Solid adenoid cystic carcinoma maxilla Deborah Cleveland, DDS,a Albert M. Abrams, DDS, II~S,~ Raymond and Janice P. Handlers, DDS,d Los Angeles, Calif SCHOOL
OF DENTISTRY,
UNIVERSITY
OF SOUTHERN
of the J. Melrose,
DDS,”
CALIFORNIA
Seven cases of solid variant of adenoid cystic carcinoma of the maxilla are reported. Clinical and radiographic characteristics disproportionate
suggest origin within the maxillary alveolar bone. Swelling was minimal and
to the extensive, diffuse bone destruction universally present. Histologic features were
typical of this neoplasm occurring in other sites and consisted of diffusely infiltrating islands of small, closely packed monomorphous cells with sparse cytoplasm, indistinct borders, and small hyperchromatic nuclei. Four of five patients with follow-up data died of their disease. This confirms the lethality of the solid variant. Rationale is presented for considering these malignancies to be of primary intraosseous origin. (ORAL SURC ORAL MED ORAL PATHOL 1990;69:470-8)
A
denoid cystic carcinoma (ACC) of salivary gland origin has been classically described as an indolent, slowly growing tumor typified by persistent growth behavior with repeated local recurrences after therapeutic intervention. Distant metastases and regional lymphatic spread may occur as late sequelae, with the patient often dying of disease, sometimes many years after the original diagnosis. The tumor displays a distinctive cribriform histomorphology, often described as “Swiss cheese” or “sievelike”; however, this terminology has proved inadequate in expressing the wide spectrum of histologic diversity that may be seen. In addition to the more characteristic cribriform architecture, areas of tubular differentiation, or of solid cellular growth, may be observed. Several authors have attempted to correlate the histopathologic subtype with the tumor’s unpredictable and deceptive growth behavior. l-l3 Although some studies have found the histologic grading of ACCs unreliable in predicting clinical course of disease,9, 11, l2 most recent data support the view that the predominance of
aFormer Resident in Oral Pathology at USC and currently tant Professor of Pathology, Temple University. bProfessor and Chairman, Section of Pathology. CProfessor of Pathology. “Associate Professor of Pathology. 7/14/19032
470
Assis-
solid growth pattern is a significant microscopic finding; these tumors are found to be unusually aggressive and are associated with a short clinical course and exceedingly poor prognosis.‘-*, “3 l3 ACCs of minor salivary glands most commonly arise within the soft tissues of the hard and soft palates but are also known to develop from mucous glands of the upper aerodigestive tract, including the nasal cavity and paranasal sinuses. The usual complaint is that of an asymptomatic mass or palpable, tumorous growth. 1,3,4, 6 1’ Although invasion into contiguous bony structures occurs with some frequency, it is generally not the preeminent clinical feature at the time of diagnosis, especially in the absence of obvious tumor. In fact, descriptions by previous authors have noted the striking lack of bone destruction by virtue of the neoplasm’s propensity for infiltration of the marrow spaces while leaving the basic trabecular architecture intact.3q 14-16Consequently, there may be little or no perceptible radiographic changes in the involved areas. The purpose of this article is to present the clinical and histopathologic data from seven additional cases of solid variant ACC of the upper jaw. In each case, the most prominent feature was the remarkable amount of atypical bone destruction seen radiographically, the extent of which was disproportionate to other presenting signs and symptoms. This distinctive combination of clinical, radiographic, and histologic
a
Solid adenoid cystic carcinoma of maxilla
Volume 69 Number 4 Table
471
1.Clinical features Presenting signs and symptoms
Patient
Age, sex
C.S.
80, M
Anterior maxilla with bilateral posterior extension
Loose teeth x 6 mo., acute onset pain, slight swelling
A.R.
50, F
Left posterior maxilla
Swelling X several weeks
J.R.
78, M
Right maxillary
H.A.
14, F
Right posterior maxilla and sinus
E.R.
59, F
Left posterior maxilla and sinus
Incidental radiographic finding 1 year before diagnosis Pain, swelling, anesthesia, diplopia, and headache X several weeks Loose teeth, nonhealing extraction site
H.S. S.H.
39, M 57, M
Right posterior maxilla Left posterior maxilla
Primary
site
sinus
Radiographic
Loose teeth, anesthesia ND*
jindings
Complete bone destruction no. 6-no. 13; slight root resorption Lytic destruction alveolar ridge no. 1 I-tuberosity Radiolucency involving maxillary sinus Lytic destruction right maxillary antrum and right ethmoidal complex Diffuse, lytic destruction no. 11 to tuberosity involving maxillary sinus; “floating teeth” Lytic destruction Large, lytic lesion associated with no. 14; root resorption
*ND. no data
features suggests to us primary origin within the maxillary alveolar bone, an unusual location that has received little attention in the literature. MATERIAL
AND METHODS
Microscopic sections from biopsy specimens of malignant salivary gland tumors of the upper jaw accessioned in the University of Southern California Oral Pathology Laboratory since 1973 and having original diagnoses of adenoid cystic carcinoma and adenocarcinoma were reexamined. Additionally, casesclassified as lobular carcinoma and undifferentiated carcinoma were reviewed. Out of a total of 75 cases,7 were determined to fulfill the histopathologic criteria of ACC solid variant and formed the basis for this study. One of the caseswas seen in consultation from Dr. Roman Carlos, Servicio De Diagnostic0 Clinica y Patologica, Guatemala, Central America. RESULTS Clinical features
(Table I)
There was no significant sex predilection; the male-to-female ratio was 4:3. The age at time of diagnosisranged from 39 to 80 years, with a mean age of 62 years. All tumors were located within the maxilla-six casesin the posterior maxilla, and one that showedthe greatest amount of destruction in the anterior segmentwith bilateral posterior extension (Fig. 1). Although expansion or swelling of the alveolar ridge was an associated clinical finding in two cases, in only one instance was a soft tissue mass the
patient’s chief complaint. The most common presenting sign was tooth hypermobility (three patients). Other clinical findings included pain (two patients) and anesthesia (two patients). One patient complained of diplopia and headache associated with the right periorbital area. Only one patient was without symptoms, the lesion being discovered incidentally on routine radiographic examination. Radiographically, the lesions were usually described as a diffuse, destructive lytic process of the maxillary bone, with or without evidence of sinus involvement. Radiographs of those patients seeking dental treatment for loose teeth demonstrated “floating teeth,” and in one instance root resorption was a feature (Figs. 1 and 2). Histopathologic
features
In all cases,the histologic appearance was that of a diffusely infiltrating neoplasm composed of undifferentiated, darkly staining cells arranged predominantly into solid islands of varying size (Figs. 3 and 4). Cytologically, the tumor cells comprising these solid areas were distinctly monomorphous and did not exhibit the nuclear pleomorphism that has been previously described by other investigators.*, lo, i7 Nuclei were small, averaging 8 to 10 pm in diameter, round to ovoid, and were characterized by a fine, evenly dispersed chromatin pattern with occasional, indistinct nucleoli. Typically, the cells were closely packed, showing scanty, ill-defined, pale cytoplasm (Fig. 5). Occasionally, this solid arrangement of tumor cells
472
Cleveland
et al.
