Diagnosis and management of pheochromocytoma.

Current Problems in Surgery 51 (2014) 151–187

Contents lists available at ScienceDirect

Current Problems in Surgery journal homepage: www.elsevier.com/locate/cpsurg

Diagnosis and management of pheochromocytoma Anatomy and histology Tumors that that secrete excessive levels of catecholamines, commonly termed “pheochromocytomas,” can arise from the adrenal gland (pheochromocytomas [PCCs]) or from the sympathetic ganglia (paragangliomas [PGLs] or extra-adrenal PCCs). The adrenal glands, also known as the suprarenal glands, are located in the retroperitoneum, superomedial to the kidneys and high up under the costal margin adjacent to the diaphragm. Histologically, the adrenal glands consist of an outer cortex and inner medulla and secrete hormones essential for normal human physiologic function. Each of the adrenal glands, in their normal size and configuration, measure approximately 3-5 cm in length, 4-6 mm in thickness, and weigh approximately 4-5 g. They are closely approximated to the superomedial aspect of the kidneys and are surrounded by a fibrous capsule of connective tissue (Gerota fascia of the kidney) outside of which is loose connective tissue and abundant perinephric and retroperitoneal fat.1 The adrenal glands are clearly distinguished from the surrounding fat by their bright yellow color and more nodular and fibrous consistency. The bright yellow color is the adrenal cortical tissue. The inner medulla, only apparent with adrenal sectioning after removal, is gray-brown in color. Despite the distinct color and appearance of the adrenal cortex, the retroperitoneal location and covering of fat and connective tissue can obscure the gland. A significant amount of dissection in the retroperitoneal and perirenal fat is often required to locate the adrenal glands during surgery. The adrenal glands are composed of 2 discrete and separate anatomical, embryologic, and functional regions: the adrenal cortex and the adrenal medulla. The outer layer, or the adrenal cortex, arises from the mesoderm during embryologic development and accounts for the majority of the gland substance. The cortex has 3 separate layers or zones, and each secretes a different set of hormones. The outermost layer is the zona glomerulosa and secretes the mineralocorticoid known as aldosterone. The primary function of aldosterone is to increase renal sodium reabsorption and potassium excretion.2 Tumors from this adrenal cortical layer that overproduce aldosterone cause a clinical syndrome termed “Conn syndrome,” and patients frequently present with hypertension and hypokalemia. The middle layer and inner regions of the cortex, the zona fasciculata and the zona reticularis, secrete glucocorticoids (cortisol) and androgens, respectively. Hormonally active tumors from these regions can cause Cushing syndrome (excess cortisol) or a virilizing syndrome (excess androgens). The innermost region of the adrenal gland is the medulla, which is derived from the same neural crest cells that comprise the sympathetic ganglia. The adrenal medulla is innervated by preganglionic fibers of the 0011-3840/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1067/j.cpsurg.2013.12.001

152

R. Hodin et al. / Current Problems in Surgery 51 (2014) 151–187

sympathetic nervous system, and both the adrenal medulla and the sympathetic ganglia give rise to the tumors that are known as PCCs. The adrenal medulla synthesizes catecholamines from the amino acid tyrosine, a process modulated by the enzyme phenylethanolamine N-methyltransferase (PNMT).3 Tumors that are derived from the adrenal cortex often have a different gross appearance compared with that of the medulla-derived PCCs, and this may be apparent during surgical resection. If sectioned after surgical removal, the cortical tumors tend to maintain the bright yellow color of the normal cortex, whereas PCCs appear more grayish brown. The adrenal glands have an abundant blood supply and hence are a common site for tumor metastases. They receive their arterial blood supply from 3 main sources: the inferior phrenic artery, the aorta, and the renal artery. The superior adrenal arteries originate from the inferior phrenic arteries, which are located superior to the adrenal gland. Each inferior phrenic artery gives off a series of branches to the ipsilateral adrenal gland and then supplies the diaphragm. The middle adrenal artery originates from the aorta, and the inferior adrenal arteries originate from the renal artery on each side. These 3 arteries provide several subsegmental branches that further divide into smaller vessels, such that at surgical resection, 3 discrete arteries supplying the adrenals are not typically identified. The arteries form a plexus within the gland and eventually coalesce into a single draining vein that requires ligation. Additional smaller accessory veins follow the anatomical course of the subsegmental arteries. The specific anatomical relationships of the right and left adrenal glands are different. An understanding of adrenal anatomy and the differences in the relationships and blood supply of the right- and left-sided glands is essential when planning surgical resection. The right adrenal gland is shaped like a pyramid and is located directly inferior to the medial portion of the right diaphragm and posteromedial to the liver. It is common to note fibrous attachments between the adrenal glands and the liver. The lateral and inferior edges are adjacent to the right kidney. The inferior vena cava (IVC) is just medial to the kidney, and the right adrenal vein drains directly into the vena cava and is typically short, measuring approximately 5-6 mm. Dissection and control of the right adrenal vein during adrenalectomy can be challenging due to the relatively short length and its direct connection to the IVC. The right adrenal gland can also extend posteriorly behind the IVC. The left adrenal gland is located between the kidney and the aorta, near the tail of the pancreas and the splenic artery. It lies at the superomedial aspect of the kidney and extends alongside its medial edge. It is adjacent to and usually directly posterior to the tail of the pancreas, although its exact relationship with the pancreas can vary. The gland lies just inferior to the diaphragm and is often closely associated with the left diaphragmatic crus. The spleen is anterior and superior to the left adrenal gland, and the left kidney is directly lateral. The aorta is just medial, and the renal vein and artery are inferior. The left adrenal vein is significantly longer than the right and usually measures approximately 30 mm, draining into the left renal vein. During surgery, it is most often located at the inferomedial aspect of the adrenal gland, and its dissection is significantly less risky than that of the right because of its longer length and greater distance from the IVC. Despite the known anatomical relationships of the adrenal glands as just described, the exact location of the glands and their associated tumors can be quite variable and detailed preoperative imaging, as described in a later section, is invaluable in determining the specific anatomical relationship to surrounding intra-abdominal and retroperitoneal structures.4 PCCs located outside the adrenal gland arise from the sympathetic ganglia, which are present along the entire sympathetic chain. These are referred to as either “PGLs” or “extra-adrenal PCCs.” Extra-adrenal PCCs account for approximately 10% of all PCCs in adults and a slightly larger percentage in children. Although the sympathetic chain extends throughout the body, from the skull base to the bladder, most extra-adrenal PCCs are located in the abdomen. The most common location is at the organ of Zuckerkandl, which is just above the aortic bifurcation near the origin of the inferior mesenteric artery. The next most common location for extraadrenal PCCs is at the junction of the left renal vein and vena cava. Overall, between the adrenal and the extra-adrenal locations, most (4 95%) PCCs are located in the abdomen. Less common locations for these lesions include the neck, chest, and urinary bladder.


153

TABLE 1 Common symptoms and signs of pheochromocytoma. Symptoms Headache Flushing Diaphoresis Palpitations Anxiety Chest pain Dyspnea Abdominal pain Diarrhea Blurred vision Dizziness Weakness and fatigue Anorexia and weight loss Polyuria and polydipsia Signs Hypertension Tachycardia Orthostatic hypotension Heart failure

Clinical presentation The clinical presentation of PCC can be highly variable and ranges from severe and dramatic symptoms to have minimal or no symptoms whatsoever in some patients. It is an uncommon tumor, with an estimated annual incidence of approximately 0.8 per 100,000 person years or an overall estimated incidence of 2-8 per million.5 Despite its known association with hypertension, most patients with elevated blood pressure do not have a PCC. The average age of presentation for a patient with PCC is approximately 40-50 years, and it is equally distributed between men and women.6 Generally speaking, PCCs can manifest in 3 different clinical scenarios: (1) patients or their physicians note the symptoms or signs of catecholamine excess; (2) an adrenal tumor is noted incidentally on a radiologic study in an asymptomatic patient or one with minimal symptoms or signs of excess catecholamines; or (3) a specific evaluation for a PCC is pursued owing to a significant family history of PCC or endocrine tumor syndrome (ie, multiple endocrine neoplasia [MEN]). Regarding symptoms of catecholamine excess, patients with PCCs can present with a variety of symptoms owing to the elevated levels of circulating catecholamines (Table 1). The catecholamines typically include epinephrine, norepinephrine, and dopamine. As described in the section on physiology and pathophysiology, PCCs in different patients can secrete variable levels of each of the different types of catecholamines and therefore present with a different clinical picture. The classic constellation of signs and symptoms in patients with a PCC consists of paroxysmal hypertension with episodes of severe headache, diaphoresis, and flushing (Table 2).7,8 Although this clinical presentation is often thought of as common in patients with a PCC, this constellation of symptoms is noted in only 40% of patients,6 and therefore more than half the TABLE 2 Classic clinical presentation in patients with pheochromocytoma, present in approximately 40% of patients. Episodic or paroxysmal hypertension Headache Diaphoresis Flushing

154


patients do not present with this more obvious clinical picture. Patients may be asymptomatic, or there may be subtle symptomatic episodes of palpitations and anxiety. The presenting symptom complex may be even vaguer, such as dizziness, dyspnea, and chest pain. Hypertension, sustained or episodic, is the most common clinical sign of PCC and is present in most patients.9 Patients can have sustained hypertension alone or in combination with more severe episodes of elevated blood pressure. They also can present with paroxysmal episodes of hypertension with normal blood pressures in between.10 Despite the frequent presence of hypertension in patients with PCCs, these tumors are relatively rare and they are diagnosed in less than 1% of patients with hypertension.11 As such, patients with elevated blood pressure should not be routinely screened for PCC in the absence of other clinical signs or symptoms. Several studies have attempted to delineate the frequency of the various symptoms noted in patients with PCCs. Headache is a common clinical symptom, present in up to 90% of symptomatic patients, and paroxysmal sweating is seen in 70%.12 Other symptoms can include visual disturbances, polyuria and polydipsia, anorexia and weight loss, and psychiatric disorders including severe anxiety. Patients may experience orthostatic hypotension resulting from a contracted plasma volume. Disturbances in carbohydrate metabolism can also occur, and they manifest as new-onset type 2 diabetes, abnormal fasting glucose levels, and insulin resistance.13 Cardiac abnormalities are often noted in patients with PCC at the time of diagnosis. The effects of hypertension and coronary artery vasoconstriction may result in cardiomyopathy or even a form of toxic myocarditis. Fortunately, these serious cardiac effects are almost always reversible after curative surgery. Rarely, patients with a PCC can present in fulminant hypertensive crisis with cardiovascular collapse and multisystem organ failure.14 Finally, unexpected instability or elevation in blood pressure during procedures, anesthesia, or surgery should lead one to suspect and rule out a PCC. Despite the fact that the symptom complexes and clinical scenarios described previously should lead clinicians to suspect a PCC, this is not always the case. Elevated blood pressure is often attributed to essential hypertension. Classic symptoms of PCC can be varied, and symptomatic episodes are often labeled as “anxiety attacks.” Palpitations are often assumed to be of primary cardiac origin. Although PCCs are rare, an astute and suspecting clinician should keep this potentially life-threatening diagnosis in mind. It is sometimes years before patients with PCC symptoms are appropriately evaluated, diagnosed, and treated. Table 3 provides a list of scenarios that should lead a clinician to suspect a PCC and consider a biochemical workup to confirm or rule out the diagnosis. PCCs can also become clinically evident when an adrenal mass is noted on a radiologic study done for an unrelated reason. Such patients may be asymptomatic; may have had subtle signs or symptoms, or both, but not have presented them; or may have been appropriately evaluated for a PCC. In the past, it was far more common for patients with a PCC to present with clinical signs and symptoms of catecholamine excess. In this current era of the widespread use of computed tomography (CT), magnetic resonance imaging (MRI), and other imaging studies, the detection of incidental adrenal masses is becoming more common and is estimated to account for the presentation of up to 40% of patients with PCCs.14,15 An adrenal “incidentaloma” is defined as an adrenal tumor noted on an imaging study performed for a reason unrelated to adrenal disease, and the estimated prevalence of this finding on CT scans is as high as 3%-5%.16,17 As outlined in the 2002 NIH consensus conference guidelines for the management of incidental adrenal masses, it is recommended that all patients with incidentally discovered adrenal tumors undergo full biochemical screening for the potential conditions associated with hormonal excess, including Conn syndrome, Cushing syndrome, and PCC.16 The typical radiologic appearance of a PCC is discussed in detail elsewhere; but generally speaking, PCCs tend to be large (4 3 cm) and have a heterogeneous appearance on CT scan. On MRI studies, they are typically bright on T2 imaging. Regardless of the appearance of an adrenal tumor on radiologic studies, the presence of any adrenal mass or tumor should prompt a full biochemical workup for hormonal productivity, including an evaluation for a PCC. The recommended biochemical testing to screen for a PCC in patients with an incidentally noted adrenal tumor is discussed in a later section.


155

TABLE 3 When to suspect a pheochromocytoma. Biochemical evaluation clearly indicated Resistant hypertension requiring multiple antihypertensive medications Hyperadrenergic episodes (anxiety or palpitations or flushing diaphoresis) Incidental adrenal tumor in an asymptomatic patient Family history of pheochromocytoma or familial predisposing syndrome

Biochemical evaluation should be strongly considered Paroxysmal or new-onset hypertension Unexplained anxiety attacks Idiopathic cardiomyopathy Hypertension or cardiomyopathy in a young patient (o 25 y) Severe hypertension or pressor response during anesthesia or sedation (ie, for colonoscopy)

A final clinical scenario for the presentation of patients with PCCs occurs when a family or patient is thought to be at high risk of developing a PCC based on a genetic predisposition. Although a majority of these tumors are sporadic, approximately 10%-20% of them are associated with a specific genetic syndrome. The 4 most common genetic disorders associated with PCCs are multiple endocrine neoplasia 2 (MEN2), von Hippel-Lindau (VHL) syndrome, neurofibromatosis type 1 (NF1), and familial PGL (Table 4).18 Patients with a catecholamine-secreting tumor associated with a genetic syndrome are more likely to have bilateral adrenal tumors or a tumor in an extra-adrenal location. Compared with patients with sporadic tumors, patients with genetically associated tumors are typically younger at the time of presentation and are more likely to be asymptomatic when diagnosed.228 This likely reflects the higher index of suspicion in patients with a family history and the subsequent biochemical or genetic screening tests, leading to an earlier diagnosis.19 All 4 of these genetic syndromes are inherited in an autosomal dominant pattern. PCC is seen in up to 50% of patients with MEN2, which is caused by an abnormality in the RET protooncogene and is characterized by medullary thyroid cancer, PCC, and parathyroid hyperplasia.20 VHL syndrome involves a mutation in a tumor suppressor gene, leading to PCCs, PGLs, cranial hemangioblastomas, renal cell carcinoma, and pancreatic tumors.21 Approximately 10%-20% of patients with VHL develop a PCC. There is an increased risk of developing a PCC with NF1. This autosomal dominant genetic syndrome is characterized by neurofibromas and multiple café au lait spots, as well as iris hamartomas (Lisch nodules) and central nervous system gliomas. Approximately 2% of patients with NF1 develop PCCs.22 Familial PGL refers to a syndrome in which patients are predisposed to developing PGLs throughout the body, which may or may not produce catecholamines.23 This genetic syndrome, also autosomal dominant, is most frequently due to a mutation in one of the succinate dehydrogenase (SDH) subunit genes (succinate dehydrogenase-B [SDHB]).24 Studies have investigated the variation in clinical presentation in patients with PCC and one of the predisposing genetic syndromes. In a study, patients with a PCC and MEN2 were compared with those with VHL.27 Interestingly, patients with a PCC and MEN2 were more symptomatic and had a higher incidence of paroxysmal hypertension compared with that of the patients with VHL PCC. The patients with MEN2 had higher levels of epinephrine metabolites (metanephrines) compared with the patients with VHL who had higher norepinephrine metabolite (normetanephrine) levels. This is likely explained by variation in levels of tyrosine TABLE 4 Genetic syndromes associated with pheochromocytoma. MEN2 (multiple endocrine neoplasia type 2) VHL (von Hippel-Lindau syndrome) NF1 (neurofibromatosis type 1) Familial paraganglioma (SDHB mutation)

156


hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and PNMT (the enzyme that converts norepinephrine to epinephrine). Patients with a known family history or one suggestive of one of the aforementioned genetic syndromes should undergo biochemical testing for a PCC when clinically indicated. This is particularly important to consider when a patient is planning a surgical or diagnostic testing procedure that may put them at risk for a hypertensive crisis. Conversely, genetic testing should be considered for certain patients with PCC, such as those with PGLs (extra-adrenal PCC), bilateral adrenal PCCs, or a family history of PCC.25 It is also advisable to consider genetic testing for young patients (age o35 years) who present with what appears to be a sporadic PCC. The genetic syndromes associated with PCCs are discussed in further detail in the section Hereditary syndromes. In summary, patients with PCC can present with a broad range of symptoms and can be asymptomatic at the time of presentation. An astute clinician should keep this diagnosis in mind when evaluating patients with subtle symptoms of catecholamine excess. Up to 20% of patients with PCC have a genetic syndrome and should undergo testing in the setting of experienced genetic counseling.

