Vol. 119 No. 2 February 2015

Swelling of the hard and soft palates Flávia Sirotheau Corrêa Pontes, DDS, PhD,a Alberto Mitsuyuki de Brito Kato, MD, MSc,b Maria Eduarda de Oliveira Pereira, DDS,a Diogo Rezende, DDS,a Felipe Paiva Fonseca, DDS, MSc,c Pablo Agustin Vargas, DDS, PhD, FRCPath,c Oslei Paes de Almeida, DDS, PhD,c and Hélder Antônio Rebelo Pontes, DDS, PhDa (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119:130-135)

CLINICAL PRESENTATION A 53-year-old female patient complaining of pain in the infraorbital region of the right side of her face for the last 2 months, but with no facial asymmetry, was referred to our service. The patient’s past dental and medical histories were noncontributory, and she denied any visual or nasal problems. Intraoral evaluation revealed an extensive asymptomatic swelling measuring approximately 35  23 mm, with a firm consistency. According to the patient, the swelling had been present for over 2 years, but with an increased rate of growth in the last 2 months. The lesion mainly had a normal-colored surface and affected the right side of the hard palate, causing expansion of the vestibular side of the alveolar ridge and extending to the anterior portion of the soft palate, where it showed a reddish and telangiectatic surface (Figure 1). T1-and T2-weighted magnetic resonance imaging (MRI) revealed a heterogeneous tumor mass, with areas of different densities completely obliterating the right maxillary sinus, superiorly extending to the floor of the orbit, and closely associated with the inferior and medial nasal turbinates. The lesion also grew inferiorly, leading to palatine compression (Figure 2). Differential diagnosis A wide range of differential diagnoses can be raised for lesions causing swellings of the upper alveolar ridge and palate; however, some clinical and radiographic features may guide diagnosticians to a more accurate provisional diagnosis before microscopic analysis. Based on the clinical appearance and MRI findings of the current case, our hypotheses included a salivary gland tumor (SGT), central ossifying fibroma, an odontogenic tumor, osteosarcoma or chondrosarcoma, and a sinonasal neoplasm extending to the oral cavity. a

Service of Oral Pathology, João de Barros Barreto University Hospital, Federal University of Pará, Belém, Brazil. b Ophir Loyola Hospital, Belém, Brazil. c Piracicaba Dental School, Oral Diagnosis Department, University of Campinas, Piracicaba, Brazil. Received for publication Mar 11, 2014; returned for revision Jul 18, 2014; accepted for publication Aug 28, 2014. Ó 2015 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.08.022

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SGTs are usually the main differential diagnosis for swellings of the palate. A number of benign and malignant SGTs should be considered, but pleomorphic adenoma is the most common.1,2 Intraorally, pleomorphic adenoma has a predilection for the palate, occurring at any age but usually affecting patients in the fourth to sixth decades of life, with a slight female preponderance.2,3 Although these features are consistent with the current case, pleomorphic adenoma normally does not present the reddish telangiectatic surface observed on the posterior region of the lesion reported. On the other hand, extensive and occasionally even aggressive cases of canalicular adenoma affecting the minor glands of the palate have been described with this clinical feature. Nonetheless, this benign salivary entity is far more common in the upper lip and buccal mucosa than in the palate.4-6 According to some authors,3 and in our own clinical experience, the superficial telangiectatic appearance described here is more frequently observed in malignancies, and because of that, the inclusion of salivary gland malignancies in the differential diagnosis would be favored over benign neoplasms, especially mucoepidermoid carcinoma, adenoid cystic carcinoma, and polymorphous low-grade adenocarcinoma, which represent the most common intraoral malignant entities of this group. They may present with a long evolution time and also more frequently affect females in the fourth to sixth decades of life.2,7 Nevertheless, the involvement of the alveolar ridge causing vestibular expansion is not typical for SGTs, and because of the presence of this characteristic, we believed that an intraosseous lesion (other than a rare central SGT) would be a better diagnostic possibility. Because of the slow growth pattern of the lesion, causing expansion of both the vestibular and palatine aspects, we also considered the possibility of a central ossifying fibroma. This benign osseous tumor is more frequently diagnosed in females in the third and fourth decades of life,8 which is consistent with our patient’s age. Radiographically, a central ossifying fibroma can present a broad spectrum of images, ranging from total radiolucency to mixed and then to a more radiopaque lesion, depending on the degree of calcification. However, central ossifying fibromas are more commonly found in the posterior region of the mandible9 and also lack the telangiectatic appearance observed in the

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Fig. 1. Extensive nonulcerated swelling involving the alveolar ridge and hard and soft palates. The tumor causes expansion of the osseous plates, and its surface becomes reddish and telangiectatic in the soft palate region.

