Malignant paraganglioma metastatic to the mandible: Case report and review of the literature

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ARTICLE IN PRESS Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2015) xxx–xxx

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Case Report

Malignant paraganglioma metastatic to the mandible: Case report and review of the literature Camilo A. Eslava a , Elías Franco-Pretto a,∗ , Valentina Sánchez b , María H. Astorquiza c a Oral and Maxillofacial Surgery Department, Hospital Militar Central, Universidad Militar Nueva Granada, Transversal 3rd # 49-00 “Imagenes Diagnosticas” Building, Fourth Floor, Bogot D.C. 110231, Colombia b Oral and Maxillofacial Surgery Department, Oral and Maxillofacial Surgery Program at Hospital Militar Central, Universidad Militar Nueva Granada, Transversal 3rd # 49-00 “Imagenes Diagnosticas” Building, Fourth Floor, Bogot D.C., Colombia c South Isle Pathology Department, Pathology Group at Hospital Militar Central, Universidad Militar Nueva Granada, Transversal 3rd # 49-00 Main Building, Third Floor, Bogot D.C., Colombia

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Article history: Received 7 August 2014 Received in revised form 28 August 2015 Accepted 1 September 2015 Available online xxx Keywords: Paraganglioma Extra-adrenal paraganglioma Malignant paraganglioma Head and neck paraganglioma Carotid body tumor

a b s t r a c t This report describes a rare case of malignant paraganglioma metastatic to the mandible in a 22-year-old male patient diagnosed with retroperitoneal malignant paraganglioma and is accompanied by a review of the literature. Clinical examination at the first presentation to the Oral and Maxillofacial Surgery Department revealed a non-tender soft growing mass localized in the right mandibular angle. Intraoral examination revealed healthy oral mucosa without expansion and without malocclusion. CT showed that the right mandibular angle was compromised with lateral and medial soft tissue displacement. In addition, CT angiography revealed that the mass was highly vascular, with the external carotid artery serving as the main blood supply. After tumor resection, histopathology revealed malignant paraganglioma metastatic to the mandible. To our knowledge, this is the second case of malignant paraganglioma metastatic to the mandible to be reported in the literature. © 2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽

1. Introduction Paraganglioma is an uncommon vascularized extra-adrenal tumor of neuroectodermal origin representing 0.012% of all tumors of the body [1]. In the head and neck region, this tumor accounts for 0.6% of all head and neck tumors, and it frequently occurs in the carotid body [2]. Paraganglioma metastatic to the mandible is not well documented in the literature. There is no consensus in the literature regarding a specific treatment modality for malignant paraganglioma of the head and neck region. Treatment modalities are difficult to establish as there are no specific clinical features differentiating benign paraganglioma from its malignant counterpart. This report reviews a case of paraganglioma with metastasis to the mandible and provides a review of the literature to discuss

夽 Asian AOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology; JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants. ∗ Corresponding author. Tel.: +507 60927298. E-mail addresses: [email protected] (C.A. Eslava), [email protected] (E. Franco-Pretto), valen [email protected] (V. Sánchez), [email protected] (M.H. Astorquiza).

the etiology, diagnosis, treatment and histopathology of malignant paraganglioma metastatic to the head and neck region. 2. Case presentation In March 2012, a 22-year-old Latin-American man from Bogot D.C., Colombia was admitted to the Oral and Maxillofacial Surgery Department at Hospital Militar Central, Bogot D.C. with persistent swelling around the right mandibular angle area lasting for four weeks. The patient denied pain or any sensorial disturbances. The patient’s past-medical history included retroperitoneal paraganglioma diagnosed in September 2011, which was treated with chemotherapy. The patient denied any family history of paraganglioma or any familial syndrome. In January 2012, during an oncology follow-up consult, the patient mentioned a three-week history of sternal pain, diaphoresis and tachycardia. Imaging work-up revealed a sternal mass. A biopsy was performed, and histopathology revealed malignant retroperitoneal paraganglioma metastatic to the sternum. The sternal mass was completely resected in January 2012. Although the retroperitoneal tumor did not resolve completely with chemotherapy, its size was reduced. The patient was then placed under follow-up observation and was admitted to our department.

http://dx.doi.org/10.1016/j.ajoms.2015.09.003 2212-5558/© 2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽

Please cite this article in press as: Eslava CA, et al. Malignant paraganglioma metastatic to the mandible: Case report and review of the literature. J Oral Maxillofac Surg Med Pathol (2015), http://dx.doi.org/10.1016/j.ajoms.2015.09.003

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Fig. 1. (A) Pre-surgical facial appearance. Slight facial asymmetry due to a growing mass localized in the right mandibular angle (arrows). (B) Panoramic image. This radiograph shows a unilocular radiolucency with uncorticated borders extending from the right proximal ramus and compromising the ipsilateral mandibular angle (arrows).

