ORIGINAL ARTICLE Mucoepidermoid of the Parotid The Mayo Clinic Experience

Derek Kofi O. Boahene, MD; Kerry D. Olsen, MD; Jean E. Lewis, MD; A. Daniel Pinheiro, MD; Vernon Shane Pankratz, PhD; Stephanie M. Bagniewski

Objective: To determine clinical and histopathologic Results: Results of clinical staging were: T1 in 56 pa- features of mucoepidermoid carcinoma of the parotid tients, T2 in 13, T3 in 1, T4 in 15, N0 in 85, N1 in 2, and gland, specifically, the relation of tumor stage and grade N2 in 2. No patient had N3 or M1 disease. All patients and treatment type with clinical outcome. underwent with or without neck dissec- tion. Seven patients received postoperative radio- Design: Retrospective clinical and histopathologic re- therapy. Tumor grade was low in 43 patients (48%), in- view. termediate in 40 (45%), and high in 6 (7%). Only 5 patients had disease progression (local recurrence in 4, Setting: Tertiary care medical center. regional recurrence in 4, and distant recurrence in 2). At latest follow-up (mean follow-up, 14.7 years), 64 pa- Patients: From 1940 to 1994, 128 patients were tients were alive without disease, 1 was alive with dis- treated at our institution for parotid mucoepidermoid ease, 2 had died of mucoepidermoid carcinoma, and 22 carcinoma. Eighty-nine of these patients had their had died of other causes. The Kaplan-Meier estimated can- first treatment at our institution; these cases were cho- cer-specific survival rates at 5, 15, and 25 years were sen for retrospective clinical and histopathologic 98.8%, 97.4%, and 97.4%, respectively. review. Conclusions: In our study, tumor grade and stage ap- Intervention: A head and neck pathologist indepen- peared to be less important than previously described. dently reviewed the pathology specimens. With adequate parotidectomy and appropriate neck dis- section, patients with mucoepidermoid carcinoma of the Main Outcome Measures: Age, symptoms, stage, treat- appear to do well, with few recurrences. ment type, tumor grade, pathological features, disease pro- gression, and survival. Arch Otolaryngol Head Neck Surg. 2004;130:849-856

UCOEPIDERMOID CARCI- ent. Intermediate cells are thought to be ca- (MEC) of the pable of differentiating into mucous or epi- is be- dermoid cells. As a result of this cellular lieved to arise from heterogeneity, the histologic composi- pluripotent reserve tion, biological behavior, and clinical course cells of the excretory ducts that are ca- of MEC vary. In their original report, Stew- M 3 pable of differentiating into squamous, co- art and colleagues defined benign and ma- lumnar, and mucous cells.1 Although MEC lignant varieties of mucoepidermoid tu- From the Departments of accounts for less than 10% of all tumors of mors. Nonetheless, subsequent metastases the salivary gland, it constitutes approxi- of a few of the previously benign tumors (Drs Boahene and Olsen) and mately 30% of all malignant tumors of the has led to all mucoepidermoid tumors being Laboratory Medicine and salivary gland.2 Among the major salivary considered carcinoma.4 They can recur, and Pathology (Dr Lewis) and , MEC occurs most frequently in the they can metastasize to regional lymph the Division of Biostatistics parotid gland. In 1945, Stewart and col- nodes or distant viscera. (Dr Pankratz and leagues3 introduced the term mucoepider- Because of the relative rarity of these Ms Bagniewski), Mayo Clinic, moid to define a distinct salivary gland tu- tumors and the remarkable variability in Rochester, Minn, and the Greater Baltimore Head & mor characterized by a mixed pattern of the their biological behavior, opinions differ Neck Associates, Baltimore, Md following 2 main cell types: epidermoid and about the appropriate classification, grad- 5-8 (Dr Pinheiro). The authors mucus-producing cells. However, a third ing, and treatment. Although some au- have no relevant financial cell type, the intermediate cell, which is not thors classify MEC into low- and high- interest in this article. mucous or fully epidermoid, is often pres- grade types, others favor a 3-tier system

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 849

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Figure 1. Low-grade mucoepidermoid carcinoma with prominent mucous Figure 3. High-grade mucoepidermoid carcinoma with predominant cells lacking nuclear atypia (hematoxylin-eosin, original magnification epidermoid cells and moderate nuclear atypia (hematoxylin-eosin, original ϫ100). magnification ϫ100).