Fig. 2. Magnetic resonance imaging (MRI) showing, in a coronal section, a hyperintense lesion involving the entire right maxillary sinus, going up to the floor of the orbit and pushing the palate down.

posterior area of the swelling. Similarly, odontogenic tumors, such as calcifying epithelial odontogenic tumors, were initially included in the differential diagnosis, in view of the alveolar ridge expansion and the long evolution time. However, this odontogenic tumor is also more frequently found in the posterior region of the mandible, usually associated with an impacted tooth, and a lesion completely filling the maxillary sinus would not be an expected presentation for this entity. Head and neck osteosarcoma and chondrosarcoma are both rare aggressive malignant bone neoplasms that have already been described in almost all sites, including the

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maxillary and sinonasal areas.10,11 There is a slight male preponderance for both entities, and patients are usually in the third to fifth decades of life. These tumors may present with a wide range of clinical signs and symptoms, but a painless swelling is the most common complaint.12,13 The radiographic appearance of osteosarcoma and chondrosarcoma may be varied, but they usually exhibit features consistent with malignancy, that is, osteolytic lesions with poorly defined borders often containing scattered radiopaque foci, more typically showing a “sun-ray” pattern.13,14 The age of the patient and the location of the lesion discussed here are consistent with a presumptive diagnosis of osteosarcoma or chondrosarcoma; however, a more destructive or invasive MRI appearance would be expected for these malignancies, instead of the well-defined, more upwardpushing growth pattern of the current case. The long evolution time of the current case, with more than 2 years of duration, made us consider these possibilities unlikely. Malignancies arising from the nasal cavity and paranasal sinuses comprise approximately 0.2% to 0.8% of malignant tumors.15 Because of the anatomic proximity of the paranasal sinuses to the orbits and skull base, most tumors extend into these structures, also affecting the oral cavity through involvement of the palate.15 Therefore, tumors arising from the maxillary sinus and nasal cavity must be included in the list of differential diagnoses when dealing with palate swellings. A number of entities can be found in this group, including epithelial (squamous cell carcinoma; sinonasal undifferentiated carcinoma; small cell carcinoma, neuroendocrine type), neuroectodermal (olfactory neuroblastoma, melanoma, Ewing sarcoma or primitive neuroectodermal tumor), mesenchymal (desmoplastic small round cell tumor, rhabdomyosarcoma, synovial sarcoma), and hematolymphoid malignancies, particularly extranodal natural killer or Tcell lymphoma.15-18 Patients affected by these tumors present a broad age range and slight gender preponderance. Sinonasal malignancies are frequently diagnosed in advanced stages as locally spread diseases, as in the present case, and usually show many nonspecific clinical characteristics. Although the clinical presentation of the current case and the long duration can exclude most of the sinonasal high-grade malignancies, they can occasionally be less aggressive, causing palate swelling and associated facial pain, as in the present case. Moreover, the extensive involvement of the maxillary sinus, as shown by MRI, favors the diagnosis of a sinonasal tumor of an intermediate degree of aggressiveness. Diagnosis and management An incisional biopsy was performed under local anesthesia, and significant bleeding occurred during the procedure. Histologic examination revealed a neoplasm

