Head and neck paragangliomas

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Author's personal copy ADVANCES IN HEAD AND NECK PATHOLOGY

Head and neck paragangliomas: what does the pathologist need to know? Ozgur Mete

proximal cervical branches of the aorta, larynx, trachea, cervical esophagus, thyroid, parathyroid, orbit, external ear, tongue, and skin.2,4e19 The most recent data suggest that at least 30e40% of PGLs are associated with inherited disease.20e28 Patients with inherited disease often present at younger ages and are more likely to have multifocal disease including pheochromocytomas arising from intra-adrenal sympathetic paraganglia. In this review, we discuss the clinical, biochemical, radiological, morphological, and molecular features of the head and neck PGLs to highlight the timely topics in this field by emphasizing the role of pathologist in the management of these neoplasms.

Abstract

The normal paraganglia

Paragangliomas can occur in a variety of anatomic locations in the head and neck region and can create diagnostic challenges for practicing pathologists. The most recent data suggest that at least 30e40% of paragangliomas are associated with inherited disease. Occasional VHL-, TMEM127-, and SDHA-related head and neck paragangliomas have been described; however, the bulk of hereditary disease in the head and neck paraganglioma is associated with SDHD, SDHC, SDHB, and SDHAF2 mutations. While the distinction of paragangliomas from other head and neck neoplasms is very important, the clinical responsibility of surgical pathologists has evolved and also includes the integration of SDHB immunohistochemistry into the routine pathology practice. In this article, we highlight an approach to clinicopathological diagnosis of head and neck paragangliomas along with a comprehensive discussion on genotypeebiochemical profile correlation and synoptic report approach in paragangliomas.

In order to better understand the clinicopathological features of head and neck paragangliomas, one has to know the basic characteristics of the normal paraganglia.

Toshitetsu Hayashi

Clinical anatomy Head and neck paraganglia is typically seen in close association with vascular structures, ganglia and nerve branches of the autonomic nervous system, especially along the cranial and thoracic branches of the glossopharyngeal and vagus nerves.29 With the exception of the carotid bodies, head and neck paraganglia are highly variable in both number and location.29,30 Four major parasympathetic paraganglia have been defined in the head and neck region as follows: (a) carotid body paraganglia, (b) jugulotympanic paraganglia, (c) vagal paraganglia, and (d) laryngeal paraganglia.29 In fact, PGLs arising from these four paraganglia refer to general locations, rather than to specific anatomic structures.29,31 Occasionally PGLs can also occur in sites other than these four anatomic structures including paravertebral cervical sympathetic ganglia.29 Tympanic PGLs arise from dispersed paraganglia along the tympanic nerve (also known Jacobson’ nerve, a branch of the glossopharyngeal nerve) in the middle ear cavity; whereas jugular PGLs arise from anatomically dispersed paraganglia near the base of the skull and lateral temporal bone.29,31 Vagal PGLs collectively encompass PGLs arising from multiple dispersed paraganglia located within or adjacent to the vagus nerve, especially at the level or just below the lower border to the ganglion nodosum.29 On the other hand, laryngeal PGLs arise from either superior or inferior components of multiple dispersed paraganglia located near the larynx, in relation to the cricoid and thyroid cartilages.11,29 For example, thyroid and laryngeal PGLs are linked to disperse elements of laryngeal paraganglia.11,14,29 Of note, rare PGLs arising from orbit, pituitary gland, pineal gland, cerebellum, sinonasal cavity, nasopharynx, along proximal cervical branches of the aorta, trachea, cervical esophagus, thyroid, parathyroid, external ear, tongue, and skin have also been described justifying the wide spectrum of PGLs arising from miscellaneous paraganglia of the head and neck region.2,4e19

