Paragangliomas are neoplasms of the paraganglia. Paragangliomas of the head and neck are rare tumors, comprising about one in 10,000 of all tumors in the head and neck area excluding intracranial tumors. A review by the surgical pathology department at Memorial Sloan-Kettering Cancer Center showed an incidence of head and neck paragangliomas accounting for 0.012% of all head and neck tumors.¹¹ The annual incidence of extra-adrenal paragangliomas is estimated at 1 in 300,000.¹² The carotid body is the most common site for paraganglioma. Carotid body tumors and jugulotympanic tumors account for approximately 80% of these, and vagal paragangliomas add another 5 %. Nasal, orbital, laryngeal, and other head and neck sites are much more rare.¹³ Significant referral pattern distortions make these numbers less reliable. Multiple paragangliomas are present in up to 22% of all patients with a paraganglioma, and these are frequently hereditary in nature with a family history of such tumors.

Approximately 10% of sporadic cases will have a concurrent second paraganglioma.^14,15,16 Multicentricity may be present in up to 22% of those with a genetic predisposition. The most common pattern of a synchronous secondary paraganglioma is a second carotid body tumor, and occurrence is present in 20% of carotid body tumors. Bilateral carotid body tumors, as well as an additional paraganglioma ipsilaterally or contralaterally present significant and challenging treatment problems due to the potential for cranial nerve deficits and loss in baroreceptor function, which results in labile hypertension.^17,18,19 Multiple tumors may be metachronous, and this has implication for surveillance for
patients with a paraganglioma. Since multicentric tumors may be metachronous, routine follow-up MRI, ¹¹¹indium pentetreotide (Octreoscan^R) or (18)F-DOPA positron emission tomography imaging is indicated.

Other than genetics, the only known predisposition for a paraganglioma is high-altitude living associated with chronic hypoxemia. Several studies show that there is an increased incidence of these tumors with high-altitude living, a 9-fold increase for those living between 2 and 3 km and 12-fold increase for those living between 3 and 4.5 km above sea level. Patients forming these tumors at higher altitude show a lower rate of bilaterality and a lesser degree of familial history of paragangliomas.^20,21,22 Rodriguez-Cuevas et al. reported a retrospective analysis of 120 cases of carotid body tumors occurring in inhabitants living at a high altitude (>2,200 m above sea level). As compared with cases occurring in populations living below 1,500 m above sea level, they noted a higher female predominance (8.3:1 vs. 2:1), a lower rate of bilaterality (5% vs. 10% -20%), and a less frequent familial history (1% vs. 7%-25%).²³ High-altitude paraganglioma has a prevalence of up to 1 in 10 in humans and 1 in 2 in bovines compared with an estimated 1 in 500,000 prevalence in humans at low altitudes.^24,25 A higher incidence of carotid body hypertrophy and carotid body tumors has also been noted in patients with chronic obstructive pulmonary disease, perhaps related to chronically low pO₂ levels.²⁶

Approximately 1 % to 3 % of paragangliomas secrete catecholamines. A five-fold increase in catecholamines is sufficient to produce symptoms. Symptoms consistent with a functioning tumor are tachycardia, excessive sweating, weight loss, and hypertension. Secreting paragangliomas account for approximately 2 % of all instances of secondary hypertension. Twenty-four hour urine collection in these patients will show elevated levels of the catecholamine metabolites, metanephrine, and VMA. Serum catecholamines will show elevated levels of norepinephrine in functioning extra-adrenal paragangliomas. Elevated serum epinephrine is indicative of a concurrent pheochromocytoma.^6,27 Paraganglioma familial syndrome subtypes 1 and 4 (PGL1 and PGL4) are associated with a higher incidence of concurrent pheochromocytoma. Conversely, multiple endocrine neoplasia type IIA (pheochromocytoma, medullary thyroid carcinoma, and parathyroid hyperplasia) and type IIB (pheochromocytoma, medullary thyroid carcinoma, parathyroid hyperplasia, and mucosal neuromas) are associated with head and neck paragangliomas.²⁸

Malignant paragangliomas represent a small subset of extra-adrenal paragangliomas that have a propensity for regional lymph nodes and distant metastatic disease, primarily to the lungs, liver, and bones. Sporadic paragangliomas have a higher rate of malignancy than familial type paragangliomas, except for PGL4 syndrome that is associated with a rate of malignancy as high as 54%, and importantly, the likelihood is site specific. Orbital and laryngeal paragangliomas have the highest rate of malignancy, approximately 25 %. With vagal paragangliomas, the rate is up to 10%, followed by jugulotympanic paragangliomas with a malignancy rate of 5%, and carotid body tumors being last at 3 % to 6 %. Unfortunately, there are no histologic criteria by which primary tumor malignancy can be diagnosed, and that determination depends on tumor present in lymph nodes or distant metastatic sites. The presence of malignancy has profound implications in the treatment of these tumors.^29,30,31 In a review of 43 cases of malignant carotid body tumors, the best locoregional control was achieved by primary resection combined with neck dissection, and followed by adjuvant radiation therapy. The interval to recurrence is long, ranging from 20 months to 20 years.³²

Overall, germline mutations can be identified in approximately 30 % of patients with head and neck paragangliomas.^33,34 Familial glomus tumors constitute approximately 20% of affected patients, for which the genetic defects are known. One subgroup (10% of all glomus tumors) appears to be caused by sporadic mutations in SDHB and SDHD.

