Benign and Malignant Pheochromocytoma

MANAGEMENT OF ENDOCRINE NEOPLASMS

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BENIGN AND MALIGNANT PHEOCHROMOCYTOMA Diagnosis, Treatment, and Follow-Up Electron Kebebew, MD, and Quan-Yang Duh, MD

Pheochromocytomas are rare. The prevalence of pheochromocytoma is 0.3% to 0.95% in autopsy series and up to 1.9% in a biochemical screening series. 54, 61 , 65 It is important to know how to diagnose and treat pheochromocytomas because they can cause significant morbidity and mortality if left untreated. Pheochromocytoma is one of the few curable causes of hypertension; it is found in 0.1 % to 1 % of hypertensive patients. It can manifest itself in the newborn (40 hours old) or in the elderly (92 years old). 65 There is no gender predilection in adults, but there is a slight female predominance in children. Similar to many other endocrine tumors, there are no accurate histologic criteria to distinguish benign from malignant pheochromocytomas. Surgical treatment, however, can relieve the symptoms and signs, regardless of whether the tumor is benign or malignant. Only 40% of pheochromocytomas present classically as a sporadic, benign, unilateral adrenal tumor in a patient with hypertension. 49 It is, therefore, a challenge to physicians to accurately diagnose and appropriately treat patients with pheochromocytoma. HISTORICAL BACKGROUND

Frankel in 1886 described bilateral adrenal tumors that were most likely pheochromocytomas. 78 They were found during the autopsy of a patient whose death was attributed to nephritis but who had complained From the Department of Surgery, University of California at San Francisco School of Medicine (EK, QYD), and the Veterans Affairs Medical Center (QYD), San Francisco, California SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 7 •NUMBER 4 •OCTOBER 1998

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of transient attacks of anxiety, palpitation, vertigo, headache, vomiting, and constipation.78 Manasse in 1896 noted the positive chromaffin reaction in these adrenal tumors. Alezais and Peyron in 1908 named the extraadrenal chromaffin positive tumors paragangliomas. Pick coined the term pheochromocytoma for chromaffin positive tumors whether they were intraadrenal or extra-adrenal.78 Roux in 1926 and Mayo in 1927 performed the first successful resections of pheochromocytoma. In neither case was the diagnosis made preoperatively.78 Vaquez and Donzelot were the first to make a premortem diagnosis of pheochromocytoma in a patient.78 By the 1950s several centers reported resection of pheochromocytomas diagnosed preoperatively. During this period, before adrenergic blockade was available, the mortality of adrenalectomy was at least 50%. Priestly of the Mayo Clinic then reported successful resection of 61 pheochromocytomas in 51 patients, without mortality. 78 This was made possible by preoperative diagnosis, followed by alpha and beta adrenergic blockade. By the 1970s, resection of pheochromocytoma had become safe because of routine use of preoperative adrenergic blockade. Sadly, as many as one third of pheochromocytomas still were diagnosed post mortem during this time.78 Now significant advances in biochemical testing, localization studies, anesthetic management, and operative technique have improved patient outcomes. PATHOLOGY

The largest collection of paraganglia cells is in the adrenal medulla. The paraganglia system can be subdivided into intra-adrenal (adrenal medulla) and extra-adrenal paraganglia cells. Further, the extra-adrenal paraganglia system can be grouped into four groups; (1) branchiomeric, (2) intravagal, (3) aortico-sympathetic, and (4) visceroautonomic.79 Not all paragangliomas are functional, that is, secrete catecholamines. The aortico-sympathetic and visceral-autonomic paragangliomas are most often functional and chromaffin positive, whereas the branchiomeric and intravagal paragangliomas are rarely functional or chromaffin positive. To avoid confusion, we will refer to all functioning paragangliomas as extraadrenal pheochromocytoma. Because some chromaffin positive paragangliomas are not functional, positive chromaffin staining alone is not sufficient for the diagnosis of pheochromocytoma. 79 Embryologically, the paraganglia system originates from neural crest cells. They differentiate and migrate to form adrenal medullary chromaffin cells, autonomic ganglion cells, and extra-adrenal paraganglionic cells. These cells are capable of synthesizing polypeptide hormones and belong to the amine precursor uptake decarboxylase (APUD) class of cells. Chromaffin cells appear brown when fixed with dichromate because of the oxidation and polymerization of the catecholamines stored in granules.78 Pheochromocytomas primarily secrete norepinephrine and sometimes epinephrine. Dopamine-secreting pheochromocytomas, however, have been reported.75 Some rare pheochromocytomas may even secrete

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ACTH, calcitonin gene-related protein (CGRP), atrial natriuretic peptide, and vasoactive intestinal protein (VIP).75 The principal catecholamines are dopamine, norepinephrine and epinephrine; they metabolize to metanephrine, normetanephrine, vanillylmandelic acid (VMA), and homovanillic acid. Figure 1 outlines the biosynthetic and metabolic pathways of the catecholamines. The N-methylating enzyme, which converts norepinephrine to epinephrine, is primarily found in the adrenal medulla and the organ of Zuckerkandl and less in other extra-adrenal pheochromocytomas. Thus, a high serum level of epinephrine suggests a tumor in the adrenal medulla or the organ of Zuckerkandl. Pheochromocytoma weighs on the average 100 g but ranges from 1 g to 4 kg. The tumor is richly vascularized with fibrous trabuculae and a lobular pattern. On section it has a pale gray to light brown color. The large tumors often have areas of necrosis, hemorrhage, and cystic degeneration. Microscopically, the chromaffin cells show cellular and nuclear pleomorphism. Diffuse or nodular medullary hyperplasia may develop into, or occur simultaneously with, a pheochromocytoma. Ninety percent of pheochromocytomas are found in the adrenal medulla, and 97% are below the diaphragm.72 •79 Approximately 10% each of pheochromocytomas are bilateral, malignant, multifocal, extra-adrenal, or found in children or associated with a familial syndrome. Thus pheochromocytoma is often referred to as the 10% tumor. EXTRA-ADRENAL PHEOCHROMOCYTOMA

