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Central mucoepidermoid tumors of the jaws
Central mucoepidermoid Report
of
nine
cases
and
tumors of the jaws review
Blair C. Browand, D.M.D.,* and Charles Loma Linda, Calif., and Atlanta, Ga. EMORY
UNIVERSITY
SCHOOL
of the
literature
A. Waldron,
D.D.S.,
M.S.D.,**
OF DENTISTRY
Nine previously unreported cases (CMET) are presented and forty-one mandible was involved in thirty-four is more common in females and has age. Most cases occur in the fourth usually resembles an ameloblastoma logically well-differentiated lesions. therapy. Regional node metastasis died as a result of their tumors.
of
central mucoepidermoid tumor of the jaws previously reported examples are reviewed. The cases and the maxilla in sixteen. The CMET been reported in patients from 1 to 85 years of and fifth decades. Radiographically, the CMET or odontogenic cyst. Most CMET’s are histoThirteen tumors recurred after various forms of was reported in four cases, and four patients
T
he central mucoepidermoid tumor of the jaws (CMET) is an uncommon lesion, and few individual surgeons or pathologists have accumulated any significant experience with this tumor. We are presenting nine previously unpublished cases from the files of the Department of Oral Pathology, Emory University School of Dentistry. Our experience with this lesion is compared with forty-one cases previously reported. Particular attention was directed to response to therapy, incidence of recurrence, and malignant behavior. Criteria for the diagnosis of CMET have been discussed by Alexander,l Silverglade, and Schultz3 and their colleagues. These include (1) presence of intact cortical plates; (2) radiographic evidence of bone destruction; (3) histopathologic confirmation; (4) positive mucin staining; (5) absence of primary This study was supported in part by United States Public Health Service Training Grant 5-T12-CA 8001. *Former American Cancer Society Fellow in Oral Pathology, Emory University School of Dentistry; at present Graduate Student in Periodontics, Loma Linda University, School of Dentistry. **Professor and Chairman, Department of Oral Pathology.
631
Oral Surg. November, 1975 Table
I. Clinical data on nine casesof central mucoepidermoid tumors Patient
15-yr.-oldCaucasian boy
S62-513 49-yr.-old Negro woman S63-454 S6?-213
Location
Maxilla, right canine to third molar area Mandible, incisor canine area
53-yr.-old Caucasian woman s64-517
Mandible, ri t central incisor to first moPar area
56-yr.-old Caucasian woman .%I-557 70-yr.-old Caucasian man S69- 1204 58Sy;b-;$l Caucasian woman
Maxilla, left molar region Mandible, right third molar area
79-yr.-old Negro woman S73-817 63Sy;4;ozllCaucasian man
Mz$ge anterior from premolar to incisbrs Mandible, right third molar area
85-yr.-old Caucasian woman S74-468
Mandible, left body and ramus area, 5 by I cm.
Mandible, right third molar
Symptoms
and duration
Swelling of unknown duration Anterior mandibular swelling reported for 3 weeks
Bluish swelling, unknown duration, drainage Swelling of unknown duration Purulent exudate and swelling for 3 days Swelling, unknown duration Sweliin for 3 weeks, raQ0.f ucency for 15 years Swelling for 5+ years, “cyst” marsupial&d without biopsy in 1969
lesions in salivary glands or other tissues that can mimic the histologic architect,ure of salivary tumors; and (6) exclusion of an odontogenic tumor. Discussions of histogenesis have embrased three main theories for the source of origin for these tumor+ 4-G: (1) mucous metaplasia of the lining epithelium of odontogenic cysts; (2) ectopic submandibular or possibly sublingual salivary gland tissue-the so-called static bone cavity or “Stafne defect”; (3) embryologically entra.pped retromolar mucous salivary gland tissue. No single theory can adequately explain the origin of all these lesions, and it may he that all three are valid. In 1957 Go&n’ described a series of 200 dentigerous cysts in which 5.5 per cent manifested mucous cells in the lining epithelium (as demonstrated by positive mucicarmine staining). In addition, a significant number of cysts demonstrated a tendency to develop ortho- or parakeratin, sebaceous cells, respiratory (ciliated pseudostratified columnar) epithelium, and lymphoid stroma complete with germinal centers, thus lending support to the theory of pluripotentiality of these cysts. A number of central mucoepidermoid tumors have manifested clinical and radiologic similarity to these cysts and, considering the above-mentioned cell pluripotentiality, odontogenic cysts must be strongly considered as a potential source of the CMET. Many authors have elaborated on the lingual cortical defect described by Stafne in 1942.8,8, lo This lesion is variously known as the Stafne defect, latent bone cyst, or static bone cavity and is comprised of submandibular salivary gland tissue in one of three configurations. It may be completely enclosed within the mandible or connected to its parent submandibular gland by a stalk or pedicle through a defect in the lingual cortical plate. In addition, it may present as a lobe or lobule of the main gland lying in a depression in the intact lingual cortical plate of the mandible. It was originally believed that this entity
Volume 40 Number 5
Central
mucoepidermoid tumors of jaws 633
Radiographs Multilocular radiolucency
Treatment En bloc excision
Multilocular radiolucency (soap-bubble appearance)
1. Enucleation and curettage 2. En bloc resection
Multilocular radiolucency involving whole body of mandible 2 cm. cystic radiolucency
Mandibular resection Enucleation
No evidence of disease, 7 years
Unilocular radiolucency
Enucleation
No evidence of disease, 6 years
Unilocular radiolucency
Enucleation
No evidence of disease, 5 years
Multicystic soap-bubble radiolucency Multilocular radiolucency
Partial mandibular resection
Multilocular
Marsupialixation, no biopsy 1969, partial enucleation 1974
No evidence of disease for 5 months, then lost to follow-up Patientrefused further surgery, residual tumor present Mucin is periodically drained from lesion, physician feels that patient cannot tolerate a sureical nrocedure
radiolucency
Incomplete enucleation
hollow-up No evidenEe of disease after 12 years Recurrence after 4 years, re-excision and no evidence of disease after 7 years No evidence of disease after 6 years, then lost to follow-up
could be found only in the posterior portion of the mandible near the angle and subjacent to the mandibular canal. However, several cases of a similar phenomenon arising from the sublingual gland have been noted in the anterior mandible.ll-I3 Since several central mucoepidermoid tumors have appeared in the molar ramus area extending below the canal4 and in the anterior canine incisor areal and in three of the Emory cases,ectopic salivary inclusions are a possible source of some of these tumors. Bhaskar,5 in 1963, described the embryologic events in the development of retromolar mucous salivary glands whereby some of these glands could theoretically become entrapped within the mandible. He reported two cases of central mucoepidermoid tumor and presented evidence to support his postulation that they had arisen from these entrapped glands. Little has been said of the origin of maxillary tumors. Metaplasia of the lining epithelium of the maxillary sinus has been considered as one possibility.6 METHODS
AND
MATERIALS
Nine cases of CMET were recovered from the files of the Department of Oral Pathology, Emory University School of Dentistry. The clinical data, radiographs, histologic material, surgical records, and follow-up information were analyzed. Not all cases demonstrated intact cortical plates, but all other criteria for CMET were met. None of the patients presented with an overlying soft-tissue mass, and all had a distinct radiolucent lesion within the maxilla or mandible. The findings in these nine casesare presented in Table I. FINDINGS
The patient group consisted of six females and three males. Seven patients were Caucasians and two were Negroes. They ranged in age from 15 to 85,
634
Brozutrrid
md
Il’aldron
Oral November,
Surg. 1975
Fig. 1. A, Marked anterior swelling in a 49-year-old Negro woman (S-63-454). H, Occlusal radiograph demonstrating a multilocular radiolucent lesion in the anterior mandible (A-63454). c, Cystic lesion in third molar region of a 70.year-old white man (S-67-557). D, Anterior mandibular central mucoepidermoid tumor in a 79-year-old Negro woman (S-73-817).