Biochemical testing The biochemical testing for PCC requires confirmation of inappropriate catecholamine production. However, catecholamine release is extremely variable as some PCCs have little to no secretory activity and some only secrete dopamine. In general, there are 3 secretory and 1 nonsecretory phenotype of PCCs. The norepinephrine phenotype lacks the enzyme PNMT that converts norepinephrine to epinephrine. This phenotype is most commonly associated with extra-adrenal PCCs and VHL mutations.26 Another phenotype is a predominant epinephrine phenotype that has increased PNMT activity and is most commonly associated with RET, NF1, and TMEM127 gene mutations. This phenotype tends to have higher intratumoral catecholamine concentrations but lower serum catecholamine concentrations than the norepinephrine phenotype.27 The last secretory phenotype is a dopamine-secreting PCC. Interestingly, the dopamine phenotype is rare, but it typically coreleases norepinephrine and is associated with SDHB and SDHD gene mutations. Exclusive release of dopamine only is extremely rare because of a lack of dopamine β-hydroxylase, which converts dopamine to norepinephrine. This phenotype can be detected by measuring serum levels of dopamine or methoxytyramine, the O-methylated metabolite of dopamine. Urinary dopamine levels are a measure of dopamine production in the renal tubules and are not useful for the detection of dopamine-secreting PCCs. Another alternative is to measure urinary or plasma 3-methoxytyramine levels, the O-methylated metabolite of dopamine. In general, dopamine release is associated with a more undifferentiated tumor and is a risk factor for malignancy.28 Finally, the nonsecretory phenotype is very rare and may also be associated with SDHB mutations. Presumably these tumors either lack TH or somehow metabolize catecholamines into inactive compounds.29 Plasma measurements of norepinephrine and epinephrine levels are a reflection of tumoral section and therefore highly variable. However, the O-methylated metabolites (normetanephrine and metanephrine) are produced continuously because of leakage from storage vesicles. Therefore, separate or fractionated measurements of normetanephrine and metanephrine levels in the urine or plasma are the best indication of the relative amounts of norepinephrine or epinephrine, or both, in the tumor tissue. From a practical clinical standpoint, screening for PCC should include urinary and plasma measurements of catecholamines and fractionated metabolites. The diagnostic sensitivity of plasma catecholamine levels is more than 96%, with a specificity of more than 85%.30 Urinary catecholamine measurements have a similar sensitivity; however, the specificity is as low as 45%.31,32 More recent research suggests that measurements of plasma free metanephrine levels or urinary fractionated metanephrine levels are the most sensitive tests to exclude PCC.30


157

In general, normal results rule out a PCC and an elevation of more than 4 times the reference interval is diagnostic of PCC.33 It is important to remember that biochemical test interpretation is not positive or negative, but rather, it provides a probability of having a PCC. Increasing age, male sex, and body mass index greater than 30 have been associated with higher baseline levels of catecholamine metabolites.34 Some investigators have advocated the use of an age-adjusted score ( 4.188 þ 0.07 [age] þ 4.516 [metanephrine] þ 3.129 [normetanephrine]), but this practice is not common.35 If one cannot distinguish a true positive from a false positive (ie, only slight elevation in catecholamine or catecholamine-metabolite levels), repeat measurements in a different laboratory or with clonidine suppression testing may be helpful. Urinary samples are relatively easy to collect. One should measure urinary creatinine level with any urine catecholamine or metabolite measurement to ensure the patient collected their urine for the correct amount of time. On the contrary, plasma samples require more sophisticated collection practices. Plasma samples should be taken from patients who are positioned supine for at least 20 minutes before collection. Ideally, the patients should fast and abstain from any food or drinks that contain caffeine for at least 24 hours before collection to avoid false-positive results. In addition, patients should not take any medications containing tricyclic antidepressants, phenoxybenzamine, or acetaminophen for at least 5 days before plasma testing as these medications have also been associated with false-positive results.33 Finally, samples should be stored at 41C immediately after collection because the levels of plasma free metanephrines may decrease at higher temperatures.36 Total catecholamine and metabolite measurements can be performed using 1 of 3 different methods. Liquid chromatography with electrochemical detection is highly accurate and precise but requires high technical skill.37 Immunoassays are a less expensive alternative but may have calibration problems that can affect accuracy and precision.38,39 Finally, liquid chromatography with tandem mass spectrometry is probably the most accurate and precise method, but it is expensive and requires more technical skill.40 Patients with high clinical suspicion for PCC, but equivocal biochemical testing, may benefit from either provocative glucagon testing or the clonidine suppression test. The glucagon test is performed by giving the patient 1 mg of intravenous glucagon and then measuring serum catecholamine levels. Unfortunately, the sensitivity of the glucagon test is too low to reliably exclude PCC and may trigger a hypertensive crisis if the patient actually has a PCC.41 Therefore, the use of glucagon in the biochemical evaluation of patients with PCC has been largely abandoned. However, the clonidine suppression test is still useful for patients with unclear biochemical screening results. This test requires the oral administration of 300 mg of clonidine to suppress catecholamine release from sympathetic nerves. Catecholamine production by intraadrenal or extra-adrenal PCC is not affected by clonidine. Plasma catecholamine or metanephrine levels are evaluated before administration of clonidine and then again after 180 minutes. Absence of suppression of plasma norepinephrine or normetanephrine strongly suggests the presence of a PCC, whereas a decrease in plasma normetanephrine levels to normal ranges after clonidine administration supports the absence of a PCC.42,43

Imaging Although radiologic imaging cannot definitively diagnose a PCC, it plays a key role in each of the following: (1) evaluation of location and extent of primary sporadic (nonhereditary) PCC, (2) evaluation of location and extent of disease associated with hereditary syndromes, (3) identification and surveillance of metastatic or metachronous disease, and (4) management of the incidental adrenal nodule. In general, the preferred imaging technique varies based on whether the diagnosis of PCC has been made (ie, clinical or serologic diagnosis vs incidental finding), whether the PCC is functional, or whether there is a suspicion of metastatic or multicentric disease (eg, SDHB mutant vs VHL-related tumors). Functional imaging, most commonly with metaiodobenzylguanidine (MIBG), somatostatin receptor scintigraphy (SRS, Octreoscan), and 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET), can localize

158


secretory tumors and metastatic disease while features including location (eg, para-aortic), vascularity, and washout characteristics can infer a nonsecreting PCC on cross-sectional anatomical imaging. Location and extent of primary sporadic PCC First-line modalities for tumor localization are usually CT or MRI. Additional benefits of these modalities include evaluation of resectability and evidence of local metastases. Both are widely available and less expensive than functional whole-body imaging studies. In patients presenting clinically with a positive result on screening serum or urine test, abdominal imaging with CT or MRI should be performed. Furthermore, if the tumor is primarily secreting epinephrine, an adrenal mass is much more likely; norepinephrine-secreting tumors can be either adrenal or extra-adrenal (most frequently abdominal).44 In sporadic PCCs, both tests identify tumors in patients with disease with high sensitivity because of moderate specificity secondary to the high prevalence of incidental adrenal nodules in the general population ( 5%).45-47 Given the ability of CT to discern tumors larger than 1 cm and that most PCCs are larger than 3 cm at presentation, CT is highly sensitive at detecting PCC (85%-94%).48 Although there are no definitive imaging characteristics to differentiate malignant vs benign adrenal tumors, the increased fat content in benign adenomatous tumors allows for high specificity. Using a threshold of 10 Hounsfield units (HU) on noncontrast CT, this modality has a sensitivity of 71% and specificity of 98% in differentiating benign from malignant tumors.49 Likewise, an absolute CT-washout value of 52% at 10-minute delay has a 100% sensitivity and 98% specificity for diagnosing benign adenomas.50 Unfortunately, PCCs can have great variance in attenuation values both in noncontrast and washout protocols. Although variable, characteristic CT findings include a solid mass with intense contrast uptake (HU 40-50) and delayed washout with necrosis and calcifications commonly present (Fig 1).48,51-53 PCCs can occasionally be cystic, contain fat (decreasing attenuation), or have calcifications.54 One should be highly suspicious of a PCC with very high attenuation (ie, 4 150 HU).55 With CT, there is some exposure to radiation and it is contraindicated in patients with contrast allergies or renal dysfunction, but there is little risk of hypertensive crisis if low-osmolar contrast is used.55 MRI has the benefit of no radiation or IV contrast; however, MRI is more expensive than CT, is more time consuming, and maintains inferior resolution. Classically, PCCs are characterized by

Fig. 1. Abdominal CT image showing intense uptake of contrast in a 4.7-cm pheochromocytoma in an SDHD-mutant tumor. (Color version of figure is available online.)


159

increased T2-weighted uptake on MR—the “light bulb sign”—in up to 70% of PCCs.56,57 PCCs are usually isointense on T1-weighted images but more intense on T2-weighted series compared with that of the liver and muscle (Fig 2).48 Classic MRI of PGLs shows intermediate signal on T1weighted images and a hypervascular, “salt-and-pepper” appearance on T2 images.58 owing to the high prevalence of adenomas (low specificity), confirmatory testing with functional imaging has been advocated by some experts.48 MIBG, SRS (Octreoscan), and 18F-FDG-PET or 18-FDA-PET are the other commonly used whole-body screening modalities that reflect functionality. These modalities are commonly used in the setting of biochemically confirmed disease with negative or inconclusive results on crosssectional imaging (ie, on CT or MRI or both) or when metastatic or metachronous lesions are suspected.59 For primary tumor localization, PET/CT (58%-77%) and MIBG (75%-90%) have similar sensitivity for both benign and malignant PCCs, both of which are inferior to CT or MRI, but both have improved specificity (83%-100%).48,60,61 Each of these “functional” techniques has advantages and disadvantages.62,63 The choice among the 3 is dependent on the user, patient, and institution. MIBG has a similar structure to norepinephrine and is taken up specifically in adrenergic tissue with I-123 or I-131 used as a radiotracer.59 Moreover, potassium iodide drops should be considered to block thyroid uptake before and for a week after scanning and medications that compete with the MIBG uptake (eg, labetalol) must be stopped for a number of days (1-3 days depending on the drug-specific pharmacokinetics) before imaging.64 In comparison with other modalities, MIBG is not as sensitive in detecting extra-adrenal PGLs and dopamine-secreting tumors (29%-44%).51,59,65,66 Most argue that whole-body imaging is unnecessary in patients with sporadic solitary PCCs found on CT or MRI but should be performed in patients with a higher suspicion of malignant (ie, large tumors 410 cm, young age at presentation) or multiple tumors (ie, hereditary disease).67 It should be noted that MIBG tracer can be taken up by normal adrenal medullary tissue. SRS is effective because of the high density of somatostatin receptors on the cell surface of PCCs. FDG-PET and FDA-PET are highly sensitive in detecting PCCs, and they are as specific as MIBG and better than MIBG or CT or MRI in detecting metastatic disease.62,68 FDG-PET appears to be most sensitive for the detection of metastatic disease. In a retrospective study of 30 patients with metastatic SDHB þ PGLs, SRS was able to detect liver metastases that were missed by the other modalities including PET. In this report, FDG-PET was 100% sensitive for detection of metastatic disease in comparison with 80% for MIBG and 88% FDA-PET.68 A large prospective study compared modalities among a cohort of patients with suspected PCC-PGL: 60 patients with solitary PCC, 95 with metastatic PCC-PGL, and 61 “normals.”62 All patients in the

Fig. 2. Classic “light bulb” sign of a pheochromocytoma on T2-weighted MR image.

160


study underwent CT or MRI, FDG-PET/CT, and MIBG SPECT/CT studies. PET/CT had the greatest sensitivity (89%), followed by CT or MRI (74%) and MIBG (50%) for metastatic disease and PET/CT (90%) and MIBG (92%) had similar specificity among the “normal” subgroup. It should be emphasized that image-guided or open biopsy of an adrenal mass is contraindicated unless PCC has been ruled out through biochemical testing. Image-guided fine-needle biopsy of PCCs has a prohibitively high rate of complications including severe hypertension, hematoma, inadequate biopsy, and possibly increased difficulty in dissecting the operative field.69 Location and extent of disease associated with hereditary syndromes In patients with affected family members, known mutations, or young age at presentation (ie, o40 years), the approach to imaging (and surgery) should be geared toward the following: (1) the characteristic phenotype of the specific mutation or (2) if the mutation is unknown, whole-body imaging to assess for multicentric (eg, MEN2) or metastatic disease (eg, in SDHB). For instance, patients with MEN2 syndrome, CT may miss up to 25% of the tumors.70 Patients with SDHB mutations have a higher likelihood of malignant tumors and metastatic disease.71,72 Therefore, functional whole-body imaging is prudent in SDH (SDHx) mutant patients and in particular SDHB mutations. A prospective, multi-institutional study of more than 200 SDHx carriers comparing CT or MRI, SRS, and MIBG concluded that the imaging evaluation should include CT of the thorax and abdomen, head and neck magnetic angiography, and SRS.73 I-123 MIBG is less sensitive (higher false-negative rate) in PGLs (and in particular dopamine-producing tumors) compared with adrenal PCC.62 Moreover, MIBG sensitivity is lower in patients with SDHB mutations in whom malignancy risk is higher.74 Therefore, if there is a known SDHB mutation, SRS and FDG-PET are preferred.68 A study compared the sensitivity of PET/CT directly with that of MIBG: PET showed better sensitivity among patients with SDHx mutations compared with sensitivity in those without (92% vs 67%) mutations whereas MIBG showed the inverse (45% sensitivity in SDHx þ vs 66% in SDHx- patients). Moreover, MIBG is less sensitive in localizing PCC-PGL in patients with MEN2 compared with those with sporadic tumors.61 SDHx and VHL-related tumors have greater avidity on FDG-PET compared with that of MEN2-related tumors.62 Screening for metastatic disease is indicated for all patients with a SDHB germline mutation–related PGL and all dopamine-secreting PCCs-PGLs because of the high frequency of metastases, with PET being the preferred modality. Identification of metastatic or metachronous disease Functional imaging with MIBG, SRS, or PET has the added value of screening for metastatic disease, particularly important in patients with a high prior risk of malignant or bilateral disease. The approach to tumor localization varies between institutions. At some institutions, MIBG is the test of choice for tumor localization when the abdomen or pelvis CT scans have unremarkable findings or in a patient with a known PGL to search for metachronous disease. However, FDGPET has shown superior accuracy in identifying and following sites of metastatic disease.62,68,75 Although SRS is less sensitive than MIBG, it is considered as the optimal functional scan for head and neck PGLs, and it can sometimes identify ectopic PCCs-PGLs missed by other modalities and can be used as a an adjunct in challenging cases.61 The approach to imaging (and surgery) should be geared toward clinical presentation, suspicion of aggressive disease, and characteristics of specific hereditary syndromes. Management of the incidental adrenal nodule It is estimated that 4%-5% of abdominal CT scans performed for other indications reveal an adrenal mass.76,77 In a large series, when discovered incidentally, PCC constituted less than 1% of adrenal tumors.32 In cases of “incidentalomas,” a hypervascular tumor, characteristic location, or


161

T2-avid MRI images can alert clinicians to a possible PGL. As indicated, biopsying any lesion suspicious for PGL before screening for PCC-PGL can result in rare but potentially lethal hypertensive crisis and other complications discussed earlier. Screening of all adrenal masses for urinary or plasma fractionated metanephrines is recommended. Adrenal venous sampling is not useful in the diagnosis and lateralization of PCC given the poor reliability of diagnostic ratios for lateralization.78 In conclusion, localization of PCCs-PGLs is challenging, largely because of the heterogeneity of the tumors and their clinical presentations. Fortunately, there are a number of options for both anatomical and whole-body imaging. Although a matter of debate, most would endorse anatomical imaging (following diagnosis with serum or urine studies) alone for probably sporadic disease without suspicious personal or family history. In the event of unremarkable findings or inconclusive localization with CT or MRI in patients with known personal or family history of hereditary syndromes or with suspicious presentation, functional imaging is essential to rule out multifocal or metastatic disease.

Preoperative preparation Drs César Roux and Charles Mayo first described adrenalectomy for PCC in 1926. However, as of 1940, the mortality rate for adrenalectomy remained very high, at approximately 50%.79 Much progress has been made over the years, such that the mortality rate for an elective adrenalectomy for PCC in a properly prepared patient is now less than 1%.80-84 The dramatic reduction in mortality for adrenalectomy in patients with PCC is largely because of the advances in perioperative care, including preoperative cardiovascular assessment and optimization, normalization of blood pressure, restoration of intravascular fluid volume, intraoperative fluid and blood pressure management, treatment and prevention of arrhythmias, and postoperative care. Preoperative cardiac testing Before undergoing adrenalectomy, patients with a PCC should undergo a standard presurgical evaluation including a thorough history, physical examination, complete blood count, basic metabolic panel, and an electrocardiogram (EKG). The EKG frequently demonstrates repolarization abnormalities, including nonspecific ST-T wave changes, an abnormal R wave, and a prolonged QTc interval, which are owing to the effect of excessive catecholamines on the myocardium. The mechanism for this “toxic” myocarditis is reduced coronary artery blood flow from catecholamine-induced coronary artery vasoconstriction. Cardiac catheterization should be considered for patients with chest pain and EKG changes, prior myocardial infarction, congestive heart failure, or decreased functional status.85 A preoperative echocardiogram may be of value in patients with a significant cardiac history or a new cardiac murmur to measure systolic, diastolic, and valvular function. Results may help to risk stratify patients and may aid in both preoperative counseling and perioperative care. Preoperative cardiac testing most commonly reveals changes consistent with hypertrophic cardiomyopathy and less often more serious dilated cardiomyopathy, which can occur because of long-term exposure to excess catecholamines. Both hypertrophic and dilated cardiomyopathies are reversible with resection of the PCC. Preoperative adrenergic blockade and intravascular volume preparation Although some authors have reported a 0% mortality and morbidity rate without α-blockade,86 it is generally recommended that all patients with a PCC undergo preoperative α-adrenergic blockade. An α-adrenergic blocker should be started at least 2 weeks (if possible) before surgery to help reduce blood pressure lability, intraoperative blood loss, and