Hereditary susceptibility to paragangliomas, mainly of the head and neck region, was recognized at least two decades ago, and led to the identification through linkage analysis of three loci on chromosomes 11 and 1, named PGL1 on 11q23, PGL2 on 11q11.3, and PGL3 on 1q21-23. Following the discovery of succinate dehydrogenase (SDH) subunit D gene (SDHD) as the gene responsible for PGL1 in familial head and neck paragangliomas, it was thereafter recognized that two other subunits of this mitochondrial enzyme, SDHC (PGL3) and SDHB (PGL4, 1p36) were associated with heritable pheochromocytoma and/or paraganglioma. To date, the gene for PGL2 has not been identified.^{20,35,36,37,38}

At present, causative gene mutations are identified in about 32% of paragangliomas-pheochromocytomas.³⁹ In the hereditary tumor syndromes: MEN2A, MEN2B, Von Hippel-Lindau and NF-1, in which a pheochromocytoma or paraganglioma presents, a causative gene mutation is seen in 17% of cases. Within the mitochondrial SDH complex, paragangliomas account for 15% of mutations.

The molecular basis for tumorigenesis in paragangliomas resides in mutations, germ line, and somatic for the most part in the genes that control SDH. The product of these multiple genes is a 4-dimer protein that catalyzes succinate to fumarate in mitochondria as the first step of oxygen-dependent glucose breakdown via the respiratory pathway. The enzyme is composed of 4 dimers, namely, SDHA, SDHB, SDHC, and SDHD, and is anchored in the internal bilipid membranes of the mitochondria. SDHA and SDHB are the proteomic components that anchor the enzyme in the membrane, while SDHC and SDHD are the proteomic components that catalyze the reaction from succinate to fumarate. This reaction is crucial to entering glucose breakdown from anaerobic to aerobic metabolism.³⁴ SDH or succinate-ubiquinone reductase is the complex II of the mitochondrial respiratory chain located in the mitochondrial matrix. SDH couples the oxidation of succinate to fumarate in the Krebs cycle with electron transfer to the terminal acceptor ubiquinone, thus leading to the generation of ATP.⁴⁰

SDH is an enzyme complex composed by four subunits encoded by four nuclear genes (SDHA, SDHB, SDHC, and SDHD). SDHC (cybL, 15 kDA, 169 amino acids) and SDHD (cybS, 12 kDa, 159 amino acids) subunits are hydrophobic and provide membrane anchor and the binding site for ubiquinone. SDHA (flavoprotein, 70 kDa, 664 amino acids) and SDHB (iron-sulfur protein, 27 kDa, 280 amino acids) are hydrophilic, with the former involved in substrate binding and oxidation and the latter in electron transfer. Both SDHB (35.4 kb, 8 exons) and SDHC (50.3 kb, 6 exons) genes are located on chromosome 1, in the short and long arm, respectively. SDHD, located on 11q23.1, spans 8.9 kb and contains four exons whereas SDHA lies on the short arm of chromosome 5 (5p15) and is composed of 15 exons spread in a genomic region of 38.4 kb. Whereas homozygote germline mutations affecting SDHA cause Leigh syndrome, a subacute necrotizing encephalomyelopathy during infancy, SDHD, SDHB, and SDHC heterozygous mutations cause a genetic
predisposition to head and neck paragangliomas and adrenal/extra-adrenal pheochromocytomas.⁴¹ This inherited tumorigenic predisposition is transmitted in an autosomal dominant fashion with age-dependent and incomplete penetrance. However, for SDHD located on chromosome 11q, a parent-of-origin effect is revealed as the disease is manifest almost exclusively when the mutation is transmitted from the father. A maternal imprinting has therefore been postulated, but despite the pattern of inheritance, SDHD shows bi-allelic expression in normal tissues and neural crest-derived tissues.^20,31

All of these genes are tumor-suppressor genes showing loss of heterozygosity (LOH): the loss of the normal allele in the tumor, in conjunction with germline mutation. This results in loss of a protein subunit that destabilizes the SDH complex and alters or abolishes its enzymatic activity.⁴²

Inactivation of the SDH complex leads to a hypoxic state with accumulation of succinate resulting in the stabilization of HIFla (hypoxia-induced factor la). Oxygen normally facilitates the degradation of HIFla through prolyl hydroxylases. As oxygen levels decline HIFla enters the nucleus and initiates the transcription of a host of genes known to be involved in tumorigenesis, including Vascular endothelial growth factor (VEGF).⁴³ VEGF and platelet-derived endothelial growth factor (PD-ECGF), as well as endothelin-1, has been found in the majority of specimens examined. It has been postulated that this was consistent with a paracrine mechanism for tumor development.^44,45