ORAL
SURG
ORAL
MED
ORAL PATHOL April 1990
Fig. 2. CaseE.R. Diffusebonedestructionand“floating” premolar in a 59-year-oldwoman.
Fig. 1. Case C.S. Destructive tumor growth featuring extensivebonelossin an 80-year-oldman. A andB feature “floating” teeth, and C revealstumor growth in both sides of the maxilla.
was interrupted by the presence of pseudocysts, or of ductlike structures lined with a single layer of cuboida1 cells that, in some instances, contained scant amounts of an amorphous, faintly eosinophilic material. I, zip ;f tliti Jbv~l~ babe>, ihs iurnora also featured neoplastic cells forming small tubular structures with
minimal stratification of the lining epithelium. In two cases, areas of more typical cribriforming were observed (Fig. 6). Although present in varying degrees, these two features were never a predominant characteristic and accounted for no more than 30% of the available tissue examined for any one case. Stromal hyalinization, which has been described as a peculiar characteristic of ACC, was an inconstant feature, being present focally in only two cases. Instead, the stroma was generally loose, of variable cellularity, and in some cases showed a striking degree of vascularity. Focal stromal mucinosis was evident in two cases. Mitoses were present in all cases to a variable extent, but no atypical forms were observed. Necrosis, a feature often described in association with solid ACC, was seen in four of the seven cases, either as comedo type or individual cell necrosis, and was usually associated with the larger tumor islands (Fig. 7). Surprisingly, perineural invasion, a noted characteristic of ACC, was observed in only one case. In the
Volume 69 Number 4
Solid adenoid cystic carcinoma of maxilla
473
Fig. 3. Low-power view of several variable sized cellular aggregates typical of solid adenoid cystic carcix40.)
noma. (H&E stain. Original magnification,
Fig. 4. Solid islands of tumor with minimal ductlike structure formation. (H&E stain. Original magnification, X 100.)
remaining cases, no nerves were identified, and it may be that the limited amount of tissue available for study precluded evaluation of this feature. Squamous metapiasia was found in one case (E.R.), a feature
bone destruction as well as intertrabecular
infiltration
that is rarely, if ever, described in ACC of salivary gland origin, but which was recently reported in an adenoid cystic-like tumor of the prostate gland.18 Microscopic verification of bone involvement was seen in five cases, four of which demonstrated actual
Follow-up data were obtained for five of seven patients. One of these (J.R.) has remained alive and without evidence of disease since receiving radiation treatment in 198 1. The remaining four patients died of their disease because of local extension or metasta-
of tumor within marrow spaces (Fig. 8). Follow-up data (Table II)
474
Cleveland et al.
ORAL
SURG
ORAL
MED
ORAL PATHOL April 1990
Fig. 5. Solid massof tumor cellswith smallnuclei containing evenly dispersedfine chromatin.Cytoplasm is scanty. (H&E stain. Original magnification, X300.)
6. Tumor aggregatesdisplayingcribriform morphology.This wasa minor componentin thesetumors. (H&E stain. Original magnification, X100.)
Fig.
sis. The time interval between the original histologic diagnosis and death ranged from 14 to 28 months. Only one (H.S.) received primary surgical treatment consisting of hemimaxillectomy and orbital exenteration; extensive local recurrence was treated by chemotherapy without success, and the patient died within 4 months. The exclusive therapy for the remaining three pa+‘--‘LIIIILU ;;-i%i;, &, group consisted of irradiation. One of these (H.A.) experienced recurrent local disease 13 months after therapy, complicated by a large, right
pleural effusion and space-occupying lesions of the liver of unknown significance as identified by computed tomography. Although not verified by examinations before or after death, these latter two findings suggest visceral metastasis to lung and liver. A second patient (C.S.) had metastases to lung, bone, and regional lymph nodes within 21 months of initial radiation treatment, with ensuing congestive heart failure and pleural effusion believed to be secondary to pulmonary metastases. The third patient (E.R.) was dead of disease within 22 months of original diagno-
Solid adenoid cystic carcinoma of maxilla
Volume 69 Number 4
Fig. 7. Early cellular magnification, X 150.)
necrosis in center
of
solid mass of adenoid
Fig. 8. Tumor islands infiltrating between bone trabeculae stain. Original magnification, X 100.)
sis and following radiation treatment without adjunctive therapy. In none of these cases were autopsies performed.