At presentation, the patient’s general condition was fair. Head and neck exam revealed a non-tender soft growing mass localized in the right mandibular angle (Fig. 1A). Intraoral examination revealed healthy oral mucosa without expansion and no malocclusion; the patient’s oral hygiene was good. A panoramic radiograph revealed radiolucency with ill-defined, uncorticated borders compromising the right ramus and mandibular angle (Fig. 1B). CT scans revealed erosion of the right mandibular angle. Additionally, CT angiography revealed a highly vascular mass occupying the right mandibular angle, and its main blood supply was the external carotid artery (Fig. 2). Neurosurgery was scheduled for embolization of the external carotid artery prior to mandibular angle bloc resection. In April 2012, the planned bloc resection was performed under general anesthesia through an intraoral mandibular vestibular approach. A well-defined reddish 35 mm 40 mm 30 mm mass was evidently protruding from the external cortical plate of the right mandibular angle. The mandibular angle was resected toward the ipsilateral second molar, and a mandibular reconstruction Threadlock TS 3.0 profile KLS Martin plate was placed (Gebr der Martin GmbH & Co. KG, Ludwigstaler Str. 132, D-78532, Tuttlingen, Germany) (Fig. 3A and B). During surgery, the patient had sustained hypertension (mean arterial pressure 150/80 mmHg) and tachycardia, which returned to normal after complete removal of the mandibular mass and without medication. Histopathology findings revealed cuboid-polygonal cells with a basophilic cytoplasm and hyperchromatic nuclei arranged in nests, consistent with the pathology observed in the retroperitoneum

(Fig. 4A). Immunohistochemistry was positive for synaptophysin, chromogranin A and enolase (Fig. 4B, C and D). In July 2012, during imaging follow up, newly developing lesions were found in the C2 and C3 vertebrae and were assessed and managed surgically by the neurosurgery-spine team. Histopathology revealed malignant paraganglioma metastatic to the cervical spine. Sixteen months after the patient was referred to the Oral and Maxillofacial Surgery Department, he arrived at the emergency room after experiencing apparently tonic-clonic seizures that lasted approximately 10 min accompanied by oppressive nonirradiated thoracic pain, frontal pain and blurred vision. The patient developed cardiopulmonary arrest and did not respond to resuscitation efforts.

3. Discussion Paragangliomas are uncommon vascularized extra-adrenal tumors of neuroectodermal origin. The reported incidence of head and neck paragangliomas ranges from 1:300,000 to 1:1,000,000 individuals, and interestingly, less than 5% of these tumors are malignant. The mean age at diagnosis is 34.5 years, and it accounts for 0.6% of all head and neck tumors [1–4]. Paraganglioma can be of sporadic or familial presentation. Sporadic forms of the disease appear as a single mass or as bilateral tumors in 10% of cases. The familial subset is associated with syndromic entities, such as multiple endocrine neoplasia type II, Von Hippel-Lindau syndrome and neurofibromatosis type 1. It was not possible to assess whether the case reported in this article was of

Fig. 2. Head and neck CT angiography. Highly vascular right mandibular mass (arrow) with a blood supply provided by the right external carotid artery (mainly provided by the right facial artery).