Recent hypotheses for the mechanism of a tumorigenesis link a decrease in apoptosis and the activation of a pseudohypoxic pathway via these mechanisms.⁴⁶ This peudohypoxia is known as the Warburg effect and is the basis for tumor imaging by F-16 PET/FDG.⁴⁷

Paraganglioma Syndrome 1: SDH Subunit D. SDH Subunit D (SDHD) is the second anchoring peptide for mitochondrial complex II in the inner mitochondrial membrane. The gene resides at 11q23 and was the first mitochondrial gene to be linked to tumorigenesis.²⁰ The proportion of mutation carriers at SDHD gene that will develop a tumor is 87% to 100% (very high penetrance).⁴⁸ SDHD is responsible for PGL1 syndrome. Patients with PGL1 commonly have multifocal tumors and very rarely malignant ones. Maternal imprinting (absence of disease transmitted by the mother) suggesting sex-specific epigenetic modifications.³⁴ Higher altitudes in SDHD/PGL1 patients show increased phenotypic severity as well as increased likelihood of developing a pheochromocytoma.⁴⁹ In a similar manner, nonsense/splicing mutations show earlier presentation of head and neck paragangliomas as well as increased incidence of pheochromocytomas.⁴⁸ It has been proposed that SDHD is a critical component of a cellular oxygen-sensing system. Mutations in SDHD may incapacitate the oxygen-sensing mechanism, leading to an apparent or real hypoxic state accompanied by chronic hypoxic stimulation and cell proliferation. Support for hypoxia-induced hyperplasia comes from evidence obtained in high-altitude physiological studies. Cows, guinea pigs, rabbits, and dogs experience carotid body hyperplasia when living at high altitudes, which exposes them to a hypoxic condition, and this has also been described in humans. Another clinical observation lending support to these theories is the finding that patients suffering from conditions resulting in hypoxemia, such as cystic fibrosis, cyanotic heart disease, and chronic obstructive pulmonary disease, experience carotid body hyperplasia, and those suffering from chronic obstructive pulmonary disease have a higher rate of carotid body tumors.^{20,21,35,36,37,38}

Paraganglioma Syndrome 2: SDH Assembly Factor 2. SDH Assem bly Factor 2 (SDHAF2) is essential for the correct flavination of SDHA and thus the function of the SDH complex.⁴⁰ This is referred to as the PGL2 locus. Mutations in SDHAF2 have been described to produce only head and neck paragangliomas, and these make a small contribution to the genetic burden of this condition.⁵⁰ SDHAF2 gene maps to chromosome 11q13 and as with the SDHD mutations there are parent-of-origin effects on expression, such that tumor development only occurs after paternal inheritance. A striking aspect of mutations on SDHAF2 is the very high level of penetrance and the development of tumors at an early age.⁴⁰

Paraganglioma Syndrome 3: SDH Subunit C. SDH Subunit C (SDHC) is one of two peptides anchoring mitochondrial complex II in the inner mitochondrial membrane. The gene resides at 1q23.3. Only 10 index cases of families with head and neck paragangliomas have been identified worldwide.⁵¹ It accounts for <1 % of all head and neck paragangliomas and is responsible for PGL3 syndrome.³⁹

Paraganglioma Syndrome 4: SDH Subunit B. SDH Subunit B (SDHB4) is the iron sulfur protein catalytic subunit of complex II. The gene resides at 1p36.1-p35.⁵² It has been identified as the susceptibility gene for PGL4 (paraganglioma syndrome 4—OMIM: #115310). Patients with head and neck paragangliomas due to mutations of SDHB gene show a high rate of malignancy at 20% to 54%. These mutations have a low level of penetrance of 25% to 40%.^21,40,53 Only 37% of SDHB mutation-positive index cases report a family history at presentation.³⁴ SDHB is known to be a significant cause of adrenal pheochromocytomas.

SDHA is a flavoprotein and the main catalytic subunit of SDH. Head and neck paragangliomas had not been associated with mutations in the gene for SDHA. However, recently a patient with an SDHA mutation and a catecholamine-secreting abdominal paraganglioma was described.⁵⁴ Congenital deficiency due to homozygous recessive mutations of SDHA gene have been described, and these patients are severely affected with early cardiomyopathy, but no development of paragangliomas.^52,55,56 Other SDHA mutations produce Leigh syndrome, a mitochondrial encephalopathy.⁵⁵ These mutations are generally missense.⁵² It has been postulated that complete loss of SDHA function as would occur with a truncating mutation would not be compatible with life.

Neurofibromatosis type 1 is also associated with both pheochromocytomas and jugulotympanic paragangliomas. Pheochromocytomas are also associated with multiple endocrine neoplasia type II with RET gene mutations, and with Von Hippel-Lindau syndrome and mutations in VHL gene.

In patients with successive generations of a family harboring the mutations, tumors develop at progressively younger ages. This finding is a good example of genetic anticipation, in which the mutation appears to be more severe with succeeding generations.