162


arrhythmias.86-90 An exception to α-adrenergic blockade may be for patients with a PCC that only secretes dopamine.91 Patients should be instructed to increase oral fluid intake and to check their blood pressure several times a day, with the expectation of postural hypotension. Patients must be cautioned about the side effects of α-adrenergic blockade including fatigue, reflex tachycardia, loose stools, dizziness, somnolence, and nasal congestion. There are several α-blockers that are commonly used in patients with PCC. Phenoxybenzamine (Dibenzyline) has been used since the 1950s and is a long-acting, noncompetitive α-antagonist. Patients are generally initiated on a regimen of 10-mg dose administered twice a day, and the dose is gradually increased by 10 mg every few days. Most patients develop orthostatic hypotension with a total dosage of 40-120 mg/d (1 mg/kg), but dosages up to 240 mg/d may be necessary.88 Dosage increases are made at night to help avoid injuries related to falls and other accidents that may occur as a result of the orthostatic hypotension. Phenoxybenzamine also blocks the α2-receptors on the presynaptic membrane, which can lead to tachycardia secondary to increased norepinephrine release by cardiac sympathetic nerve endings. This side effect can be ameliorated with the concomitant usage of β-blockers after αadrenergic blockade has been established. Another undesirable effect of phenoxybenzamine is that the α-blockade is irreversible and may result in persistent postoperative hypotension. Selective short-acting α-adrenergic blockers, doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin), are competitive α1-receptor antagonists, with little or no effect on presynaptic α2-receptors or β-receptors. When compared with phenoxybenzamine, they have a shorter duration of action, less associated reflex tachycardia, and a lower incidence of postoperative hypotension. Doxazosin has the longest half-life of the selective α-adrenergic blockers, requires only once-a-day dosing, and its effects subside rapidly after surgery. Prys-Roberts and colleagues92 at the Bristol Royal Infirmary published a dosage calculation for doxazosin in patients with a predominantly norepinephrine-secreting PCC using the formula: Doxazosin dosage in milligrams ¼ 1.48 þ (0.00066) (urinary norepinephrine in nmol/24 hours).92 Prazosin and terazosin require more frequent dosing than doxazosin, so incomplete α-adrenergic blockade may occur.87 There are few studies that compare the efficacy of phenoxybenzamine vs that of selective αadrenergic blockers. In a small retrospective study, Zhu and colleagues93 noted that patients who received 4-16 mg of doxazosin for preoperative α-adrenergic blockade experienced higher average intraoperative systolic blood pressures but less fluctuation in arterial pressures than were observed in patients who received phenoxybenzamine. In a similar study by Weingarten and colleagues, the intraoperative and postoperative results of 50 patients with PCCs who were given phenoxybenzamine were compared with those of 37 patients who were given a selective α1-blocker. Patients who received a selective α1-blocker had higher systolic blood pressures and required more intravenous crystalloid and colloid administration than patients who received phenoxybenzamine, but there were no differences in complication rates or length of stay. Of note, patients who received phenoxybenzamine also had greater frequency of postresection hypotension and required larger amounts of phenylephrine postoperatively.94 β-blockers are another commonly used class of medications in patients with PCCs, especially for patients with persistent tachycardia or hypertension after α-blockade therapy. Administration of β-blockers is typically initiated several days before surgery (or even intraoperatively) following α-adrenergic blockade and subsequently titrated to a goal heart rate of approximately 60 beats per minute.95 A common choice is propanolol (Inderal LA), a nonselective β-blocker. β-blockers should not be given before α-adrenergic blockade to avoid unopposed α-adrenergic receptor stimulation, which can cause a hypertensive crisis. β-blockers should be used cautiously in patients with severe catecholamine-related cardiomyopathy to avoid severe or “flash” pulmonary edema. Atenolol or metoprolol, cardioselective β1-blockers, may be used preferentially in these patients. Dihydropyridine calcium channel blockers, amlodipine (Norvasc), nifedipine (Adalat), or nicardipine (Cardene) may also be used as part of the preoperative preparation for patients with PCCs as an adjunct to α-adrenergic blockade or in patients who are intolerant to α-blockers.


163

Calcium channel blockers reduce arterial pressure by blocking norepinephrine-mediated calcium influx into the smooth muscle cells of the vessel wall.87 The advantage of using calcium channel blockers is that they have a shorter half-life than phenoxybenzamine and theoretically there is less postoperative hypotension. Lebuffe and colleagues96 completed a retrospective review of 105 patients with PCCs who were treated with nicardipine (20-60 mg/d divided into 3 dosages) for 3-10 days before surgery and then 20 mg orally 1 hour before surgery, followed by a nicardipine infusion (0.5-2.0 mg/kg/min) in the operating room. Approximately 62% of patients had intraoperative hypertension requiring treatment with other antihypertensive medications and the overall mortality and morbidity rates were 3% and 11%, respectively.96 Preferential use of calcium channel blockers preoperatively may be of more value in normotensive patients who have intermittent paroxysmal hypertensive episodes to avoid the side effects of orthostatic hypotension associated with the α-adrenergic blockers.88 Metyrosine (alpha-methyl-para-tyrosine, Demser) has also been used for preoperative preparation in some patients with PCCs. Metyrosine depletes adrenal catecholamine stores by inhibiting TH, the rate-limiting enzyme in catecholamine synthesis. PCCs have significantly enhanced TH activity compared with that of normal adrenal tissue.97 Some authors advocate using metyrosine in lieu of phenoxybenzamine as a first-line agent for preoperative preparation in patients with PCCs, whereas others have used metyrosine in combination with preoperative α-blockade. In a small retrospective study, Steinsapir and colleagues98 found that the combination of metyrosine with either phenoxybenzamine (n ¼ 16) or prazosin (n ¼ 6) resulted in significantly improved intraoperative hemodynamic control compared with that by phenoxybenzamine or prazosin alone.98 Metyrosine may cause extrapyramidal side effects such as sedation, depression, and galactorrhea. Because of its greater toxicity, including potential negative effects on cardiac function, most experts reserve metyrosine for patients who cannot tolerate α-blockade and β-blockade or those who have hypertension that is refractory to α-adrenergic blockade. Patients with PCC require preoperative intravascular volume resuscitation with a balanced oral electrolyte solution after starting α-blockade therapy. Some clinicians also advocate a highsodium diet ( 45 g/d) and others admit patients with PCCs for a few days before surgery to supplement intravascular volume with isotonic intravenous fluids.95 However, there is little evidence in medical literature to support the efficacy of such interventions. Ideally, a patient should receive enough preoperative volume resuscitation to have a hematocrit value that has been reduced to the normal range before surgery.99 Patients can be given a liter or more of intravenous normal saline in the preoperative holding area immediately before operation. These measures likely help to minimize severe postoperative hypotension following resection of the PCC, but there are no randomized controlled studies to confirm their efficacy. Preoperative warnings or complications Certain foods and beverages that contain tyramine may exacerbate uncontrolled catecholamine release in patients with PCC. Tyramine, a natural byproduct of bacterial fermentation, stimulates the release of 1-norepinephrine from the adrenal medulla, but its exact mechanism is unknown. Tyramine-induced enhancement of catecholamine secretion in patients with a PCC is TABLE 5 Foods to avoid for patients with pheochromocytoma. Chocolate Beer and wine Cured or smoked meats Aged cheeses (including yogurt and sour cream) Fermented soy bean or fish products (tofu, soy sauce, fish sauce, and shrimp paste) Nuts (peanuts, coconuts, and Brazil nuts) Certain fruits (raspberries, red plums, pineapples, bananas, and figs) Certain vegetables (avocados, eggplants, fava beans, snow peas, green beans, and sauerkraut)

164


well established and led to its intravenous use as a method for diagnosis of PCC.100 Patients with PCC should avoid foods that contain large amounts of tyramine (Table 5).101 Medications that may stimulate catecholamine release from the adrenal chromaffin cells should also be avoided in patients with PCC (Table 6).

Intraoperative management An important aspect of intraoperative management of patients with PCC is frequent communication between the surgical and anesthesia teams. Specific events that should be communicated between these teams include any forecasted difficulties while removing the tumor, as well as intraoperative events such as establishment of pneumoperitoneum, hemorrhage, significant blood pressure changes, tumor manipulation, and ligation of the adrenal vein.102 Tumor manipulation may stimulate sudden catecholamine release, resulting in a marked increase in blood pressure and bleeding from small vessels. Immediate cessation of tumor manipulation may be required for the anesthesiologist to normalize the blood pressure. Approximately 60% of patients with PCCs have hyperglycemia because of increased catecholamine-stimulated glycogenolysis and lipolysis.103 It is important that the anesthesia team be cautioned about overtreating hyperglycemia as any insulin administered in the operating room may worsen postoperative hypoglycemia. All patients with PCC should have an intra-arterial catheter placed before the induction of general anesthesia for blood pressure monitoring. Large-bore peripheral intravenous catheters and a central venous catheter are also recommended to help manage volume resuscitation. A pulmonary artery catheter may be of value for identifying discrepancies between left-sided and right-sided ventricular filling in a patient with significant systolic or diastolic cardiac dysfunction.103 A urinary catheter should also be placed after induction of anesthesia to provide a measurement of renal perfusion and volume status. Many different techniques have been described for the induction and maintenance of anesthesia in patients with PCC. In general, many authors advocate the use of thiopental, etomidate, and propofol for induction and then sevoflurane or isoflurane for maintenance of anesthesia.88,96 For neuromuscular blockade, the use of vecuronium or pancuronium is recommended. Some authors recommend not using succinylcholine because of the theoretical risk that muscle fasciculations could increase intra-abdominal pressure and result in increased

TABLE 6 Medications to avoid with pheochromocytoma. Opioid analgesics (oxycodone, morphine, tramadol, and heroin) and naloxone (Narcan) Intravenous glucagon Corticosteroids40-42 Tricyclic antidepressants (amitriptyline—Elavil and Endep; nortriptyline—Aventyl and Pamelor; imipramine— Tofranil; and clomipramine—Anafranil)43 Norepinephrine reuptake inhibitors43 Type-A monoamine oxidase inhibitors (phenelzine—Nardil and deprenyl—Selegiline)43 Selective serotonin reuptake inhibitors (fluoxetine—Prozac, duloxetine—Cymbalta, and paroxetine—Paxil)43 Linezolid (Zyvox)44 Antipsychotics such as droperidol, sulpiride, and chlorpromazine (Thorazine) Antiemetics such as metoclopramide (Reglan) and prochlorperazine (Compazine) Nasal decongestants that contain pseudoephedrine or phenylpropanolamine17,45 Weight-loss supplements that contain fenfluramine, amfepramone, phendimetrazine (Bontril, Adipost, and Plegine), phenylethylamine (Fenphedra), or phentermine (Adipex, Fastin, and Zantryl)17,45 Antinarcolepsy medications that contain dextroamphetamine (Dexedrine)17,45 Attention-deficit/hyperactivity disorder medications that contain amphetamine (Adderall XR) or methylphenidate (Concerta, Daytrana, Metadate, Methylin, and Ritalin)17,45 Anti-impotence supplements containing yohimbe bark extract17,45 Illegal recreational drugs such as ketamine and cocaine17,45 Chewing tobacco46,47


165

catecholamine secretion.99 Atracurium, tubocurarine, and gallamine may cause release of histamine and should be avoided.103,104 Several authors have also used dexmedetomidine (Precedex), which is a central α2-adrenoceptor agonist, for preoperative sedation and enhancement of postoperative analgesia.105 For intraoperative antihypertensive control, particularly during manipulation of the PCC, nitroprusside (Nitropress) is the preferred agent because of its rapid onset and short duration of action. Nitroprusside is an intravenous vasodilator that works by direct action on the peripheral artery and the venous smooth muscle. Fenoldopam (Corlopam) is another antihypertensive agent that has been used intraoperatively as it is a dopamine agonist that directly stimulates dopamine-1 receptors, resulting in increased peripheral vasodilatation and increased renal blood flow. The dosage of fenoldopam is typically 0.2-0.8 mg/kg/min and the metabolites are nontoxic.106 As fenoldopam stimulates diuresis, it is important to carefully monitor the patient's volume status postoperatively.107 An intravenous calcium channel blocker such as nicardipine (Cardene) may also be used. Nicardipine blocks calcium ions from entering the smooth muscle cells during depolarization, which enhances peripheral and coronary vasodilatation. Nicardipine cannot be titrated as rapidly as nitroprusside because of a longer elimination half-life of 2-4 hours. Another antihypertensive medication used during PCC resection is intravenous magnesium sulfate. In adults, a 40-60 mg/kg bolus is given intravenously before intubation and then an infusion of 2 g/h is started to inhibit catecholamine release from the adrenal medulla, enhance vasodilatation, block catecholamine receptors, and stabilize the myocardium from arrhythmias.108 If the patient continues to have dramatic fluctuations with PCC manipulation after magnesium infusion, it is likely that the patient does not have complete αblockade. In this situation, phentolamine (OraVerse) is often used to supplement the α-blockade. Phentolamine is an intravenous, competitive α1-blocker that has an immediate onset and a halflife of approximately 20 minutes. There are many case reports in the medical literature documenting the use of a continuous infusion of phentolamine to blunt large hemodynamic changes.109-112 Arrhythmias may occur during induction or maintenance of general anesthesia for PCC resection. Esmolol, propanolol, or lidocaine may be useful to manage these dysrhythmias, but caution in their administration is advised in patients with severe ventricular dysfunction. Labetalol may also be useful for PCCs that predominantly secrete epinephrine.104 Approximately 50% of patients remain hypertensive after successful resection of the PCC.103 Alternatively, once the venous drainage of the PCC is ligated, patients may experience severe hypotension. Hypotension results from a combination of the loss of catecholamine secretion from the PCC, continued α-blockade, increased systemic capacitance from antihypertensive agents, hypovolemia, and hemorrhage. Management of hypotension begins with intravascular volume replacement. Vasopressors, such as norepinephrine, phenylephrine, and dopamine, are also frequently necessary to restore normotension. It is important to always exclude hemorrhage as a cause for persistent hypotension. Intravascular volume replacement, transient use of a vasoactive agent, and time for the preoperative and intraoperative α-adrenergic agents to be eliminated is usually what is required for treatment of hypotension.

Postoperative management The mortality rate for adrenalectomy in all patients with PCC is 1%-7%, but it is less than 1% for an elective operation in a properly prepared patient.80-84 The reported morbidity rates for adrenalectomy in patients with PCC vary between 3% and 36%.80-84 The rate of postoperative myocardial infarction or stroke is less than 1%.88 Potential postoperative complications after PCC resection include life-threatening arrhythmias, splenic injury (for left-sided lesions), prolonged intubation, renal dysfunction, hypoglycemia, and persistent hypotension. In a study by Plouin and colleagues,84 these complications were independently related to the preoperative systolic blood pressure and urinary metanephrine excretion. Kinney and colleagues88 found a direct

166


correlation between preoperative urinary metanephrines and catecholamines and large tumor size with postoperative complication rates. Severe hypoglycemia after resection of PCC is an uncommon but potentially serious postoperative complication. The initial manifestation of severe hypoglycemia can be a seizure. Hypoglycemia has potentially devastating neurologic consequences.113 The etiology of postoperative hypoglycemia is multifactorial and related to catecholamine-induced depletion of glycogen stores, overstimulation of insulin production by preoperative α-blockade and hyperinsulinemia after loss of catecholamine inhibitory effect on the β2-receptors of the pancreatic islet cells.114-116 Cardiac β-blockade and the residual effects of anesthesia may mask any clinical signs or symptoms of hypoglycemia.88 As a result, blood glucose levels should be monitored for at least 24 hours after surgery and intravenous fluids being administered should include dextrose. Patients are at highest risk for hypoglycemia in the immediate postoperative period, but Jude and Sridhar117 described a patient who developed recurrent hypoglycemia on the sixth postoperative day. As most patients who undergo uncomplicated laparoscopic adrenalectomy are discharged home within several days of surgery, it is prudent to educate patients about signs, symptoms, and treatment of hypoglycemia.