tures. One head and neck pathologist (J.E.L.) with vast expe- rience in independently reviewed all the original slides to confirm the diagnosis and provide uniform tumor grading. Cases were accepted as MEC if the tumor (1) had a combination of mucous, intermediate, and epidermoid cells; (2) had solid and cystic growth patterns; and (3) had no nuclear atypia or had nuclear atypia of mild to moderate de- gree (similar to that in moderately differentiated ). However, tumors with severe nuclear atypia or marked anaplasia (Broders grade 4) were not classified as MEC. The tumor grades were classified as low, intermediate, or high on the basis of the traditional grading criteria of architectural pattern (cystic vs solid), cell type (mucous vs epidermoid), and nuclear pleomorphism. The presence of a predominant solid growth pattern, prominent epidermoid cells, or mild nuclear atypia was sufficient for the diagnosis of intermediate-grade MEC (Figure 1 and Figure 2). High-grade MEC exhibited mod- Figure 2. Intermediate-grade mucoepidermoid carcinoma with an increased erate nuclear pleomorphism within a predominantly epider- number of epidermoid cells and mild nuclear atypia (hematoxylin-eosin, moid cell population (Figure 3). With the use of modern im- original magnification ϫ100). munostains and histologic review, several cases previously designated as high-grade tumors were reclassified appropri- ately as intermediate-grade tumors. Likewise, a few high- that includes an intermediate grade. Also, discrepancies grade tumors that were misclassified as mucoepidermoid car- exist in defining the high-grade end of the spectrum for cinomas were eliminated. The following histopathologic features MEC. Several authors have recommended that a mucin- were compiled for their potential relevance in tumor behavior containing salivary gland carcinoma be classified as an and prognosis: gross size, gross extent, percentage of mucous adenosquamous carcinoma or rather than cells, percentage of epidermoid cells, cystic component, nuclear 9-11 pleomorphism, necrosis, neural invasion, vascular invasion, des- MEC if nuclear anaplasia is pronounced. Although sur- moplasia, infiltrative borders, lymphoid component, mitotic gery generally is accepted as the primary treatment for count, and status of parotid and neck lymph nodes. MEC, the extent of parotidectomy and the indications We summarized the clinical and pathological features as for neck dissection are not clear.8,12,13 mean±SD, median and range, or frequency and percentage. We We reviewed our experience with 89 cases of MEC defined the duration of follow-up as starting from the date of occurring in the parotid gland and examined the rela- the initial histologic diagnosis. We used the Kaplan-Meier tion of the histologic factors, including tumor grade and method to estimate the overall and -specific survival and stage, and type of treatment with clinical outcome. survival free of local and regional recurrence and distant me- tastasis. This study was approved by the Mayo Foundation In- METHODS stitutional Review Board for research. The cases of 128 patients with MEC of a major salivary gland diagnosed between 1940 and 1994 were available for study. Of RESULTS these 128 patients, 89 had the primary carcinoma in the pa- rotid gland and received their first treatment at Mayo Clinic, CLINICAL FEATURES Rochester, Minn. Patients who previously were treated else- where or who presented with recurrent disease were excluded The study group included 33 male (37%) and 56 female from the study group. The medical and surgical records of these (63%) patients aged 7 to 78 years (mean±SD, 49±17 years; 89 cases were reviewed for the clinical and histopathologic fea- median age, 51.9 years). Five patients were 18 years or

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 850

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 younger. A history of smoking was noted in 35 patients Nodal Status (39%), and previous radiation exposure for a condition unrelated to MEC was reported for 10 patients (11%). The status of parotid or periparotid nodes could be de- Presenting symptoms are listed in the following tabulation: termined for 86 patients. Six patients (7%) had positive parotid or periparotid nodes, and 3 (3%) had positive neck Symptom No. (%) of Patients nodes at the time of initial treatment. In 4 patients with Mass in parotid region 87 (98) known positive intraparotid nodes, metastatic lymph Pain or tenderness 13 (15) Facial nerve weakness 6 (7) nodes were also found after neck dissection. Skin ulceration 3 (3) Facial twitching 1 (1) SURGICAL TREATMENT Cervical mass separate from tumor 1 (1) Other 5 (6) Conservative total parotidectomy, defined as total re- moval of the parotid gland with preservation of the facial Some patients presented with more than 1 symptom. nerve, was the most common operation (48 patients [54%]). This was performed with neck dissection in 7 pa- PREOPERATIVE EVALUATION tients (8%) and without neck dissection in 41 (46%). The AND CLINICAL STAGING second most common operation, subtotal parotidec- tomy, was performed in 32 patients (36%), with neck dis- All patients received a thorough head and neck exami- section in 2 (2%) and without neck dissection in 30 (34%). nation. Fine-needle aspiration was performed preopera- Radical parotidectomy with sacrifice of the facial nerve was tively in 4 patients (4%). The diagnosis of MEC was made performed in 9 patients (10%). In all, neck dissection was in only 2 of the 4 aspirate samples. Magnetic resonance performed in 15 patients at the time of the primary op- imaging, computed tomography, or both was per- eration. The extent of neck dissection was select in 10 pa- formed in only 10 patients (11%). For 85 patients, the tients (11%), modified radical in 3 (3%), and radical in 2 data were adequate for clinical staging of the tumor ac- (2%). Of these 15 patients, 3 had positive cervical lymph cording to the 2002 classification of the American Joint nodes.11 In the early years of our study period, 4 patients Committee on Cancer.14 The disease stage was T1 in 56 underwent conservative enucleation of the tumor mass patients, T2 in 13, T3 in 1, T4 in 15, N0 in 85, N1 in 2, without deliberate identification and exposure of the fa- and N2 in 2. No patient had N3 or M1 disease. Fifty- cial nerve. This conservative local excision was later aban- three patients (62%) presented with clinical stage I dis- doned. Facial nerve function was intact in 71 patients ease, 13 (15%) had stage II disease, 2 (2%) had stage III (80%). In 11 patients (12%), selected branches of the fa- disease, and 17 (20%) had stage IV disease. cial nerve were resected and grafted as part of complete treatment of their primary disease. Seven patients (8%) had PATHOLOGICAL FEATURES total facial nerve resection without any nerve grafting.

