Oelkers W (1996). Adrenal insuf \201 ciency. N Engl J Med 335:1206 \200\2231212. 41-Draznin-Chap41.indd 205 4/1/2011 5:31:43 PM CHAPTER 42 Long-term glucocorticoid administration 206 Long-term glucocorticoid administration Both exogenous glucocorticoid administration and endogenous excess glucocorticoids (Cushing \200\231s syndrome) lead to a negative feedback effect on the hypothalamo \200\223pituitar y \200\223adrenal (HPA) axis, leading to suppression of both CRH and ACTH secretion and atr ophy of the zona fasiculata and reticularis of the adrenal cortex. Short-term steroids Any patient who has received glucocorticoid treatment for <3 weeks is u nlikely to have clinically signi \201 cant adrenal suppression, and if the medi- cal condi tion allows it, glucocorticoid treatment can be stopped acutely. A major stress within a we ek of stopping steroids should, however, be covered with glucocorticoids. Exceptions to this are patients who have other possible reasons for adrenocortical insuf \201 ciency, who have received >40 mg prednisolone (or equivalent), where a short course ha s been prescribed within 1 year of ces- sation of long-term therapy, or evening doses (i HP A axis suppression). Steroid cover While receiving glucocorticoid treatment and within 1 year of steroid withdra wal, patients should receive standard steroid supplementation ( Box 42.1 ) at times of stre ss, e.g., major trauma, surgery, and infection ( b p. 562) . Box 42.1 Steroid equivalents \200 1 mg hydrocortisone \200 1.25 mg cortisone acetate \200 0.25 mg prednisolone \200 0.20 mg prednisone \200 3.75 mcg dexamethasone 4 mg pre dnisolone \211 20 mg hydrocortisone \211 75 mcg dexamethasone 42-Draznin-Chap42.indd 206 3/31/2011 2:45:36 PM CUSHING \200\231S SYNDROME 207 Box 42.2 Dehydroepiandrosterone (DHEA) \200 DHEA is an abundant circulating adrenal andro gen with a production rate of 25 \200\22350 mg/day. Its levels undergo a progressive declin e with i age, and there has been interest in its physiological role. Epidemiological data suggest a link between changes in DHEA and age-related changes including an inverse relationship between DHEA and cardiovascular disea se, Alzheimer disease, and malignancy. Although animal studies have suggested potential therapeutic bene \201 t of DHEA therapy, small studies in humans have so far failed to demonstrate convincing bene \201 t otherwise and apart from short-term improvement in well-being. Recent evidence suggests that DHEA replacement in patients with Addison \200\231s disease may have bene \201 cial effects on well-being. Long-term steroids When patients are receiving supraphysiological doses (>5.0 mg prednis- o ne, or equivalent) of glucocorticoid, dose reduction depends on disease activity. Once a da ily equivalent of 5.0 mg prednisone is reached, the rate of reduction should be slower to a llow recovery of the HPA axis. If concerned about disease resolution, the rate of reduction of gluco- corticoids is determ ined by the disease process until 5.0 mg equivalent is reached. If the disease has resolved , the dose can be rapidly reduced to 5.0 mg prednisone by a reduction of 2.5 mg every 3 \200\2235 days. Once the patient is established on 5.0 mg prednisolone, consider chang- ing to hydrocortiso ne (20 mg in the morning), as this has a shorter t and will therefore lead to less prolon ged suppression of ACTH. The daily hydrocortisone dose should be reduced by 2.5 mg every 1 \200\2232 weeks or as tol erated until a dose of 10 mg is reached. After 2 \200\2233 months, a 9 A.M. cortisol is che cked 24 hours after last dose of hydrocortisone. If it is >10 mcg/dL, then hydrocortisone c an be stopped and a Cortrosyn test performed. If the 9 A.M. cortisol is <10 