Update on Pheochromocytoma and Paraganglioma from the SSO Endocrine/Head and Neck Disease-Site Work Group. Part 1 of 2: Advances in Pathogenesis and Diagnosis of Pheochromocytoma and Paraganglioma

Abstract

This first part of a two-part review of pheochromocytoma and paragangliomas (PPGLs) addresses clinical presentation, diagnosis, management, treatment, and outcomes. In this first part, the epidemiology, prevalence, genetic etiology, clinical presentation, and biochemical and radiologic workup are discussed. In particular, recent advances in the genetics underlying PPGLs and the recommendation for genetic testing of all patients with PPGL are emphasized. Finally, the newer imaging methods for evaluating of PPGLs are discussed and highlighted.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors of chromaffin tissue that may produce catecholamines.¹ Pheochromocytomas are tumors that arise from chromaffin cells within the adrenal medulla, whereas paragangliomas (PGLs) arise from extra-adrenal chromaffin cells of the sympathetic or parasympathetic paravertebral ganglia within the chest, abdomen, and pelvis. Paragangliomas also may arise from the chromaffin cells of the parasympathetic ganglia of the head and neck.

Almost all pheochromocytomas and sympathetic extra-adrenal PGLs produce, store, metabolize, and secrete catecholamines (epinephrine, norepinephrine, dopamine) or their metabolites (metanephrines, normetanephrines). Approximately 80–85% of chromaffin cell tumors are pheochromocytomas (intra-adrenal), and 15–20% are PGLs (extra-adrenal).^2–4

EPIDEMIOLOGY AND INCIDENCE

Approximately 75–80% of sympathetic PGLs arise in the abdomen and pelvis, typically in the paravertebral sympathetic ganglia at the junction of the inferior vena cava and left renal vein or organ of Zuckerkandl (aortic bifurcation near the origin of the inferior mesenteric artery). About 10% arise in the thorax, including mediastinal and pericardial locations.^5–7 Approximately 5–10% of patients have multiple or bilateral tumors.^3,8 Notably, PGLs also can arise from the parasympathetic ganglia located along the glossopharyngeal and vagal nerves in the neck and base of skull. Usually, PGLs arising from these parasympathetic nerves are not associated with catecholamine secretion.^1,9

In the United States, the annual incidence of PPGLs is about 500 to 1600 cases per year,¹⁰ which likely is an underestimation given the relatively high prevalence (0.05–0.1%) of incidentally discovered PPGLs at autopsy.^11,12 The prevalence of these rare tumors is estimated to be 1 to 2500 and 1 to 6500.¹⁰ Among adult patients with hypertension in outpatient clinics, the prevalence ranges from 0.1 to 0.6%,^4,13,14 and among children with hypertension, the prevalence is approximately 1.7%.¹⁵

Pheochromocytomas comprise about 4–8% of all adrenal incidentalomas, and approximately 21.1–57.6% of all pheochromocytomas are discovered incidentally on imaging studies.^16–22 Symptomatic patients typically present in their fourth or fifth decade of life, with a relatively equal male-to-female distribution.²³ Most of these tumors are unifocal (90–95%) and benign. About 10% (range 2–50%) of all catecholamine-secreting tumors are malignant, but the likelihood of malignancy depends on the primary site (adrenal vs. extra-adrenal) and the presence of certain germline mutations (SDHB in particular).^8,24,25

BRIEF REVIEW OF CATECHOLAMINE SYNTHESIS

Chromaffin cells synthesize norepinephrine and epinephrine from a tyrosine precursor. In brief, tyrosine is converted to DOPA, which is subsequently converted to dopamine. Dopamine then is converted to norepinephrine within storage vesicles. Norepinephrine leaks out of these vesicles and is converted in the adrenal gland to epinephrine by phenylethanolamine N-methyltransferase (PMNT) (Fig. 1). The metabolism of these catecholamines takes place within the same cells. Norepinephrine and epinephrine are O-methylated to normetanephrine and metanephrine within the same cells and slowly released into the bloodstream independently of sympathoadrenal activity. This independence provides the biologic underpinnings for the specificity of plasma and urinary metanephrines.²⁶

FIG. 1.

