Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology

INTRODUCTION — Paragangliomas are rare neuroendocrine tumors that arise from the extra-adrenal autonomic paraganglia, small organs consisting mainly of neuroendocrine cells that are derived from the embryonic neural crest and have the ability to secrete catecholamines (figure 1).

Paragangliomas are closely related to pheochromocytomas (which are sometimes referred to as intra-adrenal paragangliomas) [1] and are indistinguishable at the cellular level. Sympathetic paragangliomas usually secrete catecholamines and are located in the sympathetic paravertebral ganglia of thorax, abdomen, and pelvis. In contrast, most parasympathetic paragangliomas are nonfunctional and located along the glossopharyngeal and vagal nerves in the neck and at the base of the skull. Catecholamine-secreting paragangliomas often present clinically like pheochromocytomas with hypertension, episodic headache, sweating, and tachycardia [2]. However, the distinction between pheochromocytoma and paraganglioma is an important one because of implications for associated neoplasms, risk for malignancy, and genetic testing.

Even with modern genetic testing, the majority of paragangliomas appear to be sporadic. However, approximately one-third to one-half (in recent series) [3,4] are associated with an inherited syndrome. Some hereditary paragangliomas, particularly those arising in the skull base and neck, have been linked to pathogenic variants in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complex. In addition, susceptibility to pheochromocytomas and paragangliomas is an established component of four genetic syndromes, multiple endocrine neoplasia types 2A and 2B (MEN2), neurofibromatosis type 1 (NF1), von Hippel Lindau (VHL), and Carney-Stratakis dyad.

This topic review will cover the epidemiology, risk factors, molecular pathogenesis, histology, clinical manifestations, diagnosis, and genetic screening issues of paragangliomas arising at a variety of sites in the body. Treatment of paragangliomas, and the genetics, clinical presentation, and treatment of pheochromocytomas are covered elsewhere. (See "Paragangliomas: Treatment of locoregional disease" and "Clinical presentation and diagnosis of pheochromocytoma" and "Pheochromocytoma in genetic disorders" and "Treatment of pheochromocytoma in adults" and "Pheochromocytoma and paraganglioma in children".)

DEFINITION AND ANATOMIC ORIGIN — The terms used to describe paragangliomas have varied over time. An adrenal catecholamine-secreting tumor is widely referred to as "pheochromocytoma," although the 2004 World Health Organization (WHO) classification of tumors of endocrine organs designated these tumors as "intra-adrenal paragangliomas" rather than pheochromocytomas [1]. Some authors use the term "extra-adrenal pheochromocytoma" to describe a catecholamine-secreting tumor that arises from sympathetic paraganglia outside of the adrenal gland. Others use the collective term pheochromocytoma to describe all tumors arising in the paraganglia of the abdomen (both adrenal and extra-adrenal) and thorax [5]. However, the 2004 WHO classification used the term "extra-adrenal paraganglioma" to denote an extra-adrenal tumor of sympathetic or parasympathetic paraganglia origin, regardless of secretory status [1]. For the purpose of this review, the term paraganglioma will be used to designate both functioning (catecholamine-secreting) and nonfunctioning tumors arising in the paraganglia outside of the adrenal gland, with the term pheochromocytoma limited to those tumors that arise in the adrenal glands.

Paragangliomas can derive from either parasympathetic or sympathetic paraganglia; the two types occur with similar frequency [6]. Although indistinguishable at the cellular level, parasympathetic and sympathetic paragangliomas differ in their anatomic distribution and frequency of an underlying genetic syndrome; they also have distinct clinical features [7]:

●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.

The terminology of these tumors has evolved. They are sometimes referred to as non-chromaffin paragangliomas in distinction to metameric (chromaffin) paragangliomas, which arise from chromaffin cells found in the sympathetic paraganglia and the adrenal medulla (see below).

All were previously referred to as chemodectomas. However, this is a misnomer, since only the carotid body paraganglia act as chemoreceptors [7]; this term should no longer be used. Older terms for tumors of the jugular paraganglia (glomus jugulare) and the tympanic paraganglia (glomus tympanicum) should also no longer be used; the term jugulotympanic paraganglioma is preferred [8]. (See 'Hereditary syndromes' below.)

The majority of paragangliomas arising within the skull base and neck region are not associated with catecholamine secretion; in various reports, up to 5 percent are symptomatic from hypersecretion [9-11]. About one-half of skull base and neck paragangliomas arise in the setting of a known genetic syndrome [12,13]. (See 'Catecholamine hypersecretion' below and 'Hereditary syndromes' below.)

●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) [12]. Approximately 75 percent of sympathetic paragangliomas arise in the abdomen, most often at the junction of the vena cava and the left renal vein, or at the organ of Zuckerkandl, which resides at the aortic bifurcation near the take-off of the inferior mesenteric artery (image 2). About 10 percent arise in the thorax, including pericardial locations [14,15]. Sympathetic paragangliomas can also arise in the thyroid gland [16,17], adjacent to the thoracic spine [18], and at the level of the cauda equina [19].

The majority of paragangliomas arising outside of the skull base and neck, which are almost exclusively sympathetic, have excess catecholamine secretion (86 percent in one series [11]), almost always norepinephrine. This results in symptoms that are similar to those of an adrenal pheochromocytoma. Approximately 25 percent are part of a genetic syndrome [12].

In familial paraganglioma syndromes, paragangliomas can have multiple sites of anatomic origin and can occur with synchronous multiplicity, metachronous multiplicity, or both. (See 'Overview' below.)

EPIDEMIOLOGY — Paragangliomas are rare neoplasms. Because the clinical patterns of paraganglioma are commonly described together with those of pheochromocytoma, the specific incidence of paraganglioma is largely unknown. The combined estimated annual incidence of pheochromocytoma/paraganglioma is approximately 0.8 per 100,000 person years [20], and there are approximately 500 to 1600 cases in the United States per year [21]. However, autopsy series reveal a higher than expected prevalence, suggesting that many such tumors remain undiagnosed during life [22,23].

Most paragangliomas are diagnosed in the third to fifth decades. The mean age at diagnosis was 47 years in one study of 236 patients with benign paragangliomas [11]. However, patients with paragangliomas of the skull base and neck tend to be a little older at presentation compared with those with abdominal paragangliomas (43 versus 36 years of age in one study [24]). Patients with hereditary paragangliomas tend to develop disease about a decade earlier than do those with sporadic disease [2,25,26]. (See 'Inherited versus sporadic paraganglioma' below.)

The male to female ratio is approximately equal among patients with hereditary paraganglioma, while sporadic tumors are much more common in females (71 versus 29 percent) [27].

The majority of paragangliomas are benign. Malignant paragangliomas, as defined by metastatic behavior (see 'Histology and malignant potential' below), are less common. An estimated incidence of malignant paraganglioma in the United States in 2002 was 93 cases per 400 million persons [6].

RISK FACTORS

Hereditary syndromes — Even with modern genetic testing, most paragangliomas appear to be sporadic [6]. In about one-third to one-half of cases [3,4], a paraganglioma is a component of an inherited syndrome [27-30]; the likelihood of an inherited syndrome is higher (about 40 percent) in children [2,31]. (See "Pheochromocytoma and paraganglioma in children".)

The majority of hereditary paragangliomas, particularly those arising in the skull base and neck, have been linked to pathogenic variants in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complex. In addition, susceptibility to pheochromocytomas and paragangliomas is an established component of four genetic syndromes: multiple endocrine neoplasia types 2A and 2B (MEN2), neurofibromatosis type 1 (NF1), von Hippel Lindau (VHL) disease, and the Carney-Stratakis dyad. Most cases of hereditary paraganglioma are accounted for by pathogenic variants in SDHD, SDHB, and SDHC, VHL, and NF1 [2].

The frequency of finding a hereditary form of paraganglioma/pheochromocytoma varies depending upon family history, the location of the tumor, and clinical presentation:

●In a report of 501 consecutive patients diagnosed with pheochromocytoma or paraganglioma in 17 Italian endocrinology or hypertension centers over a four-year period, 32 percent had a germline pathogenic variant (VHL in 9.6 percent, SDH-D subunit [SDHD] in 9.3 percent, RET in 5.4 percent, SDH-B subunit [SDHB] in 4.8 percent, NF1 in 2.2 percent, and SDH-C subunit [SDHC] in 0.8 percent) [32]. The rate of germline pathogenic variants varied from 100 percent in patients with associated syndromic lesions to 12 percent in those with a single tumor and no family history (ie, apparently sporadic disease). All 15 patients presenting with both a skull base and neck paraganglioma and a pheochromocytoma or secretory paraganglioma had a germline pathogenic variant.

●A similar frequency of germline pathogenic variants was found in a large review of both malignant and benign tumors derived from five published genetic screening series, in which about 30 percent of patients with either pheochromocytoma or paraganglioma had an inherited syndrome and/or susceptibility gene; these were VHL in 9 percent, SDHD in 7.1 percent, SDHB in 5.5 percent, RET in 5.3 percent, and NF1 in 2.9 percent [6].

●Higher rates of inherited pathogenic variant were noted in a consecutive series of 110 unrelated patients with paraganglioma/pheochromocytoma derived from the medical genetics clinic at the University of Pennsylvania over an eight-year period [4]. Overall, pathogenic variants were found in 45 (41 percent), including 47 percent of those with paraganglioma only. Pathogenic variants were found in 19 of 81 patients without a family history (23 percent), and they were more common in individuals with extra-adrenal tumors compared to adrenal tumors (48 versus 29 percent), and especially in those with multiple tumors (20 of 24, 83 percent).

