|Embryonic origin|| The adrenal medulla and the extra-adrenal paraganglia are of neural crest origin (Lack, 2005; Barnes et al., 2005).|
|Etiology|| Familial inheritance (see below) and chronic hypoxia are the only known risk factors in CBP (Barnes et al., 2005; Hensen and Bayley, 2011). The role of chronic hypoxia in the development of head and neck paraganglioma other than CBP (e.g. laryngeal or jugulotympanic paraganglioma) is debated. Chronic hypoxia is known to induce paraganglia hyperplasia (Hensen and Bayley, 2011). Since the carotid body plays a central role in oxygen sensing, the latter may be involved in paraganglioma tumorigenesis. Succinate dehydrogenase (SDH) mutations in paraganglial tumors (see below) lead to succinate accumulation resulting in hypoxia-inducible factor 1 (HIF-1) stabilization through inhibition of prolyl hydroxylase-mediated degradation (Hensen and Bayley, 2011, King et al., 2006). This "pseudo-hypoxia" state leads to HIF-induced transcription of genes such as vascular endothelial growth factor (VEGF) and other growth factors.|
|Epidemiology|| Paragangliomas of the head and neck region (HN) are rare, comprising 0.6% of HN tumors and 0.03% of all neoplasms. The most frequent locations of head and neck paraganglioma are (by decreasing order) carotid body, jugulotympanic and vagal. Paragangliomas more often arise in female patients, usually in the 4th and 5th decades of life (Kimura et al., 2004). Hereditary paragangliomas commonly develop at least 10 years earlier compared to sporadic tumors (Boedeker et al., 2013).|
|Clinics|| Carotid body paraganglioma |
Carotid body paraganglioma occurs on average in the fifth decade of life with a roughly equal sex distribution. A female predilection has been noted by some, most notably in series of CBP occurring at high altitude (Lack, 2007). CBP usually presents as a slowly growing asymptomatic mass located deep to the sternocleidomastoid muscle just below the angle of the mandible. It may cause pain, hoarseness, dysphagia, headache, bruit or thrill (Barnes et al., 2005). The patient may present with Horner's syndrome due to involvement of the cervical sympathetic chain and rarely, with carotid sinus syndrome (bradycardia, syncopal episodes). Hypertension due to catecholamine secretion is exceptional. The lesion may be mistaken for an enlarged salivary gland or lymph node, a branchial cleft cyst or rarely, a carotid aneurysm. The tumor may be bilateral, especially in the familial setting. In the latter, about one third of the patients have synchronous or metachronous bilateral tumors; multicentric paragangliomas may occur outside the head and neck region. CBP has been described in Carney's triad (extra-adrenal paraganglioma, gastrointestinal stromal tumor (GIST), and pulmonary chondroma) (Carney, 2009).
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 (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 Horner's 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 (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.
On 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).
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.
|Pathology|| Macroscopic examination|
Carotid body paraganglioma usually measures between 2 and 6 cm in diameter. It appears firm, rubbery, well circumscribed and surrounded by a thin fibrous capsule. On cut surface, the appearance is heterogeneous with yellow, tan, pink, red or brown areas. Fibrosis and hemorrhage may be observed. The tumor may encase large blood vessels such as the external carotid. Jugulotympanic paraganglioma often appears as an irregular reddish mass. In jugular paraganglioma, the petrous temporal bone and the middle ear space may be replaced by tumor tissue as far as the tympanic membrane (Lack, 2007; Barnes et al., 2005). Vagal paraganglioma is oval or round and abuts directly onto the skull base. It usually ranges from 2 to 6 cm in diameter and is firm, well circumscribed and surrounded by a thin fibrous capsule. In a few instances, it may be poorly defined and locally infiltrative. It presents with a variegated appearance on cut surface or may be uniformly homogeneous. A portion of one or more large nerves, usually the vagus, is often attached (Lack, 2007; Barnes et al., 2005).
On macroscopic examination, malignant paragangliomas do not significantly differ from benign paragangliomas (except for the occasional presence of lymph node metastases). Malignant paragangliomas typically present as firm, reddish lesions. A fibrous capsule may be seen, but in most instances, the tumor is locally infiltrative. On cut surface, a variegated appearance is noted with yellow-brown, tan-pink, and/or red (hemorrhagic) areas (Lack, 2007; Barnes et al., 2005).
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).
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).