Eighty-five percent of extra-adrenal pheochromocytomas are located below the diaphragm. 79 Extra-adrenal pheochromocytomas are often multicentric. In children, about 30% of pheochromocytomas are extra-adrenal, a higher rate than in adults. 5 •42 Extra-adrenal pheochromocytomas have been found from the base of the skull to the spermatic cord. 79 They are most commonly found at the organ of Zuckerkandl (at the distal aorta and aortic bifurcation) and superior para-aortic region. Less commonly, they are found in the head, neck, thorax, bladder, and pelvis (Fig. 2). 79 Bladder tumors are usually located at the dome or trigone of the bladder and patients may present with hematuria and micturation induced symptoms. In the past, extra-adrenal pheochromocytomas were thought to account for 10% of all pheochromocytomas; however, several series report higher rates up to 30%. 79 A comprehensive review and a Cancer Registry of Sweden report 18% and 22% of pheochromocytomas to be extra-adrenal, respectively. 63• 79 In general, pheochromocytomas that are extra-adrenal are thought to be more likely to be malignant than those that are found in the adrenal gland. Malignancy rates of 0% to 76% have, however, been reported in the literature. 47•49• 72 •79 This wide discrepancy is probably caused by a lack of uniform definition of malignancy, inclusion of nonfunctioning paragangliomas, poor long-term follow-ups, and reporting bias. The most accurate study that included only functional paragangliomas, defined malignancy as metastases, and had a follow-up median of 8.8 years, found

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36% of extra-adrenal pheochromocytomas to be malignant. 42 Pheochrom-

ocytomas, whether in the adrenal gland or extra-adrenal, can be associated with multiple endocrine neoplasia (MEN) type 2A or 2B, von HippelLindau (VHL) disease, neurofibromatosis, and Carney's syndrome. 4·40·51 • 76 Patients with MEN 2A or 2B frequently have bilateral adrenal pheochromocytomas, but these patients rarely have extra-adrenal pheochromocytomas.27,70,73

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MALIGNANCY Malignant pheochromocytomas are more common in women than in men and more common in extra-adrenal tumors than in adrenal tumors. They metastasize to bone, liver, regional lymph nodes, lung, and peritoneum in order of decreasing frequency.ss Rarely, they metastasize to brain, pleura, skin, muscle, and distant lymph nodes. Although cigarette smoking and oral contraceptive pills have been found to increase the risk of all adrenal neoplasms, there were too few pheochromocytoma cases in this series to make any conclusion. 21 Pheochromocytomas in patients with familial syndromes (e.g., MEN, VHL) are less likely to be malignant, whereas pheochromocytomas in patients with a family history of malignant pheochromocytoma are more likely to be malignant. Malignant pheochromocytomas can only be accurately diagnosed if the tumor has invaded into local structures or if tumors are found in areas that normally contain no chromaffin tissues. There are otherwise no definitive histologic criteria to accurately diagnose malignant pheochromocytomas. Some characteristics, however, can help differentiate malignant from benign pheochromocytomas. It has been reported in the past that capsular and vascular invasion, mitotic figures and tumor necrosis are

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more frequent in malignant tumors. These have not been accurate predictors of malignancy. It has also been reported that malignant pheochromocytomas take up more metaiodobenzylguanidine (MIBG). 25 Some malignant pheochromocytomas, however, take up no MIBG. 71 One DNA ploidy study of 187 tumors showed that aneuploid or tetraploid DNA occurred more frequently in malignant tumors and that tumors with diploid DNA did not develop metastases. 39 Another study, however, showed three of nine patients with diploid DNA developed recurrent disease and three of four malignant pheochromocytomas were diploid.17 Thus, tumors with diploid DNA are not necessarily benign. Malignant pheochromocytomas may express more c-myc oncogene,33 whereas neuropeptide Y mRNA was more frequently expressed in benign tumors, 9 of 9, versus 4 of 11 malignant tumors. 18 Levels of neuropeptide Y and enolase are slightly higher in malignant pheochromocytomas compared with benign pheochromocytomas. 15 Reduction or loss of neurofibromatosis type I gene in pheochromocytoma without neurofibromatosis has been found and may play a role in tumorigenesis. 16 Malignant pheochromocytomas are larger than benign ones, average 8.8 cm versus 4.2 cm, respectively. A comparison of angiogenesis in benign and malignant tumors shows higher neovascularization in malignant tumors. 32 These differentiating features between malignant and benign pheochromocytomas are listed in Table 1. HEREDITARY CONDITIONS

Most pheochromocytomas (90%) are sporadic. The others have either a simple familial pattern, such as a component of a neuroectodermal disTable 1. CHARACTERISTICS OF BENIGN VERSUS MALIGNANT PHEOCHROMOCYTOMAS Benign