Chromaffin cells synthesize norepinephrine and epinephrine from phenylalanine, a tyrosine precursor. AAAD, L-aromatic amino acid decarboxylase; DBH, dopamine β-hydroxlase; L-DOPA, dihydroxyphenylalanine; PNMT, phenylethanolamine N-methyltransferase

PATHOPHYSIOLOGY

The systemic effects of PPGLs are due to the uncontrolled release of catecholamines leading to several physiologic changes and end-organ effects that can result in high cardiovascular morbidity and mortality, including arrhythmias, myocardial events, and stroke.^27–29 Almost all pheochromocytomas and sympathetic extra-adrenal PGLs are biochemically active and secrete catecholamines (epinephrine, norepinephrine, dopamine) or their metabolites.^9,10 Pheochromocytomas often secrete both norepinephrine and epinephrine, although the relative proportions may vary. Paragangliomas secrete norepinephrine exclusively because the PNMT enzyme necessary for epinephrine synthesis is found only in the adrenal medulla.

About half of patients present with paroxysmal signs and symptoms of catecholamine excess (e.g., headache, palpitations, sweating, flushing, fatigue, sustained or paroxysmal hypertension; see “Clinical Presentation” later).^2,10 Patients with predominantly epinephrine-secreting tumors are more likely to have tachycardia and tachyarrhythmias in addition to hypertension.³⁰ Exposure to prolonged or repeated norepinephrine release is associated with long periods of vasoconstriction and venous contraction, resulting in decreased circulating blood volume, which can lead to acute hypovolemia at the time of tumor removal and cessation of norepinephrine-induced vasoconstriction, highlighting the importance of preoperative alpha-blockade and volume expansion.

In addition, elevated catecholamine levels can cause increased glycogenolysis and inhibition of insulin release by islet cells, resulting in hyperglycemia.^31–33 Elevated catecholamines also can lead to stress-induced cardiomyopathy (Takotsubo cardiomyopathy) with severe left ventricular dysfunction.^28,34

Finally, although rarely seen today, pheochromocytoma crisis (multisystem organ failure, high fever, encephalopathy, and severe hypertension and/or hypotension) can progress to severe metabolic acidosis and death if not recognized and treated with urgent operative intervention after a period of stabilization with appropriate blockade and supportive care.³⁵ However, clinical judgment for emergent surgery must be used for those whose conditions deteriorate despite maximal medical therapy or extenuating circumstances such as hemorrhage or rupture of a pheochromocytoma.^35,36

CLINICAL PRESENTATION

Most commonly, patients with PPGLs present with overt clinical signs and symptoms of catecholamine excess. Persistent, sometimes worsening, hypertension is the most common clinical feature and can be paroxysmal in nature. The classically described triad of symptoms (episodic headaches, diaphoresis, and palpitations) is found in less than 25% of patients with pheochromocytoma.^1,37,38 Other symptoms may include anxiety, chest and abdominal pain, nausea and vomiting, and psychiatric manifestations. The variation in clinical symptoms also may be related to differences in secretion of epinephrine and norepinephrine and their individual effects on β1- and β2-adrenergic receptors. Epinephrine-secreting pheochromocytomas more frequently result in episodic hypertension and symptoms of palpitations, syncope, anxiety, and hyperglycemia. In contrast, norepinephrine-secreting tumors are more continuous, with headaches, sweating, and hypertension, which are less paroxysmal in nature.^1,38

Pheochromocytomas also occur in patients without elevated blood pressures. The true prevalence is unknown, although it is reported in published series to reach 55% of patients^37,39 Normotensive (“asymptomatic” or “silent”) pheochromocytomas often occur in incidentally identified adrenal tumors. Therefore, the absence of hypertension should not preclude biochemical evaluation of patients with incidental adrenal nodules or clinical symptoms otherwise suggestive of a pheochromocytoma.^1,39

The pathophysiology of sporadic, “normotensive” pheochromocytomas is unknown, although it is suggested that the cardiovascular system may become desensitized to circulating catecholamines. In contrast, it is not uncommon for patients with hereditary pheochromocytomas to have minimal elevations in plasma and urinary catecholamines or in the setting of obvious catecholamine excess biochemically to be normotensive with few, if any, clinical signs and symptoms.^{1,37,38,40,41}