mcg/dL, then continue hydrocorti- sone 10 mg for another 2 \200\2233 months and repeat the 9 A.M. corti sol. When basal cortisol is >14 mcg/dL, stop regular hydrocortisone and administer in emergency only. Supplemental steroids during intercurrent illness are not required. Cushing \200\231s syndrome Patients with Cushing \200\231s syndrome who are on metyrapone o r have recently treated disease, whatever the cause, may also have HPA axis suppression and may therefore need steroid replacement at times of stress. Further reading Baulieu E (1996). DHEA: a fountain of youth? J Clin Endocrinol Metab 81:314 7 \200\2233151. Nippoldt TB, Nair KS (1998). Is there a case for DHEA replacement? Balli \200\231re Clin Endocrinol Metab 12:507 \200\223520. 42-Draznin-Chap42.indd 207 3/31/2011 2:45:36 PM CHAPTER 43 Adrenal incidentalomas 208 Adrenal incidentalomas De \201 nition and epidemiology A true incidentaloma is an incidentally detected lesion wi th no patho- physiological signi \201 cance. It needs to be differentiated from incidental ly detected but clinically relevant masses. The incidental detection of an adrenal mass is becoming more common as i numbers of imaging procedures are performed and with technological improvements in imaging. Autopsy studies suggest an incidence of adrenal adenomas of 1 \200\2236%. Imaging studies suggest an incidence of approximately 3.5%. Importance It is important to determine whether the incidentally discovered adrenal mass is \200 Malignant \200 Functioning and associated with excess hormonal secretion Differential diagnosis of an incidentally detected adrenal nodule \200 Cortisol-secreting adrenal adenoma causing Cushing \200\231s syndrome or subclinical Cushing \200\231s syndrome (5.2%) Mineralocorticoid-secreting adrenal adenoma \200 Androgen-secreting adenoma \200 CAH \200 Adrenal carcinoma (12%) \200 Metastasis (2%) \200 Pheochromocytoma (11%) \200 A drenal cysts (5%) \200 Lipoma \200 Myelolipoma (8%) \200 Hematoma \200 Ganglioneuro ma (4%) 43-Draznin-Chap43.indd 208 3/31/2011 2:45:56 PM MANAGEMENT 209 Investigations \200 Clinical assessment for symptoms and signs of excess hormone secretion and signs of extra-adrenal carcinoma Urinary free cortisol and overnight dexamethasone suppression test \200 Urinary free cate cholamines/metadrenalines \200 Plasma free metanephrines if available ( b see p. 215) \200 Aldosterone/renin ratio if hypertensive or hypokalemic \200 A homogeneous mass with a low attenuation value (<10 HU) on CT scan is likely to be a benign adenoma. Additional tests if adrenal carcinoma suspected: \200 24-hour urinary excretion of cortic osteroid metabolites \200 DHEA, 17A OH progesterone \200 17A estradiol (in males only) \200 Testosterone, androstendione (in virilizing tumors) Management Up to 20% of patients may develop hormonal excess during follow-up. This is unli kely if the tumor is <3 cm. Cortisol is the most common excess hormone. Surgery is indicated if there is the following: Evidence of a syndrome of hormonal excess attributable to the tumor \200 Biochemical evid ence of pheochromocytoma \200 Mass diameter >4 cm (i likelihood of malignancy and de \201 nitely if >6 cm in diameter) Imaging features suggestive of malignancy (e.g., lack of clearly circumscribed margin, vascular invasion) Nonsurgical management includes the following: \200 Repeat MRI at 6 and 12 months \200 Repeat biochemical screening annually \200 In patients with tumors that remain stable on two imaging studies carried out at least 6 months apart and do not exhibit hormonal hyperse cretion over 4 years, further follow-up may not be warranted. Further reading Chidiac RM, Aron DC (1997). Incidentalomas. Endocrinol Metab Clin North Am 26:233 \200\223253. Kloos