Surgical management There are multiple operative approaches to adrenalectomy, each with certain advantages and disadvantages. The optimal approach for any given patient depends on the clinical features of the patient and their tumor(s), as well as the experience and expertise of the surgeon. The fundamental principle is to excise the tumor in a way that minimizes perioperative complications while achieving the best possible results with regard to recovery time, cosmesis, and tumor control. The key aspects of a safe adrenalectomy include exposure and visualization of the operative field so that meticulous vascular isolation and ligation can be achieved along with complete resection of the adrenal tumor avoiding capsular rupture. Laparoscopic vs open adrenalectomy Since the initial reports of laparoscopic adrenalectomy in the 1990s, this minimally invasive approach has become well accepted as the standard way to perform adrenal surgery in most cases. Although no prospective, randomized trials have been published, it is generally recognized that the laparoscopic approach to adrenalectomy provides excellent exposure and visualization of the gland, a safe means for resection, and leads to improved outcomes with regard to patient comfort and recovery times.118-123 However, there are some limitations of the laparoscopic approach, primarily in the case of tumors that are very large or malignant or both. Although no precise size criteria exist, most experienced adrenal surgeons choose an open approach for tumors greater than 7-8 cm in size. In addition, if there are signs of malignancy seen on preoperative imaging studies, including very large size or invasion of surrounding structures, then an open approach is preferred. For malignant tumors that are not extremely large ( o 7 cm), there is much controversy regarding the safety of the laparoscopic approach as some data suggest that long-term outcomes are better with an open approach. However, the data on the safety of laparoscopic vs open adrenalectomy in patients with malignant tumors focus almost completely on adrenocortical carcinoma. There is little information available regarding the optimal surgical approach in patients with suspected malignant PCCs.8,124-133 As only approximately 10% of PCCs are malignant, a laparoscopic approach is reasonable if the tumor is less than 7-8 cm in size and has no worrisome imaging features of local spread. For larger tumors, an alternative to standard laparoscopy is the hand-assisted laparoscopic approach.134 The open posterior adrenalectomy procedure has largely been replaced in recent years by the retroperitoneoscopic laparoscopic adrenalectomy. Based on a number of reports and comparisons between both the approaches, no significant differences in perioperative complications


167

have been identified between retroperitoneoscopic laparoscopic adrenalectomy and conventional laparoscopic adrenalectomy.135-139 The retroperitoneal endoscopic approach provides a direct access to the adrenal glands and does not require mobilization of adjacent organs such as the liver or the pancreas. In addition, this approach may offer a particular advantage over the transabdominal laparoscopic approach for patients with bilateral tumors, avoiding the need for repositioning that must be done for the transabdominal approach. However, the exposure is somewhat limited in the retroperitoneal approach, a particular problem in the case of large tumors. Preoperative preparation As already discussed, it is critical to adequately prepare a patient with PCC for surgery, as this pharmacologic preparation directly affects the conduct of the operation. In a well-blocked patient, manipulation of the gland during surgery may have little or no effect on blood pressure and other hemodynamic parameters. However, a patient who is not well blocked can present a major surgical challenge, as any manipulation of the gland or tumor can evoke a hypertensive surge. The timing of adrenal vein ligation during the operation should be adjusted based on the hemodynamic responses (eg, early vein ligation should be pursued in a patient who is not well blocked). There are reports of safe adrenalectomy being performed for PCC in patients who had no preoperative pharmacologic blockade. The communication between surgeon and anesthesiologist is always important during PCC surgery, but in the case of no or inadequate preoperative blockade, that communication becomes even more critical. Surgical technique General considerations Regardless of the specific approach used or the side of the tumor, certain principles are paramount for PCC surgery. The surgeon should be in close communication with the anesthesiologist and other care givers in the operating room so that hemodynamic changes are quickly identified and addressed. Behavioral alterations by the surgeon could be just a temporary avoidance of manipulation of the gland while the hemodynamic instability is addressed or might entail early ligation of the adrenal vein to minimize hormonal surges. It is important to avoid rupture of the tumor capsule as spillage of cells could lead to local recurrence of the tumor. In addition, any injury to the capsule of either the tumor itself or the normal adjacent adrenal gland would result in troublesome bleeding that can obscure the operative field and raise the difficulty of the operation. One must always assess the tumor and its relation to the surrounding structures. In some cases of tumors that are large or locally invasive or both, the surrounding organs may need to be removed en bloc. In all cases, there should be some periadrenal fatty tissue included in the resection so as to help avoid capsular tears and to ensure clear margins and an optimal oncologic outcome. Laparoscopic transabdominal left adrenalectomy The patient is generally placed in the lateral decubitus position at 901 using an inflatable bean bag or other device that can provide proper positioning along with protection of all bony prominences. Some surgeons prefer a position somewhat less than complete 901. Safe access to the peritoneal cavity can be achieved by either a direct, open technique or the use of a Veress needle. We prefer the open technique so as to minimize the risk of a rare but potentially catastrophic vascular or bowel injury with the needle. In small patients, the periumbilical site can be used for the laparoscope but the paramedian site is generally preferred as the adrenal gland can be a far distance from the umbilicus. Before the incisions for port placement, the skin and peritoneum are infiltrated with a 1% solution of lidocaine. Once the pneumoperitoneum is achieved, the other trocars are placed under direct visualization, usually an 11-mm trocar in the epigastrium, just to the left of the midline and two 5 mm trocars along the left costal margin.

168


A 301 laparoscope is generally preferred to maximize visualization. The large epigastric trocar site is used for a fan or other retractor so as to keep the spleen and tail of the pancreas out of the operative field. In thin patients, one can avoid this trocar and use just the two 5-mm trocars as the spleen and tail of the pancreas can be more easily and fully mobilized out of the operative field. The dissection is usually carried out with any suitable energy device (eg, electrocautery or Harmonic scalpel) and usually begins by taking down the splenic flexure of the colon to provide access to the Gerota fascia. The avascular plane on top of the Gerota fascia should then be accessed and dissection carried superiorly to fully mobilize the spleen and tail of the pancreas to the patient's right. This mobilization is critical and requires that the surgeon carry the dissection superiorly to the crus of the diaphragm, mobilizing the attachments of the gastric cardia. A key anatomical structure to identify is the phrenic artery or vein as this can be used to ensure that one is in the correct anatomical plane. The phrenic vessels should be followed down from the diaphragm inferiorly and the adrenal gland is always to the left of these vessels. In addition, this phrenic vessel always leads the surgeon to the adrenal vein, which drains either close to or with the phrenic vein into the renal vein. Some surgeons prefer to identify and ligate the adrenal vein early during the surgery and this is sometimes helpful in PCC cases in which there is hemodynamic instability. However, it may be safer and technically easier to more fully dissect the adrenal gland from its attachments to the retroperitoneal adipose tissue before performing the vein dissection as this mobilization of the gland will make it easier to identify and manipulate the vein. The dissection of the gland from the retroperitoneum is generally quite easy, except in rare cases of local invasion. The small periadrenal vessels can almost always be controlled with the cautery or other energy device, but in some PCC cases the vascularity may be increased such that vessels enlarge and require clipping or ligation by other means. Once the gland is completely detached from the surrounding tissues and devascularized, one can usually expect a decrease in the patient's blood pressure, especially in patients with preoperative pharmacologic blockade, as the blockade will now persist and there are no counterbalancing effects of the catecholamines. The anesthesiologist and surgeon should be in close communication during this portion of the procedure to ensure that proper vasopressor support is readily available. The gland or tumor should then be placed into an EndoCatch bag and delivered from the peritoneal cavity. It is important not to disrupt the tumor extensively during the extraction process as this could impair the ability of the pathologist to assess margins and local invasion. As such, the port site may need to be enlarged to safely extract the specimen. Laparoscopic transabdominal right adrenalectomy The right adrenalectomy procedure is carried out similar to the left side, except for specific anatomical differences that must be considered. The access and trocar sites are the same as for the left side. The lateral liver attachments are divided and a retractor is used to bring the liver in a superior location, thus providing access to the adrenal gland. A soft paddle retractor can be used and will be less likely to cause injury to the liver capsule. Again, the dissection is carried out circumferentially to detach the gland from the surrounding retroperitoneal tissues. The key anatomical structure on the right side is the vena cava, which must be handled delicately. Dissection should generally be carried out inferior to superior, separating the gland from the vena cava and then indentifying the adrenal vein for isolation and ligation. There are some cases in which multiple anomalous adrenal veins may be encountered, so this should be kept in mind. The gland often extends posterior to the vena cava but can generally be easily separated from the vein and fully resected. During the inferior dissection, when separating the adrenal gland from the kidney, one should use caution to avoid injury to the superior pole renal vessels. Conversion to an open procedure For an experienced surgeon, conversion from a laparoscopic to an open or hand-assisted laparoscopic procedure is uncommon but may be required in 5% of cases.140,141 However, if there is a significant problem with bleeding, difficulty in properly identifying the key anatomical


169

structures, or a large tumor that is found to be locally invasive, then the surgeon should have a low threshold for conversion so as to ensure a safe outcome for the patient. A subcostal incision can be used and can incorporate the epigastric and perhaps the other smaller port sites. Hand-assisted laparoscopy The use of a hand-assist device can be helpful for occasional patients with large tumors that may be difficult to manipulate using standard laparoscopic instruments. In some cases, even if the tumor can be safely removed via standard laparoscopy, an incision must be enlarged to remove the intact specimen from the abdominal cavity. The typical 7-8 cm hand-port incision may therefore not be much larger than that required for standard laparoscopy. In such cases, the addition of the hand assist can provide better exposure and enhanced ability to manipulate the tumor during the dissection. Retroperitoneoscopic adrenalectomy This represents the newest approach to the adrenal gland and essentially combines the anatomical approach used for a standard open posterior adrenalectomy with a minimally invasive technique similar to standard laparoscopy. The patient is positioned to maximize exposure of the adrenal gland, using the prone position with the hips and knees flexed at approximately 901 with respect to the spine and femur. The patient can be turned slightly onto the contralateral side to facilitate port placement and provide protection of the intra-abdominal organs, although for a bilateral adrenalectomy this turning is not done. Two 12-mm and one 5-mm trocars are generally employed. The 1st incision is usually placed below the tip of the 12th rib and the retroperitoneal space, bluntly entered deep to the ribs and diaphragm. With the index finger directly in the retroperitoneum, an incision is made laterally at the posterior axillary line and a blunt trocar is inserted. A third trocar is inserted between the first incision and the spine, along the paraspinal muscles, approximately 4 cm from the inferior border of the 12th rib. A 12-mm balloon trocar is then placed in the first incision and carbon dioxide insufflation performed to a limit of 20 mm Hg. This creates a working space for visualization of the important structures and for instrument manipulation. A critical step in this procedure is exposure of the superior pole of the kidney, and this is accomplished by opening the overlying Gerota fascia. Dissection of the superior pole of the kidney from lateral to medial results in the separation of the adrenal gland along with some surrounding perinephric fat from the kidney. After complete mobilization of the superior pole, the retroperitoneal fat containing the adrenal gland is retracted cephalad. The adrenal blood vessels are identified on the inferior and medial aspects of the adrenal gland and controlled with an energy device or standard electrocautery. As in other adrenal approaches, large arteries and the main adrenal vein are best controlled with surgical clips. The resection is performed en bloc, with meticulous attention to avoid rupture of the gland and the tumor. The adrenal gland is then separated from the peritoneum anteriorly, the insufflation decreased, and the gland placed intact into the extraction bag. When conversion to an open retroperitoneal adrenalectomy is needed, one can either proceed to an open posterior adrenalectomy or, if needed, reposition the patient for a standard open transabdominal approach. Open transabdominal adrenalectomy This is the oldest approach for adrenalectomy and can be accomplished through any one of a variety of abdominal incisions including midline, subcostal, or paramedian. The operation can be accomplished with the patient in a supine position; however, for a unilateral adrenalectomy, it is generally better to have the patient either partly or completely in a lateral decubitus position. The exposure, mobilization, and resection of the adrenal glands using an open approach are similar to that described for the laparoscopic approach. Although rare, some PCCs locally invade into the IVC (for right-sided lesions) or left renal vein (for left-sided lesions). If the right adrenal tumor invades the IVC, the resection is performed by extensively mobilizing the adjacent liver and dissecting along the lateral border of the IVC to

170


obtain proximal and distal vascular control. The involved IVC segment is resected and the defect repaired either directly or with a vascular graft. There are some cases of PCC in which tumor thrombus may extend onto the vein but without actual invasion of the wall, and in such cases, the tumor can be removed through a simple venotomy and the vein then primarily closed. If there is extensive IVC involvement vascular bypass may be necessary. It is rare for local invasion from a PCC to be so extensive as to require resection of adjacent solid organs, such as the liver, kidney, or pancreas. However, if such invasion is identified, then an en bloc resection should be performed. There is no need for surgical drain placement after adrenalectomy, except when an en bloc distal pancreatectomy is performed, in which case a drain is generally placed to control potential pancreatic leak. Open posterior adrenalectomy Open posterior adrenalectomy is performed through a paraspinous incision that is usually shaped like a hockey stick. The latissimus dorsi muscle and lumbodorsal fascia are transected and the sacrospinalis muscle is retracted medially. The 12th rib is then cleaned on all surfaces and removed up to its junction with the vertebral body. One should be careful to avoid injury to the underlying pleura as well as the subcostal nerve. The surgeon's hand can generally be used to retract the kidney inferiorly and allow identification and exposure of the adrenal gland with surrounding retroperitoneal fatty tissue. This can be controlled circumferentially with cautery followed by direct ligation of the adrenal vein. The operative technique and resection of the gland is otherwise similar to that in the open transabdominal adrenalectomy technique described earlier. Thoracoabdominal approach For very large tumors, especially with invasion of surrounding organs, a thoracoabdominal approach may provide the best exposure for a safe and oncologically sound surgical resection. The abdominal incision is usually paramedian in position and then the rib margin is transected, allowing for continued incision between ribs. The diaphragm is divided in a radial manner from the periphery to allow for wide exposure of the tumor and surrounding structures. Once the tumor is removed, the diaphragm is closed, usually with interrupted nonabsorbable mattress sutures, and the ribs are brought together with large absorbable mattress stitches. The remaining wound is then closed in layers. A chest tube is usually left in place for 1-2 days and removed once an air leak is ruled out.

Malignancy Similar to other endocrine tumors, the definition of malignancy in PCC-PGL is not always very clear because the usual clinical, histopathologic, and biochemical features are not particularly accurate in predicting biological behavior. In fact, the pathologist provides surprisingly little insight into the risk of recurrence or metastases. Rather, a diagnosis of malignancy can only be made reliably by identifying tumor deposits in tissues that do not normally contain chromaffin cells, such as the lymph nodes, liver, bone, lung, or other distant metastatic sites.142 The incidence of malignancy is associated with specific anatomical and genetic features.143-145 For example, although PCCs and PGLs are both catecholamine-secreting neuroendocrine tumors that arise from chromaffin cells, there are significant differences in terms of aggressiveness and metastatic potential as well as the association with inherited genetic syndromes. Based on the presence of metastasis, only approximately 10% of PCCs are malignant, whereas the rate is approximately 25% for PGLs. There are large differences between the familial syndromes and their risk for malignancy.71,146-148,215 Studies of familial PCC syndromes have greatly improved our understanding of the underlying pathogenic mechanisms involved in both familial as well as sporadic forms. A number of susceptibility genes have been established as playing a central role in the pathogenesis of PCCs and PGLs including the VHL tumor suppressor gene, the rearranged during


171

transfection (RET) proto-oncogene, the NF1 tumor suppressor gene, genes encoding for the 4 subunits (A, B, C, and D) of the SDH complex, and a gene encoding the enzyme responsible for flavination of the SDHA subunit (SDHAF2). Genetic testing is generally recommended for all patients with PGLs and in selected patients with PCCs. Malignancy rates are particularly high for PGLs that contain an inherited mutation in the B subunit of the SDH gene (SDHB). These patients who have PGL syndrome type 4 (PGL4) require screening for distant metastatic disease as part of the preoperative evaluation. Malignancy is much less common in the skull base and neck regions (eg, jugulotympanic tumors [2%-4%], carotid body tumors [4%-6%], and vagal tumors [10%-19%]). Malignancy in patients with MEN2 syndrome is quite low (3%-5%). Regardless of the genetic background, these patients must be followed up on a long term because metastases may appear more than 20 years after the original presentation. Because malignant skull base and neck PGLs frequently metastasize to the cervical lymph nodes, selective neck dissection at the time of primary resection is recommended. In contrast, patients with PGLs below the skull base and neck most frequently have distant metastases, most commonly to the bone, liver, and lung. The prognosis for most patients with PCC-PGL is excellent. Complete surgical resection results in high cure rates that approach 90%. However, in patients with metastatic disease, reported 5-year survival rates range widely from 12%-84%, and 10-year survival rates of 25% have been reported.30,149,150 The survival rate may depend on the primary tumor site and sites of metastases. Outcomes are most variable for patients with malignant PGLs of the skull base and neck, most of which are nonsecretory and associated with regionally limited metastases. As would be expected, prognosis is dependent on overall tumor burden, location of metastases, and rate of progression. In general, patients with brain, liver, and lung metastases tend to have a worse prognosis than do those with isolated bone lesions. The presence of distant metastatic disease can have an adverse effect on prognosis, but many PCCs-PGLs exhibit an indolent growth pattern. As such, the presence of metastases does not represent a contraindication to local intervention. Surgical debulking and other local ablative therapies can be effective options for control of recurrent or metastatic disease and certainly can provide palliation with regard to local mass effect as well as catecholamine secretion. However, a survival advantage has not been proven to result from surgical debulking procedures. In patients who are not amenable to surgery or require postoperative therapy, a number of palliative options are available including 131I-MIBG therapy, chemotherapy, radiation therapy (RT), cryoablation therapy, radiofrequency ablation (RFA) therapy, ethanol injection, tumor embolization, and peptide receptor radionuclide therapy. In addition to addressing the tumor itself, patients with functioning malignant PCCs-PGLs usually require control of catecholamine excess. Symptoms of catecholamine excess are the same for benign and malignant tumors and often include episodic hypertension, headache, palpitations, and sweating. As in patients with benign disease, symptoms of catecholamine excess can be controlled with combined α-adrenergic and β-adrenergic blockade. Response to treatment is usually evaluated using a combination of radiographic imaging and biochemical assays of fractionated metanephrines, fractionated catecholamines, and chromogranin A. PCCs-PGLs can exhibit a slow response to therapy, particularly to RT, and even successfully treated tumors demonstrate residual masses, the presence of which does not necessarily indicate treatment failure.151 It is thought that the extensive vascular elements contained within these tumors are replaced by fibrosis after treatment. In addition to tumor size, decreased IV contrast enhancement and reduced T2 signal intensity on MRI studies are generally considered evidence of local response. Metabolic imaging with FDG-PET may provide a more sensitive assessment of tumor response to treatment.152 Owing to the indolent nature of the disease, asymptomatic patients with metastatic disease may be observed as treatment-related side effects may exceed the potential benefit of therapy. However, for symptomatic patients or those with progressive disease, a multidisciplinary management approach is optimal. The first option is certainly surgical resection, and this should be attempted for all primary or metastatic lesions that are amenable. Resection usually improves symptoms by reducing hormone levels and may also prevent mass effect or invasion of adjacent

172


structures. It is important that surgical interventions be performed in centers with experience in handling such patients, given some of the nuances of preoperative, intraoperative, and postoperative management. For large, malignant tumors, an open resection is preferred, although most primary adrenal PCCs are best removed laparoscopically. Most PGLs should be removed using an open approach because of their unique anatomical locations next to critical organs and vascular structures.

