CLINICAL SEMINAR ON PHEOCHROMOCYTOMA Introduction Pheochromocytoma is a tumor that is usually benign and originates from the chromaffin cells

of the adrenal medulla. In 85% of patients , the tumor arises in the medulla; in the remaining patients, it occurs in the extra-adrenal chromaffin tissue located in or near the aorta, ovaries, spleen, or other organs. Those arising from extra-adrenal tissue are commonly known as paragangliomas.Paragangliomas are divided in to two groups; those that arise from parasympathetic associated tissues (most commonly along the cranial nerves and vagus (eg. glomus tumors,chemodectoma,and carotid body tumor ) and those that arise from sympathetic associated chromaffin tissue(often designated as extra adrenal pheochromocytomas) The name pheochromocytoma proposed by Pick in 1912 comes from the Greek words phaios (dusky) and chroma(color);it refers to the staining that occurs with tumors when they are treated with chromium salts. Anatomy and Physiology There are two adrenal glands in the human, each attached to the upper portion of a kidney. Each adrenal gland is, in reality, two endocrine glands with separate, independent functions. The adrenal medulla at the center of the gland secretes catecholamines, and the outer portion of the gland, the adrenal cortex, secretes steroid hormones . The secretion of hormones from the adrenal cortex is regulated by the hypothalamicpituitaryadrenal axis. The hypothalamus secretes corticotropinreleasing hormone (CRH), which in turn stimulates the pituitary gland to secrete ACTH. ACTH then stimulates the adrenal cortex to secrete glucocorticoid hormone (cortisol). Increased levels of the adrenal hormone then inhibit the production or secretion of CRH and ACTH. This system is an example of a negative feedback mechanism

Functions of Adrenal Medulla The adrenal medulla functions as part of the autonomic nervous system. Stimulation of preganglionic sympathetic nerve fibers, which travel directly to the cells of the adrenal medulla, causes release of the catecholamine hormones epinephrine and norepinephrine. About 90% of the secretion of the human adrenal medulla is epinephrine (also called adrenaline). Catecholamines regulate metabolic pathways to promote catabolism of stored fuels to meet caloric needs from endogenous sources. The major effects of epinephrine release are to prepare to meet a challenge (fight-or-flight response). Secretion of epinephrine causes decreased blood flow to tissues that are not needed in emergency situations, such as the gastrointestinal tract, and causes increased blood flow to tissues that are important for effective fight or flight, such as cardiac and skeletal muscle. Catecholamines also induce the release of free fatty acids, increase the basal metabolic rate, and elevate the blood glucose level. In the healthy physiologic state, hormone concentration in the bloodstream is maintained at a relatively constant level. When the hormone concentration rises, further production of that hormone is inhibited. When the hormone concentration falls, the rate of production of that hormone increases. This mechanism for regulating hormone concentration in the bloodstream is called negative feedback, which is important in the regulation of many biologic processes. Epidemiology

Pheochromocytoma is estimated to occur in 28 out of 1 million persons per year, and about 0.1% of hypertensive patients harbor a pheochromocytoma. Autopsy series reveal prevalence figures of 0.2%. The mean age at diagnosis is about 40 years, although the tumors can occur from early childhood until late in life. The "rule of tens" for pheochromocytoma states that about 10% are bilateral, 10% are extra adrenal, and 10% are malignant. However, these percentages are higher in the inherited syndromes. Etiology And Pathogenesis Pheochromocytomas and paragangliomas are well-vascularized tumors that arise from cells derived from the sympathetic (e.g., adrenal medulla) or parasympathetic (e.g., carotid body, glomus vagale) para ganglia The name pheochromocytoma reflects the black-colored staining caused by chromaffin oxidation of catecholamines. Although a variety of nomenclatures have been used to describe these tumors, most clinicians use the term pheochromocytoma to describe symptomatic catecholamine-producing tumors, including those located in extra adrenal retroperitoneal, pelvic, and thoracic sites. The term paraganglioma is used to describe catecholamine-producing tumors in the head and neck, as well as tumors that arise from the parasympathetic nervous system, which may secrete little or no catecholamines. Signs And Symptoms The signs and symptoms of a pheochromocytoma are those of sympathetic nervous system hyperactivity, including: SYMPTOMS Headache Palpitations Sweating Anxiety/nervousness Nausea/emesis Pain in chest or abdomen Weakness/fatigue Dizziness Heat intolerance Paresthesias Constipation Dyspnea Visual disturbances Seizures, grand mal