Succinate Dehydrogenase Complex Assembly Factor 2 (SDHAF2). This protein is responsible for the addition of the flavin-adenine dinucleotide (FAD) prosthetic group to form the SDHA flavoprotein. Studied mutations in the gene that codes for SDHAF2 show that this is related to high penetrance for head and neck paragangliomas.²⁰

In summary the genetic associations in these paraganglioma syndromes are as follows:

Head and neck paragangliomas are associated primarily with PGL1, PGL3, and PGL4 syndromes which correspond to the SDH genes: SDHD, SDHC, and SDHB. Multiple endocrine neoplasia and Von Hippel-Lindau that can be associated with head and neck paragangliomas correspond to the RET and VHL genes, respectively. In one study, these five genes produce 25 at-risk exons and the cost of testing all five was estimated at US$4,100/patient.⁵⁷ The same study developed an algorithm on the basis of clinical/history predictors for efficient genetic testing in head and neck paragangliomas (Fig. 27-5) (Table 27.1).

Carotid body tumors typically present as a slowly enlarging asymptomatic deep neck mass at the level of the carotid artery bifurcation. In a small minority of patients, pain is present around the tumor. Because of the association with the carotid artery, the tumors are laterally mobile, but are cephalic-caudally fixed on examination. As the tumor enlarges, a bruit may be detectable and parapharyngeal extension can result in the lateral displacement of the soft palate. Cranial nerve paralysis symptoms are unusual and present in very large tumors with superior extension toward the jugular foramen. Shamblin’s classification is commonly used to stage carotid body tumors and though this is based on intraoperative findings, it can be applied to radiologic findings prior to treatment (Table 27.2) (Fig. 27-6).

Jugular and tympanic paragangliomas occur predominantly in the fifth and sixth decades of life with an overwhelming female predominance. They are slow growing and their pattern follows pathways of least resistance in the temporal bone and surrounding skull base structures. Although tympanic and jugular paragangliomas differ in presentation in the early stages, both types produce similar symptoms related to consistent cranial nerve deficits in their later stages. Tympanic paragangliomas present early with pulsatile tinnitus and conductive hearing loss. Tympanic membrane exam suggests a red-blue middle ear mass that blanches with positive pressure on pneumatic otoscopy (Brown’s sign). With subsequent growth, there is expansion in the middle ear cleft and ossicular erosion. Extension through the tympanic membrane produces an ear canal polypoid mass that can spontaneously produce bloody otorrhea. Extension to the mastoid can occur through a number of pathways. Involvement of the facial nerve (usually in the mastoid) can produce paralysis as a presenting sign. Anterior growth toward the pericarotid air cells can involve the petrous carotid artery and occupy the Eustachian tube. Medial growth into the infralabyrinthine air cells can reach the petrous apex and petroclival area, as well as cavernous sinus. Intracranial extension is possible with extension through the jugular foramen and/or petrous apex. More infrequently, there is involvement of the otic capsule and the inner ear with attendant sensorineural hearing loss and vertigo at presentation.

Because of their site of origin within the jugular bulb, jugular paragangliomas have the capacity for early and extensive skull base invasion with involvement of cranial nerves IX through XII.
Growth through Jacobson nerve canal and the hypotympanic air cells leads to involvement of the middle ear and mastoid bone leading to conductive hearing loss, tinnitus, and facial paralysis. Intracranial involvement through the jugular foramen is frequent. Erosion of the jugulocarotid spine leads to involvement of the vertical petrous carotid artery, and further anterior extension leads to involvement of its horizontal portion. More medial extension to the infralabyrinthine air cells lead to involvement of the petrous apex. Further medial extension along this pathway leads to involvement of the clivus and cavernous sinus. Occasionally, jugular paragangliomas will escape the confines of the temporal bone and involve the infratemporal fossa and parapharyngeal space. Lower cranial nerve involvement is frequent and ranges from 38% to 58%.^58,59 Multiple cranial nerves are frequently involved in Vernet syndrome (paralysis of CNs IX, X, and XI) or Collet-Sicard syndrome (paralysis of CNs IX, X, XI, and XII). In at least 10% of jugular paragangliomas, one of these sequences is present (Fig. 27-7). The attendant symptomatology is hoarseness, swallowing difficulty, hemipalatal dysfunction with nasal air escape, shoulder motion restriction, and dysarthria due to tongue hemiparalysis. Two surgical classification systems are in wide use today. Both can be used preoperatively based on radiographic findings. The Fisch classification system makes no distinction between tympanic and jugular paragangliomas and is predicated on detailed patterns of progressive disease extension, whereas the Glasscock-Jackson system treats tympanic and jugular paragangliomas differently^27,58 (Tables 27.3 and 27.4).