Malignant

Cytology Mitosis Nuclear pleomorphism DNA ploidy

Low High Diploid

High Low Aneuploid, Diploid , Tetraploid

Gross Pathology Size Necrosis

Small Low

Large High

Histology Capsular invasion Invasion angiogensis

Rare Low

Frequent High

Molecular Biology Neuropeptide Y mRNA expression c-myc, mRNA expression

High Low

Low High

Serum Marker Elevated neuron-specific enolase

Low

High

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order or as part of multiple endocrine neoplasia (MEN) 2. Both MEN 2A and IIB include medullary thyroid carcinoma and pheochromocytoma. MEN 2A includes hyperparathyroidism, whereas MEN 2B includes mucosa! neuroma. Multiple endocrine neoplasia 2 is an autosomal dominant syndrome with nearly 100% penetrance of medullary thyroid carcinoma. Pheochromocytoma occurs in 5.53 to 100%, depending on the kindred studied, average being about 403. 20 Bilateral medullary hyperplasia is almost always present.76 The pheochromocytomas are bilateral in 70% and usually multicentric, but they are rarely extra-adrenal or malignant.2°, 76 Pheochromocytoma can be the first and only manifestation of MEN 2. 40 Because of this, a focused history and examination should be done to rule out other components of MEN 2. The management of bilateral tumor and adrenal medullary hyperplasia is discussed later, The ref proto-oncogene mutations are the cause of MEN 2. 6 Some sporadic pheochromocytomas also have ref proto-oncogene mutations. 23 MEN 2 patients with ref codon 634 mutation may be predisposed to developing pheochromocytomas, 6 Four neuroectodermal disorders are associated with pheochromocytomas. Patients with von Recklinghausen disease have neurofibromatosis and rarely pheochromocytomas. Patients with von Hippel-Lindau disease have retinal hemangiomatosis, cerebellar hemangioblastoma, pancreatic cysts or tumors, kidney cysts or cancer, and pheochromocytoma. The incidence of pheochromocytomas in patients with VHL is from 10% to 19% but with variable penetrance, ranging from 03 to 92%. 51 In VHL, pheochromocytoma can be the first (53% of cases) and only (14% of cases) manifestation. 51 The tumors are often bilateral but rarely extra-adrenal.5 1 Inactivation of a tumor suppressor gene was identified in 28 of 221 families with VHL. 51 Loss of heterozygosity (LOH) on chromosome 3p has been detected in VHL- associated pheochromocytomas, sporadic pheochromocytomas and familial pheochromocytomas. 81 The other neuroectodermal disorders that are associated with pheochromocytomas are tuberous sclerosis and Sturge-Weber syndrome. Carney's syndrome is a triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functional extra-adrenal paraganglioma. 4

PEDIATRIC PHEOCHROMOCYTOMA

Childhood pheochromocytoma is rare, accounting for only approximately 10% of all pheochromocytomas. Pheochromocytoma can present as early as 40 hours of age. 65 Pediatric pheochromocytomas are more often familial, bilateral, extra-adrenal, and associated with MEN 2. The prevalence of familial disease is from 313 to 503, depending on the series. 5 About 30% of pediatric pheochromocytomas are bilateral, similar to those with MEN, 5 Childhood pheochromocytomas are less often malignant, even with longer follow-up period than for adults. 5

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CLINICAL MANIFESTATION

Patients with pheochromocytoma may present in florid hypertensive crisis or may have no symptoms and signs. Rarely, a pheochromocytoma can truly be nonfunctioning. Undiagnosed and untreated pheochromocytoma may lead to serious sequela. The manifestations of pheochromocytoma are attributed to excess secretion of catecholamines. The symptoms may be nonspecific. The "classic triad" consists of headache, palpitation, and diaphoresis. Other nonspecific symptoms include tremulousness, abdominal pain, nausea, vomiting, chest pain, fatigue, anxiety, dizziness, constipation, diarrhea, shortness of breath, paresthesia, flushing, weight loss, bone pain, Raynaud' s phenomenon, heat intolerance, and fever (Table 2). These symptoms are often episodic and occur suddenly. These episodes, usually lasting no longer than 15 minutes, increase in severity and frequency as time progresses. 58 Micturation, physical exercise, defecation, sexual intercourse, alcohol consumption, smoking, pregnancy, parturition, general anesthesia, and invasive procedures have been identified as inciting factors of these paroxysmal attacks. Hypertension (HTN) is the foremost clinical manifestation. Three patterns of HTN have been identified: (1) sustained HTN with extreme paroxysm, (2) sustained HTN similar to essential HTN, and (3) paroxysmal HTN with intervening normotension. 46 Obviously the presence of HTN with the classic triad should prompt work-up for pheochromocytoma. Other findings include tachycardia, myadriasis, orthostatic hypototension, palpable flank mass, hypercalcemia, shock, polycythemia, hyperglycemia, lactic acidosis, cardiomegaly on chest radiograph, left ventricular hypertrophy on electrocardiogram (ECG), and retinopathy (see Table 2).

Table 2. SIGNS AND SYMPTOMS OF PHEOCHROMOCYTOMAS Symptoms

Signs

Headache Palpitations Diaphoresis Fainting episode Bone pain Weight loss Fever Anxiety Nausea/vomiting Dizziness Flushing Weakness/fatigue Abdominal pain Dyspnea Paresthesia Chest pain Constipation/diarrhea Flank pain Visual symptoms

Hypertension Hyperglycemia Tachycardia Orthostatic hypotension Palpable flank mass Hypercalcemia Shock Polycythemia Port wine hemangiomas* Thyroid tumor* Cate au lait spots Mucosal neuromas*

*In associated hereditary conditions.

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Also signs of neuroectodermal disorder and MEN 2, such as neurofibromata, cafe au lait spots, port wine hemangiomas, and thyroid tumors, should be looked for (see Table 2). DIFFERENTIAL DIAGNOSIS

The differential diagnosis includes a wide spectrum of organic and psychiatric disorders (Table 3). Most disorders can be excluded based on careful history, physical examination, and biochemical testing. Common diagnoses include essential HTN with anxiety, panic attacks, severe migraines, hyperthyroidism, menopause, and autonomic dysfunction. The symptoms caused by ingestion of amphetamines, diet pills, cocaine, and crack can mimic those of pheochromocytomas (see Table 3). SEQUELAE OF PHEOCHROMOCYTOMA

Most complications are caused by cardiovascular disease secondary to the excess catecholamine state. Hypertensive or hypotensive crisis, myocardial infarction, tachyarrhythmias, congestive heart failure, stroke, and acute pulmonary edema secondary to congestive heart failure (CHF) are the complications that occur in patients with untreated pheochromocytoma. Hypertensive crisis, hypotensive crisis, myocardial infarction, and cerebral vascular accident accounted for 75% of mortalities in untreated or undiagnosed pheochromocytomas. 45 , 65 Other reported complications include acute pancreatitis, retroperitoneal tumor hemorrhage, reTable 3. DIFFERENTIAL DIAGNOSIS OF PHEOCHROMOCYTOMAS Diagnosis

Acute mercury poisoning (acrodynia) Alcohol withdrawal Anxiety/panic disorder Autonomic dysfunction ~-Adrenergic hyper-responsive state Baroreflex failure Carcinoid Catecholamine conjugation defects Eclampsia Endocrine secretory tumors Hypertension Hyperthyroidism Monoamine oxidase inhibitor ingestion and hypertensive crisis Mitra! valve prolapse Myocarditis Paroxysmal hypertension after clonidine withdrawal Post-traumatic stress disorder exacerbation Surreptitious self-epinephrine injections Reactive hypoglycemia Various drugs: amphetamines, pseudoephedrine, phenylephrine, isoproterenol , ephedrine From Werbel SS, Ober KP: Pheochromocytoma: Update on diagnosis, localization and management. Med Clin North Am 79:1, 1995; with permission.