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 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).
| Figure 1: Paraganglioma. Chief cells arranged in the characteristic Zellballen pattern. The cell nests are separated by fibrovascular septa. Hematoxylin and eosin staining (original magnification x200).|
| Figure 2: Paraganglioma. Immunostaining for synaptophysin. Strong expression of the neuronal marker by the chief cells (original magnification x200).|
|Treatment|| Paragangliomas are slowly growing tumors. Complete surgical resection is the treatment of choice when feasible (Lee et al., 2002; Moskovic et al., 2010). Tumors involving the base of the skull may require adjuvant radiation therapy. Chemotherapy is largely ineffective. Prolonged follow-up is necessary since the neoplasm may metastasize after a long interval. |
In CBP, surgery may require sacrifice of branches of the carotid artery. The recurrence rate is between 0 and 10% and may reflect partial resection and subsequent tumor re-growth. JTP can be locally aggressive neoplasms that destroy bone and extend intracranially, and they may recur (or persist) locally. Regional and distant metastases are uncommon. Radiation therapy, and in some cases surgery, offers a high rate of cure for localized neoplasms. Options for treatment of VP include surgery, radiation therapy, and in selected cases, observation (Moskovic et al., 2010). In most cases, the vagus nerve (and sometimes other cranial nerves) has to be sacrificed. Radiation therapy may be used in case of bilateral tumor. Eight per cent of vagal paragangliomas recurs after surgery, often reflecting inadequate excision.
Because malignant paragangliomas are rare, the survival rate is only available from small case series. In one study, the 5-year overall survival was 59.5% (Lee et al., 2002). In case of metastases confined to regional lymph nodes, the 5-year survival rate was 76.8% but decreased to 11.8% for patients with distant metastases (Lee et al., 2002). Adjuvant radiation therapy seems the most appropriate treatment in case of metastatic regional lymph nodes (Lee et al., 2002; Moskovic et al., 2010). Bone metastases occur frequently in JTP whereas CBP present with both bone and lung metastases (Moskovic et al., 2010).
| MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma|
| Burnichon N, Cascó A, Schiavi F, Morales NP, Comino-Méndez I, Abermil N, Inglada-Péez L, de Cubas AA, Amar L, Barontini M, de Quirós SB, Bertherat J, Bignon YJ, Blok MJ, Bobisse S, Borrego S, Castellano M, Chanson P, Chiara MD, Corssmit EP, Giacché de Krijger RR, Ercolino T, Girerd X, Goméz-García EB, Gómez-Grañia, Guilhem I, Hes FJ, Honrado E, Korpershoek E, Lenders JW, Let&oeacute;n R, Mensenkamp AR, Merlo A, Mori L, Murat A, Pierre P, Plouin PF, Prodanov T, Quesada-Charneco M, Qin N, Rapizzi E, Raymond V, Reisch N, Roncador G, Ruiz-Ferrer M, Schillo F, Stegmann AP, Suarez C, Taschin E, Timmers HJ, Tops CM, Urioste M, Beuschlein F, Pacak K, Mannelli M, Dahia PL, Opocher G, Eisenhofer G, Gimenez-Roqueplo AP, Robledo M|
| Clin Cancer Res 2012 May 15;18(10):2828-37|
| Carotid body paragangliomas|
| Barnes L, Taylor SR|
| A clinicopathologic and DNA analysis of 13 tumors Arch Otolaryngol Head Neck Surg|
| Tumours of paraganglionic system: Introduction.|
| Barnes L, Tse LLY, Hunt JL, Michaels L.|
| In:BarnesL, EvesonJW, ReichartP,SidranskyD (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. IARC Press: Lyon 2005, pp. 362-3.|
| Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors|
| Baysal BE|
| Biochim Biophys Acta 2013 May;1827(5):573-7|
| Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes|
| Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, Henley D, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG|
| J Clin Endocrinol Metab 2006 Mar;91(3):827-36|
| Glomus jugulare tumors revisited: a ten-year statistical follow-up of 231 cases|