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formed by uniform round cells with a bland appearance, containing round nuclei with indistinct nucleoli and abundant clear to lightly eosinophilic cytoplasm, arranged in small nests, giving rise to an organoid pattern. The nests were surrounded by a delicate, thin fibrovascular supporting network. A few atypical cells could be found, but no atypical mitotic figures were seen (Figure 3). Because of the organoid growth pattern of the tumor, some entities such as olfactory neuroblastoma, paraganglioma, carcinoid tumor, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, and metastatic renal clear cell carcinoma, were included as microscopic differential diagnoses. A broad immunohistochemical panel was used, with the neoplastic round cells showing positivity for chromogranin, synaptophysin, neuronspecific enolase, and CD56. Scattered cells were also positive for S100 protein, whereas vimentin reactivity marked the stromal elements. The Ki67 proliferative index was very low (Figures 4 and 5). Reactions against pan-cytokeratin (AE1/AE3), CK7, CK8, CK18, CD99, leukocyte common antigen (LCA), desmin, glial fibrillary acidic protein, and calcitonin were negative. Although the immunohistochemical results obtained were also consistent with a diagnosis of olfactory neuroblastoma, the microscopic absence of rosettes and the location of the neoplasm not affecting the nasal cribriform plate helped rule out this diagnosis. The lack of reactivity for cytokeratins and calcitonin excluded the possibility of an atypical carcinoid tumor, whereas negativity for desmin, CD99, and LCA excluded rhabdomyosarcoma, Ewing sarcoma, and lymphomas, respectively. Alveolar soft part sarcoma was excluded due to the absence of periodic acid-Schiffepositive crystalloid materials. Clinical screening of the patient failed to find evidence of a primary cancer somewhere else, excluding the possibility of a metastatic renal cell carcinoma. Hence, given the clinical, imaging, morphologic, and immunohistochemical features, the final diagnosis of paraganglioma affecting the sinonasal tract and extending to the oral cavity was made. Treatment comprised a partial maxillectomy with wide surgical margins, but after 10 months of follow-up, a local recurrence was detected by computed tomography, and the patient was subjected to a new surgical approach. After 12 months of follow-up from the second treatment, no signs of recurrences could be seen.

DISCUSSION Paragangliomas are uncommon tumors that originate from the extra-adrenal paraganglia tissue, a complex cell system that originated from the embryologic neural crest found in different anatomic locations.18-24 Head and neck paragangliomas are rare, comprising only 0.6% of all head and neck tumors, with the incidence ranging from 1:30,000 to 1:100,000.19,22 Gender preponderance

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varies according to the affected site, but a slight female preponderance is usually described, and patients are more frequently in the fourth to sixth decades of life. The bifurcation of the carotid artery (carotid body tumor) is, by far, the most affected location in the head and neck, followed by the vagus nerve (glomus vagale tumor), jugular bulb (glomus jugulare tumor), and the middle ear (glomus tympanicum tumor). Paragangliomas affecting other sites, including the nasopharynx, larynx, thyroid, and orbit, have also been described.18-24 The present case is a rare clinical presentation of paraganglioma affecting the sinonasal structures, but a few previous reports of paraganglioma involving this anatomic location can be found in the literature.19,25,26 Moreover, primary or secondary involvement of the oral cavity is also very rare, and adequate clinical, microscopic, and immunohistochemical descriptions are not available in most of the previous reports.18,27-31 Most paragangliomas are asymptomatic, but symptoms can range from pain, hearing loss, otalgia, tinnitus, cranial neuropathy, dysphagia, facial weakness, vocal fold paresis, nasal obstruction, and epistaxis, depending on the anatomic site affected.22,32 A small proportion of tumors (1%-3% of cases) may secrete active mediators, similar to their adrenal counterparts (pheochromocytomas), causing diarrhea, hypertension, palpitations, headache, and flushing.20,32,33 In the current case, the patient presented with only infraorbital pain and tingling, probably caused by compression of the infraorbital nerve resulting from neoplastic growth, as described previously by Chapman et al.22 About 10% of head and neck paragangliomas have a familial history, with simultaneous and/or bilateral tumors being more frequently described in such cases than in spontaneous presentations (40% vs 10%, respectively).20,21,34 The great majority of paragangliomas are considered benign, but 6% to 19% of cases exhibit a malignant behavior, particularly in familial cases. Unfortunately, histologic criteria are not reliable for distinguishing between benign and malignant tumors, and malignancies can only be confirmed by eventual cervical or distant metastases or repeated local recurrences.20,21,23,34 In this case, the patient denied any familial history and did not reveal evidence of metastases or involvement of other anatomic sites. The local recurrence 10 months after the first surgery was attributed to incomplete resection due to the location of the tumor. Despite their highly suggestive microscopic appearance, paragangliomas arising in rare locations, such as the maxillary sinus, can be difficult to diagnose correctly. The histologic differential diagnoses include olfactory neuroblastoma, carcinoid tumors, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, and metastatic renal clear cell carcinoma. In these cases, immunohistochemistry will be helpful in achieving the correct diagnosis. As