RT, Gross MD, Francis IR, et al. (1995). Incidentally discovered adrenal masses. Endo cr Rev 16:460 \200\223484. Mansmann G, Lau J, Balk E, et al. (2004). The clinically inapparent adrenal mass: update in diagnosis and management. Endocr Rev 25(2):309 \200\223340. Newell-Price J, Grossman A (1996). Adrenal incidentaloma. Postgrad Med J 72:207 \200\223210 . Turner HE, Moore NR, Byrne JV, et al. (1998). Pituitary, adrenal and thyroid incidentalomas . Endocr Rel Cancer 5:131 \200\223150. Young WF Jr (2007). Clinical practice. The incidentally discovered adrenal mass. N Engl J M ed 356(6):601 \200\223610. 43-Draznin-Chap43.indd 209 3/31/2011 2:45:56 PM CHAPTER 44 Pheochromocytomas and paragangliomas 210 Pheochromocytomas and paragangliomas De \201 nition Pheochromocytomas are adrenomedullary catecholamine-secreting tumors Paraga ngliomas are tumors arising from extra-adrenal medullary neural crest derivatives, e.g., or gan of Zuckerkandl (sympathetic) or carotid body, aorticopulmonary, intravagal, or juguloty mpanic (parasymapthetic). They are usually in the head and neck, and only 25% are secretory . Incidence These are rare tumors, accounting for <0.1% of causes of hypertension. However, i t is a very important diagnosis because of the following: \200 The development of potenti ally fatal hypertensive crises \200 The reversibility of all its manifestations after sur gical removal of the tumor The lack of long-term ef \201 cacy of medical treatment \200 The appreciable incidence o f malignancy Epidemiology There is equal sex distribution, and tumors most commonly present in the third and fourth decades. Up to 50% may be diagnosed postmortem. Tumors may be bilateral, particularly where part of an inherited syn- drome ( Table 44.1 ). 44-Draznin-Chap44.indd 210 3/31/2011 2:46:21 PM EPIDEMIOLOGY 211 Table 44.1 Syndromes associated with pheochromocytomas Familial pheochromocytomas MEN-IIa and b b see p. 503 Isolated autosomal dominant trait Mutation in RET proto-oncogene (chromosome 10) Hyperparathyroidism and medullary thyroid carcinoma associated with pheochromocytoma MEN II b also associated with marfanoid phenotype b see p. 505 Mutation of VHL tumor suppressor ge ne (chromosome 3) Renal cell carcinoma, cerebellar hemangioblastoma, retinal angioma, renal and pancreatic cysts Pheochromocytomas in 25% Von Hippel \200\223Lindau syndrome b see p. 493 Neuro \201 bromatosis (NF) b see p. 490 Autosomal dominant condition caused by mutations of NF1 gene on chromosome 17 Phechromocyto mas in 0.5 \200\2231.0% Familial carotid body tumor Dominantly inherited disorder characterized by vascular tumors in the head and neck, most f requently at the carotid and bifurcation Succinate dehydrogenase gene (subunit D) Familial paraganglionoma Succinate dehydrogenase (subunits B,C,D) 44-Draznin-Chap44.indd 211 3/31/2011 2:46:21 PM CHAPTER 44 Pheochromocytomas and paragangliomas 212 Pathophysiology Sporadic tumors are usually unilateral and <10 cm in diameter. Tumors assoc iated with familial syndromes (see Box 44.1 ) are more likely to be bilateral and associate d with pre-existing medullary hyperplasia. Box 44.1 Who should be screened for the presence of a pheochromocy-toma? \200 Patients wi th a family history of MEN, VHL, neuro \201 bromatosis (NF), or SDH gene mutations Patients with paroxysmal symptoms \200 Young patients with hypertension \200 Patient de veloping hypertensive crisis during general anesthesia or surgery Patients with unexplained heart failure \200 Patients with an adrenal incidentaloma Malignancy Approximately 15 \200\22320% are malignant, and these are characterized by local invasion or distant metastasis rather than capsular invasion. Differentiating benign and malignant