Nonsurgical options Nonsurgical approaches to the treatment of metastatic lesions are limited. External beam RT at doses greater than 40 Gy can provide local tumor control and relief of symptoms for tumors at a variety of sites.153 External beam RT–induced inflammation of the lesion has been reported to cause massive catecholamine secretion and a resultant hypertensive crisis.154 Some have suggested using 131I-MIBG; however, there are no data demonstrating a survival or relapse-free survival benefit for such treatment.155-158 The diagnostic and therapeutic value of MIBG is based on its structural similarity with noradrenalin and its uptake into chromaffin cells. Radioactive 131I-MIBG functions as a semiselective agent and generally appears to be of some benefit in approximately 60% of tumors. 123I-MIBG scintigraphy can be performed to determine whether a given patient's tumor will absorb this agent. Dopamine-secreting PGLs generally do not take up 123I-MIBG. Interestingly, external beam RT abolishes the ability of these tumors to take up MIBG, a fact that must be taken into account when planning treatment. The efficacy of 131 I-MIBG in tumor shrinkage or symptom palliation, or in both, has been shown in a limited number of case series, with response rates in the 30% range and another 40% of tumors showing growth stability. Complete remission has been reported in approximately 5% of cases, whereas a decrease in hormone levels has occurred in 45%-67% of cases. Patients with soft tissue metastases rather than bone metastases appear to have a better response to this treatment. Based on the available data, treatment with 131I-MIBG should be considered in patients whose tumors display good uptake of 123I-MIBG and who are not considered candidates for surgical resection or other ablative therapies. For patients with rapidly progressive tumors or bonepredominant extensive disease, chemotherapy is a preferred option even if 123I-MIBG scintigraphy shows positive results. Thyroidal uptake of free iodide should be prevented by giving an oral saturated solution of potassium iodide 24 hours before the 123I-MIBG and daily for 10 days after therapy. Several local ablative therapies have been used in patients with metastases, including RFA, cryoablation, and percutaneous ethanol injection.159-163 In all cases, one must keep in mind that any form of tumor ablation can induce massive catecholamine secretion, so preprocedure medical preparation is required. For patients with multiple liver metastases not amenable to other methods of ablation, isolated case reports suggest benefit (decreased tumor bulk and improved symptom control) from transarterial chemoembolization.164-166

Systemic therapy Some PCCs and extra-adrenal PGLs express somatostatin receptors (as determined by positive uptake with 111In pentetreotide or PET imaging using gallium-68-labeled somatostatin analogs such as 68Ga-DOTA-TOC) and therefore could potentially benefit from therapy using radiolabeled somatostatin analogs.167-174 Long-term potential side effects of therapy with radiolabeled somatostatin analogs may include loss of renal function, pancytopenia, and myelodysplastic syndrome. The efficacy of this treatment for malignant PCCs-PGLs has been described in isolated reports and small series, generally showing only minor responses or stabilization of disease or both. Octreotide itself has been used in a few studies with small patient numbers, and the results have been mixed. Based on these limited data, octreotide should probably be reserved for patients who are not candidates for more toxic systemic treatment options.


173

Cytotoxic chemotherapy Systemic chemotherapy should be considered for patients with unresectable and rapidly progressive PCCs-PGLs and patients with high tumor burden or a large number of bone metastases. The largest studies have used various combinations of cyclophosphamide, dacarbazine, vincristine, and doxorubicin.175-180 The largest single-institution retrospective series of chemotherapy included 52 patients with progressive metastatic PCC or sympathetic extra-adrenal PGL who received a variety of the chemotherapy agents mentioned perviously.175 Of the 52 evaluable patients, 17 (33%) responded to frontline chemotherapy, including 13 with an objective tumor response (25%), and 4 (8%) with normalization of blood pressure. In 2 patients with initially unresectable tumors, the response to chemotherapy was sufficient to permit subsequent surgical excision. Responders, all of whom received a chemotherapy regimen that contained dacarbazine and cyclophosphamide, survived longer than nonresponders (median 6.4 vs 3.7 years). However, nonresponders also had significantly larger tumors (10 vs 5 cm) and a higher percentage of extra-adrenal primaries, 2 factors that are known to be associated with decreased survival. The overall survival rate of the entire cohort at 5 years was 51%. Other cytotoxic chemotherapy agents used in small numbers of patients include temozolomide, thalidomide, capecitabine, gemcitabine, docetaxel, paclitaxel, and streptozocin.181-183 Molecularly targeted therapy Sunitinib is a potent inhibitor of multiple tyrosine kinase receptors, including vascular endothelial growth factor receptors 1 and 2, platelet-derived growth factor receptors beta, KIT, FLT3, and RET. Early reports suggest utility for sunitinib in patients with malignant PCCsPGLs.184-188 The largest retrospective series included 17 patients with progressive metastatic PCCs or sympathetic PGLs who were treated with sunitinib monotherapy. Overall, 4 patients had metastatic disease that was limited to the skeleton, and response assessment in this group consisted of FDG-PET/CT only. Of 14 evaluable patients, 3 (21%) had a partial response and 5 (36%) had stable disease. Median progression-free survival was 4.1 months. Of the 14 patients with hypertension secondary to excessive catecholamine secretion, 6 eventually improved and this correlated with a reduction in the dose or number of antihypertensive medications, or both; however, blood pressure initially worsened in the 3 months after starting sunitinib in 5 patients. Besides hypertension, the most common side effects were diarrhea, hand-foot syndrome, sore mouth, and fatigue. The median overall survival of the entire group was 27 months. Although hypertension is one of the most common side effects of sunitinib, the drug can be safely used in patients with PCCs and secretory PGLs as long as strict follow-up and aggressive antihypertensive dosage adjustments are performed. Sunitinib should be initiated only after normal or near normal blood pressure is achieved with combined α-adrenergic and β-adrenergic blockade. After treatment initiation, additional antihypertensive drugs or dose increase are usually required.

Extra-adrenal lesions Often referred to as “extra-adrenal PCCs,” catecholamine-secreting PGLs (S-PGL) arise from para-aortic sympathetic ganglia derived from neural crest chromaffin cells and are located anywhere from the skull base to the urogenital tract. Like adrenal PCCs, S-PGLs can be solitary or multiple, sporadic or hereditary, and benign or malignant. Although indistinguishable microscopically, there are clear differences in hormone secretion, malignancy risk, and genetic profile between adrenal medullary and extra-adrenal lesions.144 Technically, adrenal medulla is considered a paraganglia; however, by convention, PGLs of the adrenal medulla are termed pheochromoctytomas.189 Contemporary series estimate that 25% of all PGLs are extra-adrenal, with approximately half of these being sympathetic (i.e, secretory) PGLs. Although it was

174


previously thought that only 10% of cases were hereditary, recent reports indicate that more than 50% of cases have sporadic or inherited germline mutations.190,191 S-PGLs are rare, with an estimated incidence of less than 1 per 50,000 individuals.192,193 Most PGLs manifest in the fourth and fifth decades, with sporadic tumors presenting later in life with a predominance of female patients in sporadic cases. Malignant PGLs are extraordinarily rare, estimated at less than 1 per a million individuals, although the incidence is more common than with adrenal PCCs. More than three quarters of functioning (ie, sympathetic chain) PGLs develop in the abdomen, frequently at the organ of Zuckerkandl (aortic bifurcation) or at the junction of the IVC and left renal vein. The next most common site of S-PGL is the pelvis, involving the bladder and the prostate, constituting another 10%-15% of cases. Less often, S-PGLs are found in the neck, skull base, thorax, including pericardial and paraspinal tumors, thyroid, and cauda equina.194,195 Given that the converting enzyme (PNMT) is present only in the adrenal medulla, S-PGLs almost exclusively oversecrete norepinephrine as opposed to epinephrine. Briefly, symptomatic S-PGL manifests with symptoms of catecholamine hypersecretion similar to adrenal PCC and include episodic headache, palpitations, sweating, and tachycardia. Hypertension may be continuous or episodic. Patients with bladder S-PGL can present with micturition syncope—a triad of hypertension, hematuria, and symptoms noted with urination or sexual intercourse.196 This presentation is pathognomonic of S-PGL. In the rare dopamine-producing PGLs, blood pressure may be normal or low. Contrary to prior reports, neck and skull base PGLs can oversecrete no-epinephrine or dopamine or both in approximately one-fifth of cases; therefore, serologic testing should be performed for all patients with suspicion of PGL, regardless of the location.197 Moreover, malignancy risk has been correlated with anatomical site, secretory status, and genetic mutations. The diagnostic evaluation for S-PGL is the same as for adrenal PCC, with 24-hour urinary (high specificity and few false positives) and plasma (high sensitivity and few false negatives) fractionated metanephrines and catecholamines as the preferred initial biochemical screening panel. This initial screening is indicated for patients with a typical constellation of symptoms, incidental mass found on imaging with suspicious characteristics (refer to the section Imaging), or family history of PGL.198 Although urinary metanephrines are sensitive in detecting both PCCs and S-PGLs, S-PGLs typically have relative higher norepinephrine and metabolite normetanephrine levels and lower epinephrine or metanephrine levels than adrenal PCCs have. The sensitivity of 24-hour measurements of norepinephrine, total metanephrines, dopamine, and epinephrine were 84%, 74%, 18%, and 14% sensitive (ie, “positive”), respectively, in a series of patients with S-PGL.65 A dopamine-secreting S-PGL can be detected as part of the evaluation of 24-hour urinary fractionated catecholamines; however, plasma-free dopamine and metabolite methoxytyramine measurement is more sensitive in detecting this rare subtype.65,199 If the results for biochemical screening are negative, one should consider alternate diagnoses, e.g., in the abdomen and pelvis, metastatic carcinomas, lymphomas, and sarcomas and in the mediastinum, hemangioma, thymoma, metastatic tumor (especially from renal cell and thyroid cancer), and primary neurogenic or bronchogenic tumors are other potential possibilities. Accurate imaging is needed for localization, assessment of metastases and metachronous lesions, and assessment for resectability. The most common initial structural imaging for PGLs is either abdominal and pelvic CT or MRI. Characteristic CT findings include a homogeneous mass with intense contrast uptake (HU 40-50) and delayed washout, with necrosis and calcifications commonly present.51,52 It is important that biochemical evaluation or α-blockade or both be achieved before giving ionic contrast, if that is the only option to prevent a catecholamine crisis; nonionic contrast CT is reportedly safe.55 If no S-PGL is identified in the abdomen or pelvis, imaging of the chest, head, and neck and functional imaging with MIBG, SRS, or FDG-PET should be pursued. Functional imaging can be particularly helpful in cases with a higher suspicion or risk of metastatic disease (ie, SDHB mutations). Iodine121-labeled MIBG is less sensitive (higher false-negative rate) in S-PGL (and in particular dopamine-producing tumors) compared with adrenal PCC.62 Moreover, iodine121 is concentrated in the salivary and thyroid glands, making it less sensitive in detecting neck and


175

skull base S-PGL.66 SRS is a viable alternative for suspected head and neck S-PGLs with reported 90% accuracy.200 Sensitivity and specificity of FDG-PET are similar to MIBG for primary tumor imaging and higher for metastatic disease as well as head and neck S-PGLs, so it is often preferred for whole-body imaging.62 Moreover, MIBG sensitivity is lower in patients with SDHB mutations in whom malignancy risk is higher.74 If there is a known SDHB mutation, SRS and FDG-PET are preferred.68 Novel radiotracers and protocols are under development including 18 F-dihyroxyphenylanlanine (18F-DOPA)-PET, DOTA-DPhe1, Tyr3-octreotate, and (99m) Tc-labeled hydrazinonicotinoyl-Tyr3-octreotide,201 which may improve sensitivity in S-PGL.202-205 In cases of “incidentalomas,” a hypervascular tumor or characteristic location can alert clinicians to potential PGL. One should be wary of biopsying a lesion suspicious for PGL before checking metanephrine and catecholamine levels, as biopsy can cause rare but potentially lethal hypertensive crisis. Fine-needle aspiration biopsies of PGLs are frequently misinterpreted, cause local inflammation making resection more challenging, and carry the risk of hypertensive crisis. Classic MRI studies of PGLs show intermediate signal on T1-weighted images and a hypervascular, “salt-and-pepper” appearance on T2 images.58 If found incidentally during imaging, these radiographic findings should alert clinicians of a PGL. As cross-sectional imaging is being used more often, “asymptomatic” PGLs are being discovered incidentally with increasing frequency (eg, 9% in a series).65 Screening for metastatic disease is indicated in all patients with a SDHB germline mutation–related PGL and all dopamine-secreting PGLs because of the high frequency of metastases. Secretory PGLs, especially those arising in the organ of Zuckerkandl have a high frequency of sporadic and inherited germline mutations.206,207 A genetic predisposition is more common with PGL (83%) in comparison with PCC (57%).208 It has been recommended that all patients with PGL should undergo genetic counseling and germline testing.191 This can guide surveillance frequency and intensity, potential assessment of known associated diseases, and familycounseling strategies. Although most S-PGLs are benign, the relative proportion of malignant to benign tumors in abdominal S-PGL is twice that of PCCs (approximately 15%-30% vs 10%, respectively).51 Furthermore, it has been shown that in comparison with those with adrenal PCC, patients with S-PGL have a higher incidence of metastatic disease (60% vs 25%) and have a shorter overall survival.144 The highest malignancy rates are found in patients with S-PGLs (vs PCC) and with SDHB mutations. Malignancy of PCC-PGL is challenging for a number of reasons. The World Health Organization has stated that the only definitive diagnosis of malignant disease is the presence of documented metastasis. The latency period for metastases can be quite prolonged. Likewise, local invasion is difficult to assess, given the lack of a basement membrane. Nuclear histologic features such as pleomorphism and mitotic rate can be seen in benign tumors as well. Other prognostic markers based on immunohistochemical staining have not proven to be specific.209-212 Prognostic scoring systems such as the PCC of the Adrenal gland Scales Score system are used to predict malignancy in PCC but lack reproducibility and have not been tested in PGLs.213,214 Because metastatic spread is usually to the bones, liver, and lung in S-PGL outside of the neck, functional whole-body imaging is warranted preoperatively, ideally with FDG-PET. There is no standard staging system for PCCs-PGL. The tumors are generally categorized as localized, regional, or metastatic. Reported 5-year survival rates for metastatic disease are 50%; 10-year survival rates are approximately 25%, and patients with visceral metastases have a worse prognosis compared with that of patients with skeletal metastases.71,144,215 The approach to safe preoperative α- 7 β-blockade and intraoperative management is the same for adrenal and extra-adrenal disease. As with PCCs, surgery remains the mainstay of treatment. Although metastatic disease does portend a worse prognosis, resection of the primary site should still be considered.192 Surgery is a vital component of treatment, not only for potential cure but also for palliation of locally compressive symptoms and to mitigate excess secretion of catecholamines even though surgical debulking does not improve survival.192 Radiation and arterial embolization have been used to palliate locally aggressive tumors as well. Even in cases of benign PGLs, surgery fails to cure up to 31% of patients as reported in a series of more than 200 patients from Mayo Clinic.65 An additional French series reported a 5-year

176


recurrence rate of 20% with abdominal S-PGLs, significantly more than that for PCC in their cohort.216 In syndromic disease where multiple tumors may be present, PGL-PCC always take precedence. As with all oncologic surgery, en bloc excision of abdominal tumors with care to not invade the tumor capsule is vital. “Pheochromocytomatosis” from tumor spillage has been reported.217 Given the vascularity of these tumors, ligation of efferent and afferent vessels are essential primary steps in the dissection. Open, laparoscopic, and retroperitoneal approaches have all been used, and practice is dictated by surgeon preference, tumor location, extent, and patient cormorbidity.192,218,219 Some experts recommend open surgery for malignancy.220 It is recommended that most patients with bladder PGLs, which have a high prevalence of invasion and metastasis, should undergo cystectomy.221 Following surgery for curative intent or for unresectable or metastatic disease, repeat biochemical testing is recommended to verify serologic cure at 3-6 months, then every 6-12 months for 3 years, and annually for life regardless of pathologic findings. The latency period for recurrence is reported up to 20 years and recurrence is more common in familial syndromes and PGLs (vs PCCs).222 Imaging is warranted within the first year following surgery and afterward as dictated by screening tests and symptoms. Recurrent and resectable metastatic and metachronous tumors should be treated aggressively, ideally with surgical resection. As described above in the section on Malignancy, a number of adjuvant therapies can be attempted for unresectable metastatic disease including external beam RT, RFA, ethanol injection, and chemoembolization of liver metastases.