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nal artery stenosis secondary to mass effect, kidney infarction (possibly secondary to spasm), rhabdomyolysis, renal failure, disseminated intravascular coagulation (DIC), seizures, and vasculitis. 45, 65 DIAGNOSTIC WORK-UP

Once pheochromocytoma is suspected one needs to perform biochemical tests to establish the diagnosis. Thereafter, the tumor is localized by imaging studies. Individuals that need to be screened are those that have symptoms suggestive of pheochromocytoma. Patients with paroxysmal, sudden, or severe hypertension and those who are unresponsive to antihypertensive medications need screening. Pregnant women and children with hypertension also need prompt evaluation to rule out pheochromocytoma. Individuals with a family history of pheochromocytoma, MEN 2A or 2B, VHL, or other neuroectodermal disorders (von Recklinghausen's disease, Sturge-Weber syndrome, tuberous sclerosis, and Carney's syndrome) should be screened for pheochromocytoma. All patients with incidentally discovered adrenal tumors (incidentalomas) need biochemical screening for pheochromocytoma, before resection, or fine-needle biopsy because of the potential for precipitating a pheochromocytoma crisis and death. 38 BIOCHEMICAL TESTS

There is no consensus on a single best test for screening and diagnosing pheochromocytoma. Fortunately in most patients the diagnosis is established without difficulty. Overall, measurement of plasma and urine catecholamines and urinary metanephrines have the highest sensitivity and specificity; urinary VMA is slightly less sensitive and specific. 12, 44 Although symptoms may be episodic, the excretion of catecholamines and their metabolites are usually elevated between episodes. Sometimes if the episodes are far apart then urine specimens may be normal. Some substances interfere with the measurement of catecholamines and metabolites and should be avoided to achieve correct diagnosis (Table 4). Rarely, when the clinical suspicion is high but the measurement of basal plasma or urinary catecholamines and metabolites are not diagnostic of pheochromocytoma, provocative tests might be necessary. The provocative tests, however, have poor diagnostic accuracy, and usually have significant side effects and may be potentially lethal. To avoid the need for provocative tests, plasma catecholamines or timed urinary catecholamines should be performed during episodes of symptoms. Some institutions still use outmoded fluorometric and spectrophotometric assays to measure catecholamines and metabolites. These have poor sensitivity and specificity when compared with measurement by gas chromatography- mass spectrometry or high pressure liquid chromatography (HPLC). 12, 52 The newer techniques are also less likely to have interference by diet and drugs. These assays measure urinary epinephrine,

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Table 4. DRUGS AFFECTING BIOCHEMICAL TESTS FOR PHEOCHROMOCYTOMA Exogenous Catecholamines (All the tests can have abnormal results, but high-pressure liquid chromatography and radioenzymatic assays are more specific and sensitive for catecholamines.) Nose drops, sinus and cough remedies, bronchodilators, appetite suppressants Factors Contributing to Stimulation of Endogenous Catecholamines (Plasma and urine care catecholamines are the most sensitive to these stimuli, but metanephrines and VMA can be abnormal as well.) Emotional and physical stress, operation, acute central nervous system disturbances (stroke, hemorrhage, tumor, encephalopathy), acute coronary ischemia, angiography, hypoglycemia, caffeine, nicotine, diazoxide, quinidine, erythromycin, tetracycline, isoproterenol, aspirin, acetaminophen, theophylline, drug withdrawal (ethanol clonidine), vasodilator therapy (nitroglycerine, sodium nitroprusside, and calcium channel blockers) Drugs Altering Catecholamine Metabolism Decreasing urine catecholamines a 2 -Agonists, chronic use of calcium channel blockers, angiotensin converting enzyme inhibitors, bromocriptine, a-methyldopa, chlorpromazine, guanethidine, radiographic dyes, reserpine Decreased VMA; increased catecholamines and metanephrines a-Methyldopa, MAO inhibitors Variable changes in any test Phenothiazines, tricyclic antidepressants, levodopa-drugs with prolonged half-lives may need to be discontinued for 2 to 3 weeks before accurate determinations can be made. Increased metanephrines Acetaminophen, chlorpromazine, labetalol, tetracyclines, triamterene Specific Drug Interferences Decreased metanephrines Metanephrine assay interference by the methylglucamine in radiographic contrast medium (most pronounced in urine collected the same day as the contrast medium is administered, but may last up to 72 hours) Decreased urine catecholamines Methenamine mandelate destroys catecholamines in bladder urine Decreased VMA Clofibrate aspirin, a-methyldopa, disulfiram, MAO inhibitors, phenothiazines, radiographic dyes, reserpine, imipramine Increased VMA Nalidixic acid, anileridine, methocarbamol, tetracyclines, carbidopa/levodopa, reserpine, nitroglycerin VMA = Vanillylmandelic acid; MAO = monoamide oxidase Adapted from Werbel SS, Ober KP: Pheochromocytoma: Update on diagnosis, localization and management. Med Clin North Am 79:1, 1995, with permission.

norepinephrine, dopamine, metanephrine and normetanephrine, VMA, and plasma epinephrine and norepinephrine. URINARY TESTS

Urine measurement may be done over a 24-hour period or less and reported per 24 hours, hourly, or per milligram of creatinine in the urine. Twenty-four hour urine measurement is most commonly used to measure catecholamines and metabolites. The use of total metanephrine has up to