tumors is dif \201 cult and based mainly on presence of metastases, although chromosomal ploidy may be useful. Paragangliomas are more likely to be malignant and to recur. Typical sites for metastases are retroperitoneum, lymph nodes, bone, liver, and mediastinum. Secretory products Catecholamine secretion is usually adrenaline or noradrenaline and may b e constant or episodic. Phenylethanolamine- N -methyl transferase (PNMT) is necessary for m ethylation of noradrenaline to adrenaline and is cortisol dependent. Paragangliomas (except organ of Zuckerkandl) secrete noradrenaline only, as they lack PNMT. Small adrenal tumors tend to produce more adrenaline, whereas larger adrenal tumors produc e more noradrenaline, as a proportion of their blood supply is direct rather than corticome dul- lary and therefore lower in cortisol concentrations. Pure dopamine secretion is rare and may be associated with hypoten- sion. These tumors are more likely to be malignant. Other non-catecholamine secretory products may also be produced, including VIP, neuropeptid e Y, ACTH (associated with Cushing \200\231s syn- drome), parathyroid hormone (PTH), and PT H-related peptide (PTHrP). 44-Draznin-Chap44.indd 212 3/31/2011 2:46:21 PM COMPLICATIONS 213 Clinical features Sustained or episodic hypertension is often resistant to conventional the rapy. General \200 Sweating and heat intolerance >80% \200 Pallor or \202 ushing \200 Fee ling of apprehension \200 Pyrexia Neurological \200 Headache (throbbing or constant) (65%), paresthesiae, visual disturbance, seizures Cardiovascular \200 Palpitations (65%), chest pain, dyspnea, postural hypotension GI \200 Abdominal pain, constipation, nausea Complications \200 Cardiovascular \200\224 left ventricular failure, dilated cardiomyopat hy (reversible), dysrhythmias Respiratory \200\224 pulmonary edema \200 Metabolic \200\224 carbohydrate intolerance, hy percalcemia \200 Neurological \200\224 cerebrovascular, hypertensive encephalopathy Factors precipitating a crisis \200 Straining \200 Exercise \200 Pressure on abdomen \200\224tumor palpation, bending over \200 Surgery Drugs \200 Anesthetics \200 Unopposed B-blockade \200 IV contrast agents \200 Opiat es \200 Tricyclic antidepressants \200 Phenothiazines \200 Metoclopramide \200 Gluc agon 44-Draznin-Chap44.indd 213 3/31/2011 2:46:21 PM CHAPTER 44 Pheochromocytomas and paragangliomas 214 Investigations Demonstrate catecholamine hypersecretion A 24-hour urine collection is the standard test fo r screening for a pheo- chromocytoma. In a patient with suggestive symptoms, this is usuall y suf- \201 cient to con \201 rm or exclude the diagnosis. False negatives are more common when patients are asymptomatic and early in the disease. Pa rticular care is needed in familial cases, incidenta- lomas, and those in whom a general an esthetic has precipitated a hyper- tensive episode. Metadrenalines (either urine or plasma) offer more speci \201 c diagnostic tools than meas urement of unmetabolized catecholamines and provide the best biochemical tests for diagnosi ng pheochromocytoma. 24-hour urine collection for vanillylmandelic acid (VMA)/catecholamines/ metadrenalines ( b see Table 44.2 ) Urine is collected into bottles containing acid (warn patient). Because of the episodic nature of catecholamine secretion, at least 2 \227 24-hour collect ions should be performed. It is useful to perform a collec- tion while a patient is having symptoms if episodic secretion is suspected. Table 44.2 Substances interfering with urinary catecholamine levels Increased catecholamines A-Blockers Decreased catecholamines Variable effect Mono-amine oxidase inhibitors Levodopa B-Blockers Clonidine Tricyclic antidepressants Levodopa Guanethidine