Treatment and Management of Pheochromocytoma - Essay Example

Pheochromocytoma Pheochromocytomas produce, store, and secret catecholamines, a chemical compound derived from the amino acid tyrosine. Catecholamines are hormones which are released by the adrenal glands in stressful situations or when the blood sugar is low, i.e. epinephrine (adrenaline), norepinephrine (nonadrenaline) and dopamine. The release of this hormone causes the body to prepare for physical activity (fight-or-flight response) and will usually increase the heart rate, blood pressure, blood pressure, blood glucose level or and may cause a general reaction of the sympathetic nervous system. They are usually derived from the adrenal medulla but may develop from chromaffin cells in or about sympathetic ganglia (pheochromocytomas or paragangliomas). The mechanism of catecholamine release is not well documented. It is suspected that the tumor may be caused by the changes in blood flow and necrosis within the tumor. The tumors do not contain nerves and therefore neural stimulation will not trigger catecholamine release. They also store and secrete a variety of peptides, such as endogenous opioids, neuropeptide Y, and chromagranin, which may contribute to the clinical manifestation in selected cases. The term pheochromocytoma was coined by a pathologist named Pick after the Greek work phaios, meaning dark or dusky, and chroma, meaning color - to describe the chromaffin reaction seen in adrenomedullary tumors. The term is mostly used to refer to tumors that arise from the adrenal medulla. Pheochromocytoma's most common manifestation is hypertension. Spectacular and alarming hypertensive paroxysms or crises may occur in over half the cases. Although they only occur in .1% of the hypertensive population, it is nevertheless a significant cause of high blood pressure and is correctible, if properly diagnosed and treated. If it is ignored, then it could be fatal and will put patients at risk for a lethal hypertensive paroxysm and long-term sequelae (a pathological condition resulting from a prior disease, injury or attack) of the disease. It is also an indication of the presence of a familiar disorder. An early detection may reduce the risk of metastasis. Description Pheochromocytoma is a rare disease in which tumors form in chromaffin cells of the body. Most pheochromocytomas, about 98% of the time, start inside the adrenal glands (adrenal medulla). It is a tumor which is made up of large, polyhedral, pleomorphic chromaffin cells, which is only malignant in less than 10% of the case, and which causes the adrenal glands to produce too much adrenaline. The histologic appearance will not show malignancy. A local invasion of the surrounding tissue or distant metastases will reveal malignancy. It usually affects only one of the adrenal glands, although it may also start in other parts of the body, such as the area around the heart or bladder. Pathology Statistically, pheochromocytoma occur in 1-2 out of 100,000 adults, around 80% of which are unilateral and solitary, only 10% are bilateral, and the remaining 10% are extraadrenal. Majority of these cases, about 80-90% are sporadic, and the remaining are connected to hereditary syndromes (.eg. multiple endocrine neoplasia). In pediatric patients, about are bilateral and another are extraadrenal. For yet unexplained reason, lesions are usually in the right side. Most pheochromocytomas are small, weighing less than 100 grams and are about 10 cm in diameter. They may however grow to over 3 kg in size. The tumors have vessels or ducts, or are highly vascular. Extraadrenal pheochromocytomas usually weigh 20-40 g and are less than 5 cm in diameter. Most are located within the abdomen in association with the celiac, superior mesenteric ganglia. Approximately 1% are in the thorax, 1 percent are within the urinary bladder, and less than 1% are in the neck, usually in association with the sympathetic ganglia or the extracranial branches of the ninth or tenth cranial nerves. Clinical Features Most of pheochromocytomas are not cause for worry as they are benign (noncancerous). However, they bring highly uncomfortable effects such as high blood pressure, pounding headaches, heart palpitation, flushing of the face, nausea, feeling of anxiety and vomiting. This is most common in young to mid-adult life (between 30-60 years old), occurring in males and females (with a slight preponderance in females), although it can occur in all ages, with as much as 10% of which is accounted for by the pediatric