Hereditary syndromes Although the proportion of PCCs-PGLs with identifiable genetic mutations is increasing with continued research, most tumors are still thought to be sporadic. Nearly half of PCCs-PGLs are associated with 1 of 5 genetic syndromes: VHL, multiple endocrine neoplasia type 2 (RET), NF1, the Carney-Stratakis dyad, and familial PGL syndrome.191,223 Other rare associated syndromes and susceptibility genes that have been identified include MEN 1, kinesis family member 1B (KIF1Bβ), EGL nine homolog 1 (EGLN1/PHD2), transmembrane protein 127 (TMEM127), and MYC-associated factor X (MAX).224-227 The proportion of tumors associated with familial syndromes increases with decreasing age, extra-adrenal PGLs (48% vs 29%), and with increasing number of tumors (83% in patients with more than 1 PGLs) (Table 7).191,228 Familial PCCs-PGLs is associated with mutations in genes encoding subunits of the SDH (SDHB, SDHC, and SDHD) enzyme, each correlated with specific anatomical locations, clinical presentation, and prognosis. TABLE 7 Syndromes associated with pheochromocytoma and paraganglioma. Syndrome (gene)

Associated tumors

Risk of malignancy

von Hippel-Lindau II (VHL)

PCC-PGL (25%); hemangioblastomas of retina, cerebellum, and spinal cord; clear cell renal cell carcinoma; and pancreatic neuroendocrine tumors

3%

Multiple endocrine neoplasia type II (RET)

PCC (50%), medullary thyroid carcinoma (100%), and parathyroid 3% hyperplasia (20%)

Neurofibromatosis type I (NFI)

Neurofibromas, café au lait spots, freckling, Lisch nodules, macrocephaly, and cognitive deficits

Familial PCC-PGL (succinate dehydrogenase)

Carney-Stratakis dyad (succinate dehydrogenase-B, -C, and -D)

12% 4%-31% depending on subtype


177

The genetic mutation, associated tumors, and risk of malignancy for each syndrome are summarized in Table 7. Interestingly, hereditary PCC-PGL syndromes have a higher proportion of bilateral PCCs (MEN2, VHL, and NF1) or multiple PGLs (SDHx mutation–associated syndromes).193 There have been a number of series that demonstrate an increasing number of identifiable genetic mutations in patients with PCCs-PGLs. An Italian consortium with more than 500 patients reported that 32% of patients had germline mutations (VHL 10%; SDHD 9%; RET 5%, SDHB 5%, NF1 2%, and SDHC 1%). In this series 39% of patients with multiple PCCs-PGLs had germline mutations vs only 12% of patients with a solitary PGL or PCC. Most germline-associated PCCs-PGLs were functional. Additionally, 25% of patients without a family history of the mutation were found to have a germline mutation.229 A summary of published series of PCCsPGLs found similar results with 30% of patients having one of the following mutations: VHL (9%), SDHD (7%), SDHB (6%), RET (5%), and NF1 (3%).193 VHL disease VHL disease (VHL) is driven by a mutation in the VHL tumor suppressor gene resulting in degradation of hypoxia-inducible factor.230,231 This autosomal dominantly inherited disease is manifested by a variety of tumors, including hemangioblastomas of the cerebellum, spine, and retina; clear cell renal cell cancers; PCCs-PGLs (type II only); and neuroendocrine tumors of the pancreas. Approximately 9%-10% of patients with VHL develop PCCs-PGLs, defining this subgroup as type II VHL.193,232 The prevalence of PCC-PGL and other syndromic tumors as well as rate of malignancy varies with the specific mutation.193,230,233,234 Nearly half the PCC are bilateral in VHL and frequently benign; therefore, preoperative imaging and partial adrenalectomy should be considered. Familial PGLs (SDHx) Familial PGLs are correlated with a number of different genetic mutations in the SDH tumor suppressor gene. Each of the common SDH mutations, SDHA, SDHB, SDHC, and SDHD, encodes for a different subunit of the enzyme. SDH5 encodes a coenzyme of the SDHA subunit. The SDH enzyme complex is involved in metabolism as a key component of the citric acid cycle and mitochondrial oxidative metabolism.235-238 Overall, 5 hereditary SDHx PGL syndromes (PGL1-5) have been described with SDHD, SDHAF2, SDHC, SDHB, and SDHA mutations, respectively; they are all characterized by an autosomal dominant inheritance pattern with varying penetrance (Table 8).193,238 As with VHL tumors, malignancy rates vary by type of mutation. Among patients with familial PGL syndrome, the most commonly mutated gene is SDHD, but SDHB mutations are associated with worse survival.71,72,239,240 TABLE 8 Familial paraganglioma syndromes. Familial PGL syndrome

Penetrance

PGL-PCC

Other tumors

Malignancy

PGL-1 (SDHD)

High (paternal inheritance)

92% with PGLs (22% S-PGL); unilateral; multiple

Renal cell or thyroid carcinoma

4%

PGL-2 (SDHAF2) 100%

P-PGLs; 87% multiple20,21

0%

PGL-3 (SDHC)

Incomplete

100% PGL (7% S-PGL); multiple

0%

PGL-4 (SDHB)

77%

78% PGL (71% S-PGL and 25% PCC); unilateral; multiple

PGL-5 (SDHA)

Low

P-PGL, S-PGL, and PCC; solitary

Renal cell or thyroid carcinoma7

31% –

178


PGL syndrome 1 (PGL1), defined by SDHD mutations, is the most common type of familial PGL. SDHD mutations can only be inherited paternally and are associated with high penetrance. In PGL1, PGLs are more common (93%) than PCC (24%) and are primarily parasympathetic (P-PGL), frequently multiple, and rarely malignant.228,241 PGL2 (SDHAF2 mutation) is only inherited from an affected father, is rare, and has strong penetrance. In the small number of cases reported, only P-PGLs were found, multiple tumors were common, and no malignant case was identified. PGL syndrome 3 (PGL3; SDHC mutation) is found in 4% of patients with P-PGL, there are no reported malignant cases or PCC, and penetrance is thought to be incomplete.193,242 PGL syndrome 4 (PGL4) is the second most common with mutations in SDHB.193,243 PGLs are seen more often than PCC in this subtype and multiplicity is common; however, in contrast to PGL1, PGL4 is characterized by S-PGLs occurring in 71% of cases. The penetrance of PCCs-PGLs is high. There is a higher incidence of dopaminesecreting SDHB-mutant tumors, which can manifest late, are less likely to be picked up on imaging, and are thought to be more aggressive, as compared with that of sporadic cases.66 SDHB mutations are correlated with a higher risk of malignancy and poorer survival compared with that in other SDH-related PGLs.71,72,190 Patients with SDHB-associated PGLs are on average a decade younger at presentation than sporadic cases. This age discrepancy underscores the importance of metastatic evaluation and close surveillance in patients with SDHB as well as the importance of genetic testing in all patients with PGLs. Finally, patients with PGL5 (SDHA mutation) present with both PGLs (P-PGL and S-PGL) and PCC. There were no malignant cases and unlike the other familial PGL syndromes, only solitary tumors were noted. Penetrance is thought to be low.244 Commercial screening for germline mutations in SDHD, SDHC, SDHAF2, and SDHB is available. Selective or sequential testing has been recommended based on phenotype (ie, SDHD for neck PGLs and SDHB for abdominal PGLs).245 MEN type 2 MEN2A is characterized by medullary thyroid cancer in all patients, PCC in half the patients, and parathyroid hyperplasia in 25% of pstients.193 Patients with MEN2B do not develop parathyroid disease but have the additional phenotypic manifestations including marfanoid habitus and mucosal neuromas. Patients with MEN2 have a mutation in the RET proto-oncogene, which causes activation of PIK3/AKT and MAP-kinase pathways.246 Malignancy risk and therefore recommendations for timing of prophylactic thyroidectomy in patients with MEN2 varies with the specific RET mutation.247 Bilateral PCC occurs in most cases, but extra-adrenal PGL are rare and PCC are normally benign (97%).193 Patients diagnosed with medullary thyroid carcinoma should be screened for PCC before surgery. Surgical treatment of the PCC-PGL always takes precedence over surgery for MTC or parathyroid disease. NF1 (von Recklinghausen disease) This autosomal dominant syndrome is caused by mutations in the NF1 gene. NF1 is well known for skin and neural tissue abnormalities, such as café au lait spots, peripheral neurofibromas, and central nervous system tumors—the presence of which define the disease. Soft tissue sarcomas and PCCs-PGLs are also common in this population. PCCs-PGLs develop in up to 6% of patients with NF1. As seen in MEN2, PCC is much more common than PGL ( o6% of PCC-PGL) and bilateral disease is found in 10% of those with PCCs-PGLs.8,30 Local invasion or distant metastases are reported in 12%.248 Carney-Stratakis syndrome This autosomal dominant disorder is characterized by gastrointestinal stromal tumors (c-KIT negative and PDGFα negative) and PCCs-PGLs. All patients with the Carney-Stratakis dyad develop PGL and nearly 10% also have PCC. Multiple PGLs are seen in 75% of patients, both


179

sympathetic and parasympathetic. Distinct from the other syndromes, tumors can present in childhood with a mean age of 34 years.193 Germline mutations in the SDHB, SDHC, and SDHD genes have been identified.249-252

MYC-associated factor X (MAX) In 2011, alterations in the MAX gene were identified in patients with a family history of PCC.227 Subsequently, germline MAX mutations have also been identified in individuals with PGL. In a large cohort of more than 1600 patients with PCC-PGL in whom the common known mutations (SDH, VHL and RET) were absent, germline mutations in MAX were identified in 23 patients, 7 of whom had a family history of PCC-PGL (1%).253 Gene array expression analyses have revealed 2 distinct clustering patterns for hereditary PCC-PGL tumors: the VHL-SDH cluster and the RET-NF1 cluster.254,255 Lastly, recent work has established that there is a key role for hypoxia-inducible factor in the development of hereditary PCCs-PGLs.256,257

Genetic testing Genetic testing is available for mutations in RET, VHL, NF-1, SDHD, SDHC, SDHB, SDHA, SDHAF2, and MAX genes. The decision to pursue genetic testing is a personal one and can be arbitrated by a genetic counselor. Multidisciplinary clinics held with the patient's clinician and a trained genetic counselor are ideal to communicate the effect of testing, possible treatments, and long-term prognosis, as well as the decision to test family members. It is recommended that all first-degree relatives of patients with known mutations be tested for that mutation. Specific mutations can inform the risks of bilaterality, types and presence of multiple lesions, recurrence, and malignancy risk. If a patient has a first-degree relative with an SDH mutation, screening with plasma or urine metanephrines and imaging studies (ie, CT or MRI of chest, abdomen, and pelvis) are recommended. If no remarkable findings are obtained, biochemical testing should be performed annually and imaging performed every 2-3 years. Functional imaging with MIBG or FDG-PET should be performed every 5 years. Moreover, knowing a specific mutation can guide surgical strategy: adrenalectomy in an SDHB-mutant carrier with a high risk of malignancy vs consideration of a partial adrenalectomy in patients with VHL or NF1 who have a high incidence of bilateral, benign disease. Immunohistochemistry techniques for SDHB, SDHC, and SDHD mutations are used at some institutions as a first-line screening test in surgical pathology specimens. If a PCC-PGL has positive results on immunohistochemistry, then patients are referred for germline genetic testing.258,259 As technology evolves, germline testing has become less expensive and timelier, with some laboratories now offering a complete SDHx panel. Some advocate sequential or targeted testing, for example, VHL testing in a patient with concomitant diagnosis of cerebellar hemangioblastoma, RET testing in a patient with PCC-PGL and medullary thyroid carcinoma, etc. The only exception is NF1, as the diagnosis is made clinically with a constellation of dermatologic and ocular findings. For all patients with extra-adrenal PGL, genetic testing is recommended.192 Mutations are mutually exclusive, hence if 1 mutation is identified, further testing can be avoided. If a maternal imprinting inheritance pattern is noted (meaning active only when inherited from the father), then initial testing should be for SDHD and SDHAF2 mutations. All first-degree relatives should be offered germline mutation testing for the known mutation. References 1. Perrier ND, Boger MS. Surgical anatomy. In: Linos D, van Heerden JA, eds. Adrenal Glands: Diagnostic Aspects and Surgical Therapy. New York: Springer; 2005:7. 2. Udelsman R. Adrenal. In: Norton JA, et al., ed. Surgery: Basic Science and Clinical Evidence. NY: Springer-Verlag; 2001:897–917.

180


3. Clark OH, Duh QY, Kebebew E, ed. Textbook of Endocrine Surgery. (2nd ed). Philadelphia, PA: Elsevier Saunders; 2005. 4. Cameron J, ed. Current Surgical Therapy. (7th ed). St Louis: Mosby Inc; 2001. 5. Beard CM, Sheps SG, Kurland LT, et al. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58:802. 6. Guerrero MA, Schreinemakers JM, Vriens MR, et al. Clinical spectrum of pheochromocytoma. J Am Coll Surg. 2009;209:727. 7. Angeli A, Osella G, Ali A, Terzolo M. Adrenal incidentaloma: an overview of clinical and epidemiological data from the National Italian Study Group. Horm Res. 1997;47(4-6):279–283. 8. Kebebew E, Siperstein AE, Clark OH, Duh QY. Results of laparoscopic adrenalectomy for suspected and unsuspected malignant adrenal neoplasms. Arch Surg. 2002;137(8):948–953. 9. Manger WM, Gifford RW. Pheochromocytoma. J Clin Hypertens (Greenwich). 2002;4:62. 10. Kebebew E, Duh Q-Y. Pheochromocytoma. In: Cameron J, ed. Current Surgical Therapy. (7th ed). St Louis: Mosby Inc; 2001:624–630. 11. Stein PP, Black HR. A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience. Medicine (Baltimore). 1991;70:46. 12. Bravo EL, Gifford Jr. RW. Pheochromocytoma. Endocrinol Metab Clin North Am. 1993;22:329. 13. Stenström G, Sjöström L, Smith U. Diabetes mellitus in phaeochromocytoma. Fasting blood glucose levels before and after surgery in 60 patients with phaeochromocytoma. Acta Endocrinol (Copenh). 1984;106:511. 14. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366(9486):665–675. 15. Lee JA, Zarnegar R, Shen WT, Kebebew E, Clark OH, Duh QY. Adrenal incidentaloma, borderline elevations of urine or plasma metanephrine levels, and the “subclinical” pheochromocytoma. Arch Surg. 2007;142(9):870–873. 16. Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med. 2003;138(5):424–429. 17. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. J Clin Endocrinol Metab. 2000;85 (2):637–644. 18. Neumann HP, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med. 1993;329:1531. 19. Pawlu C, Bausch B, Reisch N, Neumann HP. Genetic testing for pheochromocytoma-associated syndromes. Ann Endocrinol (Paris). 2005;66:178. 20. Neumann HP, Vortmeyer A, Schmidt D, et al. Evidence of MEN-2 in the original description of classic pheochromocytoma. N Engl J Med. 2007;357:1311. 21. Maher ER, Yates JR, Harries R, et al. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990;77:1151. 22. Walther MM, Herring J, Enquist E, et al. von Recklinghausen's disease and pheochromocytomas. J Urol. 1999;162: 1582. 23. Niemann S, Müller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000;26: 268. 24. Astuti D, Latif F, Dallol A, et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001;69:49. 25. Jiménez C, Cote G, Arnold A, Gagel RF. Review: should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes? J Clin Endocrinol Metab. 2006;91:2851. 26. van der Harst E, de Herder WW, de Krijger RR, et al. The value of plasma markers for the clinical behaviour of phaeochromocytomas. Eur J Endocrinol. 2002;147:85–94. 27. Eisenhofer G, Walther MM, Huynh TT, et al. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab. 2001;86: 1999–2008. 28. Eisenhofer G, Lenders JW, Siegert G, et al. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer. 2012;48:1739–1749. 29. Mannelli M, Pupilli C, Lanzillotti R, et al. A nonsecreting pheochromocytoma presenting as an incidental adrenal mass. Report on a case. J Endocrinol Invest. 1993;16:817–822. 30. Pacak K, Eisenhofer G, Ahlman H, et al. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 2007;3:92–102. 31. Lenders JW, Pacak K, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: which test is best? J Am Med Assoc. 2002;287:1427–1434. 32. Brain KL, Kay J, Shine B. Measurement of urinary metanephrines to screen for pheochromocytoma in an unselected hospital referral population. Clin Chem. 2006;52:2060–2064. 33. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab. 2003;88:2656–2666. 34. Deutschbein T, Unger N, Jaeger A, et al. Influence of various confounding variables and storage conditions on metanephrine and normetanephrine levels in plasma. Clin Endocrinol (Oxf). 2010;73:153–160. 35. Sawka AM, Thabane L, Gafni A, et al. Measurement of fractionated plasma metanephrines for exclusion of pheochromocytoma: can specificity be improved by adjustment for age? BMC Endocr Disord. 2005;5:1. 36. Willemsen JJ, Ross HA, Lenders JW, Sweep FC. Stability of urinary fractionated metanephrines and catecholamines during collection, shipment, and storage of samples. Clin Chem. 2007;53:268–272. 37. Darr R, Lenders JW, Hofbauer LC, et al. Pheochromocytoma—update on disease management. Ther Adv Endocrinol Metab. 2012;3:11–26. 38. Mullins F, O'Shea P, FitzGerald R, Tormey W. Enzyme-linked immunoassay for plasma-free metanephrines in the biochemical diagnosis of phaeochromocytoma in adults is not ideal. Clin Chem Lab Med. 2011;50:105–110.