SIGNS Hypertension Tachycardia/reflex bradycardia Postural hypotension(another clue to the presence of pheochromocytoma is orthostatic hypotension (a fall in systolic blood pressure greater than 20 mmHg or a fall in diastolic blood pressure greater than 10 mmHg upon standing)

Hypertension, paroxysmal Weight loss Pallor Hyper metabolism fasting hyperglycemia(due primarily to catecholamine stimulation of lipolysis (breakdown of stored fat) leading to high levels of free and the subsequent inhibition of glucose uptake by muscle cells. Further, stimulation of beta-adrenergic receptors leads to glycogenolysis and gluconeogenesis and thus elevation of blood glucose levels). tremor increased RR decreased GI motility psychosis(rare) flushing, paroxysmal(rare)

Not all patients experience all of the signs and symptoms listed The dominant sign is hypertension. Classically, patients have episodic hypertension, but sustained hypertension is also frequent. Catecholamine crises can lead to heart failure, pulmonary edema, arrhythmias, and intracranial hemorrhage. During episodes of hormone release, which can occur at very divergent intervals, patients are anxious and pale, and they experience tachycardia and palpitations. These paroxysms generally last less than an hour and may be precipitated by surgery, positional changes, exercise, pregnancy, urination (particularly bladder Pheochromocytomas), and various medications (e.g., tricyclic antidepressants, opiates, metoclopramide)s Among the presenting symptoms, episodes of palpitations, headaches, and profuse sweating are typical and constitute a classic triad. COMPLICATIONS Syncope,Cardiac dysrhythmias (sinus tachycardia, superior ventricular arrhythmias, premature contraction),Angina even in absence of CAD,Myocardial infarction,Prominent U wave, Cardiomyopathy ,Heart failure / ARF ,Aneurysm / stroke,Fatal paroxysms Diagnosis The diagnosis is based on documentation of catecholamine excess by o biochemical testing and localization of the tumor by o imaging. Testing

Blood Tests: analysis of free meta nephrine in blood plasma. High levels are indicative of pheochromocytoma. Urine Tests: Although this test is slightly less effective than plasma testing it is still considered highly effective in diagnosis. Usually the metabolites of norepinephrine and epinephrine, vanillylmandelic acid (VMA) and homovanillic acid (HVA) are found in relatively small amounts in normal humans. The increased intermittent excretion of these metabolites is indicative of the disease, but does not completely rule out other diseases which may cause the same excretion values.

Other Tests: One diagnostic test used in the past for a pheochromocytoma is to administer clonidine, a centrally-acting alpha-2 agonist used to treat high blood pressure. Clonidine mimics catecholamines in the brain, causing it to reduce the activity of the sympathetic nerves controlling the adrenal medulla. A healthy adrenal medulla will respond to the clonidine suppression test by reducing catecholamine production; the lack of a response is evidence of pheochromocytoma. The suppression test is based on the principle that catecholamine levels are normally increased through the activity of the sympathetic nervous system. In pheochromocytoma, increased catecholamine levels result from the diffusion of excess catecholamine into the circulation, bypassing normal storage and release mechanisms. Therefore, in patients with pheochromocytoma, clonidine does not suppress the release of catecholamines.

The results of the test are considered normal if 2 to 3 hours after a single oral dose of clonidine, the total plasma catecholamine value decreases at least 40% from baseline. Patients with pheochromocytoma exhibit no change in catecholamine levels. False-positive results, however, may occur in patients with primary hypertension. Another test is for the clinician to press gently on the adrenal gland. A pheochromocytoma will often release a burst of catecholamines, with the associated signs and symptoms quickly following. This method is NOT recommended because of possible complications arising from a potentially massive release of catecholamines.