Our study confirms the experience of previous investigators that the predominance of a solid pattern in ACC of the head and neck is an alarming microscopic finding, portending a higher grade malignancy characterized by rapid growth, early local recurrence, and metastasis.‘-s. lo, l3 In the present investigation, four
cystic carcinoma.
and adjacent
(H&E
47s
stain. Original
to tooth root, top right. (H&E
of five patients for whom we were able to obtain follow-up information were dead of their disease within 2% years from the time of original diagnosis. Areas of solid, cellular growth have been recognized as contributing to the overafl histologic spectrum of .4CC since some of the earliest microscopic descriptions. However, the clinical relevance of this remained obscure for many years. In 1958, Patey and Thackray” were the first to suggest that a higher grade malignancy with rapid local spread and metastasis may be associated with this solid predominant
476
Cleveland et al.
Table
II. Clinical
Patient
ORAL
course, treatment, Initial
Irradiation
A.R. J.R. H.A. E.R. H.S.
ND* Irradiation lrradiation Irradiation Right hemimaxillectomy orbital exenteration Partial maxillectomy
S.H.
ORAL
MED ORAL PATHOL April 1990
and follow-up
treatment
C.S.
SURG
Metastasis
and
Local
Bone, lungs, regional lymph nodes ND None ?lung, ?liver I .2 years ND None ND
recurrence
Follow-up
None
DODt
ND None I .2 years ND 0.75 years (treated ND
ND Alive DOD DOD DOD
2.3 years
7 years 1.3 years 1.8 iears 1.2 years
by chemotherapy) ND
*ND, no data. TDOD,
dead
of disease.
pattern that they designated as spheroidal cell carcinomata. Soon after, in 1961, James Stewart14 described a more malignant variant of ACC that exhibited a “large cell pattern” associated with central necrosis of the cellular masses and a more aggressive infiltrating behavior; both patients whose palatal tumors displayed these microscopic features were dead of their disease within 2 years of presentation. Eneroth and associates,’ on the basis of their observations that five of seven patients with poorly differentiated palatal tumors had died of their disease within 3 years, urged that ACCs be graded clinically into high- and low-grade malignant types. Eby and coworkers,3 in their review of 54 cases of head and neck ACC, recognized two distinctive subgroups based on biologic behavior: seven of nine patients remarkable for a fulminating clinical course and terminating in a fatal outcome in less than 3 years had tumors with areas of solid, cellular growth described as basaloid or anaplastic. The work that stands out as most convincing in establishing the clinical significance of the solid variant is that of Perzin and colleagues.6 In their study of 62 ACCs of major and minor salivary gland origin, which examined the impact of several parameters on clinical course (including histologic pattern, tumor size, primary site, lymph node metastasis, adequacy of surgical margins, and cellular atypia), they found that the solid predominant pattern represented the least differentiated form of ACC and carried the worst prognosis when >30% of the neoplasm demonstrated this pattern. They also described a welldifferentiated form of the disease, manifesting a tubular predominant pattern, which was associated with the best prognosis. ACCs occur in both the major and minor salivary glands as well as in association with mucous glands found scattered throughout the tracheobronchial tree aLI: U~,PGI azlvdigestive tract. It is generally considered to be the most common malignancy of the intraoral minor salivary glands, with a propensity for
development from glands of the hard and soft palates. The anatomic site of the primary tumor is known to dramatically alter survival data.6, 7, ’ ‘-I3 Although there is disagreement as to which sites carry a better prognosis, some authors agree that minor gland ACCs, especially those of the maxillary antrum and nasal cavity, behave more aggressively than others.4-6, 8, ‘I, I*, I7 Contiguity to vital anatomic structures, tumor size, late stage of detection, and the inability to gain adequate surgical margins free of tumor have been cited as contributing to the overall poorer prognosis for patients having tumors in these locations.13 These factors are compounded by the natural proclivity of ACCs toward infiltration along fascial planes and extensive perineural spread. Anatomic location and size of the primary tumor may also be related to histologic subtype although the significance of this remains unclear. Gullane and Conley *O found a predominance of cribriform and solid patterns in ACCs of the maxillary sinus. Perzin and coworker& reported cribriform and solid variants dominating in ACCs arising from minor glands of the nasal cavity and paranasal sinuses but additionally noted that tumors in these locations were larger and more extensive than better differentiated histologic forms. These data were supported in the study by Szanto and associates,* who showed that solid variant ACCs were larger, recurred frequently, and had an aggressive clinical course, usually killing the patients within 4 years. Perzin and colleagues6 have hypothesized a histologic evolution in the growth of these tumors, suggesting that as the neoplasm proliferates it evolves from the better differentiated tubular structures to cribriforming units followed by the eventual overgrowth of the individual lumina by areas of solid, cellular growth. The cases presented in this communication are unusual for the extent of atypical destruction of the maxillary alveolar bone. In most cases, this was the preeminent clinical feature, disproportionate to other
Solid adenoid cystic carcinoma of maxilla
Volume 69 Number 4
