Mucoepidermoid Carcinoma of Salivary Gland Origin A Clinicopathologic Study of 367 Cases
Ronald H. Spiro, MD, New York, New York Andrew G. Huvos, MD, New York, New York Richard Berk, MD,* New York, New York Elliot W. Strong, MD, New York, New York
Stewart, Foote, and Becker [I] in 1945 coined the term “mucoepidermoid tumor” to describe an unusual salivary neoplasm containing epidermoid and mucus-secreting cells which was thought to arise in salivary gland ducts. Credit for the first report of this tumor was ascribed to Volkman [2] in 1895; its unique histologic features had been described by others [3,4]. Review of approximately 700 major and minor salivary gland tumors seen at Memorial Hospital between 1928 and 1943 yielded only forty-five which satisfied the criteria. Based on the histologic appearance and the clinical course, these tumors were divided into a benign and a malignant group. By 1953 Foote and Frazell [5] had collected ninety-eight cases involving the major salivary glands (1.930 to 1949). Noting that metastasis had occurred with a few tumors previously classified as benign, the designations “low grade malignant” or “high grade malignant” were proposed. Clinical and pathologic correlation even suggested that separation into low, medium, and high grade malignant subgroups might prove useful. Despite more recent reports from many centers encompassing more than 1,000 cases, there is still controversy about the classification and treatment of these tumors [6-131. The present study includes some patients previously reported on [14-161, but we have deliberately excluded our experience prior to 1939 when radiation was often the only treatment and many other patients had operations which would be considered inadequate by today’s standards. Information was adequate in the sizable group of patients seen since 1939 to permit retrospective clinical staging. This has shown remarkable corre-
From the Departments of Surgery, Head and Neck Service, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. Reprint requests should be addressed to Ronald H. Spiro, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. Presented at the Joint Meeting of the American Society for Head and Neck Surgery and the Society of Head and Neck Surgeons, Toronto, Ontario, Canada, May 29-31, 1978. * Present address: 9108 Pottawattami Drive, Skokie, Illinois 60076.
Volume 136, October 1976
lation with histologic grading, which offers the clinician a new opportunity for rational treatment planning. Material During the thirty year period from 1939 through 1968, the diagnosis of mucoepidermoid carcinoma was recorded for 400 patients in the Tumor Registry of the Memorial Sloan Kettering Cancer Center. This comprised 15 per cent of all patients with salivary neoplasms, or 30 per cent of those with malignant salivary tumors seen during the same period. On review, thirty-three patients were excluded either because they received no treatment at our hospital (21 patients), the diagnosis was changed after reexamination of the slides (6 patients), or clinical or histologic material was incomplete (6 patients). This retrospective analysis is based on the remaining 367 patients. The tumor arose in the parotid gland in 254 patients (69 per cent), whereas the submaxillary gland and minor salivary glands were involved in twenty-three (6 per cent) and ninety patients (25 per cent), respectively. Forty-one per cent had received prior treatment elsewhere, most often consisting of local excision. (Table I.) The patients ranged in age from six to ninety years (median, 51 years); median age appeared to be lower for those with a parotid or minor salivary gland tumor (48 years) than for those with a lesion in the submaxillary gland (53 years). There were 197 women and 170 men, and a slight preponderance of women (54 per cent) was apparent whether the tumor arose in major or minor salivary glands. Specific etiologic factors were seldom evident in this retrospective study. In four patients radiation had been given to the face or the neck for an unrelated condition from three to thirty years previously. An antral tumor developed in another patient seventeen years after lipiodol instillation into the sinus for diagnostic evaluation of allergic symptoms. A foreign body seemed causally related in a remarkable case which was previously report&d [14]. The patient was a seven year old girl in whom a tumor developed in the left nasal cavity twenty-six months after removal of a button which had been impacted in the same area for three months. Multiple primary neoplasms were recorded in forty-six patients (13 per cent). Of these, fifteen had another tumor
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Spiro et al
TABLE I
Anatomic Site of Primary Previously Untreated
Previously Treated
Parotid gland Palate Submaxillary gland Antrum Tongue Cheek, lip mucosa Gingivae Nasal cavity Floor of the mouth Tonsil Laryngopharynx
139 16 12 9 10 9 6 2 6 4 2
115 8 11 3 1 2 4 7
1
254 (69 %) 24 (7%) 23 (6%) 12 (3%) 11(3%) 11(3%) 10 (3%) 9 (2%) 6 (2%) 4(1%) 3(1%)
Total
215
152
367 (100%)
Total
in the head and neck area, including two patients who had a metachronous mixed tumor in another salivary gland and two with a synchronous papillary carcinoma of the thyroid. The breast was the site of the second primary cancer in nine women, and one unusual patient had four separate cancers arising in the parotid gland, lung, urinary bladder, and skin. Pathology Gross Features. On gross examination, the low grade mucoepidermoid carcinomas closely resembled benign mixed tumors. They were oval and well circumscribed, but distinct encapsulation was rarely present, and a complete capsule was entirely absent at times. On sectioning, the tumor was gray-white or pinkish, lobulated, and slightly firm. Bluish, opalescent mucoid material was seen on the cut surface in some lesions, accumulating in small cystic pools. Dilated cystic spaces were seen in approximately half the patients, with completely cystic presentation in rare instances. Intermediate and high grade mucoepidermoid carcinomas were usually infiltrative growths which showed no encapsulation. Cyst formation was not as pronounced as in the low grade tumors. When present, cysts were usually hemorrhagic rather than mutinous and were centrally placed within areas of necrosis and degeneration. ConsisTABLE II
tency was homogeneously hard and occasionally gritty; the cut section was gray-white in appearance without lobulation. Microscopic Features. The term “mucoepidermoid” is an abridgment of the designation “mixed epidermoid and mucus-secreting carcinoma.” Although it is more convenient, the shorter term gives no indication that these tumors contain an intermediate type cell which is neither mucous nor fully epidermoid in character. The proportion of these three cell types may vary, and glandular or cystic formations, solid nests of neoplastic cells, or an intermingling of these growth patterns may be noted. Based upon histologic criteria which are described below, the tumors were classified either as low grade (138 patients), intermediate grade (139 patients), or high grade (82 patients). Available tissue sections in eight patients were considered inadequate for grading. In low grade mucoepidermoid carcinoma, well developed grandular or microcystic structures were seen, lined by a single layer of mucus-secreting columnar cells. In some areas these cystic spaces were bordered by papillary infoldings formed by an intermediate type cell having features of basaloid character or by epidermoid cells. Study of these intermediate or basal type cells confirmed the original findings of Foote and Frazell[5] that these cellular forms are capable of differentiation into mutinous cells or into cells with epidermoid or squamous characteristics. In the low grade lesions, microcyst formation coalescing into larger cysts was occasionally quite prominent. If the mucoid material present in the cystic spaces escaped into the surrounding salivary gland stroma, an intense inflammatory reaction (sometimes of the foreign body giant cell type) occasionally obscured the true neoplastic character of the lesion. Mucoepidermoid carcinomas of intermediate grade were characterized by solidly growing areas of epidermoid or even squamous cells or intermediate basaloid type elements with the latter cell types predominating. The papillary cystic structural infoldings showed epidermoid or basal cells quite frequently. The high grade variants displayed an increased tendency for intermediate basal and epidermoid cells to appear in solid nests or cords. Variation in the size and shape of the
Cervical Node Metastasis Total Patients
Enlarged Nodes
Status on Admission Metastasis Confirmed
Appeared Later
Total with Metastasis
Parotid gland Submaxillary gland Minor salivary gland
254 23 90
51 5 7
64 11 13
6 1 11
70 (28%) 12 (52%) 24 (27 %)
Primary Previously treated
215 152
32 32
43 45
14 4
57 (27%) 49 (32%)
Low grade Intermediate grade High grade Not graded
138 139 82 8
7 21 32 3
8 33 43 4
4 9 5
12 42 48 4
28
3 38
1 4 8
l(l%) 7 (14%) 46 (67%)
Stage I Stage II Stage Ill
462
89 50 69
(7%) (30%) (59%) (50%)
The American Journal of Surgery
Salivary Gland Mucoepidermoid
neoplastic cells, prominent nucleoli, and abundant mitotic figures were easily recognized. Glandular or cystic formatil)ns were only occasionally present. In other variants a glandular growth predominat,ed, and there were few epidermoid or basal cell elements. Microscopic study of metastatic deposits in patients with high grade tumors revealed varying proportions of epidermoid or mucinproducing tumor cells, not necessarily mimicking the p!.oportion observed in the primary salivary gland lesions
[171. The histologic differential diagnosis of high grade nucoepidermoid carcinoma required a mucin stain. If a ucicarminophilic tumor cells were completely absent, the lesion was classified as epidermoid or squamous cell carcinoma of salivary gland origin and not as mucoepidermoid cancer. Many henign mixed tumors (pleomorphic adenomas I exhibit prominent areas of squamous metaplasia, or a rare condition termed necrotizing sialometaplasia may show epidermoid traits. Mucoepidermoid carcinoma of any grade of malignancy shows no evidence of myoepithelial ctslls or the chondroid or myxochondroid matrix so characterist.ic of mixed tumors. Clinical
Findings
