1.Université dAngers, Département de Pathologie Cellulaire et Tissulaire, CHU Angers, 4, rue Larrey, 49100 Angers (AR); Université René Descartes Paris 5, Service dAnatomie Pathologique, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris (CB) France
Review on Head and Neck paragangliomas, with data on clinics, and the genes involved.
Jugulotympanic paraganglioma Jugulotympanic paraganglioma (JTP) may arise from the glomus jugulare (paraganglia located in the vicinity of the jugular bulb, jugular paraganglioma) or, less frequently, from the glomus tympanicum (paraganglia located near the middle ear surface of the promontory/medial promontory wall of the middle ear, tympanic paraganglioma) (Lack, 2007). However, in large jugulotympanic neoplasms, it may not be possible to precise the exact site of origin. JTP develops in adults in the 5th to 6th decade of life (age range 13-85 years) (Lack, 2007). Solitary JTP arises predominantly in females whereas familial cases occur mostly in men. In one large series of sporadic JTP, the female to male ratio was 6 to 1 with a mean age of 55 years (Brown, 1985). Tympanic paraganglioma is usually confined to the middle ear cavity. It may cause tinnitus or aural pulsations, and conduction type hearing loss due to involvement of the ossicles. Large tympanic paraganglioma may fill the middle ear cavity. Patients may display ear fullness or pain, otorrhea, chronic otitis media, vertigo/dizziness, and rarely, facial palsy (Lack, 2007; Barnes et al., 2005). On examination, a red vascular or bluish mass may be seen behind a bulging tympanic membrane or protruding through it into the external ear canal. Biopsy of the mass often results in severe bleeding. Similarly, patients with jugular paraganglioma may suffer from conductive type hearing loss, tinnitus, ear pain, facial palsy, and hemorrhage (Lack, 2007; Barnes et al. 2005). The lesion may extend within the petrous bone and intracranially, occasionally simulating a middle cranial fossa or cerebellopontine angle tumor. The jugular foramen syndrome results in paresis of cranial nerves IX to XII due to compression. JTP (especially hereditary forms) may be bilateral and coexist with CBP, which may also be bilateral, or with pheochromocytoma.
Vagal paraganglioma Vagal paraganglioma (VP) arises from paraganglia found within or adjacent to the vagus nerve in the vicinity of the ganglion nodosum. VP usually presents as a slowly growing asymptomatic mass at the angle of the mandible or as a bulge in the lateral oropharyngeal wall. Cranial nerve deficits are observed in one third to two thirds of patients at the time of diagnosis. Vagus nerve palsy causes ipsilateral vocal cord dysfunction, hoarseness, or dysphagia (Lack, 2007; Barnes et al., 2005). Large tumors may compress other cranial nerves (IX, XI, and XII) in the jugular foramen resulting in dysphagia, atrophy of the tongue, and shoulder weakness. Ipsilateral Horners syndrome may occur following cervical sympathetic chain impairment. Functional VP with catecholamine-induced hypertension is uncommon. Handling of such lesion during surgical removal may induce wide fluctuations in systemic blood pressure.
Laryngeal paraganglioma Laryngeal paraganglioma (LP) is a rare tumor derived either from the superior or inferior paraganglia of the larynx. The vast majority of LP arises in the supraglottic space and presents as a submucosal mass in the region of the aryepiglottic fold/false vocal cord (Lack, 2007). Only 15% occurs in the subglottis and 3% in the glottis. The right side of the larynx is more often involved than the left (ratio 2.3:1). Median age at diagnosis is 44 years (5-83 years). LP is three times more common in women than in men. The major symptom is hoarseness variably associated with dysphagia, dyspnea, stridor, dysphonia, sore throat, coughing, haemoptysis, foreign body sensation, and otalgia (Lack, 2007; Barnes et al., 2005).
Rare intrasellar and parasellar paragangliomas have been reported (Lack, 2007).