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Fig. 3. Histopathologic features. (A) A neuroendocrine neoplasia exhibiting an organoid growth pattern with evident formation of small nests, giving rise to the typical “zellballen” structures, separated by thin fibrovascular septa (H&E; 200 X). (B) Tumor cells showing an abundant lightly eosinophilic granular to clear cytoplasm, with bland, round, hyperchromic nuclei, indistinct nucleoli, and a few atypical cells (H&E; 400 X).

Fig. 4. Immunohistochemical reactions (streptavidin-biotin; 400 X). The chief cells were positive for (A) chromogranin, (B) synaptophysin, and (C) neuron-specific enolase, whereas (D) S100 positivity was seen in scattered sustentacular cells.

Fig. 5. Immunohistochemical reactions (streptavidin-biotin; 400 X). (A) Tumor cells also proved to be positive for CD56, (B) with a low Ki67 expression.

illustrated in the current case, paragangliomas usually show diffuse positivity for neuroendocrine markers, such as chromogranin, synaptophysin, neuron-specific enolase, and CD56. Reactivity for S100 and occasionally for glial fibrillary acidic protein can be seen in the so-called

sustentacular cells of paragangliomas that surround the neoplastic chief cell nests (zellballen), which are believed to represent a reactive cellular component of the neoplasm.35 This feature is helpful in differentiating paragangliomas from rhabdomyosarcoma and metastatic

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renal clear cell carcinoma. However, in the current case, only a focal staining pattern was seen for S100 protein, not completely surrounding the tumor nests, as usually described. In fact, a variation in the S100 protein staining pattern has been reported in the literature, and loss of S100-positive sustentacular cells in paragangliomas and pheochromocytomas seems to be correlated with the more aggressive clinical behavior of these entities.36-38 Tumor cells are negative for cytokeratin, differentiating paragangliomas from carcinoid tumors. Actually, carcinoid tumor was our main microscopic differential diagnosis; however, as cited above, the tumor was negative for the AE1/AE3 pan-marker and for specific cytokeratins, such as CK7, CK8 and CK18, and calcitonin. Finally, the absence of periodic acid-Schiff staining helps distinguish paraganglioma from alveolar soft part sarcoma, which would show crystals positive with this staining.21,28,39 Although there is no consensus about the optimal treatment for paragangliomas, surgery still represents the main therapeutic approach, but radiotherapy may also be used to control tumor growth.24 Local recurrences can occur, depending on the affected site and the treatment used, but a 5-year survival rate as high as 80% is frequently described.32,33 As noted above, although surgery was performed in the current case, local recurrence was seen after 10 months, and a new surgical intervention was undertaken, but no radiotherapy was applied. The patient is currently free of disease and under a strict follow-up regimen. In conclusion, sinonasal and oral involvement by paragangliomas is extremely rare, and this tumor is usually not considered in the list of differential diagnoses of lesions affecting these anatomic locations, thereby becoming a challenge for clinicians and oral pathologists. REFERENCES 1. Vargas PA, Gerhard R, Araújo Filho VJF, Castro IV. Salivary gland tumors in a Brazilian population: a retrospective study of 124 cases. Rev Hosp Clín Fac Med Sao Paulo. 2002;57:271-276. 2. Fonseca FP, Carvalho MV, Almeida OP, et al. Clinicopathologic analysis of 493 cases of salivary gland tumors in a Southern Brazilian population. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:230-239. 3. Yüce S, Uysal IÖ, Dogan M, Ersin T, Müderris S. Canalicular adenoma of the palate. J Craniofac Surg. 2012;23:e396-e398. 4. Grossmann SMC, Johann AC, Castro WH, Friedman H, Gomez RS, Mesquita RA. Anterior midline nodule of the hard palate. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:808-811. 5. Smullin SE, Fielding AF, Susarla SM, Pringle G, Eichstaedt R. Canalicular adenoma of the palate: case report and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;98:32-36. 6. Suarez P, Hammond HL, Luna MA, Stimson PG. Palatal Canalicular Adenoma: report of 12 cases and review of the literature. Ann Diagn Pathol. 1998;2:224-228.