181

39. Pillai D, Callen S. Pilot quality assurance programme for plasma metanephrines. Ann Clin Biochem. 2010;47: 137–142. 40. Lagerstedt SA, O'Kane DJ, Singh RJ. Measurement of plasma free metanephrine and normetanephrine by liquid chromatography-tandem mass spectrometry for diagnosis of pheochromocytoma. Clin Chem. 2004;50: 603–611. 41. Lenders JW, Pacak K, Huynh T, et al. Low sensitivity of glucagon provocative testing for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2010;95:238–245. 42. Lenders Eisenhofer JW, Mannelli G, Pacakk M. Phaeochromocytoma. Lancet. 2005;366:665–675. 43. Lee GR, Johnston PC, Atkinson AB, et al. A comparison of plasma-free metanephrines with plasma catecholamines in the investigation of suspected pheochromocytoma. J Hypertens. 2011;29:2422–2428. 44. Lenders JW, Willemsen JJ, Beissel T, Kloppenborg PW, Thien T, Benraad TJ. Value of the plasma norepinephrine/3, 4-dihydroxyphenylglycol ratio for the diagnosis of pheochromocytoma. Am J Med. 1992;92:147–152. 45. Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B. Incidentally discovered adrenal masses. Endocr Rev. 1995;16: 460–484. 46. Grumbach MM, Biller BM, Braunstein GD, et al. Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med. 2003;138:424–429. 47. Thompson GB, Young Jr. WF. Adrenal incidentaloma. Curr Opin Oncol. 2003;15:84–90. 48. Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab. 2004;89:479–491. 49. Boland GW, Lee MJ, Gazelle GS, Halpern EF, McNicholas MM, Mueller PR. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. Am J Roentgenol. 1998;171:201–204. 50. Blake MA, Kalra MK, Sweeney AT, et al. Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay. Radiology. 2006;238:578–585. 51. Lee JA, Duh QY. Sporadic paraganglioma. World J Surg. 2008;32:683–687. 52. Motta-Ramirez GA, Remer EM, Herts BR, Gill IS, Hamrahian AH. Comparison of CT findings in symptomatic and incidentally discovered pheochromocytomas. Am J Roentgenol. 2005;185:684–688. 53. Leung K, Stamm M, Raja A, Low G. Pheochromocytoma: the range of appearances on ultrasound, CT, MRI, and functional imaging. Am J Roentgenol. 2013;200:370–378. 54. Johnson PT, Horton KM, Fishman EK. Adrenal mass imaging with multidetector CT: pathologic conditions, pearls, and pitfalls. Radiographics. 2009;29:1333–1351. 55. Bessell-Browne R, O'Malley ME. CT of pheochromocytoma and paraganglioma: risk of adverse events with i.v. administration of nonionic contrast material. Am J Roentgenol. 2007;188:970–974. 56. Blake MA, Cronin CG, Boland GW. Adrenal imaging. Am J Roentgenol. 2010;194:1450–1460. 57. Jacques AE, Sahdev A, Sandrasagara M, et al. Adrenal phaeochromocytoma: correlation of MRI appearances with histology and function. Eur Radiol. 2008;18:2885–2892. 58. Olsen WL, Dillon WP, Kelly WM, Norman D, Brant-Zawadzki M, Newton TH. MR imaging of paragangliomas. Am J Roentgenol. 1987;148:201–204. 59. Intenzo CM, Jabbour S, Lin HC, et al. Scintigraphic imaging of body neuroendocrine tumors. Radiographics. 2007;27: 1355–1369. 60. Fujita A, Hyodoh H, Kawamura Y, Kanegae K, Furuse M, Kanazawa K. Use of fusion images of I-131 metaiodobenzylguanidine, SPECT, and magnetic resonance studies to identify a malignant pheochromocytoma. Clin Nucl Med. 2000;25:440–442. 61. van der Harst E, de Herder WW, Bruining HA, et al. [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. J Clin Endocrinol Metab. 2001;86:685–693. 62. Timmers HJ, Chen CC, Carrasquillo JA, et al. Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. J Natl Cancer Inst. 2012;104: 700–708. 63. Shulkin BL, Thompson NW, Shapiro B, Francis IR, Sisson JC. Pheochromocytomas: imaging with 2-[fluorine-18] fluoro-2-deoxy-d-glucose PET. Radiology. 1999;212:35–41. 64. Solanki KK, Bomanji J, Moyes J, Mather SJ, Trainer PJ, Britton KE. A pharmacological guide to medicines which interfere with the biodistribution of radiolabelled meta-iodobenzylguanidine (MIBG). Nucl Med Commun. 1992;13: 513–521. 65. Erickson D, Kudva YC, Ebersold MJ, et al. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab. 2001;86:5210–5216. 66. Foo SH, Chan SP, Ananda V, Rajasingam V. Dopamine-secreting phaeochromocytomas and paragangliomas: clinical features and management. Singapore Med J. 2010;51:e89–e93. 67. Taieb D, Sebag F, Hubbard JG, Mundler O, Henry JF, Conte-Devolx B. Does iodine-131 meta-iodobenzylguanidine (MIBG) scintigraphy have an impact on the management of sporadic and familial phaeochromocytoma? Clin Endocrinol (Oxf). 2004;61:102–108. 68. Timmers HJ, Kozupa A, Chen CC, et al. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol. 2007;25:2262–2269. 69. Vanderveen KA, Thompson SM, Callstrom MR, et al. Biopsy of pheochromocytomas and paragangliomas: potential for disaster. Surgery. 2009;146:1158–1166. 70. Pomares FJ, Canas R, Rodriguez JM, Hernandez AM, Parrilla P, Tebar FJ. Differences between sporadic and multiple endocrine neoplasia type 2A phaeochromocytoma. Clin Endocrinol (Oxf). 1998;48:195–200. 71. Amar L, Baudin E, Burnichon N, et al. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007;92:3822–3828. 72. Neumann HP, Pawlu C, Peczkowska M, et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. J Am Med Assoc. 2004;292:943–951.

182


73. Gimenez-Roqueplo AP, Caumont-Prim A, Houzard C, et al. Imaging work-up for screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: a multicenter prospective study from the PGL.EVA Investigators. J Clin Endocrinol Metab. 2013;98:E162–E173. 74. Fonte JS, Robles JF, Chen CC, et al. False-negative (1)(2)(3)I-MIBG SPECT is most commonly found in SDHB-related pheochromocytoma or paraganglioma with high frequency to develop metastatic disease. Endocr Relat Cancer. 2012;19:83–93. 75. Pacak K, Eisenhofer G, Carrasquillo JA, Chen CC, Whatley M, Goldstein DS. Diagnostic localization of pheochromocytoma: the coming of age of positron emission tomography. Ann N Y Acad Sci. 2002;970:170–176. 76. Bovio S, Cataldi A, Reimondo G, et al. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest. 2006;29:298–302. 77. Song JH, Chaudhry FS, Mayo-Smith WW. The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malignancy. Am J Roentgenol. 2008;190:1163–1168. 78. Freel EM, Stanson AW, Thompson GB, et al. Adrenal venous sampling for catecholamines: a normal value study. J Clin Endocrinol Metab. 2010;95:1328–1332. 79. Welbourn RB. Early surgical history of phaeochromocytoma. Br J Surg. 1987;74:594–596. 80. Favia G, Lumachi F, Polistina F, D'Amico DF. Pheochromocytoma, a rare cause of hypertension: long-term follow-up of 55 surgically treated patients. World J Surg. 1998;22:689–693. [discussion 694]. 81. Orchard T, Grant CS, van Heerden JA, Weaver A. Pheochromocytoma–continuing evolution of surgical therapy. Surgery. 1993;114:1153–1158. [discussion 1158-1159]. 82. Ulchaker JC, Goldfarb DA, Bravo EL, Novick AC. Successful outcomes in pheochromocytoma surgery in the modern era. J Urol. 1999;161:764–767. 83. Obara T, Kanbe M, Okamoto T, et al. Surgical strategy for pheochromocytoma: emphasis on the pledge of flank extraperitoneal approach in selected patients. Surgery. 1995;118:1083–1089. 84. Plouin PF, Duclos JM, Soppelsa F, et al. Factors associated with perioperative morbidity and mortality in patients with pheochromocytoma: analysis of 165 operations at a single center. J Clin Endocrinol Metab. 2001;86: 1480–1486. 85. Liao WB, Liu CF, Chiang CW, et al. Cardiovascular manifestations of pheochromocytoma. Am J Emerg Med. 2000;18: 622–625. 86. Boutros AR, Bravo EL, Zanettin G, Straffon RA. Perioperative management of 63 patients with pheochromocytoma. Cleve Clin J Med. 1990;57:613–617. 87. Bravo EL. Pheochromocytoma. Curr Ther Endocrinol Metab. 1997;6:195–197. 88. Kinney MA, Warner ME, vanHeerden JA, et al. Perianesthetic risks and outcomes of pheochromocytoma and paraganglioma resection. Anesth Analg. 2000;91:1118–1123. 89. Witteles RM, Kaplan EL, Roizen MF. Safe and cost-effective preoperative preparation of patients with pheochromocytoma. Anesth Analg. 2000;91:302–304. 90. Bogolioubov A, Keefe DL, Groeger JS. Circulatory shock. Crit Care Clin. 2001;17:697–719. 91. Organization PaPRS: Pheochromocytoma: Recommendations for Clinical Practice from the First International Symposium on Pheochromocytoma—ISP2005; 2005. 92. Prys-Roberts C, Farndon JR. Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma. World J Surg. 2002;26:1037–1042. 93. Zhu Y, He HC, Su TW, et al. Selective alpha1-adrenoceptor antagonist (controlled release tablets) in preoperative management of pheochromocytoma. Endocrine. 2010;38:254–259. 94. Weingarten TN, Cata JP, O'Hara JF, et al. Comparison of two preoperative medical management strategies for laparoscopic resection of pheochromocytoma. Urology. 2010;76:508.e506–508.e511. 95. Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92: 4069–4079. 96. Lebuffe G, Dosseh ED, Tek G, et al. The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. Anaesthesia. 2005;60:439–444. 97. Nagatsu T, Mizutani K, Sudo Y, Nagatsu I. Tyrosine hydroxylase in human adrenal glands and human pheochromocytoma. Clin Chim Acta. 1972;39:417–424. 98. Steinsapir J, Carr AA, Prisant LM, Bransome Jr ED. Metyrosine and pheochromocytoma. Arch Intern Med. 1997;157: 901–906. 99. Graham GW, Unger BP, Coursin DB. Perioperative management of selected endocrine disorders. Int Anesthesiol Clin. 2000;38:31–67. 100. Engelman K, Sjoerdsma A. A new test for pheochromocytoma. pressor responsiveness to tyramine. J Am Med Assoc. 1964;189:81–86. 101. Naila A, Flint S, Fletcher G, et al. Control of biogenic amines in food–existing and emerging approaches. J Food Sci. 2010;75:R139–R150. 102. Tauzin-Fin P, Sesay M, Gosse P, Ballanger P. Effects of perioperative alpha1 block on haemodynamic control during laparoscopic surgery for phaeochromocytoma. Br J Anaesth. 2004;92:512–517. 103. Kinney MA, Narr BJ, Warner MA. Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesth. 2002;16:359–369. 104. Whalley DG, Berrigan MJ. Anesthesia for radical prostatectomy, cystectomy, nephrectomy, pheochromocytoma, and laparoscopic procedures. Anesthesiol Clin North America. 2000;18:899–917. (x). 105. Bryskin R, Weldon BC. Dexmedetomidine and magnesium sulfate in the perioperative management of a child undergoing laparoscopic resection of bilateral pheochromocytomas. J Clin Anesth. 2010;22:126–129. 106. Connery LE, Coursin DB. Assessment and therapy of selected endocrine disorders. Anesthesiol Clin North America. 2004;22:93–123. 107. Cooper ZA, Mihm FG. Blood pressure control with fenoldopam during excision of a pheochromocytoma. Anesthesiology. 1999;91:558–560.


183

108. Minami T, Adachi T, Fukuda K. An effective use of magnesium sulfate for intraoperative management of laparoscopic adrenalectomy for pheochromocytoma in a pediatric patient. Anesth Analg. 2002;95:1243–1244. [table of contents]. 109. McMillian WD, Trombley BJ, Charash WE, Christian RC. Phentolamine continuous infusion in a patient with pheochromocytoma. Am J Health Syst Pharm. 2011;68:130–134. 110. Kobal SL, Paran E, Jamali A, et al. Pheochromocytoma: cyclic attacks of hypertension alternating with hypotension. Nat Clin Pract Cardiovasc Med. 2008;5:53–57. 111. Engelbrecht ER, Hugill JT, Graves HB. Anaesthetic management of pheochromocytoma. Can Anaesth Soc J. 1966;13: 598–606. 112. Grasselli G, Foti G, Patroniti N, et al. Extracorporeal cardiopulmonary support for cardiogenic shock caused by pheochromocytoma: a case report and literature review. Anesthesiology. 2008;108:959–962. 113. Chambers S, Espiner EA, Donald RA, Nicholls MG. Hypoglycaemia following removal of phaeochromocytoma: case report and review of the literature. Postgrad Med J. 1982;58:503–506. 114. Reynolds C, Wilkins GE, Schmidt N, et al. Hyperinsulinism after removal of a pheochromocytoma. Can Med Assoc J. 1983;129:349–353. 115. Akiba M, Kodama T, Ito Y, et al. Hypoglycemia induced by excessive rebound secretion of insulin after removal of pheochromocytoma. World J Surg. 1990;14:317–324. 116. Martin R, St-Pierre B, Moliner OR. Phaeochromocytoma and postoperative hypoglycaemia. Can Anaesth Soc J. 1979;26:260–262. 117. Jude EB, Sridhar CB. Prolonged hypoglycaemia following surgical removal of phaeochromocytoma. Postgrad Med J. 2000;76:39–40. 118. Hansen P, Bax T, Swanstrom L. Laparoscopic adrenalectomy: history, indications, and current techniques for a minimally invasive approach to adrenal pathology. Endoscopy. 1997;29:309. 119. Wells SA, Merke DP, Cutler Jr GB, et al. Therapeutic controversy: the role of laparoscopic surgery in adrenal disease. J Clin Endocrinol Metab. 1998;83:3041. 120. Brunt LM. Minimal access adrenal surgery. Surg Endosc. 2006;20:351. 121. Gumbs AA, Gagner M. Laparoscopic adrenalectomy. Best Pract Res Clin Endocrinol Metab. 2006;20:483. 122. Gagner M, Pomp A, Heniford BT, et al. Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg. 1997;226:238. 123. Lee J, El-Tamer M, Schifftner T, et al. Open and laparoscopic adrenalectomy: analysis of the National Surgical Quality Improvement Program. J Am Coll Surg. 2008;206:953. 124. Miller BS, Ammori JB, Gauger PG, et al. Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma. World J Surg. 2010;34:1380. 125. Schteingart DE, Doherty GM, Gauger PG, et al. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr Relat Cancer. 2005;12:667. 126. Gonzalez RJ, Shapiro S, Sarlis N, et al. Laparoscopic resection of adrenal cortical carcinoma: a cautionary note. Surgery. 2005;138:1078. 127. Porpiglia F, Fiori C, Daffara F, et al. Retrospective evaluation of the outcome of open versus laparoscopic adrenalectomy for stage I and II adrenocortical cancer. Eur Urol. 2010;57:873. 128. Brix D, Allolio B, Fenske W, et al. Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients. Eur Urol. 2010;58:609. 129. McCauley LR, Nguyen MM. Laparoscopic radical adrenalectomy for cancer: long-term outcomes. Curr Opin Urol. 2008;18:134. 130. Adler JT, Mack E, Chen H. Equal oncologic results for laparoscopic and open resection of adrenal metastases. J Surg Res. 2007;140:159. 131. Suzuki H. Laparoscopic adrenalectomy for adrenal carcinoma and metastases. Curr Opin Urol. 2006;16:47. 132. Lombardi CP, Raffaelli M, De Crea C, Bellantone R. Role of laparoscopy in the management of adrenal malignancies. J Surg Oncol. 2006;94:128. 133. Porpiglia F, Miller BS, Manfredi M, et al. A debate on laparoscopic versus open adrenalectomy for adrenocortical carcinoma. Horm Cancer. 2011;2:372. 134. Bennett IC, Ray M. Hand-assisted laparoscopic adrenalectomy: an alternative minimal invasive surgical technique for the adrenal gland. ANZ J Surg. 2002;72(11):801–805. 135. Callender GG, Kennamer DL, Grubbs EG, et al. Posterior retroperitoneoscopic adrenalectomy. Adv Surg. 2009; 43:147. 136. Walz MK, Alesina PF, Wenger FA, et al. Posterior retroperitoneoscopic adrenalectomy–results of 560 procedures in 520 patients. Surgery. 2006;140:943. 137. Perrier ND, Kennamer DL, Bao R, et al. Posterior retroperitoneoscopic adrenalectomy: preferred technique for removal of benign tumors and isolated metastases. Ann Surg. 2008;248:666. 138. Dickson PV, Jimenez C, Chisholm GB, et al. Posterior retroperitoneoscopic adrenalectomy: a contemporary American experience. J Am Coll Surg. 2011;212:659. 139. Constantinides VA, Christakis I, Touska P, Palazzo FF. Systematic review and meta-analysis of retroperitoneoscopic versus laparoscopic adrenalectomy. Br J Surg. 2012;99:1639. 140. Shen WT, Kebebew E, Clark OH, Duh QY. Reasons for conversion from laparoscopic to open or handassisted adrenalectomy: review of 261 laparoscopic adrenalectomies from 1993 to 2003. World J Surg. 2004;28: 1176. 141. Shen ZJ, Chen SW, Wang S, et al. Predictive factors for open conversion of laparoscopic adrenalectomy: a 13-year review of 456 cases. J Endourol. 2007;21:1333–1339. 142. DeLellis RA, Lloyd RV, Heitz PU, Eng C, ed. Pathology and Genetics of Tumours of the Endocrine Organs. WHO Classification of Tumours. Lyon, France: IARC press; 2004.