Gross Features ADJUVANT RADIOTHERAPY

On gross examination, the tumors varied in size from 0.4 Seven patients (8%) received postoperative radio- to 7.0 cm (median, 1.5 cm). The tumor extended into therapy, with doses ranging from 50 to 60 Gy. Most of the facial nerve in 5 patients (6%). The overlying skin these patients had an intermediate- or high-grade tu- was involved in 3 patients (3%) and the surrounding soft mor with clinical stage III or IV disease. One patient with tissue or muscle in 10 (11%). stage I and low-grade disease received adjuvant radio- therapy because of close surgical margins. Microscopic Features OUTCOME AND SURVIVAL A marked cystic component (ie, occupying Ͼ50% of the histologic sections examined) was present in 46 speci- The mean duration from first treatment to latest fol- mens (52%). Mucous cells constituted 2% to 90% of the low-up was 14.7 years (median, 13.8 years; range, 0-36.9 specimens (mean, 28.5%) and epidermoid cells, 0% to 95% years). At latest follow-up, 64 patients were alive with- (mean, 24.8%). Fifty specimens (56%) had no or mini- out disease, 1 was alive with disease, 2 had died of MEC, mal nuclear pleomorphism, and 36 (40%) had mild nuclear and 22 had died of other causes. pleomorphism. A lymphoid background was present in For the 65 patients alive at latest follow-up, the 79 specimens (89%). A mild to marked desmoplastic stro- mean±SD duration from their first treatment to latest fol- mal reaction was noted in all of the specimens. An infil- low-up was 14.7±8.7 years (median, 13.8 years; range, trative tumor border was noted in 17 specimens (19%) and 6 months to 36 years). The estimated overall survival for neural invasion in 13 (15%). No specimen showed vas- the study group is shown in Figure 4. The estimated cular invasion. Tumor necrosis was noted in only 1 case. overall survival rates at 5, 10, 15, 20, and 25 years after the first treatment were 96.6%, 91.3%, 79.5%, 63.8%, and Tumor Grade 54.1%, respectively. The estimated cancer-specific sur- vival rates at 5, 10, 15, 20, and 25 years after the first treat- Of the tumors, 43 (48%) were low, 40 (45%) were in- ment were 98.8%, 97.4%, 97.4%, 97.4%, and 97.4%, re- termediate, and 6 (7%) were high grade. spectively (Figure 5).

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 851

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 In all, disease progression occurred in 5 patients 100 (6%), including 4 local, 4 regional, and 2 distant disease relapses. The histopathologic characteristics of the tu- 80 mors of these 5 patients did not differ obviously from those of the group as a whole, except for an increased fre- 60 quency of an infiltrative tumor border (present in 3 of the 5 patients) (Table). Of these 5, patient 1 presented with clinical stage 40 IVA disease that was treated initially with radical Overall Survival, % parotidectomy and postoperative radiotherapy. This 20 patient experienced disease relapse in the parotid bed, temporal bone, and ipsilateral neck within 19 months after treatment. Subsequently, the patient underwent 0 5 10 15 20 25 excision of the local recurrence, neck dissection, and Time From First Treatment to Latest Follow-up, y chemotherapy but died approximately 18 months later. Patient 2 presented with clinical stage II disease Figure 4. Overall survival of 89 patients with mucoepidermoid carcinoma. that was treated with conservative total parotidectomy. Regional recurrence to the ipsilateral neck occurred 9 100 months later and a neck dissection was performed. Nearly 12 years later, the patient died of a cause unre-