Diagnostic Imaging CECT. MRI with gadolinium contrast Radioactive tracers including 131I- or 123I-metaiodobenzylguanidine (MIBG), 111In-somatostatin analogues, or 18F-dopa (or dopamine) positron-emission tomography (PET). Because these agents exhibit selective uptake in paragangliomas, nuclear imaging is particularly useful in the hereditary syndromes. Measurements of urine and plasma levels of catecholamines are the most direct and conclusive tests for over activity of the adrenal medulla. Measurements of urinary catecholamine metabolites (metanephrines [MN] and vanillylmandelic acid [VMA]) or free catecholamines are the standard diagnostic tests used in the diagnosis of pheochromocytoma. Levels can be as high as three times normal limits . A 24-hour specimen of urine is collected for determining free catecholamines, MN, and VMA; the use of combined tests increases the diagnostic accuracy of testing. A number of medications and foods (eg, coffee, tea, bananas, chocolate, vanilla, aspirin) may alter the results of these tests; therefore, careful instructions to avoid restricted items must be given to the patient. Urine collected over a 2- or 3-hour period after an attack of hypertension can be assayed for catecholamine content. Total plasma catecholamine (epinephrine and norepinephrine) concentration is measured with the patient supine and at rest for 30 minutes. To prevent elevation of catecholamine levels by the stress of venipuncture, a butterfly needle, scalp vein needle, or venous catheter may be inserted 30 minutes before the blood specimen is obtained.

 Factors that may elevate catecholamine levels must be controlled to obtain valid results; these factors include consumption of coffee or tea, use of tobacco, emotional and physical stress, and use of many prescription and over-the-counter medications (eg, amphetamines, nose drops or sprays, decongestant agents, and bronchodilators). Normal plasma values of epinephrine are 100 pg/mL (590 pmol/L); normal values of norepinephrine are generally less than 100 to 550 pg/mL (590 to 3,240 pmol/L). Values of epinephrine greater than 400 pg/mL (2,180 pmol/L) or norepinephrine values greater than 2,000 pg/mL (11,800 pmol/L) are considered diagnostic of pheochromocytoma. MALIGNANT PHEOCHROMOCYTOMA About 510% of pheochromocytomas and paragangliomas are malignant. tumors with distant metastases, most commonly found in lungs, bone, or liver, suggesting a vascular pathway of spread. Because hereditary syndromes are associated with multifocal tumor sites, these features should be anticipated in patients with germ-line mutations of RET, VHL, SDHD, or SDHB. Treatment options include tumor mass reduction; alpha blockers for symptoms; chemotherapy; and nuclear medicine radiotherapy. The prognosis of metastatic pheochromocytoma or paraganglioma is variable, with a 5-year survival of 3060%. Pheochromocytoma in Pregnancy Pheochromocytomas are occasionally diagnosed in pregnancy. Endoscopic removal, preferably in the forth to sixth month of gestation, is possible and can be followed by uneventful childbirth. Regular screening in families with inherited pheochromocytomas provides an opportunity to identify and remove asymptomatic tumors in women of reproductive age. Pheochromocytoma-Associated Syndromes 1) Neurofibromatosis type 1 (NF 1) (Von Recklinghausen's Disease): was the first described pheochromocytoma-associated syndrome . Neurofibromas are benign peripheral nerve tumors composed of proliferating Schwann cells and fibroblasts. They present as multiple, palpable, rubbery, cutaneous tumors. They are generally asymptomatic; however, if they grow in an enclosed space, e.g., the intervertebral foramen, they may produce a compressive radiculopathy or neuropathy. Aqueductal stenosis with hydrocephalus, scoliosis, short stature, hypertension, epilepsy, and mental retardation may also occur NF1 is characterized by cutaneous neurofibromas, pigmented lesions of the skin called caf au lait spots, freckling in non-sun-exposed areas such as the axilla, hamartomas of the iris termed Lisch nodules, and