and other adrenergic neuron blockers Phenothiazines Drugs containing catecholamines, e.g., decongestants Calcium channel inhibitors Metoclopramide ACE inhibitors Domperidone Bromocriptine Hydralazine Diazoxide Glyceryltrinitrate Sodium nitroprusside Nicotine Theophylline Caffeine Amphetamine 44-Draznin-Chap44.indd 214 3/31/2011 2:46:21 PM INVESTIGATIONS 215 The sensitivity of urinary VMAs ( Table 44.3 ) is somewhat less than free catecholamines or metadrenalines and also in \202 uenced by dietary intake. Tricyclic antidepressants (TCAs) and labetalol interfere with adrenaline measurements and should be stopped for 4 days. Plasma catecholamine measurement Intermittent secretion, and the short t of catecholamine s, makes this test of limited use in screening. Plasma metadrenalines may be more useful as their t is longer and offer high speci \201 city. Normal levels drawn during an episode are strongly against the diagnosis. Routine measureme nt requires controlled conditions \200\224supine and cannulated for 30 minutes, 10 mL blood drawn into a lithium heparin tube and cold spun. Plasma catecholamines are elevated by ren al failure, caffeine, nicotine, exercise, and some drugs. Plasma catecholamines 3 \227 the upper limit of normal are suspicious of a pheochromocytoma in symptomatic individuals. Catecholamine levels in asymptomatic individuals investigated for an adrenal incidentaloma or due to a familial condition are often diagnosed at an earlier stage and may therefore ha ve lower catecholamines. Suppression tests ( b see Box 44.2 ) These tests may be used to di fferentiate patients who have borderline cat- echolamine levels but may offer little advant age over the screening tests already described. \200 Clonidine 300 mcg orally \200\224fa ilure of suppression of plasma catecholamines into normal range at 120 and 180 minutes is suggestive of tumor Provocative tests These are not used routinely as they do not enhance diagnostic accuracy a nd are potentially dangerous. Table 44.3 Sensitivity and speci \201 city of tests Test Sensitivity Speci \201 city Plasma free metanephrines 99% 89% 2 \227 24-hour urinary free catecholamines 96% 95% Urinary metanephrines 93% 93% Urinary VMA 65% 95% Clonidine suppression test 97% MRI 98% 70% CT 93% 70% MIBG 80% 95% 44-Draznin-Chap44.indd 215 3/31/2011 2:46:21 PM CHAPTER 44 Pheochromocytomas and paragangliomas 216 Box 44.2 Test procedures Clonidine suppression test \200 Patient supine and cannulated for 30 minutes \200 Cloni dine 300 mcg orally \200 Plasma catecholamines measured at time 0, 120, and 180 minutes \200 Failure to suppress into the normal range is suggestive of a tumor. \200 1.5% false -positive rate in patients with essential hypertension Localization of tumor Imaging These are large tumors, in contrast to Conn \200\231s syndrome, and not easily miss ed with good-quality imaging to the bifurcation of the aorta. Approximately 98% will be det ected in the abdomen. Less than 2% are in the chest and 0.02% are in the head. Adrenal imaging with nonionic cont rast should be performed initially, then body imaging (ideally MRI) if tumor is not localized in adrenal. \200 MRI: bright hy perintense image on T2 \200 CT: less sensitive and speci \201 c \200\224less good at dis tinguishing between different types of adrenal tumors 123 I-MIBG scan ( b see Box 44.3 ) Meta -Iodobenzylguanidine is a chromaf \201 n-seeking a nalog. Imaging using MIBG is positive in 60 \200\22380% pheochromocytomas and may locate tu mors not visualized on MRI, e.g., multiple and extra-adrenal tumors. Speci \201 city is ne arly 100%. An MIBG scan is performed preoperatively to exclude multiple tumors. Phenoxybenzamine may lead to false-negative MIBG imaging, so