80 lated to MEC. Patient 3 presented with clinical stage IVA disease that was treated with conservative total parotidectomy. However, the disease recurred in the 60 parotid bed and neck 6 months later and was treated with local resection and neck dissection. However, 1 40 about 4 ⁄2 years later, biopsy results confirmed metas- tasis to the liver. The patient received chemotherapy

Cancer-Specific Survival, % Cancer-Specific but died 14 months later. Patient 4 presented with 20 clinical stage I disease that was treated with conserva- tive total parotidectomy; 41⁄2 years later, recurrent dis- ease in the parotid bed was excised. The patient was 0 5 10 15 20 25 1 Time From First Treatment to Latest Follow-up, y alive without evidence of disease 5 ⁄2 years later. Patient 5 presented with clinical stage IVA disease that Figure 5. Cancer-specific survival of 89 patients with mucoepidermoid was treated with radical parotidectomy, radical neck carcinoma. dissection, and postoperative radiotherapy. However,

Clinical and Pathological Features of 5 Patients With Disease Progression

Patient No. (Age, y/Sex)

Feature 1 (45/M) 2 (53/F) 3 (53/F) 4 (42/M) 5 (52/F) Clinical stage IVA II IVA I IVA Type of first treatment RP, RT CTP CTP CTP RP, RND, RT Recurrence Local and regional Regional Local, regional, and distant Local Local, regional, and distant Outcome DOD DOC DOD ANED ANED Pathological T stage T3 Unknown T2 T1 T1 Mayo grade 2 2 2 2 2 Cystic component* Moderate Moderate Marked Mild Mild Nuclear pleomorphism Mild None None Mild Mild Mucous cells, % 30 20 30 20 15 Epidermoid cells, % 50 30 10 40 40 Neural invasion Yes No No No Yes Vascular invasion No No No No No Infiltrative border Yes No Yes No Yes Necrosis No No No No No Mitosis per HPF magnification ϫ10 0 1 1 1 2 Gross size, cm 4.5 Unknown 4.0 1.5 2.0 AFIP grade, points/grade† 2/Low 0/Low 0/Low 2/Low 4/Low Brandwein grade, points/grade‡ 5/High 0/Low 2/Intermediate 2/Intermediate 7/High

Abbreviations: AFIP, Armed Forces Institute of Pathology; ANED, alive with no evidence of disease; CTP, conservative total parotidectomy; DOC, dead of other cause; DOD, dead of disease; HPF, high-power field; RND, radical neck dissection; RP, radical parotidectomy; RT, radiotherapy. *Greater than 50% indicates marked; 10% to 20%, mild; and greater than 20% to 50%, moderate. †Described by Goode et al.5 ‡Described by Brandwein et al.6

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 852

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 100 100

80 80

60 60

40 40

20 20 Survival Free of Local Recurrence, % Survival Free of Regional Recurrence, %

0 5 10 15 20 25 0 5 10 15 20 25 Time From First Treatment to Local Recurrence, y Time From First Treatment to Regional Recurrence, y

Figure 6. Survival free of local recurrence rate of 89 patients with Figure 7. Survival free of regional recurrence rate of 89 patients with mucoepidermoid carcinoma. mucoepidermoid carcinoma.

