Paragangliomas: Treatment of locoregional disease

INTRODUCTION — Paragangliomas are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, small organs that consist mainly of neuroendocrine (chromaffin) cells that are derived from the embryonic neural crest and have the ability to secrete catecholamines (figure 1). (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Catecholamine hypersecretion'.)

Paragangliomas are closely related to pheochromocytomas, which are sometimes referred to as intra-adrenal paragangliomas, and the two tumors are indistinguishable at the cellular level. Catecholamine-secreting sympathetic paragangliomas often present clinically like pheochromocytomas with hypertension, episodic headache, sweating, and tachycardia. However, the distinction between pheochromocytoma and paraganglioma is an important one because of implications for associated neoplasms, risk for malignancy, and genetic testing. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Histology and malignant potential' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Genetic testing'.)

Paragangliomas can derive from either parasympathetic or sympathetic paraganglia. They differ in their anatomic distribution, frequency of an underlying genetic syndrome, and clinical features (see "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Definition and anatomic origin'):

●The majority of parasympathetic ganglia-derived paragangliomas are located in the neck and skull base along the branches of the glossopharyngeal and vagus nerves (figure 2). They arise most commonly from the carotid body, less commonly from jugulotympanic and vagal paraganglia, and rarely from the laryngeal paraganglia.

A minority of skull base paragangliomas (approximately 3 to 5 percent) are symptomatic from hypersecretion [1,2]. Approximately one-half are associated with a disease-causing germline pathogenic variant. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Hereditary syndromes' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Catecholamine hypersecretion'.)

●Sympathetic paragangliomas arise outside of the adrenal gland anywhere along the sympathetic chain (figure 2) from the base of the skull (5 percent) to the bladder (image 1) and prostate (10 percent). Approximately 75 percent of sympathetic paragangliomas arise in the abdomen, most often at the junction of the vena cava and the renal veins, or at the organ of Zuckerkandl, which resides just above the aortic bifurcation near the take-off of the inferior mesenteric artery (image 2). Approximately 10 percent arise in the thorax, including pericardial locations. Sympathetic paragangliomas can also arise in the thyroid gland, adjacent to the thoracic spine, and at the level of the cauda equina.

The majority of paragangliomas arising outside of the skull base and neck are sympathetic, have excess catecholamine secretion (86 percent in one series [3]), and are almost always noradrenergic (ie, secrete predominantly norepinephrine and normetanephrine). This results in symptoms that are similar to those of an adrenal pheochromocytoma. Approximately 40 percent are associated with disease-causing germline pathogenic variants [4-6].

This topic review will cover locoregional treatment for paragangliomas at all sites. The epidemiology, risk factors, molecular pathogenesis, histology, clinical manifestations, diagnosis, and genetic screening issues for paragangliomas; locoregional treatment for pheochromocytomas; and management of advanced or metastatic pheochromocytoma/paraganglioma are covered elsewhere. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Pheochromocytoma in genetic disorders" and "Treatment of pheochromocytoma in adults" and "Pheochromocytoma and paraganglioma in children".)

RISK OF MALIGNANCY — Most paragangliomas appear to be benign, but over time, approximately 15 to 35 percent display malignant behavior [4,7]. In the absence of metastatic disease, histopathology findings cannot state whether a paraganglioma is benign or malignant. The updated WHO tumor classification of endocrine organs has replaced the term "malignant pheochromocytoma or paragangliomas" with "metastatic pheochromocytoma or paragangliomas" and recognized that all pheochromocytomas and paragangliomas have malignant potential [8]. In this context, metastases are defined as tumors where chromaffin tissue is normally not found (eg, lymph nodes, lung, liver, and bones). (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Histology and malignant potential'.)

The incidence of malignancy depends on the genetic background and anatomic site:

●Approximately 20 percent of extra-adrenal (abdominal and mediastinal) secretory paragangliomas are malignant (versus 10 percent of pheochromocytomas), whereas skull base and neck paragangliomas are usually benign.

●In the skull base and neck, malignancy is least common for jugulotympanic tumors (2 to 4 percent), slightly higher for carotid body tumors (4 to 6 percent), and highest for vagal tumors (10 to 19 percent) [9-12]. The majority of patients with malignant skull base and neck paragangliomas experience regional spread (69 percent in one report [9]) rather than distant metastases. Therefore, for patients with skull base and neck paragangliomas, many surgeons include an ipsilateral neck dissection as part of the surgical exposure to both resect the paragangliomas and identify occult metastatic disease [13]. This approach may prevent the need to reoperate in the neck for recurrent metastatic paraganglioma, which can be technically difficult [14]. (See 'Skull base and neck paragangliomas' below.)

●The highest malignancy rates are seen in paragangliomas associated with inherited pathogenic variants in the B subunit of the succinate dehydrogenase (SDHB) gene, which are usually abdominal and secretory. These patients warrant screening for distant metastatic disease as part of the preoperative evaluation. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Familial paraganglioma and SDH pathogenic variants' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Screening for synchronous and metastatic disease'.)

Patterns of malignant spread — Among patients with malignant skull base and neck paragangliomas, many (but not all [15]) series indicate that metastases are most frequently found to the cervical lymph nodes. As an example, in a series of 59 cases of malignant skull base and neck paraganglioma extracted from the National Cancer Database, metastases were restricted to the regional nodes in 69 percent of cases [9]. These data have led many to recommend selective lymph node dissection at the time of primary resection of malignant skull base and neck paragangliomas. (See 'Resection' below and 'Resection' below.)

Although outcomes of patients with regional nodal disease are better than they are with distant metastases (five-year survival 77 versus 12 percent in the above noted series from the National Cancer Database [9]), adjuvant radiation therapy (RT) is frequently recommended. (See 'Postoperative radiation therapy' below.)

In contrast to skull base and neck paragangliomas, patients with malignant paragangliomas below the skull base and neck have a higher likelihood of developing distant metastases, most commonly to the bone, liver, and lung. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Overview'.)

While the presence of distant metastatic disease has an adverse effect on prognosis, metastases do not necessarily represent a contraindication to resection, particularly for paragangliomas below the skull base and neck. Palliative surgery may be performed primarily to reduce or ameliorate a hypersecretory state, but can also release tumor pressure on surrounding tissues [16]. Additionally, if the tumor has already caused lower cranial nerve palsies, surgery typically does not add significant morbidity as the patient has likely functionally compensated for the neurologic deficits over time. A lower tumor burden can result in a significant decrease in catecholamine secretion (for functioning tumors) as well as lowered dosage of agents used for alpha- and beta-adrenergic blockade. It can also improve the response to other therapeutic approaches. A survival advantage for surgical debulking has not been shown [17]. (See 'General principles of locoregional management' below and 'Medical preparation for surgery' below.)

