161 - Cervical Substernal Extended Mediastinoscopy | General Thoracic Surgery (General Thoracic Surgery (Shields)) [2 VOLUME SET]

Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.

Title: General Thoracic Surgery, 6th Edition

> Table of Contents > Volume II > The Mediastinum > Section XXIX - Primary Mediastinal Tumors and Syndromes Associated with Mediastinal Lesions > Chapter 191 - Mediastinal Paragangliomas and Pheochromocytomas

function show_scrollbar() {}

Chapter 191

Mediastinal Paragangliomas and Pheochromocytomas

Brahm Shapiro

Mark B. Orringer

Chuong Bui

Barry L. Shulkin

Milton D. Gross

The surgical treatment of intrathoracic paragangliomas is influenced by an understanding of where these lesions may be found in the chest and the continued improvement in the diagnostic capabilities of computed tomography (CT), magnetic resonance (MR) imaging, scintigraphy with iodine 131 (¹³¹I)- and ¹²³I-metaiodobenzylguanidine (MIBG), indium 111 (¹¹¹In)-octreotide, and positron emission tomography (PET) with fluorine 18 (¹⁸F) fluorodeoxyglucose (¹⁸F-FDG) and a growing list of other PET radiopharmaceuticals as reported by three of us (BS, MDG, BLS) (2001) and Pacak and co-workers (2002). In contrast to the sympathetic ganglia, which are interconnected by the sympathetic trunks, the paraganglia are other discrete collections of cells of neural crest origin found throughout the body in the adrenal medullae, along the aorta, in walls of blood vessels, and scattered through various organs such as the heart, prostate, and ovary. It was recognized by early pathologists that tissues rich in epinephrine, such as pheochromocytomas, have an affinity for chromic salts, which stain them brown. These so-called chromaffin cells are found not only in the adrenal medulla, but in the sympathetic ganglia, paraganglia along the sympathetic chain, and the organ of Zuckerkandl, the most prominent of the paraganglia along the abdominal aorta. Tumors derived from these paraganglia have been termed paragangliomas by Glenner and Grimley (1974). Persistent, aberrant collections of chromaffin cells may be the site for development of extraadrenal pheochromocytomas, functionally active tumors (paraganglioma) of the sympathetic nervous system. Paragangliomas of the parasympathetic nervous system are generally chromaffin negative and nonsecretory with respect to catecholamines. These neoplasms have been designated by Glenner and Grimley (1974), as well as by Bird and Seiler (1991), as chemodectomas, because they most often involve the chemoreceptor tissues of the carotid body, glomus jugulare, aortopulmonary glomus, vagal body, and ciliary glomus.

Pheochromocytomas are rare tumors, the life-threatening effects of which, as noted by Freier and co-workers (1980), Bravo and Gifford (1984), Bravo (1994, 2002), and one of us (BS) and Fig (1989), are primarily mediated through the hypersecretion of catecholamines. Almost 90% of pheochromocytomas arise from the adrenal medulla. Extraadrenal pheochromocytomas constitute less than 10% of all pheochromocytomas, and less than 2% of pheochromocytomas occur in the chest. Besterman (1974), Freier (1980), one of us (BS) (1984a), another of us (MBO) (1985), van Heerden (1982) and their colleagues, as well as Cueto and McFee (1965), Bravo and Gifford (1984), Downs and Schloemperlen (1966), Edmunds (1966), Bravo (1994), and Sandur and co-workers (1999), have all noted that these tumors are often difficult to identify and challenging to diagnose and treat. Glenner and Grimley (1974), Levine and McDonald (1984), one of us (BS) and Fig (1989), and Bravo (1994) have all noted that a coordinated team approach involving endocrinologist, pathologist, radiologist, anesthesiologist, and surgeon is essential when confronting the manifold problems posed by this tumor. Nonfunctional paragangliomas have similar embryologic origins as pheochromocytomas and occur in the same sites, and although they do not cause hypercatecholaminemia, they can cause symptoms and signs through local pressure or invasion.

EMBRYOLOGY, PATHOLOGY, AND NOMENCLATURE

The embryology and anatomy of the neurogenic structures of the mediastinum are described in detail in Chapter 157 and thus are only briefly reviewed here. Approximately 6 weeks after conception, specialized cells from the neural crest give rise to the sympathetic and other autonomic ganglia

P.2763

and the adrenal medulla. McEwan and co-workers (1985) emphasized that these tissues are components of a larger neuroendocrine system, the cells of which share the property of amine precursor uptake and decarboxylation (APUD) cells.

The cells of certain paraganglia stain brown with chromate salts. This chromaffin reaction occurs in the presence of high concentrations of epinephrine, may be negative if only norepinephrine is present, and is an insensitive indicator of catecholamine synthesis and secretion; currently, far more sensitive techniques are available, including immunohistochemistry, as described by Johnson and associates (1985), and electron microscopy, as pointed out by Bird and Seiler (1991), to identify secretory granules. The practical distinction between catecholamine-secreting and nonsecreting lesions is the elevation of circulating or excreted catecholamines rather than tumor content or staining properties, as noted by Glenner and Grimley (1974), McEwan and associates (1985), and one of us (BS) and Fig (1989). Histologically, these tumors consist of clumps of large cells (pheochromocytes), often with cellular and nuclear pleomorphism, separated by capillaries (Fig. 191-1). According to Herrera and colleagues (1993), DNA ploidy may not predict malignancy. Shields (1989) and Johnson and associates (1985) have shown that synaptophysin, chromogranin, and neuron-specific enolase are present in these cells, indicating neuroendocrine differentiation, and origin from neuroectoderm. Moran and associates (1997) have reported that some lesions may contain significant quantities of intracellular melanin. The pathologic diagnosis of these tumors also has been facilitated by the use of additional immunohistochemical staining; Lloyd (1984) and Johnson (1985) and their colleagues have reported both methionine enkephalinlike and corticotropin-like immunoreactivity.

Fig. 191-1. Photomicrograph of a left atrial pheochromocytoma. The tumor consists of typical large cellular trabeculae composed of mature pheochromocytes showing marked cellular and nuclear pleomorphism and some bizarre nuclear forms. A thickened connective tissue capsule around a part of the tumor is seen in the right upper corner (original magnification 188). From Orringer MB, et al: Surgical treatment of cardiac pheochromocytomas. J Thorac Cardiovasc Surg 89:753, 1985. With permission.

