| Abstract|| |
Context: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy and its grading is greatly consequential in the management and prognosis of patients with the disease. Aims: To compare histologic grading systems in MEC of minor salivary glands. Settings and Design: Two qualitative (modified Healy and Memorial Sloan-Kettering Cancer Center [MSKCC] methods) and two quantitative (Armed Forces Institute of Pathology [AFIP] and Brandwein methods) were evaluated. Subjects and Methods: Diagnostics slides of 19 patients including one recurrent case were evaluated using the four grading systems. Statistical Analysis Used: Percentages and proportions were used. Results: Agreement across all grading system was found to be very low (32%) while there was a better agreement between AFIP and MSKCC methods (84%) between modified Healy and Brandwein (58%). The method that gave the poorest agreement with all the others was the Brandwein grading. In general, the AFIP and MSKCC methods tended to grade the tumors lower while the Brandwein and modified Healy methods seemed to grade them higher. Conclusions: Most MEC of minor salivary glands appear to be low-grade tumors. It is conceivable that some grading methods (Brandwein and modified Healy) may lead to an unnecessary escalation of management methods in these tumors. The MSKCC method may have emphasized some parameters which may not have much importance in minor salivary gland MEC. The AFIP method appears to be the most appropriate to use for the grading of minor salivary gland MEC. Further studies are required to confirm or disprove this finding.
Keywords: Histological grading, minor salivary glands, mucoepidermoid carcinoma
|How to cite this article:|
Qannam A, Bello IO. Comparison of histological grading methods in mucoepidermoid carcinoma of minor salivary glands. Indian J Pathol Microbiol 2016;59:457-62
|How to cite this URL:|
Qannam A, Bello IO. Comparison of histological grading methods in mucoepidermoid carcinoma of minor salivary glands. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Jul 21];59:457-62. Available from: http://www.ijpmonline.org/text.asp?2016/59/4/457/191765
| Introduction|| |
Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor (SGT) accounting for roughly one- third of the epithelial malignancies in the salivary glands.  In the minor salivary glands alone, studies with relatively large samples have shown that MEC prevalence could be between 46% and 52% of their malignant tumors. ,, The most commonly affected site of these minor glands is the palate. , The tumor is histologically characterized by cystic, solid, or mixed (cystic and solid) growth patterns and comprises primarily varying proportions of three cell types: mucous, epidermoid (or squamoid), and intermediate cells from one tumor to another. These cell types resemble those of the excretory ducts of salivary glands.  Clear, columnar and/or oncocytic cells may also be present. Occasionally, clear cells may be the dominant cell type within the tumor.
The outcome in MEC has been found in many studies to be significantly associated with the tumor grade unlike in tumors, such as squamous cell carcinoma (the most common epithelial malignancy of the head and neck) in which the histological tumor grade is not particularly related to the prognosis of the patient.  However, it is surprising that despite this fact, no grading system is universally accepted as the standard presently. The most commonly used ones are: the modified Healy grading, , the Armed Forces Institute of Pathology (AFIP) grading , which is recommended by the World Health Organization (WHO) for grading all salivary gland MEC,  and the Brandwein grading.  In no other, SGT is the management so clearly related to the histological grade as in MEC.  Initially, graded into only low and high grades,  MEC has been further graded into three categories in the past several decades: low, intermediate, and high grades. In general, based on the several retrospective prognostic studies, only surgical treatment is required for low-grade tumors while high-grade lesions will require multimodal therapy including surgery, neck dissection, and radiotherapy. There is no consistent agreement on what should be the standard treatment for tumors categorized as an intermediate grade. Studies comparing the various grading methods have used material comprising only the major salivary glands , or both the major and the minor glands in the same study. , The aim of this study is to compare the grading methods in MEC using those cases in our center that were seen in only the minor salivary glands to emphasize or differ in opinion with the findings of these previous studies.
| Subjects and Methods|| |
The pathology files of the oral biopsy service of the College of Dentistry, King Saud University, Riyadh, Saudi Arabia were searched for the cases of MEC diagnosed from 1984 to 2013 after obtaining the approval of the College of Dentistry Research Center (CDRC). Cases with adequate clinical data along with their original diagnostic slides which must have large enough tumor tissue (minimum of one slide per 1.2 cm tissue) and free of artifactual distortions were included in the study. The microscopic features of the previously diagnosed slides were required to meet the definition of MEC by the WHO.  Of the 23 cases that were drawn from our archive, only 20 cases with MEC of the minor salivary glands were found to meet these criteria after rereviewing of the slides by the authors.