with a mean of 58.6 years. A painless swelling or enlargement of the affected area was the most common complaint. The duration of swelling prior t,o diagnosis was difficult to ascertain in most cases, but several patients gave a reliable history of a swelling for some years prior to diagnosis. Seven of our CMET’s were located in the mandible, and two were in the maxilla. Two of the mandib-
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40 5
Central
Fig. I (Co&d). E, Central mueoepidermoid Caucasian man (S-74-441). F, A large central ramus and body of the mandible in an 85-year-old
mucoepidermoid tumors of jaws
635
tumor in third molar region of a 63-year-old mucoepidermoid tumor involving the ascending Caucasian woman (S-74-468).
ular lesions were located in the anterior region, one involved the mandible from the incisor to first molar area, and four involved the third molar-ascending ramus area. Both maxillary lesions involved the posterior maxilla. RADIOGRAPHIC
FINDINGS
Radiographically, all lesions appeared as radiolucencies with reasonably well-defined although usually scalloped margins. Lesions of the anterior mandible tended to have a “soap-bubble” appearance, while posterior lesions more frequently manifested a larger vacuolated or cystic configuration. The most frequent presumptive diagnosis was ameloblastoma or odontogenic cyst. Obvious root resorption was noted in one case, and tooth displacement in another. So far as is known, no vitality tests of involved teeth were undertaken. The two maxillary lesions appeared as multilocular or cystic radiolucencies in the posterior areas, with no apparent continuity with the maxillary sinus. Three of the seven mandibular tumors appeared in the anterior areas and approached or extended into the premolar regions. A characteristic “soap-bubble”
636
Brc
Fig. 2, A, Cystic structure lined with squamous and mucous cells. (Magnification, x100.) B, LOW-PO iwer view of transition from pseudostratified columnar epithelium to str atified squamous epithelium with mucous cells. The dark object in the lumen is a bone s:picule artifact. ( Magnification, x25.) C, Higher magnification of transition area shown in B. (Magnifica .tion, x100.)
Volume Number
Xl b
E 00. rali:
40 5
Central
mucoepidermoid
tumors
(Co&‘d). D, Nests of epidermoid cells showing squamatization. Posinophilic hyaline material in cystic lumen. (Magnification, x100.) ;erial subjacent to lining epithelium. (Magnification, x100.)
of jaws
637
( [agnific .ati ion, J Eosina ‘Ph ilic
Ornl November,
surg. 1975
appcarancc was the rule. The remaining four mandibular tumors were in the ~uola~.-alvroh~s-ra~ri~ls areas and were of a radiolucc~lit multilocular form, with the> majority of the lesions remaining above the mandibular canal (Fig. 1). MICROSCOPIC
FINDINGS
Histologically, all of our tumors were classified as well differentiated or low grade, consisting of multiple cystic structures of varying size in a mature, fibrous, connective tissue stroma. The cystic structures were lined with mucous and epidermoid cells. Mucous cells were found overlying the epidermoid cells or interspersed singly or in small groups (Fig. 2, n ) . Intermediate cells were much less frequent and were noted both in the lining epithelium and as components of clusters and nests of epidermoid cells scattered throughout the stroma. Occasionally, cysts or duetlike structures were lined with thin, flat layers of squamatoid, cuboidal, columnar, or infrequently pseudostratified columnar cells with apparent cilia (Fig. 2, B and C) . An occasional t,umor would demonstrate nests of epidermoid cells with definite squamatization in evidence (Fig. 2, D). Well-defined keratin pearls were not observed in our cases. Clear cells were not unusual but were never present in great numbers. Two tumors showed evidence of papillary projections surfaced by cuboidal or columnar cells into the cystic lumina. Cholesterol-like clefts were noted in one tumor with a resultant foreign-body react,ion (histiocytes and inflammatory cells). Most tumors demonstrated a spilled mucin phenomenon; that is, pools of mucin lying free within the stroma and without a surrounding epithelial lining. As a rule, these mucin pools elicited little or no inflammatory response. One lesion comprised, in large part, these pools with scattered ductlike structures, islands, and nests of epidermoid cells. An occasional feature was a homogenous eosinophilic hyaline substance that was different in appearance from the vacuolated, basophilic, film? presentat,ion of mu&. This eosinophilic material could be seen within the lumina of ducts and cysts or lying in small round or oval areas in nests or groups of epidermoid cells (Fig. 2, E) and in one case as a dense homogenous band, 25 to 35 microns thick, subjacent to the epithelial lining of a cystic structure. This substance appears similar to the material noted by Eversole and associateP and found by them to be negative for amyloid when stained with thioflavin T and Congo red. The significance of this substance is unknown (Fig. 2, F). TREATMENT
AND
FOLLOW-UP
Various treatments were employed in the Emory cases from conservative enucleation to partial jaw resection, with only one recurrence. This occurred in a very large tumor of the anterior mandible originally treated by curettage. Recurrent tumor was noted 4 years after the original operation. Surgical re-excision resulted in a cure, and the patient was free of evidence of tumor until her death of a cerebrovascular accident in December, 1974, 7 years after her second surgical procedure, Six caseswere followed 4 or more years without evidence of recurrence, but two of these have recently been lost to follow-up. One case is less than 3 years old and two cases are approximately 1 year old.