Keywords catecholamines; genotypeephenotype correlation; paragangliomas; hydroxylase

succinate

dehydrogenase;

synoptic

report;

tyrosine

Introduction Head and neck paragangliomas (PGLs) are neuroendocrine neoplasms arising from chief cells of the paraganglia.1 These neoplasms account for approximately 3% of all PGLs.2 Head and neck PGLs often present with a slow-growing painless mass in middle-aged adults.3 PGLs can occur in a variety of anatomic locations in the head and neck regions; however, the most common sites are the carotid bodies. Less frequently these neoplasms can originate from the skull base and temporal bone regions along the length of the vagus nerve, sellar region, pineal gland, cerebellum, sinonasal cavities, nasopharynx, along

Toshitetsu Hayashi MD Consultant Pathologist, Department of Pathology, University Health Network, Toronto, Ontario, Canada; Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan. Conflicts of interest: none declared. Ozgur Mete MD Consultant Endocrine Pathologist, Department of Pathology, University Health Network, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Endocrine Oncology Site Group, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Conflict of interest: none declared.

DIAGNOSTIC HISTOPATHOLOGY 20:8

Functional histology The paraganglia are of neuroectodermal origin, and are found among or near the components of the autonomous nervous system.29,30 Even at the earliest developmental stage, primitive precursor cells that will be differentiating into neural, glial, and neuroendocrine cells have the ability to produce catecholamines.

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In contrast to adrenal medulla, primitive cells disappear from the paraganglia during the second trimester of pregnancy.30 Neuroendocrine cells of the sympathetic paraganglia (e.g. adrenal medulla, pre- and paravertebral paraganglia) are often termed as chromaffin cells due to their strong reaction with chromate salts reflecting their high capacity of oxidation and polymerization of the catecholamines within the neurosecretory granules; whereas those associated with parasympathetic nervous system are known as chief cells.29,31 From a functional perspective both chromaffin and chief cells can synthesize and release different catecholamines depending on their association with autonomous system.30 Normal paraganglia, especially the carotid bodies are divided by thick fibrous septa into variable number of lobes. Lobes are further divided by thin septa into small lobules; lobules contain nests of chief cells surrounded by a delicate sustentacular network.29,32 Chief cells contain numerous membrane-bound secretory granules or electron dense-core vesicles measuring from 60 to 450 nm.33 Similar to other neuroendocrine cells, neurosecretory granules may vary in size, shape, and electron-density, reflecting differences in the secretory products stored along with the functional state.33 The carotid bodies and aorticopulmonary paraganglia are chemoreceptors stimulated by hypoxia, hypercapnia, and low pH.29,31,34e39 Hyperplastic changes have been described in carotid body and vagal paraganglia from patients with cardiac and pulmonary conditions leading to chronic hypoxia as well as in normal individuals living at high altitude.34e39 While a precise detailed physiological role has not been established for the majority of other head and neck paraganglia, a chemoreceptor role has also been postulated in vagal and laryngeal paraganglia through the reflex changes mediated by the ganglion nodosum and via regulating air flow during the respiratory cycle, respectively.29,31