Various nomenclatures have been used for the paragangliomas. Catecholamine-secreting adrenomedullary tumors are termed pheochromocytomas, whereas secretory lesions derived from extraadrenal paraganglia may be termed either extraadrenal pheochromocytomas or functioning paragangliomas. We favor and use the former term. Nonsecretory extraadrenal lesions are termed nonfunctioning paragangliomas or simply paragangliomas. The specialized paragangliomalike lesions, such as chemodectomas, glomus jugulare tumors, aortic body tumors, and lesions of parasympathetic origin, seldom secrete excessive quantities of catecholamines, as reported by Glenner and Grimley (1974) and Gopalakrishnan (1978), McEwan (1985), and Skodt (1995) and their co-workers. This is also true of the primitive and malignant tumors of the sympathoadrenal system, such as neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, which occur primarily in childhood, as noted by one of us (BS) (1987), Sisson and co-workers (1984b, 1987), and two of us (BLS, BS) (1998).

Because many thoracic nonchromaffin paragangliomas are benign, asymptomatic, and uncommon, relatively few of these tumors have been reported. However, many more have been and continue to be reported since the introduction of MIBG scintigraphy and other modern imaging modalities. They can occur both within the visceral compartment of the mediastinum and in the paravertebral sulci and, as indicated by Routh and co-workers (1982) and Bundi (1974), are often an incidental finding on chest radiography. They tend to be soft, highly vascular, and histologically consist of nests of oval cells separated by reticulin. Mitoses are usually absent. It is often difficult to characterize these tumors as malignant from histologic appearance alone. Histologically, they resemble pheochromocytomas, but functionally do not secrete catecholamines. Olson and Salyer (1978), in their review of aortic body paragangliomas, found that almost half of these tumors were associated with aggressive mediastinal invasion. Resection of chemodectomas is in most cases relatively easily accomplished, but as noted by Ashley and Evans (1966), marked vascularity may preclude their complete resection. In such situations, only biopsy may be indicated. Reviews by Gopalakrishnan (1978), Levi (1982), and Herrera (1993) and their colleagues have documented six cases of cardiac chemodectomas, all of which were nonsecretory.

Glenner and Grimley (1974) categorized the paraganglia into four subgroups based on distribution, innervation, and microscopic appearance: branchiomeric paraganglia (derived from the brachial arch structures), intravagal, aorticosympathetic, and visceral autonomic (see Chapter 157). The branchiomeric group includes the orbital, jugulotympanic, intercarotid, subclavian, laryngeal, aorticopulmonary, coronary, and pulmonary paraganglia. The intravagal paraganglia are the nodose and jugular ganglia of

P.2764

the vagus nerve. Pantanowitz and Sareli (1989) describe simultaneous occurrence of invasive branchiomeric and intravagal lesions in the same patient. The aorticosympathetic paraganglia are the sympathetic ganglion chain. Finally, the visceral autonomic paraganglia include those in the liver and biliary tree, bladder wall, and mesenteric vessels. According to Gopalakrishnan (1978), Levi (1982), one of us (BS) (1985), Hui (1987), and Cane (1996) and their associates, the middle mediastinal (visceral compartment) pheochromocytomas arise either from brachial arch derived structures (i.e., the coronary or aorticopulmonary paraganglia) or from visceral autonomic paraganglia of the atrium or interatrial septum. Bird and Seiler (1991) have noted that all of these paraganglia are capable of storing intracellular catecholamines. Pheochromocytomas are those paraganglia that store and secrete catecholamines and may occur in any of the four paraganglia groups. In addition, islands of carotid body type chemoreceptive tissues also are found in the pericardium, as one of us (BS) and associates (1984a), as well as Dresler and co-workers (1998), have reported.

CLINICAL PRESENTATION

Approximately 10% of patients with sympathoadrenal tumors have multiple primary lesions, according to Bravo (1994). In the vast majority, this is caused by bilateral adrenal pheochromocytomas, often associated with the multiple endocrine neoplasia (MEN) type 2 syndromes. In the case of thoracic primary tumors, the presence of an additional paraganglioma should raise the possibility of Carney's (1979) triad (i.e., multiple extraadrenal pheochromocytomas, pulmonary hamartomas, and gastric leiomyosarcomas) as suggested by Argos (1993) and Grace (1981) and their associates. Thus, a patient who continues to have symptoms, signs, or biochemical abnormalities after resection of an adrenal pheochromocytoma should be subjected to a careful search for extraadrenal pheochromocytoma, with specific attention directed toward the mediastinum as a possible site of involvement. Multiple tumors may develop synchronously or asynchronously after the successful removal of a first lesion, according to Hoffman and co-workers (1982) and Bravo (1994, 2002), as well as one of us (BS) and associates (1982) and Herrera (1993), Dunn (1986), and Peiffert (1990) and their colleagues. In this clinical situation, it may be difficult to distinguish between local recurrence, second primary, and metastatic lesions, as noted by one of us (BS) and co-workers (1984b).

Histology of the primary tumor may give clues to malignant potential in the form of nuclear atypia, vascular invasion, and necrosis, but none of these is diagnostic, as one of us (BS) and co-workers (1984b) and Herrera and associates (1993) have recorded. Conversely, entirely benign-appearing lesions may metastasize widely, and the only definitive proof of malignancy is the unequivocal presence of metastases. Even this definition may be problematic, because multiple primary lesions are seen to arise from the widely distributed sympathoadrenal system and are confused with metastases, unless lesions occur in sites such as bone or lymph nodes. Scott (1982), one of us (BS) (1982, 1984a), and Herrera (1993) and colleagues have observed that even benign lesions may recur if not completely excised. Tumor rupture or piecemeal resection may result in widespread seeding, leading to many of the problems of frankly metastatic disease, as one of us (BS) and Fig (1989) and one of us (BS) and co-workers (1984b) have pointed out.

The true incidence of sympathomedullary neurogenic tumors is unknown. Between 0.1% and 0.5% of hypertensive patients may harbor pheochromocytomas. Population-based postmortem studies by Glenner and Grimley (1974) revealed many lesions not suspected during life, and this is true for the mediastinum as well, according to Geisler (1985) and Herrera (1993) and their associates. Manger and Gifford (1982), and van Heerden and co-workers (1982) have noted that nearly 90% are benign and curable. Only approximately 2% of lesions occur in the thorax, and of these the majority (80%) arise from the aorticosympathetic paraganglia and occur in the paravertebral sulci, as reported by Freier (1980) and McNeill (1970) and their colleagues, as well as by two of us (MDG, BS), Levine and McDonald (1984), Pampari and Lacerenza (1958), one of us (BS) and Fig (1989), and Bravo (1994).