population. There is no racial predilection reported. The clinical features and morbidity of these tumors are due predominantly to the release of catecholamines. The most common manifestation of pheochromocytoma is hypertension. In over half of these cases, patient will have alarming and highly spectacular hypertensive paroxysms or crises. Most of time, a hypertensive crisis, paroxysmal symptom suggestive of seizure disorder or anxiety attack, or a hypertension that responds poorly to conventional treatment, will bring attention to pheochromocytoma. Sometimes, although uncommon, unexplained hypotension or shock in association with surgery or trauma might suggest pheochromocytoma. Most have hypertension in association with headaches, excessive sweating, and/or palpitations. Pheochromocytoma occurs in approximately .1% of the hypertensive population but is, nevertheless, an important correctible cause of high blood pressure. Indeed it is usually curable if properly diagnosed and treated but may be fatal if undiagnosed or mistreated. Postmortem series indicate that the majority of pheochromocytomas are unsuspected clinically even when the tumor is related to the fatal outcome. Hypertension. This is the most common manifestation, and sustained in 60% of the cases, although there is also a significant blood pressure liability, which if left untreated for a long time may lead to heart disease, stroke, and other major health problems. Half of those with sustained hypertension will have distinct crisis of paroxysms. The remaining 40% will only have high blood pressure during an attack. The hypertension is often severe, occasionally malignant, and may be resistant to treatment with standard antiphypertensive drugs. Paroxysms or crises. These occur in over half of the patients, and the symptoms are often similar with each attach in an individual patient, which may be frequent or sporadic, at intervals as long as weeks or months. The frequency, interval and severity may increase as time goes on. The attack is usually sudden, and may last for minutes, hours or even longer. Headache, profuse sweating, palpitations, and apprehension, often with a sense of impending doom, are common. Pain in the chest, which may be associated with nausea or vomiting, pallor or flushing, elevated blood pressure, often accompanied by tachycardia, may be experienced. Prior to the paroxysm attack, a person suffering from this may vomit. A particular stimulus may induce an attack, but in other, there may be no clear and defining event that will trigger an attack. Although anxiety may accompany the attacks, the other way around is not usually true, that is, an anxiety attack does not necessarily a trigger. Other distinctive clinical features. The most common symptom is a sign of increased metabolic rate, such as profuse sweating, and mild to moderate weight loss. Orthostatic hypotension is a consequence of diminished plasma volume and blunted sympathetic reflexes. Both these factors predispose a patient with unsuspected phechromocytoma to hypotension or shock during surgery or trauma. Sinus tachycardia, sinus bradycardia, supraventricular arrhythmias, and ventricular premature contractions have been noted. Angina and acute myocardial infarction may occur even in the absence of coronary artery disease. The inducement of the increase in catecholamine in myocardial oxygen consumption, and sometimes coronary spasms may play a role in these ischemic events. In some cases, where ischemia or infarction is absent, electrocardiographic changes, including non-specific ST-T wave changes, prominent U waves, left ventricular strain patterns, and right and left bundle branch blocks may be present. Cardiomyopathy, either congestive with myocarditis and myocardial fibrosis or hypertrophic with concentric or asymmetric hypertrophy, may be associated with heart failure and cardiac arrhythmias. Noncardiogenic pulmonary edema may be due to either shifts in extracellular fluid, altered capillary permeability, or increased pulmonary venous tone. The suppression of insulin and the stimulation of hepatic glucose output will impair the carbohydrate intolerance of over half of the patients. However, there is no cause for concern as this intolerance will disappear once the tumor is removed, and therefore, insulin treatment is not necessary. The decrease in plasma volume may elevate hematocrit (the percentage by volume of packed red blood cells in a given sample of blood after centrifugation). In rare instances, production of erhthropoietrin by the tumor