disease recurred in the parotid bed and neck at 9 and 100 16 months, respectively. Also, results of a biopsy con- firmed distant metastases to the skin of the lower back. All sites of recurrence were widely excised and 80 the patient was alive with no evidence of disease after more than 20 years of follow-up. Thus, only 2 of these 60 5 patients died of mucoepidermoid carcinoma, and both of them had locoregional recurrence of disease. The Kaplan-Meier estimated rates of survival free 40 of local recurrence rate at 5, 10, 15, and 25 years after the first treatment were 96.6%, 95.2%, 95.2%, and 20 95.2%, respectively (Figure 6). The estimated rates Survival Free of Distant Recurrence, % of survival free of regional recurrence at 5, 10, 15, and 25 years after the first treatment were 95.4%, 94.1%, 0 5 10 15 20 25 94.1%, and 94.1%, respectively (Figure 7). The esti- Time From First Treatment to Distant Recurrence, y mated rate of survival free of distant metastases at 5, Figure 8. Survival free of distant recurrence rate of 89 patients with 10, 15, and 25 years after the first treatment was mucoepidermoid carcinoma. 97.6% (Figure 8). Survival analysis for individual clinical and patho- logical features (age, sex, grade, clinical stage, nodal sta- Specific etiologic factors for MEC were not evident tus, and type of surgical treatment) was not possible be- in our study. Several reports have implicated exposure cause of the small number of adverse events. None of the to ionizing radiation, with latency periods ranging from 6 patients who had high-grade MEC experienced dis- 7 to 32 years.18,19 Ten patients in our series had previous ease progression. radiation to the head and neck as part of the treatment for unrelated diseases such as acne and disease. COMMENT Unlike squamous cell carcinoma of the oropharynx, in which smoking has been implicated as a strong risk fac- Mucoepidermoid carcinoma is the most frequently di- tor, smoking has not been shown to be strongly associ- agnosed malignancy of the salivary gland. Among the ma- ated with MEC. In our series, there was a predominance jor salivary glands, the parotid gland is most commonly of nonsmokers compared with current or previous smok- involved.15,16 Our study has documented the Mayo Clinic ers (44 vs 33 patients). Mucoepidermoid of experience with 89 cases of MEC occurring in the pa- the parotid gland characteristically present as a painless rotid gland. We sought to examine the relation of tumor mass 2 to 3 cm in diameter at initial discovery. With high- grade and stage and type of treatment with clinical out- grade lesions, pain and rapid growth can be prominent. come. However, even with prolonged follow-up, dis- Without pain or facial weakness, pleomorphic ease progression occurred in only 5 patients, resulting is usually the first clinical impression. This may result in 2 deaths. in undertreatment when one is not guided by pathologi- Consistentwithotherreports,12,13,17 MECoccurredmost cal findings of frozen-section analysis. In our series, all frequently between the third and fifth decades of life (mean of the patients presented with a 0.4- to 7.0-cm mass in age, 49 years) in our patients. Our youngest patient was 7 the parotid gland. Only 15% of patients had pain or ten- years. Similar to other series that have shown a slight fe- derness, and only 1 had palpable cervical adenopathy at male preponderance,12,13 female patients were affected 1.7 initial presentation. Marked cystic features constituting times more often than male patients in our series. more than 50% of the histologic section were encoun-