Paragangliomas are usually solitary, particularly in adults, but two or more separate tumors may be present. Occasional examples of paragangliomatosis have been reported (Karasov et al., 1982). When multiple, the tumors may appear synchronously or asynchronously. In case of additional paragangliomas, it is usually a carotid body or less frequently, a jugulotympanic tumor. ImagingOn imaging, paraganglioma appears as a homogeneous, hypervascular, well-defined soft tissue mass. A heterogeneous enhancement may be observed if hemorrhage or thrombosis has occurred. Large tumors may erode the surrounding bone (e.g. labyrinth, jugular foramen). On magnetic resonance imaging (MRI), the tumor appears as a well-defined hypointense mass with areas of signal void on T1-weighted sequences. On T2-weighted images, the signal is usually hyperintense. MRI provides high resolution but is less sensitive compared to CT scan for identifying bone erosion or destruction (Lack, 2007; Barnes et al., 2005). On angiography, there is direct involvement of the carotid bifurcation in CBP with a lyre-like widening of the common artery bifurcation in lateral views. Vagal paragangliomas are located well above the carotid bifurcation and typically displace both external and internal carotid arteries anteromedially (Lack, 2007). Octreotide scintigraphy helps confirm the neuroendocrine nature of the neoplasm and detect occult paragangliomas. The role of functional imaging procedures in the diagnosis of HNPG has increased in the last 10 to 15 years (Hensen et al., 2013). 123I-meta-iodobenzyl-guanidine (123I-MIBG) or 111In-pentetreotide scintigraphy is useful when in doubt of the diagnosis and in whole-body screening for functional paraganglial tumors, particularly in familial settings (Chen et al., 2010). The 18F-fluorodeoxyglucose-PET (18F-FDG-PET) is also useful in screening for multiple tumors and in detecting metastases (Chen et al., 2010).
Malignant paraganglioma The diagnosis of malignant paraganglioma usually depends upon the demonstration of metastases to sites such as regional lymph nodes, liver, lung, or bone (i.e. paraganglial cells in non-neuroendocrine tissue). Aggressive local growth, large tumor size, encirclement of carotid vessels, incorporation of nerves, or invasion near the base of the skull also suggests malignancy, although definitive evidence is provided by metastases (Lack, 2007). Most head and neck paragangliomas are benign tumors. Parasympathetic paragangliomas (head and neck region), in contrast to their sympathetic counterparts (trunk, pelvis), are more often familial and less likely to be malignant. Malignant paragangliomas, as their benign counterparts, mainly arise from the carotid body, in the middle ear (jugulotympanic tumors), along the course of the vagus nerve, and exceptionally in the orbit, nasal cavity, paranasal sinuses, nasopharynx, larynx, trachea, and thyroid (Barnes et al., 2005). Malignancy rates up to 10% in HNPG have been reported but those rates vary from study to study. According to one study, 2-13% of CBP are malignant (Barnes and Taylor, 1990). Between 6% and 19% of vagal tumors have been reported to be malignant. For other head and neck locations, malignancy concerns less than 10% of PG (for example, 2 to 4% for JTP) (Lee et al., 2002). The highest malignancy rate was reported for nasal and paranasal PG (24%), followed by vagal (10%), jugulotympanic (5.1%), carotid body (1.41%), and laryngeal PG (1.36%) (Rinaldo et al., 2004). Sporadic (non-familial) CBP are more likely to be malignant than those that are familial (12% versus 2.5%). Malignant paraganglioma may develop in adults at any age (20-80 years old). The median age at first diagnosis in the US National Cancer Data Base was 44 years (Lee et al., 2002). In another series, the mean age was 35 years at diagnosis with 53% of patients being older than 40 (Moskovic et al., 2010). The sex ratio was approximately 1:1 in the cohort reported by Lee et al. (2004). In the series reported by Moskovic et al. (2010), 69% of the patients were males.
Multicentric paragangliomas must be distinguished from true metastases. Most metastases are present at diagnosis or less than 5 years after initial presentation. However, some may be apparent 10 to 20 years after the diagnosis of the primary tumor.