Laryngeal PGLs can present with airway obstruction or other symptoms related to compression of the adjacent structures.48 From a clinical symptomatology perspective, the vast majority of parasympathetic head and neck PGLs are considered clinically silent neoplasms; however, this may not be true in all cases since the determination of functional status should be based on biochemical testing but not on clinical symptoms alone. Moreover, catecholamines are not continuously released and biochemical testing is better aimed at measuring the metabolites of dopamine (methoxytyramine), norepinephrine (normetanephrine) and epinephrine (metanephrine) in the urine and/or plasma.43 Similar to other neuroendocrine tumors, PGLs can synthetize and secrete various other peptide hormones that can also cause varied clinical syndromes.42 B-mode and/or color duplex sonography are often used as the first screening step for cervical PGLs. Imaging of carotid, tympanic, and jugular PGL lesions can easily be done using CT or MRI. However, specific identification of a PGL requires functional imaging modalities such as I-MIBG single-photon emission computed tomography (SPECT), 18F-FDOPA or 18F-FDG positron emission tomography (PET).20,42,49e52 The anatomic site along with the functional status of a tumor determines the right choice of imaging modality.20,42,49e52 Use of I-MIBG SPECT or 18F-FDOPA PET is useful for identifying sympathetic PGLs including pheochromocytomas.20,52 On the other hand, primary or metastatic PGLs with low catecholamine content can be detected by using 18F-FDG PET.20,52 Recent data suggest genotypeephenotype correlations in PGLs and pheochromocytomas with respect to tumor distribution, catecholamine production, and risk of metastasis.20,22,42 While genetic data are being changed every day, the most recent data suggest that at least 30e40% of these tumors are associated with at least 13 susceptibility genes (NF-1, RET, VHL, HIF2a, TMEM127, KIF1Bbeta, MAX, PHD2/EGLN1, SDHA, SDHB, SDHC, SDHD, SDHAF2).20e28 Germline mutations of these susceptibility genes have been identified in approximately 70% of patients before age 10 and 60% of patients presenting before age 18.53 Somatic mutations of some of these susceptibility genes also occur in about 14% of sporadic PGLs and pheochromocytomas.20,22,54e56 Tumors associated with VHL, SDHx, and HIF2a mutations are linked to a pseudohypoxic pathway, so-called cluster 1, and RET, NF-1, TMEM127, and MAX mutations are linked to a cluster rich in kinase receptor signaling and its downstream pathways, socalled cluster 2.20,22,42 Giving the genotypeephenotype correlations in these tumors, the current management guidelines require the determination of catecholamine profile of PGLs.20,22,24,42,43 Patients with VHL-related PGLs show increased norepinephrine/normetanephrine, whereas SDH-related tumors (especially those associated with SDHB mutations) show increased dopamine/methoxytyramine and can sometimes show increased norepinephrine/normetanephrine.20,22,42,43 On the other hand, NF-1, TMEM127, MAX, and RET-related tumors show increased epinephrine/metanephrine.20,22,42,43 HIF2a shows similar phenotype to VHL and SDH-related tumors.22 Head and neck PGLs are less frequently associated with cluster 2 disease. While occasional VHL-, TMEM127-, and SDHA-related head and neck PGLs have been described, the bulk of hereditary disease in the head and neck PGLs is associated with SDHD, SDHC, SDHB, and

The impact of clinical, biochemical and radiologic findings Paraganglia are biochemically active neuroendocrine organs that synthetize and secrete catecholamines (dopamine, norepinephrine, and epinephrine). Dopamine-secreting PGLs can cause emesis, and diuresis; however, norepinephrine-producing PGLs are often associated with hypertension, and epinephrineproducing tumors are associated with tachyarrhythmia.40,41 In humans, the major source of epinephrine is the adrenal medulla; however, dopamine and/or norepinephrine can be released from any paraganglia, but especially from parasympathetic paraganglia.42,43 In contrast to sympathetic PGLs, dopamine excess in patients with head and neck PGLs is present in approximately 20% of cases and does not cause typical clinical symptoms attributable to norepinephrine or epinephrine excess.44 Therefore, the vast majority of the head and neck PGLs are detected either due to symptoms related to mass effect or as incidentalomas in radiologic studies. Tympanic PGLs can present with tinnitus and aural pulsations, and rarely with conduction-type hearing loss, vertigo, dizziness, otorrhea, and facial palsy.45 Jugular PGLs may sometimes mimic a cerebellopontine angle tumor or a skull base neoplasm, or may destruct the petrous bone and present as a middle ear polyp.46 Both carotid body and vagal PGLs often present with slow-growing neck masses that can sometimes be associated with cranial nerve palsies.47


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SDHAF2 mutations.20,22 Of note, patients with SDH-related PGLs or pheochromocytoma can also be associated with other tumors including pituitary adenomas, gastrointestinal stromal tumors, renal cell carcinomas, and gastroenteropancreatic neuroendocrine tumors.20,57