may cause a true erythorcytosis. When there is secretion of parathyroid hormone-related protein from an abnormal location within the body, hypercalcemia occur. Fever and inflammation in the body can also occur in association with the production of interleukin 6. An increase in temperature will usually mean that there is an artificial increase in catecholamine. Vasoconstriction is caused by a decrease in heat dissipation. Polyuria, or excessive urination, may occur. Rhabdomyolysis with myoglobinuric renal failure may also result from extreme vasoconstriction with muscle ischemia. Where a pheochromocytoma is located in the wall of the urinary bladder, paroxysms in relation to excessive urination may result. The relative small size and the tumor's location within the bladder causes the symptoms, thus, the elevation in the excretion of catecholamine may be minimal or appear normal. Blood in urine may also be present. The tumor may be seen using a lighted instrument called cystoscope in the urethra. Genetics Studies show that hereditary predisposition for pheochromocytoma is between 20-30%, mostly occurring at a younger age than when the tumor is sporadic. Age must therefore be considered and is a very important factor in deciding whether a patient should be tested for disease-causing genes. It is important to secure a complete clinical work-up and to do a specialized genetic consultation to collect family history, outline the potential repercussions of genetic testing, and to obtain appropriate informed consent. An underlying hereditary condition may be uncovered through a detailed medical and family history. If the patient has no family history of pheochromocytoma or paraganglioma, then descriptions of sudden death of family member previously attributed to a cardiovascular events, which were insufficiently explained, should be scrutinized as this could suggest an increased probability of hereditary disease, particularly because it is currently considered that at least 50% of catecholamine-producing tumors remain undiagnosed until death. In approximately 5% of the cases, phechromocytoma is inherited as an autosomal dominant trait either alone or in combination with other abnormalities. Mortality/Morbidity Undiagnosed and untreated pheochromocytomas may result in serious morbidity or mortality, although it is rare. The most severe complication is pheochromocytoma crisis, which includes any manifestation of obtundation, as well as shock, disseminated intravascular coagulopathy, seizures, rhabdomyolysis, acute renal failure and death. Other complications include the reactivation of Graves disease or transient thyrotoxicosis, as well as hypercalcemia as a result of tumor secretion of a parathyroid hormone-related protein, noncardiogenic pulmonary edema, acute abdomen, and renal infarction, among others. It is worth repeating that there is a high risk of provoking hypertensive crisis during the manipulation of an adrenal gland. Adverse drug interactions Caution must be exercised in the administration of drugs to patients with pheochromocytoma because of numerous possible drug reactions. For example, drugs, such as opiates, histamine, adrenocorticotropin, saralasin and glucagon can cause severe paroxysms, sometimes fatal, because they release catecholamines directly to the tumor. On the other hand, drugs that mimic the actions of the sympathetic nervous system called the sympathomimetic amines, and administered on the patient intravenously will cause an increase in the blood pressure. Finally, drugs such as tricyclic antidepressants or adrenergic blocking agents such as guanethidine, greatly enhances the benefits of circulating catecholamines. It bears repeating therefore, that careful administration of drugs must be exercised in the administration of drugs on patients with known or suspected pheochromocytoma. Associated diseases Pheochromocytoma is associated with: (1) medullary carcinoma of the thyroid in the multiple endocrine neoplasia (MEN) syndrome types 2a and 2b. It should be noted that periodic screening should be done on patients who are at risk for MEN 2a and 2b by taking 24-hr urine sample for catecholamines. Epinephrine should also be measured. (2) hyperparathyroidism in MEN 2a (3) Hypercalcemia, resolving after tumor resection (4) About 10-25% association with von Hippel-Lindau disease may be as high as 10 to 25%. Many of these are detected only after death. (5) There is a 15-20% incidence of cholelithiasis (6) Cushing's syndrome is a rare association, usually a consequence of ectopic