GENERAL PRINCIPLES OF LOCOREGIONAL MANAGEMENT — Options for locoregional management can include observation, surgical resection, or radiation therapy (RT). In general, resection is preferred for localized paragangliomas arising below the neck and for all catecholamine-secreting paragangliomas or paragangliomas arising from any site that are symptomatic. Less invasive approaches, such as conventionally fractionated external beam RT (EBRT) or stereotactic body RT (SBRT), may provide high rates of long-term disease control (defined as no tumor growth) for skull base and neck paragangliomas and for non-skull base and neck paragangliomas that are unresectable, but they do not offer the same degree of symptom relief that is accomplished with resection [18]. (See 'Primary radiation therapy' below and 'Radiation therapy' below.)

An algorithmic approach to locoregional management of paragangliomas is outlined in the algorithm (algorithm 1).

General surgical principles — Some patients with an inherited syndrome predisposing to paraganglioma may have concurrent multiple tumors (eg, von Hippel Lindau disease with cerebellar hemangioblastoma, renal cell carcinoma, and pancreatic islet cell tumors). In general, treatment of the catecholamine-secreting tumor typically takes clinical priority and is resected first. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

Preoperative evaluation — A presumptive preoperative diagnosis of a paraganglioma can usually be made using biochemical and radiographic testing (algorithm 2).

Prior to resection, blood pressure checks and catecholamine secretion should be assessed biochemically in all patients with suspected paraganglioma, even if they do not present with a clinical picture of catecholamine hypersecretion. Undiagnosed catecholamine hypersecretion in patients without symptoms of catecholamine excess is not uncommon and can cause major morbidity and mortality during resection. In fact, if severe labile hypertension occurs during anesthetic induction or early in the resection of a cervical, perinephric, lower abdominal, or pelvic mass that is not yet known to be catecholamine-secreting paraganglioma, the presumptive diagnosis of a catecholamine-secreting tumor should be made and the case aborted, with return for definitive resection only after evaluation and adrenergic blockade is performed. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Diagnosis'.)

For patients with a catecholamine-secreting tumor, radiologic imaging can provide information about tumor localization. For nonsecretory tumors, imaging characteristics are frequently sufficiently distinctive (by location and a high degree of vascularity) to permit a presumptive preoperative diagnosis of paraganglioma. The most commonly used tests are ultrasound, cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI), 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) integrated with CT (PET/CT), I-123 metaiodobenzylguanidine (MIBG) scintigraphy, and somatostatin receptor-based imaging using indium-111 pentetreotide single-photon emission CT (Octreoscan) or integrated PET/CT using gallium Ga-68 DOTATATE (Ga-68 DOTATATE) or gallium Ga-68 DOTATOC (Ga-68 DOTATOC). Radiographic screening for metastatic disease (typically using FDG PET or Ga-68 DOTATATE/Ga-68 DOTATOC PET) is indicated for patients with germline succinate dehydrogenase (SDHB) pathogenic variants, given the high rate of malignant paraganglioma in this subset, but is usually not warranted for other groups unless there are symptoms or signs that raise suspicion for the presence of metastatic disease. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Diagnosis' and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Screening for synchronous and metastatic disease'.)

Most patients should proceed directly to surgery without benefit of a preoperative biopsy. Preoperative biopsy (incisional or by fine needle aspiration [FNA]) is contraindicated in a patient suspected of having any type of catecholamine-secreting tumor as well as for most paragangliomas. The findings on biopsy are of little value, particularly for skull base and neck paragangliomas. In addition to the challenge of establishing the correct diagnosis, biopsy may result in severe hemorrhage or subsequent fibrosis, with subsequent difficulty with definitive surgery. FNA or a core needle biopsy may be indicated in a patient who has suspected distant metastatic disease to establish the diagnosis and permit optimal treatment planning, but even in this setting, functional imaging with 123-I-MIBG or Ga-68 DOTATATE/Ga-68 DOTATOC PET/CT is diagnostic. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Tissue diagnosis'.)

Role of arteriography — Although tumor extent is often well demonstrated by CT and/or MRI, vascularity is best studied with digital subtraction angiography [19]. In addition to demonstrating displacement of blood vessels, potential vessel compromise by tumor invasion, and the adequacy of the intracranial circulation if internal carotid artery sacrifice is necessary, arteriography can also reveal previously unsuspected synchronous paragangliomas [20,21]. However, selective arteriography is not essential in the evaluation of skull base and neck paragangliomas unless preoperative embolization is being considered prior to surgery. (See 'Preoperative arterial embolization of skull base and neck paragangliomas' below.)

To avoid precipitating a catecholamine crisis, all patients suspected of having a paraganglioma should have negative biochemical results for catecholamine hypersecretion before interventional imaging and/or tumor manipulation, or should undergo alpha-adrenergic blockade prior to arteriography or embolization.

Medical preparation for surgery — Patients with undiagnosed catecholamine-secreting tumors who undergo surgery for other reasons (and who therefore have not undergone preoperative adrenergic blockade) have high rates of perioperative morbidity due to hypertensive crisis, malignant arrhythmias, and multiorgan failure. For this reason, some form of preoperative pharmacologic preparation is indicated for all patients with catecholamine-secreting neoplasms. The one exception is skull base and neck tumors, which are typically nonfunctional; if fractionated metanephrines and catecholamines are normal, these tumors do not require blockade prior to surgery. (See 'Risk of malignancy' above.)

Preoperative medical therapy is aimed at controlling hypertension, preventing a hypertensive crisis during surgery, and providing volume expansion to reverse catecholamine-induced blood volume contraction preoperatively in order to prevent severe hypotension after tumor removal. There are several approaches to medical therapy in preparation for surgery in patients with catecholamine-secreting tumors. Combined alpha- and beta-adrenergic blockade, calcium channel blockers, and metyrosine have all been used successfully. No randomized controlled trials have compared the different approaches, and there is no universally accepted method. Our approach parallels that used prior to resection of a pheochromocytoma; this subject is discussed elsewhere. (See "Treatment of pheochromocytoma in adults", section on 'Medical preparation for surgery'.)

Intraoperative/postoperative management — Resecting a catecholamine-secreting tumor is a high-risk surgical procedure, and an experienced surgeon/anesthesiologist team is required. Prior to surgery, it is appropriate and important for the surgeon to assess the adequacy of adrenergic blockade that has been administered by themselves or other caregivers, so that she/he can optimize the degree of blockade before proceeding on to a safe operation. The goal of preoperative adrenergic blockade and volume expansion is to achieve a normal heart rate, blood pressure, and urine output throughout the surgery (figure 3).

