Annals of DIAGNOSTIC PATHOLOGY VOL 4, NO 6 DECEMBER 2000 ORIGINAL ARTICLES Salivary Gland Tumors of the Mandible Fernando Martı́nez-Madrigal, MD, Keyla Pineda-Daboin, MD, Odele Casiraghi, MD, and Mario A. Luna, MD Primary central salivary gland carcinomas of the mandible are uncommon neoplasms. Consequently, their proper diagnosis is often in doubt. We retrospectively studied the cases of 16 patients treated at The University of Texas M. D. Anderson Cancer Center and the Institut Gustave Roussy from 1950 to 1990. Patients ranged in age from 24 to 76 years (mean, 51 years). Nine patients were women and seven were men. Each case involved either the angle or the posterior body of the mandible. Swelling, pain, and trismus were the most frequent complaints. For all patients, radiography revealed a cystic defect resembling an osteolytic odontogenic lesion or metastasis. Five histologic types of carcinoma were diagnosed: seven cases of mucoepidermoid carcinoma (five low-grade and two high-grade), four cases of adenoid cystic carcinoma, two cases of adenocarcinoma, two cases of acinic-cell carcinoma, and one case of epithelial-myoepithelial carcinoma. All patients were treated with wide surgical excision. Eight patients received postoperative irradiation. Five patients with low-grade mucoepidermoid carcinoma, two with acinic-cell carcinoma, and one with epithelial-myoepithelial carcinoma were free of disease 2 to 15 years after initial treatment (mean, 6.2 years). Two patients with adenoid cystic carcinoma are living with lung metastasis. The remaining six patients died of their carcinomas within 4 years after initial treatment. Because of their unique morphology and clinical behavior, these tumors should be distinguished from other intraosseous neoplasms of the mandible, including those with clear-cell patterns. Ann Diagn Pathol 4: 347-353, 2000. Copyright © 2000 by W.B. Saunders Company Index Words: Salivary gland neoplasms, mandible, mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic-cell carcinoma, epithelial-myoepithelial carcinoma E CTOPIC salivary gland tissue has been reported in a wide variety of locations, including the thyroid, the pituitary, the middle ear, the maxilla, and the mandible.1-3 Neoplastic transformation of heterotopic salivary tissue is rare, and most From the Department of Pathology, Instituto de Investigaciones Biomédicas de Michoacán, Morelia, Michoacan, México; the Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and the Department of Pathology A, Institut Gustave Roussy, Villejuif, France. Address reprint requests to Mario A. Luna, MD, Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 85, Houston, TX 77030. Copyright © 2000 by W.B. Saunders Company 1092-9134/00/0406-0004$10.00/0 doi:10.1053/adpa.2000.19395 reported cases are in the upper cervical lymph nodes and in the mandible.1 When neoplastic transformation occurs centrally within the mandible, the radiologic and clinical presentation may mimic that of odontogenic tumors, and a final diagnosis can be obtained only after histologic examination.4 Careful gross and microscopic examination of the surgical specimen should be done to exclude the possibility of any connection with the mucosal cover of the oral cavity. Mucoepidermoid carcinomas are the most frequently reported types of primary central salivary gland carcinomas of the mandible.4,5 Much less common are adenoid cystic carcinomas, adenocarcinomas, and acinic-cell carcinomas.6-15 Recently, two cases of hyalinizing clearcell carcinomas of the mandible were reported.9 Annals of Diagnostic Pathology, Vol 4, No 6 (December), 2000: pp 347-353 347 348 Martı́nez-Madrigal et al This retrospective study describes 16 patients with primary salivary gland carcinomas arising centrally within the mandible treated at the University of Texas M. D. Anderson Cancer Center (Houston, TX) and the Institut Gustave Roussy (Villejuif, France). The clinicopathologic features of these carcinomas are analyzed, and the probable histogenesis of salivary gland neoplasms arising centrally within the mandible is briefly discussed. Material and Methods The files of the Departments of Pathology and Head and Neck Surgery of M. D. Anderson Cancer Center and the Institut Gustave Roussy were searched for cases of primary central salivary gland carcinoma of the mandible. The clinical data, radiographs, histologic