History

Fact Explanation
Headache Due to hypertensive encephalopathy. In pheochromocytoma, continuously elevated BP causes vasodilation of cerebral blood vessels , resulting in hypoperfusion and ischemia of brain. [1]
Palpitation From any cardiac arrhythmia producing changes in heart rate, rhythm, or contraction pattern due to elevations in catecholamines. And also patients with orthostatic hypotension commonly sense palpitations caused by sinus tachycardia on standing.
Sweating Due to rise in body temperature secondary to rise in metabolic rate. [2]
Anxiety Catecholamines increase alertness although epinephrine usually evokes more anxiety and fear. [2]
Weight loss Norepinephrine and epinephrine exert metabolic effects that include glycogenolysis in liver and skeletal muscle,mobilization of free fatty acids (FFA), increased plasma lactate, and stimulation of the metabolic rate. [2]
Chest pain The increase in cardiac contractility along with myocardial hypoxia can result in acute or chronic ischemia and myocardial infarction. [1]
Abdominal pain High amounts of catecholamines, resulting in vasospasm in the visceral arterioles, which causes decreased blood flow and intestinal ischemia.[1]
Visual blurring Due to mydriasis due to sympathetic overdrive
Tremulousness Due to excess catecholamine level
References
  1. ZUBER, Samuel M., et al. Hypertension in Pheochromocytoma: Characteristics and Treatment. Endocrinology and metabolism clinics of North America [online]. PubMed. June 2011, vol. 40(2) . 295–311. [viewed 06 March 2014]. Available from: doi:10.1016/j.ecl.2011.02.002. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094542/.html
  2. BARRETT, Kim E., et al. Ganong’s Review of Medical Physiology. 24th ed. McGraw-Hill Medical, 5 April 2012.

Examination

Fact Explanation
Tachycardia Norepinephrine and epinephrine both increase the force and rate of contraction of the heart. Th ese responses are mediated by β 1 receptors. [1] And also patients with orthostatic hypotension sense sinus tachycardia on standing.
Orthostatic hypotension Reduced responsiveness of the vasculature to norepinephrine due to down-regulation of alpha-adrenergic receptors [2]
Pallor Cutanous vasoconstriction doe to excess catecholamine level
Hypertension Action of circulating catecholamines on cardiovascular adrenergic receptors. Norepinephrine (NE)-secreting tumors are usually associated with sustained hypertension. Tumors that secrete relatively large amounts of epinephrine (E) together with NE are associated with episodic hypertension. [3] Stimulation of β1 receptors will also result in release of renin, which will increase mean arterial blood pressure by converting angiotensinogen to angiotensin I.
Hyperglycemia Epinephrine and norepinephrine both cause glycogenolysis. Th ey produce this eff ect via β-adrenergic receptors that increase cyclic adenosine monophosphate (cAMP), with activation of phosphorylase, and via α-adrenergic receptors that increase intracellular Ca 2+. [1]
Arrhythmia ( E.C.G changes) Th e catecholamines also increase myocardial excitability, causing extrasystoles and, occasionally, more serious cardiac arrhythmias. [1]
Papilledema Increased intra cranial pressure due to hypertensive encephalopathy [4]
References
  1. BARRETT, Kim E., et al. Ganong’s Review of Medical Physiology. 24th ed. McGraw-Hill Medical, 5 April 2012.
  2. STREETEN, D. H.,et al. Mechanisms of orthostatic hypotension and tachycardia in patients with pheochromocytoma. American journal of hypertension [online]. PubMed. August 1996, vol. 9(8). 760–769. viewed 03 March 2014]. http://www.ncbi.nlm.nih.gov/pubmed/8862222/.html
  3. BRAVO, Emmanuel L., et al. Pheochromocytoma: State-of-the-Art and Future Prospects. Endocrine Reviews[online]. Endocrine press. August 2003, vol. 24(4). 539–553. [viewed 06 March 2014]. Available from: doi:10.1210/er.2002-0013. http://press.endocrine.org/doi/full/10.1210/er.2002-0013.html
  4. ZUBER, Samuel M., et al. Hypertension in Pheochromocytoma: Characteristics and Treatment. Endocrinology and metabolism clinics of North America [online]. PubMed. June 2011, vol. 40(2) . 295–311. [viewed 06 March 2014]. Available from: doi:10.1016/j.ecl.2011.02.002. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094542/.html