These cases comprised 19 primary tumors and 1 recurrent case from one of the primary tumors. The demographic and clinical data of the patients were collected from the files including the age, gender, and location of MEC as well as tumor presentation, duration, risk factor exposure, and nodal involvement. The previous histopathological grading (if reported) of our cases was not taken into consideration for this study. Before regrading the slides, some tumor parameters which were not universal to all the grading systems were assessed including the presence or absence of circumscribed borders, lymphocytic host response, keratinization, and stromal desmoplasia. The tumors were then graded by evaluating the slides related to each case for four 3-tiered grading methods (two qualitative and two point-based methods), respectively: (i) the modified Healy grading, , (ii) the Memorial Sloan-Kettering Cancer Center (MSKCC) grading,  (iii) the AFIP grading , and the Brandwein grading  [Table 1] and [Figure 1]. The final grades using all the methods for each case were then compared [Table 2]. The recurrent tumor which was analyzed separately was that of patient number 13 which occurred 38 months after the treatment of the primary tumor. The primary tumor affected the palate, and the maxillary antrum and recurrence occurred at these sites as well as the lateral wall of the nose. This recurrent tumor was included in the study to evaluate if a change of histopathological grading (particularly an upgrading) can occur in a long-term recurrent tumor with any of the grading systems (e.g., as an evidence of de-differentiation). Scoring by both authors based on the criteria of all four methods was identical in approximately 85% of cases. In discordant cases, scoring did not differ by more than one grade (only in cases scored as intermediate and high).
|Figure 1: Grading of mucoepidermoid carcinoma (Armed Forces Institute of Pathology). (Low grade a and b) Large cystic spaces with mucous secretion lined by mucous and epidermoid cells and intermediate cells (a, 400 μ m; b, 200 μ m). (Intermediate grade c and d) c - Well circumscribed lesion with fewer cystic spaces and more solid areas; d - Intermediate grade, predominantly clear, and epidermoid cells (c, 4 mm; d, 200 μ m). (High grade e and f) Solid tumors with the squamoid elements exhibiting anaplasia: Nuclear hyperchromatism, prominent nucleoli, and pleomorphism. Very rare mucous cells seen (e, 50 μ m; f, 70 μ m) (H and E, all)|
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|Table 1: The modified Healy, Memorial Sloan - Kettering Cancer Center, Armed Forces Institute of Pathology and Brandwein systems for grading of salivary gland mucoepidermoid carcinoma|
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|Table 2: Comparison of the four grading systems used for mucoepidermoid carcinoma of minor salivary gland in 19 primary tumors and one recurrent tumor|
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| Results|| |
Nineteen cases of primary MEC and a recurrent case from one of the 19 patients were included in this study. Eleven patients were males while 8 were females. The patients' ages ranged from 11 to 80 years (median 35 years). The great majority of the tumors were located in the palate with the chief presenting complaint being painless swelling. Most patients presented before 6 months of noticing their lesions, although one patient with maxillary sinus tumor with palatal extension reported that the lesion had been present for 12 years [Table 3]. This latter patient also presented with a recurrent lesion 38 months after the treatment of his primary tumor.
|Table 3: Clinicopathologic and demographic features of 19 patients with primary minor salivary gland mucoepidermoid carcinoma|
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Initial analysis of all the tumors showed that only 7 cases demonstrated complete or partial border circumscription, 6 cases showed significant lymphocytic host response at the tumor periphery or within the tumor while stromal desmoplasia was observed in 14 cases. None of the tumors showed keratinization within the lesion. As part of the grading systems employed, careful screening of all the surgical slides for neural invasion showed that none of the cases demonstrated this parameter. There were only three cases of bone invasion, two in primary tumors, and one in the recurrent tumor. Five cases of vascular invasion were seen (four primary, one recurrent). Six cases showed true invasion as small nests. Only two cases of tumor necrosis were observed, one primary, and one recurrent tumor.