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 853

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 tered in more than half of the tumors. Thus, cystic le- ever, in a review of MEC of major and minor salivary sions identified in the parotid gland during physical ex- glands, Spiro et al13 found a preponderance of low- amination or on ultrasonography should not be dismissed grade tumors in patients with lower-stage disease. There- as benign lesions. Preoperative fine-needle aspiration may fore, the finding of better survival for patients with lower- yield a diagnosis of malignancy and facilitate preopera- grade lesions may be a case of confounding variables, tive surgical planning. Nevertheless, fine-needle aspira- whereby lower-grade lesions are associated with better tion is not required in all cases and was performed in only survival only because they are associated with less ad- 4 of our patients. The routine use of imaging studies is vanced disease stage. debated, and magnetic resonance imaging or computed In our series, only 5 patients had disease progres- tomography was performed in only 10% of our patients. sion. We examined the clinical and histopathologic fea- We find that imaging studies are useful when the full ex- tures of this group, checking for characteristics that might tent of the tumor cannot be palpated, when tumor infil- distinguish them (Table). All 5 patients (3 women and tration into adjacent structures is suspected clinically, or 2 men) ranged in age from 42 to 53 years. In the study when the likelihood of regional lymph node spread is high. of malignant salivary tumors by O’Brien et al,26 patients Since MEC was first described, various grading younger than 60 years fared better than older ones. In schemes have been proposed.20 Some pathologists have addition, they found no significant difference between classified MEC into low- and high-grade types, but more male and female patients. Their study, however, in- recently most have used a 3-tiered grading system that cluded major and minor tumors of the salivary gland from includes an intermediate grade.5-7,10,21 Even so, tumor grade all sites and all histologic subtypes. We were not able to is dependent on the interpretation of the pathologist, and, perform survival analysis for age and sex because of the as pointed out recently, uniform interpretation is lack- limited number of adverse outcomes in our series. Of in- ing when different pathologists grade MEC.6 Also, dis- terest, all 5 patients with disease progression had inter- agreement remains about the appropriate upper bound- mediate-grade (grade 2) lesions. The histologic features ary of nuclear anaplasia acceptable for diagnosis of MEC. in various grading systems include the degree of nuclear In our study, we classified tumors as low, interme- pleomorphism, proportion of the cystic component, mi- diate, or high grade on the basis of traditional grading totic rate, presence or absence of necrosis, neural inva- criteria. We specifically excluded fully anaplastic tu- sion, vascular invasion, and infiltrative tumor borders. mors (severe or marked nuclear atypia [Mayo grade 4]) Although the numbers are small, we could not discern a that others might have classified as high-grade MEC. Most significant difference between this group of 5 patients and of our cases were low- or intermediate-grade MEC, and the rest of the study group except for a tendency toward only 7% were high-grade lesions, which is lower than the more infiltrative tumor borders (3 of the 5 tumors). How- percentage reported in other series.5,10,13,17 The inclu- ever, an assessment for the presence or absence of infil- sion of anaplastic carcinomas in the category of high- trative tumor borders, as suggested by Brandwein et al,6 grade MEC in other studies may have affected the sta- may be important; the tumor in 3 (60%) of the 5 pa- tistical relation between grade and survival. We were tients with disease progression exhibited this feature, in unable to confirm statistically a multitude of histologic contrast to 14 (17%) of the 84 patients without disease variables that have been regarded as potentially impor- progression. tant in grading and clinical outcome. This is at variance Among the 5 patients with disease progression, with what others have reported.10,13,21 We attempted to 3 had stage IVA, 1 had stage II, and 1 had stage I disease. apply histologic grades as recommended by Goode et al5 The 2 patients who died of MEC presented with clinical and Brandwein et al6 to cases of MEC that had disease stage IV disease. Survival analysis for tumor grade and progression, but because of the low number of adverse disease stage was not possible because of the small num- events, we could not statistically compare the predictive ber of adverse events. value of these grading schemes. Many studies that ex- Further analysis of the recurrences showed that most amined the relation between MEC histologic grade and were locoregional, with distant recurrence occurring in clinical outcome included major and minor tumors of the only 2 patients (Table). Others22,27 have found a greater salivary gland.10,17,22,23 However, the clinical behavior of proportion of distant recurrences, but even in those stud- MEC may vary by site.13,24 Certainly, the treatment of MEC ies most of the patients with distant recurrence also had and the ability to obtain tumor-free margins vary by site, concomitant locoregional recurrence or had experi- as does the distribution of tumor grade and stage. Minor enced multiple locoregional recurrences. Thus, our small salivary glands are more likely to have higher-grade MECs number of distant recurrences may be related to the lower and more advanced stage tumors,10,15 and a minor sali- number of locoregional recurrences. vary gland site itself may be associated with worse sur- The other important variable affecting survival is ad- vival. Therefore, comparison of high- and low-grade le- equacy of surgical excision margins. Patients with posi- sions may show worse survival for the former because tive margins are more likely to have locoregional recur- of a greater proportion of minor salivary gland sites with rence, regardless of tumor grade, than those with negative high-grade lesions. For these reasons, when analyzing the resection margins.10,21,26,28 Nonetheless, the relation be- clinical behavior and outcome of patients with MEC, the tween the type of surgical treatment for MEC and sur- data must be analyzed independently by site. vival has not been clearly examined. However, a higher Several studies have shown that staging parotid gland proportion of patients in our study appear to have had lesions, including MEC, according to the American Joint total parotidectomy than occurred in other studies. For Committee on Cancer is predictive of survival.13,25 How- instance, in the series of 63 cases of parotid MEC re-