Both sexes and all ages appear to be affected. The peak incidence was reported by Freier (1980) and Hodgkinson (1980) and their co-workers, one of us (BS) and Fig (1989), and Bravo (1994) to occur in the third and fourth decades of life. Children are occasionally affected, according to two of us (BLS, BS) (1998), as well as by Di Stefano (1983), Tcherdakoff (1974), and Petit (2000) and their associates. In approximately 10% of cases, pheochromocytomas are associated with various familial neurocristopathic syndromes, which has been noted by Manger and Gifford (1977), Bravo (1994), one of us (BS) and Fig (1989), and Levine and McDonald (1984). These, according to Valk and co-workers (1981), include MEN type 2a syndrome [medullary thyroid cancer, multigland hyperparathyroidism, and pheochromocytomas (usually bilateral intraadrenal)], and MEN 2b syndrome (medullary thyroid cancer, mucosal ganglioneuromatosis, thickened corneal nerves, and pheochromocytomas). Von Hippel-Lindau disease (retinal angiomatosis, cerebellar hemangioblastoma, pheochromocytoma, renal cell carcinoma, and other tumors) has been reported by Hoffman (1982), Atuk (1998), and Bender (1997) and their colleagues. Neurofibromatosis has been reported by Kalff and co-workers (1982) (caf au lait spots, axillary freckling, multiple neuromas, and, occasionally, pheochromocytomas). The syndrome of bilateral familial carotid body tumors has been recorded by Dunn and co-workers (1986) and simple familial pheochromocytoma by Glowniak (1985) and Tcherdakoff (1974) and their co-workers. The association of multiple extraadrenal paragangliomas with pulmonary hamartomas and gastric

P.2765

leiomyosarcomas, known as Carney's triad (1979), does not appear to be familial, according to Argos (1993) and Grace (1981) and their associates.

Pheochromocytoma Syndrome

Hypertension is the hallmark of pheochromocytoma; it may be persistent with superimposed paroxysms, or purely paroxysmal, as observed by one of us (BS) and Fig (1989) and Bravo (1994, 2002). Occasionally, episodic hypertension may alternate with hypotension. The hypertension also may manifest one or more of the following features: early age of onset, malignant course, resistance or paradoxic response to therapy, and hypertensive crises, which may be spontaneous or triggered by anesthesia, angiography, trauma, or labor and delivery, as recorded by Fitzgerald (1995) and Mitra (1995) and their co-workers, as well as by Wooster and Mitchell (1981), two of us (MDG, BS) (1989), the same two of us (BS, MDG) (1991), and Bravo (1994, 2002). Pickering and colleagues (2000) reported a case of a cardiac pheochromocytoma that presented during pregnancy. As with all hypertension, it may lead to stroke, heart failure, or renal insufficiency; the hypercatecholaminemia may lead to a specific form of cardiomyopathy. The hypertension also may be associated with hypermetabolism, weight loss, and various degrees of glucose intolerance, including frank diabetes. In addition, paroxysmal symptom complexes may occur, which are described as spells, characterized by various combinations of vascular headache, pallor, diaphoresis, anxiety, nausea, vomiting, palpitations, and chest or abdominal pain, according to Bravo (1994) and one of us (BS) and Fig (1989). Tachycardia may occur, but severe hypertensive paroxysms may be associated with reflex bradycardia, as observed by two of us (MDG, BS) (1989) and Petit and co-workers (2000). The intense vasoconstriction leads to significant hypovolemia and, in some cases, increased hematocrit. According to Awoke and Perlstein (1985), dopamine-secreting tumors may not cause significant hypertension.

Mass Effects

As Smit and associates (1984) reported, pheochromocytomas may, in addition to the effects of catecholamine hypersecretion, exert local pressure effects, whereas nonsecreting paragangliomas present only with local mass effects, according to Sharma (1993) and Rutegard (1992) and their colleagues. The latter may thus be larger at the time of presentation. Many are discovered incidentally on chest radiography performed for other reasons. Within the chest, lesions in the paravertebral sulci may cause nerve root compression, spinal cord compression, or both if they invade the neural canal; Horner's syndrome may be observed if the tumors interrupt the thoracocervical sympathetic outflow. Lesions arising close to the coronary arteries may compress them and cause angina, as noted by Stowers and co-workers (1987). Large lesions may compress lung parenchyma. Mediastinal lesions in the visceral compartment may compress structures, particularly low-pressure thin-walled veins or cardiac atria, or may affect the recurrent laryngeal nerve.

Metastatic Disease

The overall frequency of malignancy in pheochromocytoma is 10%, but extraadrenal primary tumors appear to have a greater metastatic potential, perhaps 20% or more, than adrenal medullary tumors, as pointed out by one of us (BS) and associates (1984b) and Bravo (1994), as well as by Gellad (1980), McEwan (1985), Voci (1982), Lamy (1994), and Herrera (1993) and their colleagues. Malignant lesions have a propensity to spread to bone, as noted by one of us (BS) and co-workers (1984b) and by Scharf (1973), and Lamy (1994) and their colleagues, where the deposits may cause bone pain and pathologic fractures, but are often asymptomatic, as reported by Heindel and colleagues (2002). Other common routes of spread are aggressive local invasion and spread to regional lymph nodes, lung, or liver. Rarely, metastases to brain, skin, or serous cavities have been described. Metastases may become clinically evident after long latent intervals after apparent cure, and thus lifelong follow-up is recommended by Gellad (1980) and one of us (BS) and co-workers (1984b).

Ectopic Hormonal Syndromes Other than Hypercatecholaminemia

Given the APUD cell origin of pheochromocytomas and paragangliomas, it is not surprising that a wide range of syndromes not attributable to catecholamine hypersecretion, but rather to the ectopic production of other humoral factors can occur, as recorded by one of us (BS) and Fig (1989), as well as by Von Moll (1987) and Vinik (1986) and their associates. Although rare, these syndromes may be important and include Cushing's syndrome (ectopic adrenocorticotropic hormone, polycythemia), ectopic erythropoietinlike factors, hypercalcemia (ectopic parathyroid hormonelike factors), and secretory diarrhea (ectopic vasoactive intestinal polypeptide). A wide range of peptide hormones may be present in tumors without giving rise to clinical syndromes, according to Vinik and co-workers (1986). Hypercalcemia also may occur because of hyperparathyroidism in the MEN 2 syndromes or widespread skeletal metastases. Widely metastatic medullary thyroid cancer in MEN 2 syndrome may lead to diarrhea and flushing caused by high levels of calcitonin and other hormonal factors.