During the procedure, the surgeon should communicate frequently with the anesthesiologist especially upon incision, at the time of division of the venous supply, and during tumor manipulation. The anesthesiologist must employ appropriate vascular access and monitoring devices, including a urinary bladder catheter. The anesthesiologist must be prepared to counteract alpha- and beta-adrenergic catecholamine-induced cardiovascular effects with short-acting medications (eg, nitroprusside, phentolamine, nicardipine, lidocaine), and should communicate with the surgeon if such methods require use and when such methods are discontinued. Intraoperatively, cardiovascular and hemodynamic variables must be monitored closely, with continuous measurement of intra-arterial pressure and heart rhythm. For patients with heart failure or decreased cardiac reserve, monitoring of pulmonary capillary wedge pressure is indicated. Fluid administration and output should be carefully monitored.

In the immediate postoperative period, continued monitoring of blood pressure, heart rate, and blood glucose levels is recommended [22]. With proper adrenergic-blockade and intraoperative management, a postoperative intensive care unit bed is uncommonly required at major centers.

Preoperative arterial embolization of skull base and neck paragangliomas — In patients with nonfunctioning skull base and neck paragangliomas, preoperative embolization of the tumor's main arterial supply within 48 hours of surgery may help to reduce tumor size, bleeding, and other complications associated with removal of large tumors of the skull base and neck, thus facilitating resection [21,23-38]. However, since embolization is an invasive and potentially dangerous procedure (possible severe side effects include skin necrosis, blindness, cranial nerve deficits, stroke, and death), the risk of potential complications has to be weighed against the advantages. The risk of these severe complications is generally low, ranging from 0 to 13 percent [21,23,25,29-34,39].

There is no consensus as to the indications for preoperative arterial embolization of skull base and neck paragangliomas [40,41]. Some use size criteria (typically >3 cm) to select patients for this approach [23,31,32,42,43]. Others use disease stage. Many consider that preoperative angiographic embolization is indicated in patients with class C and D jugular paragangliomas, without which it would not be possible to completely resect the tumors [21,34,39,43,44], while others also recommend it for Shamblin class III carotid body tumors as well (table 1) [39]. Still others advocate preoperative embolization for all tumors except tympanic paragangliomas that are confined to the middle ear cavity [21].

General radiation therapy principles — RT is most often used for treatment of non-catecholamine secreting apparent benign paragangliomas of the skull base and neck where resection would require extensive sacrifice of critical vascular and/or neural structures, and for those with recurrent tumor after previous surgery. The role of RT in the management of malignant paragangliomas is discussed in detail elsewhere. (See "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease", section on 'Radiation therapy'.)

Apparent benign paragangliomas of the skull base and neck may slightly regress but are not expected to decrease in volume following RT. The definition of "cure" in the context of RT is similar to that which is used for other in situ benign tumors (ie, durable radiographic and clinical stability). When defined in this way, durable disease control can be achieved in >90 to 95 percent of apparent benign skull base and neck paragangliomas after conventionally fractionated EBRT or SBRT [45-70]. However, tumors do not often regress in size. As a result, locally symptomatic lesions should be strongly considered for surgical resection whenever anatomically feasible, whether strictly for palliation or for cure. (See 'Skull base and neck paragangliomas' below.)

Target-definition — In the management of paragangliomas, the gross tumor volume (GTV) target for RT is the grossly visible disease as defined by contrast-enhanced CT, MRI, or both. Typically there is no clinical target volume (CTV) expansion to cover the possibility of subclinical involvement that extends beyond the GTV unless the gross disease is poorly defined. The planning target volume (PTV) is the GTV with a uniform expansion for setup uncertainty that is 1 to 5 mm depending on the system of immobilization and image-guidance. These target definitions are used for both conventionally fractionated RT and stereotactic radiosurgery.

Delivery — RT for paragangliomas can be delivered using both conventionally fractionated and radiosurgical approaches. (See 'Conventionally fractionated radiation therapy' below and 'Stereotactic body radiation therapy' below.)

Conventionally fractionated radiation therapy — Conventionally fractionated RT refers to the delivery of EBRT in doses of 1.8 to 2 Gy daily, five days per week. Doses used for treatment of paragangliomas in the skull base and neck range from 45 to 50.4 Gy in 1.8 to 2 Gy fractions to the PTV. Doses <40 Gy have been associated with an increased risk of local recurrence [71]. Doses >45 to 50 Gy are not associated with improved local control, but may contribute to higher rates of post-treatment sequelae [72-74]. Immobilization of the head and neck is generally achieved by the use of an aquaplast mask that covers the head and possibly shoulders depending on the location of the paraganglioma.

Postoperative radiation therapy — The role of postoperative (adjuvant) RT after resection of a benign paraganglioma is undefined. In general, RT is usually considered if there has been incomplete tumor removal or complete resection of regionally metastatic (malignant) paraganglioma, although the data supporting a benefit of RT in either situation are retrospective and not robust [9,75]. (See "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease", section on 'Radiation therapy'.)

Stereotactic body radiation therapy — Single-fraction SBRT, which is also referred to as stereotactic radiosurgery (SRS) when the target is intracranial, refers to the delivery of a high ablative dose of radiation to a small target with stereotactic precision in one session. SBRT relies on rigid immobilization using stereotactic devices, as well as the ability to position, confirm, and reposition the patient as needed immediately prior to the treatment. This concept of "image-guidance" can be achieved by several commercially available systems. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

SBRT for paragangliomas is generally limited to tumors of the skull base and neck that are <3 cm, but this parameter is heavily dependent on the dose chosen as well as the collateral dose to surrounding normal tissues. Radiosurgery doses for paraganglioma are generally 12 to 15 Gy in a single fraction [64-69,75-79]. SBRT can also be "hypofractionated," which refers to fractionation of the total dose between two and five sessions, each with a dose per fraction that is between those used for conventional RT and single-fraction SRS treatments.

Long-term disease control rates are extremely high after SBRT. Because both conventionally fractionated and SBRT approaches lead to very high local control rates (>90 to 95 percent), the advantage of SBRT is one of convenience for properly selected patients.

Radiation side effects — Acute and long-term sequelae after RT are related to the dose received to adjacent normal tissues. These may include transient mucositis, skin reactions within the radiation field, middle ear effusion, long-term decreased hearing, hypopituitarism, and xerostomia. These risks are dependent on proximity of the target to the normal tissues. However, modern radiation planning techniques and established guidelines have minimized the risk of permanent and severe toxicities [80-83]. Severe late effects such as osteomyelitis, brain necrosis, and bone necrosis are extremely rare in the modern era. (See "Acute complications of cranial irradiation" and "Delayed complications of cranial irradiation".)