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tumors
of jaws
639
Neither of the most recent tumors has been completely excised. In one case, the patient refused a second surgical procedure when the lesion was incompletely removed by the original enucleation. In the second case, the patient’s physician felt that the 85-year-old woman could not physically endure a surgical procedure, and she is currently being maintained by periodic drainage of the collected tumor mucin. REVIEW
OF THE LITERATURE
Although isolated examples of CMET were reported as early as 1939,15 the first comprehensive review was published in 1968 by Smith, Dahlin, and Waite,4 who reported nine casesfrom the Mayo Clinic and reviewed twenty-two previously reported examples. We have reviewed twenty-two cases included in their article. While we have same reservations that several of the older reports may not have been true examples of primary intrabony mucoepidermoid tumors, all of their caseshave been included as part of our statistical evaluation. A search of the English-language literature since the report by Smith and associates yielded an additional ten cases.1,293917,19320 One of these cases*Owas included in series of reported mucoepidermoid tumors, and detailed clinical information on this specific case was not available. The ages of reported patients ranged from 1 to 77, with an average of 43.4 years. The peak incidence occurred in the fourth and fifth decades. The age range for CMET generally coincides with that reported for mucoepidermoid tumors arising in the major and minor salivary glands. Twenty-three females and sixteen males were affected in the previously reported cases. The sex of two patients was not stated. The racial origin of many patients was not stated, and no conclusion regarding any racial predilection can be drawn. Like their counterparts in the major and minor salivary glands, many CMET’s appear to have a long duration before diagnosis and treatment. Smith and co-authors4 reported that an average duration of 5 years prior to diagnosis was not unusual. A swelling or mass, pain, and paresthesia were the most common presenting complaints. The mandible was involved in twenty-seven cases,and t,he maxilla in fourteen. A significant number of the mandibular lesions were located in third molar angle-ramus area. The maxillary lesions generally involved the molar-sinuspalatal area. No anterior maxillary lesions have been noted. The data on forty-one cases from the literature and nine cases in the present series are presented in Table II. Most reported caseshave been described as radiographically radiolucent and often multilocular. A few lesions were reported as diffusely destructive with vague or poorly defined borders. The most frequent clinical and radiographic diagnosis was ameloblastoma or dentigerous cyst. The microscopic appearance of CMET is similar to that noted in mucoepidermoid tumors arising in salivary glands. The three basic cell types are present in varying proportions, dominated mostly by mucous and epidermoid cells, with lesser numbers of intermediate cells. Although consistent criteria for grading have not been used in the cases reported in the literature, it appears
Oral Surg. November, 1975
II. Central mucoepidermoid tumors (41 casesfrom literature, Emory IJniversity School of Dentistry)
Table
Age
cases) Mean Sex Male Female Not stated (46
9 casesfrom
I-85 years years
41.5
:; 2
Location
Maxilla Mandible
Signs
and
:: symptoms or enlargement
Swelling Pain or paresthesia Drainage or exudate
25 17 4
that the vast majority of reported cases would fall into the well-differentiated category. A variety of treatments have been employed, including conservative enucleation and curettage, wide surgical excision, en bloc resection, partial and radical jaw resection with or without lymph node dissection, electrocoagulation, and radiation therapy. “Conservative” therapy has been employed in about 40 per cent of reported cases,while various forms of more extensive therapy have been used in the remaining cases. Review of the forty-one previously reported cases and the nine casesin the present series showed thirteen instances of recurrence, four instances of metastasis, and four deaths attributable to the tumor. One additional patient died of postoperative complications. All instances of metastasis were restricted to regional lymph nodes. Tumor deaths were the result of uncontrolled local growth or regional metastasis. Table III shows the outcome in relation to type of therapy for forty-one cases from the literature and the nine cases in the present report. DISCUSSION
For the purposes of patient management and estimation of prognosis, most authors have assumedthat the CMET behaves in a manner similar to its counterpart in the major and minor salivary glands. The somewhat unpredictable nature of mucoepidermoid tumors of salivary gland origin is well known. Although originally described in both benign and malignant forms,21 the occasional uncontrolled local growth and/or metastasis of a histologically benign mucoepidermoid tumor has led many to consider all of these lesions as carcinomas.** This concept is not universally accepted, and the studies of Eneroth,23 Gray and associates,z4 Thackray and Lucas,25 and Melrose and colleagueszohave shown that the majority of mucoepidermoid tumors pursue a relatively benign course and are curable when adequately treated. The results of this study demonstrate a wide variation in prognosis and response to therapy of the CMET. Among the fifty casesincluded in our study, thirteen tumors have recurred, four have metastasized, and four resulted in death
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Table
40 5
Central
III. Results of therapy in fifty
mucoepidermoid tumors of jaws
cases of central mueoepidermoid tumor
1 No. ofcases 1 Recurrence Treatment details not given Conservative treatment* Conservative treatment and radiation Marginal exoisiont Marginal excision and radiation Radical resectionS Radiation
2:
641
11
Metastasis 2
1
Deaths 2
1 ;
1 1
; 1 So
13
1
28
4
i-
*Includes enueleation, curettage, and marsupialization, with or without coagulation. t En bloc excision with margin of bone. #Hemimaxilleetomy or mandibulectomy, with or without node dissection. $One additional patient died of postoperative complications after radical resection.
of the patients. One additional death was reported as being due to postoperative complications. Three of the deaths in Smith’s study4 were caused by uncontrolled local growth of a histologically low-grade tumor. Dhawan and colleagues17 reported one death resulting from tumor metastasis and another from postsurgical complications. Of the thirteen tumors that recurred, eleven were treated initially by conservative surgical means, one was treated initially by conservative surgery plus radiation, and one had been treated by marginal resection and radiation. Of the four reported cases with metastasis, two were treated initially by conservative means, one by marginal excision, and one by radical resection. Some of the reviewed cases were published after rather short periods of follow-up, and it is possible that additional tumors may have recurred or metastasized subsequent to publication. The benign behavior of the Emory cases is in contrast to the aggressive behavior reported in some other cases. Only one of our six patients eligible for 5-year follow-up study demonstrated recurrence. The initial treatment in this patient consisted of curettage. A recurrence 4 years later was treated by limited marginal resection, and the patient remained free of the disease until her death from a cerebrovascular accident ‘7 years later. Three patients treated by enucleation and/or curettage and two treated initially by marginal or radical resection have remained free of disease for ,5 to 12 years. One patient was lost to follow-up 4 months after marginal resection. Our two most recent patients are presently being followed with persistent disease. One patient has refused further treatment after partial enucleation of the mandibular tumor, and an elderly female patient was not treated because of medical complications. The results of our study unfortunately do not present a clear picture as to the preferred therapy for the CMET. A radical surgical approach appears obviously indicated for clinically aggressive, rapidly growing lesions, particularly if the biopsy demonstrates a poorly differentiated tumor. Radiation therapy has been employed with success in some cases.4 The preferred therapy for the well-differentiated, largely cystic, and clinically slow-growing central lesion remains a matter of controversy. Alexander? and Dhawan’? and their co-authors recommend wide surgical excision as a minimum procedure. Smith’s
642
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Oral
surg.