Primary Tumor. An asymptomatic swelling was the presenting symptom in 190 of 254 patients (75 per cent) who had a parotid tumor. Pain was infrequently associated (! 3 patients), but preceded the appearance of a mass on rare occasion (4 patients). Almost 60 per cent of previously untreated patients had been aware of the lesion for a year or less, but intervals of five to more than twenty years e.apsed in nineteen patients before a physician was consulted. Parotid tumors usually presented as a solitary mass confined t,o the body or tail of the gland (76 per cent), but occasionally arose deep to the facial nerve in the so-called deep “lobe” (7 patients) or involved accessory parotid tissue anterior to the body of the gland (3 patients). Only s.x patients with an untreated parotid lesion of low histologic grade had a tumor that exceeded 3 cm in size. The size exceeded 3 cm in forty-six of seventy-eight patients (59 per c,?nt) who had an intermediate or high grade tumors. Skin fixation to the tumor was observed in only one previously untreated patient who had a low grade parotid lesion; fixation to the skin or deeper tissues and/or ulceration were evident in thirty patients (38 per cent) who had intermediate or high grade tumors. Partial or complete facial nerve palsy was observed in ten and fourteen previously untaeated patients (17 per cent), respectively, none of whom had a low grade lesion. Based on available data in 98 of 115 previously treated patients who had a parotid primary, the tumor was a solitary mass in sixty-eight and was multinodular in four. As with previously untreated patients, high grade tumors were usually larger. Partial or complete facial nerve palsy was noted in twenty patients (20 per cent), and twenty-one others had nerve dysfunction related to treatment elsewhere. Induration, rather than a discrete mass, was the only finding in twenty-six patients who were evaluated soon
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1978
Carcinoma
after surgery had been performed at another hospital. If these patients are excluded, almost two thirds of those with obvious recurrent tumor showed fixation or ulceration. Of the twenty-three patients who had a submaxillary gland tumor, twenty noted an asymptomatic swelling and three reported pain in association with a mass. Seven of tweive previously untreated patients were aware of the tumor for less than one year; a mass had been present from ten to twenty years in three others. All patients had a solitary mass except for two who had only induration after submaxillary gland excision elsewhere. Tumor size was recorded in nineteen patients and exceeded 3 cm in twelve (63 per cent). Much diversity was apparent in ninety patients who had mucoepidermoid carcinoma of minor salivary (mucus) gland origin. As with other minor salivary tumors, the palate was most often involved (24 patients). This was followed in order of decreasing frequency by the antrum (12 patients), cheek or lip mucosa (II), tongue (ll), gingivae (lo), nasal cavity (9), floor of the mouth i61, tonsil (4), larynx (2), and pharyngeal wall (1). Tumor size was recorded in sixty-one of sixty-five patients who had a mouth primary and was less than 2 cm in twenty-six patients (43 per cent), 2.1 to 4 cm in twenty-five (41 per cent), and more than 4 cm in ten (16 per cent). Mucosal ulceration was apparent in nine patients, but only three had clinical evidence that the mandible or maxilla was involved by tumor. Each of the twelve patients with an antral primary and seven of nine with a nasal tumor had a sizable lesion with clinical or radiographic evidence of bone destruction. Of the two patients with laryngeal primaries, one had a sizable epiglottic tumor and the other had a small glottic primary involving the anterior commissure. Ceroical Metastasis. Metastasis to cervical lymph nodes occurred in 106 patients (29 per cent). This was confirmed at the time of initial treatment in eighty-eight. patients and occurred subsequently in eighteen others. (Table II.) Nodal involvement occurred more often in those who had a submaxillary gland primary and was present on admission in more than half the patients who had a high grade parotid lesion which was recurrent after treatment elsewhere. Although nodal enlargement was seldom apparent when those with minor salivary lesions were first examined, the incidence recorded during the course of the disease was similar to that observed in patients with parotid lesions. Clinical Staging. Data were sufficient to permit retrospective clinical staging in 206 of 215 patients with a previously untreated tumor. Criteria which we have previously described were used for those who had a parotid or submaxillary lesion [15,16]. Patients who had a minor salivary tumor were classified according to accepted criteria for epidermoid carcinoma arising in the oral cavity, pharynx, larynx, or sinuses [18]. There were eighty-nine patients (43 per cent) with stage I disease, fifty (24 per cent) with stage II, and sixty-seven (33 per cent) with stage III. When subdivided according to histologic grade, stage I disease was seen most often in patients with tumors of low histologic grade, whereas stage III lesions were almost always of intermediate or high histologic grade. (Table III.)
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Spiro et al
TABLE Ill
Relationship of Histologic Grade to Clinical Stage
Stage I
Stage II
Stage Ill
Total
Low grade Intermediate grade High grade
57 (64%) 27 (30%) 5 (6%)
21(42%) 19 (38%) 10(20%)
6(9%) 32 (50%) 26(41%)
84 78 41
Total
89 (100%)
50 (100%)
64 (100%)
203’
l
Excludes 12 of 215 primary cases’lacking stage or grade.
Treatment Parotid Gland. Surgery was the only modality used in 229 patients who had a parotid primary (90 per cent), and eight others received preoperative or postoperative radiation in conjunction with excision. External radiation, radon seed implantation, or combinations of both were used in seventeen patients during the early years of this study. (Table IV.) Subtotal parotidectomy sparing the branches of the facial nerve was the operation most often performed (82 patients; 36 per cent). Early in the study forty-eight patients underwent an even more conservative local excision without deliberate exposure of the nerve. Total parotidectomy with preservation of the seventh nerve was possible in four patients. Of the remainder, seventy-two patients had one nerve branch or more resected in conjunction with subtotal or total parotidectomy and thirtyone required radical total parotid resection with sacrifice of most of the facial nerve. Of 145 patients who had either stage III disease or tumor which was locally recurrent, sacrifice of all or part of the nerve was required in ninety (52 per cent), thirty of whom underwent radical total parotidectomy which sometimes included portions of skin, masseter muscle, or the adjacent mandible. In contrast, a conservative parotid operation which preserved facial nerve function was possible in seventy-eight of eighty-nine patients (88 per cent) who had stage I or stage II lesions. Radical neck dissection was part of the initial treatment in 77 of the 237 patients (32 per cent) who had surgery, fifty-one of whom had clinical evidence of cervical node enlargement. No cervical metastases were found in eight TABLE IV
of the latter patients, but elective neck dissection in twenty-six others confirmed the presence of occult lymph node involvement in seventeen. Neck dissection was seldom performed in patients who had stage I or stage II tumors (3 of 90 patients; 3 per cent) or those with a lesion of low histologic grade (7 of 93 patients; 8 per cent). In contrast, radical neck dissection was performed in 14 of 28 patients (50 per cent) with an untreated high grade tumor, and 47 of 108 previously treated patients (44 per cent) who had surgery regardless of histologic grade. Submaxillary Gland. All twenty-three patients in this group were treated surgically. Submaxillary dissection was performed in four of twelve previously untreated patients, whereas six underwent radical neck dissection. The inferior margin of the mandible was resected with the gland, and hemimandibulectomy was required in conjunction with radical neck dissection in the two remaining patients, both of whom had stage III tumors. Only one patient underwent local excision of a recurrent submaxillary tumor. Neck dissection was performed for recurrence in nine others (with inferior marginal mandibulectomy in 3), whereas one patient required combined resection, including hemimandibulectomy and excision of the floor of the mouth. Minor Salivary. Of ninety patients who had a tumor arising in minor salivary glands, eighty-four (93 per cent) were treated surgically; external radiation was used in the remaining six. Local excision was feasible in thirty-three of sixty-three patients (52 per cent) who had a surgically treated mouth primary, two of whom received external radiation as well. A more radical excision including a portion of the maxilla or mandible was required in the remaining thirty patients. Only one of eighteen patients who had surgery for an antral or nasal cavity tumor had a lesion that was suitable for local excision, in this case a small polypoid lesion in the nasal cavity. The others required subtotal maxillectomy or radical maxillectomy with orbital exenteration, depending upon the extent of the tumor. Total laryngectomy was performed in two patients who had a laryngeal primary. One patient with a pharyngeal wall tumor underwent pharyngolaryngectomy.
Treatment of Parotid Lesions
Stage I Irradiation Implant External irradiation External irradiation and implant Surgery’ Excision of primary Enucleation Subtotal parotidectomy sparing facial nerve Total parotidectomy sparing facial nerve Subtotal parotidectomy, part of facial nerve taken Total parotidectomy, part or all of facial nerve taken Extended total parotidectomy, facial nerve resected Radical neck dissection l
464
Stage II
Stage Ill
Not Staoed
2 5
1 1
2 4 1 7 11 12 24
1
1
22 33 2 5 1
6 15
2
1
4 1
1 1 3
Previously Treated
Total
1 2 4
2 5 10
17 30 1 21 21 18 47
48 82 4 37 35 31 77
Includes 8 patients who received preoperative or postoperative radiation.
The American Journal of Surgery
Salivary Gland Mucoepidermoid
A total of t’ourteen patients (17 per cent), all with intermediate or high grade tumors, underwent radical neck dissection, eleven of whom had a mouth primary. Enlarged nodes were apparent in f’ive of’ the latter patients, and six underwent elective neck dissection in conjunction with r: dical excision of the primary tumor, including mandihulectomy (the so-called “commando” operation). Susp+Jct.ed cervical metastasis was t.he reason for lymphadenr:ctomy in IWO patient.s with an antral primary and in one
with a tumor involving the larynx.