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98% sensitivity for the diagnosis of pheochromocytoma.59 Methylglucamine (radiology iodine contrast media) may falsely lower total metanephrine measurement for up to 72 hours after its use. HPLC measurement of fractionated catecholamines (norepinephrine greater than 80 µg/24 hr, epinephrine greater than 20 µg/24 hr and dopamine greater than 400 µg/ 24 hr) are very sensitive but less specific for the diagnosis of pheochromocytoma. Using the levels of norepinephrine greater than 170 µg/24 hr or epinephrine greater than 35 µg/24 hr would increase the specifity to over 95% while maintaining a high sensitivity.58 Dopamine measurement is less useful for diagnosis because very few pheochromocytomas secrete only dopamine. Excessive dopamine secretion may be evident by the clinical presentation of tachycardia, polyuria, and hypotension. Methyldopa or mandelamine may affect the result of dopamine level. Initial measurement of total urinary metanephrines, followed by confirmation with fractional catecholamines, makes the diagnosis of pheochromocytoma without further workup in nearly all cases. PLASMA TESTS

It is generally felt that measurements of plasma catecholamine is not as accurate as urinary assays. Many physiologic and pathologic states can affect the level of plasma catecholamine (see Table 4). Accurate results can only be obtained by avoiding improper sample drawing. Noise, stress, discomfort, or use of caffeine, nicotine and some foods can increase the plasma catecholamine levels. An IV should be placed at least 30 minutes before a sample is drawn with the patient remaining supine throughout. It is necessary to measure epinephrine and norepinephrine because some tumors will only secrete one or the other. A specificity of 95% and sensitivity of 85% is reported using the threshold of norepinephrine greater than 2000 pg/mL or epinephrine greater than 200 pg/mL.58 The use of a lower threshold would decrease the specificity of the test. Markedly elevated plasma levels are most helpful when they are measured during an episode of severe hypertension or during a symptomatic episode. PROVOCATIVE TESTS

Before accurate biochemical tests were developed, provocative testing was used to produce hypertension in pheochromocytoma patients. Glucagon, histamine, metoclopramide, tyramine, and naloxone were used to induce hypertension in patients suspected to have pheochromocytomas. They soon fell out of favor because of significant morbidity and mortality from the tests. Rarely, the glucagon stimulation test and the clonidine suppression test may still be used when the results of basal levels of urinary and plasma catecholamines and metabolites are equivocal and the clinical suspicion is high. The goal of the provocative tests is to separate patients who have low activity pheochromocytomas from patients who do not have pheochrom-

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ocytomas but have increased sympathetic discharge. Glucagon is used to provoke catecholamine secretion from pheochromocytomas with low activity. After drawing a basal level of catecholamine, the patient is given an IV bolus of 1 to 2 mg of glucagon. A positive result is defined as at least a threefold increase or stimulated level greater than 2000 pg/mL in plasma catecholamine measured 1 to 3 minutes after administration of glucagon.2 Continuous monitoring of blood pressure is mandatory because severe hypertension may ensue. If the patient becomes severely hypertensive, he or she should be treated with phentolamine or sodium nitroprusside. Nifedipine, 10 mg orally, may be used as prophylaxis against severe hypertension because it will not affect catecholamine release and its measurement. The reported sensitivity and specificity for the glucagon stimulation test is 81 % and 100%, respectively.14 A suppression test may be used to make the diagnosis of pheochromocytomas in patients with moderately increased levels of plasma catecholamine (1000 to 2000 pg/mL), with or without hypertension. 2 Clonidine suppression test is the most commonly used. Clonidine inhibits the neurogenically mediated catecholamine release but does not inhibit the release of catecholamine from pheochromocytomas.2 A normal clonidine test is when basal levels of plasma norepinephrine plus epinephrine decrease below 500 pg/mL within 2 to 3 hours after 0.3 mg of oral clonidine. 2 Hypotension is a potential danger, especially in those on other antihypertensive and beta-adrenergic blocking agents. Bravo reports a falsepositive and false-negative rate of only 2% for the clonidine suppression test. 2 If the glucagon stimulation test and clonidine suppression test are not diagnostic then a pheochromocytoma is extremely unlikely.

CHROMOGRANIN A

Chromogranin A is an acidic, monomeric protein that is stored and released with catecholamines in the adrenal medulla. A few studies have evaluated its use in the diagnosis of pheochromocytoma. Secretion and measurement of chromogranin A are not affected by drugs used to treat pheochromocytoma. One series found plasma chromogranin A to be a useful adjunct to the diagnosis of pheochromocytoma with a sensitivity of 83% and specificity of 96%. 64 Chromogranin A, however, has poor specificity in patients with renal insufficiency and should be used in conjunction with plasma catecholamine. 3

LOCALIZATION

Once the diagnosis of pheochromocytoma is made, the tumor should be localized and the extent of disease identified. CT scan, MR image and MIBG are the best localization studies. Each of these studies may be more desirable in a given clinical situation. Angiography and selective venous sampling for catecholamine are less accurate, rarely necessary, and may

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cause significant complications. Plain film radiography, urography, and tomography are largely of historic interest. CT Scan

Since 97% of pheochromocytomas are intra-abdominal and 90% intraadrenal, CT scan of the abdomen will rarely miss a lesion. Most pheochromocytomas are greater then 3 cm in diameter and are very rarely less than 2 cm. Thus, they are within the detection limits of the routine abdominal CT scan with sections thickness of 1 cm or adrenal specific CT scan with section thickness of 3 to 5 mm (Fig. 3). The scan should encompass the body from the diaphragm to at least the aortic bifurcation so as

Figure 3. See legend on opposite page

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not to miss the most common site of extra-adrenal pheochromocytoma, the organ of Zuckerkandl. Glucagon may precipitate a hypertensive crisis (see Provocative Tests discussed earlier) and should not be used. Intravenous contrast during CT scan can also elevate plasma catecholamines and lead to a hypertensive crisis in patients who have not been treated with alpha-adrenergic blockers. The disadvantages of CT scan in evaluating pheochromocytoma are (a) radiation exposure, (b) less accurate for detecting extra-adrenal tumor, (c) poor tissue characterization (cannot definitively diagnose pheochromocytoma), (d) intravenous contrast may be required, and (e) no functional data are obtained. Advantages include (a) better patient compliance than with MR imaging, (b) it can be done rapidly, (c) it provides good anatomic information, and (d) it is readily available. 9 The sensitivity of CT scan for pheochromocytoma is 85% to 95% and specificity is 70% to 100%.9•50• 74 MR IMAGING

MR imaging has become more widely available. Several studies report high sensitivity and specificity for localizing pheochromocytomas in the adrenal, over 95% and 100%, respectively. 9 •50• 74 It has some advantages over CT scan. There is no radiation exposure, no need for IV contrast, and surgical clips produce no artifact. 9 Pheochromocytoma has a characteristic brightness on T2-weighted images (see Fig. 3). 7 MR imaging is the procedure of choice in pregnant women because of no radiation risk to the

c Figure 3 (Continued). A left peri-aortic, inferior to the renal vessels, extra-adrenal pheochromocytoma in a patient with a history of multiple pheochromocytomas A, CT scan. B, T1weighted with gadolinium MR image. C, MIBG.