secretion of ACTH by the pheochromocytoma, or less commonly, by a coexistent medullary carcinoma of the thyroid. It is necessary to remove a pheochromocytoma before a thyroid or parathyroid surgery. Although, current medical knowledge does not associate pheochromocytoma with neurofibromatosis, the following manifestations must be noted in cases of incomplete forms of neurofibromatosis; (1) caf au lait spots (2) vertebral abnormalities, or kyphoscoliosis If the foregoing enumerations are present, especially in hypertensive patients, then pheochromocytoma should be suspected. Diagnosis When a patient is suspected of having pheochromocytoma, the best medical tests so far, to establish a diagnosis is the urine test, where urine is collected continuously for 24-hours. This is most efficacious in hypertensive patients showing the symptoms of pheochromocytoma at the time of the collection of urine. An increase in the level of secretion of catecholamines or its metabolites is an indication of pheochromocytoma. A discussion of the older tests and their efficacy will be done elsewhere in this paper, particularly, in the section under pharmacologic tests. Biochemical Diagnosis The most widely used test is the measurement of urinary catecholamine levels, although the measurement of urinary catecholamine metabolites or plasma catecholamines is also recommended. "The following considerations apply to all the urinary tests: (1) Despite claims for the adequacy of determinations made on random urine samples, analysis of a full 24-hours urine sample is preferable. Creatinine should be determined as well to assess the adequacy of the collection. (2) Where possible, the collection should be made when the patient is at rest, no medication, and without recent exposure to radiographic contrast media. Where it is not practical to discontinue all medications, drugs known to specifically interfere in the assays (vanillymandelic acid, the metanephrines, and unconjugated or free catecholamines), should be avoided. (3) The urine should be acidified and refrigerated during and after collection. (4) With high-quality assays, dietary restrictions are minimal and should be specified by the laboratory performing the analyses. (5) Although most patients with pheochromocytoma excrete increased catecholamines and catecholamine metabolites, the yield is increased in patients with paroxysmal hypertension if a 24-hr urine collection is initiated during a crisis" (Isselbacher, 1994). Technological advances and medical breakthroughs have resulted in a better understanding of the workings of catecholamine. Thus, to date, measuring metanephrines (normetanephrine and metanephrine) separately in the urine or plasma yields the best result as this test is more sensitive to measurement of the parent catecholamines. Anent the foregoing discussion, the following should be observed to maximize the benefits of the test: (1) To maximize the sensitivity of the measurement, the interval in the taking of plasma and urine should be carefully studied and planned to ensure optimum diagnosis (2) The continuous nature of biochemical test results should be factored in the step-by-step planning of the diagnosis. If it is difficult to ascertain pheochromocytoma because the clinical features and the urinary tests are borderline, then plasma catecholamines should be measured. If the basal level of catecholamines are elevated, then pheochromocytoma may be present. It should be noted however that this is not conclusive since some patients with phechromocytoma (approximately 1/3) have normal or slightly elevated basal values. By including agents that suppress sympathetic nervous system activity, the test becomes more useful. The plasma catecholamine level for normal subjects and patients with essential hypertension may be reduced by clonidine and ganglionic blocking agent, but have little effect in patients with pheochromocytoma. But if clodinine does not suppress plasma or urinary levels, a diagnosis of pheochromocytoma is supported especially if they have elevated or borderline basal catecholamine values. Pharmacologic tests The old provocative and adrenolytic tests are no longer in use because of the current method for the measurement of catecholamines and catecholamine metabolites in urine. These two old tests are nonspecific and have considerable risks in using them. However, just because they have been rendered obsolete by a newer method, they should not be discarded yet, as a modified use of the adrenolytic test may serve as therapeutic trial in a