Results
‘Y’uro’* Rate. Considering the known disparity in results of treatment for a low grade tumor as comp.-lred wit,h an intermediate or a high grade tumor, “cure” rates were calculated by the direct method for each group. Of those with low grade tumors, 81,66, and 48 per cent, were alive and without evidence of recurrence five, ten, and fifteen years after treatment, respectively. Comparable absolute cure rates for patients who had an intermediate or high grade lesion were 46, 36, and 25 per cent, respectively. It is customary to exclude as indeterminate those patients who had no evidence of recurrence when they died of other causes or were lost to follow-up. According to this more relevant assessment, the “net,” or determinate, five, ten, and fifteen year cure rates were 92,90, and 82 per cent when the tumor was of’ low histologic grade, or 49, 42, and 33 per cent in those with an intermediate or high grade tumor. (‘[‘able V.) Local TrPatmQn,t Failure. Based on adequate infc.,rmation available in 335 of 355 patients who were treated in expectation of cure, tumor recurred at the primary site in eighty-seven (26 per cent). In most instances, local recurrence was evident within one year, but in five previously untreated patients with a low or intermediate grade tumor, disease-free int,ervals ranged from eight to fourteen years. Local failure occurred in less than 10 per cent of patients who had a low grade lesion (or a clinical stage I or stage II tumor without regard to microscopic appearance). In contrast, recurrence of the primary tL,mor was noted in almost 40 per cent of those who had a lesion which was of intermediate or high grade. Uncontrolled tumor in the neck was a problem in fort,y-eight patients (16 per cent), all but ten of whom had evidence of recurrence at the primary site and/or distant metastasis. In all, initial treatment failed to control tumor in the primary site or in the ipsilateral lymph nodes in 135 patients, I1 2 of whom underwent from one to as many as seven addit,ional therapeutic efforts. Surgery. radiation, or combinations of both modalities Volume 136, October
1978
TABLE
V
“Cure”
Carcinoma
Rate bv the Direct Method
Low Grade Patients eligible Alive without evidence of disease Indeterminate cases Absolute cure Determinate cure Intermediate, High Grade Patients eligible Alive without evidence of disease Indeterminate cases Absolute cure Determinate cure
5 Years
10 Years
15 Years
138 112 16 81% 92%
132 87 35 66% 90%
113 54 47 48% 82%
229 105 14 46% 49%
225 80 33 36% 42%
199 49 51 25% 33%
subsequently controlled local or neck recurrence in eighteen patients (16 per cent). Distant Metastasis. Metastasis to distant sites occurred in 50 of 342 patients (15 per cent) for whom we had adequate follow-up information. The incidence was as high as 35 per cent in patients who had a high grade or clinical stage III tumor but was much lower in previously untreated patients (11 per cent) and in those who had a low or intermediate grade tumor (2 and 16 per cent, respectively). Distant metastasis occurred less often in patients who had a minor salivary primary (8 per cent) as compared with those with a parotid or submaxillary gland lesion (17 and 25 per cent, respectively). (Table VI.) Clinical findings suggested disseminated disease in twenty-three patients, and pulmonary metastases were evident in fourteen. Skeletal or brain metastases were documented in eight and five others, respectively. Only nine patients survived more than one year after distant metastasis was confirmed, and the longest survival was thirty-nine months.. Factors Influencing Survival. The histologic grade and clinical stage of the tumor were the factors which most influenced the outcome after therapy. (Table VII.) Five year determinate cure rates varied from 97 to 83 to 28 per cent in patients with clinical stage I, II, and 111 lesions. Similarly, the cure rate in those with a low, intermediate, or high grade tumor was 92, 63, and 27 per cent, respectively. The interrelationship between these two factors can be demonstrated by subdividing 110 previously untreated patients who had an intermediate or a high grade tumor according to the clinical stage. Cure rates varied from 97 per cent in patients with stage I disease (32 eligible; 31 alive and well) to 73 per cent in those with stage II disease (26 eligible; 19 alive and well) to 19 per cent in those with stage III disease (52 eligible; 10 alive and well). Results seemed to be better in younger patients and in women, but this is at least partially explained by the higher incidence of smaller, low grade tumors
465
Spiro et al
TABLE VI
Distant Metastasis
All patients Parotid gland Submaxillary Minor salivary Primary cases Previously treated Low grade Intermediate grade High grade No grade Stage I Stage II Stage Ill l
Total
No Data
365 254 23 90 215 152 138 139 82 8 89 50 69
25 21 3 1 8 17 5 5 13 2 2 1 2
342 233 20 89 207 135 133 134 69 6 87 49 67
No. with Metastasis 50 (15%) 39 (17%) 4 (25%) 7 (8%) 23(11%) 27 (20%) 3 (2%)” 21 (16%) 24 (35%) 2 (33%) 1(2%) 21 (31%)
All previously treated.
in these subgroups. As with salivary neoplasms of other histologic type, pain was an unfavorable prognostic sign [19,20]. Higher cure rates were observed in patients treated for a minor salivaryor parotid gland primary. Despite similarity to those with parotid lesions with respect to stage and grade, the salvage was appreciably lower in patients treated for a submaxillary tumor. The unfavorable impact of prior therapy was more apparent when patients treated for obvious recurrence were separated from those treated because previous therapy was considered inadequate. Tumor-related facial nerve palsy in patients with parotid lesions and bone involvement in those with a minor salivary primary were both ominous signs. Few patients were salvaged when cervical metastases were present initially. Comments
Mucoepidermoid carcinoma is the most frequently encountered malignant salivary neoplasm. Our experience with young patients who had a malignant lesion in the parotid gland has indicated that all but a few will prove to have mucoepidermoid carcinoma of low histologic grade [21]. The possible etiologic relationship of prior irradiation noted in four of our patients has been reported by others [22-241. More remarkable was the high incidence of a second primary breast cancer in our female patients. This observation, made ten years ago by Berg, Hutter, and Foote [25] and corroborated by others [26], suggests that hormonal factors deserve further investigation. Regardless of the difference in histologic appearance, we consider all mucoepidermoid tumors to be malignant. This is a view shared by many investigators [10,12,27], but others contend that a benign variety exists, which they prefer to call “mucoepider466
Determinate Patients
moid tumor” [6,13,28]. Our experience includes six patients who died as a direct consequence of uncontrolled tumor which was of low histologic grade. Distant metastasis was documented in three, and one other surviving patient with a tonsillar primary had multiple ipsilateral cervical node metastases when first seen. It seems clear that aggressive local growth and distant metastasis are occasionally seen with tumors that some pathologists would consider histologically “benign.” With rare exception these patients had a bulky lesion which was persistent after inadequate treatment elsewhere. In only one instance, a patient who died with pulmonary metastases, did the tumor show evidence of anaplastic change as the disease progressed. The present study clearly confirms the prognostic value of the clinical staging system we have previously proposed for malignant major salivary gland tumors [15,16]. We have also found it useful to stage minor salivary carcinoma according to the accepted criteria for epidermoid carcinoma involving the same anatomic area [18]. Our data indicate that the histologic grade of a mucoepidermoid tumor can usually be anticipated by the clinical findings alone. A bulky lesion showing fixation or nerve involvement or nodal metastasis (stage III) was almost always of intermediate or high histologic grade, whereas a small, freely movable tumor (stage I) was rarely of high histologic grade. Moreover, when there was a discrepancy between the grade and the stage of a tumor (that is, high grade, stage I or low grade, stage III), the outcome was most influenced by the clinical stage rather than by the histologic appearance. Although many of the patients in this study were treated long before the evolution of current concepts in clinical staging, the type of surgery performed was clearly based upon the extent of the tumor and not upon histologic appearance per se. A conservative operation (which spared the facial nerve whenever The American Journal of Surgery
Salivary