these scans should be preformed before commencing this drug. Box 44.3 Drugs interfering with MIBG uptake in pheochromocytoma* \200 Opioids \200 Coca ine \200 Tramadol \200 Tricyclic antidepressants Amitriptyline \200 Imipramine \200 Sympathomimetics Phenylpropanolamine, pseudoephedrine, amphetamine, dopamine, salbutamol Antihypertensives/cardiovascular agents Labetalol, metoprolol, amiodarone, reserpine, guanethidine, calcium channel blockers nifedipine and amlodipine, ACE inhibitors captopril and enalapril Should be discontinued 7 \200\22314 days prior to scan. 44-Draznin-Chap44.indd 216 3/31/2011 2:46:21 PM INVESTIGATIONS 217 18F \202 uorodopamine PET scanning is superior to MIBG in localizing met- astatic disease. No K + iodide is necessary to block thyroid uptake. Positron emission tomography (PET) [18F] \202 uorodeoxyglucose ana- log [11C]metahydroxyep hedrine (mHED) have both been used as radionucleotides. (FDG) and the norepinephrine Current data are insuf \201 cient to determine which radionucleotide has the greatest sensitivity and speci \201 city. Sensitivity is better than MIBG and approaches 100%, but speci \201 city is worse with false positives being reported. Venous sampling This is used to localize a pheochromocytoma/paraganglioma if imaging is unh elpful. Caution: A- and B-blockade should be administered before the procedure. Reversal of the ratio of noradrenaline to adrenaline ( N <1) in the adre- nal vein is suggestive of a pheochromocytoma. Screening for associated conditions Up to 24% of patients with apparently sporadic pheochro mocytomas may have a familial disorder. Therefore, high-risk patients should be screened fo r the presence of associated conditions, even if asymptomatic. Screening can be performed e ither by looking for associated clinical manifestations or by genetic testing. Genetic testing in nonsyndromic pheochromocytoma has shown a hereditary predisposition in 2 4%, of which 45% had germ-line mutations in VHL, 20% had mutations in RET, 18% mutations in SDHD, and 17% mutations in SDHB. MEN (p. 504) \200 Serum calcium \200 Serum calcitonin (pheochromocytomas precede medull ary thyroid carcinoma in 10%) VHL (p. 494) \200 Opthalmoscopy \200\224retinal angiomas are usually the \201 rst manif estation \200 MRI posterior fossa and spinal cord \200 US of kidneys \200\224if not ade quately imaged on MRI of adrenals NF1 (see p. 490) \200 Clinical examination for caf -au-lait spots and cutaneous neuromas Indications for screening for genetic conditions as a cause for a pheochromocytoma \200 B ilateral tumors \200 Extra-adrenal tumor including head and neck \200 Age of onset (<50 years 45% positive, >40 years 7% positive, >50 years 1% positive) \200 Malignancy 44-Draznin-Chap44.indd 217 3/31/2011 2:46:21 PM CHAPTER 44 Pheochromocytomas and paragangliomas 218 Management Medical It is essential that any patient be fully prepared with A- and B-blockade before re ceiving IV contrast or undergoing a procedure such as venous sampling or surgery. A-Blockade must be started before B-blockade to avoid precipitating a hypertensive crisis due to unopposed A-adrenergic stimulation. \200 A -blockade \200\224 begin phenoxybenzamine, as soon as diagnosis is made. Start at 10 mg 2 \227 day by mouth, and increase up to 20 mg 4 \227 day. B -blockade \200\224use a B-blocker such as propranolol 20 \200\22380 mg q8h by mouth 48 \200\22372 hours after starting phenoxybenzamine and with evidence of adequate A-blockade b lockade (generally noted by a postural fall in BP). Treatment is started in the hospital. Monitor BP, pulse, and hematocrit. The goal is a BP o f 130/80 or less sitting and 100 mg systolic standing, pulse 60 \200\22370 sitting and 70 \200\22380 standing. Reversal