A. Types

1. Spontaneous (non-syndromic) - sporadic, ~90% of cases
2. Hereditary (syndromic) ~10% of cases
3. Cell Types
   1. Neuroendocrine etiology derived from adrenal medulla
   2. Chromaffin cells which produce catecholamines
   3. About 90% of tumors are associated with adrenal glands
   4. Remaining 10% are found in extra-adrenal abdominal and in thoracic locations
4. All tumors of the autonomic nervous system

B. Pathogenesis

1. Von-Hippel-Lindau Syndrome (VHL)
   1. 40% develop Pheo
   2. VHL due to mutations in the VHL gene on chromosome 3p25
   3. Normal VHL protein blocks elongin, a translational control factor
   4. Some c-ret mutations are associated with VHL Disease
2. Multiple Endocrine Neoplasia (MEN) Types IIa and IIb
   1. Pheo and medullary thyroid carcinoma are common to both types
   2. MEN IIb due to RET mutations at codon 634
   3. MEN 2 arises from mutations of the RET gene on chromosome 10
   4. MEN-2B is usually caused by germ-line mutations in the RET gene
   5. MEN-2A may be caused by non-germ-line mutations in the RET gene
3. Neurofibromatosis Type 1 (NF1)
   1. <10% of NF1 patients develop Pheo
   2. NF1 gene mutations (chromosome 17q11) cause NF1
   3. NF1 protein is a GTP activating protein (GAP) involved in signalling and cell cycle
   4. Protein behaves like a tumor suppressor, regulates RAS signalling
   5. Occurs in about 1:3500 persons
4. Associated with Paraganglioma Syndromes (PGL) [3,8]
   1. Pheo associated with paragangliomas in various PGL syndromes
   2. Paragangliomas also automonic nervous system tumors in the head and neck area
   3. Most paragangliomas are non-functioning
   4. PGL syndrome 1 associated with succinate dehydrogenase subunit D (SDHD) mutations
   5. PGL syndrome 4 associated with SDH subunit B (SDHB) mutations
   6. SDH subunit C mutations are also found in paragangliomas, nearly always benign [8]
   7. >25% of patients with head and neck paragangliomas carry SDH mutations
   8. SDH encode mitochondrial enzymes involved in oxidative phosphorylation
5. Sporadic [4]
   1. 24% of patients with defined germline mutations
   2. VHL mutations most common
   3. RET mutations next most common
   4. SDHB and SDHD mutations also found (often with paragangliomas)
6. In patients with pheochromocytoma, germline analyses of VHL, SDHA, SDHB, SDHD, and RET genes are recommended

C. Presentation [5]

1. Typically presents as paroxysms of symptoms and signs
   1. Mean age of patients at presentation is around 42 years (depends on etiology)
   2. May also present in children
2. Intermittent symptoms and signs means clinical diagnosis is difficult
   1. Headaches ~75%
   2. Palpitations ~65%
   3. Sweating / Diaphoresis ~65%
   4. Pallor ~40%
   5. Major sign is sustained hypertension (HTN) ~55%
   6. HTN emergency may occur including cerebral compromise (with severe headaches)
   7. Chronic or acute renal failure (with renal aplasia) can occur
   8. Orthostatic hypotension on background of HTN (range 10-50%)
   9. Anxiety/Panic ~30%
3. HTN in Pheo
   1. ~55% sustained, 25% paroxysmal, 4% pregnancy
   2. Severe HTN and cardiac dysfunction may occur with fatal results

D. Screening [6]

1. Metanephrines
   1. Metanephrines are 0-methylated metabolites of catecholamines
   2. Metanephrines include normetanephrine and metanephrine
   3. Plasma combined metanephrine levels are the best screening tests for Pheo [6]
   4. Normal plasma free metanephrines exclude the diagnosis of Pheo
   5. Plasma metanephrines are also used to monitor recurrence or tumor growth
2. Urinary 24 hour metanephrines or plasma catecholamine levels are confirmatory
3. Serum catecholamines may be elevated, but disease is paroxysmal (may be normal)
4. Plasma chromagranin A levels elevated in >80% of patients (96% specific) [7]
5. Clonidine suppression test or glucagon stimulation test may be confirmatory

E. Differential Diagnosis (Panel 3, Ref [1])

1. Endocrine
   1. Hyperthyroidism
   2. Carcinoid
   3. Hypoglycemia
   4. Medullar thyroid carcinoma
   5. Mastocytosis
   6. Menopausal syndrome
2. Cardiovascular
   1. Heart Failure
   2. Arrhythmias
   3. Ischemic heart disease
   4. Baroreflex failure
3. Neurological
   1. Migraine
   2. Stroke
   3. Diencephalic epilepsia
   4. Meningioma
   5. Postural orthostatic tachycardia syndrome (POTS)
4. Miscellaneous
   1. Porphyria
   2. Panic disorder or anxiety
   3. Factitious disorder - including due to drugs such as ephedrine
   4. Drug treatments - such as monoamine oxidase (MAO) inhibitors
   5. Illegal drugs - such as cocaine, amphetamines