Please cite this article in press as: Eslava CA, et al. Malignant paraganglioma metastatic to the mandible: Case report and review of the literature. J Oral Maxillofac Surg Med Pathol (2015), http://dx.doi.org/10.1016/j.ajoms.2015.09.003

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Fig. 3. (A) Resection product. A well-defined reddish mass and the right mandibular angle, which was fractured at the inferior border, are shown. (B) Immediate reconstruction. A reconstruction plate was immediately placed in order to maintain facial contour and mandibular function.

sporadic or familial presentation due to the lack of equipment to confirm or discard genetic mutation [1,2]. Peters et al. [5] reported a case of mandibular paraganglioma. Facial asymmetry, ipsilateral lower lip, cheek and teeth numbness and cortical bone expansion were the main clinical features observed in that case. Peters suggested that these features were present because paraganglioma behaves as a space-occupying tumor in this bone, causing compression of the inferior alveolar nerve. These symptoms and clinical findings, except for sensorial disturbance, are consistent with those found in this report. Specific symptoms depend on the tumor location. To our knowledge, this is the second case of mandibular paraganglioma reported in the literature, and this disease has not been adequately documented in the literature.

Mitochondrial enzymatic defects have been implicated in tumorigenesis; however, the exact mechanism by which mitochondrial somatic mutations cause tumor growth is still not known. Paraganglioma is the first model to associate heritable mitochondrial defects with cancer. There is a strong link between heritable succinate dehydrogenase (SDH) mutations and uncontrolled cellular proliferation in the paraganglia [6]. SDH is a mitochondrial enzyme complex involved in electron transfer and is composed of four subunits (SDHA, SDHB, SDHC, and SDHD). Mutations in the SDHB, SDHC, and SDHD subunits cause a genetic predisposition for head and neck paraganglioma. Paternal transmission of SDHD mutations more frequently predispose individuals to multifocal head and neck paraganglioma in 89%–99% of cases, with multiple tumors in 30%–55% of cases (most of which are

Fig. 4. Histopathology and immunohistochemistry analysis of mandibular angle resection product under light microscope at 40X. (A) Hematoxylin & eosin staining reveals cuboid, polygonal cells (Type I) with basophilic cytoplasm containing abundant granules and enlarged and hyperchromatic nuclei (arrowhead). These Type I cells are arranged in nests (Zellballen s pattern) separated by fibrovascular septae, surrounded by a single layer of flattened cells (type II) and embedded in a fibro-vascular stroma. Type I cells stained positive for chromogranin A (B), enolase (C), and synaptophysin (D). These findings confirm malignant paraganglioma metastatic to the mandible.

Please cite this article in press as: Eslava CA, et al. Malignant paraganglioma metastatic to the mandible: Case report and review of the literature. J Oral Maxillofac Surg Med Pathol (2015), http://dx.doi.org/10.1016/j.ajoms.2015.09.003

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benign (93%–100%)). In contrast, SDHB mutations are more likely to predispose individuals to malignant paraganglioma. There is no experimental evidence that explains why maternal transmission of SDHD mutations rarely causes paraganglioma [6,7]. The penetrance and population genetics of SDHD mutations appear to be influenced by pulmonary chronic disease and environmental factors (altitude); living at higher altitudes increases the phenotypic severity of paraganglioma. Sporadic cases can develop in a chronic hypoxic environment without mutation [8]. Interestingly, the patient presented in this article had lived almost his entire life in Bogot D.C., Colombia, which is the third highest capital city in South America at 2625 m (8612 feet) above sea level. The location and extent of head and neck paraganglioma are evaluated by computer tomography (CT) and magnetic resonance imaging (anatomic imaging) and are useful for detecting synchronous paragangliomas [9–11]. Both imaging modalities have >90% sensitivity, but lack specificity [12]. Angiography and angio CT are the best imaging modalities for surgical approach planning. Tumors detected by CT or MRI can also be screened for secretory activity and/or metastatic activity by means of functional imaging agents that accurately target the catecholamine metabolism that is present in chromaffin cells. These include I-metaiodobenzylguanidine (MIBG) scintigraphy and F-fluorodopamine and F-fluorodihydroxiphenylalanine positron emission tomography (PET) [12]. However, Timmers et al. [13] stated that metastatic lesions of SDHB-related secreting paragangliomas are best assessed with F-fluorodeoxyglucose PET (FDG-PET), which has been demonstrated to be superior to other functional imaging techniques. It was not possible to screen for the secretory activity of the tumor in the case presented in this report due to lack of equipment at the institution. Nuclear pleomorphism, mitotic activity, and vascular perineural invasion are not reliable features for determining biologic behavior or establishing differences between benign and malignant paraganglioma because those histologic features are equally observed in both subtypes. Evidence of lymph node and/or distant metastases is the ultimate criteria for malignancy. Invasion to adjacent structures does not indicate malignancy [14–16]. In this case the tumor had a preponderance of polygonal cells with basophilic cytoplasm containing abundant granules and enlarged and hyperchromatic nuclei, with increased nuclear/cytoplasmic ratio. Interestingly, invasive growth pattern, mitotic figures and other histopathological features suggestive of malignancy were absent. Papaspyrou et al. [17] performed surgical resection on 137 head and neck paragangliomas with a recurrence rate of 19%. The authors emphasized that treatment of paraganglioma must be individualized based on the patient’s age, medical condition, tumor site and size and number of occurrences. Although a multidisciplinary approach is advocated, to our knowledge, there is no standardized treatment for head and neck malignant paraganglioma, apparently