P.2766

BIOCHEMICAL DIAGNOSIS

Two clinical settings exist in which it is appropriate to perform biochemical studies to document catecholamine hypersecretion: (a) to investigate symptoms and signs that suggest the presence of a pheochromocytoma, although only 2% of these will be thoracic in location; and (b) to establish the presence of catecholamine hypersecretion in patients presenting with a mediastinal mass, which might be a pheochromocytoma. Young and co-workers (1989), Bravo and Gifford (1984), Bravo (1994, 2002) and three of us (BS, MDG, BLS) (2001) have pointed out that considerable controversy exists as to which particular biochemical measurements or combination of measurements are the most reliable, and the choice may often depend on local availability and laboratory expertise.

Plasma Catecholamine Measurements

When interpreting the results of catecholamine assays, Bravo and Gifford (1984) and Bravo (1994) emphasize the importance of awareness of the potential for drug interference with certain assays and the effects on catecholamine release caused by upright posture, hypovolemia, pain, or stress caused by other medical conditions, such as heart failure. The plasma catecholamine concentrations are highly labile and, to be valid, must be collected in the supine, fasted, euvolic state via an intravenous cannula inserted at least 30 minutes before sampling. As noted by the aforementioned researchers, as well as by Scott (1982), Hanson (1991), Young (1989), and Hartgrink (2001) and their colleagues, measurement of either total catecholamines or fractionation into epinephrine, norepinephrine, and dopamine is possible. Metanephrines have been measured in plasma as well as in urine by Lenders and co-workers (1995).

Urinary Catecholamine Measurements

Urinary catecholamine measurements may be determined on 24-hour, overnight 12-hour which one of us (BS) and Fig (1989) as well as Bravo (1994, 2002) prefer or 2- to 3-hour timed collections. For screening purposes, the total free catecholamines may suffice, according to Young and associates (1989). Vanillylmandelic acid, the final metabolic product of epinephrine and norepinephrine, is excreted in the largest quantities, but certain assays may be invalidated by dietary phenolic acids and vanillin, unless urine is collected while the patient is on a special diet. Determination of intermediate metabolites, the metanephrines, is also widely advocated for the diagnosis of pheochromocytoma. These may be further fractionated into normetanephrine and metanephrine, as suggested by Hanson (1991) and Young (1989) and their co-workers. Engelman and Hammond (1968) suggested that marked elevation of the epinephrine or epinephrine metabolites suggests an adrenal, rather than an extraadrenal, tumor.

Platelet Catecholamine and Other Measurements

Determination of platelet catecholamines, which reflect the mean plasma catecholamine concentration and do not fluctuate rapidly; plasma dopamine -hydroxylase and chromogranin, which are cosecreted with catecholamines; and neuron-specific enolase also have been used diagnostically, but are not generally available, as noted by one of us (BS) and Fig (1989).

Suppressive and Provocative Tests

The diagnostic use of the hypotensive response to phentolamine and the pressor response to tyramine, glucagon, and histamine must be considered obsolete, as suggested by one of us (BS) and Fig (1989) and Bravo (1994). A pressor and hypercatecholaminemic response to intravenous metoclopramide (10 mg) has been advocated by Plouin and associates (1976). Currently, only the clonidine suppression test is widely used. This central -adrenergic agonist normally reduces sympathetic tone, and thus catecholamine secretion. In contrast, pheochromocytomas are not innervated, are thus functionally autonomous, and the catecholamine levels do not decrease in response to the drug. This test probably should be reserved for those patients with equivocal baseline biochemistry. Bravo and Gifford (1984) and Bravo (1994) described a protocol in which serial plasma catecholamine samples are obtained before and for several hours after the oral administration of 300 g of clonidine. A variation published by MacDougall and colleagues (1988) involves the determination of urinary catecholamines and their metabolites.

We advocate the measurement of baseline, urinary free catecholamines, metanephrines, and vanillylmandelic acid, as well as plasma catecholamines, because a small proportion (15%) of patients with hypersecretory tumors are missed if only one parameter is examined. The clonidine suppression test may be most useful in those cases with suspicious, but nondiagnostic, baseline catecholamine levels.

PREOPERATIVE TUMOR LOCALIZATION OF MEDIASTINAL PHEOCHROMOCYTOMAS

In the case of pheochromocytomas, as with most hypersecretory endocrine neoplasms, the condition should be suspected clinically and diagnosed by hormonal measurements, after which it is appropriate to perform medical imaging procedures to localize the tumors. It is essential to correctly locate all tumor deposits, because only complete surgical extirpation results in cure. A detailed knowledge of the precise location and anatomic relationships of the lesions is of great value in the planning of successful surgery, as noted by three of us (BS, MDG, BL) (2001), Bravo and Gifford (1984), Bravo (1994, 2002), and one of us (BS) and Fig (1989), as well as by Freier (1980) and Scott (1982) and their associates. Failure

P.2767

to consider the possibility of paracardiac lesions leads to failure to locate these lesions in life, and early reported cases were found only at autopsy, according to Hodgson and co-workers (1984).

Chest Radiography and Esophagography

Chest radiography often discloses the presence of tumors arising in the paravertebral sulci, although other modalities are often required to depict fully the extent and relationships of the lesion to contiguous structures. Paracardiac lesions may lead to alterations of the contour of the cardiac atria, or aorticopulmonary window, but these are often subtle, and their significance may not be apparent until the lesion has been detected by other means, such as MIBG scintigraphy. Pulmonary metastases and skeletal deposits also may be evident. Contrast esophagography may help define lesions arising from the atria and impressing or invading the esophagus, as described by one of us (BS) and colleagues (1984a) and Lacquet and Moulijn (1976) (Fig. 191-2).

Nuclear Medicine Techniques

One of us (BS) and associates (1984b) have suggested that the technetium 99m (^99mTc)-diphosphonate bone scan may be useful for screening the entire skeleton for metastases, because bone is a common site of metastasis. Gated blood pool studies may be used for determination of left ventricular ejection fraction and wall motion in suspected catecholamine-induced cardiomyopathy or myocardial infarction. Similarly, thallium scintigraphy may be used, as suggested by one of us (MBO) and co-workers (1985) and one of us (BS) (1987) to evaluate impaired myocardial blood flow, caused by coronary artery involvement by tumor or injury during resection.