November, 1975
group4 recommended total en bloc resection of maxillary CMET’s and stated t,hat mandibular lesions could be adequately treated by enucleation and eleetrocoagulation or by conservative local cscision. On the other hand, we hare noted good results following simple enucleation, and similar good results have been noted by others.‘, 3 The answer to this problem must await the reporting of additional cases with adequate follow-up information. Although many prefer to designate all of these tumors as “carcinomas,” we believe that the designation “mucoepidermoid tumor” is more appropriate. While some tumors may pursue an unpredictable course, the accumulating evidence indicates that the majority of mucoepidermoid tumors neither recur nor metastasize if adequately treated. As Thackray and SobinZ6 have stated: “There seems to be no more necessity to change the name to mucoepidermoid carcinoma if a tumor happens to metastasize than there is justification for calling those that have not yet done so adenomas.” REFERENCES
H. H.: Central Mucoepidermoid Tumor R. W., Duperis, R.. H., and Holton, (Carcinoma) of the Mandible, J. Oral Surg. 32: 541-547, 1974. Mucoepidermoid Tumors of Silverglade, 1~. B., Alvares, 0. F., and Olech, E.: Central the Jaws; Review of the Literature and Case Report, Cancer 22: 650.653, 1968. Schultz, W., and Whitten, J. B., Jr.: Mueoepidermoid Carcinoma in the Mandible: Report of a Case. J. Oral Sure. 27: 337-340, 1969. Smith, R: L., Dahlin, “D. C., and Waite, D. E.: Mucoepidermoid Carcinomas of the Jawbones, J. Oral Surg. 26: 387-393, 1968. Bhaskar, S. N.: Central Mucoepidermoid Tumors of the Mandible, Cancer 16: 721-726, 1963. A Textbook of Oral Pathology, ed. 3, Shafer, W. G., Hine, M. K., and Levy, B. M.: Philadelphia, 1974, W. B. Saunders Company, p. 231. Gorlin, R. J.: Potentialities of Oral Epithelium Manifest by Mandibular Dentigerous Cysts, ORAL SURG. 10: 271-284, 1957. Stafne, E. C.: Bone Cavities Situated Near the angle of the Mandible, J. Am. Dent. Assoc. 29: 1969-1972, 1942. Amaral. W. J.. and Jacobs. D. S.: Aberrant Salivarv Gland Defect in the Mandible; Report bf a Case, ORAL SUR;. 14: 748-752, 1961. U Hayes, H.: Aberrant Submaxillary Gland Tissue Presenting as a Cyst of the Jaw; Report of a Case. ORAL SURG. 14: 313-316. 1961. Richard, h. L., and Ziskind, J.: iberrant Salivary Gland Tissue in Mandible, ORAL SURG. 10: 1086-1090, 1957. Araiche. M.. and Brodc. H.: Aberrant Salivarv Gland Tissue in Mandible, ORAL SURG. 12: 727:729.,1959. ’ Miller, A. ‘S., and Winnick, M.: Salivary Gland Inclusion in the Anterior Mandible; Report of a Case With a Review of the Literature on Aberrant Salivarv ” Gland Tissue and Neoplasms, ORAL SURG. 37: 790-797, 1971. Szerlip, L. : Cystic Mucoepidermoid Tumor; Report of a Case, ORAI, SURG. 9: 584. 588, 1956. Lepp, H., cited by Hertz, J.: Mucus-Secreting Tumors of the Jaws, Acta Chir. Stand. 103: 276-292. 1952. Ito, H., Soda, T., Nakajima, T., Ono, T., and Hirose, 8.: Central Mucoepidermoid Tumor of the Mandible; Report of Case, Bull. Tokyo Med. Dent. CT&. 16: 251259, 1969. Dhawan, I. K., Bhargava, S., and Nayak, N. C., et al.: Central Salivary Gland Tumors of Jaws. Cancer 26: 211-217. 1970. Eversole, L. R., Rovin, S., and Sabes, W. R.: Mucoepidermoid Carcinoma of Minor Salivarv Glands: ReDort of 17 Cases with Follow-UD. J. Oral Surp. 30: 107-112. 1972. Eversore, L. R., gab&, W. R., and Rovin, S. : Aggr&$ive Growth &d Neoplastic’ Potential of Odontogenic Cysts, Cancer 35: 270-282, 1975. Melrose, R. J., Abrams, A. A., and Howell, F. V.: Mucoepidermoid Tumors of the Intraoral Minor Salivary Glands : A Clinicopathologic Study of 54 Cases, J. Oral Pathol. 2: 314-325. 1973. Stewart, I?. W., Foote, F. W., Jr., and Becker, W. F.: Mucoepidermoid Tumors of Salivary Glands, Ann. Surg. 122: 820-844, 1945.
1. Alexander,
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
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22. Healey, W. V., Perzin, K. H., and Smith, L.: Mucoepidermoid Carcinoma Gland Origin: Classification, Clinical-Pathologic Correlation and Results Cancer 26: 368-388, 1970. 23. Eneroth, Carl-Magnus: Histological and Clinical Aspects of Parotid Oto-Laryngol., Supp. 191, 1964. 24. Gray, J. M., Hendrix, R. C., and French, A. J.: Mucoepidermoid Tumors Glands, Cancer 16: 183-194, 1963. 25. Thackray, A. C., and Lucas, R. B.: Tumors of the Major Salivary Glands, 1974, U. 5. Armed Forces Institute of Pathology. 26. Thackray, A. C., and Sobin, L. H.: Histological Typing of Salivary (International Histological Classification of Tumors, No. 7), Geneva, 1972, Organization, p. 23.