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fetus. MR imaging, however, is not as commonly available, costs more than CT, and requires a longer examination period. Patients are less compliant with MR imaging because of claustrophobia. CT and MR are accurate for evaluating periaortic lymph nodes and liver metastases.

META-1000-BENZYLGUANIDINE

MIBG is iodine-131 or iodine-123 tagged meta-iodo-benzylguanidine that is similar to norepinephrine in structure. MIBG is taken up and concentrated within adrenergic vesicles in the adrenal medullary cells. Uptake is proportional to the number of vesicles present. Normal adrenal medulla does not take up enough MIBG to produce an image. Only APUD tumors produce an image on scintigraphy. MIBG is most useful for localizing recurrent pheochromocytomas or multiple extra-adrenal pheochromocytomas.26,50 It is the only study that provides functional status of the tumor. Certain drugs, such as tricyclic antidepressants, guanethidine and labetalol, have been reported to block MIBG uptake and should be withheld before a MIBG study. 2 The thyroid gland uptake of iodine should be blocked with Lugol's solution or SSKI to avoid unintended thyroid ablation and hypothyroidism. MIBG offers certain advantages over MR image and CT. Extra-adrenal pheochromocytoma can be detected by a whole body scan. MIBG also provides functional data (see Fig. 3). The disadvantages include radiation exposure, high cost, less availability, and poor anatomic information requiring follow-up MR image or CT scan. The reported sensitivity of MIBG ranges from 77% to 89% and specificity from 88% to 100%.9,36,50,74 An echocardiogram maybe required to rule out extra-adrenal pheochromocytomas that are intra-cardiac, although gated MR image and MIBG will probably detect these lesions. Octreotide scan and positron emission tomography (PET) scan have been reported to detect pheochromocytomas.28·29·37 These studies, however, are still considered investigationaL Table 5 compares the indications and limitations of MR imaging, CT, and MIBG. In one series, MR image, CT, and MIBG were all in agreement in 79% of cases, MIBG and CT in 84%, MIBG and MR imaging in 86%, and MR imaging and CT in 93%. 74 MR imaging, CT, and MIBG are complementary studies. Obviously certain clinical situations will dictate one modality over another or the need for concurrent studies. CT and MR image are the preferred initial imaging choices. If multiple or metastatic disease is suspected, however, MIBG should be the initial study, followed-up with CT and MR image for anatomic definition.

MANAGEMENT

The only effective treatment of pheochromocytoma is surgical excision. Surgical treatment is almost always indicated whether the tumor is benign or malignant Because of effective preoperative and intraoperative

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Table 5. CHARACTERISTICS OF IMAGING TECHNIQUES FOR LOCALIZATION OFPHEOCHROMOCYTOMA Correlation Imaging Technique CT

MR imaging

CT

MR

MIBG

Imaging 100%

93%

100%

MIBG

Advantages

Disadvantages

84%

Good anatomic detail; Radiation; no functional data; poor with extra-adregood patient complinal pheochromocytoma ance 86% Good anatomic detail; Expensive; poor patient compliance; functional no radiation; no condata unreliable trast media; some functional data 100% Definite functional Radiation; poor anatomic detail data; excellent for extra-adrenal pheochromocytoma

From Pommier RF, Brennan MF: Management of adrenal neoplasms. Curr Probl Surg 28:657, 1991; with permission.

medical management, surgical resection has acceptable morbidity and mortality, as low as 1% and 16%, respectively.B,s9, 7s Medical Management

The principles of medical management are treatment of hypertension, expansion of intravascular volume, and control of arrhythmias. Several classes of antihypertensive agents have been used with success. Most commonly used is phenoxybenzamine, a long acting alpha-pre and postsynaptic adrenergic antagonist. It is usually started 1 to 3 weeks before operation at a dose of 10 mg a day. The dose is then gradually increased, as tolerated by the patient, up to as much as 300 to 400 mg a day. The dose is usually limited by side effects of alpha-adrenergic blockade, such as orthostatic hypotension, tachycardia, nasal congestion, nausea, and abdominal pain. Adequate alpha blockade can be defined as normotension, well-controlled hypertension, or the development of side-effects. Specific criteria are (1) supine arterial pressure not greater than 160/90, (2) orthostatic hypotension should be present but not greater than 80/ 45, (3) electrocardiogram without ST segment or T wave changes for at least 2 weeks, and (4) no more than one premature ventricular contraction every 5 minutes.2 Prazosin is another alpha-adrenergic blocking agent that has been used. It is shorter acting and may have an advantage over phenoxybenzamine of avoiding postoperative hypotension. Also, reflex autonomic tachycardia is not a problem because prazosin selectively blocks the alpha1 adrenergic receptor. Treatment doses for prazosin is 2 to 5 mg every 6 to 8 hours. Other selective alpha-1 adrenergic antagonists used are doxazosin (Cordura) 16 mg a day or terazosin 1 to 20 mg a day. Labetalol, a competitive alpha-1 and beta-adrenergic antagonist has also been used with success. 2 It is an antihypertensive and an antiarrhythmic drug. The dose of labetalol is 400 mg to 1600 mg a day. Preferential alpha or beta blockade, however, is difficult to attain with labetalol. Calcium channel blockers can also be used to control blood pressure