Since the original description of MIBG as a tracer for pheochromocytoma by Sisson and co-workers (1981, 1984a), Chatal and Charbonnel (1985), Lynn (1984, 1985), one of us (BS) (1984a, 1984b, 1985) and colleagues, and Pacak and colleagues (2002), as well as three of us (BS, MDG, BLS) (2001) and Bravo (2002) have shown that scintigraphy, with MIBG labeled with either ¹³¹I or ¹²³I, is highly sensitive (85% to 90%) and specific (98%) for the location of pheochromocytomas and paragangliomas of all types. The technique is noninvasive, safe, and particularly well suited to screening the entire body for tumor deposits. Nakajo (1983a), one of us (BS) (1984a, 1984b, 1995b), Fisher (1985), Saad (1983), Maurea (1993), Hanson (1991), Zagar (1995), Tenenbaum (1995), and Feltynowski (1990) and our and their associates, as well as Heufelder and Hofbauer (1996) and two of us (BLS, BS) (1998) have reported MIBG to be especially efficacious for the location of extraadrenal lesions and metastatic deposits. Smit (1984) and Von Moll (1987) and their associates have reported that both catecholamine-secreting and nonsecreting lesions may be depicted by MIBG scintigraphy. The image quality using ¹²³I-MIBG is superior to that of ¹³¹I-MIBG, and the former can be used for three-dimensional cross-sectional depiction of lesions by single-photon emission computed tomography, according to one of us (BLS) and colleagues (1986), and to Velilla Marco (1991), Weissman (1994) and Banzo (1991) and their co-workers. After the detection of an abnormal focus of MIBG uptake by scintigraphy, the superimposition of scintigraphically depicted normal structures may be useful in determining tumor location (Fig. 191-3), as recommended by Basoglu (1996), one of us (BS) (1984a, 1984b, 1987), Kao (1992), and van Gils (1991) and colleagues, as well as by one of us (BS) and Sisson (1988) and Shirkoda and Wallace (1984). Francis (1983), Quint (1987), Cornford (1992), Jonsson (1994), and Kawasuji (1989) and their co-workers, and one of us (BS) (1987), all noted that further detailed anatomic relationships can then be derived from MIBG-directed CT or MR imaging scans and more recently by coregistered CT/MIBG scans. MIBG, labeled with ¹³¹I, is commercially available in many countries, including the United States, whereas ¹²³I-MIBG remains an investigational drug in the United States.

MIBG undergoes limited metabolism and is mostly excreted unchanged, as shown by Mangner and associates (1986). Tissue uptake is dependent on active processes and may be interfered with by certain drugs, particularly tricyclic antidepressants, sympathomimetics, and labetalol, according to Khafagi (1989), one of us (BS) (1984c), and Tobes (1985) and co-workers. Nakajo and co-workers (1983b) reported that normal myocardial MIBG uptake may be reduced when hypercatecholaminemia is present.

An alternative, highly effective radiopharmaceutical approach is the use of radiolabeled somatostatin analogues for the in vivo scintigraphic depiction of somatostatin receptor binding, as reported by one of us (BS) (1995) and Hoefnagel (1994, 1995), as well as by Tenenbaum (1995), Muros (1998), and one of us (BS) and co-workers (1995b), and three of us (BS, MDG, BLS) (2001).

Somatostatin Receptor Scintigraphy

Somatostatin is a 14 or 28 amino acid cyclic peptide first described for its suppressive effects on growth hormone. It has a wide spectrum of biological actions, including acting as a hormone in the hypothalamic-pituitary portal circulation, enterohepatic portal circulation, and probably the general circulation; a neurotransmitter in the central and peripheral nervous systems; a paracrine transmitter in the stomach, gut, and other sites; an immunologic modulator of lymphocytes; and an autocrine modulator of its own secretion, according to the investigations of Hoefnagel (1994, 1995) and Krenning (1993, 1995), Kwekkeboom (1993), and Lamberts (1991) and their co-workers. Somatostatin receptors, of which five subtypes exist, are widely distributed on the cell membranes of many neuroendocrine tissues, epithelia,

P.2768

P.2769

and lymphocytes, as well as the tumors derived from these tissues. The development of the long-acting somatostatin analogue octreotide, which resists enzymatic degradation, led to the subsequent ¹³¹I tyrosylated analogue and ¹¹¹In-diethylenetriaminepentaacetic acid (DTPA) octreotide, which have served as radiopharmaceuticals for depicting somatostatin receptors in vivo, as described by the aforementioned researchers. ¹¹¹In-DTPA octreotide is administered intravenously in a dose of 6 mCi and imaging performed between 12 and 48 hours. Uptake is normally observed in the pituitary, thyroid gland, liver, spleen, kidney, gut, and bladder. Reduction of gut uptake by laxatives is advisable. Single-photon emission tomography is generally helpful in locating abnormal foci of tracer uptake. Scintigraphy with ¹¹¹In-DTPA octreotide for the location of pheochromocytomas has a similar sensitivity (85% to 90%) as MIBG scintigraphy, but the technique is more difficult to interpret because of the intense and complex normal biodistribution of the radiopharmaceutical. This tracer is accumulated by a wide range of lesions, including various neuroendocrine lung cancers, lymphomas, and inflammatory disorders, which, particularly in the case of thoracic pheochromocytomas, decreases the specificity of the study. In contrast, MIBG uptake is highly specific, as shown by two of us (BLS, BS) (1998) and Tenenbaum (1995) and Leung (1997) and their associates. Nevertheless, ¹¹¹In-DTPA octreotide is efficacious in the location of pheochromocytomas, particularly when the MIBG result is suspected of being falsely negative, and is superior to MIBG in the case of chemodectomas and some other nonsecretory paragangliomas, as reported by Hoefnagel (1994, 1995), and Krenning (1993, 1995), Kwekkeboom (1993), and Muros (1998) and their colleagues.

Fig. 191-2. The need for pericardiotomy for midmediastinal pheochromocytomas. A. Normal chest radiograph in a 19-year-old woman in venous sampling of plasma catecholamine levels localized her pheochromocytoma to the midmediastinum. She underwent an exploratory thoracotomy at another hospital, and no tumor was found. Posteroanterior (B) and lateral (C) views via esophagography show an extrinsic displacement of the esophagus in the subcarinal region by the tumor. Surgical clips from the initial exploration are visible in the subcarinal region (arrows). D. Chest CT scan shows a left atrial pheochromocytoma (arrow), which was localized with an iodine 131 metaiodobenzylguanidine scan. The tumor was soft and flattened in its intrapericardial location, and failure to perform a pericardiotomy at the thoracic exploration led to the surgeon's inability to locate it.