Reprint requests to: Dr. Charles A. Waldron Emory University School 1462 Clifton Rd., N.E. Atlanta, Ga. 30322
of Dentistry
of
643
of Salivary Treatment,
Tumors, of
Acta Salivary
Washington, Gland World
Tumors Health
of
nine
cases
and
tumors of the jaws review
Blair C. Browand, D.M.D.,* and Charles Loma Linda, Calif., and Atlanta, Ga. EMORY
UNIVERSITY
SCHOOL
of the
literature
A. Waldron,
D.D.S.,
M.S.D.,**
OF DENTISTRY
Nine previously unreported cases (CMET) are presented and forty-one mandible was involved in thirty-four is more common in females and has age. Most cases occur in the fourth usually resembles an ameloblastoma logically well-differentiated lesions. therapy. Regional node metastasis died as a result of their tumors.
of
central mucoepidermoid tumor of the jaws previously reported examples are reviewed. The cases and the maxilla in sixteen. The CMET been reported in patients from 1 to 85 years of and fifth decades. Radiographically, the CMET or odontogenic cyst. Most CMET’s are histoThirteen tumors recurred after various forms of was reported in four cases, and four patients
T
he central mucoepidermoid tumor of the jaws (CMET) is an uncommon lesion, and few individual surgeons or pathologists have accumulated any significant experience with this tumor. We are presenting nine previously unpublished cases from the files of the Department of Oral Pathology, Emory University School of Dentistry. Our experience with this lesion is compared with forty-one cases previously reported. Particular attention was directed to response to therapy, incidence of recurrence, and malignant behavior. Criteria for the diagnosis of CMET have been discussed by Alexander,l Silverglade, and Schultz3 and their colleagues. These include (1) presence of intact cortical plates; (2) radiographic evidence of bone destruction; (3) histopathologic confirmation; (4) positive mucin staining; (5) absence of primary This study was supported in part by United States Public Health Service Training Grant 5-T12-CA 8001. *Former American Cancer Society Fellow in Oral Pathology, Emory University School of Dentistry; at present Graduate Student in Periodontics, Loma Linda University, School of Dentistry. **Professor and Chairman, Department of Oral Pathology.
631
Oral Surg. November, 1975 Table
I. Clinical data on nine casesof central mucoepidermoid tumors Patient
15-yr.-oldCaucasian boy
S62-513 49-yr.-old Negro woman S63-454 S6?-213
Location
Maxilla, right canine to third molar area Mandible, incisor canine area
53-yr.-old Caucasian woman s64-517
Mandible, ri t central incisor to first moPar area
56-yr.-old Caucasian woman .%I-557 70-yr.-old Caucasian man S69- 1204 58Sy;b-;$l Caucasian woman
Maxilla, left molar region Mandible, right third molar area
79-yr.-old Negro woman S73-817 63Sy;4;ozllCaucasian man
Mz$ge anterior from premolar to incisbrs Mandible, right third molar area
85-yr.-old Caucasian woman S74-468
Mandible, left body and ramus area, 5 by I cm.
Mandible, right third molar
Symptoms
and duration
Swelling of unknown duration Anterior mandibular swelling reported for 3 weeks
Bluish swelling, unknown duration, drainage Swelling of unknown duration Purulent exudate and swelling for 3 days Swelling, unknown duration Sweliin for 3 weeks, raQ0.f ucency for 15 years Swelling for 5+ years, “cyst” marsupial&d without biopsy in 1969
lesions in salivary glands or other tissues that can mimic the histologic architect,ure of salivary tumors; and (6) exclusion of an odontogenic tumor. Discussions of histogenesis have embrased three main theories for the source of origin for these tumor+ 4-G: (1) mucous metaplasia of the lining epithelium of odontogenic cysts; (2) ectopic submandibular or possibly sublingual salivary gland tissue-the so-called static bone cavity or “Stafne defect”; (3) embryologically entra.pped retromolar mucous salivary gland tissue. No single theory can adequately explain the origin of all these lesions, and it may he that all three are valid. In 1957 Go&n’ described a series of 200 dentigerous cysts in which 5.5 per cent manifested mucous cells in the lining epithelium (as demonstrated by positive mucicarmine staining). In addition, a significant number of cysts demonstrated a tendency to develop ortho- or parakeratin, sebaceous cells, respiratory (ciliated pseudostratified columnar) epithelium, and lymphoid stroma complete with germinal centers, thus lending support to the theory of pluripotentiality of these cysts. A number of central mucoepidermoid tumors have manifested clinical and radiologic similarity to these cysts and, considering the above-mentioned cell pluripotentiality, odontogenic cysts must be strongly considered as a potential source of the CMET. Many authors have elaborated on the lingual cortical defect described by Stafne in 1942.8,8, lo This lesion is variously known as the Stafne defect, latent bone cyst, or static bone cavity and is comprised of submandibular salivary gland tissue in one of three configurations. It may be completely enclosed within the mandible or connected to its parent submandibular gland by a stalk or pedicle through a defect in the lingual cortical plate. In addition, it may present as a lobe or lobule of the main gland lying in a depression in the intact lingual cortical plate of the mandible. It was originally believed that this entity
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Central
mucoepidermoid tumors of jaws 633
Radiographs Multilocular radiolucency
Treatment En bloc excision
Multilocular radiolucency (soap-bubble appearance)
1. Enucleation and curettage 2. En bloc resection
Multilocular radiolucency involving whole body of mandible 2 cm. cystic radiolucency
Mandibular resection Enucleation
No evidence of disease, 7 years
Unilocular radiolucency
Enucleation
No evidence of disease, 6 years
Unilocular radiolucency
Enucleation
No evidence of disease, 5 years
Multicystic soap-bubble radiolucency Multilocular radiolucency
Partial mandibular resection
Multilocular
Marsupialixation, no biopsy 1969, partial enucleation 1974
No evidence of disease for 5 months, then lost to follow-up Patientrefused further surgery, residual tumor present Mucin is periodically drained from lesion, physician feels that patient cannot tolerate a sureical nrocedure
radiolucency
Incomplete enucleation
hollow-up No evidenEe of disease after 12 years Recurrence after 4 years, re-excision and no evidence of disease after 7 years No evidence of disease after 6 years, then lost to follow-up
could be found only in the posterior portion of the mandible near the angle and subjacent to the mandibular canal. However, several cases of a similar phenomenon arising from the sublingual gland have been noted in the anterior mandible.ll-I3 Since several central mucoepidermoid tumors have appeared in the molar ramus area extending below the canal4 and in the anterior canine incisor areal and in three of the Emory cases,ectopic salivary inclusions are a possible source of some of these tumors. Bhaskar,5 in 1963, described the embryologic events in the development of retromolar mucous salivary glands whereby some of these glands could theoretically become entrapped within the mandible. He reported two cases of central mucoepidermoid tumor and presented evidence to support his postulation that they had arisen from these entrapped glands. Little has been said of the origin of maxillary tumors. Metaplasia of the lining epithelium of the maxillary sinus has been considered as one possibility.6 METHODS
AND
MATERIALS
Nine cases of CMET were recovered from the files of the Department of Oral Pathology, Emory University School of Dentistry. The clinical data, radiographs, histologic material, surgical records, and follow-up information were analyzed. Not all cases demonstrated intact cortical plates, but all other criteria for CMET were met. None of the patients presented with an overlying soft-tissue mass, and all had a distinct radiolucent lesion within the maxilla or mandible. The findings in these nine casesare presented in Table I. FINDINGS
The patient group consisted of six females and three males. Seven patients were Caucasians and two were Negroes. They ranged in age from 15 to 85,
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Fig. 1. A, Marked anterior swelling in a 49-year-old Negro woman (S-63-454). H, Occlusal radiograph demonstrating a multilocular radiolucent lesion in the anterior mandible (A-63454). c, Cystic lesion in third molar region of a 70.year-old white man (S-67-557). D, Anterior mandibular central mucoepidermoid tumor in a 79-year-old Negro woman (S-73-817).