presenting signs and symptoms. Bone involvement is a well-known characteristic of ACC; however, its significance has received little attention in the literature. In their study of 242 cases of ACC of major and minor salivary glands, Spiro and colleagues” found a positive correlation between bone invasion and survival: of 75 minor salivary gland tumors demonstrating bone invasion, the lo-year determinant “cure” rate was 7% as compared to 32% for 65 minor salivary gland neoplasms not showing this feature. Szanto and colleagues* considered bone invasion to be an ominous finding. Of 38 cases of ACC in which bone sections were made available for examination, 24 showed bone involvement, with only one patient free of tumor at the termination of their study. In both reports, an asymptomatic swelling was stated to be the most common presenting symptom; however, radiographic findings were not included as part of their studies. Although swelling was noted in some of our cases, the extent of bone destruction seen radiographically makes it seem unlikely that the neoplasms arose primarily from the mucous glands of the hard and soft palates with secondary bone involvement without greater evidence of an actual tumor mass. Origin in the minor glands of the maxillary antrum or paranasal sinuses is another possibility. However, the constellation of signs and symptoms usually associated with ACCs arising in these locations including prominent pain, nasal complaints (discharge, obstruct&, epistaxis), significant cheek swelling, anesthesia, and visual disturbances was exhibited by only one of the patients in the present study. Our data suggest to us a primary intraosseous origin within the maxilla for the cases being reported. Salivary gland tumors are known to arise centrally within the jawbones but are considered uncommon. The tumor most frequently reported is the central mucoepidermoid tumor (CMET) occurring most commonly in the posterior mandible.*” 22 They occur with less frequency in the anterior mandible and in the molar-sinus-palatal area of the maxilla.22 There have been no reported cases of CMET in the anterior maxilla. Histogenetically, they are thought to arise from intrabony enclavements of heterotopic salivary gland tissue, from mucous glandular inclusions within the retromolar pad area, or from mucous metaplasia within the lining epithelium of odontogenic cysts.2’. 22 Within the maxilla, similar inclusions of salivary gland tissue may exist but have not yet been reported as such. Mucous glands, however, are known to be constituents of the incisive canal and have been reported in as many as 3 1% of nasopalatine duct cysts by Abrams and associates.23 That such glands may have been the origin of the tumor in one of our patients
477
(C.S.) is suggested by the degree of bone destruction of the anterior maxilla seen radiographically without evidence of a tumor mass. Primary intraosseous ACCs are rare. A review of the English-language literature revealed a total of 20 cases of ACCs of the jawbones, 8 of which occurred in the maxilla. 16,24-30Whereas specific criteria have been defined by previous authors in the diagnosis of CMET (including intact cortical plates, radiographic evidence of bone destruction, histopathologic confirmation, and the exclusion of metastatic disease3’* 32), no such criteria exist for the diagnosis of central ACC. Within the maxilla, this assessment is made especially difficult by the prevalence of minor salivary glands scattered throughout the antral and nasal mucous membranes. Without correlation of radiographic and clinical features, a lesion interpreted as originating within the maxilla may, in reality, be a tumor of mucosal origin with secondary bone involvement. The converse is also a possibility, and it may be that some of those cases previously reported as ACC of the antrum may indeed be of primary intraosseous origin. In summary, the ACCs herein reported are considered unusual for the striking degree of bone destruction seen in contrast to the amount of soft tissue involvement, suggesting that they arose centrally within the maxillary jawbone. Histologically, each tumor displayed a solid predominant growth pattern and exhibited the unusually aggressive biologic behavior expected of a high-grade malignancy. We support the view that solid variant ACCs of salivary gland origin be designated as such by the pathologist, and additionally suggest that those tumors displaying extensive bone involvement be considered especially lethal. We wish to acknowledge Mr. Larry Eisenberg for his help in preparation of the manuscript and to the following persons for contributing their cases and for providing followup information: Drs. S. Shaun Daneshgar, Ross Prout, Jay R. Weiner, Richard S. Polacheck, and Roman Carlos.
REFERENCES I
f:ncroth
C-b{.
ii~crlmnn
1
Lloberger
G. )Jdcnoid
cystic
car-
cinoma of the palate. Acta Otolaryngol 1968:66:248-60. L. Variakojis D, Archer FL, Feldman SA, Moody RA. Rapidly progressing adenoid cystic carcinoma. Arch Otolaryngol 1970;92:90-3. 3. Eby LS, Johnson DS, Baker HW. Adenoid cystic carcinoma of the head and neck. Cancer 1972;29:1160-8. 4 Tarpley TM. Giansanti JS. Adenoid cystic carcinoma-analysis of fifty oral cases. ORAI. SURG ORAL MED ORAL PATHOL 1976;41:484-97. 5. Nochomovitz LE, Kahn LB. Adenoid cystic carcinoma of the salivary gland and its histologic variants-a clinicopathologic study of thirty casts. ORAI SURG ORAL MED ORAL PATHOL ‘917;44:394-404.
6. Perzin KH, Gullane P, Cloirmont AC. Adenoid
cystic
carci-
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7.
8.
9. IO.
1 I.
12. 13.
14. 15.
16. 17. 18.
19.
20.
Cleveland et al.
nomas arising in salivary glands-a correlation of histologic features and clinical course. Cancer 1978;42:265-82. Game1 JW, Font RL. Adenoid cystic carcinoma of the lacrimal gland: the clinical significance of a basaloid histologic pattern. Human Path01 1982;13:219-25. Szanto PA, Luna MA, Tortoledo ME, White RA. Histologic grading of adenoid cystic carcinoma of the salivary glands. Cancer 1984;54:1062-9. Marsh WL, Allen MS. Adenoid cystic carcinoma: biologic behavior in 38 patients. Cancer 1979;43:1463-73. Santucci M, Bondi R. Histologic-prognostic correlations in adenoid cystic carcinoma of major and minor salivary glands of the oral cavity. Tumori 1986;72:293-300. Spiro RH, Huvos AG, Strong EW. Adenoid cystic carcinoma of salivary origin: a clinicopathologic study of 242 cases. Am J Surg 1974;128:512-20. Spiro RH, Huvos AG, Strong EW. Adenoid cystic carcinoma: factors influencing survival. Am J Surg 1979;138:579-83. Nascimento AG, Amaral A, Prado L, Kligerman J, Silveira T. Adenoid cystic carcinoma of salivary glands: a study of 61 cases with clinicopathologic correlation. Cancer 1986;57: 312-9. Stewart J. Carcinoma of salivary glands showing the cylindroma pattern. Br J Surg 1961;49:241-5. Smith LC, Lane N, Rankow RM. Cylindroma (adenoid cystic carcinoma)-a report of 58 cases. Am J Surg 1965;110:5 1926. Bradley JC. A case of cylindroma of the mandible. Br J Oral Surg 1968;5:186-93. Horree WA. Adenoid cystic carcinoma of the maxilla. Arch Otolaryngol 1974; 100:469-72. Youne RH. Frierson HF. Mills SE. Kaiser JS. Talbot WH. Bhan>K. Adenoid cysticllike tumor of the prostate gland. A report of two cases and review of the literature on “adenoid cysticcarcinoma” oftheprostate. Am J Clin Path01 1988;89:4956. Patey DH, Thackray AC. The treatment of parotid tumours in the light of a pathological study of parotidectomy material. Br J Surg 1958;45:477-87. Gullane PJ, Conley J. Carcinoma of the maxillary sinus-a correlation of the clinical course with orbital involvement,
ORAL SURG ORAL MED
21.