Fig. 191-3. Scintigraphic studies in a patient with left atrial pheochromocytoma. A. Iodine 131 metaiodobenzylguanidine (MIBG) scintiscan. Posterior image of chest (left panel). Right lateral image of chest (right panel). Arrow indicates site of abnormal ¹³¹I-MIBG uptake. L, normal liver; M, external marker along spine; SP, normal splenic uptake of ¹³¹I-MIBG. B. Technetium 99m labeled red blood cell blood pool images with an abnormal focus of ¹³¹I-MIBG uptake superimposed. Anterior image of chest (left panel). Right lateral image (right panel). A, aortic arch; H, cardiac blood pool; K, kidney. C. ^99mTc-metadiphosphonate bone scan with region of abnormal ¹³¹I-MIBG uptake superimposed. Right posterior oblique image (left panel). K, kidney; S, spine; ST, sternum. From Shapiro B, et al: The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 87:814, 1984a. With permission.

Finally, PET has been used to depict these lesions. The radiopharmaceuticals used include carbon 11 (¹¹C)-hydroxyephedrine, ¹¹C-epinephrine, and ¹⁸F-6-fluorodopamine which have tissue uptake mechanisms similar to those of MIBG, and ¹⁸F-fluorodeoxyglucose, which exploits the enhanced glycolytic metabolism present in many tumors, as reported by Neumann (1996), one of us (BS) (1995b), another of us (BLS) (1992, 1993), and Pacak (2002) and our and their associates. The fluorodeoxyglucose scan result may be positive when the MIBG result is negative. Combined CT/PET imaging with ¹⁸F-fluorodeoxyglucose provides simultaneous high-resolution anatomic and functional localization and may be useful in defining complicated anatomy in the chest, neck, and elsewhere.

Chest Computed Tomography

Chest computed tomography (CT) remains the single most important anatomic imaging procedure for defining the location and anatomic relationships of mediastinal pheochromocytomas and paragangliomas, as reported by Glazer and co-workers (1984). One of us (MDG) (1983), Francis (1983), Glazer (1984), Jonsson (1994), Chang (1991), Blandino (1992), Cane (1996), and Spizarny (1987) and colleagues, point out that dynamic CT after the bolus injection of contrast may be important in defining paracardiac lesions because, owing to their highly vascular nature, they may be inseparable from the cardiac chambers and great vessels during slow infusion of contrast (Figs. 191-4 and 191-5). Studies without contrast may have entirely negative results, as reported by Jonsson and co-workers (1994). Noorda and co-workers (1996)

P.2770

reported that invasion into the intervertebral foramina by lesions in the paravertebral sulci may require the use of bone windows or intrathecal contrast instillation, or both, to fully delineate the lesion. CT images may be rendered suboptimal by the presence of metallic clips or sutures from previous surgery and by inadequate fat planes in emaciated patients. Although CT is excellent at depicting the anatomy of lesions, the appearances of pheochromocytomas and paragangliomas are not distinctive, and thus may be confused with other mass lesions, such as neurofibromas, in a patient with neurofibromatosis, as Moncada and co-workers (1982) have emphasized. The site to be studied by dynamic CT may be determined by prior MIBG scintigraphy, according to Shirkoda and Wallace (1984), as well as Glazer (1984) and Jonsson (1994) and their associates.

Fig. 191-4. Dynamic CT scans of the chest in a patient with left atrial pheochromocytoma. A. Enhancement of cardiac chambers and aorta 15 seconds after the bolus injection of contrast with the nonenhanced pheochromocytoma of the left atrium indicated by an arrow. B. After equilibration of contrast medium, the atrial chambers and tumor are enhanced to the same degree. From Shapiro B, et al: The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 87:814, 1984a. With permission.

Fig. 191-5. CT scan of the chest with contrast enhancement shows large atrial tumor (arrows). From Shapiro B, et al: The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 87:814, 1984a. With permission.

Nuclear Magnetic Resonance Imaging

Nuclear magnetic resonance (MR) imaging offers a number of potential advantages, including the absence of ionizing radiation, the high intrinsic contrast of flowing blood (signal void), which reduces the need for intravenous contrast, and the ability to display images in the transaxial, coronal, sagittal, and oblique planes. The technique also has the potential for in vivo tissue characterization, which, although not completely specific, may be useful in that pheochromocytomas and paragangliomas usually have high T₂-weighted signal intensity, as suggested by Quint (1987), Sahin-Akyar (1997), Jonsson (1994), Falke (1990), van Gils (1991), and Hamilton (1997) and their colleagues. Cardiac movement artifact may be minimized by electrocardiographic gating, as pointed out by Mader and co-workers (1997). Orr and colleagues (1997) have suggested that the paramagnetic contrast medium gadolinium-DTPA may be used to depict the highly vascular nature of these tumors. In studying thoracic lesions, MR imaging is probably most valuable in defining the relationships of tumors in the region of the great vessels and cardiac chambers, neural foramina, and the spinal canal, in which situations, as noted by Fisher (1985), Olsen (1987), and Quint (1987) and their co-workers, as well as by one of us (BS) and Fig (1989), and Conti (1986), Blandino (1992), Hamilton (1997), Cane (1996), and Fisher (1985) and their associates, it may be somewhat superior to CT.

P.2771

Echocardiography

Echocardiography may have a role in defining intrapericardial lesions, as reported by Mandak (1996), Cane (1996), and Cueto-Garcia (1985) and their co-workers. Glazer and associates (1984) have suggested that the less than optimal sensitivity of this modality is probably caused mainly by the lack of an adequate chest wall acoustic window to evaluate the entire surface of the pericardium. This is especially true of the posterior atrial region, which may be better evaluated with an endoesophageal transducer. Epicardial fat or loculated pericardial effusions may be confused with tumor masses. In our experience, CT and MR imaging appear to be more effective techniques.