with a mean of 58.6 years. A painless swelling or enlargement of the affected area was the most common complaint. The duration of swelling prior t,o diagnosis was difficult to ascertain in most cases, but several patients gave a reliable history of a swelling for some years prior to diagnosis. Seven of our CMET’s were located in the mandible, and two were in the maxilla. Two of the mandib-
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Fig. I (Co&d). E, Central mueoepidermoid Caucasian man (S-74-441). F, A large central ramus and body of the mandible in an 85-year-old
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tumor in third molar region of a 63-year-old mucoepidermoid tumor involving the ascending Caucasian woman (S-74-468).
ular lesions were located in the anterior region, one involved the mandible from the incisor to first molar area, and four involved the third molar-ascending ramus area. Both maxillary lesions involved the posterior maxilla. RADIOGRAPHIC
FINDINGS
Radiographically, all lesions appeared as radiolucencies with reasonably well-defined although usually scalloped margins. Lesions of the anterior mandible tended to have a “soap-bubble” appearance, while posterior lesions more frequently manifested a larger vacuolated or cystic configuration. The most frequent presumptive diagnosis was ameloblastoma or odontogenic cyst. Obvious root resorption was noted in one case, and tooth displacement in another. So far as is known, no vitality tests of involved teeth were undertaken. The two maxillary lesions appeared as multilocular or cystic radiolucencies in the posterior areas, with no apparent continuity with the maxillary sinus. Three of the seven mandibular tumors appeared in the anterior areas and approached or extended into the premolar regions. A characteristic “soap-bubble”
636
Brc
Fig. 2, A, Cystic structure lined with squamous and mucous cells. (Magnification, x100.) B, LOW-PO iwer view of transition from pseudostratified columnar epithelium to str atified squamous epithelium with mucous cells. The dark object in the lumen is a bone s:picule artifact. ( Magnification, x25.) C, Higher magnification of transition area shown in B. (Magnifica .tion, x100.)
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(Co&‘d). D, Nests of epidermoid cells showing squamatization. Posinophilic hyaline material in cystic lumen. (Magnification, x100.) ;erial subjacent to lining epithelium. (Magnification, x100.)
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appcarancc was the rule. The remaining four mandibular tumors were in the ~uola~.-alvroh~s-ra~ri~ls areas and were of a radiolucc~lit multilocular form, with the> majority of the lesions remaining above the mandibular canal (Fig. 1). MICROSCOPIC
FINDINGS
Histologically, all of our tumors were classified as well differentiated or low grade, consisting of multiple cystic structures of varying size in a mature, fibrous, connective tissue stroma. The cystic structures were lined with mucous and epidermoid cells. Mucous cells were found overlying the epidermoid cells or interspersed singly or in small groups (Fig. 2, n ) . Intermediate cells were much less frequent and were noted both in the lining epithelium and as components of clusters and nests of epidermoid cells scattered throughout the stroma. Occasionally, cysts or duetlike structures were lined with thin, flat layers of squamatoid, cuboidal, columnar, or infrequently pseudostratified columnar cells with apparent cilia (Fig. 2, B and C) . An occasional t,umor would demonstrate nests of epidermoid cells with definite squamatization in evidence (Fig. 2, D). Well-defined keratin pearls were not observed in our cases. Clear cells were not unusual but were never present in great numbers. Two tumors showed evidence of papillary projections surfaced by cuboidal or columnar cells into the cystic lumina. Cholesterol-like clefts were noted in one tumor with a resultant foreign-body react,ion (histiocytes and inflammatory cells). Most tumors demonstrated a spilled mucin phenomenon; that is, pools of mucin lying free within the stroma and without a surrounding epithelial lining. As a rule, these mucin pools elicited little or no inflammatory response. One lesion comprised, in large part, these pools with scattered ductlike structures, islands, and nests of epidermoid cells. An occasional feature was a homogenous eosinophilic hyaline substance that was different in appearance from the vacuolated, basophilic, film? presentat,ion of mu&. This eosinophilic material could be seen within the lumina of ducts and cysts or lying in small round or oval areas in nests or groups of epidermoid cells (Fig. 2, E) and in one case as a dense homogenous band, 25 to 35 microns thick, subjacent to the epithelial lining of a cystic structure. This substance appears similar to the material noted by Eversole and associateP and found by them to be negative for amyloid when stained with thioflavin T and Congo red. The significance of this substance is unknown (Fig. 2, F). TREATMENT
AND
FOLLOW-UP
Various treatments were employed in the Emory cases from conservative enucleation to partial jaw resection, with only one recurrence. This occurred in a very large tumor of the anterior mandible originally treated by curettage. Recurrent tumor was noted 4 years after the original operation. Surgical re-excision resulted in a cure, and the patient was free of evidence of tumor until her death of a cerebrovascular accident in December, 1974, 7 years after her second surgical procedure, Six caseswere followed 4 or more years without evidence of recurrence, but two of these have recently been lost to follow-up. One case is less than 3 years old and two cases are approximately 1 year old.
