in light of this finding.
Univariate analysis also was used to assess the effects of individual treatment interventions on prognosis for all patients. Neck dissection, positive surgical margins, and radiotherapy were all found to be significantly associated with decreased OS and DFS. We did not detect an improvement in survival for patients who underwent adjuvant radiotherapy or neck dissection. It is interesting to note that radiotherapy was associated with lower OS and DFS. This was likely because patients with more advanced disease receiving this treatment. Furthermore, when histologic grade was controlled, there was no improvement noted in the average survival for patients who received radiotherapy compared with those who did not in both the high-grade and intermediate-grade groups. In the high-grade group alone there was no significant difference in OS or DFS based on adjuvant XRT. In the intermediate-grade group, DFS was significantly worse (P = .030) for the 4 of 14 patients who received XRT. Three of those 4 patients had positive margins as well. Again, none of those patients died of disease. At the end of the study, 2 patients had no evidence of disease and 2 were alive with disease. Neck dissection was found to have a significant effect on OS only. Of the 20 patients who underwent neck dissection, 13 had N+ disease. As an independent predictor, neck dissection was associated with decreased survival in the high-grade group and no change in the intermediate-grade group.
Multivariate analysis demonstrated that among demographic factors, tumor characteristics, and treatment factors, only histologic grade significantly affected both OS and DFS. In addition, age was found to have a significant effect on OS, and surgical margin status was found to significantly affect DFS (Table 4). This analysis indicates that the prognosis of MEC patients may be predicted by histologic grade, and that age and surgical margin status are important determinants as well.
For all groups, positive surgical margins were associated with decreased DFS. This is especially important to note in this population. Many patients with cancer in the parotid gland are often left with a positive margin because of preservation of the facial nerve during superficial parotidectomy. Given such poor survival outcomes with high-grade MEC, surgeons may need to consider more radical surgical excision, including possible sacrifice of the facial nerve. However, continued investigation of this issue is clearly warranted. In the intermediate-grade group, 2 of 3 patients with positive surgical margins developed disease recurrence. Although this was a very small number, none of the intermediate-grade MEC patients died of disease despite tumor recurrence.
In the current study, the outcomes for patients with intermediate-grade MEC were very different from those with high-grade MEC. Unfortunately, 61% of high-grade MEC patients (12 of 23 patients) developed some form of tumor recurrence and 52% (10 of 16 patients) died of disease. Within the group of high-grade MEC patients, 7 patients who had positive margins were treated with postoperative radiotherapy and subsequently developed tumor recurrence. Six of these 7 patients died of disease. Although there were 7 patients who were not treated with radiotherapy at time of presentation, only 2 remained alive without disease at the time of last follow-up. One of them died of other causes at 202 months.
The current study was limited by a relatively small sample size and the length of follow-up. This is a common issue in the MEC literature, given the relative rarity of this cancer, although it is the most common of the salivary gland malignancies. A recent report by Aro et al22 suggested that intermediate-grade MEC was similar to high-grade disease. However, that study had relatively few cases of intermediate-grade MEC (7 of 52 cases; 13.5%) and the investigators used the AFIP criteria, which tends to downgrade MEC and potentially lead to undertreatment. In the future, collaborative work across institutions with a uniform grading classification for MEC may help to alleviate this problem by allowing researchers to combine results.
We have pointed out the similarities between low-grade and intermediate-grade MEC in terms of OS and disease recurrence, as well as the significant difference between intermediate-grade MEC and high-grade MEC. This appears to divide patients into 3 distinct groups: 1) those with low-grade tumors who did not die of disease or develop tumor recurrence; 2) those with intermediate-grade tumors who have a low rate of tumor recurrence that does not significantly affect the length of survival or cause death from disease; and 3) those with high-grade tumors who are at increased risk for disease recurrence and death because of disease.
Some investigators have reported that the survival of patients with MEC is closely related to histologic grade as well as clinical stage (tumor size).6, 9, 17, 19, 23, 24 In a study including 127 MEC patients, Spiro et al25 found significantly improved survival in patients with low-grade salivary gland malignancies (including MEC, acinic cell carcinoma, and adenocarcinoma) compared with those with high-grade MEC. They studied the interaction between clinical stage and histologic grade and found that survival was almost comparable in patients with low-stage and high-stage/low-grade tumors, although this finding was not statistically significant. This underscores the need for further investigation into predictors of prognosis for MEC.
Recently, immunohistochemical markers, such as terminal deoxynucleotidyl transferase (TdT)-mediated biotinylated deoxyuridine-triphosphate (dUTP)-biotin nick-end labeling (TUNEL), p53 and Ki-67, have been reported to be correlated with decreased survival, DFS, tumor grade, stage, and local and distant metastasis in salivary gland malignancies.26–29 Other studies have shown the prognostic value of the fusion transcript MECT1-MAML2, which has been associated with favorable clinicopathologic outcomes, including longer OS and DFS and lower rates of distant metastases.30–34 These potential biomarkers, along with continued analysis of clinical outcomes, will allow us to optimize MEC therapeutic approaches.
The results of the current study confirm the utility of the Brandwein histologic grading scheme. This system delineates patients with poor prognosis (high grade) from those with better prognosis (intermediate and low grade). In addition, this system further classifies patients with good prognosis by their susceptibility to cancer recurrence: intermediate-grade patients have a low rate of disease recurrence and low-grade patients have a significantly lower, almost negligible, recurrence rate. These findings support the treatment paradigm used at our institution for intermediate-grade MEC patients. We recommend wide surgical excision of the primary lesion with particular emphasis on obtaining negative surgical margins to avoid local recurrence. In the presence of clinically positive neck metastasis, neck dissection is performed. With the current histologic grading system, adjuvant radiotherapy may be reserved for treatment failure, which presents as locoregional recurrence. Our findings also demonstrate the difficulty associated with the treatment of patients with high-grade MEC. The poor overall prognosis of these patients indicates the need for aggressive surgical intervention and adjuvant radiotherapy. In addition, novel biomarkers and targeted therapies need to be explored to optimize therapeutic approaches to MEC.