THERAPEUTIC APPROACH AT SPECIFIC SITES AND OUTCOMES

Skull base and neck paragangliomas — Management of skull base and neck paragangliomas is based upon retrospective data; there are no prospective trials to guide the therapeutic strategy. The optimal approach to therapy depends on symptomatology, size, location, the relationship between the tumor and neurovascular structures, as well as the age and general health of the patient [11,29,46,84-87].

Prior to initiating therapy, all patients with skull base and neck paragangliomas should receive a complete examination of the head and neck region as well as swallowing and voice evaluation to assess for lower cranial nerve function. Surgical resection in patients with intact neurologic function carries significant morbidity compared with those who already have these neurologic deficits from the tumor but have chronically compensated for such deficits over time [13].

Treatment options include resection, primary radiation therapy (RT), or initial observation. The benefits and potential risks of all treatment options have to be taken into consideration in selecting the therapeutic approach. However, in general, our approach to the initial management of locoregional paragangliomas is as follows (algorithm 1):

●Resection is preferred for patients with catecholamine-secreting tumors; those that are locally symptomatic from tumor bulk, whenever anatomically feasible; and younger patients with head and neck paragangliomas who wish to avoid the long-term sequelae of RT.

●RT is an appropriate alternative for patients with non-catecholamine secreting apparent benign paragangliomas of the skull base and neck who have normal preoperative lower cranial nerve function and in whom resection would require extensive sacrifice of critical vascular and/or neural structures, and for those with recurrent tumor after previous surgery.

●Initial observation is an acceptable approach for individual patients who have small (eg, <1 cm) asymptomatic, nonsecreting paragangliomas that can be closely monitored to assess the natural history.

Initial observation — Historically, surgical resection was the treatment of choice for all skull base and neck paragangliomas. However, these tumors display a wide spectrum of clinical behavior. The variable growth rate, along with the fact that the majority (90 percent or more) are nonfunctioning, is an important consideration in determining whether to intervene therapeutically versus pursue an initial period of surveillance. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Clinical presentation'.)

The potentially indolent nature of these tumors can be illustrated by the following reports:

●Some series estimate tumor doubling time to be between 4.2 and 13.8 years [21,64].

●In a retrospective study of 130 paragangliomas, 30 percent of the tumors were observed and the rest were subjected to surgery or radiation. During ten years of follow-up, over half of the observed tumors did not grow [88].

●A retrospective analysis included 48 patients with a skull base and neck paraganglioma (20 carotid body, 17 vagal body tumors, 11 jugulotympanic) who were followed without active treatment for an average of four years [89]. The median growth rate was 1 mm annually (range 0.3 to 5 mm per year), and the median tumor doubling time was four years (range 0.6 to 21.5 years). While 75 percent of tumors 0.8 to 4.5 cm in diameter showed active growth, less than one-half of lesions either smaller than 0.8 cm or larger than 4.5 cm in diameter grew during the period of observation.

●In another study, 43 patients with 47 tumors (28 carotid body, 19 vagal) were observed initially because of patient preference (n = 15), advanced age (n = 12), or preexisting contralateral cranial nerve deficits (n = 11) [90]. Thirty patients were asymptomatic, five presented with cranial nerve abnormalities, four had dysphagia, two had pulsatile tinnitus, and two had isolated Horner syndrome. No patient presented with lymphadenopathy, rapid growth, or pain. Patients were followed serially with cross-sectional imaging (either computed tomography [CT] or magnetic resonance imaging [MRI]). The mean greatest dimension at presentation was 2.6 cm (mean 1 to 7.2). With a mean follow-up time of five years (range 1 to 17), 19 tumors (42 percent) remained stable in size, 17 (38 percent) grew, and 9 (20 percent) reduced in size. Of the 17 tumors that grew, the mean growth was 0.2 cm per year. There did not appear to be a trend toward growth or regression based upon initial tumor size.

We advocate therapeutic intervention for all patients with symptomatic skull base and neck paragangliomas. However, initial observation is an acceptable approach for individual patients who have small (eg, <1 cm) asymptomatic, nonsecreting jugular and carotid body paragangliomas that can be closely monitored to assess the natural history [91]. Our approach is consistent with that of the British Skull Base Society, which advocates for an initial period of surveillance for many patients with skull base and neck paragangliomas, with the following exceptions [92]:

●Tympanic paragangliomas

●Jugular paragangliomas with troublesome conductive hearing loss, pulsatile tinnitus, or impending or actual facial nerve weakness

●Significant brainstem compression

●Secretory tumors

●Cranial nerve dysfunction related to tumor burden

●Clinical evidence of rapid growth

●Malignant disease

●Patient choice

Close follow-up is mandatory, as the risk of neural injury after resection may be higher with larger tumors. Recommendations from the British Skull Base Society include interval imaging with contrast-enhanced MRI of the head and neck for all patients under initial surveillance [92]. CT of the skull base and neck with contrast is also an acceptable alternative imaging modality. The initial imaging should be at six months, and annually thereafter. The interval may be increased for those tumors that are stable over time (eg, a sporadic stable tumor could be scanned annually for three years, biannually for six years, and every three years thereafter). Surveillance may be stopped in older adult patients with isolated stable tumors.

In addition, if germline genetic testing is positive for a pathogenic variant in a gene that predisposes to paraganglioma, patients should also have a screening MRI of the thorax, abdomen, and pelvis at least once every two to three years to screen for new tumors [92]. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Familial paraganglioma and SDH pathogenic variants'.)

For sporadic nonsecretory tumors, no further endocrine follow-up is required [92]. However, for those with an identified pathogenic variant or multiple tumors, surveillance should include annual plasma fractionated metanephrines or 24-hour urine for fractionated metanephrines and catecholamines, which, if raised, should prompt further imaging of the thorax, abdomen, and pelvis to assess for a new secreting tumor.

Cervical paragangliomas — For cervical (carotid body, vagal, perithyroid) paragangliomas, we suggest therapeutic intervention rather than observation for symptomatic or large (eg, >2 cm) tumors. The optimal approach to therapy depends on symptomatology, size, location, the relationship between the tumor and neurovascular structures, as well as the age and general health of the patient. Resection is generally preferred for catecholamine-secreting tumors and those that are locally symptomatic from tumor bulk, if the tumor can be resected completely without significant compromise or sacrifice of critical neurovascular structures. RT is an appropriate alternative for patients with non-catecholamine secreting apparent benign paragangliomas of the skull base and neck who have normal preoperative lower cranial nerve function and in whom resection would require extensive sacrifice of critical vascular and/or neural structures, and for those with recurrent tumor after previous surgery.