●In many series, hereditary predisposition is more common with paragangliomas as compared to pheochromocytomas [4,33]. In one study of patients with paraganglioma or pheochromocytoma who were referred for genetic testing, pathogenic variants were found in 83 percent of the individuals with paraganglioma versus 57 percent of those with pheochromocytoma [33]. (See "Pheochromocytoma in genetic disorders".)

●The incidence of hereditary paraganglioma is particularly high among Dutch patients with a skull base and neck paragangliomas; in one series, 80 percent had a positive family history, of whom 99.5 percent carried a pathogenic variant in one of the SDHx genes [34].

●The frequency of germline pathogenic variants is likely to increase as new susceptibility genes are discovered.

Based on these data, genetic screening is advised for all patients diagnosed with a paraganglioma. (See 'Genetic testing' below.)

Familial paraganglioma and SDH pathogenic variants — Pathogenic variants in the genes encoding different subunits of the SDH enzyme complex have been linked to hereditary pheochromocytoma/paraganglioma [13,35-37]. The SDH complex plays a central role in energy metabolism as both an enzyme of the tricarboxylic acid cycle and as complex II of the mitochondrial respiratory chain, involved in oxidative metabolism and electron transfer [35,36,38-42].

SDHA, SDHB, SDHC, and SDHD are four nuclear genes that encode the four subunits (A, B, C, D) of the SDH mitochondrial enzyme. A fifth nuclear gene, SDHAF2 (also known as SDH5), encodes a protein that is required for flavination of the SDHA subunit. Collectively, these are known as the SDHx genes, and they are believed to function as tumor suppressor genes.

Five hereditary SDHx paraganglioma syndromes have been described with different pathogenic variants in each type; they are all characterized by an autosomal dominant inheritance pattern with varying penetrance [6]. Tumor risk and malignancy rates vary by type of pathogenic variant. Among patients with familial paraganglioma syndrome, the most commonly mutated gene is SDHD [6,27].

●PGL1 – Paraganglioma syndrome 1 (PGL1) is associated with pathogenic variants in SDHD at gene locus 11q23 and is the most common type of familial paraganglioma syndrome. SDHD is a putatively maternally imprinted gene (ie, the risk of developing paragangliomas is limited to offspring who inherit the pathogenic variant from their father) [43]. Paternally inherited pathogenic variants are highly penetrant by age 50 (approximately 50 percent) [2,6]. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Causes of non-Mendelian inheritance'.)

SDHD pathogenic variants are particularly common in Dutch patients with skull base and neck paragangliomas. In a series of 236 patients with a skull base and neck paraganglioma referred to one Dutch referral center over 60 years, 83 percent carried a SDHD pathogenic variant, and a single founder pathogenic variant accounted for 72 percent of all individuals with skull base and neck paraganglioma [34].

The phenotype includes both paragangliomas and pheochromocytomas. In a series of 289 affected patients, paragangliomas were present in 93 percent, while pheochromocytomas were less common (24 percent) [6]. The paragangliomas were usually parasympathetic (84 percent) and often multiple (56 percent), but rarely malignant (4 percent).

●PGL4 – Paraganglioma syndrome 4 (PGL4) is associated with pathogenic variants in SDHB at gene locus 1p36.1-35 and is the second most common type of familial paraganglioma. SDHB pathogenic variants are also associated with renal cell carcinoma [5,44,45]. (See "Hereditary kidney cancer syndromes", section on 'Succinate dehydrogenase deficiency'.)

The phenotype includes both paragangliomas and pheochromocytomas. In a pooled analysis of 378 affected patients with SDHB pathogenic variants, paraganglioma was more common than pheochromocytoma (78 versus 25 percent), and the paragangliomas were usually sympathetic (71 percent) and sometimes multiple (21 percent) [6]. The penetrance of pheochromocytoma/paraganglioma is estimated to be about 25 percent by age 50 [5], and only 10 percent of currently investigated SDHB patients have a positive family history [21].

SDHB-related paragangliomas are usually extra-adrenal and typically present with an abdominal, pelvic, or thoracic catecholamine-secreting tumor. However, these individuals are also at risk for skull base and neck paragangliomas [2,46]. SDHB-mutated paragangliomas typically secrete norepinephrine rather than epinephrine, and some can secrete dopamine. (See 'Diagnosis' below.)

In general, PGL4 is associated with greater morbidity and mortality than other SDHx paraganglioma syndromes [47]. SDHB pathogenic variant carriers develop disease at a relatively young age [2,48,49]. In one report, the mean age at diagnosis was 28 versus 39 years for patients with sporadic paragangliomas [49]. Patients with SDHB-related paragangliomas also sometimes secrete dopamine (which is associated with a poorer prognosis [21]). SDHB pathogenic variants are also associated with a higher malignancy rate (21 to 79 percent) than other types of SDHx-associated familial paraganglioma syndromes [2,6,21,27,32,49,50]. In a series of 195 patients, metastatic bone disease was present in 7 of 13 patients with SDHB pathogenic variants and in none of 68 patients with SDHD or SDHC pathogenic variants [27]. If a patient with a paraganglioma has an identified SDHB pathogenic variant, evaluation for metastatic disease is indicated. (See 'Screening for synchronous and metastatic disease' below.)

●PGL3 – Paraganglioma syndrome 3 (PGL3) is associated with pathogenic variants in SDHC at locus 1q21. SDHC pathogenic variants are rare, but have been detected in up to 4 percent of patients with parasympathetic paragangliomas [51]. In a combined analysis of 42 affected patients, all tumors were benign paragangliomas (93 percent parasympathetic, 7 percent sympathetic, 17 percent multiple), and there were no pheochromocytomas [6]. At least one case of a malignant paraganglioma with distant metastases caused by a SDHC germline pathogenic variant has been reported, although malignancy is probably rare [52].

Penetrance is unknown, but appears to be low given that only 20 to 25 percent of known patients report a family history [6].

●PGL2 – Paraganglioma syndrome 2 (PGL2) is associated with pathogenic variants in the gene for SDH complex assembly factor 2 (SDHAF2), which is located at gene locus 11q12.2 [53]. To date, PGL2 has been diagnosed only in patients with an affected father, which may indicate maternal imprinting [54]. However, the disorder is quite rare [55] and has been reported only in two European kindreds. Among 15 affected patients, penetrance was nearly 100 percent by age 45, and only parasympathetic paragangliomas were observed, which were multiple in 87 percent of cases [6].

●PGL5 – Paraganglioma syndrome 5 (PGL5) is associated with pathogenic variants in SDHA, which comprises 15 exons and encodes a 2390-bp transcript. Two missense (p.Arg585Trp and p.Arg589Trp) and one nonsense pathogenic variant (p.Arg31X) have been reported in individuals with PGL5, which comprises both paraganglioma and pheochromocytoma [3,56]. In the combined group of six patients with SDHA pathogenic variants, five had paraganglioma (three sympathetic and two parasympathetic), and one had pheochromocytoma; the mean age at presentation was 40, and no patients had metastases or multiple tumors. Interestingly, the identified SDHA pathogenic variants were also seen in low frequencies in a healthy control group, suggesting that the penetrance of paraganglioma/pheochromocytoma in SDHA pathogenic variant carriers is low [56].

All patients with paraganglioma should be screened for germline pathogenic variants in SDHD, SDHC, SDHAF2, and SDHB [42], among other pathogenic variants. (See 'Genetic testing' below.)

Other associated autosomal dominant hereditary syndromes — Other autosomal dominant hereditary syndromes that include pheochromocytoma/paraganglioma include MEN2, NF1, VHL, and the Carney-Stratakis dyad.

MEN2 — MEN2A is characterized by medullary thyroid cancer, pheochromocytoma/paraganglioma, and primary parathyroid hyperplasia. MEN2B is characterized by medullary thyroid cancer, pheochromocytoma/paraganglioma, but not hyperparathyroidism. The genetic defect in these disorders is an inherited pathogenic variant in RET, a proto-oncogene on chromosome 10q11.2 that encodes a transmembrane receptor tyrosine kinase that is expressed in urogenital and neural crest precursor cells. Gain of function RET pathogenic variants cause MEN2A and MEN2B syndromes, while inactivating RET pathogenic variants predispose to Hirschsprung disease, with some clinical overlap. (See "Classification and genetics of multiple endocrine neoplasia type 2" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Congenital aganglionic megacolon (Hirschsprung disease)".)

In the MEN2 syndromes, bilateral adrenal pheochromocytomas are common (63 percent) but paragangliomas are only rarely seen [6]; however, phenotype varies by specific mutated codon.

NF1 — Neurofibromatosis type 1 (von Recklinghausen disease) is a neurocutaneous genetic syndrome caused by pathogenic variants in the NF1 gene. The range of clinical findings includes café au lait spots, peripheral neurofibromas, neurocognitive abnormalities, central nervous system tumors, soft tissue sarcomas, and other tumors, including pheochromocytomas/paragangliomas. NF1 is a tumor suppressor gene on chromosome 17q11.1. NF1 pathogenic variants are often acquired rather than inherited and thus can give rise to a mosaic phenotype [57]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

Pheochromocytomas and sympathetic paragangliomas occur in 0.1 to 6 percent of NF1 patients [58], but are found at autopsy in 3 to 13 percent of affected individuals [59]. Pheochromocytoma is much more frequent (95 percent; 14 percent bilateral) than is paraganglioma (6 percent) [6]. Paragangliomas that occur in the setting of NF1 are typically periadrenal in location. NF1 can often be diagnosed or excluded by physical examination for neurofibromas and café au lait spots.