Vagal paragangliomas account for 5% of all head and neck paragangliomas and originate in that nerve where the paraganglia are diffusely distributed in the superior, middle, and inferior vagal ganglia. There is a female preponderance of 3:1. Tumors originating superiorly will often present with a dumbbell appearance, with an intracranial component in the posterior cranial fossa. Tumors originating inferiorly will extend into the poststyloid compartment of the parapharyngeal space. Vagal paragangliomas are frequently associated with multiple cranial neuropathies at presentation in up to 50% of patients. The vagus nerve is affected most commonly, followed by the hypoglossal and the spinal accessory nerves (Fig. 27-8).⁶⁰

CT with contrast is an excellent imaging choice for the diagnosis and delineation of paragangliomas. Since these tumors are highly vascular, early and intense contrast enhancement is seen. The relation of the tumor to the external and internal carotid arteries, as well as the jugular vein makes this modality essentially diagnostic.⁶² The delineation of the pattern of invasion of the temporal bone and skull base is indispensable in treatment, especially preoperative planning. Carotid body tumors display the characteristic splaying of the internal and external carotid arteries by a circumscribed mass occupying the carotid bifurcation. These tumors displace the ICA posterior and laterally. Vagal lesions typically displace the ICA anteriorly and occupy the high parapharyngeal space, with or without involvement of the skull base. Jugulotympanic paragangliomas can be distinguished in their early phases, especially when a tympanic paraganglioma is confined to the tympanic cavity. Characteristic patterns of bone destruction occur with jugulotympanic paragangliomas. These include erosion of the jugulotympanic spine, enlargement of the jugular foramen with bone destruction, and involvement of the middle ear and mastoid.^62,63 Multiplain reconstruction of high-resolution CT scans—axial, sagittal, and coronal—is of great assistance in the planning of operative management of these tumors. Middle ear and/or Eustachian tube involvement will create obstructive fluid accumulation in the aerated spaces of the temporal bone, including the mastoid (Fig. 27-9).

MRI is a complementary and equally important imaging modality in the evaluation and treatment of head and neck paragangliomas. MR with gadolinium contrast serves three purposes: delineation of the tumor in question, surveillance and detection of concurrent paragangliomas of the head and neck, and confirmation of the diagnosis of paraganglioma. The classic, “salt and pepper” appearance of paragangliomas on T2-weighted images is due to the high-flow vascular voids that are essentially pathognomonic. Paragangliomas show intense signal enhancement with gadolinium contrast.⁶⁴ Fat-suppressed sequences are exceptionally useful in delineating the extent of the tumor. Patterns of carotid artery displacement can be accurately determined distinguishing carotid body tumors from vagal paragangliomas.⁶⁴ More importantly in tumors with intracranial extension, intradural versus extradural involvement can be appreciated, and the relationship of the tumor to important intracranial structures can be delineated. Specialized techniques such as MR angiography and contrast time-of-flight three-dimensional angiography increase the sensitivity of the diagnosis of concurrent tumors, but do not supplant selective angiography in the preoperative planning setting (Figs. 27-10 and 27-11).^65,66

With the evolution of detailed MR and CT techniques, angiography plays a much more limited role in the diagnosis of head and neck paragangliomas, but is still very important in preoperative planning of these tumors. Angiography provides a detailed map of tumor blood supply and venous drainage, demonstrates the tumor-flow dynamics, and details the general vascular anatomy of the head and neck and intracranial space. Importantly, fourvessel cerebral angiography provides qualitative and quantitative flow studies of the cerebral circulation. This angiographic information creates the ability and access for the preoperative preparation provided by superselective embolization of the feeding arterial supply to the tumor. Bleeding is thus decreased intraoperatively.

Arterial supply of carotid body tumors is derived directly from the feeding vessels to the carotid body that is typically hypertrophied in the presence of a tumor.^27,58,67 Arterial supply of jugulotympanic tumors is well defined when these tumors are early in their development and invariably involves the ascending pharyngeal artery. As these tumors grow, they recruit additional blood supply that comes from the internal carotid circulation via the caroticotympanic arteries. With invasion of the posterior fossa and medial extension of the tumor toward the cavernous sinus, additional vascular recruitment is possible through the posterior circulation by means of the vertebral arteries through the clival anastomoses, as well as the cavernous sinus microcirculation. This is especially important in the preoperative embolization of these tumors. Assessing tolerance to interruption of the ICA is of paramount importance for extensive paragangliomas
that involve the ICA because of its vulnerability to injury during surgery, or where a planned internal carotid resection is contemplated. An angiographic balloon occlusion test involves the use of a femoral-artery-introduced catheter guided ultimately into the internal carotid, which is temporarily occluded usually at the carotid siphon within the cavernous sinus. This helps to determine whether there will be neurologic deficit.^17,19 During occlusion, several methods of neurologic monitoring testing can be utilized. In order of decreasing sensitivity, they are clinical neurologic examination, electroencephalography (EEG), and quantitative blood-flow examination through xenon CT concurrent examination. Xenon CT angiography is a precise quantitative study with the best sensitivity, but is rarely available and cumbersome (Fig. 27-12).^68,69