of A-mediated vasoconstriction may lead to hemodilution (chec k Hb preoperatively). To ensure complete blockade before surgery, IV phenoxybenzamine (1 mg/kg over 4 hours in 10 0 mL 5% dextrose) is administered on the 3 days before surgery. There is less experience wi th competetive A-adrenergic blockade such as prazosin. Surgical Surgical resection is curative in most patients, leading to normotension in at lea st 75%. Mortality from elective surgery is <2%. It is essential that the anesthetic and surgical te ams have expertise of management of phechromocytomas perioperatively. Surgery may be laparoscopic if the tumor is small and apparently benign. Careful perioperat ive anesthetic management is essential, as tumor han- dling may lead to major changes in BP and also occasionally cardiac arrythmias. Phentolamine, nitroprusside, or IV nicardipine are useful to treat periop- erative hyperten sion, and esmolol or propranolol for perioperative arryth- mias. Hypotension (e.g., after t umor devascularization) usually responds to volume replacement, but occasionally requires i notropic support. Follow-up Cure is assessed by 24-hour urine free catecholamine measurement, but since catec holamines may remain elevated for up to 10 days following surgery, these should not be perf ormed until 2 weeks postoperatively. Lifelong follow-up is essential to detect recurrence of a benign tumor, or metastasis from a malignant tumor, as it is impossible to exclude malig- nancy on a histological specimen. Chromogranin A is also a useful marker (falsely elevated with proton pump therapy, steroids, and renal failure). 44-Draznin-Chap44.indd 218 3/31/2011 2:46:21 PM MANAGEMENT 219 Malignancy Malignant tumors require long-term A- and B-blockade. The tyrosine kinase inhibi tor A- methylparatyrosine may help control symptoms. High-dose 131 I MIBG can be used to tr eat metastatic disease. Chemotherapy with cyclophosphamide, vincristine, adriamycin , and d acar- bazine has been associated with symptomatic improvement. Radiotherapy can be useful palliation in patients with bony metastases. Prognosis Hypertension may persist in 25% patients who have undergone successful tumor remo val. \200 5-year survival for benign tumors is 96%, and the recurrence rate is <10%. 5-year survival for malignant tumors is 44%. \200 SHB gene mutation is associated with a shorter survival. Further reading Astuti D, Latif F, Dallol A, et al. (2001). Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to famili al paraganglioma. Am J Hum Genet 69:49 \200\22354. Erickson D, Kudva YC, Ebersold MJ, et al. (2001). Benign paragangliomas: clinical presentat ion and treatment outcomes in 236 patients. J Clin Endocrinol Metab 86(11):5210 \200\223521 6. Gimm O, Armanios M, Dziema H, et al. (2000). Somatic and occult germ-line mutations in SDHD , a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res 60(24):6822 \200\2236825. Ilias I, Yu J, Carrasquillo JA, et al. (2003). Superiority of 6-[18F]- \202 uorodopamine p ositron emission tomography versus [131I]-metaiodobenzylguanidine scintigraphy in the local ization of metastatic pheochromocytoma. J Clin Endocrinol Metab 88(9):4083 \200\2234087. Kudva YC, Sawka AM, Young WF Jr (2003). The laboratory diagnosis of adrenal pheochromocy- t oma: the Mayo Clinic experience. J Clin Endocrinol Metab 88(10):4533 \200\2234539. Lenders JWM, Pacak K, Walther MM, et al. (2002) Biochemical diagnosis of pheochromocytoma: Which test is best? JAMA 287(11):1427 \200\2231434. Neumann HP, Bausch B, McWhinney SR, et al. (2002). Germ-line mutations in nonsyndromic pheo - chromocytoma. N Engl J Med 346(19):1459 \200\2231466. 44-Draznin-Chap44.indd 219 3/31/2011 2:46:21 PM This page intentionally left blank