Microscopic examination Paraganglioma is a neuroendocrine neoplasm composed of chief and sustentacular cells arranged in a characteristic nesting ("Zellballen") pattern (Lack, 2007; Barnes et al., 2005). The chief cells, which are more numerous than the sustentacular cells, display a relatively uniform alveolar arrangement. The sustentacular cells are flattened cells located at the periphery of the Zellballen and are impossible to identify in routinely stained sections. A prominent capillary network is present between the clusters of neoplastic cells. CBP harbors a higher density of chief cells compared to normal carotid body paraganglia. Neoplastic chief cells usually have an abundant, finely granular, eosinophilic cytoplasm containing neurosecretory granules (filled with catecholamines). The sustentacular cells are devoid of such granules. Cell borders may be well-defined with polygonal or angular contours. Vacuolar cytoplasmic changes may be seen. Nuclei may be round to oval with pseudoinclusions. Nuclear pleomorphism, hyperchromasia, and occasional mitotic figures are not indicative of malignancy (Lack, 2007; Barnes et al., 2005). Paraganglioma is often well-demarcated, surrounded by a fibrous capsule. Areas of capsule deficiency should not be regarded as true capsular invasion. Some paragangliomas display areas of hemorrhage or fibrosis. In CBP, the tumor may involve the adventitia of the carotid. Remnants of the normal carotid body may be seen. Compared to other paragangliomas, JTP tend to more vascular and cell nests are less uniform and frequently smaller. Some JTP present with marked sclerosis (Lack, 2007; Barnes et al., 2005).
Malignant paraganglioma As already mentioned, a tumor is considered malignant only if there is metastasis to regional lymph nodes or to more distant sites, such as the lungs or bones. There are no accepted histopathological or immunohistochemical criteria for the diagnosis of malignancy in PG. Local compression and erosion of surrounding structures are generally not accepted as a sign of malignancy. Nuclear pleomorphism, mitoses, necrosis, vascular or perineural invasion are not reliable prognostic factors in paragangliomas; the same is true for the Ki-67 proliferation index (Barnes et al., 2005).
Immunohistochemistry The chief cells express synaptophysin, chromogranin A, and neuron-specific enolase. They do not express cytokeratin or S100 protein. Conversely, sustentacular cells express S100 protein as well as GFAP (glial fibrillary acidic protein). Immunostaining for S100 protein shows elongated, stellate or dendritic sustentacular cells at the periphery of the Zellballen (Lack, 2007; Barnes et al., 2005). According to some, biologically aggressive paragangliomas might have a reduced number of sustentacular cells (and express fewer neuropeptides) compared to benign lesions (Barnes et al., 2005).n normal paraganglia, the chief cells express SDH subunit B. In case of an SDH mutation (whatever the SDH subunit involved), as seen in some hereditary paraganglial tumors (see below), the staining for SDHB in neoplastic chief cells will be weaker or abolished. The sustentacular cells will still display positive staining, serving as an internal control. The SDHB staining will be retained in other hereditary tumor syndromes (e.g. von Hippel-Lindau or Multiple Endocrine Neoplasia type 2 (MEN2) syndrome) (see below). Such an immunostaining may guide the geneticist to which gene is involved in the disease pathogenesis.
Differential diagnosisDifferential diagnosis includes carcinoid tumor, medullary thyroid carcinoma, anaplastic carcinoma, metastatic melanoma and renal cell carcinoma (Barnes et al., 2005). The differential diagnosis of JTP comprises middle ear adenoma/adenomatous neoplasm, meningioma, hemangiopericytoma, and metastatic renal cell carcinoma. Meningioma involving the jugular foramen can mimic the more common JTP. Schwannoma can also involve the jugular foramen (Barnes et al., 2005).
Audrey Rousseau ; Cécile Badoual
Head and Neck: Paraganglioma: an overview
Atlas Genet Cytogenet Oncol Haematol. 2015-05-01
Online version: http://atlasgeneticsoncology.org/solid-tumor/6202/favicon/js/lib/gene-explorer/