 Pseudoarthrosis of the tibia. Patients with NF1 are at increased risk of developing nervous system neoplasms, including plexiform neurofibromas, optic pathway gliomas, ependymomas, meningiomas, astrocytomas, and pheochromocytomas.Neurofibromas may undergo secondary malignant degeneration and become sarcomatous. Mutation of the NF1 gene on chromosome 17 causes von Recklinghausen's disease. The NF1 gene is a tumor-suppressor gene; it encodes a protein, neurofibromin, which modulates signal transduction through the ras GTPase pathway. Pheochromocytomas occur in only about 1% of these patients and are located predominantly in the adrenals. Malignant pheochromocytoma is not infrequent. 2)Von HippelLindau Syndrome: consists of retinal, cerebellar, and spinal hemangioblastomas, which are slowly growing cystic tumors. Hypernephroma, renal cell carcinoma, pheochromocytoma, and benign cysts of the kidneys, pancreas, epididymis, or liver may also occur. Erythropoietin produced by hemangioblastomas may result in polycythemia. Mutation of the von Hippel Lindau (VHL) gene on chromosome 3p, a tumor-suppressor gene, causes this disorder. VHL encodes a protein with multiple functions, including modulation of signal transduction in response to cellular hypoxia 3) Multiple endocrine neoplasia type 2A and type 2B (MEN 2A, MEN 2B) Autosomal dominant disorder It consists of pheochromocytoma, medullary carcinoma of thyroid, and hyperparathyroidism. Both types of MEN 2 are caused by mutations in RET (rearranged in transfection), which encodes a tyrosine kinase MEN 2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism MEN 2B also includes MTC and pheochromocytoma, as well as multiple mucosal neuromas, though it typically lacks hyperparathyroidism Patients with MEN2-related pheochromocytoma often lack hypertension or other symptoms because they secrete epinephrine. Prophylactic thyroidectomy is being performed in many carriers of RET mutations; pheochromocytomas should be excluded before surgery in these patients.

Medical Management During an episode or attack of hypertension, tachycardia, anxiety, and the other symptoms of pheochromocytoma, the patient is placed on bed rest with the head of the bed elevated to promote an orthostatic decrease in blood pressure PHARMACOLOGIC THERAPY The patient may be moved to the intensive care unit for close monitoring of ECG changes and careful administration of alpha adrenergic blocking agents (eg, phentolamine ) or smooth muscle relaxants (eg, sodium nitroprusside) to lower the blood pressure quickly. Phenoxy benzamine, a long-acting alpha-blocker, may be used when the blood pressure is stable to prepare the patient for surgery. Beta-adrenergic blocking agents, such as propranolol, may be used in patients with cardiac dysrhythmias or those not responsive to alpha-blockers.

 Alpha adrenergic and beta-adrenergic blocking agents must be used with caution because patients with pheochromocytoma may have increased sensitivity to them. Still other medications that may be used preoperatively are catecholamine synthesis inhibitors, such as alpha-methyl-p-tyrosine . These are occasionally used when adrenergic blocking agents do not reduce the effects of catecholamines. SURGICAL MANAGEMENT The definitive treatment of pheochromocytoma is surgical removal of the tumor, usually with adrenalectomy. Transabdominal approach: for familial disease Flank approach: for solitary tumor Laproscopic: if tumor <6cm Bilateral adrenalectomy may be necessary if tumors are present in both adrenal glands. Patient preparation includes control of blood pressure and blood volumes; usually this is carried out over 7 to 10 days. Phentolamine or phenoxybenzamine may be used safely without causing undue hypotension. Other medications (metyrosine [Demser] and prazosin [Minipress]) have been used to treat pheochromocytoma. The patient needs to be well hydrated before, during, and after surgery to prevent hypotension. Manipulation of the tumor during surgical excision may cause release of stored epinephrine and norepinephrine, with marked increases in blood pressure and changes in heart rate. Therefore, use of sodium nitroprusside and alpha-adrenergic blocking agents may be required during and after surgery. Exploration of other possible tumor sites is frequently undertaken to ensure removal of all tumor tissue. As a result, the patient is subject to the stress and effects of a long surgical procedure, which may increase the risk of hypertension postoperatively. Corticosteroid replacement is required if bilateral adrenalectomy has been necessary. Corticosteroids may also be necessary for the first few days or weeks after removal of a single adrenal gland. Intravenous administration of corticosteroids (methylprednisolone sodium succinate [SoluMedrol]) may begin the evening before surgery and continue during the early postoperative period to prevent adrenal insufficiency. Oral preparations of corticosteroids (prednisone) will be prescribed after the acute stress of surgery diminishes. Hypotension and hypoglycemia may occur in the postoperative period because of the sudden withdrawal of excessive amounts of catecholamines. Therefore, careful attention is directed toward monitoring and treating these changes. Blood pressure is expected to return to normal with treatment; however, one third of patients continue to be hypertensive after surgery. This may result if not all pheochromocytoma tissue was removed, if pheochromocytoma recurs, or if the blood vessels were damaged by severe and prolonged hypertension. Several days after surgery, urine and plasma levels of catecholamines and their metabolites are measured to determine whether surgery was successful. Maintenance of adequate BP control for 2 weeks before surgery is an important aspect of management. At first the treatment should be initiated with the noncompetitive alpha adrenergic blocker Phenoxy benzamine . The initial dose is 10 mg BD It is increased until the clinical manifestations are controlled or side effects appear. CONTRAINDICATIONS