Recent studies also have shown that cardiovascular complications secondary to chronic catecholamine stimulation can occur in up to 20% of patients with pheochromocytomas, and pheochromocytoma-induced cardiomyopathies are increasingly reported.^42–44 A recent review of the literature suggested that two types of pheochromocytoma-related cardiomyopathies may exist: (1) Takotsubo (‘stress’) cardiomyopathy, associated with more acute changes and a higher rate of left ventricular recovery and (2) more chronic cardiomyopathies, including dilated cardiomyopathies and acute heart failure, with lower rates for recovery of left ventricular function.⁴² This variability highlights the importance of considering the diagnosis of PPGLs for patients with a newly diagnosed Takotsubo cardiomyopathy or unexplained dilated cardiomyopathy and, conversely, appropriate cardiac evaluation for patients with a diagnosis of PPGLs.^42,44

BIOCHEMICAL WORKUP

Patients suspected of PPGLs should undergo biochemical testing to either confirm or rule out the disease. The metabolites of epinephrine and norepinephrine, metanephrines and normetaphrines,⁴⁵ have been isolated aid in diagnosis and are superior to circulating catecholamines.^46,47 However, the ideal test with both high sensitivity and specificity has been debated. The two best methods in current use are measurement of 24-h excretion of fractionated metanephrines and measurement of plasma-free metanephrines. Evidence for both tests with details of the testing methods has been extensively reviewed.¹ The plasma test has very high sensitivity (90–100%), with slightly lower specificity (79–100%). The urinary test of fractionated metanephrines generally has been slightly lower in both sensitivity and specificity, but a head-to-head comparison between plasma and urinary metanephrines using mass spectrometry has never been completed. Therefore, at this writing, both plasma and urinary metanephrines should be considered for diagnosing or ruling out pheochromocytoma. The plasma test has significant advantages in terms of convenience.

Given the rarity of PPGLs and the pretest probability of 1%, the rate of false-positives will be high. Yu and Wei⁴⁸ reviewed a large single-institution experience with testing for pheochromocytomas and found a false-positive rate for both plasma-free and urinary-fractionated metanephrines of 19–21%. The causes of the false-positive findings included physiologic variation, laboratory errors, and drug interference with measurement. Medications known to cause interference include phenoxybenzamine, tricyclic antidepressants, acetaminophen, labetalol, sotalol, alpha-methyldopa, buspirone, monoamine oxidase (MAO) inhibitors, sympathomimetics, cocaine, sulfasalazine, and levodopa.^1,49 Patients should be instructed to hold acetaminophen 5 days before testing. Repeat testing may be prudent after medications have been adjusted and the patient is in supine position for testing.¹ If medications cannot be adjusted, a clonidine suppression test may be performed to rule out false-positives.⁴⁹

It should be emphasized that mild elevations seen with either the urinary or plasma test should be viewed with suspicion, as should abnormalities seen during unusual or stressful events (e.g., hospitalization for unrelated reasons). Repeated testing including both urinary and plasma tests often is advisable when the diagnosis is not clear.

GENETIC BASIS AND TESTING OF PHEOCHROMOCYTOMAS AND PARAGANGLIOMAS

Pheochromocytoma and paragangliomas are among the most common inherited tumors, with up to 30–40% arising from an attributable germline mutation.⁵⁰ The old axiom of pheochromocytomas characterized by the rule of tens (10% familial) is no longer accurate because many new tumor syndromes have been identified and characterized during the past 15 years.⁵¹ Currently, it is recommended that all patients with a diagnosis of PPGL should be referred for genetic evaluation regardless of their age or family history.⁵² If an inherited syndrome is identified, the management of the patient and affected family members will be determined by the specific mutation.⁵³

To date, more than 20 genes have been identified as playing a role in tumor development, as either a germline (inherited) or somatic (non-inherited) mutation. The specific gene mutation provides insight into the pathophysiology and biologic behavior of the PPGL. Table 1 groups genes by their function and transcriptional profile.⁵⁴ The first group includes genes that contribute to dysregulation of hypoxia-inducible factor (HIF), which includes von Hippel-Lindau (VHL) disease, the succinate dehydrogenase subunits (SDHA, SDHB, SDHC, SDHD), succinate dehydrogenase complex assembly factor 2 (SDHAF2), egl-9 prolyl hydroxylase 1 and 2 (EGLN1/2), malate dehydrogenase 2 (MDH2), and fumarate hydratase (FH). These tumors are characterized by an upregulation of HIF without hypoxia. In general, these tumors tend to be more aggressive than those associated with other genetic alterations. Particularly, the SDHB mutation has been associated with an increased risk of malignant behavior.⁵⁵ These tumors (except VHL) are more commonly extra-adrenal and have a noradrenergic phenotype.