material, surgical records, and follow-up information were analyzed. All cases met the following criteria: radiographic evidence of bone destruction, presence of an intact cortical plate, histologic confirmation of salivary gland neoplasm, absence of any primary lesion in the salivary glands, exclusion of odontogenic tumor, and absence of any connection between the tumor and the mucosal surface as determined by analysis of serial sections of the tumor specimen. The three specimens that had clear-cell patterns (cases 14, 15, and 16) were stained with the periodic acid-Schiff reagent with and without diastase digestion and Alcian blue. Immunohistochemical studies of these three specimens were performed. Results Fifteen patients treated at M. D. Anderson Cancer Center and five patients treated at the Institut Gustave Roussy between 1950 and 1990 were found. Four patients of the Institut Gustave Roussy were excluded from the study because they had evidence of connection between the intramandibular tumor and the oral mucosal surface. The 16 study patients ranged in age from 24 to 76 years (mean, 51 years). Nine patients were women and seven were men. Each case involved the angle or the posterior body of the mandible (Table 1). Pain, swelling, and trismus were the most frequent complaints. All patients showed radiographic evidence of bone destruction and an intact cortical plate (Fig 1). Gross examination of the specimens revealed multilocular intraosseous lesions (Fig 2). Histologic and clinical data for all patients are summarized in Table 1. Histologically, the types of carcinomas were as follows: seven patients had mucoepidermoid carcinoma (Fig 3), four had adenoid cystic carcinoma (Fig 4), two had adenocarcinoma, two had acinic-cell carcinoma (Fig 5), and one had epithelial myoepithelial carcinoma (Figs 6, 7) similar to conventional salivary gland tumors. Acinic-cell carcinoma presented as a clear-cell tumor: periodic acidSchiff reaction and periodic acid-Schiff diastase digestive reaction were strongly positive, as was amylase reaction by immunohistochemistry. Table 1. Features, Treatment, and Follow-up of Sixteen Patients With Salivary Gland Tumors of the Mandible Case Age (yr)/ Sex Site in Mandible Type Treatment Status Follow-up (yr) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 49/F 53/M 56/M 65/M 58/F 71/F 51/M 51/M 48/M 24/F 35/F 33/F 24/F 48/F 76/M 56/F Body Angle Body Angle Angle Angle Body Angle Body Angle Angle Body Angle Angle Body Angle MEC-LG MEC-LG MEC-LG MEC-LG MEC-LG MEC-HG MEC-HG ADC ADC ADC ADC AD AD ACC ACC EMC MM MM MM MM MM HM ⫹ XRT HM ⫹ XRT HM ⫹ XRT HM ⫹ XRT HM ⫹ XRT HM ⫹ XRT HM ⫹ XRT HM ⫹ XRT MM ⫹ XRT MM ⫹ XRT HM NED NED NED NED NED DOD DOD DOD DOD LWD LWD DOD DOD NED NED NED 15 8 6 7 10 3 2 4 3 7 5 4 3 12 2 8 Abbreviations: MED, mucoepidermoid carcinoma; LG, low-grade; HG, high-grade; ADC, adenoid cystic carcinoma; AD, adenocarcinoma; ACC, acinic-cell carcinoma; EMC, epithelial-myoepithelial carcinoma; MM, marginal mandibulectomy; HM, hemimandibulectomy; XRT, radiotherapy; NED, no evidence of disease; DOD, died of disease; LWD, living with disease. Salivary Gland Tumors of the Mandible 349 Figure 1. Isolated portion of a Panorex radiograph showing a lytic lesion with irregular margins in the left body and ramus of the mandible. All patients were treated by wide surgical excision. Eight patients received postoperative irradiation. Five patients with low-grade mucoepidermoid carcinoma, two patients with acinic-cell carcinoma, and one patient with epithelial-myoepithelial carcinoma were disease-free from 2 to 15 years after initial treatment (mean, 6.2 years). Two patients with adenoid cystic carcinoma are alive with lung metastasis. The remaining six patients died of their carcinomas within 4 years after initial treatment. Discussion Our study of 16 patients with salivary gland carcinomas of the mandible demonstrates the clinicopathologic features that distinguish these tumors from other cancer types. Salivary gland carcinomas located centrally within the mandible are rare, comprising less than 0.4% of all salivary gland carcinomas. In a study of 426 minor salivary gland tumors from 11 institutions, Waldron et al16 noted only six (1.4%) intraosseous mucoepidermoid carcinomas. Brookstone and Huvos4 found only six cases (0.37%) of salivary gland carcinoma of the mandible among 2,000 patients with sialocarcinomas registered from 1950 to 1990 in the Tumor Registry at the Memorial Sloan-Kettering Cancer Center in New York. We found 16 patients among 5,400 (0.29%) patients treated during the same period for salivary gland carcinomas at The University of Texas M. D. Anderson Cancer Center in Houston, Texas, and the Institut Gustave Roussy in Villejuif, France. Specific criteria have been established for con- Figure 2. Bisected gross specimen showing a multilocular tumor. 