Radionuclide imaging of paragangliomas targets the biochemical pathways of catecholamine synthesis, storage, and secretion by chromaffin tumor cells. A variety of different imaging techniques exist: ¹²³I-metaiodobenzylguanidine (MIBG), ¹⁸F-3,4 dihydroxyphenylalanine ( ¹⁸F-DOPA-PET), ¹⁸F-fluorodopamine ( ¹⁸F-FDA PET), ¹⁸F-fluoro-2-deoxyglucose ( ¹⁸F-FDG-PET), and Indium octreotide scanning (¹¹¹In-octreoscan).^70,71

Different functional imaging agents target paraganglioma tumor cells through different mechanisms. ¹²³I- and ¹³¹I-labeled MIBG and ¹⁸F-FDA are actively transported into neurosecretory granules of catecholamine-producing cells via the vesicular monoamine transporters after uptake into cells by the norepinephrine transporter. In contrast, ¹⁸F-DOPA enters the cell via the amino acid transporter, a biochemical phenomenon based on the capability of paraganglioma and other neuroendocrine tumors to take up, decarboxylate, and store amino acids along with their biogenic amines. Instead of targeting catecholamine pathways, ¹⁸F-FDG enters the cell as the glucose transporter, and its accumulation is an index of increased glucose metabolism. While ¹¹¹In octreoscan images indicate somatostatin type 2 receptors that are expressed in paragangliomas.^17,18

¹¹¹Inoctreoscan specificity and sensitivity is approximately 90% in head and neck paragangliomas, a fact that makes it a very effective screener for secondary tumors as well as a postoperatively screen for recurrent disease when structural studies like CT and MRI may be compromised. ¹²³I-MIBG shows similar sensitivities and specificities. Malignant and metastatic paragangliomas are best imaged with ¹⁸F-FDG-PET, which shows sensitivities of 74% to 88%.^17,18

It is increasingly understood that there is a link between genotype-specific tumor biology and imaging. For example ¹⁸F-FDG-PET has an excellent sensitivity for paragangliomas due to SDHB-associated mutation. The SDHB gene encodes for subunit B of the mitochondrial SDH complex II that catalyzes the oxidation of succinate to fumarate in the Krebs cycle and feeds electrons to the respiratory chain, which ultimately leads to the generation of ATP (oxidative phosphorylation). Higher glucose requirements for anaerobic metabolism explains the increased ¹⁸F-FDG uptake by malignant SDHB-related paragangliomas.⁷¹

Superselective angiography is invaluable in surgical planning for paragangliomas. This sophisticated technology provides an arterial map that not only identifies the feeding blood vessels, but also provides the flow dynamics of the tumor. This is especially useful with larger tumors in which multiple feeding vessels from both the internal and external circulation may be present with anastomoses between the external and internal carotid systems.⁷² Similarly, the ICA can be evaluated for structural integrity and areas of constriction or irregularity that might suggest vessel involvement and the potential need for its sacrifice. The venous phase of angiography is equally important in identifying the draining vessels and especially in jugulotympanic paragangliomas, the degree of occlusion of the jugular bulb, sigmoid sinus, and jugular vein.

Equally important is the angiographic evaluation of adequate cerebral circulation in the event of ICA disruption or sacrifice. There are many methods for assessing for adequate contralateral cerebral circulation. Xenon CT scanning with concurrent balloon occlusion is a quantitative analysis of cerebral flow and is the most precise method of cerebral circulation evaluation though it is cumbersome and not readily available.^68,69 Temporary balloon occlusion of the carotid with monitoring of the clinical neurologic examination in the presence of a patent circle of Willis is easier to perform and also very reliable. EEG monitoring can be performed during balloon occlusion, as well as hypotensive challenge during the period of balloon occlusion. Approximately 93 % of patients can tolerate sacrifice of the carotid artery based on the appropriate angiographic evaluation. It should be noted that intraoperative conditions may be different in terms of cerebral delivery of oxygen than those in the angiographic suite.¹⁹ Tolerance with temporary internal carotid occlusion does not predictably avoid the possibility of a delayed postoperative cerebrovascular ischemic event. The venous outflow of the ipsilateral and contralateral sigmoid and jugular systems should be noted, especially in jugulotympanic paragangliomas. Because of the possibility of a postoperative venous stroke, a contralateral hypoplastic or absent jugular system constitutes a contraindication (Fig. 27-14).^73,74,75

Embolization is a very useful adjunct to surgery of large paragangliomas, and when done by an experienced endovascular team, carries a very low morbidity rate. The obvious risk of embolization
is the escape of embolizing particles into the cerebral circulation with all risk of stroke. This can occur through external-internal carotid circulation anastomoses or flow reversal from the arterial supply of the tumor. The advantages of embolization are tumor shrinkage and decreased blood flow that in large tumors have profound benefits. Less intraoperative bleeding is generally associated with a much easier dissection—more obvious tissue planes and less risk to normal anatomic structures, especially cranial nerves. Importantly, such a circumstance lessens the likelihood of requiring transfusion. Larger paragangliomas have multiple arterial feeding vessels that require superselective angiography. Using these methods, each successive embolization devascularizes additional compartments of the tumor until an absence of a tumor “blush” is achieved. It is essential that surgery be performed within 48 hours of embolization to avoid recruitment of collateral circulation. The inflammatory tumor reaction that has been reported following embolization is countered somewhat by the administration of steroids (Fig. 27-15).^72,76