(PNET), pituitary adenoma, meningioma, melanoma, sarcomas, and thyroid neoplasms.42,58 While recognition of the anatomic distribution of normal paraganglia, biochemical and radiological features suggestive of PGLs provide essential information for practicing pathologists, appropriate use of immunohistochemical markers is required to distinguish head and neck paragangliomas from other neoplasms. The first step starts with the confirmation of neuroendocrine differentiation. The commonly used markers defining neuroendocrine differentiation are chromogranin-A and synaptophysin. One has to remember that synaptophysin and chromogranin-A can be expressed in a variety of neuroendocrine tumors. Therefore, the possibility of a PGL should be questioned when dealing with a keratin- and transcription factor-negative neuroendocrine tumor (NET). The diagnosis of PGL should be confirmed with positivity for tyrosine hydroxylase, the rate limiting enzyme in the catecholamine synthesis (Figures 1e3).42

Diagnostic steps in the assessment of paragangliomas Grossly, these neoplasms are firm lesions that may show regions of hemorrhage or cystic degeneration. They often have a thin pseudocapsule attached to neurovascular structures. PGLs can sometimes display clear cell change, spindle cell change, oncocytic change, pigmented cells, angiomatoid areas, and prominent sclerosis that can mimic metastatic carcinomas with clear cell change, metastatic or primary neuroendocrine carcinomas of various head and neck organs, primitive neuroectodermal tumor

Steps in the diagnostic assessment of head and neck paragangliomas

Chromogranin-A (+) and synaptophysin (+)

Tyrosine hydroxylase (– )

Tyrosine hydroxylase (+)

Negative for keratins AE1/AE3, CAM5.2 Negative for transcription factors TTF-1 (–), PAX8 (–), CDX2 (–) Negative for some secretory peptides PTH, monoclonal CEA

No evidence of catecholamine excess

Unusual anatomic locations

Carotid body*

PGL

Increased blood and/or urinary catecholamines or their metabolites *Dopamine/methoxytyramine *Norepinephrine/normetanephrine *Epinephrine/metanepinephrine

Loss of SDHB expression

Intact SDHB expression

Genetic testing for SDHx genes SDHD SDHB SDHC SDHA SDHAF2

Genetic testing for other genes associated with inherited disease

The diagnosis of PGL cannot be rendered PGL Additional studies including ultrastructure, other site-specific transcription factors and hormones are required to better characterize this lesion

Carotid body* refers to anatomically well defined parasympathetic paraganglia of the head and neck region in this algorithm. It is known that parasympathetic paragangliomas of the head and neck region can sometimes be focally positive or even negative for tyrosine hydroxylase. This pattern can also be seen in chromogranin-A. *Dopamine, *Norepinephrine, and *Epinephrine refer to parent catecholamines.

Figure 1


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Figure 2 Carotid body paraganglioma. Carotid body paragangliomas often present with firm nodular lesions and have a thin pseudocapsule attached to neurovascular structures (a). Carotid body parangliomas often display an acinar (zellballen) growth pattern (b). Positivity for chromogranin-A (c) and tyrosine hydroxylase (d) is usually weaker and more variable in parasympathetic than in sympathetic paragangliomas. Carotid body paragangliomas can sometimes be negative for chromogranin-A and tyrosine hydroxylase. The identification of S100-positive sustentacular network is often linked to paragangliomas (e); however, this finding is not specific for paragangliomas and can be seen in other neuroendocrine neoplasms.

S100-positive sustentacular network is often referred to PGLs; however, this finding is not specific for PGLs, since S100-positive sustentacular cells can be identified in other NETs including pituitary adenomas.59 Moreover, positivity for chromogranin-A and tyrosine hydroxylase is usually weaker and more variable in parasympathetic than in sympathetic PGLs and can sometimes be negative especially in carotid body PGLs (Figures 1 and 2).60 In such scenarios, negativity for transcription factors (TTF-1, PAX8, CDX-2, and etc.), hormones including PTH and monoclonal calcitonin, monoclonal CEA, and keratins is required when dealing with a tyrosine hydroxylase-negative carotid body or thyroid PGL (Table 1). Similar to NETs of various sites, some PGLs selectively express chromogranin-B rather than chromogranin-A. Of note, the ultrastructural examination based on the demonstration of catecholamine containing neurosecretory granules is limited to unusual neoplasms since the diagnostic features of PGLs are now identified by tyrosine hydroxylase immunohistochemistry (Figures 1e3). While PGLs are keratin negative, those arising from filum terminale (cauda equina) can show positivity for keratins.29,42,61