Hypertensive nephropathy Hypertensive retinopathy Myocarditis Increased platelet aggregation Stroke Heart failure

Postoperative Management Volume replacement is treatment of choice if hypo tension occur either during sx or in the postoperative period. The volume of fluid required is often large (.5 to 1.5 times the patients total blood volume) during the first 24 to 48 hrs. after removal of the tumor Any attempt to collect specimens for a residual tumor should be delayed atleast 5 to 7 days post surgery to be certain that the large increase in both plasma and urinary catecholamines produced by surgery have dissipated. COMPLICATIONS Intraoperative: Extreme rise in BP,Cardiac dysrhythmias Postoperative:Extreme fall in BP Prognosis The long term survival of patients after successful removal of a benign pheochromocytoma is essentially the same as that of age related normal. Approximately 25% of patients remain hypertensive ,but this is usually easily controlled with medication. NURSING MANAGEMENT Risk for fluid volume deficit r/t hypotension hemorrhage & shock Monitor vital signs shock, hemorrhage Give IV fluids as prescribed Administer IV vasopressors as prescribed Carefully measure hourly urine output Assess the client closely for manifestations of adrenal insufficiency

Fear & anxiety related to impending surgery Assess the level of anxiety of client Establish trusting relationships Encourage ventilation of feelings Explain about surgery in simple words Provide reinforcement regarding prognosis & assist in attaining goals Explain purpose of corticosteroids Risk for altered nutrition r/t high metabolic rate promoting rest & relief from stress providing diet high in vitamins minerals & calories. Encourage fluid intake Prohibiting beverages containing caffeine Administering prescribed sedatives Knowledge deficit r/t disease management

 Assess the knowledge level of the patient Explain about disease complication management & prognosis Provide explanation in simple words Clarify doubts Teach post operative care Acute pain r/t surgery , headache Assess nature intensity & location of pain Provide comfortable position Avoid tension on suture line Splint the incision while coughing& turning. Teach relaxation technique Monitor vital signs Provide a calm & quiet environment Administer analgesics as per order Ineffective family coping related to diagnosis of disease Assess the familys perception of disease Identify any misconceptions guilt fear etc Determine degree of emotional or financial stress Include family members in client care Provide opportunity for family group sessions Encourage for screening CONCLUSION Disease with frightening symptoms. Continuous support during the therapy. Due to its familial predisposition, other family members should be evaluated for the disease Regular follow up is necessary as it can recur. REFERENCES Brunner & Suddarths , textbook of Medical Surgical Nursing, 10th edition Black MJ, Medial Surgical Nursing 3rd edition www.pubmed.com www.wikepedia.org,www.emedicine.com Harrisons principals of internal medicine, 15th edition GF Mccarkle, frank Sternberg , cancer nursing, 2nd edition