Journal of Surgical Oncology 46: 100-106 (1991)

Mucoepidermoid Carcinoma of the Salivary Glands: A Reappraisal of the Influence of

Tumor Differentiation on Prognosis

ANA LUiSA CLODE, MD, ISABEL FONSECA, MD, J. ROSA SANTOS, MD, AND

JORGE SOARES, MD, iwc

Servico de Patologia Morfoldgica (A.L.C., I.F., /.S.) and Clinica Oncologica I (I.R.S.), lnstituto Portugues de Oncologia de Francisco Cent;/, Centro de Lisboa, Lisbon, Portugal

Thirty-nine cases of mucoepidermoid carcinoma of the salivary glands were reviewed for a reappraisal of the influence of the grade of differentiation on the outcome of the disease. The age of the patients ranged between 7 and 84 years. Fifteen patients were females and 24 males. The tumors were located at the parotid gland (n=30), the submaxillary gland (n= I), the soft palate (n=5) and the oral mucosa NOS (n=3). At presentation 4 tumors were intraglandular and 35 extraglandu- lar; three patients had lymph node metastases and one patient lung metastases. The grade of differentiation was assessed using the criteria of Healey et al. Twelve tumors were classified as grade I, 17 as grade 11, and 10 as grade 111. Follow-up information was obtained with a duration of 5-144 months (mean 44.7 months). Six cases recurred locally and 5 developed metastases. Five years cumulative survival was 100% for grade I, 70.1% for grade 11, and 47.2% for grade 111. The results point to the usefulness of the assessment of the grade of differentiation as a guide to anticipate the outcome of the disease.

KEY WORDS: location, metastases, follow-up prognosis

INTRODUCTION Mucoepidermoid carcinoma of the salivary glands was

recognized as a separate entity, among the group of the salivary gland neoplasia, by Stewart et al., in 1945 [I] . It was described as having a peculiar morphology and an indolent course with mild clinical behavior [ 11. However, cases with considerable morbidity and aggressive out-

Since there is no single reliable marker for predicting the clinical course of the mucoepidermoid carcinoma, the histopathologic Pattern remains a useful tool for the prognostic evaluation of these tumors. We used a series of 39 mucoepidermoid carcinoma with long time follow-

study in an attempt to reappraise the influence of the degree Of differentiation On prognosis.

come have been reported and usually are associated with a solid pattern, an infiltrative growth and cells with anaplasia [2-51.

Mucoepidermoid carcinomas are composed by three cell types in variable amounts: mucus-secreting cells, epidermoid cells and intermediate cells [3], Healey et al. in 1970 proposed a classification of mucoepidermoid carcinoma into three grades based on the relative amounts of mucous structures and squamous areas and stressed their correlation with the prognosis [3]. Low-grade tumors usually followed a benign course whereas high grade or grade I11 tumors carried significant morbidity 13,6,71. (0 1991 Wiley-Liss, Inc.

MATERIALS AND METHODS The present series includes 39 cases of mucoepider-

moid carcinoma of salivary gland origin, primarily treated at the Instituto Portugu6s de Oncologia de Fran- cisco Gentil (Centro de Lisboa), between 1962 and 1989. The tumors were reevaluated with regard to histological features and grading of malignancy in an attempt to correlate them with the clinical course.

Accepted for publication September 13, 1990 Address reprint requests to Dr. Ana Luisa Clode, Servip de Patologia Morfolbgica, Instituto Portugues de Oncologia, Rua Prof. Lima Basto, 1093 Lisboa Codex, Portugal.

Mucoepidermoid Cancer of the Salivary Glands 101

The tumors were selected from an initial group of 57 cases retrieved in the laboratory files and classified under the heading of “mucoepidermoid” and “epidermoid car- cinoma” of the salivary glands. Eighteen of these cases were excluded after reclassification and because of inadequacy of material for re-evaluation. In the former group we excluded 9 epidermoid tumors located at the parotid gland since the patients had a previous diagnosis of primary squamous carcinoma in the vicinity. The available material of the remaining 9 cases was not considered enough to unequivocally accept the tumor as originating in the salivary gland.

All patients were treated by surgery with complete excision of the tumor by gland and periglandular tissue removal. In 19 of them complementary radiotherapy was given. All 39 tumors studied had been fixed in unbuffered formalin and paraffin embedded. New sections were obtained from every case and stained with H&E and periodic acid-Schiff (PAS) for mucin. The sections were reviewed by two of us (ALC,IF) with regard to the tumor margins for evaluating the type of growth and the cell composition for the grade of differentiation, without previous knowledge of follow-up data.