patient in hypertensive crisis with features suggestive of pheochromocytoma. One of the effects of taking phentolamine is an immediate lowering of the blood pressure by at least 35/25 within 2-15 minutes. The effect must be verified biochemically because the response to the drugs is not an accurate indication. However, provocative tests should not be done on patients with normal blood pressure. They are dangerous on these kinds of patients. Nevertheless, for patients with paroxysmal hypertension whose basal catecholamine levels could not diagnosed, a glucagon provocative test may be useful. But normal or hypertensive patients will be almost immune to the effects of glucagon their blood pressure or plasma catecholamine levels, unlike the patients with pheochromocytoma, who will feel the increase of their blood pressure and circulating catecholamine levels. The increase of plasma catecholamine concentration may also not raise a patient's blood pressure. But there were instances when a patient with pheochromocytoma's blood pressure was elevated after being given glucagon, thus, care must be exercised. Thus, the blood pressure must always be monitored, with adequate intravenous access, and there should be phentolamine which must be administered in case the blood pressure increases. Differential diagnosis The manifestations of pheochromocytoma can take on many and varied and must be carefully considered and excluded when the patients have suggestive clinical features. A 24-hour urine test can exclude pheochromocytoma in: (1) patients with essential hypertension and overactive adrenal glands (such as tachycardia), sweating and increased cardiac output, and (2) in patients with anxiety attacks associated with blood pressure elevations. However, the urine must be collected several times during the attack so that the diagnosis is more accurate. In difficult cases, the suppression of clonidine suppression (discussed above) and glucagon stimulation tests (also discussed above) may be helpful. It should be noted that an increase in blood pressure due to the withdrawal of clonidine or the use of monoamine oxidasecan look like paroxysms and pheochromocytoma. Artificially induced increase in blood pressure can be produced through the use of sympathomimetic amines in psychiatrically disturbed patients. Stages of Pheochromocytoma Once pheochromocytoma is found, tests, called staging, will be done on the patient, as follows: (1) Where the tumor is located in one area of the body and has not spread to other tissues, this is the localized benign pheochromocytoma stage. For most patients diagnosed with pheochromocytoma, the tumor does not spread and is not cancerous. (2) However, where the cancer has moved to the lymph nodes (small bean-shaped structures which fight infection) in the area or to other tissues around the cancer, then it is the regional pheochromocytoma stage. (3) If the cancer spreads to other parts of the body, it is in the metastatic pheochromocytoma stage. (4) Finally, a treated cancer which comes back, either in the same region or has metastasized to other parts is in the recurrent pheochromocytoma stage. Treatment and Management The most definitive treatment for patients with pheochromocytoma is surgical resection, that is, the tumor is usually removed by laparoscopy. To prepare for surgery, the following are suggested: (1) Increase in plasma volume (2) Liberal salt and fluid intake (3) alpha-adrenergic receptor and antagonists, to prevent vasoconstriction because of catecholamine, must be administered. This is the preoperative management and increases the success rate. (4) Phenoxybenzamine, a long-acting nonselective noncompetitive blocker, must also be administered, to ensure a long-lived noncompetitive alpha-receptor blockade, with incremental increases to control blood pressure and to stop the paroxysms. The increase must gradual and blood pressure must carefully monitored and taken in a supine and upright position. Phenoxybenzomine must be given 10-14 days before surgery, between 40-80 mg per day. During the period of preparation for the surgery, the combination of alpha-receptor blockade and a liberal salt intake will hopefully normalize the plasma volume. Prior to the phenoxybenzamine takes effect, intravenous phentolamine may be given to treat paroxysms. In some cases, prazosin is given to a select number of patients. It has been determined that 1.5-2.5 mg every 6 hours can control blood pressure and paroxysms. It has not been determined though how an alpha-adrenergicand antagonists