possible in patients with parotid lesions) usually eradicated the primary tumor in patients who had a stage I or II lesion. Local recurrence or metastasis occurred frequently in those who had a stage III or extensive recurrent tumor despite radical resection which often involved sacrifice of adjacent soft tissue, bone, or nerves. There was little evidence to suggest that the local ccntrol rate might have been better if extensive operations had been performed in more patients. The lower cure rate observed in those with mucoepidermoid carcinoma arising in the submaxillary gland suggests that initial surgery may have been inadequate in some patients. As with malignant submaxillary tumors of other histologic type, all but a few patients underwent simple excision of the involved glsnd (with or without neck dissection) rather than radical resection of the primary tumor [16]. It could also be argued that lower cure rates are due to the higher proportion of intermediate or high grade lesicms in those with a submaxillary gland primary. Radical neck dissection was performed in conjunct,ion with excision of the primary tumor in all patients who had clinical evidence of cervical node metastasis, 13 per cent of whom had negative specimens. Our policy of elective lymphadenectomy in selected patients with high grade tumors and no apparent adenopathy seems vindicated by the fact that occult cervical metastases were found in two thirds of the surgical specimens. With the possible exception of sinus cases, the data suggest that radical neck dissection should be considered in any patient who has a T3 tumor without evidence of node metastasis, regardless of its histologic appearance. Aside from the fact that cervical metastasis will develop in most patients at some time in the course of the disease, the enhanced access to a bulky or deeply infiltrative tumor which is provided by neck dissection may facilitate more adequate re:;ection of the primary. Several recent reports suggest that adjunctive radiation deserves more of a role in the treatment of malignant salivary tumors [29-321. Years ago, the poor response usually seen when locally advanced or unresectable salivary cancers were irradiated led to th2 assumption that these tumors were radioresistant. The fact remains that remarkable responses were occasionally noted under the most unfavorable of circumstances. In two patients treated early in this study, local control was achieved by external radiaticn and a combination of beam therapy and interstitial implant despite evidence of tumor-related facial nerve dysfunction. The effectiveness of postoperative irradiation is currently inferred from uncontrolled studies which
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1978
TABLE VII
Gland Mucoepidermoid
Factors influencing 5 Year Determinate “Cure”
Age o-29 yr 30-59 yr
160 yr Sex Men Women Symptoms None (incidental finding) Painless mass Pain at some time Facial nerve palsy Neck mass Others Unknown Previous Treatment None No residual tumor Microscopic residual only Gross recurrence Location Parotid gland Submaxillary gland Minor salivary glands Clinical Stage II III Histologic Grade Low Intermediate High No grade Status of Facial Nerve (parotid cases) Normal Partial or complete palsy Dysfunction due to treatment elsewhere No comment Cervical Node Metastasis Never Previously excised Present on admission Developed subsequently Bone Involvement, (minor salivary cases) No Yes
Carcinoma
Patients Eligible
Alive and Well
66 183 89
60 (91%) 116 (63%) 40 (45%)
146 189
76 (51%) 140 (,74%)
15 225 22 19 4 7 46
12 (80%) 167 (74%) 9(41%) 1(5%)
193 13 19 113
131 13 15 57
233 22 83
148 (64%) 10 (45%) 58 (70%)
78 46 61
76 (97%) 38 (83%) 17 (28%)
122 129
3 (43%) 24 (52 %) (68%) (100%) (79%) (50%)
8
112 81 21 2
(92%) (63%) (27%) (25%)
148 41 21 44
115 6 11 25
(78%) (15%) (52%) (57%)
233 4 83 18
196 3 10 7
(84%) (75%) (12%) (39%)
78
55 28
45 (82%) 13 {46%)
suggest a significant decrease in local recurrence when teletherapy is given for suspected microscopic re’sidual tumor [32]. More recently in our hospital, selected patients with stage III disease or bulky recurrent tumor have received postoperative radiation in full therapeutic dosage to the primary tumor and the ipsilateral neck. It will be years before the number of patients receiving adjunctive radiation proves adequate for valid comparison with t.he earlier treatment group matched according to histology and stage. Meanwhile, we disagree with the suggestion that all patients with parotid cancer should receive wide field postoperative radiation in high dosage 1331. We believe that the excellent results after surgery in
467
Spiro et al
favorable cases do not justify indiscriminate radiation for all patients. Any small improvement in results achieved in those with a good prognosis might well be overshadowed by the inevitable increase in morbidity and potentially hazardous late sequellae. Summary and Conclusions
A thirty year experience with 367 patients who had mucoepidermoid carcinoma of salivary origin is reviewed. The tumor arose in the parotid gland in 254 patients. The presentation and clinical course depended significantly on whether the tumor was low, intermediate, or high grade in histologic appearance. Metastasis and tumor-related death were occasionally noted in patients with low grade lesions, suggesting that even the most innocuous-appearing mucoepidermoid tumor has malignant potential. Significant correlation was demonstrated between the clinical stage of a tumor and its histologic appearance. Stage I tumors were usually of low histologic grade and were effectively controlled by conservative surgical procedures. Radical operations were often ineffective in patients with stage III tumors, most of which proved to be of high histologic grade. Considering the poor prognosis in the latter patients, adjunctive therapy in the form of postoperative external radiation seems indicated. In our experience, “cure” rates in patients who had intermediate or high grade lesions varied widely, depending upon the stage of the tumor. This strongly suggests that therapeutic decisions should not be based on histologic appearance alone. Acknowledgment: We wish to thank Ms. Rosanne Ribaudo for her secretarial assistance.
References 1. Stewart FW, Foote FW, Becker WF: Mucoepidermoid tumors of salivary. glands. Ann Surg 122: 620, 1945. 2. Volkmann I: Uber endotheliale Geschwulste zugleich ein Beitrag zu den Speicheldrusen und Gaumentumoren. Dfsch Z Chir 41: 1, 1695. 3. De MN, Tribedi BP: A mixed epidermoid and mucus-secreting carcinoma of the parotid gland. J Patho/ Bacterial 49: 432, 1939. 4. Masson P, Berger L: Epitheliomas a double metaplasie de la parotide. Bull Cancer 13: 366, 1924. 5. Foote FW Jr, Frazell EL: Tumors of the major salivary glands. Cancer 6: 1065, 1953. 6. Bhaskar SN, Bernier JL: Mucoepidermoid tumors of major and minor salivary glands: clinical features, histology, variations, natural history and results of treatment for 144 cases. Cancer 15: 801, 1962. 7. Gray JM, Hendrix RC, French AJ: Mucoepidermoid tumors of salivary glands. Cancer 16: 183, 1963. 6. Jakobsson PA, Blanck C, Eneroth CM: Mucoepidermoid carcinoma of the parotid gland. Cancer 22: 111, 1968.
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9. Thorvaldsson SE, Beahrs OH, Woolner LB, Simons JN: Mucoepidermoid tumors of the major salivary glands. Am J Surg 120: 432, 1970. 10. Healey WV, Perzin KH, Smith L: Mucoepidermoid carcinoma of salivary gland origin; classification, clinical-pathologic correlation and results of treatment. Cancer 26: 368, 1970. 11. Eversole LR: Mucoepidermoid carcinoma, review of 815 reported cases. J Oral Surg 28: 490, 1970. 12. Eneroth CM, Hjertman L, Moberger G, Soderberg G: Mucoepidermoid carcinomas of the salivary glands, with special reference to the possible existence of a benign variety Acta Otolaryngol73: 68, 1972. 13. Koblin I, Koch H: On the nature of mucoepidermoid tumors of major and minor salivary glands. J Maxillofac Surg 2: 19, 1974. 14. Spiro RH, Koss LG, Hajdu SI, Strong EW: Tumors of minor salivary origin; a clinicopathologic study of 492 cases. Cancer31: 117,1973. 15. Spiro RH, Huvos AG, Strong EW: Carcinoma of the parotid gland. A clinicopathologic study of 288 primary cases. Am J Surg 130: 452, 1975. 16. Spiro RH, Hajdu SI, Strong EW: Tumors of the submaxillary gland. Am J Surg 132: 463, 1976. 17. Saksela E, Grahne B, Siirala V: Clonal pattern of metastasis in a case of malignant mucoepidermoid tumor of the palatal salivary gland. Acfa Otolaryngol71: 430, 1971. 18. American Joint Committee for Cancer Staging and End Results Reporting: Manual for Staging of Cancer. Chicago, 1977, p 27. 19. Spiro RH, Huvos AG, Strong EW: Adenoid cystic carcinoma of salivary origin. Am J Surg 128: 512. 1974. 20. Spiro RH, Huvos AG, Strong EW: Acinic cell carcinoma of salivary origin, a clinicopathologic study of 67 cases. Cancer 41: 924, 1978. 21. Castro EB, Huvos AG, Strong EW, Foote FW Jr: Tumors of the major salivary glands in children. Cancer 29: 312, 1972. 22. Ju D: Salivary gland tumors occurring after irradiation of the head and neck area. Am J Surg 116: 5 18, 1968. 23. Belsky JL, Takeichi N, Yamamoto T, Cihak RW, Hirose F, Ezaki H, lnoue S, Blot WJ: Salivary gland neoplasms following atomic radiation. Cancer 35: 555, 1975. 24. Rice DH, Batsakis JG, McClatchey KD: Postirradiation malignant salivary gland tumor. Arch Otolaryngol 102: 699, 1976. 25. Berg JW, Hutter RV, Foote FW: The unique association between salivary gland cancer and breast cancer. JAMA 204: 771. 1968. 26. Prior P, Waterhouse AH: Second primary cancers in patients with tumours of the salivary glands. Br J Cancer 36: 362, 1977. 27. Rawson AJ, Howard JM, Royster HP, Horn RC Jr: Tumors of the salivary glands; clinicopathologic study of 160 cases. Cancer 3: 445, 1950. 28. Thackray AC, Lucas RB: Tumors of the major salivary glands, p 60. Atlas of Tumor Pathology, 2nd series, fats 10. Washington DC, Armed Forces Institute of Pathology, 1974. 29. Stewart JG, Jackson AW, Chew MK: The role of radiotherapy in the management of malignant tumors of the salivary glands. Am J Roentgen01 102: 100, 1968. 30. Jakobsson PA, Eneroth CM: Variations in radiosensitivity of various types of malignant salivary gland tumors. Acta Otolaryngol263: 186, 1970. 31. Guillamondegui OM, Byers RM, Luna MA, Chiminazzo H, Jesse RH, Fletcher GH: Aggressive surgery in treatment for parotid cancer; the role of adjunctive postoperative radiotherapy. Am J Roentgen01 123: 49, 1975. 32. Fu KK, Leibel SA, Levine ML, Friedlander LM, Boles R, Phillips TL: Carcinoma of the major and minor salivary glands: analysis of treatment results and sites and causes of failures. Cancer 40: 2882, 1977. 33. Kagan AR, Nussbaum H, Handler S, et al: Recurrences from malignant salivary gland tumors. Cancer 37: 2600. 1976.