| Brown JS|
| Laryngoscope 1985 Mar;95(3):284-8|
| Coexistence of paraganglioma/pheochromocytoma and papillary thyroid carcinoma: a four-case series analysis|
| Bugalho MJ, Silva AL, Domingues R|
| Fam Cancer 2015 Jun 14|
| NET network|
| Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P, Gaillard D, Chabrier G, Chabolle F, Coupier I, Thieblot P, Lecomte P, Bertherat J, Wion-Barbot N, Murat A, Venisse A, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP; PGL|
| The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas J Clin Endocrinol Metab|
| Carney triad: a syndrome featuring paraganglionic, adrenocortical, and possibly other endocrine tumors|
| Carney JA|
| J Clin Endocrinol Metab 2009 Oct;94(10):3656-62|
| The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer|
| Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K; North American Neuroendocrine Tumor Society (NANETS)|
| Pancreas 2010 Aug;39(6):775-83|
| MAX mutations status in Swedish patients with pheochromocytoma and paraganglioma tumours|
| Crona J, Maharjan R, Delgado Verdugo A, Stalberg P, Granberg D, Hellman P, Björklund P|
| Fam Cancer 2014 Mar;13(1):121-5|
| Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity|
| Dahia PL|
| Nat Rev Cancer 2014 Feb;14(2):108-19|
| Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background|
| Fishbein L, Nathanson KL|
| Cancer Genet 2012 Jan-Feb;205(1-2):1-11|
| Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia|
| Gill AJ|
| Pathology 2012 Jun;44(4):285-92|
| Coexistence of gastrointestinal stromal tumors (GISTs) and pheochromocytoma in three cases of neurofibromatosis type 1 (NF1) with a review of the literature|
| Gorgel A, Cetinkaya DD, Salgur F, Demirpence M, Yilmaz H, Karaman EH, Tutuncuoglu P, Oruk G, Bahceci M, Sari AA, Altinboga AA, Paker I|
| Intern Med 2014;53(16):1783-9|
| High prevalence of occult paragangliomas in asymptomatic carriers of SDHD and SDHB gene mutations|
| Heesterman BL, Bayley JP, Tops CM, Hes FJ, van Brussel BT, Corssmit EP, Hamming JF, van der Mey AG, Jansen JC|
| Eur J Hum Genet 2013 Apr;21(4):469-70|
| Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma|
| Hensen EF, Bayley JP|
| Fam Cancer 2011 Jun;10(2):355-63|
| Somatic loss of maternal chromosome 11 causes parent-of-origin-dependent inheritance in SDHD-linked paraganglioma and phaeochromocytoma families|
| Hensen EF, Jordanova ES, van Minderhout IJ, Hogendoorn PC, Taschner PE, van der Mey AG, Devilee P, Cornelisse CJ|
| Oncogene 2004 May 20;23(23):4076-83|
| Models of parent-of-origin tumorigenesis in hereditary paraganglioma|
| Hoekstra AS, Devilee P, Bayley JP|
| Semin Cell Dev Biol 2015 Jun 9|
| Paragangliomatosis with numerous catecholamine-producing tumors|
| Karasov RS, Sheps SG, Carney JA, van Heerden JA, DeQuattro V|
| Mayo Clin Proc 1982 Sep;57(9):590-5|
| Extra-adrenal paraganglioma: carotid body, jugulotympanic, vagal, laryngeal, aortico-pulmonary.|
| Kimura N, Chetty R, Capella C, et al.|
| In: DeLellis RA, Lloyd RV, Heitz PU, Eng C (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of Endocrine Organs. IARC Press: Lyon 2004, pp. 159-61.|
| Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer|
| King A, Selak MA, Gottlieb E|
| Oncogene 2006 Aug 7;25(34):4675-82|
| SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas|
| Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP, van Dooren MF, de Herder WW, Tissier F, Plouin PF, van Nederveen FH, Dinjens WN, Gimenez-Roqueplo AP, de Krijger RR|
| J Clin Endocrinol Metab 2011 Sep;96(9):E1472-6|
| National Cancer Data Base report on malignant paragangliomas of the head and neck|
| Lee JH, Barich F, Karnell LH, Robinson RA, Zhen WK, Gantz BJ, Hoffman HT; American College of Surgeons Commission on Cancer; American Cancer Society|
| Cancer 2002 Feb 1;94(3):730-7|
| Papilledema and Vision Loss Caused by Jugular Paragangliomas|
| Lertakyamanee P, Srinivasan A, De Lott LB, Trobe JD|