because of its rare occurrence. Despite a multidisciplinary treatment approach, in this case the patient’s disease persisted and disseminated. Conflict of interests There is no duplicate publication of this article. Neither the author, nor any coauthor of this article has any neither financial nor commercial association within the past years that might pose a potential or real conflict of interest. Institutional funding was not necessary since histopathology processing and analysis are part of diagnostic services provided by Hospital Militar Central. References [1] Sevilla MA, Llorente JL, Tapia JP, Garc a G, Suarez V, Pelaza A, et al. Head and neck paragangliomas: revision of 89 cases in 73 patients. Acta Otorrinolaringol Esp 2007;58:94–100. [2] Chapman DB, Lippert D, Geer CP, Edwards HD, Russell GB, Rees CJ, et al. Histopathologic, and radiographic indicators of malignancy in head and neck paragangliomas. Otolaryngol Head Neck Surg 2010;143:531–7. [3] Rinaldo A, Ferlito A. Which paragangliomas of the head and neck have a higher rate of malignancy? Oral Oncol 2004;40:458–60. [4] Jin HR, Lee OJ, Ahn Y. Nasal cavity paraganglioma with malignant transformation: a case report. Auris Nasus Larynx 2008;35:137–9. [5] Peters E, Richards A, Hille J, Phillips J. Malignant neuroendocrine tumor presenting in the mandible. Head Neck 1991;13:234–8. [6] Barbara O, Stratakis C. SDH mutations in tumourigenesis and inherited endocrine tumours. J Intern Med 2009;266:19–42. [7] Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet 2003;113:228–37. [8] Baysal B. Clinical and molecular progress in hereditary paraganglioma. J Med Genet 2008;45:689–94. [9] Bravo EL, Tarazi RC, Gifford RW, Stewart BH. Circulating and urinary catecholamines in pheochromocytoma. Diagnostic and pathophysiologic implications. N Engl J Med 1979;301:682–6. [10] Koopamans KP, Jager PL, Kema IP, Kerstens MN, Albers F, Dullaart RP. 111noctreotide is superior to 123I-metaiodobenzulguanidine for scintigraphic detection of head and neck paragangliomas. J Nucl Med 2008;49:1232–7. [11] Neves F, Huwart L, Jourdan G, Reizine D, Herman P, Vicaut E, et al. Head and neck paragangliomas, Value of contrast-enhanced 3D MR angiography. AJNR Am J Neuroradiol 2008;29:883–9. [12] Maurea S, Cuocolo A, Reynolds JC, Neumann RD, Salvatore M. Diagnostic imaging in patients with paragangliomas. Computed tomography, magnetic resonance and MIBG scintigraphy comparison. Q J Nucl Med 1996;40:365–71. [13] Timmers HJ, Kozupa A, Chen CC, Carrasquillo JA, Ling A, Eisenhofer G, et al. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol 2007;25:2262–9. [14] Nguyen QA, Gibbs PM, Rice DH. Malignant nasal paraganglioma: a case report and review of the literature. Otolaryngol Head Neck Surg 1995;113:157–61. [15] Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 2002;26:551–66. [16] van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 2009;10:764–71. [17] Papaspyrou K, Mann WJ, Amedee RG. Management of head and neck paragangliomas: review of 120 patients. Head Neck 2009;31:381–7.

Please cite this article in press as: Eslava CA, et al. Malignant paraganglioma metastatic to the mandible: Case report and review of the literature. J Oral Maxillofac Surg Med Pathol (2015), http://dx.doi.org/10.1016/j.ajoms.2015.09.003