TABLE 1.

Clustering of inherited pheochromocytoma and paraganglioma syndromes

Cluster 1: pseudohypoxia	Cluster 2: kinase signaling
VHL	RET
SDHA, SDHB, SDHC, SDHD	NF1
SDHAF2	TMEM127
FH	MAX
EGLN1/2 (PHD1)
MDH2
Generally, more aggressive	Generally, more pheochromocytomas with an adrenergic phenotype

Cluster 3 (Wnt signaling) represents only genes with nonfamilial associations

The second group includes genes that affect the kinase-signaling pathway involving PI3K/mTOR. These genes include the RET proto-oncogene (multiple endocrine neoplasia [MEN] 2A and 2B), neurofibromin 1 (NF1), and the more recently associated genes, namely, transmembrane protein 127 (TMEM127) and Myc-associated factor X (MAX). The tumors in this cluster tend to be predominantly adrenal in origin with an adrenergic phenotype.

VHL

The VHL syndrome, arising from mutations in the VHL gene, is characterized by a variety of tumors including cerebellar and spinal hemangioblastomas, retinal hemangiomas, clear cell renal carcinomas, pancreatic neuroendocrine tumors, and cysts and cystadenomas of the pancreas, epididymis, and broad ligament.⁵⁶ Central nervous system hemangioblastomas are the dominant cause of mortality.⁵³ Pheochromocytomas and rarely PGLs are seen in about 20% of patients, usually with a young age of onset. Up to one half of pediatric patients presenting with PPGLs are found to have VHL.⁵⁷ Tumors are frequently of adrenal origin and produce dominantly norepinephrine instead of epinephrine.⁵⁸ Metastatic pheochromocytomas are rare (5%).

MEN2

The MEN2 syndromes are caused by activating mutations in the RET proto-oncogene. Both MEN2A and MEN2B are characterized by medullary thyroid cancer, with a penetrance near 100%. Patients with MEN2B and medullary thyroid cancer present at an earlier age with aggressive characteristics. Patients with MEN2A also have hyperparathyroidism, whereas patients with MEN2B frequently have neuromas and a Marfanoid habitus. Both syndromes are characterized by pheochromocytomas, with a penetrance of about 50% for both types.⁵³ Frequently, bilateral disease is observed. Therefore, a cortical-sparing approach to surgery is favored by some surgeons to avoid steroid dependence and the risk of adrenal crisis. Metastatic pheochromocytomas and extra-adrenal PGLs are quite rare (about ≤ 1%).

NF1

Neurofibromatosis type 1 is characterized by the development of multiple neuromas, with up to 15% developing malignant peripheral nerve sheath tumors.⁵⁹ The penetrance of pheochromocytomas in these cases is only 1–5%. Almost all these tumors are adrenal in origin. Metastatic pheochromocytomas are reported 7–12% of the time. Virtually all patients with NF1 and a pheochromocytoma will show cutaneous manifestations on the physical exam.⁵⁸

PARAGANGLIOMA SYNDROMES TYPES 1 TO 5 (SDH COMPLEX)

The PGL syndromes arise from genes encoding the succinate dehydrogenase (SDH) enzyme. The SDH complex, composed of four subunits (SDHA, SDHB, SDHC, and SDHD), oxidizes succinate to fumarate as part of the electron transport chain within the mitochondrial inner membrane. Mutations cause destabilization of the SDH complex, resulting in stabilization of HIF leading to tumor formation. The fifth gene identified as causing PGL is SDHAF2, which flavinates SDHA. These syndromes are more commonly associated with PGL (including head and neck PGLs) than the previously described syndromes, but pheochromocytomas are seen in all five types. Both the SDHD and SDHAF2 germline mutations leading to PPGLs are almost always inherited paternally and have evidence of complicated maternal imprinting.⁵⁸ The SDHB mutations are distinguished by a higher rate of malignancy, reported to be 30–70%.⁵⁸ The morbidity of SDHB inherited tumors is frequently related to metastatic disease rather than catecholamine and metabolite production.