Furthermore, gangliocytic PGLs that consist of variably of a mixture of epithelioid neuroendocrine cells, Schwann-like and scattered ganglion-like cells, can show keratin positivity in the epithelioid cells.29,61 Some authors consider this phenomenon to indicate divergent epithelial differentiation giving rise to tyrosine hydroxylase expression in these PGLs.61 Similar to other NETs, recent guidelines suggest that the proliferation rate (mitotic activity and Ki-67 labeling index) should be provided in PGLs.42 Although it is uncommon, composite PGLs also exist in the head and neck region. The term composite PGL should be defined when a neoplasm combines features of PGL with those of malignant peripheral nerve sheath tumor, ganglioneuroma, ganglioneuroblastoma, and neuroblastoma.42 The identification of multifocal disease (multiple PGLs, or PGL and pheochromocytoma) is one of the signs of inherited disease. The presence of a thick vascular capsule and/or clear cell change may raise the suspicion of a VHL-related PGL.42,62 Loss of SDHB expression is regarded as a surrogate marker for familial paraganglioma syndromes caused by any SDH mutation; therefore SDHB immunohistochemistry has become a part of the

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Figure 3 Jugulotympanic paraganglioma. Magnetic Resonance Imaging studies identified a jugulotympanic paraganglioma (arrows indicate the mass, a). H&E-stained sections reveal an epithelioid neoplasm showing neuroendocrine features (b). The tumor is diffusely and strongly positive for chromograninA (c) and tyrosine hydroxylase (d) confirming the diagnosis of paraganglioma. S100 protein highlights sustentacular network (e). There is no loss of SDHB expression in this tumor (f ). Please note that internal controls (endothelial cells) also show positivity for SDHB (f ).

routine assessment of these neoplasms (Figures 1 and 4).42 The loss of SDHB expression does not only allow for the identification of SDH-related tumors, but also provides important prognostic data due to high frequency of malignant disease associated with SDHB mutations.20,22,42,43 However, the interpretation of SDHB expression can sometimes be challenging, since SDHD-related tumors can display a blush like weak background positivity without the stronger cytoplasmic granular positivity seen in internal control tissue (e.g. endothelial cells) (Figure 4).20,63 Recent data also highlight that commercial antibodies against SDHA can also be used to detect SDHA mutations.42,64 Recently, Mete et al. proposed a new standardized synoptic reporting approach for PGLs and pheochromocytomas to ensure an appropriate and accurate diagnosis of these neoplasms and optimize patient care (Table 1).42

predict malignant behavior in PGLs. According to the 2004 WHO classification of endocrine tumors, malignancy of PGLs is determined by the presence of metastases to sites where paraganglial tissue is not formally found (e.g. bone, lymph node, etc) (Figure 5).65 Therefore, it is important to remember the geographic distribution of normal paraganglia and one has not to consider multifocal disease associated with inherited syndromes as evidence of metastatic disease. Large tumor size (>5 cm) and SDHB mutations are the most important risk factors for malignant (metastatic) disease in head and neck PGLs.27,42

Treatment options The optimal clinical management of PGLs depends on their location, extent and genotypeephenotype correlation. Surgical resection is the main treatment option for PGLs for resectable tumors.20 Since head and neck PGLs are in close association with adjacent neurovascular structures, complete excision can sometimes be challenging and postoperative neurologic deficits can occur. Therefore, irradiation therapy, stereotactic radiosurgery or

Diagnosis of malignant disease Although the criteria of malignancy for these tumors are still debated among pathologists, no single histologic parameter can


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Proposed synoptic reporting template for paraganglioma and pheochromocytoma42

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Table 1 (continued)