VHL — VHL disease is manifested by a variety of benign and malignant tumors, including hemangioblastomas of the cerebellum and spine, retinal angiomas, clear cell renal cell cancers, pheochromocytomas/paragangliomas, and neuroendocrine tumors of the pancreas. VHL syndrome is caused by germline inactivating pathogenic variants in the VHL gene, a tumor suppressor gene on chromosome 3p25-26, whose products regulate the oxygen dependence of hypoxia-inducible factor (HIF). (See "Molecular biology and pathogenesis of von Hippel-Lindau disease" and "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

Between 10 and 34 percent of VHL patients develop noradrenergic pheochromocytomas/paragangliomas [6,53]. Kindreds with type 2 disease are at higher risk of developing pheochromocytoma/paraganglioma than are those with type 1 disease, and missense variants in VHL are more frequent than deletions or nonsense/frameshift variants in the type 2 families who develop pheochromocytomas/paragangliomas [60].

Even within these families, chromaffin tumor expression varies widely by the type of pathogenic variant:

●In a retrospective comparison of 130 pheochromocytoma/paragangliomas from two large type 2 VHL kindreds, carriers of the Y98H and Y112H missense variants had high expression of chromaffin tumors (Y98H, 57 percent by age 50; Y112H, 56 percent by age 50), but when such tumors were expressed, the rate of paraganglioma differed by pathogenic variant (Y98H, 14 percent versus Y112H, 28 percent) [61]. Moreover, patients with the Y112H pathogenic variant were significantly older at diagnosis, more likely to secrete vanillylmandelic acid (VMA) alone and less likely to secrete only norepinephrine, had more synchronous multifocality (60 versus 40 percent), experienced lower rates of surgical cure (76 versus 100 percent), had a higher malignancy rate (20 versus 5 percent), and had a worse prognosis.

●The Y112H VHL pathogenic variant appears to have significant branch-specific expressivity. In one branch of a large kindred, retinal angioma predominated (86 percent) and no paragangliomas were seen, while in another branch of the kindred, retinal angiomas were uncommon (11 percent) and pheochromocytoma/paraganglioma predominated (100 percent, of which 24 percent were paragangliomas) [62].

Carney-Stratakis dyad — The Carney-Stratakis dyad is an autosomal dominant disorder with incomplete penetrance [63]. It is characterized by the dyad of gastrointestinal stromal tumors (GISTs) and paragangliomas (sympathetic or parasympathetic, 73 percent multiple), which are not associated with pathogenic variants in KIT or the platelet-derived growth factor receptor alpha, but in many are attributed to germline pathogenic variants of SDHB, SDHC, or SDHD [64-66]. Most cases present in childhood. Carney-Stratakis dyad should be distinguished from the Carney triad (GIST, paraganglioma [sympathetic or parasympathetic], and pulmonary chondroma), which is rare (fewer than 100 cases are reported), affects predominantly young females, and no genetic link has been discovered [6,63,67,68]. (See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'GIST syndromes in pediatric and AYA patients' and "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors", section on 'KIT/PDGFRA wild-type GISTs' and "Pheochromocytoma and paraganglioma in children".)

Other pathogenic variants — In 2011, loss of function pathogenic variants in the MAX (MYC-associated factor X) gene were identified in patients with familial pheochromocytoma [69]. Subsequently, germline MAX pathogenic variants have also been identified in individuals with paraganglioma. In a series of 1694 unrelated individuals with pheochromocytoma or paraganglioma in whom pathogenic variants in other genes such as SDHX, VHL and RET were not identified, germline pathogenic variants in MAX were identified in 23 index patients, all of whom had a pheochromocytoma, and six of whom also had a paraganglioma (only one of which arose in the skull base or neck) [70]. Seven of the 23 MAX-positive patients had a positive family history. The authors concluded that MAX pathogenic variants were responsible for 1.12 percent of pheochromocytoma/paragangliomas in patients without other known pathogenic variants.

The MAX gene is located on chromosome 14q23.3. It encodes MAX protein, which belongs to the basic helix-loop-helix leucine zipper (bHLHZ) family and which interacts with MYC and MXD1 to form the MYC-MAX-MXD1 network of transcription factors that regulate cell proliferation, differentiation, and apoptosis. The absence of MAX protein in tumors of affected individuals and the loss of heterozygosity of the wild-type allele in tumor DNA confirms the tumor suppressor role of MAX in humans [69].

Chronic hypoxia — Apparently sporadic carotid body paragangliomas are more frequent in patients living at high altitudes and in the settings of cyanotic congenital heart disease and chronic obstructive lung disease [71-73]. The reason for the association between high-altitude residence and paragangliomas of the carotid body is unclear. Specifically, the role of chronic hypoxia in the etiology of high-altitude tumors remains uncertain.

The prevalence of skull base and neck paraganglioma in high altitude areas is up to 1 in 10 in humans, and almost one in two in bovines, compared with a low-altitude prevalence of 1 in 500,000 or less [71,74]. For unclear reasons, most high-altitude paragangliomas (86 to 96 percent) arise in females. (See "Medical management of cyanotic congenital heart disease in adults", section on 'Pheochromocytoma and paraganglioma'.)

SDHx pathogenic variants lead to the stabilization of hypoxia-inducible factor-1 (HIF-1), a key factor in the hypoxia response. Although acute environmental hypoxia leads to activation of HIF-1 (figure 3), little is known about the effects of chronic sustained hypoxia on the activity of HIF-1 in the carotid body. (See 'Molecular pathogenesis' below.)

SDHB gene pathogenic variants have been described in a Mexican family living at high altitude, two of whom had paragangliomas [46]. In a separate study, gain-of-function somatic pathogenic variants of EPAS1, which encodes for HIF-2alpha, were found in pheochromocytomas and paragangliomas in four of five patients (80 percent) who presented with cyanotic congenital heart disease [75].

INHERITED VERSUS SPORADIC PARAGANGLIOMA — There are several aspects of the clinical presentation that can suggest a familial as compared to sporadic etiology:

●Patients with hereditary paraganglioma tend to develop disease about a decade earlier than do those with sporadic paragangliomas [2]. For patients with SDHD or SDHB pathogenic variants, 50 percent present by ages 31 and 35, respectively, and over three-quarters of patients will present by age 50 in both of these syndromes [2,31]. (See 'Epidemiology' above and 'Familial paraganglioma and SDH pathogenic variants' above.)

●Multiple paragangliomas are present in 17 to 85 percent of hereditary pheochromocytoma/paraganglioma patients, compared to only 1.2 percent of sporadic cases [32,56,76,77].

●VHL-related paragangliomas always secrete norepinephrine and do not secrete epinephrine [21,61,78].

●Hereditary paragangliomas occur with equal frequency in males and females, but sporadic paragangliomas are much more common in females (71 versus 29 percent) [27].

●Bilateral pheochromocytomas (which occur in RET, VHL, NF1) do not appear to occur together with multiple paragangliomas (which occur in SDHx syndromes) [6]. Patients with multiple paragangliomas are almost certain to have hereditary disease [53,79].

●Among patients with sympathetic paragangliomas, the likelihood of a hereditary syndrome is 25 percent. (See 'Hereditary syndromes' above.)

SDHB pathogenic variant-related paragangliomas can secrete dopamine along with norepinephrine and are usually extra-adrenal. Dopamine-secreting tumors tend to present late with mass effect rather than with symptoms related to catecholamine hypersecretion. They are also less likely to take up metaiodobenzylguanidine (MIBG) and often develop distant metastases [50,80]. (See 'Familial paraganglioma and SDH pathogenic variants' above and 'Histology and malignant potential' below.)

MOLECULAR PATHOGENESIS — The molecular pathogenesis of both sporadic and hereditary paraganglioma is incompletely understood, but there are some data to support the involvement of hypoxia-inducible factors (HIFs) in at least some cases, as indicated by the following observations:

●HIFs are transcription factors that activate several genes that promote adaptation and survival under hypoxic conditions; they control energy, iron metabolism, erythropoiesis, and development.

●VHL and SDHx pathogenic variants are linked by their ability to cause a so-called pseudohypoxic response by stabilizing HIFs under normoxic conditions (normally, hypoxia is the stimulus to increase cellular levels of HIFs) [81]. Hypoxia-inducible factor-1 alpha and 2 alpha (HIF-1 and HIF-2) are two of the major proteins regulated by VHL.

Paragangliomas harboring pathogenic variants in VHL and SDHx genes are characterized by HIF stabilization, dysregulation, and overexpression [81-86]. Furthermore, microarray studies reveal that hereditary pheochromocytomas and paragangliomas cluster into two distinct groups based upon their transcription profile. Tumors with VHL pathogenic variants resemble those with pathogenic variants in any of the SDHx genes, and the transcription signature associated with the VHL/SDH cluster is associated with angiogenesis, hypoxia, and a reduced oxidative response, suggesting common molecular pathways in the development of these tumors [3,87-89]. In contrast, tumors associated with RET, NF1, TMEM127, or MAX pathogenic variants (the RET/NF1 cluster) display a signature of genes involved in translation initiation, protein synthesis, and kinase signaling.

●Somatic gain of function pathogenic variants in the HIF gene (which encodes the alpha subunit of HIF-2) are associated with Pacak-Zhuang syndrome, a disease characterized by early onset polycythemia vera, sporadic multiple paragangliomas, and somatostatinoma [90,91]. These pathogenic variants result in HIF proteins with a longer half-life that upregulated downstream genes, including erythropoietin, which led to polycythemia. This and other reports of somatic HIF-2 pathogenic variants in patients with sporadic pheochromocytomas and paragangliomas support the relevance of hypoxia-related mechanisms in the pathogenesis of these tumors [92-94]. (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'EPAS1 mutations' and "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease", section on 'Other targeted agents'.)

●A link between paragangliomas and hypoxia/HIF is consistent with the findings that persons exposed to chronic hypoxia due to dwelling at high altitude appear to have a higher prevalence of paraganglioma as compared to those living at sea level. (See 'Epidemiology' above.)