Histopathologic grading using the four types of three-tiered grading system shows that only 6 of the 19 primary tumors (32%) showed a general agreement among the four grading systems [Table 2]. This value increased to 12 cases (63%) when the modified Healy grading is compared with both MSKCC and AFIP grading systems. The agreement between the MSKCC and AFIP was the highest at 84% of cases (16/19 cases). There was generally a poor agreement between the three other grading systems and the modified Brandwein grading. The highest agreement between the latter and any of the other three was found in relation to the modified Healy in 11 cases (58%). Comparison of the modified Brandwein with MSKCC and AFIP grading showed agreement in only 32% of cases (6 out of 19). In general, both the AFIP and MSKCC systems tend to favor lower grading of tumors while the modified Healy and the Brandwein systems favored higher grading. The recurrent tumor was graded as high by all the four grading systems.
| Discussion|| |
In most retrospective studies of malignant minor SGTs, MEC was found to be the most common malignancy although some studies have found adenoid cystic carcinoma to be the most common. ,, Histological grading and tumor staging are among the most important tools in the hands of clinicians in determining the appropriate management and prognostication in patients presenting with salivary gland MEC. Unlike tumor staging which is uniformly applied all over the world (TNM staging), lack of consensus on which histological parameter(s) should be accorded importance in grading has made it impossible to agree on the grading system for MEC that can be universally applied. Regarding the latter, only the multiparametric three-tiered system derived by workers from AFIP seemed to have been originally developed for minor SGTs  before being subsequently applied to MEC of major salivary glands.  The other grading systems have been applied mainly to MEC of major salivary glands and/or patient populations comprising MEC affecting both gland types.
One of the most consistent arguments against the use of histological grading in the selection of management method for patients with MEC is its degree of reproducibility among different examiners.  The introduction of numerical scoring of well-defined parameters in both the AFIP and the Brandwein grading seemed to have reduced the effectiveness of this argument as no parameter is unlikely to be missed out while being individually scored. However, the continuous use of the more subjective methods such as the modified Healy, and the introduction of newer qualitative methods such as the MSKCC's points to lack of complete trust in the quantitative systems. Using these grading systems, we found that applying the AFIP and Brandwein methods is easier and that subjectivity was eliminated to the barest minimum in comparison to the qualitative methods.
MEC of the minor salivary glands, especially those of the palate and buccal mucosa have generally tended to be of low or intermediate grades with an indolent clinical course. However, there are always outliers that behave aggressively resulting in recurrence, and sometimes death of the patient. , It was therefore not surprising that in this retrospective study of our 20 cases from 19 patients, only 3 of them were classified as high grade using the AFIP grading system. The Brandwein grading which was originally developed as a modification to the AFIP grading because some investigators believed that the latter is prone to downgrading some MEC, upgraded many of our cases to 12 high-grade tumors. Despite minor differences, the MSKCC grading was very similar to AFIP grading. In our hands, the modified Healy grading similarly upgraded some of the tumors compared to AFIP and MSKCC grading. However, tumor upgrading was still less common with modified Healy in comparison to the Brandwein grading. A previous report  found a strong agreement when the modified Healy was compared with Brandwein grading.
Most MECs are of low or intermediate grade,  and even more so those of the minor glands  as borne out in our cases here. By its nature, the Brandwein grading seemed to upgrade most of these lesions. It is noteworthy that despite having more parameters than AFIP, this latter grading system needs the presence of just a single parameter to move into intermediate grade, or in the presence of just two parameters, to become high grade. The implication of higher grading is that patients are going to be subjected to more aggressive forms of management. Excision with wide margin usually suffice in minor salivary gland MEC, and bone resection is only necessary in cases with bone invasion.  More aggressive treatment may be recommended in cases with lymphovascular invasion in conjunction with clinical and radiological findings such as ultrasound with or without fine needle aspiration cytology of the neck nodes, magnetic resonance imaging, or computed tomography for the invasion of surrounding structures, etc., The Brandwein grading system has been found useful in the previous studies comprising a mixture of major and minor SGTs. , Advocacy for its use in minor salivary gland, MEC is undermined by its tendency to upgrade many of the tumors.