Table 1


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(malignant) disease can be challenging and may require combinations of chemotherapy (including cisplatin, vincristine, and dacarbazine).68 Radiolabelled MIBG is offered in some hospitals while external beam radiation is typically palliative for symptomatic skeletal involvement.69,70 Recent data also suggest the role of sunitinib and sorafenib in the treatment of metastatic (malignant) disease.71,72 Similar to sunitinib and sorafenib treatment, there seems to have a therapeutic rationale for antiangiogenic treatment with monoclonal anti-VEGF antibodies, especially in cluster 1 PGLs.20 HIF-1a inhibitors have shown antitumoral effect in xenografts and also seem to be promising particularly for SDHB-related malignant PGLs.73

Conclusions Genetic testing and screening for inherited PGLs is now an important component of the diagnostic and clinical management algorithms of these patients. The appropriate patient management requires a complete integration and evaluation of clinical, genetic, biochemical, imaging, and pathologic findings. While the distinction of PGL from other tumors is very important, the clinical responsibility of surgical pathologists has evolved and also includes the integration of SDHB immunohistochemistry into the routine pathology practice. A

Figure 4 Loss of SDHB expression in SDHx-driven paragangliomas. Loss of SDHB expression is regarded as a surrogate marker for inherited paraganglioma syndromes caused by any SDH mutation; therefore SDHB immunohistochemistry has become a part of the routine assessment of these neoplasms. Both figures (a) and (b) show loss of granular positivity in the tumor. The interpretation of SDHB expression can sometimes be challenging, since SDHD-related tumors can display a blush like weak background positivity (b). The absence of granular positivity similar to endothelial cells is a sign of the loss of SDHB expression (a and b).

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Figure 5 Metastatic (malignant) paraganglioma. Malignancy of paragangliomas is determined by the presence of metastases to sites where paraganglial tissue is not formally found. In this photomicrograph, a metastatic paraganglioma in the lymph node is illustrated. The metastatic tumor was positive for tyrosine hydroxylase and showed loss of SDHB expression. The patient was found to have a SDHB-related carotid body paraganglioma.


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sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer 2012; 118: 2804e12. Gonias S, Goldsby R, Matthay KK, et al. Phase II study of highdose [131I] metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 2009; 27: 4162e8. Safford SD, Coleman RE, Gockerman JP, et al. Iodine -131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma. Surgery 2003; 134: 956e62. Lin Y, Li Q, Huang W, et al. Successful treatment of paraganglioma with sorafenib: a case report and brief review of the literature. Onco Targets Ther 2013; 6: 1559e62. Joshua AM, Ezzat S, Asa SL, Evans AJ, Broom R, Knox JJ. Rationale and evidence for the use of sunitinib in metastatic paraganglioma. J Clin Endocrinol Metab 2009; 94: 5e9. Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G. Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther 2004; 3: 233e44.

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The possibility of a paraganglioma should be questioned when dealing with a keratin- and transcription factor-negative neuroendocrine tumor. The diagnosis of paraganglioma should be confirmed with positivity for tyrosine hydroxylase, especially in unusual localizations. Positivity for chromogranin-A and tyrosine hydroxylase is usually weaker and more variable in parasympathetic than in sympathetic paragangliomas and can sometimes be negative especially in carotid body paragangliomas. The identification of S100-positive sustentacular network is often linked to paragangliomas; however, this finding can also be seen in other neuroendocrine neoplasms. At least 30e40% of paragangliomas are associated with inherited disease. The bulk of hereditary disease in the head and neck paraganglioma is associated with SDHD, SDHC, SDHB, and SDHAF2 mutations. Loss of SDHB expression is regarded as a surrogate marker for inherited paraganglioma syndromes caused by any SDH mutation. Malignancy of paragangliomas is determined by the presence of metastases to sites where paraganglial tissue is not formally found. Genotype-biochemical phenotype correlation exists in paragangliomas, and predicts the likelihood of metastasis. The optimal clinical management of head and neck paragangliomas depends on their location, extent and genotypee phenotype correlation.