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in patients with pheochromocytoma. They cause less orthostatic hypotension than alpha-adrenergic blockers.75 Angiotensin-converting enzyme (ACE) inhibitors have also been successfully used to manage hypertension in patients with pheochromocytoma.59 Metyrosine inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis (see Fig. 1), and can be used when antihypertensive agents are not effective. It reduces catecholamine production by 50% to 80% with doses of 1000 to 4000 mg. 75 The side effects of metyrosine include extrapyramidal neurologic signs, crystalluria, diarrhea, and anxiety. 75 Beta-blockers may be required preoperatively for patients with persistent tachycardia, history of arrhythmias, or persistent extrasystole. Propranolol is usually used, in doses of 10 to 40 mg every 6 to 8 hours. Beta-blockers should not be used until the patient has received adequate alpha-blockade because the resulting unopposed alpha effect could worsen vasoconstriction leading to hypertensive crisis, CHF, and pulmonary edema. Preoperative volume repletion is important to avoid hypotension after resection. Patients with pheochromocytoma have intravascular volume depletion caused by a persistent vasoconstricted state. They often have hemoconcentration and lactic acidosis. Oral salt and fluid intake with antihypertensive agent is often adequate to re-expand the intravascular volume. One will observe hemodilution with a lower-stable hematocrit once the patient is euvolemic. 46 During the operation the patient should be carefully monitored, and drugs that stimulate catecholamine secretion should be avoided. An arterial line is required to monitor blood pressure continuously. It is preferably placed in a large vessel (femoral artery) to avoid complications caused by arterial spasm. A central venous line is used to monitor volume status because aggressive fluid resuscitation is often required. In patients with CHF and coronary artery disease, a pulmonary artery line (SwanGanz) is helpful for optimal management of fluid resuscitation and cardiac function assessment. Stress during induction for general anesthesia should be avoided. Inhaled anesthetic agents with the least cardiac depressant effect are preferable. Isoflurane and enflurane have been used safely. Muscle relaxants, such as vecuronium, that have less hypertensive effect should be used. Sodium nitroprusside, phentolamine, and nitroglycerin are antihypertensive agents used intraoperatively. Sodium nitroprusside has immediate onset and a short half-life allowing almost instantaneous blood pressure control. Build up of cyanide, a metabolite of sodium nitroprusside, becomes a concern if excessive amount is used. Phentolamine is a short acting alpha blocker. Ventricular arrhythmias can be managed with intravenous lidocaine and tachyarrhythmias with esmolol, a short-acting beta blocker. OPERATIVE APPROACH

The principles of pheochromocytoma resection are complete tumor resection, avoidance of tumor seeding, minimal tumor manipulation, control of vascular supply and drainage of tumor, and hemostasis. Often a

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drop in blood pressure is noted when the adrenal vein is ligated. Whenever the tumor is manipulated the anesthetist should be informed because the patient can become hypertensive. Adrenalectomy can be performed by way of an open anterior (transabdominal), open thoracoabdominal, open posterior (retroperitoneal), lateral transabdominal laparoscopic, or posterior retroperitoneal laparoscopic approach. In the past an open anterior approach was the standard because it allowed complete exploration and inspection for potential tumor foci. With the accuracy of the new preoperative localizing imagining studies, however, there is little need for exploration in areas in which a tumor has not been identified preoperatively. The results of a focused exploration and excision are comparable to those with general exploration. 48 Open thoracoabdominal approach may be necessary for a very large tumor and gives the best exposure. The long incision and the thoracotomy, however, add to its morbidity. Open anterior (midline or subcostal) approach allows for complete evaluation for the contralateral gland and other intraperitoneal disease. Patients usually have ileus, postoperative pain, and prolonged convalescence and may have pulmonary complications because of the laparotomy. The posterior approach has certain advantages over the anterior approach, such as decreased blood transfusion requirement, shorter hospitalization, is technically easier in patients with a history of laparotomy and peritonitis, and decreased overall morbidity. The drawbacks are limited exposure, allowing resection of only smaller tumors (less than 5 cm), inability to explore for intraperitoneal or contralateral disease, and the need for bilateral incisions to perform bilateral adrenalectomy. Laparoscopic adrenalectomy has been found to decrease hospitalization time, transfusion requirement, postoperative analgesia requirement, and convalescence. 8• 19•62 Tumors larger than 6 cm, however, may be more difficult to resect laparoscopically. With experience the operative time is decreased and larger tumors can be resected. There is no significant difference in morbidity or efficacy between the lateral transabdominal and posterior retroperitoneal laparoscopic approaches. 8 Technically, the lateral laparoscopic approach is preferable for larger tumors (greater than 6 cm) and allows some exploration of the abdominal cavity with specific identification of potential liver metastases.8 In contrast, the posterior approach is preferable for patients with previous laparotomy, history of peritonitis, and small bilateral adrenal tumors. Laparoscopic resection for malignant pheochromocytoma is controversial. In the absence of obvious local invasion or metastatic disease a laparoscopic approach is acceptable according to some endocrine surgeons. Because of the complex perioperative management and potential intraoperative complications, laparoscopic adrenalectomy should be performed by surgeons experienced in endocrine surgery and laparoscopic surgery.

PREGNANCY Pheochromocytoma in pregnancy is associated with high morbidity and mortality for mother and fetus. If the diagnosis is made during preg-

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nancy the mortality and morbidity for the mother are 11 % and 46%.JO If the diagnosis is made during or after delivery, the mortality and morbidity are 40% and 56%. 10 The diagnosis, therefore, needs to be made as early as possible. Elevation in the levels of catecholamine is not normal in pregnancy. Localization is best with MR imaging to avoid the risk of radiation. Ultrasound has limited use late in pregnancy because of the large gravid uterus. MIBG for localization is contraindicated if the pregnancy is to be carried to term because radioactive iodine would potentially be injurious to the fetus. CT scan may be used in the second or third trimester, weighing the risk-benefit ratio. Medical and surgical management is largely dictated by the gestational age at diagnosis and by whether the patient wishes to complete the pregnancy. In early pregnancy, if the patient decides to terminate the pregnancy, she should receive alpha and beta blockade, followed by termination of pregnancy and immediate tumor resection. If the patient decides to carry the pregnancy to term, she should receive alpha and beta blockade, after being informed of the increased risk of fetal demise.JO Resection is best performed during the second trimester if possible as medical control is seldom successful. 10 Late in pregnancy, medical management is used to bridge the pregnancy to term, followed by elective cesarean section and immediate tumor resection under the same anesthetic. Vaginal delivery is avoided because it may precipitate a hypertensive crisis. If medical management is not successful and fetal distress occurs, delivery by hysterotomy followed by adrenalectomy has been successful. JO