Resection — Complete surgical resection for cervical (carotid body, vagal, perithyroid) paragangliomas was historically considered the treatment of choice for cervical paragangliomas [11,84,85,93]. Cure rates after complete resection of a benign carotid body tumor are 89 to 100 percent [47,84,93-95]. Although few data are available, long-term control of disease was reported in 93 percent of vagal paragangliomas in a systematic review of 211 cases [45]. Cure rates are lower in patients with regional nodal metastases (five-year survival 77 percent in one series from the National Cancer Database [9]) and adjuvant RT is frequently recommended, although its benefits are unproven. (See 'Postoperative radiation therapy' above.)

Resection of carotid body tumors is performed via a transcervical approach. Special care must be taken to avoid injury to the cranial nerves. Especially in Shamblin class III tumors (table 1), there is also the potential for injury to the common or internal carotid artery. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Staging'.)

For patients with a vagal paraganglioma, the affected vagal nerve usually has to be sacrificed during surgery [21,45]. Attempts to preserve nerve function almost always result in postoperative nerve palsy, and there is a risk of inadequate tumor resection [96].

Rarely, cervical paragangliomas arise in proximity to the thyroid; most of these are probably a subset of laryngeal paragangliomas [97]. Intraoperatively, thyroid-associated paragangliomas are often densely adherent to surrounding tissues, including the recurrent laryngeal nerve. However, aggressive local resection should be performed, as it can achieve a long disease-free interval [97,98]. The aggressive local behavior of these tumors does not correspond to a potential for malignancy, as there are no reports of malignant thyroid-associated paragangliomas in the literature.

Given that the majority of cervical paragangliomas are benign, routine radical lymph node dissection is not advised. However, some experts recommend sampling or selective ipsilateral neck dissection of regions IIA, IIB, and III to exclude or verify nodal metastases at the time of resection and to improve exposure (figure 4) [14,39,99]. A role for sentinel node biopsy has been suggested but is not established [14].

The major morbidity associated with surgery is related to postoperative cranial nerve dysfunction [11,21,30,45,84,85,100,101]; other less common serious complications include stroke and bleeding:

●In a retrospective, multicenter series of 95 patients treated for a carotid body tumor over a 26-year period, surgery was complicated by stroke, bleeding, or cranial nerve injury in 1, 6, and 19 percent of patients, respectively [11]. Risk is higher for larger tumors, as multiple cranial nerves are involved. In one report, the diameter of the carotid body tumors in resections resulting in nerve palsy was significantly larger than in those procedures in which nerve palsy did not occur (4.6 versus 3.1 cm) [96].

●Similarly, for vagal paragangliomas, cranial nerve damage is the most frequent postoperative complication [45,84]. In a systematic review of published reports, 147 cranial nerves were damaged preoperatively in 211 patients undergoing resection for a vagal paraganglioma, and this increased to 445 cranial nerve palsies after surgery; the vagus nerve was functionally preserved in only 11 patients [45].

It is largely because of the high rates of cranial nerve dysfunction that conventionally fractionated external beam RT (EBRT) or stereotactic body RT (SBRT) have emerged as reasonable alternatives to surgery for situations where tumor resection is likely to result in significant compromise or sacrifice of critical neurovascular structures. However, as noted above, these less invasive approaches may provide high rates of long-term disease control for asymptomatic head and neck paragangliomas, but they do not offer the same degree of symptom relief that is accomplished with resection. (See 'General principles of locoregional management' above and 'Primary radiation therapy' below.)

Primary radiation therapy — RT is a reasonable alternative to surgery, particularly if resection would require sacrifice of critical vascular and/or neural structures, for those with recurrent tumor after previous surgery, and in the setting of a contralateral vagal nerve palsy.

When defined in this way, at doses between 45 and 56 Gy, long-term tumor control rates for carotid body paragangliomas are 90 to 96 percent [47-51].

Two RT series containing vagal paragangliomas have been published:

●In one report of 17 paragangliomas, disease control was achieved in all patients with a mean duration of follow-up of 8.5 years [47].

●In a second series of 18 vagal paragangliomas, which included 14 treated exclusively with RT, no local recurrence or death due to disease occurred, with a median follow-up of 4.2 years [52].

Permanent cranial nerve deficits seem to be less common after RT of cervical paragangliomas when compared with results of surgical resection [21,45,47,51,64]. However, there is a small and poorly defined risk for radiation-related tumor formation (see "Radiation-associated sarcomas" and "Head and neck sarcomas", section on 'Risk factors'). In the vast majority of patients, this risk does not pose a relevant risk. It unclear whether the risk is greater when treating a patient with a suspected germline pathogenic variant. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Hereditary syndromes'.)

Management of bilateral tumors — Multiple tumors occur in up to one-third of cases [102]. Resection of bilateral carotid body tumors may cause baroreflex failure syndrome, which is characterized by severe, constant hypertension in the first 24 to 72 hours after surgery, followed by labile hypertension and hypotension, headaches, emotional instability, and palpitations [103,104]. For patients with bilateral carotid body paragangliomas, surgical excision of the smaller tumor should be done first; if vagus and hypoglossal nerves are functional, contralateral surgery may be performed [102]. Conversely, in case of injury of these nerves, no contralateral tumor excision should be performed given that bilateral neurological deficits with dramatic consequences might occur. In these cases, RT is appropriate for the opposite tumor. (See 'Primary radiation therapy' above.)

Bilateral vagal body paragangliomas require a nonoperative approach for one side (typically conventionally fractionated EBRT or SBRT) since bilateral surgical excision would cause dramatic bilateral vagus nerve paralysis, resulting in the need for permanent tracheostomy and enteral feeding [92,101,102,105,106].

Jugulotympanic paragangliomas — As is the case with cervical paragangliomas, factors that play a role in the selection of optimal therapy include location, tumor size and extent, the age and general health of the patient, and, particularly with jugular paragangliomas, the presence of pre-therapeutic cranial nerve deficits. For patients with tympanic paragangliomas (Fisch class A and B, (table 1)), surgical resection (tympanoplastic surgery) is the treatment of choice [92] if there are no contraindications to general anesthesia.

Optimal treatment for jugular paragangliomas and for more advanced tympanic paragangliomas is more controversial. The critical anatomic location and vascularity of these tumors make surgical resection complex, and there is a significant risk of serious complications, particularly for advanced (eg, Fisch class C and D (table 1)) tumors, in which there is a high risk of postoperative cranial nerve dysfunction. Because of this, we suggest RT rather than resection for most patients, unless they are symptomatic from catecholamine secretion or tumor bulk. Ideally, treatment should be administered using intensity-modulated or fractionated stereotactic radiotherapy [92].

Resection — Until the development of microsurgical techniques and modern interventional neuroradiology, potentially life-threatening vascular complications were frequent, rates of postoperative cranial nerve deficits were high, and due to incomplete resection, the vast majority of jugulotympanic paragangliomas recurred. With modern techniques, local control can be achieved, even with extensive jugular paragangliomas, in 80 to 90 percent of cases. Local control rates are higher, 86 to 100 percent, for benign tumors in which gross total resection can be achieved [21,29,46,70,84,86,87,107].