The American Journal of Surgery
Ronald H. Spiro, MD, New York, New York Andrew G. Huvos, MD, New York, New York Richard Berk, MD,* New York, New York Elliot W. Strong, MD, New York, New York
Stewart, Foote, and Becker [I] in 1945 coined the term “mucoepidermoid tumor” to describe an unusual salivary neoplasm containing epidermoid and mucus-secreting cells which was thought to arise in salivary gland ducts. Credit for the first report of this tumor was ascribed to Volkman [2] in 1895; its unique histologic features had been described by others [3,4]. Review of approximately 700 major and minor salivary gland tumors seen at Memorial Hospital between 1928 and 1943 yielded only forty-five which satisfied the criteria. Based on the histologic appearance and the clinical course, these tumors were divided into a benign and a malignant group. By 1953 Foote and Frazell [5] had collected ninety-eight cases involving the major salivary glands (1.930 to 1949). Noting that metastasis had occurred with a few tumors previously classified as benign, the designations “low grade malignant” or “high grade malignant” were proposed. Clinical and pathologic correlation even suggested that separation into low, medium, and high grade malignant subgroups might prove useful. Despite more recent reports from many centers encompassing more than 1,000 cases, there is still controversy about the classification and treatment of these tumors [6-131. The present study includes some patients previously reported on [14-161, but we have deliberately excluded our experience prior to 1939 when radiation was often the only treatment and many other patients had operations which would be considered inadequate by today’s standards. Information was adequate in the sizable group of patients seen since 1939 to permit retrospective clinical staging. This has shown remarkable corre-
From the Departments of Surgery, Head and Neck Service, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York. Reprint requests should be addressed to Ronald H. Spiro, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. Presented at the Joint Meeting of the American Society for Head and Neck Surgery and the Society of Head and Neck Surgeons, Toronto, Ontario, Canada, May 29-31, 1978. * Present address: 9108 Pottawattami Drive, Skokie, Illinois 60076.
Volume 136, October 1976
lation with histologic grading, which offers the clinician a new opportunity for rational treatment planning. Material During the thirty year period from 1939 through 1968, the diagnosis of mucoepidermoid carcinoma was recorded for 400 patients in the Tumor Registry of the Memorial Sloan Kettering Cancer Center. This comprised 15 per cent of all patients with salivary neoplasms, or 30 per cent of those with malignant salivary tumors seen during the same period. On review, thirty-three patients were excluded either because they received no treatment at our hospital (21 patients), the diagnosis was changed after reexamination of the slides (6 patients), or clinical or histologic material was incomplete (6 patients). This retrospective analysis is based on the remaining 367 patients. The tumor arose in the parotid gland in 254 patients (69 per cent), whereas the submaxillary gland and minor salivary glands were involved in twenty-three (6 per cent) and ninety patients (25 per cent), respectively. Forty-one per cent had received prior treatment elsewhere, most often consisting of local excision. (Table I.) The patients ranged in age from six to ninety years (median, 51 years); median age appeared to be lower for those with a parotid or minor salivary gland tumor (48 years) than for those with a lesion in the submaxillary gland (53 years). There were 197 women and 170 men, and a slight preponderance of women (54 per cent) was apparent whether the tumor arose in major or minor salivary glands. Specific etiologic factors were seldom evident in this retrospective study. In four patients radiation had been given to the face or the neck for an unrelated condition from three to thirty years previously. An antral tumor developed in another patient seventeen years after lipiodol instillation into the sinus for diagnostic evaluation of allergic symptoms. A foreign body seemed causally related in a remarkable case which was previously report&d [14]. The patient was a seven year old girl in whom a tumor developed in the left nasal cavity twenty-six months after removal of a button which had been impacted in the same area for three months. Multiple primary neoplasms were recorded in forty-six patients (13 per cent). Of these, fifteen had another tumor
461
Spiro et al
TABLE I
Anatomic Site of Primary Previously Untreated
Previously Treated
Parotid gland Palate Submaxillary gland Antrum Tongue Cheek, lip mucosa Gingivae Nasal cavity Floor of the mouth Tonsil Laryngopharynx
139 16 12 9 10 9 6 2 6 4 2
115 8 11 3 1 2 4 7
1
254 (69 %) 24 (7%) 23 (6%) 12 (3%) 11(3%) 11(3%) 10 (3%) 9 (2%) 6 (2%) 4(1%) 3(1%)
Total
215
152
367 (100%)
Total
in the head and neck area, including two patients who had a metachronous mixed tumor in another salivary gland and two with a synchronous papillary carcinoma of the thyroid. The breast was the site of the second primary cancer in nine women, and one unusual patient had four separate cancers arising in the parotid gland, lung, urinary bladder, and skin. Pathology Gross Features. On gross examination, the low grade mucoepidermoid carcinomas closely resembled benign mixed tumors. They were oval and well circumscribed, but distinct encapsulation was rarely present, and a complete capsule was entirely absent at times. On sectioning, the tumor was gray-white or pinkish, lobulated, and slightly firm. Bluish, opalescent mucoid material was seen on the cut surface in some lesions, accumulating in small cystic pools. Dilated cystic spaces were seen in approximately half the patients, with completely cystic presentation in rare instances. Intermediate and high grade mucoepidermoid carcinomas were usually infiltrative growths which showed no encapsulation. Cyst formation was not as pronounced as in the low grade tumors. When present, cysts were usually hemorrhagic rather than mutinous and were centrally placed within areas of necrosis and degeneration. ConsisTABLE II
tency was homogeneously hard and occasionally gritty; the cut section was gray-white in appearance without lobulation. Microscopic Features. The term “mucoepidermoid” is an abridgment of the designation “mixed epidermoid and mucus-secreting carcinoma.” Although it is more convenient, the shorter term gives no indication that these tumors contain an intermediate type cell which is neither mucous nor fully epidermoid in character. The proportion of these three cell types may vary, and glandular or cystic formations, solid nests of neoplastic cells, or an intermingling of these growth patterns may be noted. Based upon histologic criteria which are described below, the tumors were classified either as low grade (138 patients), intermediate grade (139 patients), or high grade (82 patients). Available tissue sections in eight patients were considered inadequate for grading. In low grade mucoepidermoid carcinoma, well developed grandular or microcystic structures were seen, lined by a single layer of mucus-secreting columnar cells. In some areas these cystic spaces were bordered by papillary infoldings formed by an intermediate type cell having features of basaloid character or by epidermoid cells. Study of these intermediate or basal type cells confirmed the original findings of Foote and Frazell[5] that these cellular forms are capable of differentiation into mutinous cells or into cells with epidermoid or squamous characteristics. In the low grade lesions, microcyst formation coalescing into larger cysts was occasionally quite prominent. If the mucoid material present in the cystic spaces escaped into the surrounding salivary gland stroma, an intense inflammatory reaction (sometimes of the foreign body giant cell type) occasionally obscured the true neoplastic character of the lesion. Mucoepidermoid carcinomas of intermediate grade were characterized by solidly growing areas of epidermoid or even squamous cells or intermediate basaloid type elements with the latter cell types predominating. The papillary cystic structural infoldings showed epidermoid or basal cells quite frequently. The high grade variants displayed an increased tendency for intermediate basal and epidermoid cells to appear in solid nests or cords. Variation in the size and shape of the
Cervical Node Metastasis Total Patients
Enlarged Nodes
Status on Admission Metastasis Confirmed
Appeared Later
Total with Metastasis
Parotid gland Submaxillary gland Minor salivary gland
254 23 90
51 5 7
64 11 13
6 1 11
70 (28%) 12 (52%) 24 (27 %)
Primary Previously treated
215 152
32 32
43 45
14 4
57 (27%) 49 (32%)
Low grade Intermediate grade High grade Not graded
138 139 82 8
7 21 32 3
8 33 43 4
4 9 5
12 42 48 4
28
3 38
1 4 8
l(l%) 7 (14%) 46 (67%)
Stage I Stage II Stage Ill
462
89 50 69
(7%) (30%) (59%) (50%)
The American Journal of Surgery
Salivary Gland Mucoepidermoid
neoplastic cells, prominent nucleoli, and abundant mitotic figures were easily recognized. Glandular or cystic formatil)ns were only occasionally present. In other variants a glandular growth predominat,ed, and there were few epidermoid or basal cell elements. Microscopic study of metastatic deposits in patients with high grade tumors revealed varying proportions of epidermoid or mucinproducing tumor cells, not necessarily mimicking the p!.oportion observed in the primary salivary gland lesions
[171. The histologic differential diagnosis of high grade nucoepidermoid carcinoma required a mucin stain. If a ucicarminophilic tumor cells were completely absent, the lesion was classified as epidermoid or squamous cell carcinoma of salivary gland origin and not as mucoepidermoid cancer. Many henign mixed tumors (pleomorphic adenomas I exhibit prominent areas of squamous metaplasia, or a rare condition termed necrotizing sialometaplasia may show epidermoid traits. Mucoepidermoid carcinoma of any grade of malignancy shows no evidence of myoepithelial ctslls or the chondroid or myxochondroid matrix so characterist.ic of mixed tumors. Clinical
Findings