MEN The surgical management of pheochromocytomas in patients with MEN 2 is controversial, specifically whether prophylactic adrenalectomy is justified. Arguments for bilateral adrenalectomy are risk of malignancy, risk of metachronous pheochromocytoma and its related complication, and the low incidence of Addisonian crisis after bilateral adrenalectomy. In one series, 55% of the patients required completion adrenalectomy of the contralateral side at an average follow-up of 4.8 years, and these patients had few Addisonian complications over 11 years average followup.73 In another series, however, 52% of the patients developed contralateral disease at an average of 11.9 years after initial unilateral resection and 25% of patients after bilateral adrenalectomy experienced at least one episode of Addisonian crisis.27 One patient died and none developed malignant pheochromocytoma.27 In another series, all patients with tumors greater than 5 cm had a metachronous lesion in the contralateral adrenal gland.7° Others have attempted subtotal, cortical sparing, adrenalectomy. These patients had a recurrence rate of 21 %, no postoperative Addisonian crisis, and 93 % of patients did not require steroid replacement. 30 The risk for malignant pheochromocytoma in patients with MEN 2 is very low, except in those with a strong family history of malignant pheochromocytoma. If the patient is compliant, one can wait to resect the contralateral adrenal gland only if a pheochromocytoma develops.

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MALIGNANCY

The main treatment for malignant tumor is resection and catecholamine blockade. If the tumor is inoperable or if there is residual disease after resection, chemotherapy, high-dose MIBG, and external radiation therapy are options with limited efficacy. MIBG is used to localize recurrent or metastatic disease, it also serves to identify tumors that can potentially be treated by high dose 131 1-MIBG. The largest study of MIBG therapy for malignant pheochromocytoma to date showed no complete responders. The overall transient response rate was 60% (30% partial tumor response and 54% complete or partial hormonal response). 25 Patients with hormonal response (decreased catecholamine levels) had better blood pressure control and symptomatic relief. 25 All hormonal and tumor responses were transient with a median of 26 months and 36 months, respectively. 25 Toxicity of MIBG includes transient hypertension, mild leukopenia, thrombocytopenia, and pancytopenia. These resolved on successive treatment. Pancytopenia was found in a patient with heavy bone tumor burden. Soft-tissue lesions and smaller tumors respond best to MIBG therapy.25 The reason for the transient response or resistance to therapy in some tumors is attributed to the heterogeneity of MIBG uptake and possible selection of resistant clones. Several reports of single and combination chemotherapy regimen for malignant pheochromocytoma have shown variable response in small groups of patients. Because neuroblastoma has an 80% response rate to the regimen of cyclophosphamide, vincristine and darcarbazine, most studies of chemotherapy for malignant pheochromocytoma have evaluated this regimen, but had at best transient response. The largest series showed a 57% overall response, 79% hormonal response, and 21 % tumor response. 1 As with other regimens, no complete response was reported. 1 Hormonal response correlated well with objective improvement of performance and normalization of blood pressure. 1 External beam radiation is primarily helpful for palliation of painful bone metastases. Arterial embolization of a metastatic liver lesion has been reported to give transient response. 67 Radioiodine-labeled octreotide has also been used to treat malignant pheochromocytoma, showing only transient symptomatic relief in two patients. 24 Malignant pheochromocytoma should be resected if possible and the patient treated with alpha-adrenergic blockade. For residual tumor, patients can be treated with MIBG or chemotherapy with cyclophosphamide, vincristine, and darcarbazine. Thus, the disease-free survival may be prolonged. If the tumor is inoperable, the patient should be treated with alpha-adrenergic blockade. MIBG and chemotherapy are offered for symptomatic relief if catecholamine blockade alone is insufficient. Bone metastasis may be resected or irradiated for palliation. FOLLOW-UP AND PROGNOSIS It may be difficult to rule out malignancy and possible future recurrence after resection and supposed cure from pheochromocytoma. Recur-

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rent pheochromocytoma has been reported up to 20 years after apparent cure.67 Lifetime follow-up is thus prudent. Patients are evaluated every 6 months to one year. A careful history should be taken regarding symptoms of catecholamine excess or metastases. Blood pressure should be monitored, and biochemical assays performed. Routine imaging studies, in the absence of recurrent disease by biochemical assays, are not useful. MIBG study should be performed if there are biochemical findings of recurrence. Patients with benign pheochromocytoma have almost normal life expectancy after resection but with up to a 6.5% recurrence rate. 72 Patients with malignant pheochromocytomas have a 5-year survival rate of 30% to 50% .13·2s,3s,47 Malignant tumors may recur early or late. The extent and location of recurrent pheochromocytoma affect patient survival. Those with pulmonary and liver metastases have a worse prognosis.ss

CONCLUSION

Pheochromocytomas are rare but have significant morbidity and mortality. Unfortunately no accurate histologic or clinical criteria exists to make the distinction between benign and malignant pheochromocytoma. The diagnosis of pheochromocytoma can accurately be made with catecholamines and metabolites biochemical assay and the tumor localized by CT, MR imaging, or MIBG imaging. A focused, complete surgical resection of a pheochromocytoma cures the patient. Laparoscopic adrenalectomy is safe for benign and small pheochromocytomas. Chemotherapy, radiation therapy, and MIBG therapy are at best palliative for malignant pheochromocytoma. Life-long follow-up is recommended.

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Address reprint requests to Quan-Yang Duh, MD Surgical Service Veterans Affairs Medical Center 4150 Clement St #112 San Francisco, CA 94121