Differential Diagnoses

Fact Explanation
Hyperthyroidism [1] Increased basal metabolic rate & sympathetic overdrive produce similar symptoms & signs. low TSH & High T3 / T4 levels are diagnostic of hyperthyroidism.
Panic disorder [1] A panic attack is a response of the sympathetic nervous system. During a panic attack, the fear response is out of proportion for the situation, which often is not threatening. [2]
Carcinoid syndrome [1] Carcinoid tumors produce vasoactive substances like serotonin which cause flushing of the skin, secretory diarrhea and abdominal cramps. Diagnosis is made by measuring serotonin metabolite 5-HIAA in a 24-hour urine collection. [2]
Hypoglycemia [1] Hypoglycemia induce symptoms & signs of sympathetic nervous system stimulation due to release of counterregulatory hormones (epinephrine/adrenaline and glucagon). Bedside capillary blood sugar measurements will help in diagnosis.
Menopausal syndrome [1] Reduced levels of estrogen causes vasomotor symptoms including hot flushes and night sweats. There will be a history of menstrual abnormalities.
Ischemic heart disease [1] There is a surge of catecholamines together with ischemic pain which closely mimic an exacerbation of pheochromocytoma. Unlike myocardial infarction due to heart disease, pheochromocytoma patients with no past medical history of heart disease will appear to have normal coronary arteries during the angiography along with normal levels of cardiac enzymes. [3]
References
  1. SHAH, Urvi., et al. PHEOCHROMOCYTOMA: IMPLICATIONS IN TUMORIGENESIS AND THE ACTUAL MANAGEMENT. Minerva endocrinologica [online]. PMC . June 2012, vol. 37(2). 141–156 [viewed 03 March 2014]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409463/.html
  2. MANNELLI, Massimo., et al. Subclinical Phaeochromocytoma. Best practice & research. Clinical endocrinology & metabolism [online]. PubMed . August 2012, vol. 26(4). 507–515 [viewed 03 March 2014]. Available from: doi: 10.1016/j.beem.2011.10.008. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413196/.html
  3. ZUBER, Samuel M., et al. Hypertension in Pheochromocytoma: Characteristics and Treatment. Endocrinology and metabolism clinics of North America [online]. PubMed. June 2011, vol. 40(2) . 295–311. [viewed 06 March 2014]. Available from: doi:10.1016/j.ecl.2011.02.002. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094542/.html