22.
23. 24.
25. 26. 27. 28.
29.
30. 31. 32.
ORAL PATHOL April 1990
pterygoid erosion, or pterygopalatine invasion and cervical metastases. J Otolaryngol 1983;12:141-5. Miller AS, Winnick M. Salivary gland inclusion in the anterior mandible. Report of a case with a review of the literature on aberrant salivary gland tissue and neoplasms. ORAL SURG ORAL MED ORAL PATHOL 1971;31:790-7. Browand BC, Waldron CA. Central mucoepidermoid tumors of the jaws. Report of nine cases and review of the literature. ORAL SURG ORAL MED ORAL PATHOL 1975;40:63 l-43. Abrams AM, Howell FV. Bullock WK. Nasonalatine cvsts. ORAL SURG ORAL MED URAL PATHOL 1963;1b:306-32. ’ Stall HC, Marchetta FC, Schobinger R. Malignant epithelial tumors of the mandible and maxilfa. Arch Pathol 1957;64:23944. Bumsted WD. Cylindroma of the mandible. ORAL SURG ORAL MED ORAL PATHOL 1955;8:546-55. Dhawan IK, Bhargava S, Nayak NC, Gupta RK. Central salivary gland tumors of jaws. Cancer 1970;26:211-7. Slavin G, Mitchell RM. Adenoid cystic carcinoma of the mandible. Br J Surg 1971;58:546-8. Yoshimura Y, Hasegawa K, Wada T, Fujita K, Kawakatsu K. Metastasis of adenoid cystic carcinoma of the mandible to the gasserian ganglion. J Am Dent Assoc 1978;96:469-73. Kaneda T, Nobusuke M, Takeuchi M, Yamashita T. Primary central adenoid cystic carcinoma of the mandible. J Oral Maxillofac Surg 1982;40:741-5. Hirota J, Osak;T. Primary central adenoid cystic carcinoma of the mandible. J Oral Maxillofac Surg 1989;47:176-9. Schultz W, Whitten Jr JB. Mucoepidermoid carcinoma of the mandible: report of case. J Oral Surg 1969;27:337-40. Silverglade LB, Alvares OF, Oleck E. Central mucoepidermoid tumors of the jaws. Review of the literature and case report. Cancer 1968;22:650-3.
Reprint requests to: Albert M. Abrams, DDS, MS School of Dentistry University of Southern California University Park Los Angeles, California 90089-0641
OF DENTISTRY,
UNIVERSITY
OF SOUTHERN
of the J. Melrose,
DDS,”
CALIFORNIA
Seven cases of solid variant of adenoid cystic carcinoma of the maxilla are reported. Clinical and radiographic characteristics disproportionate
suggest origin within the maxillary alveolar bone. Swelling was minimal and
to the extensive, diffuse bone destruction universally present. Histologic features were
typical of this neoplasm occurring in other sites and consisted of diffusely infiltrating islands of small, closely packed monomorphous cells with sparse cytoplasm, indistinct borders, and small hyperchromatic nuclei. Four of five patients with follow-up data died of their disease. This confirms the lethality of the solid variant. Rationale is presented for considering these malignancies to be of primary intraosseous origin. (ORAL SURC ORAL MED ORAL PATHOL 1990;69:470-8)
A
denoid cystic carcinoma (ACC) of salivary gland origin has been classically described as an indolent, slowly growing tumor typified by persistent growth behavior with repeated local recurrences after therapeutic intervention. Distant metastases and regional lymphatic spread may occur as late sequelae, with the patient often dying of disease, sometimes many years after the original diagnosis. The tumor displays a distinctive cribriform histomorphology, often described as “Swiss cheese” or “sievelike”; however, this terminology has proved inadequate in expressing the wide spectrum of histologic diversity that may be seen. In addition to the more characteristic cribriform architecture, areas of tubular differentiation, or of solid cellular growth, may be observed. Several authors have attempted to correlate the histopathologic subtype with the tumor’s unpredictable and deceptive growth behavior. l-l3 Although some studies have found the histologic grading of ACCs unreliable in predicting clinical course of disease,9, 11, l2 most recent data support the view that the predominance of
aFormer Resident in Oral Pathology at USC and currently tant Professor of Pathology, Temple University. bProfessor and Chairman, Section of Pathology. CProfessor of Pathology. “Associate Professor of Pathology. 7/14/19032
470
Assis-
solid growth pattern is a significant microscopic finding; these tumors are found to be unusually aggressive and are associated with a short clinical course and exceedingly poor prognosis.‘-*, “3 l3 ACCs of minor salivary glands most commonly arise within the soft tissues of the hard and soft palates but are also known to develop from mucous glands of the upper aerodigestive tract, including the nasal cavity and paranasal sinuses. The usual complaint is that of an asymptomatic mass or palpable, tumorous growth. 1,3,4, 6 1’ Although invasion into contiguous bony structures occurs with some frequency, it is generally not the preeminent clinical feature at the time of diagnosis, especially in the absence of obvious tumor. In fact, descriptions by previous authors have noted the striking lack of bone destruction by virtue of the neoplasm’s propensity for infiltration of the marrow spaces while leaving the basic trabecular architecture intact.3q 14-16Consequently, there may be little or no perceptible radiographic changes in the involved areas. The purpose of this article is to present the clinical and histopathologic data from seven additional cases of solid variant ACC of the upper jaw. In each case, the most prominent feature was the remarkable amount of atypical bone destruction seen radiographically, the extent of which was disproportionate to other presenting signs and symptoms. This distinctive combination of clinical, radiographic, and histologic
a
Solid adenoid cystic carcinoma of maxilla
Volume 69 Number 4 Table
471
1.Clinical features Presenting signs and symptoms
Patient
Age, sex
C.S.