| J Neuroophthalmol 2015 Jun 12|
| Profiling of somatic mutations in phaeochromocytoma and paraganglioma by targeted next generation sequencing analysis|
| Luchetti A, Walsh D, Rodger F, Clark G, Martin T, Irving R, Sanna M, Yao M, Robledo M, Neumann HP, Woodward ER, Latif F, Abbs S, Martin H, Maher ER|
| Int J Endocrinol 2015;2015:138573|
| Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas|
| McInerney-Leo AM, Marshall MS, Gardiner B, Benn DE, McFarlane J, Robinson BG, Brown MA, Leo PJ, Clifton-Bligh RJ, Duncan EL|
| Clin Endocrinol (Oxf) 2014 Jan;80(1):25-33|
| Malignant head and neck paragangliomas: is there an optimal treatment strategy? Head Neck Oncol|
| Moskovic DJ, Smolarz JR, Stanley D, Jimenez C, Williams MD, Hanna EY, Kupferman ME|
| 2010 Sep 23;2:23 doi: 10|
| Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites|
| Neumann HP, Sullivan M, Winter A, Malinoc A, Hoffmann MM, Boedeker CC, Bertz H, Walz MK, Moeller LC, Schmid KW, Eng C|
| J Clin Endocrinol Metab 2011 Aug;96(8):E1279-82|
| Pheochromocytoma: recommendations for clinical practice from the First International Symposium|
| Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM, Tischler AS; International Symposium on Pheochromocytoma|
| October 2005 Nat Clin Pract Endocrinol Metab|
| Renal carcinoma associated with succinate dehydrogenase B mutation: a new and unique subtype of renal carcinoma|
| Paik JY, Toon CW, Benn DE, High H, Hasovitz C, Pavlakis N, Clifton-Bligh RJ, Gill AJ|
| J Clin Oncol 2014 Feb 20;32(6):e10-3|
| Clinical relevance of phenotype/genotype correlations in the diagnosis and therapy of pheochromocytomas/paragangliomas|
| Parenti G, Zampetti B, Rapizzi E, Ercolino T, Giaché V, Fucci R, Mannelli M|
| Q J Nucl Med Mol Imaging 2013 Jun;57(2):112-21|
| SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes|
| Pasini B, Stratakis CA|
| J Intern Med 2009 Jul;266(1):19-42|
| Long-term follow-up after en bloc resection and reconstruction of a solitary paraganglioma metastasis in the first lumbar vertebral body: a case report|
| Richter A, Halm HF, Lerner T, Liljenqvist UR, Quante M|
| J Med Case Rep 2011 Feb 1;5:45|
| Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer|
| Ricketts CJ, Shuch B, Vocke CD, Metwalli AR, Bratslavsky G, Middelton L, Yang Y, Wei MH, Pautler SE, Peterson J, Stolle CA, Zbar B, Merino MJ, Schmidt LS, Pinto PA, Srinivasan R, Pacak K, Linehan WM|
| J Urol 2012 Dec;188(6):2063-71|
| Hereditary Pheochromocytoma|
| Santos P, Pimenta T, Taveira-Gomes A|
| Int J Surg Pathol 2014 Jun 5;22(5):393-400|
| Cervical sympathetic chain paraganglioma: a report of 2 cases and a literature review|
| Seth R, Ahmed M, Hoschar AP, Wood BG, Scharpf J|
| Ear Nose Throat J 2014 Mar;93(3):E22-7|
| Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas|
| Welander J, Södererkvist P, Gimm O|
| Endocr Relat Cancer 2011 Dec 1;18(6):R253-76|
| Succinate dehydrogenase (SDH) D subunit (SDHD) inactivation in a growth-hormone-producing pituitary tumor: a new association for SDH? J Clin Endocrinol Metab|
| Xekouki P, Pacak K, Almeida M, Wassif CA, Rustin P, Nesterova M, de la Luz Sierra M, Matro J, Ball E, Azevedo M, Horvath A, Lyssikatos C, Quezado M, Patronas N, Ferrando B, Pasini B, Lytras A, Tolis G, Stratakis CA|
| 2012 Mar;97(3):E357-66 doi: 10|
| Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect|
| Yeap PM, Tobias ES, Mavraki E, Fletcher A, Bradshaw N, Freel EM, Cooke A, Murday VA, Davidson HR, Perry CG, Lindsay RS|
| J Clin Endocrinol Metab 2011 Dec;96(12):E2009-13|
| Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: a systematic review and meta-analysis|
| van Hulsteijn LT, Dekkers OM, Hes FJ, Smit JW, Corssmit EP|
| J Med Genet 2012 Dec;49(12):768-76|
| Genomic imprinting in hereditary glomus tumours: evidence for new genetic theory|
| van der Mey AG, Maaswinkel-Mooy PD, Cornelisse CJ, Schmidt PH, van de Kamp JJ|
| Lancet 1989 Dec 2;2(8675):1291-4|