F. Localization of the Tumor [1]

1. CT scan typically used for diagnosis and is good for visualizing adrenals
2. MRI is better than CT for non-adrenal Pheo with bright T2 signal of tumor
3. Failure to localize tumor may indicate need for whole body CT
4. Additional Modalities
   1. 131-Iodine-metaiodobenzylguanidine (MIBG) nuclear medicine scans are available
   2. Various positron emission tomographic (PET) methods are now available
   3. PET scans use 18F-6-fluorodopamine or 11C-hydroxyephedrine for localization
5. Location of pheochromocytoma ("10% rules")
   1. 10% extra-abdominal
   2. 10% bilateral adrenal
   3. 10% other abdominal (non-adrenal)
   4. 10% malignant
   5. 10% familial

G. Treatment [1,5]

1. Hypertensive crisis is treated with nitroprusside, labetolol, phentolamine (alpha blockade)
2. Perioperative Preparation [5]
   1. Once acute issues around HTN have been addressed
   2. Reverse sympathetic stimulation
   3. Alpha adrenergic blockers are critical pre-operatively
   4. Phenoxybenzamine (non-competitive) or doxazosin (competitive) are oftern used
   5. Oral phenoxbenzamine or doxazosin usually begun 10-14 days prior to surgery
   6. ß-adrenergic blockers may not be required (are mainly used for arrhythmia control) and should only be used AFTER alpha-adrenergic blockers are given
   7. ß-blockade prior to alpha-blockade can precipitate a hypertensive crisis
   8. Labetolol has stronger actions on ß- than on alpha-adrenergic receptors
   9. Calcium channel blockers (dihydropyridine) may be used for additional blood pressure control
   10. Volume repletion must accompany alpha-adrenergic blockade to maintain perfusion
   11. Clonidine, a central alpha2-adrenergic agonist, to minimize sympathetic stimulation
   12. Phenotolamine (intravenous alpha1/2-adrenergic antagonist) used intraoperatively for blood pressure control
   13. Alpha-methyl-p-tyrosine (metirosine) may be used for 2-3 weeks to deplete catechols
3. Surgical Resection
   1. Either open or laparoscopic procedure is carried out
   2. Laparoscopic removal is now the procedure of choice
4. Surgical Issues [1]
   1. Patients at high risk for surgery due to vascular instability
   2. Main problem is hypertensive crisis during surgery (acute catecholamine release)
   3. Alpha- ± ß-adrenergic blockade perioperatively are fairly effective
   4. Laparoscopic procedure has reduced pain, recovery time, compared with open surgery
   5. Hypotension after tumor removal is common, due to catecholamine withdrawal
   6. Partial adrenalectomy is sometimes used to maintain adequate adrenal cortical function
   7. Close surveillance is required for at least 24 hours after surgery
   8. Both hypotension and hypoglcyemica are main concerns postoperatively
   9. Hypotension mitigated with fluids, occasionally ephedrine or vasopressin
   10. Hypoglycemia related to rebound hyperinsulinemia after tumor removal
5. Plasma chromagranin A levels can be used to monitor therapy [7]
6. Over time, blood pressure medicines may be reduced or withdrawn
   1. Postoperative hypotension is common and must be monitored
   2. Volume repletion including adequate salt intake is critical
   3. Labetolol is typically used in chronic setting
   4. ACE inhibitors are usually added if needed in chronic setting
7. Malignant Pheo [1]
   1. No effective treatment currently available
   2. Radical surgery is most effective
   3. Symptomatic treatment as above, particularly with metirosine
   4. Treatment with combination chemotherapy generally not effective
   5. Treatment with 131-iodine-MIBG provides <5% complete, ~30% partial responses
   6. Higher doses of 131-I-MIBG appear more effective and are being investigated

References

1. Lenders JWM, Eisenhofer G, Mannelli M, Pacak K. 2005. Lancet. 366(9486):665
2. Conlin PR and Faquin WC. 2001. NEJM. 344(17):1314 (Case Record)
3. Heumann HPH, Pawlu C, Peczkowska M, et al. 2004. JAMA. 292(8):943
4. Neumann HPH, Bausch B, McWhinney SR, et al. 2002. NEJM. 346(19):1459
5. Kohane DS, Ingelfinger JR, Nimkin K, Wu CL. 2005. NEJM. 352(21):2223
6. Lenders JWM, Pacak K, Walther MM, et al. 2002. JAMA. 287(11):1427
7. Taupenot L, Harper KL, O'Connor DT. 2003. NEJM. 348(12):1134
8. Schiavi F, Boedeker CC, Bausch B, et al. 2005. JAMA. 294(16):2057