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Neither of the most recent tumors has been completely excised. In one case, the patient refused a second surgical procedure when the lesion was incompletely removed by the original enucleation. In the second case, the patient’s physician felt that the 85-year-old woman could not physically endure a surgical procedure, and she is currently being maintained by periodic drainage of the collected tumor mucin. REVIEW
OF THE LITERATURE
Although isolated examples of CMET were reported as early as 1939,15 the first comprehensive review was published in 1968 by Smith, Dahlin, and Waite,4 who reported nine casesfrom the Mayo Clinic and reviewed twenty-two previously reported examples. We have reviewed twenty-two cases included in their article. While we have same reservations that several of the older reports may not have been true examples of primary intrabony mucoepidermoid tumors, all of their caseshave been included as part of our statistical evaluation. A search of the English-language literature since the report by Smith and associates yielded an additional ten cases.1,293917,19320 One of these cases*Owas included in series of reported mucoepidermoid tumors, and detailed clinical information on this specific case was not available. The ages of reported patients ranged from 1 to 77, with an average of 43.4 years. The peak incidence occurred in the fourth and fifth decades. The age range for CMET generally coincides with that reported for mucoepidermoid tumors arising in the major and minor salivary glands. Twenty-three females and sixteen males were affected in the previously reported cases. The sex of two patients was not stated. The racial origin of many patients was not stated, and no conclusion regarding any racial predilection can be drawn. Like their counterparts in the major and minor salivary glands, many CMET’s appear to have a long duration before diagnosis and treatment. Smith and co-authors4 reported that an average duration of 5 years prior to diagnosis was not unusual. A swelling or mass, pain, and paresthesia were the most common presenting complaints. The mandible was involved in twenty-seven cases,and t,he maxilla in fourteen. A significant number of the mandibular lesions were located in third molar angle-ramus area. The maxillary lesions generally involved the molar-sinuspalatal area. No anterior maxillary lesions have been noted. The data on forty-one cases from the literature and nine cases in the present series are presented in Table II. Most reported caseshave been described as radiographically radiolucent and often multilocular. A few lesions were reported as diffusely destructive with vague or poorly defined borders. The most frequent clinical and radiographic diagnosis was ameloblastoma or dentigerous cyst. The microscopic appearance of CMET is similar to that noted in mucoepidermoid tumors arising in salivary glands. The three basic cell types are present in varying proportions, dominated mostly by mucous and epidermoid cells, with lesser numbers of intermediate cells. Although consistent criteria for grading have not been used in the cases reported in the literature, it appears
Oral Surg. November, 1975
II. Central mucoepidermoid tumors (41 casesfrom literature, Emory IJniversity School of Dentistry)
Table
Age
cases) Mean Sex Male Female Not stated (46
9 casesfrom
I-85 years years
41.5
:; 2
Location
Maxilla Mandible
Signs
and
:: symptoms or enlargement
Swelling Pain or paresthesia Drainage or exudate
25 17 4
that the vast majority of reported cases would fall into the well-differentiated category. A variety of treatments have been employed, including conservative enucleation and curettage, wide surgical excision, en bloc resection, partial and radical jaw resection with or without lymph node dissection, electrocoagulation, and radiation therapy. “Conservative” therapy has been employed in about 40 per cent of reported cases,while various forms of more extensive therapy have been used in the remaining cases. Review of the forty-one previously reported cases and the nine casesin the present series showed thirteen instances of recurrence, four instances of metastasis, and four deaths attributable to the tumor. One additional patient died of postoperative complications. All instances of metastasis were restricted to regional lymph nodes. Tumor deaths were the result of uncontrolled local growth or regional metastasis. Table III shows the outcome in relation to type of therapy for forty-one cases from the literature and the nine cases in the present report. DISCUSSION
For the purposes of patient management and estimation of prognosis, most authors have assumedthat the CMET behaves in a manner similar to its counterpart in the major and minor salivary glands. The somewhat unpredictable nature of mucoepidermoid tumors of salivary gland origin is well known. Although originally described in both benign and malignant forms,21 the occasional uncontrolled local growth and/or metastasis of a histologically benign mucoepidermoid tumor has led many to consider all of these lesions as carcinomas.** This concept is not universally accepted, and the studies of Eneroth,23 Gray and associates,z4 Thackray and Lucas,25 and Melrose and colleagueszohave shown that the majority of mucoepidermoid tumors pursue a relatively benign course and are curable when adequately treated. The results of this study demonstrate a wide variation in prognosis and response to therapy of the CMET. Among the fifty casesincluded in our study, thirteen tumors have recurred, four have metastasized, and four resulted in death
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III. Results of therapy in fifty
mucoepidermoid tumors of jaws
cases of central mueoepidermoid tumor
1 No. ofcases 1 Recurrence Treatment details not given Conservative treatment* Conservative treatment and radiation Marginal exoisiont Marginal excision and radiation Radical resectionS Radiation
2:
641
11
Metastasis 2
1
Deaths 2
1 ;
1 1
; 1 So
13
1
28
4
i-
*Includes enueleation, curettage, and marsupialization, with or without coagulation. t En bloc excision with margin of bone. #Hemimaxilleetomy or mandibulectomy, with or without node dissection. $One additional patient died of postoperative complications after radical resection.