350 Martı́nez-Madrigal et al Figure 3. (Left) Intraosseous low-grade mucoepidermoid carcinoma of mandible. (Hematoxylin-eosin, magnification ⫻40.) (Right) Hematoxylin-eosin. (Magnification ⫻100.) firming the central origin of salivary gland tumors involving the mandible4,5: (1) absence of any connection between the oral mucosal surface and the lesion in the mandible or maxilla (because malignant carcinomas that develop in minor salivary glands may infiltrate the bone by direct extension), (2) radiographic evidence of bone destruction, (3) presence of an intact cortical plate, (4) histologic confirmation of salivary gland neoplasm, (5) absence of any primary lesions within the salivary glands, and (6) exclusion of the diagnosis of odontogenic carcinoma. The origin of salivary gland tumor tissue within the jawbone is presumed to be a maternal salivary gland. Salivary gland inclusions usually occur in bone spaces located near the angle of the mandible, where they have a consistent position and radiographic appearance.2 Only a few salivary gland inclusions have been found in the anterior mandible (in the incisor region or between the canines and first molars).2 As several investigators have stated, no single theory of histogenesis is applicable to all cases of salivary gland tumors of the mandible.4,5,7,17 True cases of central pleomorphic or monomorphic adenoma and adenoid cystic carcinoma do not arise from a metaplasia of odontogenic cysts5,6 and must therefore originate from (1) enclaved retromolar Figure 4. Characteristic cylindromatous structures in an intramandibular adenoid cystic carcinoma. (Hematoxylin-eosin, magnification ⫻40.) Salivary Gland Tumors of the Mandible 351 Figure 5. Acinic-cell carcinoma with alternating groups of clear and granular cells. (Hematoxylin-eosin, magnification ⫻40.) mucous glands during embryological development of the jawbones, (2) submandibular and sublingual glands closely apposed in bony defects or cavities in the lingual cortex of the mandible, or (3) fragments of submandibular and sublingual glands that have undergone embryologic evagination. Another speculative source also has been proposed for the origin of central mucoepidermoid carcinomas: metaplasia in an odontogenic cyst or in the epithelial rests of Malassez.5,17,18 Two of seven patients with mucoepidermoid carcinoma in the present series had odontogenic cysts, supporting the theory of neoplastic or metaplastic cellular transformation. The radiographic appearance of central salivary gland tumors of the mandible often resembles that of an osteolytic odontogenic lesion. However, several characteristics of the radiographic appearance may help to verify the histopathologic type of central carcinoma of the mandible. In a series of 36 cases of central carcinomas of the jaws reported by Chiang and Chih, most lesions with osteolytic destruction were primary intraosseous carcinomas, most lesions with multilocular destruction were salivary gland carcinomas, and most lesions with unilocular destruction were malignant changes in odontogenic cysts.19 The histology of central salivary gland neoplasms in the mandible is identical to that of their salivary Figure 6. Intramandibular epithelialmyoepithelial carcinoma. (Hematoxylin-eosin, magnification ⫻40.) 