help in the management of pheochromocytoma, but it can be surmised that they are used as antihypertensive agent during the workup period for patients suspected of having pheochromocytoma, because as discussed above, they can prevent the increase of blood pressure. For those with high blood pressure, nitroprussides and possibly angiotensin-converting enzyme inhibitors are recommended. (5) After the alpha adrenergic agents have been given, it is time for beta-adrenergic receptor blocking agents since without the alpha blockade, blood pressure may increase. Tachycardia sometimes developed in the induction of alpha-adrenergic blockade, thus necessitating the induction of beta blockade. Starting from a dose of 10 mg, the dose may be taken 3 to 4 times a day, increased only when necessary. Beta blockade, especially if strengthened by anesthetic agents, is most effective for arrhythmia induced by the introduction of catecholamine. Preoperative localization of the tumor If the location of the tumor is established while the patient is being prepared for the operation, then surgery will go a little more smoothly by the use of computed tomography (CT) or magnetic resonance imaging of the adrenals to identify intradrenal lesions, or conventional roentgenograms and CT of the chest to identify intrathoracic lesions. If these do not suffice, then abdominal aortography may be used to identify extraadrenal pheochromocytomas within the abdomen. Failing these, venous sampling may be done. An additional localization technique involves a scintiscan. Surgery The best places to perform the surgery are in centers with experience in the preoperative, anesthetic, and intraoperative management of pheochromocytoma, as in these cases, the surgical mortality is 2-3%. During the surgery, the following should be closely monitored: (1) continuous recording of arterial pressure (2) central venous pressure (3) electrocardiogram; and (4) in the presence of cardiac disease or if congestive failure has been present, pulmonary capillary wedge pressure. Adequate fluid replacement is crucial. In case of low blood pressure, it is better to replace volume than to administer vasoconstrictors. Hypertension and cardiac arrhythmias are most likely to occur anytime during the administration of anesthesia, intubation, and manipulation of the tumor. Most of the time, the introduction of phentolamine intravenously will control the blood pressure, but there may instances when nitroprusside may be required. To treatment tachycardia or ventricular ectopy, propranolol may be given. Pheochromocytoma in pregnancy If a pregnant patient diagnosed with pheochromocytoma is not completely prepared, then spontaneous labor and vaginal delivery may happen which is disastrous for mother and the fetus. Thus, care must be made in these situations, and phenoxybenzamine must be administered if the patient is in the early stages of pregnancy, and the tumor to be removed immediately, although there is the danger of abortion. In the third trimester, the pregnant woman must be given adrenergic blocking agents, and when the fetus becomes viable, then the baby may be delivered by caesarean section. Afterwards, the tumor is removed. No adverse effects have been noted in the administration of adrenergic blocking agents, although there have not been enough studies to determine its safety. Pediatric patients Studies show that only about 1% of children with hypertension are affected with pheochromocytoma. However, pediatric patients (between 88-92%) with pheochromocytoma have a higher risk of sustained hypertension than in adults, but a lower incidence of intermittent hypertension. Unfortunately, there is a higher percentage of extra-adrenal pheochromocytomas in children than in adults. Neuroblastoma is the most common tumor in children. It is difficult to tell apart pheochromocytomas from neuroblastomas and ganglioneuromas. This means that the incidence of hypertension is lower with neuroblastomas since the tumors produce a large amount of catecholamine precursors. The technique for localization of tumors is the same for adult and children. Unresectable and malignant tumors There will be times when surgery is not an option, such as in cases of metastatic or locally invasive tumor in patients with intercurrent illness, then it would be necessary that a long-term medical care is planned and managed. If the adrenergic blocking agents have no effect on the signs and symptoms of pheochromocyotma, metyrosine may be required, inhibits tyrosine hydroxylase, diminishes