These findings suggest a critical role for HIF or hypoxia in the development or growth of these tumors, although their precise role in tumor development remains uncertain.

HISTOLOGY AND MALIGNANT POTENTIAL — Paragangliomas are highly vascular tumors that are typically associated with blood vessels (carotid artery, jugular bulb) and neural structures [95]. Grossly, paragangliomas have a fleshy, pink to red brown to gray appearance due to hemorrhage or fibrosis.

The histologic diagnosis of a paraganglioma/pheochromocytoma is usually straightforward, especially when biochemical testing has shown excess catecholamine metabolites in serum or urine. (See 'Diagnosis' below.)

Histologically, paragangliomas have a thin capsule and are composed of round or polygonal epithelioid cells arranged in compact cell nests or trabecular patterns (the so-called Zellballen appearance) (picture 1) [96-99]. Spindle-shaped sustentacular or supporting cells are found peripheral to the chief cell nests. The chief cells have centrally located nuclei with finely clumped chromatin and a moderate amount of eosinophilic, granular cytoplasm. Tumors of higher grade are characterized by a progressive loss in the relationship between chief cells and sustentacular cells, and a decrease in the overall number of sustentacular cells.

Paragangliomas may be mistaken histologically for a variety of tumors, including meningioma, nerve sheath tumor, hemangiopericytoma, adult rhabdomyoma, melanoma, sarcoma, and metastatic carcinoma. Immunohistochemical staining typically confirms the neuroendocrine nature of the chief cells with diffuse, strong positivity for neuron-specific enolase (NSE), synaptophysin, and/or chromogranin, and usually negative staining for keratins [98,99]. Ultrastructurally, chief cells contain dense core neurosecretory granules (100 to 200 nm), which are the sites of catecholamine storage. Sustentacular cells are negative for neuroendocrine markers but may be S-100 or glial fibrillary acidic protein (GFAP)-positive.

Histologic determination of malignancy is not straightforward. It is difficult to predict, on the basis of histologic findings, whether a paraganglioma is benign or malignant, for several reasons. Paragangliomas tend to occur in sites where basement membrane penetration, the hallmark of malignancy in many epithelial tumors, cannot be assessed; they have a low incidence of metastasis, often with a long latency (sometimes as much as 20 years), and soft tissue invasion is a poor predictor of metastasis [100].

Histologic features such as nuclear pleomorphism, necrosis, mitotic rate, and local invasion may be seen in benign paragangliomas and are not diagnostic of malignancy. Although DNA ploidy is abnormal in the majority of carotid body tumors and vagal paragangliomas, it is of limited value in predicting prognosis [97,101]. A variety of immunohistochemical and other prognostic markers have been evaluated for association with malignancy in adrenal pheochromocytomas and paragangliomas [102,103], with mixed results to date. According to the 2004 World Health Organization (WHO) criteria, the only true indicator of malignant behavior is metastatic spread [1].

Several attempts have been made to devise histologic scoring systems to aid in the diagnosis of a malignant pheochromocytomas/paraganglioma [104-106]. The best known is the PASS (Pheochromocytoma of the Adrenal gland Scales Score) system, which tallies 12 histological features with weighted values of 1 or 2 (table 1) [106]. Some studies suggest that a PASS score <4 reliably predicts a benign lesion, while values over 6 are most often seen with malignant tumors [106-108]; others report a lack of reproducibility or reliability in the prediction of malignant behavior [109-111]. There are no data applying the PASS score to extra-adrenal paragangliomas. As a result, whether the PASS scoring system has utility in predicting future development of metastases in paragangliomas remains unclear.

Malignant paraganglioma is more common in patients with SDHB pathogenic variants than in those with other SDHx pathogenic variants or with sporadic disease [27,49]. Other than SDHB pathogenic variants, a large review found no differences in the malignancy rates of hereditary and sporadic pheochromocytoma/paraganglioma [6]. For paraganglioma patients in whom SDHB pathogenic variant is identified, evaluation for disseminated disease is indicated. (See 'Familial paraganglioma and SDH pathogenic variants' above and 'Screening for synchronous and metastatic disease' below.)

STAGING — Several staging systems have been proposed for carotid body tumors and jugulotympanic paraganglioma, although none have been widely adopted [112-115]. Few studies report their results based upon any staging system, making it difficult to compare results between studies.

Carotid body paragangliomas are classified according to the Shamblin criteria (image 3) [113]:

●Class I tumors are localized with splaying of the carotid bifurcation but little attachment to the carotid vessels

●Class II tumors partially surround the carotid vessels

●Class III tumors intimately surround the carotids

For jugulotympanic paragangliomas, the McCabe/Fletcher staging system, which was based upon older studies such as plain radiographs and retrograde jugulography, is outdated [114]. The staging systems proposed by Fisch and Glasscock/Jackson are currently preferred (table 2) [112,115-117].

There are no widely used staging systems for paragangliomas below the neck. The eighth edition of the American Joint Committee on Cancer (AJCC) Tumor, Node, Metastasis (TNM) staging manual includes a new staging system for pheochromocytoma and paraganglioma (table 3). (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Staging'.)

CLINICAL PRESENTATION AND DIAGNOSIS

Overview — Overall, compared with pheochromocytomas, paragangliomas are more often asymptomatic at presentation. However, the clinical presentation of paragangliomas is variable and depends upon tumor location, catecholamine secretion, and other factors.

Extra-adrenal paragangliomas can arise within a variety of sites in the skull base and neck, thorax, or abdomen and pelvis; location is closely tied to clinical presentation (see 'Definition and anatomic origin' above):

●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). Carotid body tumors are the most common paragangliomas of the skull base and neck region (60 percent), followed by jugulotympanic and vagal paraganglioma; rarely, the laryngeal paraganglia are involved [11,95-97,101,118,119]. Most (80 to 90 percent) are nonfunctional, and symptoms result from mass effect.

●Sympathetic paragangliomas arise outside of the adrenal gland anywhere along the sympathetic chain from the base of the skull (5 percent) to the bladder (image 1) and prostate (10 percent) (figure 2) [12]. Approximately 75 percent arise in the abdomen, most often at the junction of the vena cava and the left renal vein, or at the organ of Zuckerkandl, which resides at the aortic bifurcation near the take-off of the inferior mesenteric artery (image 2). About 10 percent arise in the thorax, including pericardial locations [14,15]. Sympathetic paragangliomas can also arise in the thyroid gland [16,17], adjacent to the thoracic spine [18], and cauda equina [19].

Most sympathetic paragangliomas are functional and present with catecholamine hypersecretion; a minority present with pain or other symptoms related to mass effect.

●Other less common presentations include upper gastrointestinal hemorrhage (for a nonfunctioning retroperitoneal paraganglioma [120]), back or chest pain, cough, dyspnea or hoarseness (with a mediastinal paraganglioma), exercise-induced nausea and vomiting [121], or a presentation with metastatic disease (which most commonly involves the regional nodes, lung, bone and liver) [122-127].

In addition to variability in relation to location, paragangliomas can also be solitary or multiple, sporadic or hereditary, and benign or malignant. Contemporary series reported in the 10 to 15 years since the discovery of predisposing hereditary syndromes have disproven the once-taught "Rule of 10 Percent" for the clinical patterns of pheochromocytoma/paraganglioma, which is now outmoded (10 percent bilateral/multiple, 10 percent familial, 10 percent extra-adrenal, 10 percent malignant [128]). Specifically for paraganglioma, it is now thought that about 26 percent are multiple and one-third to one-half (in recent series) are associated with an hereditary syndrome; about 15 to 20 percent of all catecholamine-secreting tumors are extra-adrenal [129]. Multiplicity is far more common for hereditary cases (17 to 85 versus only about 1.2 percent of sporadic cases). (See 'Hereditary syndromes' above and 'Inherited versus sporadic paraganglioma' above.)

The incidence of metastatic disease 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. The highest malignancy rates are seen in paragangliomas associated with SDHB pathogenic variants, which are usually abdominal and secretory [21,130-132]. (See 'Hereditary syndromes' above and 'Inherited versus sporadic paraganglioma' above.)

In general, four types of presentation are described [12], in approximate descending order of frequency based on retrospective data without routine secretory testing: mass effect, catecholamine hypersecretion, asymptomatic as an incidental finding on radiographic imaging, or asymptomatic found on screening of a proven pathogenic variant carrier. Mode of presentation in a series of 236 patients with benign paraganglioma, stratified according to tumor location, is outlined elsewhere (table 4) [11].

Diagnostic algorithm — The diagnosis of a secretory paraganglioma is typically made by measurements of urinary and/or plasma fractionated metanephrines and catecholamines (algorithm 1). However, biochemical testing is indicated for all paragangliomas, even if clinically non-functional. (See 'Diagnosis' below.)

Radiologic imaging is an important component of assessment, both for secretory and nonsecretory paragangliomas. Imaging can provide information about tumor localization in the setting of a catecholamine-secreting tumor, and for nonsecretory tumors, imaging characteristics are frequently sufficiently distinctive (by location and a high degree of vascularity) to permit a presumptive preoperative diagnosis of a paraganglioma.

The most commonly used tests are computed tomography (CT), magnetic resonance imaging (MRI), angiography, radioisotope imaging using metaiodobenzylguanidine (MIBG), positron emission tomography (PET), and integrated PET/CT. The preferred radiopharmaceutical used for PET depends on the pathogenic variants, which influence the receptor expression and metabolite expression of the various paragangliomas. Options include 18F-fludeoxyglucose (FDG), 18F-fluorodihydroxyphenylalanine (FDOPA), and the somatostatin receptor-based radiopharmaceuticals gallium Ga-68 DOTATATE and gallium Ga-68 DOTATOC [133-138]. Use of somatostatin receptor-based radiopharmaceuticals with PET imaging is superior to FDG-PET in some patients. The decision on whether to use PET-based imaging and the type of radiopharmaceutical agent should be individualized based on identified genetic pathogenic variants (table 5), the performance of past imaging, and the availability of imaging modalities and/or radiopharmaceutical agents.