80, M
Anterior maxilla with bilateral posterior extension
Loose teeth x 6 mo., acute onset pain, slight swelling
A.R.
50, F
Left posterior maxilla
Swelling X several weeks
J.R.
78, M
Right maxillary
H.A.
14, F
Right posterior maxilla and sinus
E.R.
59, F
Left posterior maxilla and sinus
Incidental radiographic finding 1 year before diagnosis Pain, swelling, anesthesia, diplopia, and headache X several weeks Loose teeth, nonhealing extraction site
H.S. S.H.
39, M 57, M
Right posterior maxilla Left posterior maxilla
Primary
site
sinus
Radiographic
Loose teeth, anesthesia ND*
jindings
Complete bone destruction no. 6-no. 13; slight root resorption Lytic destruction alveolar ridge no. 1 I-tuberosity Radiolucency involving maxillary sinus Lytic destruction right maxillary antrum and right ethmoidal complex Diffuse, lytic destruction no. 11 to tuberosity involving maxillary sinus; “floating teeth” Lytic destruction Large, lytic lesion associated with no. 14; root resorption
*ND. no data
features suggests to us primary origin within the maxillary alveolar bone, an unusual location that has received little attention in the literature. MATERIAL
AND METHODS
Microscopic sections from biopsy specimens of malignant salivary gland tumors of the upper jaw accessioned in the University of Southern California Oral Pathology Laboratory since 1973 and having original diagnoses of adenoid cystic carcinoma and adenocarcinoma were reexamined. Additionally, casesclassified as lobular carcinoma and undifferentiated carcinoma were reviewed. Out of a total of 75 cases,7 were determined to fulfill the histopathologic criteria of ACC solid variant and formed the basis for this study. One of the caseswas seen in consultation from Dr. Roman Carlos, Servicio De Diagnostic0 Clinica y Patologica, Guatemala, Central America. RESULTS Clinical features
(Table I)
There was no significant sex predilection; the male-to-female ratio was 4:3. The age at time of diagnosisranged from 39 to 80 years, with a mean age of 62 years. All tumors were located within the maxilla-six casesin the posterior maxilla, and one that showedthe greatest amount of destruction in the anterior segmentwith bilateral posterior extension (Fig. 1). Although expansion or swelling of the alveolar ridge was an associated clinical finding in two cases, in only one instance was a soft tissue mass the
patient’s chief complaint. The most common presenting sign was tooth hypermobility (three patients). Other clinical findings included pain (two patients) and anesthesia (two patients). One patient complained of diplopia and headache associated with the right periorbital area. Only one patient was without symptoms, the lesion being discovered incidentally on routine radiographic examination. Radiographically, the lesions were usually described as a diffuse, destructive lytic process of the maxillary bone, with or without evidence of sinus involvement. Radiographs of those patients seeking dental treatment for loose teeth demonstrated “floating teeth,” and in one instance root resorption was a feature (Figs. 1 and 2). Histopathologic
features
In all cases,the histologic appearance was that of a diffusely infiltrating neoplasm composed of undifferentiated, darkly staining cells arranged predominantly into solid islands of varying size (Figs. 3 and 4). Cytologically, the tumor cells comprising these solid areas were distinctly monomorphous and did not exhibit the nuclear pleomorphism that has been previously described by other investigators.*, lo, i7 Nuclei were small, averaging 8 to 10 pm in diameter, round to ovoid, and were characterized by a fine, evenly dispersed chromatin pattern with occasional, indistinct nucleoli. Typically, the cells were closely packed, showing scanty, ill-defined, pale cytoplasm (Fig. 5). Occasionally, this solid arrangement of tumor cells
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et al.
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Fig. 2. CaseE.R. Diffusebonedestructionand“floating” premolar in a 59-year-oldwoman.
Fig. 1. Case C.S. Destructive tumor growth featuring extensivebonelossin an 80-year-oldman. A andB feature “floating” teeth, and C revealstumor growth in both sides of the maxilla.
was interrupted by the presence of pseudocysts, or of ductlike structures lined with a single layer of cuboida1 cells that, in some instances, contained scant amounts of an amorphous, faintly eosinophilic material. I, zip ;f tliti Jbv~l~ babe>, ihs iurnora also featured neoplastic cells forming small tubular structures with
minimal stratification of the lining epithelium. In two cases, areas of more typical cribriforming were observed (Fig. 6). Although present in varying degrees, these two features were never a predominant characteristic and accounted for no more than 30% of the available tissue examined for any one case. Stromal hyalinization, which has been described as a peculiar characteristic of ACC, was an inconstant feature, being present focally in only two cases. Instead, the stroma was generally loose, of variable cellularity, and in some cases showed a striking degree of vascularity. Focal stromal mucinosis was evident in two cases. Mitoses were present in all cases to a variable extent, but no atypical forms were observed. Necrosis, a feature often described in association with solid ACC, was seen in four of the seven cases, either as comedo type or individual cell necrosis, and was usually associated with the larger tumor islands (Fig. 7). Surprisingly, perineural invasion, a noted characteristic of ACC, was observed in only one case. In the
Volume 69 Number 4
Solid adenoid cystic carcinoma of maxilla
473
Fig. 3. Low-power view of several variable sized cellular aggregates typical of solid adenoid cystic carcix40.)