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 854

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 ported by Jakobsson et al,12 only 5 patients underwent rence. In our study, only 4 patients had clinically posi- what could be termed parotidectomy. The study of Hea- tive nodes. Nonetheless, 15 underwent neck dissection ley et al22 included 42 patients with parotid MEC, only (mostly selective neck dissection). There were no cases 11 of whom underwent total parotidectomy, and as many of contralateral nodal metastases at initial presentation, as 12 underwent less than a superficial parotidectomy. and all regional recurrences were in the ipsilateral neck. In the series of Spiro et al,13 48 patients underwent enucle- The rate of nodal metastases in MEC varies depending ation alone and 82 underwent subtotal parotidectomy that on the series, but it appears to be a predictor of sur- spared the facial nerve. Other types of operations have vival.13 Not unexpectedly, the inclusion of tumors with been performed less often. anaplastic features as high-grade MEC would lead to In contrast to these reports, most patients treated the finding of more patients with cervical lymph node at Mayo Clinic underwent conservative total parotidec- metastases.29 tomy, whereby all parotid tissue was removed and the There appears to be a further decrease in survival facial nerve was preserved. This was the procedure of as patients are followed up beyond 5 years. This has been choice for high-grade tumors. Partial or total facial pointed out by others and stresses the importance of ad- nerve resection was performed when there were intra- equate follow-up.13,22 operative findings of gross nerve involvement. In addi- tion, conservative total parotidectomy was performed CONCLUSIONS for low- and intermediate-grade tumors when frozen- section evidence indicated involvement of intraparotid For low- and intermediate-grade parotid MEC with a pri- nodes. In patients with clinical N0 disease, selective mary lesion adequately excised by means of subtotal pa- nodal dissection addressing high and midjugular nodes rotidectomy, if the intraparotid nodes in the superficial was performed for high-grade tumors and other tumors lobe are negative, then the deep lobe and neck nodes do with positive intraparotid nodes. We believe that this not need further treatment. If any intraparotid node is type of aggressive treatment may well account for the positive, the deep lobe should be addressed with a con- few treatment failures in our series. This approach al- servative total parotidectomy along with a selective neck lows complete removal of the primary tumor and all dissection. Also, a dissection of regional lymph node ba- possible metastatic foci to intraparotid nodes. More- sins should be performed in cases of suspicious adenopa- over, the functional status of the facial nerve was com- thy and in those with more advanced-stage and higher- pletely preserved in 80% and partially preserved in grade lesions. When treated in this fashion, parotid MEC 12%. Two cases illustrate this treatment approach. appears to be a highly curable disease. Nonetheless, fol- First, an 11-year-old boy presented with a slowly grow- low-up should continue for an extended time to rule out ing parotid mass noted during the course of 5 years. He late recurrence. was completely asymptomatic and had clinical N0 neck findings. Superficial parotidectomy completely re- Submitted for publication April 21, 2003; final revision re- moved the parotid tumor. Results of frozen-section ceived September 30, 2003; accepted November 5, 2003. analysis showed a low- to intermediate-grade mucoepi- This study was presented at the Combined Otolaryn- dermoid carcinoma with 1 positive intraparotid node. A gological Spring Meeting, Head and Neck Section; May 5, conservative total parotidectomy with selective neck 2003; Nashville, Tenn. dissection addressing high and midjugular nodes was Correspondence: Kerry D. Olsen, MD, Department of then completed. This revealed a positive intraparotid Otorhinolaryngology, Mayo Clinic, 200 First St SW, Roch- node in the deep lobe. The neck nodes were all nega- ester, MN 55905 ([email protected]). tive. In the second case, a 67-year-old woman presented with a 2-cm parotid mass completely excised with a su- REFERENCES perficial lobe parotidectomy. Results of frozen-section analysis revealed an intermediate-grade lesion with 1 1. Batsakis JG. Salivary gland neoplasia: an outcome of modified morphogenesis positive intraparotid node. A conservative total paroti- and cytodifferentiation. Oral Surg Oral Med Oral Pathol. 1980;49:229-232. dectomy was then completed, but no additional posi- 2. Cornog JL, Gray SR. Surgical and clinical pathology of salivary gland tumors. tive intraparotid nodes were identified. A selective neck In: Rankow RM, Polayes IM, eds. Disease of the Salivary Glands. Philadelphia, dissection was then performed and yielded 2 metastatic Pa: WB Saunders Co; 1976:99-142. nodes. 3. Stewart FW, Foote FW Jr, Becker WF. Muco-epidermoid tumors of salivary glands. Ann Surg. 1945;122:820-844. The small number of treatment failures in our se- 4. Foote FW Jr, Frazell EL. Tumors of the major salivary glands. Cancer. 1953;6: ries limits our power to detect differences in survival ac- 1065-1133. cording to grade, tumor stage, type of surgical treat- 5. Goode RK, Auclair PL, Ellis GL. Mucoepidermoid carcinoma of the major sali- ment, and other variables. It suggests that if MEC is vary glands: clinical and histopathologic analysis of 234 cases with evaluation treated aggressively with conservative total parotidec- of grading criteria. Cancer. 1998;82:1217-1224. 6. Brandwein MS, Ivanov K, Wallace DI, et al. Mucoepidermoid carcinoma: a clini- tomy, tumor grade and stage become less important for copathologic study of 80 patients with special reference to histological grading. predicting survival because of uniformly excellent dis- Am J Surg Pathol. 2001;25:835-845. ease control. Furthermore, most recurrences in our se- 7. Nascimento AG, Amaral LP, Prado LA, Kligerman J, Silveira TR. Mucoepider- ries were in the parotid bed, which attests to the need moid carcinoma of salivary glands: a clinicopathologic study of 46 cases. Head Neck Surg. 1986;8:409-417. for adequate control at the initial operation. Generally, 8. Califano L, Zupi A, Massari PS, Giardino C. Indication for neck dissection in car- patients who die of MEC have distant metastases, but cinoma of the parotid gland: our experience on 39 cases. Int Surg. 1993;78:347- they also usually have associated locoregional recur- 349.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 855