184


143. Chen H, Sippel RS, O'Dorisio MS, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39:775. 144. Ayala-Ramirez M, Feng L, Johnson MM, et al. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab. 2011;96:717. 145. Eisenhofer G, Bornstein SR, Brouwers FM, et al. Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer. 2004;11:423. 146. Sisson JC, Shulkin BL, Esfandiari NH. Courses of malignant pheochromocytoma: implications for therapy. Ann N Y Acad Sci. 2006;1073:505. 147. Moskovic DJ, Smolarz JR, Stanley D, et al. Malignant head and neck paragangliomas: is there an optimal treatment strategy? Head Neck Oncol. 2010;2:23. 148. Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257:60. 149. Schlumberger M, Gicquel C, Lumbroso J, et al. Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases. J Endocrinol Invest. 1992;15:631. 150. Andersen KF, Altaf R, Krarup-Hansen A, et al. Malignant pheochromocytomas and paragangliomas—the importance of a multidisciplinary approach. Cancer Treat Rev. 2011;37:111. 151. Mukherji SK, Kasper ME, Tart RP, Mancuso AA. Irradiated paragangliomas of the head and neck: CT and MR appearance. Am J Neuroradiol. 1994;15:357. 152. Argiris A, Mellott A, Spies S. PET scan assessment of chemotherapy response in metastatic paraganglioma. Am J Clin Oncol. 2003;26:563. 153. Fishbein L, Bonner L, Torigian DA, et al. External beam radiation therapy (EBRT) for patients with malignant pheochromocytoma and non-head and -neck paraganglioma: combination with 131I-MIBG. Horm Metab Res. 2012;44:405. 154. Teno S, Tanabe A, Nomura K, Demura H. Acutely exacerbated hypertension and increased inflammatory signs due to radiation treatment for metastatic pheochromocytoma. Endocr J. 1996;43:511. 155. Safford SD, Coleman RE, Gockerman JP, et al. Iodine-131 metaiodobenzylguanidine is an effective treatment for malignant pheochromocytoma and paraganglioma. Surgery. 2003;134:956. 156. Shapiro B, Sisson JC, Wieland DM, et al. Radiopharmaceutical therapy of malignant pheochromocytoma with [131I] metaiodobenzylguanidine: results from ten years of experience. J Nucl Biol Med. 1991;35:269. 157. Shilkrut M, Bar-Deroma R, Bar-Sela G, et al. Low-dose iodine-131 metaiodobenzylguanidine therapy for patients with malignant pheochromocytoma and paraganglioma: single center experience. Am J Clin Oncol. 2010;33:79. 158. Gonias S, Goldsby R, Matthay KK, et al. Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol. 2009;27:4162. 159. McBride JF, Atwell TD, Charboneau WJ, et al. Minimally invasive treatment of metastatic pheochromocytoma and paraganglioma: efficacy and safety of radiofrequency ablation and cryoablation therapy. J Vasc Interv Radiol. 2011;22:1263. 160. Mamlouk MD, vanSonnenberg E, Stringfellow G, et al. Radiofrequency ablation and biopsy of metastatic pheochromocytoma: emphasizing safety issues and dangers. J Vasc Interv Radiol. 2009;20:670. 161. Wood BJ, Abraham J, Hvizda JL, et al. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer. 2003;97:554. 162. Pacak K, Fojo T, Goldstein DS, et al. Radiofrequency ablation: a novel approach for treatment of metastatic pheochromocytoma. J Natl Cancer Inst. 2001;93:648. 163. Cozzi PJ, Englund R, Morris DL. Cryotherapy treatment of patients with hepatic metastases from neuroendocrine tumors. Cancer. 1995;76:501. 164. Hidaka S, Hiraoka A, Ochi H, et al. Malignant pheochromocytoma with liver metastasis treated by transcatheter arterial chemo-embolization (TACE). Intern Med. 2010;49:645. 165. Watanabe D, Tanabe A, Naruse M, et al. Transcatheter arterial embolization for the treatment of liver metastases in a patient with malignant pheochromocytoma. Endocr J. 2006;53:59. 166. Takahashi K, Ashizawa N, Minami T, et al. Malignant pheochromocytoma with multiple hepatic metastases treated by chemotherapy and transcatheter arterial embolization. Intern Med. 1999;38:349. 167. Mundschenk J, Unger N, Schulz S, et al. Somatostatin receptor subtypes in human pheochromocytoma: subcellular expression pattern and functional relevance for octreotide scintigraphy. J Clin Endocrinol Metab. 2003;88:5150. 168. Gulenchyn KY, Yao X, Asa SL, et al. Radionuclide therapy in neuroendocrine tumours: a systematic review. Clin Oncol (R Coll Radiol). 2012;24:294. 169. Cecchin D, Schiavi F, Fanti S, et al. Peptide receptor radionuclide therapy in a case of multiple spinal canal and cranial paragangliomas. J Clin Oncol. 2011;29:e171. 170. Garkavij M, Nickel M, Sjögreen-Gleisner K, et al. 177Lu-[DOTA0,Tyr3] octreotate therapy in patients with disseminated neuroendocrine tumors: analysis of dosimetry with impact on future therapeutic strategy. Cancer. 2010;116:1084. 171. Koriyama N, Kakei M, Yaekura K, et al. Control of catecholamine release and blood pressure with octreotide in a patient with pheochromocytoma: a case report with in vitro studies. Horm Res. 2000;53:46. 172. Lamarre-Cliche M, Gimenez-Roqueplo AP, Billaud E, et al. Effects of slow-release octreotide on urinary metanephrine excretion and plasma chromogranin A and catecholamine levels in patients with malignant or recurrent phaeochromocytoma. Clin Endocrinol (Oxf). 2002;57:629. 173. Invitti C, De Martin I, Bolla GB, et al. Effect of octreotide on catecholamine plasma levels in patients with chromaffin cell tumors. Horm Res. 1993;40:156.


185

174. Plouin PF, Bertherat J, Chatellier G, et al. Short-term effects of octreotide on blood pressure and plasma catecholamines and neuropeptide Y levels in patients with phaeochromocytoma: a placebo-controlled trial. Clin Endocrinol (Oxf). 1995;42:289. 175. Ayala-Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer. 2012;118:2804. 176. Nomura K, Kimura H, Shimizu S, et al. Survival of patients with metastatic malignant pheochromocytoma and efficacy of combined cyclophosphamide, vincristine, and dacarbazine chemotherapy. J Clin Endocrinol Metab. 2009;94:2850. 177. Patel SR, Winchester DJ, Benjamin RS. A 15-year experience with chemotherapy of patients with paraganglioma. Cancer. 1995;76:1476. 178. Huang H, Abraham J, Hung E, et al. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer. 2008;113:2020. 179. Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med. 1988;109:267. 180. Bravo EL, Kalmadi SR, Gill I. Clinical utility of temozolomide in the treatment of malignant paraganglioma: a preliminary report. Horm Metab Res. 2009;41:703. 181. Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401. 182. Mora J, Cruz O, Parareda A, et al. Treatment of disseminated paraganglioma with gemcitabine and docetaxel. Pediatr Blood Cancer. 2009;53:663. 183. Kruijtzer CM, Beijnen JH, Swart M, Schellens JH. Successful treatment with paclitaxel of a patient with metastatic extra-adrenal pheochromocytoma (paraganglioma). A case report and review of the literature. Cancer Chemother Pharmacol. 2000;45:428. 184. Joshua AM, Ezzat S, Asa SL, et al. Rationale and evidence for sunitinib in the treatment of malignant paraganglioma/ pheochromocytoma. J Clin Endocrinol Metab. 2009;94:5. 185. Jimenez C, Cabanillas ME, Santarpia L, et al. Use of the tyrosine kinase inhibitor sunitinib in a patient with von Hippel-Lindau disease: targeting angiogenic factors in pheochromocytoma and other von Hippel-Lindau diseaserelated tumors. J Clin Endocrinol Metab. 2009;94:386. 186. Hahn NM, Reckova M, Cheng L, et al. Patient with malignant paraganglioma responding to the multikinase inhibitor sunitinib malate. J Clin Oncol. 2009;27:460. 187. Park KS, Lee JL, Ahn H, et al. Sunitinib, a novel therapy for anthracycline- and cisplatin-refractory malignant pheochromocytoma. Jpn J Clin Oncol. 2009;39:327. 188. Ayala-Ramirez M, Chougnet CN, Habra MA, et al. Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab. 2012;97:4040. 189. Barnes L, Evenson JW, Reichart P, Sidreansky D, ed. Tumours of the Paraganglionic System: Introduction. Lyon, France: IARC press; 2005. 190. Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res. 2012;44:328–333. 191. Fishbein L, Merrill S, Fraker DL, Cohen DL, Nathanson KL. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013;20:1444–1450. 192. Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas. 2010;39:775–783. 193. Welander J, Soderkvist P, Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2011;18:R253–R276. 194. Armstrong MJ, Chiosea SI, Carty SE, Hodak SP, Yip L. Thyroid paragangliomas are locally aggressive. Thyroid. 2012;22:88–93. 195. Matsumoto M, Abe K, Baba H, et al. Paraganglioma of the cauda equina: a report of two cases with unusual histopathological features. Clin Neuropathol. 2012;31:39–43. 196. Deng JH, Li HZ, Zhang YS, Liu GH. Functional paragangliomas of the urinary bladder: a report of 9 cases. Chin J Cancer. 2010;29:729–734. 197. van Duinen N, Steenvoorden D, Kema IP, et al. Increased urinary excretion of 3-methoxytyramine in patients with head and neck paragangliomas. J Clin Endocrinol Metab. 2010;95:209–214. 198. Sawka AM, Jaeschke R, Singh RJ, Young Jr. WF. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab. 2003;88:553–558. 199. Eisenhofer G, Goldstein DS, Sullivan P, et al. Biochemical and clinical manifestations of dopamine-producing paragangliomas: utility of plasma methoxytyramine. J Clin Endocrinol Metab. 2005;90:2068–2075. 200. Bustillo A, Telischi F, Weed D, et al. Octreotide scintigraphy in the head and neck. Laryngoscope. 2004;114:434–440. 201. Kayani I, Bomanji JB, Groves A, et al. Functional imaging of neuroendocrine tumors with combined PET/CT using 68 Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) and 18F-FDG. Cancer. 2008;112:2447–2455. 202. Chen L, Li F, Zhuang H, Jing H, Du Y, Zeng Z. 99mTc-HYNIC-TOC scintigraphy is superior to 131I-MIBG imaging in the evaluation of extraadrenal pheochromocytoma. J Nucl Med. 2009;50:397–400. 203. Hoegerle S, Ghanem N, Altehoefer C, et al. 18F-DOPA positron emission tomography for the detection of glomus tumours. Eur J Nucl Med Mol Imaging. 2003;30:689–694. 204. Treglia G, Cocciolillo F, de Waure C, et al. Diagnostic performance of 18F-dihydroxyphenylalanine positron emission tomography in patients with paraganglioma: a meta-analysis. Eur J Nucl Med Mol Imaging. 2012;39:1144–1153.

186


205. Fiebrich HB, Brouwers AH, Kerstens MN, et al. 6-[F-18]fluoro-l-dihydroxyphenylalanine positron emission tomography is superior to conventional imaging with (123)I-metaiodobenzylguanidine scintigraphy, computer tomography, and magnetic resonance imaging in localizing tumors causing catecholamine excess. J Clin Endocrinol Metab. 2009;94:3922–3930. 206. Lodish MB, Adams KT, Huynh TT, et al. Succinate dehydrogenase gene mutations are strongly associated with paraganglioma of the organ of Zuckerkandl. Endocr Relat Cancer. 2010;17:581–588. 207. Klein RD, Jin L, Rumilla K, Young Jr. WF, Lloyd RV. Germline SDHB mutations are common in patients with apparently sporadic sympathetic paragangliomas. Diagn Mol Pathol. 2008;17:94–100. 208. Laird AM, Gauger PG, Doherty GM, Miller BS. Paraganglioma: not just an extra-adrenal pheochromocytoma. Langenbecks Arch Surg. 2012;397:247–253. 209. Eisenhofer G, Tischler AS, de Krijger RR. Diagnostic tests and biomarkers for pheochromocytoma and extra-adrenal paraganglioma: from routine laboratory methods to disease stratification. Endocr Pathol. 2012;23:4–14. 210. Pinato DJ, Ramachandran R, Toussi ST, et al. Immunohistochemical markers of the hypoxic response can identify malignancy in phaeochromocytomas and paragangliomas and optimize the detection of tumours with VHL germline mutations. Br J Cancer. 2013;108:429–437. 211. Clarke MR, Weyant RJ, Watson CG, Carty SE. Prognostic markers in pheochromocytoma. Hum Pathol. 1998;29: 522–526. 212. Kimura N, Watanabe T, Noshiro T, Shizawa S, Miura Y. Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol. 2005;16: 23–32. 213. Strong VE, Kennedy T, Al-Ahmadie H, et al. Prognostic indicators of malignancy in adrenal pheochromocytomas: clinical, histopathologic, and cell cycle/apoptosis gene expression analysis. Surgery. 2008;143:759–768. 214. Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol. 2002;26:551–566. 215. Young AL, Baysal BE, Deb A, Young Jr. WF. Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. J Clin Endocrinol Metab. 2002;87:4101–4105. 216. Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab. 2005;90:2110–2116. 217. Bosca Robledo A, Ponce Marco JL, Belda Ibanez T, Meseguer Anastasio MF, Gomez Gavara C. Pheochromocytomatosis: a risk after pheochromocytoma surgery. Am Surg. 2010;76:E122–E124. 218. Janetschek G, Finkenstedt G, Gasser R, et al. Laparoscopic surgery for pheochromocytoma: adrenalectomy, partial resection, excision of paragangliomas. J Urol. 1998;160:330–334. 219. Mitchell J, Siperstein A, Milas M, Berber E. Laparoscopic resection of abdominal paragangliomas. Surg Laparosc Endosc Percutan Tech. 2011;21:e48–e53. 220. Adjalle R, Plouin PF, Pacak K, Lehnert H. Treatment of malignant pheochromocytoma. Horm Metab Res. 2009;41: 687–696. 221. Cheng L, Leibovich BC, Cheville JC, et al. Paraganglioma of the urinary bladder: can biologic potential be predicted? Cancer. 2000;88:844–852. 222. van Heerden JA, Roland CF, Carney JA, Sheps SG, Grant CS. Long-term evaluation following resection of apparently benign pheochromocytoma(s)/paraganglioma(s). World J Surg. 1990;14:325–329. 223. Burnichon N, Briere JJ, Libe R, et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet. 2010;19:3011–3020. 224. Schlisio S, Kenchappa RS, Vredeveld LC, et al. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008;22:884–893. 225. Ladroue C, Carcenac R, Leporrier M, et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N Engl J Med. 2008;359:2685–2692. 226. Qin Y, Yao L, King EE, et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet. 2010;42:229–233. 227. Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43:663–667. 228. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–1466. 229. Mannelli M, Castellano M, Schiavi F, et al. Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009;94: 1541–1547. 230. Woodward ER, Maher ER. von Hippel-Lindau disease and endocrine tumour susceptibility. Endocr Relat Cancer. 2006;13:415–425. 231. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260:1317–1320. 232. Shuin T, Yamasaki I, Tamura K, Okuda H, Furihata M, Ashida S. von Hippel-Lindau disease: molecular pathological basis, clinical criteria, genetic testing, clinical features of tumors and treatment. Jpn J Clin Oncol. 2006;36:337–343. 233. Woodward ER, Eng C, McMahon R, et al. Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL. Hum Mol Genet. 1997;6:1051–1056. 234. Nielsen SM, Rubinstein WS, Thull DL, et al. Genotype-phenotype correlations of pheochromocytoma in two large von Hippel-Lindau (VHL) type 2A kindreds with different missense mutations. Am J Med Genet A. 2011;155A:168–173. 235. Baysal BE, Ferrell RE, Willett-Brozick JE, et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science. 2000;287:848–851.


187

236. Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet. 2000;26: 268–270. 237. Astuti D, Hart-Holden N, Latif F, et al. Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clin Endocrinol (Oxf). 2003;59:728–733. 238. Benn DE, Gimenez-Roqueplo AP, Reilly JR, et al. Clinical presentation and penetrance of pheochromocytoma/ paraganglioma syndromes. J Clin Endocrinol Metab. 2006;91:827–836. 239. Bayley JP, Kunst HP, Cascon A, et al. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol. 2010;11:366–372. 240. Kunst HP, Rutten MH, de Monnink JP, et al. SDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011;17:247–254. 241. Astuti D, Douglas F, Lennard TW, et al. Germline SDHD mutation in familial phaeochromocytoma. Lancet. 2001;357: 1181–1182. 242. Schiavi F, Boedeker CC, Bausch B, et al. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene. J Am Med Assoc. 2005;294:2057–2063. 243. Ricketts CJ, Forman JR, Rattenberry E, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD. Hum Mutat. 2010;31:41–51. 244. Korpershoek E, Favier J, Gaal J, et al. SDHA immunohistochemistry detects germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas. J Clin Endocrinol Metab. 2011;96:E1472–E1476. 245. Young Jr. WF, Abboud AL. Editorial: paraganglioma—all in the family. J Clin Endocrinol Metab. 2006;91:790–792. 246. Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2:851–856. 247. Wells Jr. SA, Santoro M. Targeting the RET pathway in thyroid cancer. Clin Cancer Res. 2009;15:7119–7123. 248. Walther MM, Herring J, Enquist E, Keiser HR, Linehan WM. von Recklinghausen's disease and pheochromocytomas. J Urol. 1999;162:1582–1586. 249. Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med. 2009;266:43–52. 250. Janeway KA, Kim SY, Lodish M, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2011;108:314–318. 251. Matyakhina L, Bei TA, McWhinney SR, et al. Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. J Clin Endocrinol Metab. 2007;92:2938–2943. 252. Pasini B, McWhinney SR, Bei T, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008;16:79–88. 253. Burnichon N, Cascon A, Schiavi F, et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 2012;18:2828–2837. 254. Eisenhofer G, Huynh TT, Pacak K, et al. Distinct gene expression profiles in norepinephrine- and epinephrineproducing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Relat Cancer. 2004;11:897–911. 255. Hensen EF, Goeman JJ, Oosting J, et al. Similar gene expression profiles of sporadic, PGL2-, and SDHD-linked paragangliomas suggest a common pathway to tumorigenesis. BMC Med Genomics. 2009;2:25. 256. Favier J, Gimenez-Roqueplo AP. Pheochromocytomas: the (pseudo)-hypoxia hypothesis. Best Pract Res Clin Endocrinol Metab. 2010;24:957–968. 257. Pollard PJ, El-Bahrawy M, Poulsom R, et al. Expression of HIF-1alpha, HIF-2alpha (EPAS1), and their target genes in paraganglioma and pheochromocytoma with VHL and SDH mutations. J Clin Endocrinol Metab. 2006;91:4593–4598. 258. Gill AJ, Benn DE, Chou A, et al. Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010;41:805–814. 259. van Nederveen FH, Gaal J, Favier J, et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 2009;10:764–771.

Pheochromocytoma: present diagnosis and management.

Diagnosis and management of pheochromocytoma: a practical guide to clinicians.

Pheochromocytoma and paraganglioma: diagnosis, genetics, management, and treatment.

Diagnosis and treatment of pheochromocytoma during pregnancy.

Management of pheochromocytoma during pregnancy.

[Pheochromocytoma: update on diagnosis and therapy].

Intrarenal pheochromocytoma: preoperative angiographic diagnosis.

[Biological diagnosis of pheochromocytoma in 2014].

Pheochromocytoma management, outcomes and the role of cortical preservation.

Update on Modern Management of Pheochromocytoma and Paraganglioma.

Cervical pheochromocytoma: a rare localization and a difficult diagnosis.

Measurement of plasma methoxyamines for the diagnosis of pheochromocytoma.

Differential diagnosis of a fulminant myocarditis: the pheochromocytoma crisis.

Surgical management of pheochromocytoma with the use of metyrosine.

Rapid sequence excretory urography in the diagnosis of pheochromocytoma.

Improvement of preoperative management in patients with adrenal pheochromocytoma.

Perioperative Management of Severe Hypertension during Laparoscopic Surgery for Pheochromocytoma.

Surgical management of pheochromocytoma in a 13-week pregnant woman.

Laparoscopic cortical sparing adrenalectomy for pediatric bilateral pheochromocytoma: anesthetic management.

Hemoptysis: diagnosis and management.

Thymoma: diagnosis and management.

Hyphema: diagnosis and management.

Syncope: diagnosis and management.

Diagnosis and management of psoriasis.