For patients with symptomatic tympanic paragangliomas (Fisch class A and B, (table 1)), surgical resection (tympanoplastic surgery) represents the treatment of choice if there are no contraindications to general anesthesia [21,44,108]. These tumors become symptomatic (pulsatile tinnitus, conductive hearing loss) at an early stage in the majority of cases, and complete resection can be accomplished in most with a low risk of damage to the lower cranial nerves. (See 'Initial observation' above.)

Optimal treatment for jugular paragangliomas is more controversial, particularly for advanced tumors. While resection is possible for Fisch class C and D tumors (table 1) using an infratemporal or juxtacondylar approach, there is a high risk of postoperative cranial nerve dysfunction because of the intimate association of these tumors with the lower cranial nerves [21,29,45,46,84,87]. The results of surgery can best be illustrated by a systematic review of retrospective published series that included 1084 patients with jugular paragangliomas who were treated with a variety of surgical approaches; surgical control (defined as alive without evidence of disease during the entire follow-up period) was achieved in 85 percent of cases [45]. There were 1183 preoperative cranial neuropathies, which increased to 2148 postoperatively; thus, surgery resulted in 965 new cranial nerve deficits. Importantly, hearing loss was not included in this analysis because of lack of reporting in most series. The incidence of "dead ears" after surgery in four series totaling 266 cases of jugular paraganglioma was 45 percent [87,109-111].

With the goal of preserving lower cranial nerve function, which may involve subtotal resection, recommendations from the British Skull Base Society list the following indications for surgery [92]:

●Ear canal bleeding or persistent discharge

●Troublesome pulsatile tinnitus

●Conductive hearing loss

●Arteriovenous shunting

●Secreting tumors

●Significant brainstem compression

●Malignant disease

●Failure of RT to control growth

In most cases of a planned subtotal resection, this approach is strategically coupled with postoperative RT to maximize local control and prevent the need for future salvage surgery.

Radiation therapy — A major advantage of primary RT for jugulotympanic paragangliomas is avoidance of the morbidity of resection while offering a high probability of tumor control. However, as noted above, while less invasive approaches such as RT may provide high rates of long-term disease control for asymptomatic head and neck paragangliomas, they do not offer the same degree of symptom relief that is accomplished with resection. (See 'General principles of locoregional management' above and 'General radiation therapy principles' above.)

Durable local control is reported in 89 to 98 percent of patients [45-52]. These results are achieved with fewer lower cranial nerve deficits than after resection [45,47,112], and some patients with established cranial neuropathies improve. As an example, in a systematic review that included 461 patients with a jugular paraganglioma who were treated with conventional fractionation RT, there were 242 cranial neuropathies prior to treatment, and with a mean duration of follow-up of 113 months, this decreased to 232 after RT [45].

However, a number of serious complications are reported after RT for a jugular paraganglioma, including temporal bone osteomyelitis, temporal bone necrosis, pituitary insufficiency, brain necrosis, and sensorineural hearing loss [45,47]. In the review of 461 patients treated with RT for a jugular paraganglioma, there were 57 serious complications (12 percent), including 9 deaths (2 percent) [45]. Rates of radiation-related toxicities may be improved by more modern three-dimensional planning techniques.

SBRT is being used with increasing frequency for jugular and other skull base and neck paragangliomas; efficacy can be illustrated by the following reports:

●In a meta-analysis of 19 studies totaling 335 patients with a paraganglioma of the jugular ganglion who were treated with SBRT, 97 percent achieved tumor control (unchanged or reduced tumor volume), and 95 percent achieved clinical control (unchanged or improved clinical status) [67]. When the analysis was limited to the eight studies that reported a mean follow-up time of >36 months, 96 percent achieved tumor control, and 95 percent achieved clinical control. (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)

●Additional information on the success of SBRT as compared with surgical resection for jugular paragangliomas comes from a second meta-analysis of 109 reports totaling 869 patients treated with surgery or SBRT for a Fisch class A, B, C, or D tumor (table 1) [113]. Gross total resection (GTR) was performed in 351, subtotal resection (STR) alone in 82, STR plus SBRT in 97, and SBRT alone in 339 patients. A greater fraction of patients undergoing SBRT alone had Fisch class D tumors (57 percent) than patients undergoing GTR (19 percent), STR (29 percent), or STR plus SBRT (9 percent). Data from 46 studies providing a range of follow-up were pooled to assess tumor control rate (lack of recurrence in patients undergoing GTR or lack of documented growth in patients undergoing SBRT and STR). With long-term follow-up (which varied from a median of 71 to 96 months), pooled estimates of the rates of tumor control after treatment were as follows:

•GTR: 86 percent (95% CI 81-91).

•STR: 69 percent (95% CI 57-82).

•STR plus SBRT: 71 percent (95% CI 53-83).

•SBRT alone: 95 percent (95% CI 92-99).

•Patients who underwent GTR had worse rates of cranial nerve (CN) deficits in CN IX (38 versus 9.7 percent), X (26 versus 9.7 percent), and-XI (40 versus 12 percent) than did those receiving SBRT; rates of CN XII deficits were not significantly different (18 versus 8.7 percent).

However, the number of symptomatic patients was not reported in this analysis, nor were rates of symptom control after each of these treatments.

Paragangliomas below the neck — We suggest complete surgical resection for cure rather than RT for all potentially resectable paragangliomas arising below the neck, including the thorax, abdomen, or pelvis (algorithm 1).

The surgical approach may need to address several synchronous tumors. Because of the risk of tumor spillage [114], it is essential to employ circumferential en bloc oncologic technique with no entry of the tumor capsule. To this end, it is taught that the patient should be gently mobilized away from the tumor and not vice versa. Paragangliomas are notably hypervascular; thus, although early division of the outflow vein(s) is optimal for maintaining hemodynamic stability, oncologic mobilization and resection is frequently assisted by early division of the multiple inflow vessels.

Abdominal — Approaches to resection of abdominal paragangliomas may be either open or endoscopic (which may be laparoscopic or posterior retroperitoneal). As with pheochromocytomas (intra-adrenal paragangliomas), endoscopic removal of extra-adrenal paragangliomas is the preferred surgical approach in experienced hands, and when it is anatomically feasible [16,53-56,115-119]. Although there are less published data than for laparoscopic adrenalectomy in the case of a pheochromocytoma, laparoscopic procedures reduce postoperative morbidity, hospital stay, and expense compared with conventional laparotomy. A retroperitoneal endoscopic approach is appropriate for some suprarenal paragangliomas, while a transperitoneal approach is used for infrarenal tumors [57]. An endoscopic approach is contraindicated for patients with large tumors, surgically unfavorable anatomy (eg, multiple small paragangliomas arising at the root of the small bowel mesentery), or radiographic or clinical evidence of local invasion [4,22], and may be relatively contraindicated for patients with either dopamine-secreting tumors or SDHB germline pathogenic variants because of the high rate of malignancy [22,58,59]. (See "Treatment of pheochromocytoma in adults", section on 'Adrenalectomy'.)