Tissue diagnosis — A presumptive preoperative diagnosis of a paraganglioma can usually be made using biochemical and radiographic testing. In either case (functioning or nonfunctioning paragangliomas), definitive diagnosis requires review of tissue histopathology. This is usually accomplished at the time of resection.

A biopsy (incisional or by fine needle aspiration [FNA]) is contraindicated in a patient suspected of having paraganglioma unless the results of biochemical screening for catecholamine secretion are first negative or the patient is prepared with alpha-adrenergic blockade, because otherwise it can cause severe hypertension from catecholamine crisis.

Most clinicians consider that FNA biopsy is of little value for paraganglioma. In the skull base and neck, a correct diagnosis of a paraganglioma may be possible using FNA, but it is difficult [139]. Aspirates can be mistaken for many different neoplasms, including neurofibroma, neurofibrosarcoma, malignant melanoma, different forms of thyroid cancer, as well as metastases from a carcinoma [140]. In addition to the questionable diagnostic value, biopsy may result in severe hemorrhage or subsequent fibrosis at the operative site, with subsequent difficulty with definitive surgery [95,141,142].

The following sections will cover the clinical presentation, differential diagnosis, and diagnostic strategy based upon the type of presentation.

Catecholamine hypersecretion — Most paragangliomas arising below the neck and approximately 5 percent of skull base and neck paragangliomas produce and secrete catecholamines.

Biochemically, chromaffin cells accumulate catecholamines (dopamine, norepinephrine, epinephrine) into subcellular chromaffin granules in an ATP-dependent chemiosmotic process [143]. Within these dense-core granules, catecholamines are then stored by binding to chromogranin A. Metabolic degradation (to metanephrine, normetanephrine, and VMA) occurs independently of secretion; thus metanephrine and normetanephrine levels are commonly measured diagnostically in plasma and urine. (See "Treatment of pheochromocytoma in adults".)

Clinical presentation — As with pheochromocytomas, tumor production of vasoactive catecholamines by paragangliomas leads to symptoms of catecholamine excess, of which hypertension is the most common feature. However, in a series of 236 patients with benign paraganglioma at any location, catecholamine hypersecretion was found in 40 of 128 screened patients (31 percent), and only 38 of 128 of had documented hypertension [11]. The absence of sustained hypertension does not remove the need to screen for catecholamine hypersecretion in patients with paraganglioma.

Hypertension may be continuous or intermittent and often paroxysmal. Hypertensive crises are frequently associated with episodic headache, sweating, and tachycardia/palpitations, referred to as the "classic triad." If all three symptoms present together (which is uncommon), the specificity for a catecholamine-secreting tumor is approximately 90 percent [144]. However, the classic triad of symptoms was present in only 40 percent of 40 patients with pheochromocytoma/secretory paraganglioma in one series and none of 46 with a skull base and neck paraganglioma [24]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Classic triad'.)

Paroxysmal signs and symptoms or "spells," a consequence of episodic secretion of catecholamines, provide compelling evidence for a catecholamine-secreting tumor. Spells may be either spontaneous or precipitated by postural change, anxiety, medications (eg, beta-adrenergic antagonists, metoclopramide, anesthetic agents, corticosteroids), exercise, or maneuvers that increase intra-abdominal pressure (eg, change in position, lifting, defecation, exercise, colonoscopy, pregnancy, trauma). (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Indications for testing'.)

Micturition syncope is the clinical hallmark of a catecholamine-secreting bladder paraganglioma. The triad of hypertension, hematuria, and symptoms on micturition or sexual activity is considered almost diagnostic of the condition, and is reported variably in 50 to 100 percent of such patients [145]. Some patients have only painless hematuria [146].

Normal blood pressure or even hypotension is common with dopamine-producing paragangliomas, which are quite rare and tend to present late with mass effect; they are also more likely to develop recurrence and malignant spread than are paragangliomas that secrete epinephrine or norepinephrine [50].

Additional symptoms of a functioning paraganglioma include forceful palpitations, tremor, pallor, dyspnea, generalized weakness, and panic attack-type symptoms. Chronic constipation is the rule in patients with functional tumors. Less common signs and symptoms associated with catecholamine-secreting tumors include orthostatic hypotension (that may reflect a low plasma volume), visual blurring, papilledema, weight loss, polyuria, polydipsia, constipation, fever, hyperglycemia, leukocytosis, psychiatric disorders, and rarely, secondary erythrocytosis due to overproduction of erythropoietin. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Less common symptoms and signs'.)

As noted above, skull base and neck paragangliomas present with catecholamine hypersecretion less often than do abdominal and pelvic paragangliomas. It was once thought that functional hormone secretion was very uncommon with skull base and neck paragangliomas, reportedly occurring in 1 to 3 percent of cases [95,147]. However, observational data indicate that up to 20 percent of skull base and neck paragangliomas (average 5 percent) present with catecholamine excess [9,11,79]. For this reason and also because synchronous tumor below the skull base and neck is not uncommon, secretory testing for hypersecretion is appropriate prior to surgery for patients with skull base and neck paraganglioma.

Differential diagnosis — Sympathetic activity is also increased in several conditions other than paraganglioma and pheochromocytoma. Although catecholamine-secreting paragangliomas may present clinically in a manner that is similar to adrenal pheochromocytomas, normal blood pressure or even hypotension may be seen in patients with dopamine-producing paragangliomas. Another difference is that although pheochromocytomas can ectopically secrete additional hormones such as corticotropin, calcitonin, vasoactive intestinal polypeptide, or renin [148], this is not a known feature of paraganglioma.

In addition to pheochromocytoma, the differential diagnosis of a catecholamine-secreting paraganglioma includes a wide range of other conditions; these are outlined elsewhere (table 6). (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Approaches for specific patient groups'.)

Diagnosis — The diagnosis of a secretory paraganglioma is typically made by measurements of urinary and/or plasma fractionated metanephrines and catecholamines (algorithm 1) [149].

The intratumoral metabolism of catecholamines to metanephrines (norepinephrine to normetanephrine, and epinephrine to metanephrine, respectively) occurs independently of catecholamine release by the tumor. For this reason, and due to the fact that paragangliomas are frequently multifocal and may be associated with concurrent pheochromocytomas, biochemical testing is indicated in every patient with a paraganglioma, even if they do not present with a clinical picture of catecholamine hypersecretion.

Biochemical testing for paragangliomas generally parallels that for adrenal pheochromocytomas; however, there are some differences in catecholamine secretion between pheochromocytomas and paragangliomas that may affect test interpretation:

●Paragangliomas are unlikely to secrete epinephrine, possibly because the enzyme phenylethanolamine N-methyltransferase (PNMT), which converts norepinephrine to epinephrine, requires cortisol as a cofactor. This affects the sensitivity of 24-hour urine collection, as illustrated by the following reports:

•In a comparative study of 23 pheochromocytomas and 17 abdominal/pelvic paragangliomas, catecholamine metabolites were elevated in 87 percent of pheochromocytomas and 88 percent of paragangliomas, but mean levels of urinary metanephrines were significantly lower for paragangliomas (3.3 versus 19.3 micromol/24 hours), while urinary normetanephrine levels were higher (48.1 versus 17.5 micromol/24 hours) [24]. The 24-hour urinary catecholamine metabolites were normal in eight of nine patients with skull base and neck paraganglioma who underwent screening.

•The sensitivity and specificity of urinary measurements of metanephrines and catecholamines was addressed in a series of 236 patients with benign paragangliomas, of whom 40 with benign hyperfunctioning paragangliomas underwent 24-hour urine collection [11]. The sensitivity of 24-hour measurements of norepinephrine, total metanephrines, dopamine, and epinephrine were 84, 74, 18, and 14 percent, respectively.

In general, 24-hour urine collection for norepinephrine and fractionated metanephrines is more sensitive for paragangliomas than is 24-hour collection for epinephrine. However, MEN2-related pheochromocytomas/paragangliomas almost always secrete epinephrine rather than norepinephrine [21,78].

●SDHB pathogenic variant-related paragangliomas can secrete dopamine along with norepinephrine. (See 'Familial paraganglioma and SDH pathogenic variants' above.)

There are major regional, institutional, and international differences in the approach to the biochemical diagnosis of catecholamine-secreting tumors, and there is still no consensus as to the "best test." Our suggested approach to testing based upon the patient's clinical presentation is outlined (algorithm 1), described below, and is similar to our approach in patients with pheochromocytoma, which is discussed in more detail elsewhere. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Approach to initial evaluation'.)

Localizing the tumor — For patients with catecholamine-secreting paraganglioma, biochemical confirmation of the diagnosis should be followed by radiologic evaluation to locate the tumor [150,151], not the other way around (algorithm 1). Sympathetic paragangliomas arise anywhere along the sympathetic chain from the base of skull to the bladder and prostate, including pericardial locations [14,15,152]. About 10 percent of catecholamine-secreting tumors are extra-adrenal, but 95 percent are within the abdomen and pelvis [153]. Although any site containing paraganglionic tissue may be involved, the most common extra-adrenal locations of catecholamine-secreting paragangliomas are the superior and inferior abdominal paraaortic areas (75 percent of extra-adrenal tumors); the urinary bladder (10 percent) (image 1); the thorax (10 percent); and the skull base, neck, and pelvis (5 percent).