Peri- and intratumoral neoplastic vascular invasion (lymphatic and venous vessels), mitotic rate, perineural infiltration and presence of necrosis were also evaluated in every case.

Tumors were graded according to the criteria advanced by Healey et al. [3], into three grades: well, moderately, and poorly differentiated, depending on the predominant cell type. Tumors were classified as well-differentiated or grade I when they had more than 50% of mucous cell component. Grade I1 tumors showed 10 to 50% of mucus structures and in grade 111, or poorly differentiated tumors, the mucous structures formed less than 10% of the neoplastic area.

The clinical charts of all the patients were reviewed for the following data: age, sex, location of the tumor and staging at presentation. Follow-up information on local recurrences, regional and distant metastases and present clinical status was obtained. The follow-up period ranged between 5 and 144 months (mean 44.7 months) or until death.

Statistical analysis was performed, using the actuarial survival method to evaluate the influence of grade of differentiation on prognosis and the evaluation of exten- sion of the tumor on prognosis. The results were com- pared using the Mantel-Haenszel test and were consid- ered significantly positive for a P value of <0.05 with a 95% confidence interval.

RESULTS Thirty-nine cases of mucoepidermoid carcinoma of

salivary gland origin were included in the present series. They were retrieved from the files of the ServiGo de

n. of cases 101

. “ 1 MPLES

FEMALES 6 l

” (10 10-20 20-30 30-40 40-50 50-60 60-70 70-80 )80

years

Fig. 1. Age and sex distribution of the patients.

Patologia Morfol6gica of Instituto Portugds de Oncolo- gia de Francisco Gentil (Centro de Lisboa), during a 27-year period. This series excluded 18 cases previously classified as mucoepidermoid carcinoma that were asso- ciated with a primary squamous/adenosquamous cell carcinoma of other sites (n=9) or had not enough available material for reevaluation (n= 9).

The age of the patients ranged between 7 and 84 years, mean age being 50.9221.2 years. The incidence curve distribution showed a peak at the first decade and a second peak at the sixth and seventh decades (Fig. 1). Fifteen patients were females (38.5%) and 24 were males (61.5%). Most tumors were located at the major salivary glands (n=31); one was a submandibulary gland tumor, and 30 were in the parotid gland, 21 on the left and 9 on the right side. The remaining 8 cases originated in the minor salivary glands: 5 on the soft palate and 3 in the oral mucosa NOS. At presentation, 35 tumors were extraglandular (89.7%) including 27 major gland neopla- sia and all the minor gland tumors. All intraglandular tumors (10.3%) were located at the parotid gland.

Two distinct architectural types were identified, i.e., solid and cystic, both formed by varying amounts of mucous, epidermoid and intermediate cells. More rarely, clear and columnar cells also contributed to the neoplasia organization. In our series, 19 cases showed a predom- inantly cystic arrangement and 20 a solid pattern. Cystic spaces were lined by cuboidal mucous cells and occa- sional columnar cells, intermingled with intermediate- type cells (Fig. 2A, B). These basal-like cells were smaller and displayed round, dark nuclei (Fig. 3).

In tumors exhibiting a solid pattern with squamous-

102 Clode et al.

~ ~ ~~

Fig. 2. Low grade (grade I) mucoepidermoid carcinoma. A: The tumor shows a cystic pattern with cavities filled by mucus and lined by mucin-secreting cells. The cystic structures are separated by fibrous

stroma. (H&E.) x36. B: The neoplastic tissue contains mucin- secreting cells intermingled with smaller intermediate-type cells. (H&E.) X 160.

Fig. 3. Moderately differentiated (grade 11) mucoepidermoid carci- noma. The tubular structures are lined by stratified epithelial cells mostly of intermediate type. A few goblet mucin-secreting cells are apparent. (H&E.) X 160.

Fig. 4. Poorly differentiated (grade 111) mucoepidermoid carcinoma. Squamous aspect of the neoplastic proliferation with a few discernible lumina. Minute foci of necrotic cells associated with polymorphonu- clear cell infiltrate. (PAS stain.) X 160.

appearance, mucin-secreting cells were almost incon- spicuous and intracytoplasmic lumina were only discern- ible after PAS staining (Fig. 4).

Grade I neoplasms consisted of mucin-containing cystic or tubular structures and lined by mucus secreting cells. There were scarce solid areas composed predomi- nantly of intermediate cells. Grade I11 neoplasms almost always consisted of epidermoid cells with small amounts of intermediate cells also present. Grade I1 neoplasia showed architectural and cytological features of both types, with more than 30% of the tumor mass formed by solid aggregates of neoplastic cells.

Twelve tumors fulfilled the aforementioned criteria to be classified as grade I (30.8%),17 as grade I1 (43.6%), and 10 as grade I11 neoplasia (25.6%).