Qualitative grading in MEC appears simple. For practical uses, however, it was discovered that while using these methods, we often instinctively recognize a feature that gives higher grading to MEC, especially in the presence of many low-grade features. Among these features that imbue higher grading using these methods in our cases were desmoplasia (or prominent stroma) and lack of encapsulation of the tumor, which are important components of both the modified Healy and MSKCC grading methods. It has been previously argued that these two characteristics make it, especially difficult to determine if the epithelial component is invading the normal fibrous tissue, or if both the epithelial component and the stroma are actually parts of the neoplasm.  This should be a very important consideration when grading MEC of minor salivary glands where fibrous tissues normally separate salivary gland lobules.  For the purpose of this study, all tumors were graded qualitatively as prescribed by the two methods without any preconceived bias. The efficacy of both MSKCC  and the modified Healy grading methods has been respectively demonstrated in major salivary gland MEC. , However, in our opinion, they may be prone to causing an upgrade of low-grade minor salivary gland MEC to intermediate and even high-grade tumors due to the lack of regard to the differences of minor salivary gland MEC from those of major glands concerning some "complicating' parameters (e.g., desmoplasia which is rather common, and tumor circumscription which is rather uncommon in minor salivary gland MEC). Moreover, the MSKCC method advocated the use of mitosis and necrosis as the most objective criteria in MEC of major salivary glands.  Our experience with minor salivary glands is that these parameters are rarely seen and are obviously not as important in their grading as cystic component and atypia (or anaplasia). It will be interesting to see the results of MSKCC method applied to minor salivary gland MEC by other centers.
Comparing the agreement in grading categorization between all the methods, lack of consensus was found to be about 65% which was higher than obtained in a similar study on major SGTs.  Agreement between grading systems is far more likely to be seen when tumors are graded as high or low grades, but not intermediate grade. This is a testament to the imperfection that is associated with classifying MEC as an intermediate grade tumor. Careful microscopic inspection showed that the most important parameters in the grading of MEC in our cases were the amount of cystic component of the tumors and anaplasia (atypia). Other parameters which are considered in MEC grading were either seen in only very few of our cases or entirely absent. Vascular invasion of MEC was seen in five cases (four primary and one recurrent tumors). We did not find neural invasion in any of the tumors. Only two tumors (one primary and one recurrent) showed tumor necrosis. Bone invasion was found in three tumors (two primaries and one recurrent). Increased mitosis was seen in only two tumors. These findings seemed to suggest that there may be differences in the expression of various histological characteristics of MECs of the minor salivary glands in comparison to those of the major gland.  Most of the cases in this study were seen on the palate.
Regarding the assessment of individual histological parameters, most were easily assessed although we were surprised that anaplasia seen in our cases was 55% (11/20). This value appeared high compared with some previous studies, especially those done in major salivary glands.  However, it is suggested that our finding is in line with other previous studies.  The AFIP grading method defined the term as the presence of nuclear or cellular pleomorphism, alteration in nuclear-cytoplasmic ratio, enlarged or multiple nucleoli, and/or hyperchromatism. In our study, we used this definition by AFIP. Goode et al.  have emphasized that anaplasia is often difficult for pathologists to assess.
We do not know why tumor necrosis was minimal in our cases. Tumor necrosis is generally believed to be rare in palatal and retromolar area MEC  which supports our finding. Interestingly, the palate is home to the reactive ischemic necrotic lesion secondary to trauma called necrotizing sialometaplasia although this is of a different etiology from necrosis induced by the presence of a malignant tumor. Neural invasion has been included as an important grading criterion in most grading system despite no conclusive proof of its influence in MEC prognosis.
The two cases with bone invasion occurred in the retromolar area and in the maxillary sinus and the palate. Tumors of the retromolar areas have been noted to have increased propensity for bone invasion.  MECs involving sinonasal tracts have also been considered controversial as their origin may be of surface rather than glandular, and they are rather not amenable to local excision.  The patient in our case carried the tumor for over 12 years before seeking treatment. At the time, the tumor was graded as intermediate (except by Brandwein method which originally classified it as high grade). This tumor recurred again 3 years after the initial surgery and was graded as high grade by all the grading methods. Since this recurrent tumor was upgraded by the three of the four grading system, it is interesting to speculate that it is an example of MEC that underwent de-differentiation over time.
| Conclusion|| |
Due to the very small number of cases that could be drawn from our archives and lack of sufficient follow-up data - a major limitation of this work - we can only suggest that another look at data from large oncologic centers is needed. We propose that AFIP grading system, as advised by the WHO,  is probably the most effective for minor salivary gland MEC. We hope that much larger studies will confirm that neural invasion, mitosis, and necrosis are equally as important in the grading of minor salivary gland MEC as in the major glands as previously well-documented by various studies. ,,, Any grading method used should be combined with TNM staging of the tumor to make management decisions that will give the best outcomes in patients with these tumors.
The authors acknowledge the support rendered by the CDRC toward the actualization of this work.
Financial support and sponsorship
The CDRC support is acknowledged.
Conflicts of interest
There are no conflicts of interest.
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Department of Oral Medicine and Diagnostic Sciences, College of Dentistry, King Saud University, P.O. Box 60169, Riyadh 11545
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]