CT or MRI of the abdomen and pelvis is usually performed first. Either test is reasonable and the choice depends on a variety of issues (see "Clinical presentation and diagnosis of pheochromocytoma", section on 'Imaging'):

●With CT, there is some exposure to radiation but no risk of exacerbation of hypertension if current radiographic contrast agents are given. CT with low-osmolar contrast is safe for patients with catecholamine-secreting tumors, even without alpha- or beta-adrenergic blockade pretreatment.

●With MRI, there is neither radiation nor dye. Although inferior to the spatial resolution attainable by CT, this more expensive test can distinguish paragangliomas from other masses.

●In patients with the MEN2 syndrome, CT may miss about one-quarter of the tumors [154]. In a selected group of patients with a 40 percent incidence of pheochromocytoma, the respective positive and negative predictive values of CT were 69 and 98 percent [151], but it is not known yet whether these exact performance parameters apply also to paragangliomas.

If abdominal and pelvic CT or MRI is negative in the presence of clinical and biochemical evidence of a catecholamine-secreting tumor, the next step is cross-sectional imaging of the thorax/head and neck and/or radioisotope (functional) imaging.

Radioisotope imaging — Radioisotope imaging, which is much more expensive, may be indicated in the diagnostic algorithm if cross sectional imaging is negative. In addition, radioisotope imaging is of value to screen for metastatic disease in patients who have a high likelihood of having a malignant paraganglioma (eg, SDHB pathogenic variant). (See 'Screening for synchronous and metastatic disease' below.)

●Metaiodobenzylguanidine – MIBG is a compound resembling norepinephrine that is taken up by adrenergic tissue. A MIBG scan using iobenguane I-123 (diagnostic) can detect tumors not detected by CT or MRI, or multiple tumors when CT or MRI is positive [155]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Additional imaging'.)

For localization of a paraganglioma, I-123 imaging is associated with a higher false-negative rate (29 to 44 percent [11,156]) than it is for pheochromocytoma [12], but the test does offer a total-body survey, which can be helpful in diagnosing or localizing synchronous tumors or metastases. Another problem for skull base and neck paragangliomas is that I-123 is accumulated in the salivary glands, and this may interfere with proper diagnosis [157,158]. Finally, false-negative rates are high with dopamine-producing paragangliomas [50,80]. If I-123 is the utilized radiotracer, the patient's thyroid gland uptake of I-123 should be blocked with potassium iodide drops [12].

●Indium-111 pentetreotide (OctreoScan) – Paragangliomas, like some other neuroendocrine tumors, have a high density of somatostatin type 2 receptors on their cell surface and can be imaged using In-111 pentetreotide (OctreoScan) [159-161]. However, where available, positron-emitting radiolabeled somatostatin analogs are preferable to 111-In pentetreotide scintigraphy because of their enhanced spatial resolution.

One study evaluated preoperative 111-In pentetreotide in 21 patients undergoing surgery for a presumed skull base and neck paraganglioma [159]. Scans were positive in 16 patients with paraganglioma and negative in three with other pathology. The overall test accuracy was 90 percent, and the sensitivity and specificity was 94 and 75 percent, respectively.

●PET imaging – Conventional PET imaging utilizes the tracer FDG to detect hypermetabolic tumor in patients with pheochromocytoma/paraganglioma with a high degree of sensitivity [162-164]. More recent studies show that FDG-PET is as specific as is MIBG for detection of the primary tumor and metastases and more sensitive than I-123 and CT/MRI for detection of metastatic disease [162,164]. The utility of integrated FDG-PET/CT imaging as compared with I-123 and conventional cross sectional imaging with CT or MRI was directly addressed in a prospective study of 216 patients with suspected pheochromocytoma/paraganglioma, 60 of whom had nonmetastatic pheochromocytoma/paraganglioma, 95 had metastatic pheochromocytoma/paraganglioma, and 61 did not have pheochromocytoma/paraganglioma, after a detailed evaluation [162]. For the primary tumor, the sensitivity of PET/CT for nonmetastatic tumors was similar to that of I-123 but less than that of CT/MRI (77, 75, and 96 percent, respectively). Among the patients who had paraganglioma/pheochromocytoma ruled out, specificity was comparable (90, 92, and 90 percent, respectively). When the analysis was limited to 26 paragangliomas of the head and neck, PET/CT was more sensitive than I-123 (85 versus 52 percent). Among patients with metastatic disease, sensitivity was greater for PET/CT than for I-123. (See 'Screening for synchronous and metastatic disease' below.)

Several positron-emitting radiolabeled somatostatin analogs have emerged (such as gallium Ga-68 DOTATATE and gallium Ga-68 DOTATOC) that, in combination with high-resolution PET integrated with CT, may improve the detection and staging of a variety of neuroendocrine tumors, including paraganglioma [157,165-174]. In early studies, these novel PET modalities offered higher spatial resolution than conventional 111-In pentetreotide somatostatin receptor-based scintigraphy (ie, Octreoscan) and were associated with improved sensitivity for detection of small lesions [171,172]. For example, gallium Ga-68 DOTATATE PET/CT was prospectively compared with FDG-PET/CT and CT/MRI in 22 patients with non-germline-associated pheochromocytoma or paraganglioma [172]. Gallium Ga-68 DOTATATE PET/CT showed a lesion-based detection rate of 97.6 percent, whereas FDG-PET/CT and CT/MRI showed detection rates of 49.2 (p <0.01) and 81.6 percent (p <0.01), respectively [172]. In a separate study, gallium Ga-68 DOTATATE PET/CT was prospectively studied in 17 patients with SDHB-related metastatic pheochromocytoma or paraganglioma and had a lesion-based detection rate of 98.6 percent, compared with 85.8 percent for FDG, 61.4 percent for FDOPA, 51.9 percent for FDG-PET/CT, and 84.8 percent for CT/MRI [171].

A kit for preparation of gallium Ga-68 DOTATATE injection as a radioactive diagnostic agent for PET imaging (Netspot) is approved by the US Food and Drug Administration (FDA) [175]. A second FDA-approved PET radionuclide, gallium Ga-68 DOTATOC, appears to have comparable diagnostic accuracy to gallium Ga-68 DOTOTATE [176,177].

The approach to tumor localization varies between institutions. At some institutions, MIBG is the test of choice for tumor localization when the abdomen/pelvis CT is negative, or in a patient with a known paraganglioma to search for metachronous disease. However, FDG-PET or gallium Ga-68 DOTATATE PET/CT are preferred for identifying and following sites of metastatic disease. (See 'Screening for synchronous and metastatic disease' below.)

Mass and/or mass effect

Head and neck paragangliomas — Paragangliomas tend to be smaller in the skull base and neck than those that arise outside of this region (mean volume 17 versus 94 cm³ in one report [11]).

Clinical presentation — Carotid body tumors typically present as painless, gradually enlarging masses located in the upper part of the neck below the angle of the jaw [178-180]. In later stages, dysphagia, deficits of cranial nerves VII, IX, X, XI and XII, and hoarseness or a Horner syndrome may result from pressure on the vagus or sympathetic nerves [122,179]. Physical examination discloses a rubbery non-tender mass in the lateral neck that is more freely movable in the horizontal plane than vertically, referred to as a positive Fontaine's sign [179]. There may be a carotid bruit or the tumor may be pulsatile.

Jugulotympanic paragangliomas are slow-growing lesions that usually present with pulsatile tinnitus with or without conductive hearing loss [116,181]. In one report, 90 percent of patients with a jugular foramen paraganglioma had pulsatile tinnitus and 81 percent had hearing loss. In patients with a jugular paraganglioma, there may be lower cranial nerve deficits as well (facial nerve paralysis, vertigo, hoarseness, and paralysis of lower cranial nerves). Physical examination may reveal a bluish pulsating mass behind the tympanic membrane.

Vagal paragangliomas (image 4) most commonly arise from the inferior nodose ganglion, but they can occur at any point along the course of the cervical vagal nerve. As a result, there is a wide variety of clinical symptoms including dizziness, blurred vision, facial droop, dysphagia, neck mass, pain, cranial nerve deficits, or Horner syndrome [182].

Rarely, cervical paragangliomas can also arise from or in proximity to the thyroid gland [16,183].

Paragangliomas that are located within the dura can also present with symptoms of neurologic compression.

Differential diagnosis — The differential diagnosis of a nontender lateral neck mass in adults includes lymphadenopathy, branchial cleft cysts, salivary gland tumors, neurogenic tumors, and aneurysms of the carotid artery. This subject is discussed in detail elsewhere. A tentative diagnosis of a paraganglioma can often be made based upon characteristic findings on ultrasound or cross-sectional imaging. (See "Differential diagnosis of a neck mass".)

The differential diagnosis of a mass in the jugular foramen includes schwannoma, meningioma, neurinomas, and endolymphatic sac tumors of the middle ear (which are associated with VHL). In one report, schwannomas and meningiomas were less likely to present with pulsatile tinnitus and conductive hearing loss but more likely to present with hoarseness. A comparison of symptoms and findings for all three types of tumors presenting in the jugular foramen is presented elsewhere (table 7) [116]. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease", section on 'Endolymphatic sac tumors of the middle ear' and "Vestibular schwannoma (acoustic neuroma)" and "Epidemiology, pathology, clinical features, and diagnosis of meningioma".)

The differential diagnosis of pulsatile tinnitus is outlined in the table (table 8).

Thyroid-associated paragangliomas, although quite rare, should be considered in the differential diagnosis of other hypervascular thyroid nodules as primary thyroid neoplasms [183]. Particularly in a patient with MEN2, the diagnosis of a thyroid-associated paraganglioma should be entertained with a FNA biopsy suggestive of medullary thyroid carcinoma and with unremarkable serum calcitonin levels. (See "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Color Doppler flow patterns' and "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)

The differential diagnosis of paragangliomas located within the dura includes other intradural tumors and leptomeningeal carcinomatosis. (See "Intradural nerve sheath tumors" and "Clinical features and diagnosis of leptomeningeal disease from solid tumors".)