Primary Tumor. An asymptomatic swelling was the presenting symptom in 190 of 254 patients (75 per cent) who had a parotid tumor. Pain was infrequently associated (! 3 patients), but preceded the appearance of a mass on rare occasion (4 patients). Almost 60 per cent of previously untreated patients had been aware of the lesion for a year or less, but intervals of five to more than twenty years e.apsed in nineteen patients before a physician was consulted. Parotid tumors usually presented as a solitary mass confined t,o the body or tail of the gland (76 per cent), but occasionally arose deep to the facial nerve in the so-called deep “lobe” (7 patients) or involved accessory parotid tissue anterior to the body of the gland (3 patients). Only s.x patients with an untreated parotid lesion of low histologic grade had a tumor that exceeded 3 cm in size. The size exceeded 3 cm in forty-six of seventy-eight patients (59 per c,?nt) who had an intermediate or high grade tumors. Skin fixation to the tumor was observed in only one previously untreated patient who had a low grade parotid lesion; fixation to the skin or deeper tissues and/or ulceration were evident in thirty patients (38 per cent) who had intermediate or high grade tumors. Partial or complete facial nerve palsy was observed in ten and fourteen previously untaeated patients (17 per cent), respectively, none of whom had a low grade lesion. Based on available data in 98 of 115 previously treated patients who had a parotid primary, the tumor was a solitary mass in sixty-eight and was multinodular in four. As with previously untreated patients, high grade tumors were usually larger. Partial or complete facial nerve palsy was noted in twenty patients (20 per cent), and twenty-one others had nerve dysfunction related to treatment elsewhere. Induration, rather than a discrete mass, was the only finding in twenty-six patients who were evaluated soon
Volume
136,
October
1978
Carcinoma
after surgery had been performed at another hospital. If these patients are excluded, almost two thirds of those with obvious recurrent tumor showed fixation or ulceration. Of the twenty-three patients who had a submaxillary gland tumor, twenty noted an asymptomatic swelling and three reported pain in association with a mass. Seven of tweive previously untreated patients were aware of the tumor for less than one year; a mass had been present from ten to twenty years in three others. All patients had a solitary mass except for two who had only induration after submaxillary gland excision elsewhere. Tumor size was recorded in nineteen patients and exceeded 3 cm in twelve (63 per cent). Much diversity was apparent in ninety patients who had mucoepidermoid carcinoma of minor salivary (mucus) gland origin. As with other minor salivary tumors, the palate was most often involved (24 patients). This was followed in order of decreasing frequency by the antrum (12 patients), cheek or lip mucosa (II), tongue (ll), gingivae (lo), nasal cavity (9), floor of the mouth i61, tonsil (4), larynx (2), and pharyngeal wall (1). Tumor size was recorded in sixty-one of sixty-five patients who had a mouth primary and was less than 2 cm in twenty-six patients (43 per cent), 2.1 to 4 cm in twenty-five (41 per cent), and more than 4 cm in ten (16 per cent). Mucosal ulceration was apparent in nine patients, but only three had clinical evidence that the mandible or maxilla was involved by tumor. Each of the twelve patients with an antral primary and seven of nine with a nasal tumor had a sizable lesion with clinical or radiographic evidence of bone destruction. Of the two patients with laryngeal primaries, one had a sizable epiglottic tumor and the other had a small glottic primary involving the anterior commissure. Ceroical Metastasis. Metastasis to cervical lymph nodes occurred in 106 patients (29 per cent). This was confirmed at the time of initial treatment in eighty-eight. patients and occurred subsequently in eighteen others. (Table II.) Nodal involvement occurred more often in those who had a submaxillary gland primary and was present on admission in more than half the patients who had a high grade parotid lesion which was recurrent after treatment elsewhere. Although nodal enlargement was seldom apparent when those with minor salivary lesions were first examined, the incidence recorded during the course of the disease was similar to that observed in patients with parotid lesions. Clinical Staging. Data were sufficient to permit retrospective clinical staging in 206 of 215 patients with a previously untreated tumor. Criteria which we have previously described were used for those who had a parotid or submaxillary lesion [15,16]. Patients who had a minor salivary tumor were classified according to accepted criteria for epidermoid carcinoma arising in the oral cavity, pharynx, larynx, or sinuses [18]. There were eighty-nine patients (43 per cent) with stage I disease, fifty (24 per cent) with stage II, and sixty-seven (33 per cent) with stage III. When subdivided according to histologic grade, stage I disease was seen most often in patients with tumors of low histologic grade, whereas stage III lesions were almost always of intermediate or high histologic grade. (Table III.)
463
Spiro et al
TABLE Ill
Relationship of Histologic Grade to Clinical Stage
Stage I
Stage II
Stage Ill
Total
Low grade Intermediate grade High grade
57 (64%) 27 (30%) 5 (6%)
21(42%) 19 (38%) 10(20%)
6(9%) 32 (50%) 26(41%)
84 78 41
Total
89 (100%)
50 (100%)
64 (100%)
203’
l
Excludes 12 of 215 primary cases’lacking stage or grade.
Treatment Parotid Gland. Surgery was the only modality used in 229 patients who had a parotid primary (90 per cent), and eight others received preoperative or postoperative radiation in conjunction with excision. External radiation, radon seed implantation, or combinations of both were used in seventeen patients during the early years of this study. (Table IV.) Subtotal parotidectomy sparing the branches of the facial nerve was the operation most often performed (82 patients; 36 per cent). Early in the study forty-eight patients underwent an even more conservative local excision without deliberate exposure of the nerve. Total parotidectomy with preservation of the seventh nerve was possible in four patients. Of the remainder, seventy-two patients had one nerve branch or more resected in conjunction with subtotal or total parotidectomy and thirtyone required radical total parotid resection with sacrifice of most of the facial nerve. Of 145 patients who had either stage III disease or tumor which was locally recurrent, sacrifice of all or part of the nerve was required in ninety (52 per cent), thirty of whom underwent radical total parotidectomy which sometimes included portions of skin, masseter muscle, or the adjacent mandible. In contrast, a conservative parotid operation which preserved facial nerve function was possible in seventy-eight of eighty-nine patients (88 per cent) who had stage I or stage II lesions. Radical neck dissection was part of the initial treatment in 77 of the 237 patients (32 per cent) who had surgery, fifty-one of whom had clinical evidence of cervical node enlargement. No cervical metastases were found in eight TABLE IV
of the latter patients, but elective neck dissection in twenty-six others confirmed the presence of occult lymph node involvement in seventeen. Neck dissection was seldom performed in patients who had stage I or stage II tumors (3 of 90 patients; 3 per cent) or those with a lesion of low histologic grade (7 of 93 patients; 8 per cent). In contrast, radical neck dissection was performed in 14 of 28 patients (50 per cent) with an untreated high grade tumor, and 47 of 108 previously treated patients (44 per cent) who had surgery regardless of histologic grade. Submaxillary Gland. All twenty-three patients in this group were treated surgically. Submaxillary dissection was performed in four of twelve previously untreated patients, whereas six underwent radical neck dissection. The inferior margin of the mandible was resected with the gland, and hemimandibulectomy was required in conjunction with radical neck dissection in the two remaining patients, both of whom had stage III tumors. Only one patient underwent local excision of a recurrent submaxillary tumor. Neck dissection was performed for recurrence in nine others (with inferior marginal mandibulectomy in 3), whereas one patient required combined resection, including hemimandibulectomy and excision of the floor of the mouth. Minor Salivary. Of ninety patients who had a tumor arising in minor salivary glands, eighty-four (93 per cent) were treated surgically; external radiation was used in the remaining six. Local excision was feasible in thirty-three of sixty-three patients (52 per cent) who had a surgically treated mouth primary, two of whom received external radiation as well. A more radical excision including a portion of the maxilla or mandible was required in the remaining thirty patients. Only one of eighteen patients who had surgery for an antral or nasal cavity tumor had a lesion that was suitable for local excision, in this case a small polypoid lesion in the nasal cavity. The others required subtotal maxillectomy or radical maxillectomy with orbital exenteration, depending upon the extent of the tumor. Total laryngectomy was performed in two patients who had a laryngeal primary. One patient with a pharyngeal wall tumor underwent pharyngolaryngectomy.
Treatment of Parotid Lesions
Stage I Irradiation Implant External irradiation External irradiation and implant Surgery’ Excision of primary Enucleation Subtotal parotidectomy sparing facial nerve Total parotidectomy sparing facial nerve Subtotal parotidectomy, part of facial nerve taken Total parotidectomy, part or all of facial nerve taken Extended total parotidectomy, facial nerve resected Radical neck dissection l
464
Stage II
Stage Ill
Not Staoed
2 5
1 1
2 4 1 7 11 12 24
1
1
22 33 2 5 1
6 15
2
1
4 1
1 1 3
Previously Treated
Total
1 2 4
2 5 10
17 30 1 21 21 18 47
48 82 4 37 35 31 77
Includes 8 patients who received preoperative or postoperative radiation.
The American Journal of Surgery
Salivary Gland Mucoepidermoid
A total of t’ourteen patients (17 per cent), all with intermediate or high grade tumors, underwent radical neck dissection, eleven of whom had a mouth primary. Enlarged nodes were apparent in f’ive of’ the latter patients, and six underwent elective neck dissection in conjunction with r: dical excision of the primary tumor, including mandihulectomy (the so-called “commando” operation). Susp+Jct.ed cervical metastasis was t.he reason for lymphadenr:ctomy in IWO patient.s with an antral primary and in one
with a tumor involving the larynx.