GENETIC TESTING

Previously, genetic testing was recommended for patients who were young at diagnosis or had a family history or evidence of multifocal disease. Currently, the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors recommend that all patients with PPGLs undergo genetic testing regardless of age or family history.⁵² Likewise, the Endocrine Society and the European Society of Endocrinology recommend that genetic testing be considered for all patients.^1,60 A recent study suggested that preoperative genetic testing affects the surgical approach at the initial operation. In particular, patients with an SDHB mutation, which typically represents more aggressive and malignant disease, were more likely to undergo an open rather than a minimally invasive approach.⁶¹

Next generation sequencing (NGS), introduced in 2005, has become the gold standard for genetic testing because it is more efficient and cost-effective than previous sequencing techniques. A consensus statement on NGS testing for patients with inherited PPGL details the variety of associated genes and standardizes reporting.⁶² With NGS, it is relatively straightforward to test the 10 to 15 most common predisposing genes. The genes typically tested are EGLN1, FH, KIF1B, MAX, MEN1, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL. The genes typically are sequenced and evaluated for exon deletions and duplications. Due to the complexity of interpreting the results and potential health and life insurance implications, it is ideally recommended that patients meet with a genetics counselor before genetic testing.

Although surgical resection typically is the optimal therapy for these tumors, efficacious treatment for metastatic disease is suboptimal, consisting of ¹³¹I-MIBG (FDA approved), chemotherapy, targeted therapy, and potentially Lu-177 DOTATATE (currently in trial), which is discussed in part 2 of this review. By understanding the genetic background of these tumors, both germline and somatic, personalized targeting of these pathways should be possible in the future. In addition, germline testing allows the surgeon and clinician to personalize surgical approaches and determine the extent of adrenalectomy.

RADIOLOGIC EVALUATION

In general, the radiologic workup for PPGLs should be performed only after biochemical confirmation of disease. Anatomic imaging with computed tomography (CT), magnetic resonance imaging (MRI), or both is critical for surgical planning and should be performed for every patient. Functional imaging methods, which use radiotracers dependent on catecholamine metabolism and secretion, glucose metabolism, or tumor somatostatin receptor status, have been demonstrated to have variable sensitivities and specificities related to location and extent of disease as well as the genetic status of the patient. Figure 2 shows a patient with a pheochromocytoma who underwent anatomic and functional imaging.

FIG. 2.

A patient with a 3.34-cm right paraganglioma shown by a computed tomography (CT) axial slice and b CT coronal slice. The patient underwent a c 68-gallium dotatate scan, which showed high avidity

ANATOMIC IMAGING

Often, CT is the first imaging performed for patients with PPGLs, and in the setting of a seemingly sporadic small (< 3 cm) tumor confined to the adrenal may be the only imaging required.⁶³ If adrenal protocol CT is obtained, unlike lipid-rich adenomas, pheochromocytomas will measure more than 10 Hounsfield on non-contrasted images and have marked enhancement on arterial phase images as well as delayed venous washout.^64,65 The patterns of enhancement may vary depending on the size of the lesion and the presence of intra-tumor hemorrhage or necrosis. The imaging characteristics of paragangliomas are similar to those of pheochromocytomas, commonly identified as a hypervascular, para-aortic mass. A finding of bilateral adrenal or extra-adrenal lesions on CT should raise concern for a hereditary syndrome.

For PPGLs, MRI is not as commonly used. Typically, an MRI shows increased signal intensity on T2-weighted imaging (light bulb sign), and as with CT, variable patterns of post-contrast enhancement. Unlike lipid-rich adenomas, no signal dropout is observed on chemical shift imaging.⁶⁶ With PGLs, a “salt and pepper” appearance may be described on T1- and T2-weighted images secondary to areas of hyperintense foci (slow flow or hemorrhage) interspersed with areas of signal void (high-velocity flow through serpiginous vessels).⁶⁷

For head and neck PGLs, a combination of both CT and MRI techniques may be useful. Contrast-enhanced three-dimensional magnetic resonance angiography has been reported to improve tumor detection and differentiation from other neoplasms such as schwannoma, plasmacytoma, meningioma, and vascular malformations,⁶⁸ although CT may permit better evaluation of temporal bone extension at the jugular foramen and hypotympanum.^66,69