The correlation between the degree of differentiation and the extension of the neoplasia beyond the capsule of the gland, the vascular invasion and the mitotic count is shown in Table I. Three of the four intraglandular cases were grade I carcinoma. The six tumors that occurred in children and adolescents also belonged to this group of well-differentiated neoplasia.

The extraglandular tumors were predominantly grade I1 (n= 16) and grade I11 (n= 10) (Table I). From the three patients exhibiting cervical lymph node metastases at presentation, 2 had grade I1 tumors and 1 a grade I11 tumor, respectively.

Intra- and peritumoral invasion of vessels by neoplastic cells was found in 15 tumors (Table I). In the remaining 24 cases, the presence of vascular invasion, either venous or lymphatic, could not be demonstrated. We found lymphatic vessel permeation by tumor cells in 1 grade I tumor, in 8 grade I1 tumors and in 4 poorly differentiated grade I11 tumors. Two of the grade I1 tumors and 1 of the grade I11 tumors had concomitant venous invasion by neoplastic cells. Only one tumor had perineural invasion apparently unrelated to vessels.

Mitotic activity was not a prominent feature in all tumors. In 20 cases, including all grade I tumors, mitotic figures were absent; in the remaining 19 tumors, mitotic count ranged from 1 to 5 mitoses. The higher values were observed in grade 111 neoplasia.

At the end of the observation period, 20 patients were alive and well (51.3%), 5 were alive with disease (12.8%), and 9 died of disease (23.1%); five patients died of other causes (12.8%) and were excluded from the survival curves. There were no complications in patients with tumor confined to the salivary glands, the survival being 100% for these intraglandular tumors.

The cumulative survival of the tumor collective is shown in Figure 5. The data concerning the evolution of the tumors subdivided into 3 groups according to their degree of differentiation is summarized in Table 11. Six tumors recurred, 24-36 months after surgery. One of

Mucoepidermoid Cancer of the Salivary Glands

TABLE 1. Correlation Between Local Extension of Tumor, Presence of Vascular Invasion and Number of Mitosis With Grade of Differentiation*

103

Local Vascular extension invasion Mitosis Grade of

differentiation IG EG No Yes < 1 > 1

I (n = 12) 3 9 11 1 11 1 I1 (n = 17) 1 16 9 8 6 11 I11 (n = 10) 0 10 4 6 3 7

* IG, intraglandular; EG, extraglandular.

11-39 60

I

20 ~

1

Fig. 5. Cumulative survival of the tumor collective.

them recurred three times. This was a grade I1 neoplasm and was located at the parotid gland, being extra- glandular at presentation. Two recurrent tumors occurred in patients, both adolescents with grade I neoplasia, being located one at the soft palate and the other at the parotid gland. Both were extraglandular at presentation and no locoregional or distant metastases were noticed 60 and 120 months after the second surgery, respectively. Two patients with grade I1 neoplasms and 1 with a grade I11 had metastases in ipsilateral cervical lymph nodes (7.7%). One patient bearing a poorly differentiated neoplasm developed lung metastases, and another patient developed lung and bone metastases and died of the disease.

The cumulative survival at five years was of 100% for grade I tumors and 70.1% for grade I1 neoplasms. For grade I11 tumors that value at 2 years was 42.7% since no grade I11 patient was alive 5 years after the operation (Fig. 6).

DISCUSSION We studied a series of 39 mucoepidermoid carcinomas

in order to evaluate different morphological parameters,

104 Clode et al.

TABLE 11. Morbidity and Mortality Correlated With Degree of Differentiation*

Grade of period (mean) differentiation AWD REC MET DOD DOC (mo)

Follow-up

I (n = 12) 10 1 0 0 1 65.6 I1 (n = 17) 8 4 4 2 4 54.0 111 (n = 10) 2 1 2 7 0 15.7

Total (n = 39) 20 6 6 9 5 44.7

* AWD, alive without disease; REC, recurrence; MET, metastases; DOD, dead of disease; DOC, dead of other causes.

9; 9 nn

I

- Grade I - Grade I1 - - - - - - Grade Ill

Fig. 6. Actuarial survival of the patients divided into three groups according to degree of differentiation,

with emphasis on the degree of differentiation, and to correlate it with the outcome of the disease.

As shown in Figure 1, mucoepidermoid carcinoma occurred both in the children and adolescent group of patients (first peak) and in the adult group, the latter with a peak in the sixth and seventh decades. This agrees with previous published series that also found a similar pattern of age distribution of patients in this tumor type [6,7-91.