Results
‘Y’uro’* Rate. Considering the known disparity in results of treatment for a low grade tumor as comp.-lred wit,h an intermediate or a high grade tumor, “cure” rates were calculated by the direct method for each group. Of those with low grade tumors, 81,66, and 48 per cent, were alive and without evidence of recurrence five, ten, and fifteen years after treatment, respectively. Comparable absolute cure rates for patients who had an intermediate or high grade lesion were 46, 36, and 25 per cent, respectively. It is customary to exclude as indeterminate those patients who had no evidence of recurrence when they died of other causes or were lost to follow-up. According to this more relevant assessment, the “net,” or determinate, five, ten, and fifteen year cure rates were 92,90, and 82 per cent when the tumor was of’ low histologic grade, or 49, 42, and 33 per cent in those with an intermediate or high grade tumor. (‘[‘able V.) Local TrPatmQn,t Failure. Based on adequate infc.,rmation available in 335 of 355 patients who were treated in expectation of cure, tumor recurred at the primary site in eighty-seven (26 per cent). In most instances, local recurrence was evident within one year, but in five previously untreated patients with a low or intermediate grade tumor, disease-free int,ervals ranged from eight to fourteen years. Local failure occurred in less than 10 per cent of patients who had a low grade lesion (or a clinical stage I or stage II tumor without regard to microscopic appearance). In contrast, recurrence of the primary tL,mor was noted in almost 40 per cent of those who had a lesion which was of intermediate or high grade. Uncontrolled tumor in the neck was a problem in fort,y-eight patients (16 per cent), all but ten of whom had evidence of recurrence at the primary site and/or distant metastasis. In all, initial treatment failed to control tumor in the primary site or in the ipsilateral lymph nodes in 135 patients, I1 2 of whom underwent from one to as many as seven addit,ional therapeutic efforts. Surgery. radiation, or combinations of both modalities Volume 136, October
1978
TABLE
V
“Cure”
Carcinoma
Rate bv the Direct Method
Low Grade Patients eligible Alive without evidence of disease Indeterminate cases Absolute cure Determinate cure Intermediate, High Grade Patients eligible Alive without evidence of disease Indeterminate cases Absolute cure Determinate cure
5 Years
10 Years
15 Years
138 112 16 81% 92%
132 87 35 66% 90%
113 54 47 48% 82%
229 105 14 46% 49%
225 80 33 36% 42%
199 49 51 25% 33%
subsequently controlled local or neck recurrence in eighteen patients (16 per cent). Distant Metastasis. Metastasis to distant sites occurred in 50 of 342 patients (15 per cent) for whom we had adequate follow-up information. The incidence was as high as 35 per cent in patients who had a high grade or clinical stage III tumor but was much lower in previously untreated patients (11 per cent) and in those who had a low or intermediate grade tumor (2 and 16 per cent, respectively). Distant metastasis occurred less often in patients who had a minor salivary primary (8 per cent) as compared with those with a parotid or submaxillary gland lesion (17 and 25 per cent, respectively). (Table VI.) Clinical findings suggested disseminated disease in twenty-three patients, and pulmonary metastases were evident in fourteen. Skeletal or brain metastases were documented in eight and five others, respectively. Only nine patients survived more than one year after distant metastasis was confirmed, and the longest survival was thirty-nine months.. Factors Influencing Survival. The histologic grade and clinical stage of the tumor were the factors which most influenced the outcome after therapy. (Table VII.) Five year determinate cure rates varied from 97 to 83 to 28 per cent in patients with clinical stage I, II, and 111 lesions. Similarly, the cure rate in those with a low, intermediate, or high grade tumor was 92, 63, and 27 per cent, respectively. The interrelationship between these two factors can be demonstrated by subdividing 110 previously untreated patients who had an intermediate or a high grade tumor according to the clinical stage. Cure rates varied from 97 per cent in patients with stage I disease (32 eligible; 31 alive and well) to 73 per cent in those with stage II disease (26 eligible; 19 alive and well) to 19 per cent in those with stage III disease (52 eligible; 10 alive and well). Results seemed to be better in younger patients and in women, but this is at least partially explained by the higher incidence of smaller, low grade tumors
465
Spiro et al
TABLE VI
Distant Metastasis
All patients Parotid gland Submaxillary Minor salivary Primary cases Previously treated Low grade Intermediate grade High grade No grade Stage I Stage II Stage Ill l
Total
No Data
365 254 23 90 215 152 138 139 82 8 89 50 69
25 21 3 1 8 17 5 5 13 2 2 1 2
342 233 20 89 207 135 133 134 69 6 87 49 67
No. with Metastasis 50 (15%) 39 (17%) 4 (25%) 7 (8%) 23(11%) 27 (20%) 3 (2%)” 21 (16%) 24 (35%) 2 (33%) 1(2%) 21 (31%)
All previously treated.
in these subgroups. As with salivary neoplasms of other histologic type, pain was an unfavorable prognostic sign [19,20]. Higher cure rates were observed in patients treated for a minor salivaryor parotid gland primary. Despite similarity to those with parotid lesions with respect to stage and grade, the salvage was appreciably lower in patients treated for a submaxillary tumor. The unfavorable impact of prior therapy was more apparent when patients treated for obvious recurrence were separated from those treated because previous therapy was considered inadequate. Tumor-related facial nerve palsy in patients with parotid lesions and bone involvement in those with a minor salivary primary were both ominous signs. Few patients were salvaged when cervical metastases were present initially. Comments
Mucoepidermoid carcinoma is the most frequently encountered malignant salivary neoplasm. Our experience with young patients who had a malignant lesion in the parotid gland has indicated that all but a few will prove to have mucoepidermoid carcinoma of low histologic grade [21]. The possible etiologic relationship of prior irradiation noted in four of our patients has been reported by others [22-241. More remarkable was the high incidence of a second primary breast cancer in our female patients. This observation, made ten years ago by Berg, Hutter, and Foote [25] and corroborated by others [26], suggests that hormonal factors deserve further investigation. Regardless of the difference in histologic appearance, we consider all mucoepidermoid tumors to be malignant. This is a view shared by many investigators [10,12,27], but others contend that a benign variety exists, which they prefer to call “mucoepider466
Determinate Patients
moid tumor” [6,13,28]. Our experience includes six patients who died as a direct consequence of uncontrolled tumor which was of low histologic grade. Distant metastasis was documented in three, and one other surviving patient with a tonsillar primary had multiple ipsilateral cervical node metastases when first seen. It seems clear that aggressive local growth and distant metastasis are occasionally seen with tumors that some pathologists would consider histologically “benign.” With rare exception these patients had a bulky lesion which was persistent after inadequate treatment elsewhere. In only one instance, a patient who died with pulmonary metastases, did the tumor show evidence of anaplastic change as the disease progressed. The present study clearly confirms the prognostic value of the clinical staging system we have previously proposed for malignant major salivary gland tumors [15,16]. We have also found it useful to stage minor salivary carcinoma according to the accepted criteria for epidermoid carcinoma involving the same anatomic area [18]. Our data indicate that the histologic grade of a mucoepidermoid tumor can usually be anticipated by the clinical findings alone. A bulky lesion showing fixation or nerve involvement or nodal metastasis (stage III) was almost always of intermediate or high histologic grade, whereas a small, freely movable tumor (stage I) was rarely of high histologic grade. Moreover, when there was a discrepancy between the grade and the stage of a tumor (that is, high grade, stage I or low grade, stage III), the outcome was most influenced by the clinical stage rather than by the histologic appearance. Although many of the patients in this study were treated long before the evolution of current concepts in clinical staging, the type of surgery performed was clearly based upon the extent of the tumor and not upon histologic appearance per se. A conservative operation (which spared the facial nerve whenever The American Journal of Surgery
Salivary