Angiography

Noninvasive techniques, such as CT, MR imaging, and ¹³¹I- or ¹²³I-MIBG scintigraphy, have reduced the need for angiographic procedures, such as whole-body venous sampling of catecholamines for the location of pheochromocytomas, as suggested by Allison (1983), Bjork (1959), Hoffman (1982), Palubinskas (1980), Imafuku (1986), and Haouzi (1989) and their co-workers. Nevertheless, they retain a role in those cases in which a highly detailed depiction of vascular anatomy in terms of tumor blood supply, vascular invasion, or encasement is helpful in the planning of a curative resection, as noted by one of us (MBO) and associates (1985) and by Cane (1996), Imafuku (1986), Orenstein (1984), and Drucker (1987) and their colleagues. Haouzi and co-workers (1989) reported on a case in which MIBG, CT, and echography all failed to reveal a large tumor supplied by the coronary arteries and which was depicted only by angiography. Drucker and associates (1987) reported embolization of the feeding left sixth and seventh intercostal arteries by steel coil occlusion devices that was accomplished preoperatively to reduce the marked vascularity of the tumor. Angiography is thus especially helpful in the evaluation of paracardiac lesions, which may derive their blood supply from, or encase, the coronary arteries (Fig. 191-6), as pointed out by Gomi (1994), Fitzgerald (1995), Jebara (1992), and Cane (1996) and their co-workers.

Fig. 191-6. A. Dynamic CT scan of the chest in a patient with left atrial pheochromocytoma. Regions of interest are defined as the tumor (T), right atrium (R), and pulmonary artery (P). B. Graphic representation of x-ray attenuation in the different regions of interest shows sequential peaks enhancement of the right atrium (R) at 13 seconds, pulmonary artery (P) at 21 seconds, and ascending aorta (A) at 29 seconds after bolus injection of contrast. The tumor (T) shows maximal enhancement at 37 to 44 seconds, at which time the major vascular structures are nearly equally enhanced. Maximum differentiation between tumor and vascular structures is achieved after 13 to 29 seconds. C. Coronary angiogram shows large atrial tumor (arrows), fed by tortuous tumor vessels (V). From Shapiro B, et al: The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 87:814, 1984a. With permission.

Fig. 191-7. Iodine 131 metaiodobenzylguanidine (MIBG) scintigraphy of a patient with left atrial pheochromocytoma and metastatic disease. A. Posterior head and neck. Metastases in the cervical spine are indicated by arrows. Normal uptake of ¹³¹I-MIBG is seen in the salivary glands (S). B. Anterior head and neck. Metastases in the cervical spine and skull are indicated by arrows. Normal uptake of ¹³¹I-MIBG is seen in the salivary glands (S) and nasopharynx (N). C. Posterior chest and abdomen. Metastases in the costovertebral junctions and lumbar spine are indicated by small arrows, and residual atrial pheochromocytoma is indicated by the large arrow. Normal uptake of ¹³¹I-MIBG is seen in the liver (L). D. Anterior abdomen and pelvis. Metastases in the lumbar spine and left pelvic brim are indicated by arrows. Normal uptake of ¹³¹I-MIBG is seen in the liver (L). Surface markers: A, axillae; I, iliac crests; C, costal margins. From Shapiro B, et al: The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 87:814, 1984a. With permission.

Fig. 191-8. Recurrent left atrial pheochromocytoma in a 45-year-old man occurring 1.5 years after initial resection. A. Anterior chest view of iodine 131 metaiodobenzylguanidine (MIBG) scintigram (0.5 mCi) that demonstrates normal liver uptake (L), faint normal ventricular uptake (open arrow), and questionable faint abnormal uptake in the atrial region (arrow). m, surface radioactive marker. B. Anterior chest view of ¹²³I-MIBG scintigram (10.0 mCi), which demonstrates normal liver uptake (L), normal ventricular uptake (open arrow), normal gut uptake (G), and definite abnormal uptake in the atrial region (arrow). The superiority of the ¹²³I-MIBG images is obvious. C. A high-resolution GE 8800 CT scan (1-cm thick section obtained after intravenous administration of bolus of contrast material) shows a possible soft tissue mass below the right pulmonary artery in the region of the left atrium (arrow), but surgical clips from the surgery degrade the computed tomographic image, making interpretation difficult. D. ¹²³I-MIBG single-photon emission CT reconstructions in transaxial, vertical long, horizontal long, and short axes of the heart demonstrate recurrent left atrial pheochromocytoma (arrows). C and D from Lynn MD, et al: Pheochromocytoma and the normal adrenal medulla: improved visualization with ¹²³I scintigraphy. Radiology 155:789, 1985. With permission.

Fig. 191-9. Patient with Carney's triad with previous gastrectomy for gastric leiomyosarcoma and resection of abdominal paraaortic pheochromocytoma represented with recurrent pheochromocytoma symptoms and biochemical abnormalities. Iodine 131 metaiodobenzylguanidine scintigraphy with the region of the left ventricular myocardium indicated on simultaneous thallium 201 study (M). A. Left lateral view. Tumor in the region of the aortic arch (arrows). Free ¹³¹I uptake in the thyroid (T). B. Posterior chest and abdomen view. Normal liver uptake (L). Note that the region of the liver shows no focal areas of increased ¹³¹I-metaiodobenzylguanidine uptake. Arrows define the tumor in the region of the aortic arch.

Fig. 191-10. Abdominal CT scan in a patient with Carney's triad with previous gastrectomy for gastric leiomyosarcoma and resection of an abdominal paraaortic pheochromocytoma represented with recurrent pheochromocytoma symptoms and biochemical abnormalities. CT scan shows multiple liver metastases, which did not concentrate iodine 131 metaiodobenzylguanidine, and which were caused by leiomyosarcoma rather than pheochromocytoma.

P.2772

P.2773

Choice of Imaging Procedure

When pheochromocytoma is suspected on clinical and biochemical grounds, initial localization is best performed by MIBG or OctreoScan scintigraphy or, alternatively, by abdominal CT followed by chest CT. One of us (BS) and associates (1984c) and three of us (BS, MDG, BLS) (2001) have suggested that the latter technique should follow MIBG scanning if this study result is believed to be falsely negative. Hamilton (1997), Basoglu (1996), and Fisher (1985) and their colleagues concur with this suggestion. Even when a tumor is initially disclosed by an anatomic imaging modality, such as CT scanning, MIBG or OctreoScan scintigraphy may be valuable in disclosing otherwise occult recurrent or second primary tumors or metastases, the presence of which would significantly alter management, as noted by Shirkoda and Wallace (1984), as well as by one of us (BS) (1984c) and Fisher (1985) and co-workers, and by Hoefnagel (1995) (Figs. 191-7, 191-8, 191-9 and 191-10). Uptake of MIBG by a mass lesion would indicate a neuroendocrine type of tumor before resection or biopsy (Figs. 191-9, 191-10 and 191-11). The depiction of somatostatin receptors on a lesion by OctreoScan is also suggestive of a neuroendocrine tumor, but is significantly less specific than MIBG. PET with ¹⁸F-FDG or other PET radiopharmaceuticals provides excellent high-quality images for tumor localization (Figs. 191-12 and 191-13).