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 9. Gray JM, Hendrix RC, French AJ. Mucoepidermoid tumors of salivary glands. 21. Hicks MJ, el-Naggar AK, Byers RM, Flaitz CM, Luna MA, Batsakis JG. Prognos- Cancer. 1963;16:183-194. tic factors in mucoepidermoid carcinomas of major salivary glands: a clinico- 10. Evans HL. Mucoepidermoid carcinoma of salivary glands: a study of 69 cases pathologic and flow cytometric study. Eur J Cancer B Oral Oncol. 1994;30B:329- with special attention to histologic grading. Am J Clin Pathol. 1984;81:696-701. 334. 11. Rosai J. Major and minor salivary glands. In: Rosai J, ed. Ackerman’s Surgical 22. Healey WV, Perzin KH, Smith L. Mucoepidermoid carcinoma of salivary gland Pathology. Vol 1. 2nd ed. St Louis, Mo: Mosby Year Book Inc; 1996:815-856. origin: classification, clinical-pathologic correlation, and results of treatment. Can- 12. Jakobsson P, Blanck C, Eneroth CM. Mucoepidermoid carcinoma of the parotid cer. 1970;26:368-388. gland. Cancer. 1968;22:111-124. 23. Clode AL, Fonseca I, Santos JR, Soares J. Mucoepidermoid carcinoma of the 13. Spiro RH, Huvos AG, Berk R, Strong EW. Mucoepidermoid carcinoma of sali- salivary glands: a reappraisal of the influence of tumor differentiation on prog- vary gland origin: a clinicopathologic study of 367 cases. Am J Surg. 1978;136: nosis. J Surg Oncol. 1991;46:100-106. 461-468. 24. Olsen KD, Devine KD, Weiland LH. Mucoepidermoid carcinoma of the oral cav- 14. Greene FL, Page DL, Fleming ID, et al, eds. AJCC Cancer Staging Manual. 6th ity. Otolaryngol Head Neck Surg. 1981;89:783-791. ed. New York: Springer-Verlag NY Inc; 2002. 25. Kane WJ, McCaffrey TV, Olsen KD, Lewis JE. Primary parotid malignancies: 15. Spiro RH. Salivary : overview of a 35-year experience with 2807 pa- a clinical and pathologic review. Arch Otolaryngol Head Neck Surg. 1991;117: tients. Head Neck Surg. 1986;8:177-184. 307-315. 16. Ostman J, Anneroth G, Gustafsson H, Tavelin B. Malignant salivary gland tu- 26. O’Brien CJ, Soong SJ, Herrera GA, Urist MM, Maddox WA. Malignant salivary mours in Sweden 1960-1989: an epidemiological study. Oral Oncol. 1997;33: tumors: analysis of prognostic factors and survival. Head Neck Surg. 1986;9: 169-176. 82-92. 17. Guzzo M, Andreola S, Sirizzotti G, Cantu G. Mucoepidermoid carcinoma of the 27. Accetta PA, Gray GF Jr, Hunter RM, Rosenfeld L. Mucoepidermoid carcinoma of salivary glands: clinicopathologic review of 108 patients treated at the National salivary glands. Arch Pathol Lab Med. 1984;108:321-325. Cancer Institute of Milan. Ann Surg Oncol. 2002;9:688-695. 28. Hicks MJ, el-Naggar AK, Flaitz CM, Luna MA, Batsakis JG. Histocytologic grad- 18. Kaste SC, Hedlund G, Pratt CB. Malignant parotid tumors in patients previously ing of mucoepidermoid carcinoma of major salivary glands in prognosis and sur- treated for childhood cancer: clinical and imaging findings in eight cases. AJR vival: a clinicopathologic and flow cytometric investigation. Head Neck. 1995; Am J Roentgenol. 1994;162:655-659. 17:89-95. 19. Spitz MR, Batsakis JG. Major salivary gland carcinoma: descriptive epidemiol- 29. Regis De Brito Santos I, Kowalski LP, Cavalcante De Araujo V, Flavia Logullo ogy and survival of 498 patients. Arch Otolaryngol. 1984;110:45-49. A, Magrin J. Multivariate analysis of risk factors for neck metastases in surgi- 20. Batsakis JG. Staging of salivary gland neoplasms: role of histopathologic and cally treated parotid carcinomas. Arch Otolaryngol Head Neck Surg. 2001;127: molecular factors. Am J Surg. 1994;168:386-390. 56-60.

(REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 130, JULY 2004 WWW.ARCHOTO.COM 856

©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021