Tumor location may affect choice of an open or endoscopic procedure. Although abdominal paragangliomas rarely invade surrounding structures, they may have several very short arterial vessels coming directly off the aorta, and in addition, they can lie deep in the pelvis adjacent to structures that require protection, such as the ureter and/or the iliac vein.

Thoracic — Although successful treatment using an endoscopic approach has been described [60,61,120], resection of thoracic/mediastinal paragangliomas usually requires an open approach, and may require cardiac bypass and reconstruction if the left atrium and/or great vessels are involved [62,121-129].

Bladder — Resection of a bladder paraganglioma (image 1) may be accomplished by radical cystectomy or partial cystectomy [130-134]. If present, enlarged ipsilateral lymph nodes should be removed. Although apparent successful removal may be achieved via transurethral resection, paraganglioma is not a mucosal tumor, and it always recurs when such an approach is taken [133,135]. Most experts recommend partial cystectomy as the preferred operation given the possibility of multifocality and tumor recurrence, especially if the tumor is deeply invasive [133].

Role of postoperative RT — One report documented the role for EBRT for advanced/unresectable malignant paraganglioma and pheochromocytoma [18]. The treatment sites in a cohort of 41 patients with 107 sites treated included bone (69 percent), soft tissue (30 percent), and liver (1 percent). With a mean follow-up of 9.7 years, local control at 5 years was 81 percent for all lesions [18]. (See "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease".)

Outcomes — In at least one series of 192 patients with a pheochromocytoma or secretory extra-adrenal paraganglioma (n = 25), the five-year probability of tumor recurrence among those with an extra-adrenal paraganglioma was 20 percent (95% CI 2.4-38) [116]. Overall, recurrences were more frequent after resection of an extra-adrenal paraganglioma as compared with an adrenal tumor (33 versus 14 percent) and in those with an inherited predisposition than in those with apparently sporadic disease (33 versus 13 percent).

POSTTREATMENT SURVEILLANCE — Long-term follow-up for recurrent or metastatic disease is necessary after treatment of a primary paraganglioma.

The risk of a local recurrence following total-surgical resection or radiotherapy is <10 percent, but the risk of continued growth following subtotal resection (in the absence of postoperative radiation therapy [RT]) is significant. Clinicians must remain vigilant for local recurrence as well as for the development of new paragangliomas outside of the head and neck, particularly among patients with multiple tumors, metastatic disease, or an identified genetic pathogenic variant. These groups should have long-term (ie, life-long) radiologic and clinical follow-up [92]. In a series of 272 patients with metastatic pheochromocytoma and paraganglioma, synchronous metastases were found in 35 percent of patients [136], whereas in 65 percent of patients metastases developed at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis [136].

Findings on pathology (whether thought to favor benign or malignant paraganglioma) should not impact the decision for annual life-long follow-up. A significant proportion of patients with apparently benign paraganglioma (31 percent in one combined series of benign skull base and neck, thoracic, and abdominal paragangliomas [3]) will have persistent or recurrent disease or develop metachronous primary tumor(s). The interval between treatment of a primary tumor and appearance of a recurrence or metastasis may be long, with some recurrences reported up to 53 years after the initial diagnosis [20,47,136-140]. With routine long-term follow-up, the malignancy rate has been higher than suspected previously (16 percent at 10 years in one report of combined pheochromocytoma/secretory paraganglioma) [116]. Recurrence is more likely in familial paraganglioma or with extra-adrenal tumors.

For resected patients, within three months of surgery, we repeat biochemical screening and imaging in patients with catecholamine-secreting paraganglioma. Normalized levels of urinary fractionated metanephrines and catecholamines or plasma fractionated metanephrines and negative imaging are a prerequisite to a determination of operative cure [4].

We obtain radiographic imaging of the primary site, typically magnetic resonance imaging (MRI), three to four months postresection. For those head and neck paragangliomas treated with subtotal resection, a baseline MRI scan should be undertaken 8 to 12 weeks following surgery, and repeated annually for at least three years [92]. The interval can be increased to alternate years for the subsequent six years, and then every three years thereafter.

For secretory tumors, we perform a history and physical examination, monitoring of blood pressure and biochemical markers every 6 to 12 months for the first three years after resection, then life-long annual biochemical testing [22], and obtain imaging studies only as clinically indicated. For those patients with nonfunctioning paragangliomas, we obtain biochemical studies and imaging annually initially, and then decrease the frequency of testing. Biochemical testing should be continued life-long [22]. The choice of imaging strategy is empiric. However, we tend to choose MRI over computed tomography (CT) for patients with an inherited disease-causing pathogenic variant because of the desire to avoid irradiation. For patients who had 18-fluorodeoxyglucose (FDG)-avid disease on a preoperative positron emission tomography (PET) scan, post-treatment surveillance is reasonably accomplished by serial PET scans.

Annual plasma fractionated metanephrines are also appropriate for those with nonsecretory tumors who have a genetic predisposition syndrome. Rising levels should prompt radiographic imaging of the thorax, abdomen, and pelvis to assess for a new tumor.

This approach is consistent with those of the National Comprehensive Cancer Network [141] for posttreatment surveillance in patients with resected pheochromocytoma/paraganglioma. They suggest monitoring blood pressure and biochemical markers every 6 to 12 months for the first three years after resection, then annually to year 10, and obtaining imaging studies only as clinically indicated. For patients with locally unresectable disease or distant metastases, the guidelines recommend monitoring blood pressure and biochemical markers every three to four months, and imaging as clinically indicated.

Recurrent, synchronous, or metachronous paraganglioma lesions should be managed aggressively, with an attempt at definitive surgery or RT, if feasible.

Recommendations for follow-up of patients managed initially with active surveillance are provided above. (See 'Initial observation' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pheochromocytoma and paraganglioma".)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology – Paragangliomas are rare tumors that arise from widely dispersed, specialized neural crest cells (chromaffin cells) that are associated with autonomic ganglia and have the ability to secrete neuropeptides and catecholamines (figure 1). While most paragangliomas secrete catecholamines, they can also be nonfunctional, particularly those arising in the skull base and neck. Paragangliomas can derive from either parasympathetic or sympathetic ganglia, and the clinical features vary by this type of origin (see 'Introduction' above and "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease", section on 'Introduction'):

•Parasympathetic ganglia-derived paragangliomas are located almost exclusively in the neck and skull base, arising from the carotid body, jugular, and tympanic paraganglia.