of the patients. One additional death was reported as being due to postoperative complications. Three of the deaths in Smith’s study4 were caused by uncontrolled local growth of a histologically low-grade tumor. Dhawan and colleagues17 reported one death resulting from tumor metastasis and another from postsurgical complications. Of the thirteen tumors that recurred, eleven were treated initially by conservative surgical means, one was treated initially by conservative surgery plus radiation, and one had been treated by marginal resection and radiation. Of the four reported cases with metastasis, two were treated initially by conservative means, one by marginal excision, and one by radical resection. Some of the reviewed cases were published after rather short periods of follow-up, and it is possible that additional tumors may have recurred or metastasized subsequent to publication. The benign behavior of the Emory cases is in contrast to the aggressive behavior reported in some other cases. Only one of our six patients eligible for 5-year follow-up study demonstrated recurrence. The initial treatment in this patient consisted of curettage. A recurrence 4 years later was treated by limited marginal resection, and the patient remained free of the disease until her death from a cerebrovascular accident ‘7 years later. Three patients treated by enucleation and/or curettage and two treated initially by marginal or radical resection have remained free of disease for ,5 to 12 years. One patient was lost to follow-up 4 months after marginal resection. Our two most recent patients are presently being followed with persistent disease. One patient has refused further treatment after partial enucleation of the mandibular tumor, and an elderly female patient was not treated because of medical complications. The results of our study unfortunately do not present a clear picture as to the preferred therapy for the CMET. A radical surgical approach appears obviously indicated for clinically aggressive, rapidly growing lesions, particularly if the biopsy demonstrates a poorly differentiated tumor. Radiation therapy has been employed with success in some cases.4 The preferred therapy for the well-differentiated, largely cystic, and clinically slow-growing central lesion remains a matter of controversy. Alexander? and Dhawan’? and their co-authors recommend wide surgical excision as a minimum procedure. Smith’s
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group4 recommended total en bloc resection of maxillary CMET’s and stated t,hat mandibular lesions could be adequately treated by enucleation and eleetrocoagulation or by conservative local cscision. On the other hand, we hare noted good results following simple enucleation, and similar good results have been noted by others.‘, 3 The answer to this problem must await the reporting of additional cases with adequate follow-up information. Although many prefer to designate all of these tumors as “carcinomas,” we believe that the designation “mucoepidermoid tumor” is more appropriate. While some tumors may pursue an unpredictable course, the accumulating evidence indicates that the majority of mucoepidermoid tumors neither recur nor metastasize if adequately treated. As Thackray and SobinZ6 have stated: “There seems to be no more necessity to change the name to mucoepidermoid carcinoma if a tumor happens to metastasize than there is justification for calling those that have not yet done so adenomas.” REFERENCES
H. H.: Central Mucoepidermoid Tumor R. W., Duperis, R.. H., and Holton, (Carcinoma) of the Mandible, J. Oral Surg. 32: 541-547, 1974. Mucoepidermoid Tumors of Silverglade, 1~. B., Alvares, 0. F., and Olech, E.: Central the Jaws; Review of the Literature and Case Report, Cancer 22: 650.653, 1968. Schultz, W., and Whitten, J. B., Jr.: Mueoepidermoid Carcinoma in the Mandible: Report of a Case. J. Oral Sure. 27: 337-340, 1969. Smith, R: L., Dahlin, “D. C., and Waite, D. E.: Mucoepidermoid Carcinomas of the Jawbones, J. Oral Surg. 26: 387-393, 1968. Bhaskar, S. N.: Central Mucoepidermoid Tumors of the Mandible, Cancer 16: 721-726, 1963. A Textbook of Oral Pathology, ed. 3, Shafer, W. G., Hine, M. K., and Levy, B. M.: Philadelphia, 1974, W. B. Saunders Company, p. 231. Gorlin, R. J.: Potentialities of Oral Epithelium Manifest by Mandibular Dentigerous Cysts, ORAL SURG. 10: 271-284, 1957. Stafne, E. C.: Bone Cavities Situated Near the angle of the Mandible, J. Am. Dent. Assoc. 29: 1969-1972, 1942. Amaral. W. J.. and Jacobs. D. S.: Aberrant Salivarv Gland Defect in the Mandible; Report bf a Case, ORAL SUR;. 14: 748-752, 1961. U Hayes, H.: Aberrant Submaxillary Gland Tissue Presenting as a Cyst of the Jaw; Report of a Case. ORAL SURG. 14: 313-316. 1961. Richard, h. L., and Ziskind, J.: iberrant Salivary Gland Tissue in Mandible, ORAL SURG. 10: 1086-1090, 1957. Araiche. M.. and Brodc. H.: Aberrant Salivarv Gland Tissue in Mandible, ORAL SURG. 12: 727:729.,1959. ’ Miller, A. ‘S., and Winnick, M.: Salivary Gland Inclusion in the Anterior Mandible; Report of a Case With a Review of the Literature on Aberrant Salivarv ” Gland Tissue and Neoplasms, ORAL SURG. 37: 790-797, 1971. Szerlip, L. : Cystic Mucoepidermoid Tumor; Report of a Case, ORAI, SURG. 9: 584. 588, 1956. Lepp, H., cited by Hertz, J.: Mucus-Secreting Tumors of the Jaws, Acta Chir. Stand. 103: 276-292. 1952. Ito, H., Soda, T., Nakajima, T., Ono, T., and Hirose, 8.: Central Mucoepidermoid Tumor of the Mandible; Report of Case, Bull. Tokyo Med. Dent. CT&. 16: 251259, 1969. Dhawan, I. K., Bhargava, S., and Nayak, N. C., et al.: Central Salivary Gland Tumors of Jaws. Cancer 26: 211-217. 1970. Eversole, L. R., Rovin, S., and Sabes, W. R.: Mucoepidermoid Carcinoma of Minor Salivarv Glands: ReDort of 17 Cases with Follow-UD. J. Oral Surp. 30: 107-112. 1972. Eversore, L. R., gab&, W. R., and Rovin, S. : Aggr&$ive Growth &d Neoplastic’ Potential of Odontogenic Cysts, Cancer 35: 270-282, 1975. Melrose, R. J., Abrams, A. A., and Howell, F. V.: Mucoepidermoid Tumors of the Intraoral Minor Salivary Glands : A Clinicopathologic Study of 54 Cases, J. Oral Pathol. 2: 314-325. 1973. Stewart, I?. W., Foote, F. W., Jr., and Becker, W. F.: Mucoepidermoid Tumors of Salivary Glands, Ann. Surg. 122: 820-844, 1945.
1. Alexander,
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
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22. Healey, W. V., Perzin, K. H., and Smith, L.: Mucoepidermoid Carcinoma Gland Origin: Classification, Clinical-Pathologic Correlation and Results Cancer 26: 368-388, 1970. 23. Eneroth, Carl-Magnus: Histological and Clinical Aspects of Parotid Oto-Laryngol., Supp. 191, 1964. 24. Gray, J. M., Hendrix, R. C., and French, A. J.: Mucoepidermoid Tumors Glands, Cancer 16: 183-194, 1963. 25. Thackray, A. C., and Lucas, R. B.: Tumors of the Major Salivary Glands, 1974, U. 5. Armed Forces Institute of Pathology. 26. Thackray, A. C., and Sobin, L. H.: Histological Typing of Salivary (International Histological Classification of Tumors, No. 7), Geneva, 1972, Organization, p. 23.
Reprint requests to: Dr. Charles A. Waldron Emory University School 1462 Clifton Rd., N.E. Atlanta, Ga. 30322
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