Carotid Body Tumors. Smaller carotid body tumors can be approached through a transverse neck incision, but the removal of larger ones is facilitated by an oblique/vertical incision along the anterior border of the sternocleidomastoid muscle. Proximal and distal tumor dissection identifies the common, internal and external carotid arteries and jugular vein. Vessel loop control is achieved on the appropriate vessels. Carotid bypass precautions should be readily available. The cephalic extent of the large tumors can make control at the skull base substantially more difficult. The entire course of the ICA is then exposed, and usually it is noted to be displaced posterolaterally. A subadventitial plane of dissection must be done with extreme care. The tumor may require splitting in configurations in which it encases the ICA. In a similar fashion, the external carotid artery is then addressed. Encasement and infiltration of the external carotid artery may necessitate vessel sacrifice, although this should be avoided when possible. Ligation of this artery for control of blood flow to the tumor is ineffective since it usually does not alter the main supply, and, additionally, the collateral circulation is not infrequent (Figs. 27-16 and 27-17).

The dissection of the tumor at the bifurcation of the carotid is done as a last step since this site is the most vulnerable breaching the artery. As the site of origin (carotid body) of these tumors, the association with the arterial wall is its most intimate. The surrounding cranial nerves associated with carotid body
tumors usually show marked hyperemia of the vasa nervosum of the sheath. In larger tumors, these nerves—vagus, hypoglossal, and glossopharyngeal—may be intimately involved and their dissection can cause dysfunction.

Jugulotympanic Paragangliomas. Small tympanic paragangliomas (Glascock-Jackson type I, Fisch Class A) can be approached through a transcanal/inferiorly based tympanomeatal flap. Embolization of these tumors is not required. Bipolar electrocautery microforceps can be used to shrink the tumor and resect it. Larger tympanic paragangliomas confined to the middle ear and/or mastoid, but that do not breach the bone overlying the jugular bulb or the jugulocarotid spine, can be exposed through a combined postauricular/endaural approach with a canal-wall-up mastoidectomy and extended facial recess approach inferiorly that sacrifices the chorda tympani and removes the vaginal process of the tympanic bone to expose the hypotympanum.

When the jugular bulb is involved, a combined temporal/cervical approach is required. An extended mastoidectomy and extended facial recess approach is performed with skeletonization of the sigmoid sinus and exposure of the jugular bulb through the retrofacial air cells. The ICA is dissected superiorly and controlled. Cranial nerves IX, X, and XI are identified and traced proximally and distally. The internal jugular vein is then ligated superiorly and dissected toward the jugular bulb in the neck. The sigmoid sinus is occluded and ligated above the tumor extension. Contralateral venous outflow should be verified through preoperative studies. When occlusion of the sigmoid sinus is performed, this should be done in a manner that avoids interfering with the outflow from the anastomotic vein of Labbe, which drains the temporoparietal cortex and thereby avoids the risk of a venous stroke.⁷⁷ Once the sigmoid sinus is opened and the jugular vein is ligated inferiorly, hemostatic agents can be injected to gently occlude the inferior petrosal veins. This provides blood-free visualization of the jugular bulb and improves the microsurgical dissection at the pars nervosa of the jugular bulb, the site most likely to sustains cranial nerve injury. Dissection of the tumor should proceed with irrigating bipolar electrocautery. At the level of the jugular bulb, the dissection should be undertaken with extreme
caution since the cranial nerve rootlets of the glossopharyngeal and the vagus are at their most vulnerable. In jugulotympanic paragangliomas, these rootlets are displaced medially and are thus in a favorable position. If the tumor does not extend into the pars nervosa/medial jugular bulb compartment, preservation of the cranial nerves is desirable.⁷⁸