•Sympathetic paragangliomas arise outside of the adrenal gland anywhere along the sympathetic chain from the base of the skull (5 percent) to the bladder.

•Most paragangliomas are benign, but approximately 15 to 35 percent are malignant. Metastatic spread is the only reliable indicator of malignant potential. (See 'Risk of malignancy' above.)

●Preoperative evaluation – All patients with paragangliomas should be tested for hypersecretion of catecholamines by measuring fractionated metanephrines and catecholamines in a 24-hour urine collection or blood, even if they do not present with a clinical picture of catecholamine hypersecretion. (See 'Preoperative evaluation' above and "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology", section on 'Diagnosis'.)

●Treatment options – Options for locoregional management can include observation, surgical resection, or radiation therapy (RT (algorithm 1)). In general, resection is the preferred approach for localized paragangliomas arising below the neck and for all catecholamine-secreting paragangliomas arising at any site. Less invasive approaches, such as conventionally fractionated external beam RT (EBRT) or stereotactic body RT (SBRT), may provide high rates of long-term disease control for head and neck paragangliomas or for non-head and neck paragangliomas that are unresectable, but they do not offer the same degree of symptom relief that is accomplished with resection. (See 'General principles of locoregional management' above.)

•For all patients undergoing surgery for a catecholamine-secreting neoplasm, some form of preoperative pharmacologic preparation is indicated. An exception are patients with skull base and neck tumors that are nonfunctional by biochemical testing; pharmacologic blockade may not be necessary for these typically benign tumors. (See 'Medical preparation for surgery' above.)

●Small, asymptomatic skull base and neck paraganglioma – For patients with small (<1 cm), asymptomatic paraganglioma of the skull base and neck, we suggest a period of initial observation to monitor for evidence of tumor growth or the development of symptoms rather than immediate treatment (Grade 2C). (See 'Initial observation' above.)

●Cervical paragangliomas – For cervical (carotid body, vagal, parathyroid) paragangliomas, we suggest therapeutic intervention rather than observation for symptomatic or large (>2 cm) tumors (Grade 2C). The optimal approach to therapy depends on symptomatology, size, location, the relationship between the tumor and neurovascular structures, as well as the age and general health of the patient. In general (see 'Cervical paragangliomas' above):

•Indications for surgery – Resection is preferred for catecholamine-secreting tumors and those that are locally symptomatic from tumor bulk, whenever anatomically feasible.

Oncologic en bloc techniques should be utilized if the paraganglioma is being resected with intent to cure. Sampling or selective ipsilateral neck dissection of regions IIA, IIB, and III to exclude or verify nodal metastases at the time of resection may be considered, particularly for patients with vagal paragangliomas, which are associated with the highest rates of nodal spread (figure 4). (See 'Resection' above and 'Patterns of malignant spread' above.)

In an adequately alpha-adrenergic blocked patient, preoperative embolization of a large skull base and neck tumor's main arterial supply within 48 hours of surgery may help to reduce tumor size, bleeding, and other complications associated with removal, thus facilitating resection. (See 'Preoperative arterial embolization of skull base and neck paragangliomas' above.)

•Indications for RT – RT is an appropriate alternative for patients with non-catecholamine secreting benign paragangliomas of the skull base and neck who have normal preoperative lower cranial nerve function and in whom resection would require extensive sacrifice of critical vascular and/or neural structures and for those with recurrent tumor after previous surgery. Conventionally fractionated RT and SBRT both represent appropriate noninvasive alternatives to surgical resection.

Benign paragangliomas of the skull base and neck may slightly regress but are not expected to decrease in volume following RT. The definition of "cure" in the context of RT is similar to that which is used for other benign tumors (ie, durable radiographic and clinical stability). When defined in this way, durable disease control can be achieved in >90 to 95 percent of benign skull base and neck paragangliomas after conventionally fractionated external beam RT or SBRT. (See 'Conventionally fractionated radiation therapy' above and 'Stereotactic body radiation therapy' above.)

Toxicities from RT are generally transient and manageable. The risks of severe long-term sequelae have been improved by modern radiation planning and treatment techniques. (See 'Radiation side effects' above.)

●Jugulotympanic paragangliomas – For patients with jugulotympanic paragangliomas (Fisch class A and B, (table 1)), surgical resection (tympanoplastic surgery) is preferred if there are no contraindications to general anesthesia. (See 'Jugulotympanic paragangliomas' above.)

•Optimal treatment for jugular paragangliomas and for more advanced tympanic paragangliomas is more controversial. The critical anatomic location and vascularity of these tumors make surgical resection complex, and there is a significant risk of serious complications, particularly for advanced (eg, Fisch class C and D (table 1)) tumors, in which there is a high risk of postoperative cranial nerve dysfunction. Because of this, we suggest RT rather than resection for most patients, unless they are symptomatic from catecholamine secretion or tumor bulk. (See 'Radiation therapy' above.)

●Paragangliomas below the neck – We suggest complete surgical resection rather than RT for all potentially resectable paragangliomas arising in the thorax, abdomen, or pelvis (Grade 2B). Because of the risk of tumor spillage, it is essential to employ circumferential en bloc oncologic technique with every attempt to avoid entry of the tumor capsule. (See 'Paragangliomas below the neck' above.)

•When anatomically feasible, endoscopic (laparoscopic or posterior endoscopic) approaches are preferred for resection of abdominal paraganglioma, as long as the tumor is not large or locally invasive. (See 'Abdominal' above.)

•Resection of thoracic/mediastinal paraganglioma usually requires an open approach and may require cardiac bypass. (See 'Thoracic' above.)

•Resection of bladder paraganglioma may be accomplished by radical cystectomy or partial cystectomy. If present, enlarged ipsilateral lymph nodes should be removed. (See 'Bladder' above.)

●Posttreatment surveillance – Long-term follow-up for recurrent or metastatic disease is necessary after treatment of a primary paraganglioma. (See 'Posttreatment surveillance' above.)

•We obtain radiographic imaging and biochemical testing for catecholamine secretion three to four months postresection.

•For those patients with catecholamine-secreting tumors, we perform history and physical examination, monitoring of blood pressure, and follow-up biochemical markers every 6 to 12 months for the first three years after resection, then lifelong annual biochemical testing.

•In those patients with nonfunctioning paragangliomas it is reasonable to obtain biochemical studies and imaging annually for several years and then decrease the frequency of testing. Biochemical testing should be carried out lifelong.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Derrick Lin, MD; Sally E Carty, MD, FACS; and Kevin Oh, MD, who contributed to earlier versions of this topic review.