possible in patients with parotid lesions) usually eradicated the primary tumor in patients who had a stage I or II lesion. Local recurrence or metastasis occurred frequently in those who had a stage III or extensive recurrent tumor despite radical resection which often involved sacrifice of adjacent soft tissue, bone, or nerves. There was little evidence to suggest that the local ccntrol rate might have been better if extensive operations had been performed in more patients. The lower cure rate observed in those with mucoepidermoid carcinoma arising in the submaxillary gland suggests that initial surgery may have been inadequate in some patients. As with malignant submaxillary tumors of other histologic type, all but a few patients underwent simple excision of the involved glsnd (with or without neck dissection) rather than radical resection of the primary tumor [16]. It could also be argued that lower cure rates are due to the higher proportion of intermediate or high grade lesicms in those with a submaxillary gland primary. Radical neck dissection was performed in conjunct,ion with excision of the primary tumor in all patients who had clinical evidence of cervical node metastasis, 13 per cent of whom had negative specimens. Our policy of elective lymphadenectomy in selected patients with high grade tumors and no apparent adenopathy seems vindicated by the fact that occult cervical metastases were found in two thirds of the surgical specimens. With the possible exception of sinus cases, the data suggest that radical neck dissection should be considered in any patient who has a T3 tumor without evidence of node metastasis, regardless of its histologic appearance. Aside from the fact that cervical metastasis will develop in most patients at some time in the course of the disease, the enhanced access to a bulky or deeply infiltrative tumor which is provided by neck dissection may facilitate more adequate re:;ection of the primary. Several recent reports suggest that adjunctive radiation deserves more of a role in the treatment of malignant salivary tumors [29-321. Years ago, the poor response usually seen when locally advanced or unresectable salivary cancers were irradiated led to th2 assumption that these tumors were radioresistant. The fact remains that remarkable responses were occasionally noted under the most unfavorable of circumstances. In two patients treated early in this study, local control was achieved by external radiaticn and a combination of beam therapy and interstitial implant despite evidence of tumor-related facial nerve dysfunction. The effectiveness of postoperative irradiation is currently inferred from uncontrolled studies which
Volume
136,
October
1978
TABLE VII
Gland Mucoepidermoid
Factors influencing 5 Year Determinate “Cure”
Age o-29 yr 30-59 yr
160 yr Sex Men Women Symptoms None (incidental finding) Painless mass Pain at some time Facial nerve palsy Neck mass Others Unknown Previous Treatment None No residual tumor Microscopic residual only Gross recurrence Location Parotid gland Submaxillary gland Minor salivary glands Clinical Stage II III Histologic Grade Low Intermediate High No grade Status of Facial Nerve (parotid cases) Normal Partial or complete palsy Dysfunction due to treatment elsewhere No comment Cervical Node Metastasis Never Previously excised Present on admission Developed subsequently Bone Involvement, (minor salivary cases) No Yes
Carcinoma
Patients Eligible
Alive and Well
66 183 89
60 (91%) 116 (63%) 40 (45%)
146 189
76 (51%) 140 (,74%)
15 225 22 19 4 7 46
12 (80%) 167 (74%) 9(41%) 1(5%)
193 13 19 113
131 13 15 57
233 22 83
148 (64%) 10 (45%) 58 (70%)
78 46 61
76 (97%) 38 (83%) 17 (28%)
122 129
3 (43%) 24 (52 %) (68%) (100%) (79%) (50%)
8
112 81 21 2
(92%) (63%) (27%) (25%)
148 41 21 44
115 6 11 25
(78%) (15%) (52%) (57%)
233 4 83 18
196 3 10 7
(84%) (75%) (12%) (39%)
78
55 28
45 (82%) 13 {46%)
suggest a significant decrease in local recurrence when teletherapy is given for suspected microscopic re’sidual tumor [32]. More recently in our hospital, selected patients with stage III disease or bulky recurrent tumor have received postoperative radiation in full therapeutic dosage to the primary tumor and the ipsilateral neck. It will be years before the number of patients receiving adjunctive radiation proves adequate for valid comparison with t.he earlier treatment group matched according to histology and stage. Meanwhile, we disagree with the suggestion that all patients with parotid cancer should receive wide field postoperative radiation in high dosage 1331. We believe that the excellent results after surgery in
467
Spiro et al
favorable cases do not justify indiscriminate radiation for all patients. Any small improvement in results achieved in those with a good prognosis might well be overshadowed by the inevitable increase in morbidity and potentially hazardous late sequellae. Summary and Conclusions
A thirty year experience with 367 patients who had mucoepidermoid carcinoma of salivary origin is reviewed. The tumor arose in the parotid gland in 254 patients. The presentation and clinical course depended significantly on whether the tumor was low, intermediate, or high grade in histologic appearance. Metastasis and tumor-related death were occasionally noted in patients with low grade lesions, suggesting that even the most innocuous-appearing mucoepidermoid tumor has malignant potential. Significant correlation was demonstrated between the clinical stage of a tumor and its histologic appearance. Stage I tumors were usually of low histologic grade and were effectively controlled by conservative surgical procedures. Radical operations were often ineffective in patients with stage III tumors, most of which proved to be of high histologic grade. Considering the poor prognosis in the latter patients, adjunctive therapy in the form of postoperative external radiation seems indicated. In our experience, “cure” rates in patients who had intermediate or high grade lesions varied widely, depending upon the stage of the tumor. This strongly suggests that therapeutic decisions should not be based on histologic appearance alone. Acknowledgment: We wish to thank Ms. Rosanne Ribaudo for her secretarial assistance.
References 1. Stewart FW, Foote FW, Becker WF: Mucoepidermoid tumors of salivary. glands. Ann Surg 122: 620, 1945. 2. Volkmann I: Uber endotheliale Geschwulste zugleich ein Beitrag zu den Speicheldrusen und Gaumentumoren. Dfsch Z Chir 41: 1, 1695. 3. De MN, Tribedi BP: A mixed epidermoid and mucus-secreting carcinoma of the parotid gland. J Patho/ Bacterial 49: 432, 1939. 4. Masson P, Berger L: Epitheliomas a double metaplasie de la parotide. Bull Cancer 13: 366, 1924. 5. Foote FW Jr, Frazell EL: Tumors of the major salivary glands. Cancer 6: 1065, 1953. 6. Bhaskar SN, Bernier JL: Mucoepidermoid tumors of major and minor salivary glands: clinical features, histology, variations, natural history and results of treatment for 144 cases. Cancer 15: 801, 1962. 7. Gray JM, Hendrix RC, French AJ: Mucoepidermoid tumors of salivary glands. Cancer 16: 183, 1963. 6. Jakobsson PA, Blanck C, Eneroth CM: Mucoepidermoid carcinoma of the parotid gland. Cancer 22: 111, 1968.
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9. Thorvaldsson SE, Beahrs OH, Woolner LB, Simons JN: Mucoepidermoid tumors of the major salivary glands. Am J Surg 120: 432, 1970. 10. Healey WV, Perzin KH, Smith L: Mucoepidermoid carcinoma of salivary gland origin; classification, clinical-pathologic correlation and results of treatment. Cancer 26: 368, 1970. 11. Eversole LR: Mucoepidermoid carcinoma, review of 815 reported cases. J Oral Surg 28: 490, 1970. 12. Eneroth CM, Hjertman L, Moberger G, Soderberg G: Mucoepidermoid carcinomas of the salivary glands, with special reference to the possible existence of a benign variety Acta Otolaryngol73: 68, 1972. 13. Koblin I, Koch H: On the nature of mucoepidermoid tumors of major and minor salivary glands. J Maxillofac Surg 2: 19, 1974. 14. Spiro RH, Koss LG, Hajdu SI, Strong EW: Tumors of minor salivary origin; a clinicopathologic study of 492 cases. Cancer31: 117,1973. 15. Spiro RH, Huvos AG, Strong EW: Carcinoma of the parotid gland. A clinicopathologic study of 288 primary cases. Am J Surg 130: 452, 1975. 16. Spiro RH, Hajdu SI, Strong EW: Tumors of the submaxillary gland. Am J Surg 132: 463, 1976. 17. Saksela E, Grahne B, Siirala V: Clonal pattern of metastasis in a case of malignant mucoepidermoid tumor of the palatal salivary gland. Acfa Otolaryngol71: 430, 1971. 18. American Joint Committee for Cancer Staging and End Results Reporting: Manual for Staging of Cancer. Chicago, 1977, p 27. 19. Spiro RH, Huvos AG, Strong EW: Adenoid cystic carcinoma of salivary origin. Am J Surg 128: 512. 1974. 20. Spiro RH, Huvos AG, Strong EW: Acinic cell carcinoma of salivary origin, a clinicopathologic study of 67 cases. Cancer 41: 924, 1978. 21. Castro EB, Huvos AG, Strong EW, Foote FW Jr: Tumors of the major salivary glands in children. Cancer 29: 312, 1972. 22. Ju D: Salivary gland tumors occurring after irradiation of the head and neck area. Am J Surg 116: 5 18, 1968. 23. Belsky JL, Takeichi N, Yamamoto T, Cihak RW, Hirose F, Ezaki H, lnoue S, Blot WJ: Salivary gland neoplasms following atomic radiation. Cancer 35: 555, 1975. 24. Rice DH, Batsakis JG, McClatchey KD: Postirradiation malignant salivary gland tumor. Arch Otolaryngol 102: 699, 1976. 25. Berg JW, Hutter RV, Foote FW: The unique association between salivary gland cancer and breast cancer. JAMA 204: 771. 1968. 26. Prior P, Waterhouse AH: Second primary cancers in patients with tumours of the salivary glands. Br J Cancer 36: 362, 1977. 27. Rawson AJ, Howard JM, Royster HP, Horn RC Jr: Tumors of the salivary glands; clinicopathologic study of 160 cases. Cancer 3: 445, 1950. 28. Thackray AC, Lucas RB: Tumors of the major salivary glands, p 60. Atlas of Tumor Pathology, 2nd series, fats 10. Washington DC, Armed Forces Institute of Pathology, 1974. 29. Stewart JG, Jackson AW, Chew MK: The role of radiotherapy in the management of malignant tumors of the salivary glands. Am J Roentgen01 102: 100, 1968. 30. Jakobsson PA, Eneroth CM: Variations in radiosensitivity of various types of malignant salivary gland tumors. Acta Otolaryngol263: 186, 1970. 31. Guillamondegui OM, Byers RM, Luna MA, Chiminazzo H, Jesse RH, Fletcher GH: Aggressive surgery in treatment for parotid cancer; the role of adjunctive postoperative radiotherapy. Am J Roentgen01 123: 49, 1975. 32. Fu KK, Leibel SA, Levine ML, Friedlander LM, Boles R, Phillips TL: Carcinoma of the major and minor salivary glands: analysis of treatment results and sites and causes of failures. Cancer 40: 2882, 1977. 33. Kagan AR, Nussbaum H, Handler S, et al: Recurrences from malignant salivary gland tumors. Cancer 37: 2600. 1976.
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