OOOO February 2015 7. Pires FR, Pringle GA, Almeida OP, Chen SY. Intra-oral minor salivary gland tumors: a clinicopathological study of 546 cases. Oral Oncol. 2007;43:463-470. 8. Ribeiro ACP, Carlos R, Díaz KP, Gouvêa AF, Vargas PA. Bilateral central ossifying fibroma affecting the mandible: report of an uncommon case and critical review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol. 2011;111:e21-e26. 9. Ribeiro ACP, Carlos R, Speight PM, et al. Peritrabecular clefting in fibrous dysplasia of the jaws: an important histopathologic feature for differentiating fibrous dysplasia from central ossifying fibroma. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114: 503-508. 10. Bertoni F, Bacchini P, Hogendoorn PCW. Chondrosarcoma. In: Fletcher CD, Unni KK, Mertena F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: WHO IARC Press; 2002:247-251. 11. Raymond AK, Ayala AG, Knuutila S. Osteosarcoma. In: Fletcher CD, Unni KK, Mertena F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: WHO IARC Press; 2002:264-270. 12. Junior AT, Alves FA, Pinto CA, Carvalho AL, Kowalski LP, Lopes MA. Clinicopathological and immunohistochemical analysis of twenty-five head and neck osteosarcomas. Oral Oncol. 2003;39:521-530. 13. Pontes HA, Pontes FS, Abreu MC, et al. Clinicopathological analysis of head and neck chondrosarcoma: three case reports and literature review. Int J Oral Maxillofac Surg. 2012;41:203-210. 14. Prado FO, Nishimoto IN, Perez DE, Kowalski LP, Lopes MA. Head and neck chondrosarcoma: analysis of 16 cases. Br J Oral Maxillofac Surg. 2009;47:555-557. 15. Bridge JA, Bowen JM, Smith RB. The small round blue cell tumors of the sinonasal area. Head Neck Pathol. 2010;4:84-93. 16. Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol. 2002;15: 264-278. 17. Iezzoni JC, Mills SE. “Undifferentiated” small round cell tumors of the sinonasal tract. Differential diagnosis update. Am J Clin Pathol. 2005;124:S110-S112. 18. Tashiro M, Nagasel M, Nakajima T, Akita S, Nemoto K. Malignant paraganglioma. Report of a case and review of the Japanese literature. J Cranio Maxillofac Surg. 1988;16:324-329. 19. Mouadeb DA, Chandra RK, Kennedy DW, Feldman M. Sinonasal paraganglioma: endoscopic resection with 4-y follow-up. Head Neck. 2003;25:1077-1081. 20. Pellitteri PK, Rinaldo A, Myssiorek D, et al. Paragangliomas of the head and neck. Oral Oncol. 2004;40:563-575. 21. Weiss SW, Goldblum JR, Folpe AL. Enziger and Weiss’s Soft Tissue Tumors. 5th ed. St. Louis, MO: Mosby; 2007. 22. Chapman DB, Lippert D, Geer CP, et al. Clinical, histopathologic, and radiographic indicators of malignancy in head and neck paragangliomas. Otolaryngol Head Neck Surg. 2010;143:531-537. 23. Mendenhall WM, Amdur RJ, Vaysberg M, Mendenhall CM, Werning JW. Head and neck paragangliomas. Head Neck. 2011;33:1530-1534. 24. Destito D, Bucolo S, Florio A, Quattrocchi C. Management of head and neck paragangliomas: a series of 9 cases and review of the literature. Ear Nose Throat J. 2012;91:366-375. 25. Talbot AR. Paraganglioma of the maxillary sinus. J Laryngol Otol. 1990;104:248-251. 26. Jin HR, Lee OJ, Ahn Y. Nasal cavity paraganglioma with malignant transformation: a case report. Auris Nasus Larynx. 2008;35:137-139. 27. Peters E, Richards A, Hille J, Phillips J. Malignant neuroendocrine tumor presenting in the mandible. Head Neck. 1991;13: 234-238.

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Reprint requests: Hélder Antônio Rebelo Pontes, DDS, PhD Service of Oral Pathology João de Barros Barreto University Hospital Federal University of Pará Belém, Brazil [email protected]

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