Investigations - for Diagnosis

Fact Explanation
Clonidine suppression test Clonidine is a centrally acting alfa 2 agonist & is unable to suppress the secretion of epinephrine and norepinephrine in pheochromocytoma [1] Before performing the clonidine suppression test it is important to rule out the intake of any medications such as beta-blockers, thiazide diuretics and tricyclic antidepressants by the patient that might cause false positive results [2] Test is indicated in patients with plasma metanephrine values above the upper reference limit. [3]
CT scan Once the diagnosis of pheochromocytoma is made with a positive biochemistry it is necessary to locate the tumor for surgical resection. CT scan is used to localize adrenal tumors > 1 cm and extra adrenal tumors > 2 cm [2]
MRI scan MRI with or without gadolinium enhancement is superior for the detection of extra-adrenal tumors. [2] MRI preferred in children and pregnant or lactating women due to concerns regarding radiation exposure [3]
123 I-MIBG or 131 I-MIBG scintigraphy It use a norepinephrine precursor compound (Iodine labeled metaiodobenzylguanadine) to localize the hypersecretory adrenergic tissue. [1] The expression of catecholamine plasma membrane and vesicular transporter systems in tumor cells is usually abundant; this enables imaging with MIBG to accumulated within adrenergic tissues. Test can be influenced by medications such as nasal decongestants, antihypertensives (such as labetalol), antidepressants, and antipsychotics, cocaine; all have to be withheld for 1–3 days. Thyroid blocking is advocated for all procedures involving [131I]/[123I]MIBG [4]
Positron emission tomography (PET) It has superior spatial resolution and low radiation exposure. [2] PET is useful in imaging of metastatic pheochromocytoma because of its ability to specifically localize small tumors distributed throughout the body. [1]
References
  1. ADLER, Joel T., et al. Pheochromocytoma: Current Approaches and Future Directions. The Oncologist [online]. PubMed. 1 July 2008, vol. 13(7). 779–793 [viewed 03 March 2014]. Available from: doi:10.1634/theoncologist.2008-0043. http://theoncologist.alphamedpress.org/content/13/7/779#cited-by.html
  2. SHAH, Urvi., et al. PHEOCHROMOCYTOMA: IMPLICATIONS IN TUMORIGENESIS AND THE ACTUAL MANAGEMENT. Minerva endocrinologica [online]. PMC . June 2012, vol. 37(2). 141–156 [viewed 03 March 2014]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409463/.html
  3. CHEN, Herbert ., et al. The NANETS Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors: Pheochromocytoma, Paraganglioma & Medullary Thyroid Cancer. Pancreas [online]. PubMed. August 2010, vol. 39(6). 775–783. [viewed 03 March 2014]. Available from: doi:10.1097/MPA.0b013e3181ebb4f0. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419007/.html
  4. ILIAS, Ioannis., et al. Current role of MIBG in the diagnosis of pheochromocytoma and medullary thyroid cancer. Seminars in nuclear medicine [online]. PubMed. September 2011, vol. 41(5) . 364–368. [viewed 08 March 2014]. Available from: doi: 10.1053/j.semnuclmed.2011.03.003. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415306/.html

Investigations - Followup

Fact Explanation
Annual check-ups of blood pressure measurement and urine or plasma metanephrine levels As it is not possible to predict the long-term outcome of a tumor initially and hence patients with seemingly benign tumors also need follow up to detect recurrence or malignancy. [1]
References
  1. SHAH, Urvi., et al. PHEOCHROMOCYTOMA: IMPLICATIONS IN TUMORIGENESIS AND THE ACTUAL MANAGEMENT. Minerva endocrinologica [online]. PMC . June 2012, vol. 37(2). 141–156 [viewed 03 March 2014]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409463/.html

Investigations - Screening/Staging

Fact Explanation
Urinary and plasma metanephrines level Metanephrines are metabolites of the catecholamines which released continuously from the tumor independent of the time of catecholamine release. Blood sampling should be performed at a supine position after about 15–20 mins of i.v. catheter insertion. Food, caffeinated beverages, strenuous physical activity, or smoking are not permitted at least about 8–12 hours before the testing.[1], [2]
Urinary or plasma catecholamines level The test results are not reliable as catecholamine secretion can be intermittent thus causing false negative results. If a urinary collection is done, it is advisable to measure twice to account for the episodic nature of pheochromocytoma. Tricyclic antidepressants can cause a false-positive result with the measurement of urinary atecholamines [3]
Genetic testing (VHL, SDHB, SDHD genes) It helps predict prognosis for the patient, risk for the family and helps guide therapy. It is important in patients who are <45 years, with multiple tumors, extra-adrenal tumors, family history, metastatic tumors and increased dopamine secretion.
References
  1. SHAH, Urvi., et al. PHEOCHROMOCYTOMA: IMPLICATIONS IN TUMORIGENESIS AND THE ACTUAL MANAGEMENT. Minerva endocrinologica [online]. PMC . June 2012, vol. 37(2). 141–156 [viewed 03 March 2014]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409463/.html
  2. CHEN, Herbert ., et al. The NANETS Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors: Pheochromocytoma, Paraganglioma & Medullary Thyroid Cancer. Pancreas [online]. PubMed. August 2010, vol. 39(6). 775–783. [viewed 03 March 2014]. Available from: doi:10.1097/MPA.0b013e3181ebb4f0. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419007/.html
  3. ADLER, Joel T., et al. Pheochromocytoma: Current Approaches and Future Directions. The Oncologist [online]. PubMed. 1 July 2008, vol. 13(7). 779–793 [viewed 03 March 2014]. Available from: doi:10.1634/theoncologist.2008-0043. http://theoncologist.alphamedpress.org/content/13/7/779#cited-by.html