The peak corresponding to the first two decades confirms the well known high frequency of mucoepider- moid carcinoma among the very rare malignant tumors of salivary glands occurring in that age group. In a retro- spective study of a personal series of 24 cases we found that 5 out of 7 malignant tumors were mucoepidermoid carcinomas [ 81.

The predominance of the male sex observed in the present series and also reported by Spiro et al. [ lo] contradicts most published series [ 1 1-1 31. We admit that

geographical differences might explain the male sex prevalence of mucoepidermoid carcinoma in some pop- ulations, namely in the area of Southern Portugal.

The cumulative survival for the tumor collective, as illustrated in Figure 5 , demonstrates the rather good prognosis of mucoepidermoid carcinoma. This fact would justify the designation of mucoepidermoid “tumor” in- stead of “carcinoma”, that was favored by some inves- tigators [7,12,14,15].

However, regarding the clinical evolution of the tu- mors we can consider that two groups occupy opposite ends of a spectrum of biological behaviour. At one end are locally infiltrative tumors with frequent vascular invasion and tendency to metastasize; and at the other end the tumors that pursue an almost benign non-invasive course.

Although in the present series we found a considerably higher number of cases with unfavorable prognosis compared to what is generally reported [2,6,16], this difference can be explained by the fact that the group studied deals with an oncology hospital-based series. The relatively high percentage of cases with aggressive be- havior in the present series is an additional argument to support the proposal of the WHO’S panel to designate definitely these tumors as “mucoepidermoid carcinomas”

The histological classification used to grade the dif- ferentiation of the tumors, based on the architectural and cytological criteria advanced by Healey et al. [3] corre- lated significantly with the outcome of the disease. This reinforces the authors’ assumption of its value for prog- nostication of mucoepidermoid carcinoma. Well differ- entiated tumors, or grade I, showed a fairly good evolution, whereas patients bearing grade I11 tumors followed almost always an unfavorable outcome with considerable morbidity. After 5 years, the cumulative survival curves showed marked differences, the survival rate decreasing significantly from grade I tumors to grade

1171.

I1 and grade I11 neoplasia, respectively of 10070, 7096, and 42%. The differences between the survival curves of the patients grouped according to the three grades of differentiation were statistically significant.

Mucoepidermoid carcinomas that occurred in the pe- diatric group had an excellent prognosis since all the patients were free of disease at the end of the follow-up period. This fits well with the fact that all of those tumors were grade I, well-differentiated neoplasia. The two recurrent cases were extraglandular at presentation and had no complications after the second surgery, confirm- ing the excellent overall cure rate observed in the pediatric group [8,9,19,20].

The degree of differentiation seems not to correlate with the invasiveness of the neoplasia. This is illustrated by the fact that three-fourths of the grade I tumors were extraglandular on presentation, as shown in Table I. This leads one to accept those properties (tumor differentiation and invasion capacity) as distinctive characteristics ex- hibited by the neoplastic phenotype.

Vascular invasion was almost never observed in grade I tumors, but this feature could also not be demonstrated in a considerable number of grade I1 and grade I11 tumors. However, retrospective studies always have limitations for evaluating accurately vascular invasion due to the number of samples available for reexamination.

The proliferative activity of the tumor assessed by the number of mitotic figures is related to the grade of differentiation. Although accepting that mitotic count is a rather crude method to evaluate the malignancy of a tumor [21], it is not surprising that tumors with less differentiated patterns were associated with a higher number of mitoses as observed in this series. However, large series are needed to substantiate any definite conclusions regarding the relationship between grading, invasiveness and proliferative activity of the mucoepi- dermoid carcinomas.

The group of tumors with intermediate grade (grade 11) differentiation has the largest range of potential evolu- tion, from the “very benign” tumors (8 cases) to ones carrying morbidity and mortality (8 cases with recur- rences and/or metastases, 2 being fatal). This fact makes it difficult for the pathologist to give an opinion about the outcome of the neoplastic disease of an individual case. Other methods may eventually be used as predicting tools in order to determine more accurately the prognosis of the grade I1 mucoepidermoid carcinomas. Cytometric DNA ploidy evaluation has recently been claimed to be useful for this purpose [16,22].

CONCLUSION Mucoepidermoid carcinoma is unquestionably a ma-

lignant tumor, although frequently following an indolent course. This biological behavior is especially associated

Mucoepidermoid Cancer of the Salivary Glands 105

with younger age and tumors confined to the salivary gland and exhibiting a well-differentiated pattern. The degree of differentiation of mucoepidermoid carcinoma of the salivary glands seems, therefore, to remain a useful guide to evaluate the prognosis of these neoplasms.

ACKNOWLEDGMENT This study was supported by a grant from the Nucleo

Regional do Sul da Liga Portugesa Contra0 Cancro.

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