Those more advanced tumors that involve the vertical and/or horizontal petrous carotid artery and possible intracranial extension require a postauricular infratemporal fossa approach. These approaches begin with an extended mastoidotomy, removal of the external auditory canal, tympanic membrane, malleus, and incus. The external canal is permanently closed, which condemns the patient to a profound ipsilateral conductive hearing loss. The peritubal and pericarotid air cells are removed and the intrapetrous carotid artery is skeletonized proximal to the tumor extent. This may involve sacrifice of the middle meningeal artery and removal of the foramen spinosum as well as the foramen ovale if the tumor has extended toward the cavernous sinus. Tumor is removed from the carotid, middle ear, and sigmoid/jugular bulb/jugular vein (Fig. 27-18). Tumor extension to the medial jugular bulb compartment and/or intracranially places the nerve rootlets of cranial nerves IX, X, and XI in a vulnerable position, and more frequently than not, it is necessary to sacrifice them. If there is no such extension, an effort is made to gently dissect the tumor away from the nerves. The Eustachian tube should be permanently occluded to avoid postoperative cerebrospinal fluid rhinorrhea. Intracranial extension is addressed by opening the dura in the presigmoid area down to the tumor extension at the level of the jugular bulb. Tumor extension toward the petrous apex and clivus may necessitate a translabyrinthine/transcochlear approach. In these approaches, the facial nerve is mobilized out of the fallopian canal in its vertical and horizontal portion to the geniculate ganglion. This will result in temporary facial paralysis due to interruption of the blood supply to the nerve as well as the retraction anterosuperiorly.^27,58,79 Incomplete recovery of facial nerve function is a possible outcome. Reconstruction with temporoparietal fascia flap or temporalis muscle alone is done at the conclusion to assist healing and prevent a cerebrospinal fluid leak. Lumbar drainage for a limited period of time in the immediate postoperative recovery may be indicated for the prevention of a cerebrospinal fluid leak. When cranial nerves have been sacrificed, immediate surgical amelioration with a concurrent vocal cord medialization and a pharyngoplasty with cricoesophageal myotomy at the same sitting have been recommended.

Technical refinements include the juxtacondylar approach as well as the transjugular craniotomy.⁷⁸ These modifications both shift the surgical angle of approach posteriorly. The advantages are that they obviate the need for facial nerve transposition and improve the control and preservation of the lower cranial nerves in the jugular foramen. The limitation is that they cannot address tumor involvement in the petrous carotid artery area.

Vagal Paragangliomas. Most vagal paragangliomas originate in the nodose (inferior) ganglion that is situated 2 cm below the jugular foramen. Their bidirectional growth along the vagus results in involvement of the jugular bulb superiorly and poststyloid parapharyngeal space inferiorly. The ICA is displaced anteriorly.⁶⁰ Vagal paragangliomas originating in the superior and middle ganglia that are situated within the jugular foramen cause early skull base invasion with intracranial extension. The surgical techniques to approach these tumors are identical to those for jugulotympanic paragangliomas when the skull base is involved. The inferior extent of vagal paragangliomas requires detaching the digastric muscle from its origin and removing the styloid process to access the parapharyngeal space extension. Sacrifice of the vagus nerve in these tumors is inevitable. With involvement of the jugular foramen and skull base, additional cranial
nerve deficits are to be expected as these tumors extend medial to the cranial nerve rootlets, within the pars nervosa of the jugular foramen.

Early series of paraganglioma surgery reported a stroke rate of 10% to 20%; recent series report rates of 0% to 2%. Because of contemporary diagnostic methods, preoperative planning, and microsurgical techniques, the risk of injury or need for internal carotid sacrifice is minimal. For carotid body tumors, the risk of injury and need for vessel sacrifice is size specific with tumors larger than 5 cm likely requiring carotid reconstruction. In addition, preoperative findings of stenosis and irregularity on angiography and/or circumferential involvement on MRI with loss of the pericarotid adventia make preoperative preparation for carotid resection and reconstruction critically important.^80,81,82,83

Vagal paragangliomas differ from carotid body tumors and jugulotympanic tumors because they are not intimately associated with the carotid artery. In advanced vagal and jugulotympanic lesions, however, the ICA can be completely encased by tumor within the petrous portion. With adequate surgical exposure and microsurgical technique, injury should be infrequent in experienced hands. Internal carotid sacrifice in this location is fraught with problems; therefore, if sacrifice is contemplated, consideration for alternate treatment in these instances is important. If the vessel is at high risk for injury within the petrous carotid portion, and the patient has safely passed balloon occlusion testing, permanent preoperative occlusion of the carotid distal to the tumor should be considered.

Reported more recently, a novel approach to the artery that is particularly at risk for injury is to place a vascular endoprosthesis and then perform the surgery several weeks later. Fibrosis around the self-expanding stent creates a leak-proof artery. This has the advantage of reducing blood flow to the tumor, as well as preventing vascular injury.⁸⁴

Surgery for removal of bilateral carotid body tumors results in loss of the baroreceptor reflex with bilateral denervation of the carotid sinus. In the immediate postoperative period, this results in labile refractory hypertension, tachycardia, diaphoresis, and headache that is treated with sodium nitroprusside. Long-term treatment is control with clonidine.⁸⁵ This complication is more than theoretical, and in this bilateral circumstance, alternative therapy should be considered for one of the tumors.

The risk to the lower cranial nerves in surgery for paragangliomas is location and tumor size specific. In decreasing order of risk these tumors pose to injury: vagal, jugulotympanic, and carotid body paragangliomas. Size of lesion is especially important in vagal and jugulotympanic paragangliomas. Tumors with extensive skull base involvement, intracranial and/or infratemporal fossa extension are likely to have extensive involvement of the lower cranial nerves with at least one nerve involved, and oftentimes, multiple nerve deficits preoperatively. Involvement of the facial nerve with preoperative paralysis is a sign of such extensive involvement.^{27,58,59,86,87}