Diagnosis — For skull base and neck paragangliomas, the initial evaluation may include ultrasound or cross sectional imaging (CT or MRI). On ultrasound, a carotid body tumor typically presents as a solid, well-defined, hypoechoic tumor with a splaying of the carotid bifurcation [184,185]. Duplex sonography typically indicates the mass to be hypervascular, although the absence of hypervascularity does not exclude the diagnosis [185].

The classic CT findings of a paraganglioma at any site include a homogeneous mass with unenhanced Hounsfield units in the 40 to 50 range [12]. There is intense enhancement following administration of intravenous contrast and delayed washout. Cystic changes, necrosis, and internal calcifications are commonly described [186].

CT is the best initial test for suspected jugulotympanic paraganglioma since it represents the best method to evaluate the extent of temporal bone destruction, which is used to classify tumors according to the Fisch classification, an important aspect of selecting the operative approach. (See 'Staging' above.)

For skull base and neck paragangliomas, tumor location, displacement of major vessels, and patterns of involvement of invasion of surrounding structures may permit the distinction between carotid body and vagal or jugulotympanic paragangliomas [184,187-189]:

●Carotid body tumors typically displace the common carotid bifurcation with posterolateral displacement of the internal carotid artery [187].

●Vagal paragangliomas displace both the internal and external carotid arteries anteriorly and are associated with erosion and widening of the jugular foramen.

Jugular paragangliomas may be distinguished from tympanic tumors based upon early involvement of the skull base, erosion of the spine, and destruction of the ossicular chain, which is unusual for tympanic tumors [187-191].

To avoid precipitating a catecholamine crisis, all patients who are suspected of having a paraganglioma should have negative biochemical results for catecholamine hypersecretion or undergo alpha blockade before ionic contrast is administered for a CT scan. Use of nonionic contrast material (which is more common) is considered safe [190,191].

Although CT is the test of choice for evaluation of bone involvement, gadolinium-enhanced MRI provides superior definition of the relationship of paragangliomas to adjacent vascular and skull base structures and is recommended in guidelines from the Endocrine Society [149] (image 3). MRI is also complementary to CT in patients with jugulotympanic paragangliomas for the detection of dural infiltration and intradural tumor growth, as well as to exclude other tumor entities arising in this area. MRI is also the initial imaging test of choice in children and pregnant women, as well as in those with an allergy to CT contrast dye [149].

On T1-weighted MRI, paragangliomas typically have a background tumor matrix of intermediate signal density, with scattered areas of signal void, reflecting high-flow blood vessels (image 3) [95]. On T2-weighted images, an intense hypervascular appearance is present with classic "salt and pepper" appearance in most lesions larger than 1.5 cm, reflecting signal voids intermixed with regions of focally intense signal intensity [95,192]. These MRI findings are not specific for paraganglioma and may be seen with other hypervascular tumors (eg, metastatic renal cell or thyroid carcinoma). However, the typical smooth contour, signal characteristics, and location of paraganglioma coupled with the history and physical examination should enable a correct diagnosis to be made.

Other sites

Clinical presentation — Most paragangliomas outside of the skull base and neck present with symptoms of catecholamine excess. (See 'Catecholamine hypersecretion' above.)

However, a few patients (4 percent in one series of 81 patients with benign paragangliomas below the neck) have biochemically silent disease that presents with symptoms related to an abdominal mass [11]. In addition, dopamine-secreting extra-adrenal paragangliomas, which are quite rare and associated with SDHB pathogenic variants, tend to present late with mass effect rather than with symptoms of hypersecretion. (See 'Familial paraganglioma and SDH pathogenic variants' above.)

Approximately 2 percent of paragangliomas are found in the mediastinum, where they most commonly present as an anterior or posterior mediastinal mass, less commonly as a middle mediastinal mass [152,193-196]. Although the clinical presentation may be due to catecholamine secretion (50 to 85 percent of cases), some patients present with symptoms (chest or back pain, cough, hoarseness, dyspnea) related to mass effect [15,123,193,197]. Patients may also present with symptoms referable to metastatic disease; in several series, the incidence of malignancy ranges from 10 to 69 percent [198-200].

Differential diagnosis — The differential diagnosis of an abdominal mass is broad and includes carcinomas, lymphomas, and soft tissue sarcomas including gastrointestinal stromal tumors and desmoid tumors.

●(See "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma".)

●(See "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma".)

●(See "Clinical presentation, diagnosis, and prognosis of gastrointestinal stromal tumors".)

●(See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

●(See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)

●(See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

●(See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy".)

The differential diagnosis of a contrast-enhancing mediastinal tumor on radiographic imaging includes mediastinal hemangioma, epithelioid hemangioendothelioma, Castleman disease, choriocarcinoma, thymoma, and metastatic tumor (especially from renal cell cancer). The differential diagnosis of an enhancing mass in the posterior mediastinum includes metastatic tumor (eg, renal cell, thyroid cancer), an aortic aneurysm, and a primary neurogenic or bronchogenic tumor. (See "Approach to the adult patient with a mediastinal mass".)

Diagnosis — Imaging characteristics are frequently sufficiently distinctive (by location and vascularity) to permit a presumptive preoperative diagnosis of a paraganglioma. The classic CT findings of a paraganglioma at any site are a homogeneous mass with unenhanced CT attenuation of Hounsfield units in the 40 to 50 range [12], intense enhancement following administration of intravenous contrast, and delayed washout. Cystic changes, necrosis, and internal calcifications are commonly described [186].

Incidental finding — With the more widespread use of cross-sectional imaging, pheochromocytomas and paragangliomas may be discovered incidentally on an imaging study obtained for another reason (image 5). In one series, 9 percent of patients with benign paragangliomas presented in this way [11]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Asymptomatic patients'.)

Pathogenic variant carriers — For patients who are carriers of a SDHx pathogenic variant, we obtain biochemical and imaging studies to screen for paragangliomas. As with pheochromocytomas, paragangliomas are often diagnosed in patients (and their family members) who are found to be a carrier of a familial disease-conferring germline pathogenic variant. (See "Pheochromocytoma in genetic disorders".)

Prospective studies to guide the clinician in the frequency and type of testing are limited, and our approach is as follows:

●Biochemical testing – Biochemical testing for fractionated metanephrines in plasma or in a 24-hour urine collection should be performed annually in all SDHx pathogenic variant carriers.

●Imaging studies – Imaging studies are advised because paragangliomas may be nonfunctioning or may be detected before catecholamine-secretory autonomy is evident.

•SDHB, SDHC, and at-risk SDHD or SDHAF2 (eg, paternally inherited) pathogenic variant carriers should have cross-sectional imaging (CT or MRI) of the skull base and neck, chest, abdomen, and pelvis every two to three years. I-123 MIBG scintigraphy or gallium Ga-68 DOTATATE PET/CT should be performed every five years.

SCREENING FOR SYNCHRONOUS AND METASTATIC DISEASE — Among the tests that can provide a total-body survey, which can be helpful in diagnosing or localizing synchronous tumors or metastases, are metaiodobenzylguanidine (MIBG) scanning, 111-In pentetreotide (OctreoScan), and positron emission tomography (PET) scanning. Given available data, we prefer the use of either 18F-fludeoxyglucose (FDG) or gallium Ga-68 DOTATATE PET CT (see 'Radioisotope imaging' above):

●Iobenguane I-123 (diagnostic) can detect tumors not detected by CT or MRI, or multiple tumors when CT or MRI is positive [155]. A problem with MIBG scanning is that false-negative scans are most commonly found in patients with SDHB-related paraganglioma, which are most likely to display malignant behavior [158]. Guidelines from the Endocrine Society suggest the use of iobenguane I-123 (diagnostic) scintigraphy as a functional imaging modality in patients with metastatic paraganglioma detected by other imaging modalities only when radiotherapy using iobenguane I-131 (therapeutic) is planned.

●Preoperative 111-In pentetreotide can sometimes identify unexpected foci of disease [160]. As an example, in one retrospective study of 30 patients with SDHB-positive paragangliomas, 111-In pentetreotide identified two patients with liver metastases that were missed by other modalities including FDG-PET [164].

●FDG-PET appears to be more sensitive than either iobenguane I-123 (diagnostic) or CT for the detection of metastatic disease (see 'Radioisotope imaging' above):

•A retrospective study of 30 patients with SDHB-related paragangliomas (29 with metastatic disease) reported 100 percent sensitivity (per patient) for detection of metastases with FDG-PET, versus 80 percent for iobenguane I-123 (diagnostic) and 88 percent for 18F-fluorodihydroxyphenylalanine (FDOPA)-PET [164]. Ninety percent of the body regions that were falsely negative on MIBG and FDOPA-PET scanning were detected by FDG-PET. However, in two patients, 111-In pentetreotide detected liver lesions that were not evident by any other functional imaging modality.