Management - General Measures

Fact Explanation
Antihypertensive medication. All patients (even those with apparent normal levels of catecholamines) should receive appropriate preoperative medical management to block the effects of released catecholamines. The drugs used are mentioned below.[1]
Phenoxybenzamineis Irreversible, nonselective, noncompetitive alpha blocker, can result in reflex tachycardia
Prazosin, doxazosin and terazosin Competitive, shorter acting, selective alpha 1 agents & does not result in reflex tachycardia
Labetalol A combined alpha plus beta blocker
Propranolol, atenolol or metoprolol. Clinical symptoms of beta-receptor stimulation such as palpitations, anxiety, and chest pain and may need a beta-blocker. A beta-blocking agent should never be used in absence of an alpha-blocking agent as that could precipitate a hypertensive crisis. [1]
Metyrosine A competitive inhibitor of tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. It crosses the blood brain barrier and hence has sedative and depressant effects on the brain. Therefore this drug is used only in patients with severe hypertension uncontrolled with other medications.
Dihydropyridine calcium channel blockers They are useful in patients who are normotensive but have paroxysmal episodes of hypertension, because they are less likely to cause significant orthostatic hypotension or overshoot hypotension. Reduction in arterial blood pressure results from inhibition of norepinephrine-mediated transmembrane calcium influx in vascular smooth muscle [2]
References
  1. SHAH, Urvi., et al. PHEOCHROMOCYTOMA: IMPLICATIONS IN TUMORIGENESIS AND THE ACTUAL MANAGEMENT. Minerva endocrinologica [online]. PMC . June 2012, vol. 37(2). 141–156 [viewed 03 March 2014]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409463/.html
  2. ADLER, Joel T., et al. Pheochromocytoma: Current Approaches and Future Directions. The Oncologist [online]. PubMed. 1 July 2008, vol. 13(7). 779–793 [viewed 03 March 2014]. Available from: doi:10.1634/theoncologist.2008-0043. http://theoncologist.alphamedpress.org/content/13/7/779#cited-by.html

Management - Specific Treatments

Fact Explanation
Laparoscopic adrenalectomy It is safe and effective approach in most patients with a benign pheochromocytoma less than 6 cm, because this technique results in less postoperative pain, a shorter hospital stay, quicker recovery, and better cosmesis when compared with an open surgical approach. Laparoscopic adrenalectomy and posterior retroperitoneoscopic adrenalectomy are both safe and effective approaches in patients with pheochromocytomas. Retroperitoneoscopic approach results in decreased operative time, blood loss, and postoperative length of stay compared with laparoscopic adrenalectomy. [1]
Open adrenalectomy This procedures is reserved for very large tumors or extra-adrenal tumors in locations difficult to remove laparoscopically. [1]
131I-MIBG therapy 131I-MIBG is an analogue of norepinephrine, which is sequestered in neurosecretory granules of chromaffin cells. [2] It is indicated in patients with malignant inoperable 123I-MIBG positive pheochromocytomas or paragangliomas. Thyroid blockade with potassium iodide is necessary to protect the gland from radiation. The main side effects of this therapy are vomiting and rise in blood pressure (early side effects) and myelotoxicity and hypothyroidism inspite of blockage (late side effects) [1]
Chemotherapy In rapidly progressing metastatic pheochromocytomas. [1]
Radiofrequency ablation, cryoablation or arterial embolization Used to control disease locally to alleviate symptoms like pain and hypertension related to the tumor and to prolong a patient's functionality. [1]
References
  1. SHAH, Urvi., et al. PHEOCHROMOCYTOMA: IMPLICATIONS IN TUMORIGENESIS AND THE ACTUAL MANAGEMENT. Minerva endocrinologica [online]. PMC . June 2012, vol. 37(2). 141–156 [viewed 03 March 2014]. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409463/.html