catecholamine production by the tumor, and often simplifies chronic management. In cases of malignant pheochromocytoma, there are instances when they recur in the retroperitoneum and will quickly metastasize mostly in the bone and lung. Radiotheraphy is useless, but a combination chemotheraphy may have some limited effect on the malignancy. Prognosis and follow-up There is 95% percent chance that the operated patient may survive for the next five years. There is a very low rate of recurrence at around 10 percent of the cases. Postoperative, the excretion of catecholamine will return to normal in about 1 week, and should be measured to ensure complete tumor removal. Also, the patient must be careful and should have his catecholamine excretion reassessed if there are symptoms which suggest pheochromocytoma, to be done every year or for several years, in case no symptoms appear for a long period. However, if the pheochromocytoma is malignant, survival for the next 5 years is less than half the others, or lower than 50%. Together with the tumor, hypertension is removed in about 3 out of 4 patients. For those not so lucky, antihypertensive agents can control the recurring hypertension. The usual cause of the recurring hypertension for the last-mentioned group is either underlying essential hypertension or irreversible vascular damage induced by catecholamines. Conclusion Technology has been evolving so fast and thus, this will markedly affect the management of patients with pheochromocytoma. To date, several diagnostics tools are used to evaluate this disease. A careful and thoughtful evaluation of how to integrate the tests will be cost-effective and increase the accuracy of the diagnosis and the localization of the tumor. There is still no available cure for a malignant pheochromocytoma to date. Neither are there reliable histopathologic markers to diagnose malignancy or assess prognosis. Establishing a wealth of information on malignancy will go far in curing pheochromocytoma. It should be noted however, that histopathology is a time-tested and relatively inexpensive diagnostic tool. The future of pathology might involve a more definitive assessment of malignancy. But before this can happen, focus must be made on long-term medical management, so that those suffering will have better care and possibly beat their odds as it seems that there is a gap in the knowledge in this particular area. Works Cited: 1. Pacak, K.; Eisenhofer, G.; Ahlman, H.; Bornstein, S.R.; Gimenez-Roqueplo, A-P.; Grossman, A.; Kimura, N.; Mannelli, M.; McNicol A.M. Tischler, A.S. (2007) "Pheochromocytoma: Recommendations for Clinical Practice from the First International Symposium." Nature Clinical Practice Endocrinology & Metabolism 2007; 3(2): 92-102. Medscape. 30 October 2008 2. Kobal, S.; Paran, E.; Jamali, A.; Mizrahi, S.; Siegel, R.; Leor, J. (2008) Pheochromocytoma : Cyclic Attacks of Hypertension Alternating With Hypotension." Nature Clinical Practice Cardiovascular Medicine 2008; 5(1): 53-57. Medscape. 30 October 2008 3. Rodriguez-Hermosa JI; Roig-Garcia, J.; Girones-Vila, J.; Ruiz-Feliu b.; Costa-Lima, e.; Recasens-Sala, M.; Codina-Cazador, A. (2008) "Laparoscopic Adrenalectomy for a Large Pheochromocytoma in a Morbidly Obese Patient." Obesity Surgery 2008 Oct 23 [Epub ahead of print]. PubMed. 30 October 2008 4. Kim L.; Holland, AJ.; Srinivasan, S.: Cowell, CT; Benn, DE; Robinson, BG. (2008) "Paediatric bilateral adrenal phaeochromocytomas in association with a novel mutation in the von Hippel Lindau gene." Journal of Pediatrics and Child Heath 2008 Sep; 44(9): 514-6. PubMed. 30 October 2008 5. Wu, HW.; Liou, WP.; Chou, CC.; Chen YH; loh, CH; Wang, HP. (2008) "Pheochromocytoma presented as intestinal pseudo-obstruction and hyperamylasemia." The American Journal of Emergency Medicine, 2008 October;26(8):971.e1-4. PubMed. 30 October 2008 6. Sakamaki, Y.; Yasukawa, M.; Kido, T. (2008) "Pheochromocytoma of the posterior mediastinum undiagnosed until the onsel of intraoperative hypertension." General Thoracic and Cardiovascular Surgery, 2008 Oct;56(10):509-11. Epub 2008 Oct 15. PubMed. 30 October 2008 7. Cheung, YW; Spevack, DM. (2008) "Single left ventricle and pheochromocytoma." Congenital Heart Disease, 2008 Sep;3(5):355-8. PubMed. 30 October 2008 8. Bessell-Browne, R.; O'Malley, M. (2007) "CT of Pheochromocytoma and Paraganglioma: Risk of Adverse Events with IV Administration of Nonionic Contrast Material." American Journal of Roentgenology, 2007;188(4):970-974. 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