noma. (H&E stain. Original magnification,
Fig. 4. Solid islands of tumor with minimal ductlike structure formation. (H&E stain. Original magnification, X 100.)
remaining cases, no nerves were identified, and it may be that the limited amount of tissue available for study precluded evaluation of this feature. Squamous metapiasia was found in one case (E.R.), a feature
bone destruction as well as intertrabecular
infiltration
that is rarely, if ever, described in ACC of salivary gland origin, but which was recently reported in an adenoid cystic-like tumor of the prostate gland.18 Microscopic verification of bone involvement was seen in five cases, four of which demonstrated actual
Follow-up data were obtained for five of seven patients. One of these (J.R.) has remained alive and without evidence of disease since receiving radiation treatment in 198 1. The remaining four patients died of their disease because of local extension or metasta-
of tumor within marrow spaces (Fig. 8). Follow-up data (Table II)
474
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Fig. 5. Solid massof tumor cellswith smallnuclei containing evenly dispersedfine chromatin.Cytoplasm is scanty. (H&E stain. Original magnification, X300.)
6. Tumor aggregatesdisplayingcribriform morphology.This wasa minor componentin thesetumors. (H&E stain. Original magnification, X100.)
Fig.
sis. The time interval between the original histologic diagnosis and death ranged from 14 to 28 months. Only one (H.S.) received primary surgical treatment consisting of hemimaxillectomy and orbital exenteration; extensive local recurrence was treated by chemotherapy without success, and the patient died within 4 months. The exclusive therapy for the remaining three pa+‘--‘LIIIILU ;;-i%i;, &, group consisted of irradiation. One of these (H.A.) experienced recurrent local disease 13 months after therapy, complicated by a large, right
pleural effusion and space-occupying lesions of the liver of unknown significance as identified by computed tomography. Although not verified by examinations before or after death, these latter two findings suggest visceral metastasis to lung and liver. A second patient (C.S.) had metastases to lung, bone, and regional lymph nodes within 21 months of initial radiation treatment, with ensuing congestive heart failure and pleural effusion believed to be secondary to pulmonary metastases. The third patient (E.R.) was dead of disease within 22 months of original diagno-
Solid adenoid cystic carcinoma of maxilla
Volume 69 Number 4
Fig. 7. Early cellular magnification, X 150.)
necrosis in center
of
solid mass of adenoid
Fig. 8. Tumor islands infiltrating between bone trabeculae stain. Original magnification, X 100.)
sis and following radiation treatment without adjunctive therapy. In none of these cases were autopsies performed.
Our study confirms the experience of previous investigators that the predominance of a solid pattern in ACC of the head and neck is an alarming microscopic finding, portending a higher grade malignancy characterized by rapid growth, early local recurrence, and metastasis.‘-s. lo, l3 In the present investigation, four
cystic carcinoma.
and adjacent
(H&E
47s
stain. Original
to tooth root, top right. (H&E
of five patients for whom we were able to obtain follow-up information were dead of their disease within 2% years from the time of original diagnosis. Areas of solid, cellular growth have been recognized as contributing to the overafl histologic spectrum of .4CC since some of the earliest microscopic descriptions. However, the clinical relevance of this remained obscure for many years. In 1958, Patey and Thackray” were the first to suggest that a higher grade malignancy with rapid local spread and metastasis may be associated with this solid predominant
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Cleveland et al.
Table
II. Clinical
Patient
ORAL
course, treatment, Initial
Irradiation
A.R. J.R. H.A. E.R. H.S.
ND* Irradiation lrradiation Irradiation Right hemimaxillectomy orbital exenteration Partial maxillectomy
S.H.
ORAL
MED ORAL PATHOL April 1990
and follow-up
treatment
C.S.
SURG
Metastasis
and
Local
Bone, lungs, regional lymph nodes ND None ?lung, ?liver I .2 years ND None ND
recurrence
Follow-up
None
DODt
ND None I .2 years ND 0.75 years (treated ND
ND Alive DOD DOD DOD
2.3 years
7 years 1.3 years 1.8 iears 1.2 years
by chemotherapy) ND
*ND, no data. TDOD,
dead
of disease.