FUNCTIONAL IMAGING

Historically, ¹²³I-metaiodobenzylguanidine (MIBG) has been the primary functional imaging method for patients with PPGLs. As a guanethidine precursor, MIBG is taken up by presynaptic adrenergic neural cells after intravenous administration. As reported, ¹²³I-MIBG has a sensitivity of nearly 90% and specificity of 70–100% for isolated pheochromocytomas.^70,71 However, its sensitivity in the detection of extra-adrenal, metastatic, and recurrent PPGLs generally is low^70–72 and it has been largely replaced by newer techniques. Currently, ²³I-MIBG is most commonly indicated for the pre-therapy evaluation of patients with metastatic PPGLs who may be candidates for ¹³¹I-MIBG internal radiotherapy.^64,73 The routine use of MIBG scanning is not recommended because it can be misleading as often as it is helpful.⁷⁴ It still may be useful in highly selected cases such as for patients with negative genetic screens and those with bilateral adrenal lesions, both of which are possibly pheochromocytomas based on CT and/or MRI findings. However, this is an uncommon scenario, found in only 1 of 340 patients reported by Rao et al.⁷⁴ Although physiologic uptake is expected in the salivary glands, heart, liver, spleen, and urinary collecting system, it is important to remember that patients undergoing ¹²³I-MIBG need to be pretreated with supersaturated potassium iodide solution to prevent uptake by the thyroid.

Positron emission tomography (PET)/CT using a variety of radiotracers has been evaluated in patients with PPGLs. In a cohort of patients at the National Institutes of Health (NIH), Timmers et al.⁷² compared ¹⁸F-3,4-dihydroxyphenylalanine (¹⁸F-DOPA), ¹⁸F-dopamine (¹⁸F-FDA) PET, 18F-fluordeoxyglucose (¹⁸F-FDG), and ¹²³I-MIBG for the detection of tumors in patients with localized, metastatic, and hereditary PPGLs. They identified similar sensitivities (on the order of 80%) among these techniques for patients with localized PPGLs, but found that ¹⁸F-FDA was superior to ¹⁸F-DOPA and ¹²³I-MIBG in localizing metastatic disease. Notably, at this writing, ¹⁸F-FDA is available only at the NIH. For patients with SDHB mutations, ¹⁸F-FDG PET/CT demonstrated the highest sensitivity in detecting metastases.

Because ¹⁸F-FDG is dependent on glucose uptake and metabolism, the authors proposed that this finding may be explained by SDHB-associated alteration in oxygen metabolism resulting in increased glycolysis and intracellular glucose requirements. Subsequent work by this group and others has further illustrated the existence of radiographic genotype–phenotype correlations in PPGL patients.^75,76 Specifically, a higher degree of ¹⁸F-FDG uptake is observed in SDHx- and VHL-associated PPGLs than in MEN2- or NF1-related tumors. These findings correlate with well-described mutational and pathophysiologic clusters (clusters 1 and 2, as previously described) of PPGLs into pseudohypoxia-driven (SDHx and VHL) and kinase-signaling (MEN2 and NF1) subtypes.⁷⁷ Whereas ¹⁸F-FDG PET/CT has a high sensitivity for SDHx and VHL (pseudohypoxia cluster)-associated tumors, ¹⁸F-DOPA PET/CT appears to have improved performance in sporadic as well as in MEN2 and NF1 (kinase signaling cluster)-related PPGLs^72,78 and is the more appropriate functional imaging choice for these patients. Furthermore, ¹⁸F-DOPA PET/CT is the preferred functional method for non-SDHx head and neck PGL.^78,79

Like many other neuroendocrine neoplasms, PPGLs express somatostatin receptors that can be exploited for tumor detection. Although ¹¹¹In-pentetreotide (octreoscan) currently has a very limited, if any, role in the imaging of these tumors, a growing body of literature has consistently demonstrated the superiority of (⁶⁸Ga)-DOTATATE PET/CT in the detection of PPGLs compared with other functional imaging methods.^80–84 Given these findings as well as its growing availability within the United States, future recommendations are likely to incorporate (⁶⁸Ga)-DOTATATE PET/CT as the primary functional imaging technique for PPGLs.

CONCLUSION

The PPGLs are rare neuroendocrine tumors with a variable presentation that require specialized management and treatment by experienced and expert endocrine surgeons, endocrinologists, and anesthesiologists. A biochemical workup is required for any patient suspected of PPGL. The genetic etiology of PPGLs has a strong impact on subsequent management and operative approach. Once the diagnosis has been confirmed, a radiologic workup is initiated to identify the PPGL, although a large number of PPGLs currently are being discovered incidentally. In the second part of this review, the perioperative management, surgical approach, pathologic features of malignancy, optimal surveillance, and management of advanced disease are discussed.