●The utility of integrated FDG-PET/CT imaging as compared to iobenguane I-123 (diagnostic) and conventional cross sectional imaging with CT or MRI in patients with suspected paraganglioma/pheochromocytoma was directly addressed in a prospective study of 216 patients, 60 of whom had nonmetastatic pheochromocytoma/paraganglioma, 95 had metastatic disease, and 61 were found not to have pheochromocytoma/paraganglioma, after a detailed evaluation [162]. For detection of metastases, sensitivity was greater for PET/CT and CT/MRI than for iobenguane I-123 (diagnostic) (FDG-PET, 89 percent; CT/MRI, 74 percent; iobenguane I-123 (diagnostic), 50 percent); among patients with bone metastases, the sensitivity of PET/CT was higher than that of CT/MRI (94 versus 77 percent). Although the number of patients with hereditary nonmetastatic pheochromocytoma/paraganglioma was low, there was a suggestion of greater sensitivity of PET/CT among patients with SDHx pathogenic variants compared with those without (92 versus 67 percent), while iobenguane I-123 (diagnostic) seemed to perform worse in those with the SDHx pathogenic variant (sensitivity 45 versus 66 percent in SDHx-negative patients). Among the patients who had pheochromocytoma/paraganglioma ruled out, the specificity of PET/CT was similar to that of iobenguane I-123 (diagnostic) (90 versus 92 percent).

In our view and that of the Endocrine Society [149], FDG-PET or Ga-68-DOTATATE PET-CT are preferred over MIBG to screen for and follow sites metastatic disease.

GENETIC TESTING

Indications — We and others [21] advise germline genetic testing for all patients with paraganglioma. A standard genetic testing panel is clinically available for the most common pathogenic variants: RET, VHL, NF-1, SDHD, SDHC, SDHB, SDHA, SDHAF2, TMEM127, and MAX.

Genetic testing assists in estimating the chance of recurrence, either metachronous or malignant, and in determining the correct follow-up algorithm for associated syndromic manifestations. As an example, in a series of 417 patients with pheochromocytoma or paraganglioma of the skull base and neck without features suggesting an inherited syndrome, 12 percent carried SDHD or SDHB pathogenic variants [5]. SDHD carriers had a higher incidence of skull base and neck paragangliomas and multifocality while those with SDHB pathogenic variants had an increased frequency of malignant disease.

Genetic counseling before and after germline genetic testing is a key step so that patients and families understand the implications of genetic testing, impact on diagnosis and treatment, and the familial risk of transmission.

There are several reports that support use of an immunohistochemical staining procedure (IHC) for determining which patients should undergo the more expensive genetic analysis. Pathogenic variants in the SDHB, C, and D genes but not VHL, RET, or NF1 lead to absent or weak staining with antibodies against SDHB [201,202]; similarly, IHC has been used to predict germline SDHA pathogenic variants [56]. However, this practice is not widespread and is not done at our institutions.

Approach to genetic testing — The approach to genetic testing is rapidly evolving. Although some guidelines, including the Endocrine Society Clinical Guidelines, provide decisional algorithms for sequential genetic testing [6,49], this approach is no longer used at many institutions. In addition, clinical reference laboratories offer a genetic testing panel for the most common pathogenic variants: RET, VHL, NF-1, SDHD, SDHC, SDHB, SDHA, SDHAF2, TMEM127, and MAX. Our approach to genetic testing is as follows:

●Targeted germline pathogenic variant testing should be performed in those patients presenting with findings consistent with a paraganglioma-related syndrome. For example:

•VHL disease – Germline pathogenic variant testing for von Hippel Lindau (VHL) disease should be recommended for those patients with a paraganglioma and retinal angiomas, cerebellar hemangioblastoma, or pancreatic islet cell tumors. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

•MEN2 – Although paraganglioma is rare in the setting of multiple endocrine neoplasia type 2, RET proto-oncogene testing should be obtained in patients presenting with paraganglioma and medullary thyroid carcinoma. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

•NF1 – In the setting of neurofibromatosis type 1 (NF1), frequently the dermatologic (eg, multiple large café au lait spot, axillary freckling, or subcutaneous neurofibromas) or ocular (Lisch nodules) findings are diagnostic and germline pathogenic variant testing is superfluous. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

●For those patients with paraganglioma who lack a syndromic presentation, we suggest the following approach:

•Tests for pathogenic variants in the following genes should be ordered: RET, VHL, NF-1, SDHD, SDHC, SDHB, SDHA, SDHAF2, TMEM127, and MAX [203].

•If kindred show a typical maternal imprinting inheritance pattern (ie, the gene is only active if inherited from the father), then SDHD and SDHAF2 should be ordered first. (See "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)

If a pathogenic variant is discovered, all first-degree relatives should be offered germline genetic testing for the known pathogenic variant or syndrome (VHL disease, MEN2, NF1) [21].

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, highly vascular neoplasms that arise from widely dispersed specialized neural crest chromaffin cells that are associated with autonomic ganglia and have the ability to secrete catecholamines (figure 1). Paragangliomas are closely related to pheochromocytomas, many secrete catecholamines, and can cause clinical symptoms. (See 'Introduction' above.)

●Clinical features – Paragangliomas can derive from either parasympathetic or sympathetic ganglia, and the clinical features and location vary by this type of origin (see 'Definition and anatomic origin' above):

•Parasympathetic paragangliomas (neck and skull base) – Parasympathetic ganglia-derived paragangliomas are located almost exclusively in the neck and skull base, arising most often from the carotid body and jugulotympanic paraganglia. They are non-functional.

•Sympathetic paragangliomas (base of skull to bladder) – 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 secrete catecholamines.

●Hereditary paragangliomas – Approximately 30 percent of all paragangliomas are hereditary and associated with paraganglioma syndromes. The paraganglioma syndromes 1, 3, and 4 (PGL1, 3, 4) make up the majority of familial cases. (See 'Hereditary syndromes' above.)

•The most common types are PGL1, which is associated with pathogenic variants of the succinate dehydrogenase subunit D (SDHD) gene, and PGL4, which is caused by SDH subunit B (SDHB) pathogenic variants. (See 'Familial paraganglioma and SDH pathogenic variants' above.)

•Other autosomal dominant hereditary syndromes that include pheochromocytoma/paraganglioma include multiple endocrine neoplasia types 2A and 2B (MEN2), neurofibromatosis type 1 (NF1), and von Hippel Lindau (VHL) disease. (See 'Other associated autosomal dominant hereditary syndromes' above.)

•Multiple paragangliomas (either synchronous or metachronous) occur more frequently in patients with hereditary pheochromocytoma/paraganglioma compared with those with sporadic disease. (See 'Inherited versus sporadic paraganglioma' above.)

•Although most paragangliomas are benign, those associated with SDHB pathogenic variants and some types of VHL are more likely to be malignant. There are no consistent histologic signs of malignant behavior; the only reliable indicator is the development of metastases. (See 'Histology and malignant potential' above and 'Familial paraganglioma and SDH pathogenic variants' above.)

●Clinical presentation – The clinical presentation of paraganglioma is highly variable (table 4). (See 'Clinical presentation and diagnosis' above.)

•Patients can be symptomatic from excessive catecholamine secretion with episodic hypertension, tachycardia, palpitations, sweating, pallor, headache, or nonspecific abdominal or flank pain. (See 'Catecholamine hypersecretion' above.)

•Patients with a skull base and neck paraganglioma typically present with a painless neck mass (carotid body tumor), or pulsatile tinnitus with or without conductive hearing loss (jugulotympanic paraganglioma). (See 'Mass and/or mass effect' above.)

•Other patients can be asymptomatic with a tumor diagnosed incidentally on CT, or they are diagnosed because they have been identified as a carrier of a disease-conferring germline pathogenic variant. (See 'Incidental finding' above and 'Pathogenic variant carriers' above.)

●Screening carriers of a SDHx pathogenic variant – For patients who are carriers of a SDHx pathogenic variant, we obtain biochemical and imaging studies to screen for paragangliomas. (See 'Pathogenic variant carriers' above.)

●Diagnosis of secretory paraganglioma – The diagnosis of a secretory paraganglioma can usually be made by measurements of urinary and/or plasma fractionated metanephrines and catecholamines (algorithm 1). (See 'Diagnosis' above.)

•Biochemical testing is indicated for all patients with a paraganglioma, even if they present without symptoms of catecholamine excess.

•For catecholamine-secreting tumors, biochemical diagnosis should be followed by radiological evaluation (typically either CT or MRI of the abdomen and pelvis) to locate the tumor. If abdominal and pelvic CT or MRI is negative, the next step is cross-sectional imaging of the thorax/head and neck and/or radioisotope (functional) imaging using 18F-fludeoxyglucose (FDG) positron emission tomography (PET) or metaiodobenzylguanidine (MIBG). (See 'Localizing the tumor' above.)

●Diagnosis of nonsecretory paraganglioma – The diagnosis of a nonsecretory paraganglioma or a paraganglioma in an unusual location, for which biochemical testing may not have been done due to lack of clinical suspicion, is usually based on characteristic radiographic findings. For suspected paragangliomas below the neck, cross sectional imaging with either CT or MRI is an acceptable initial test. For skull base and neck paragangliomas, the initial test may be an ultrasound, CT, or MRI (see 'Diagnosis' above):

•Ultrasound is a good initial diagnostic study for patients with a suspected carotid body paraganglioma.

•Both MRI and CT are typically needed for a suspected jugulotympanic paraganglioma given that the information derived from each study is complementary.

●Imaging for metastatic disease

•Integrated FDG-PET/CT and Ga-68-DOTATATE PET CT scanning are more sensitive than MIBG for detecting metastatic disease and are preferred for screening for and following metastatic disease. (See 'Screening for synchronous and metastatic disease' above.)

•Screening for metastatic disease is indicated in all patients with a SDHB germline pathogenic variant-related paraganglioma and all dopamine-secreting paragangliomas because of the high frequency of metastases. (See 'Radioisotope imaging' above and 'Catecholamine hypersecretion' above.)

●Genetic testing in all patients with paraganglioma – In all patients with paragangliomas, genetic testing should be obtained to screen for germline pathogenic variants in SDH and other genes. (See 'Genetic testing' above and 'Approach to genetic testing' above.)

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