pattern that they designated as spheroidal cell carcinomata. Soon after, in 1961, James Stewart14 described a more malignant variant of ACC that exhibited a “large cell pattern” associated with central necrosis of the cellular masses and a more aggressive infiltrating behavior; both patients whose palatal tumors displayed these microscopic features were dead of their disease within 2 years of presentation. Eneroth and associates,’ on the basis of their observations that five of seven patients with poorly differentiated palatal tumors had died of their disease within 3 years, urged that ACCs be graded clinically into high- and low-grade malignant types. Eby and coworkers,3 in their review of 54 cases of head and neck ACC, recognized two distinctive subgroups based on biologic behavior: seven of nine patients remarkable for a fulminating clinical course and terminating in a fatal outcome in less than 3 years had tumors with areas of solid, cellular growth described as basaloid or anaplastic. The work that stands out as most convincing in establishing the clinical significance of the solid variant is that of Perzin and colleagues.6 In their study of 62 ACCs of major and minor salivary gland origin, which examined the impact of several parameters on clinical course (including histologic pattern, tumor size, primary site, lymph node metastasis, adequacy of surgical margins, and cellular atypia), they found that the solid predominant pattern represented the least differentiated form of ACC and carried the worst prognosis when >30% of the neoplasm demonstrated this pattern. They also described a welldifferentiated form of the disease, manifesting a tubular predominant pattern, which was associated with the best prognosis. ACCs occur in both the major and minor salivary glands as well as in association with mucous glands found scattered throughout the tracheobronchial tree aLI: U~,PGI azlvdigestive tract. It is generally considered to be the most common malignancy of the intraoral minor salivary glands, with a propensity for
development from glands of the hard and soft palates. The anatomic site of the primary tumor is known to dramatically alter survival data.6, 7, ’ ‘-I3 Although there is disagreement as to which sites carry a better prognosis, some authors agree that minor gland ACCs, especially those of the maxillary antrum and nasal cavity, behave more aggressively than others.4-6, 8, ‘I, I*, I7 Contiguity to vital anatomic structures, tumor size, late stage of detection, and the inability to gain adequate surgical margins free of tumor have been cited as contributing to the overall poorer prognosis for patients having tumors in these locations.13 These factors are compounded by the natural proclivity of ACCs toward infiltration along fascial planes and extensive perineural spread. Anatomic location and size of the primary tumor may also be related to histologic subtype although the significance of this remains unclear. Gullane and Conley *O found a predominance of cribriform and solid patterns in ACCs of the maxillary sinus. Perzin and coworker& reported cribriform and solid variants dominating in ACCs arising from minor glands of the nasal cavity and paranasal sinuses but additionally noted that tumors in these locations were larger and more extensive than better differentiated histologic forms. These data were supported in the study by Szanto and associates,* who showed that solid variant ACCs were larger, recurred frequently, and had an aggressive clinical course, usually killing the patients within 4 years. Perzin and colleagues6 have hypothesized a histologic evolution in the growth of these tumors, suggesting that as the neoplasm proliferates it evolves from the better differentiated tubular structures to cribriforming units followed by the eventual overgrowth of the individual lumina by areas of solid, cellular growth. The cases presented in this communication are unusual for the extent of atypical destruction of the maxillary alveolar bone. In most cases, this was the preeminent clinical feature, disproportionate to other
Solid adenoid cystic carcinoma of maxilla
Volume 69 Number 4
presenting signs and symptoms. Bone involvement is a well-known characteristic of ACC; however, its significance has received little attention in the literature. In their study of 242 cases of ACC of major and minor salivary glands, Spiro and colleagues” found a positive correlation between bone invasion and survival: of 75 minor salivary gland tumors demonstrating bone invasion, the lo-year determinant “cure” rate was 7% as compared to 32% for 65 minor salivary gland neoplasms not showing this feature. Szanto and colleagues* considered bone invasion to be an ominous finding. Of 38 cases of ACC in which bone sections were made available for examination, 24 showed bone involvement, with only one patient free of tumor at the termination of their study. In both reports, an asymptomatic swelling was stated to be the most common presenting symptom; however, radiographic findings were not included as part of their studies. Although swelling was noted in some of our cases, the extent of bone destruction seen radiographically makes it seem unlikely that the neoplasms arose primarily from the mucous glands of the hard and soft palates with secondary bone involvement without greater evidence of an actual tumor mass. Origin in the minor glands of the maxillary antrum or paranasal sinuses is another possibility. However, the constellation of signs and symptoms usually associated with ACCs arising in these locations including prominent pain, nasal complaints (discharge, obstruct&, epistaxis), significant cheek swelling, anesthesia, and visual disturbances was exhibited by only one of the patients in the present study. Our data suggest to us a primary intraosseous origin within the maxilla for the cases being reported. Salivary gland tumors are known to arise centrally within the jawbones but are considered uncommon. The tumor most frequently reported is the central mucoepidermoid tumor (CMET) occurring most commonly in the posterior mandible.*” 22 They occur with less frequency in the anterior mandible and in the molar-sinus-palatal area of the maxilla.22 There have been no reported cases of CMET in the anterior maxilla. Histogenetically, they are thought to arise from intrabony enclavements of heterotopic salivary gland tissue, from mucous glandular inclusions within the retromolar pad area, or from mucous metaplasia within the lining epithelium of odontogenic cysts.2’. 22 Within the maxilla, similar inclusions of salivary gland tissue may exist but have not yet been reported as such. Mucous glands, however, are known to be constituents of the incisive canal and have been reported in as many as 3 1% of nasopalatine duct cysts by Abrams and associates.23 That such glands may have been the origin of the tumor in one of our patients
477
(C.S.) is suggested by the degree of bone destruction of the anterior maxilla seen radiographically without evidence of a tumor mass. Primary intraosseous ACCs are rare. A review of the English-language literature revealed a total of 20 cases of ACCs of the jawbones, 8 of which occurred in the maxilla. 16,24-30Whereas specific criteria have been defined by previous authors in the diagnosis of CMET (including intact cortical plates, radiographic evidence of bone destruction, histopathologic confirmation, and the exclusion of metastatic disease3’* 32), no such criteria exist for the diagnosis of central ACC. Within the maxilla, this assessment is made especially difficult by the prevalence of minor salivary glands scattered throughout the antral and nasal mucous membranes. Without correlation of radiographic and clinical features, a lesion interpreted as originating within the maxilla may, in reality, be a tumor of mucosal origin with secondary bone involvement. The converse is also a possibility, and it may be that some of those cases previously reported as ACC of the antrum may indeed be of primary intraosseous origin. In summary, the ACCs herein reported are considered unusual for the striking degree of bone destruction seen in contrast to the amount of soft tissue involvement, suggesting that they arose centrally within the maxillary jawbone. Histologically, each tumor displayed a solid predominant growth pattern and exhibited the unusually aggressive biologic behavior expected of a high-grade malignancy. We support the view that solid variant ACCs of salivary gland origin be designated as such by the pathologist, and additionally suggest that those tumors displaying extensive bone involvement be considered especially lethal. We wish to acknowledge Mr. Larry Eisenberg for his help in preparation of the manuscript and to the following persons for contributing their cases and for providing followup information: Drs. S. Shaun Daneshgar, Ross Prout, Jay R. Weiner, Richard S. Polacheck, and Roman Carlos.
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f:ncroth
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ii~crlmnn
1
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G. )Jdcnoid
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Reprint requests to: Albert M. Abrams, DDS, MS School of Dentistry University of Southern California University Park Los Angeles, California 90089-0641