352 Martı́nez-Madrigal et al Figure 7. Epithelial-myoepithelial carcinoma demonstrating clear-cell pattern surrounding ductal structures. (Hematoxylin-eosin, magnification ⫻100.) gland counterparts and usually does not pose diagnostic difficulties. The principal differential diagnosis for mucoepidermoid carcinomas is metastasis from other primary carcinomas and cystic odontogenic lesions, especially the sialodontogenic cyst, also called the glandular odontogenic cyst.18,20,21 The presence of intermediate cells and multilocular destruction would favor the diagnosis of mucoepidermoid carcinoma.21 In the case of salivary glands with predominantly clear-cell components (epithelial-myoepithelial carcinoma, hyalinizing clear-cell carcinoma, and acinic-cell carcinoma),22 the differential diagnosis of clear-cell odontogenic tumors (clear-cell odontogenic carcinoma and clear-cell calcifying epithelial odontogenic tumor) is the most difficult.23-28 All of these odontogenic neoplasms will show odontogenic epithelium if enough histologic sections are examined.23-28 Metastatic renal-cell carcinoma should always be considered in the differential diagnosis of clear-cell tumors.23 Metastatic melanoma and thyroid carcinoma may sometimes have a clear-cell appearance. Immunohistochemical stains are useful in diagnosing these two carcinomas.23 Central mucoepidermoid carcinoma and adenoid cystic carcinoma are the only salivary gland tumors with documentation sufficient to allow clinicopathologic analysis.4-6,17 Other salivary gland carcinomas are presented in single case reports or in small series with insufficient documentation. Brookstone and Huvos4 indicated that only six (9%) of 66 patients with central mucoepidermoid carcinomas with adequate follow-up had evidence of metastatic disease, whereas eight (50%) of 16 patients with central adenoid cystic carcinoma had metastases. In a series of 66 patients with central mucoepidermoid carcinomas reported by Waldron and Koh,17 the metastatic rate was 12% (eight patients), the recurrence rate was 26% (17 patients), and the mortality rate was only 9% (six patients). In the present series, two deaths (29%) occurred among patients with mucoepidermoid carcinoma; both patients had high-grade carcinoma. In contrast, of four patients with adenoid cystic carcinoma, two died of carcinoma and two are alive with tumor. The insidious clinical course that characterizes adenoid cystic carcinoma may be due to the tumor’s propensity to infiltrate nerves, perineural spaces, and tissue planes. Surgery is the predominant treatment modality for central salivary gland tumors of the mandible.4-7 Surgical treatment has ranged from enucleation or curettage to en bloc or radical excision. Several patients have also received radiotherapy.17 Enucleation with or without electrocoagulation is associated with the highest rate of recurrence (45%), but no method of treatment completely eliminates the potential for recurrence. As recorded in the review by Waldron and Koh,17 rates of metastasis and mortality were highest in patients who had received hemimaxillectomy or hemimandibulectomy. However, this finding likely reflects an advanced stage of disease at the time of initial treatment. The treatment approach in the 16 cases described was as follows. Small tumors were treated with marginal mandibulectomy. If tumor histology in these Salivary Gland Tumors of the Mandible cases indicated high-grade disease, radiotherapy was given postoperatively. Large tumors were treated with mandibulectomy. If the carcinoma was of a high histologic grade, if perineural invasion was present, or if the tumor had invaded soft tissues, radiotherapy was administered postoperatively. Neck dissection was performed only when metastasis in the cervical lymph nodes was suspected. Brookstone and Huvos4 have emphasized that without the help of clinical staging, any recommendations for treatment are of limited value. The investigators propose a staging system for salivary gland tumors within the mandible. Lesions that are located within undisturbed, intact cortical bone and overlying periosteum and that show no signs of cortical expansion offer the best prognosis and therefore indicate stage I disease. Stage II disease is characterized by lesions surrounded by intact cortical bone that has undergone some degree of expansion. An instance of cortical perforation, breakdown of the overlying periosteum, or nodal metastatic spread is categorized as stage III disease. Logically, a 6-cm mucoepidermoid carcinoma confined to an otherwise undisturbed mandible offers a more favorable prognosis than a 1-cm mucoepidermoid carcinoma that aggressively invades the floor of the mouth following lingual expansion and perforation of the cortical bone. Our findings support this staging system. Although salivary gland tumors arising within the mandible are uncommon, their importance should not be minimized. 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