Fig. 191-11. CT scan of the chest in a patient with Carney's syndrome with previous gastrectomy for gastric leiomyosarcoma and resection of an abdominal paraaortic pheochromocytoma. The patient returned with recurrent pheochromocytoma symptoms and biochemical abnormalities. Iodine 131 metaiodobenzylguanidine scintigraphy shows a primary pheochromocytoma (arrows) related to the aortic arch (A), which corresponds to the area of abnormal ¹³¹I-metaiodobenzylguanidine uptake.

Fig. 191-12. Patient with recurrent thoracic pheochromocytoma. Transverse image of fluorodeoxyglucose (FDG) PET scan (left), transverse image of indium 111 pentetreotide single-photon emission computed tomography scan (middle), and CT scan show abnormal soft tissue between the right and left main-stem bronchi (right). There is high uptake of both FDG and pentetreotide in the mass. The mass was surgically removed and proven to represent recurrent pheochromocytoma.

Fig. 191-13. A 60-year-old patient with metastatic pheochromocytoma. A. CT scan shows right mediastinal mass. B. A PET carbon 11 scan shows markedly increased uptake, consistent with metastatic pheochromocytoma.

P.2774

PREOPERATIVE AND INTRAOPERATIVE MANAGEMENT

Considerable controversy exists as to the need for preoperative pharmacologic preparation of patients with pheochromocytoma. Modern anesthesia, cardiovascular monitoring, and perhaps the availability of adrenergic blocking drugs have greatly reduced the risks of surgery, as reviewed by Bravo and Gifford (1984) and Hoffman (1982), Modlin (1979), and van Heerden (1982) and their associates, as well as by one of us (BS) and Fig (1989), two of us (BS, MDG) (1991), and Bravo (1994), and by Lewis (1994) and Shibata (1990) and their colleagues.

-Adrenergic Blockade

Although some authorities, such as Pinaud and co-workers (1985), believe that preoperative -adrenergic blockade is not routinely required, the majority of investigators, including Herrera and associates (1993), two of us (BS, MDG) (1991), one of us (BS) and Fig (1989), and Bravo (1994), recommend this. The drug of choice is phenoxybenzamine, a nonselective -blocker. This is begun 1 to 2 weeks before surgery, starting with a dose of 10 mg twice a day, which is increased every second day. The end point is normotension or near normotension, with slight postural hypotension, and elimination or reduction of paroxysmal spells. The final dosages required are typically 40 to 120 mg/day. Because this drug has a prolonged action, a potential exists for postoperative hypotension when the catecholamine levels are normalized. For this reason, Desmonts (1977) and Jones (1979) and their colleagues, as well as one of us (BS) and Fig (1989), recommend that it may be wise to reduce or halt administration for 24 to 48 hours before surgery.

Alternative drugs include prazosin, a selective ₁-antagonist. Its shorter action means that the dose may be more rapidly escalated, and Nicholson and co-workers (1983) believe it may cause less postoperative hypotension. Although in a study of various available drugs used for -blockade by Kocak and colleagues (2002) there were no differences in the degree of blockade achieved or side effects from either phenoxybenzamine, prazosin or doxazone. Labetalol, which has both - and -blocking properties, also may be used, but it should be noted, as pointed out by Khafagi and associates (1989) and Navaratnarajah and White (1984), that this drug interferes with the performance of MIBG scintigraphy.

-Adrenergic Blockade

-Adrenergic blockade is only occasionally required in cases of persistent, significant tachycardia or supraventricular tachyarrhythmia, according to Herrera and co-workers (1993), one of us (BS) and Fig (1989), and two of us (BS, MDG) (1991). These drugs should only be used once -blockade is established because unopposed blockade of vasodilatory -receptors in the vasculature can result in marked -adrenergic agonism, which leads to intense vasoconstriction and hypertensive crisis, as pointed out by Hull (1986), Navaratnarajah and White (1984), and two of us (BS, MDG) (1991). The negative inotropism of -blockade may occasionally precipitate cardiac failure.

-Methylparatyrosine and Other Agents

-Methylparatyrosine inhibits tyrosine hydroxylase, which is the rate-limiting step in catecholamine biosynthesis, and thus reduces catecholamine levels in pheochromocytoma. This drug, as noted by Bravo (1994), is occasionally useful in patients who are intolerant of -blockade. Typical dosage starts at 0.5 g/day and may be increased to 4.0 g. Robinson and co-workers (1977), as well

P.2775

as one of us (BS) and Fig (1989) have noted side effects to include sedation, depression, and parkinsonism.

Cardiac Dysfunction

Both supraventricular and ventricular arrhythmias may occur and should be treated similarly to those arising intraoperatively. As pointed out by Van Vliet and co-workers (1966), cardiac failure caused by catecholamine cardiomyopathy may occur. If hypertensive, such patients may improve with control of blood pressure. It should be noted that patients with severe pump failure may be normotensive, despite intense vasoconstriction. Care should be exercised with the use of diuretics, because these patients are usually significantly volume contracted. Cardiac glycosides should be used in minimal effective doses, because hypercatecholaminemia sensitizes the heart to arrhythmia. Scharf and associates (1973) reported that -methylparatyrosine, by reducing catecholamine levels, may cause significant reversal of cardiomyopathy in some cases.

Volume Repletion

Deoreo and colleagues (1974) noted that by reducing catecholamine-induced vasoconstriction, preoperative -blockade normally results in a correction of the contracted intravascular volume. Fluid loading without -blockade has been advocated as an alternative, but, as noted by Modlin and co-workers (1979), carries the risk for congestive heart failure.

Transfusion Requirements

All pheochromocytomas and paragangliomas are highly vascular tumors, and their resection carries the risk for severe life-threatening intraoperative hemorrhage. This is particularly true of middle mediastinal-visceral compartment lesions, as pointed out by Awoke and Perlstein (1985) and Williams (1994) and Saad (1983) and their co-workers. For elective surgery, generous provision of blood products should be made. The vasoconstriction and hypovolemia that occur with pheochromocytomas probably preclude elective preoperative blood banking or autotransfusion. This is, however, possible with nonsecreting paragangliomas. Hauss and associates (1985) have suggested that intraoperative blood salvage is also feasible.

Intermediary Metabolism

Because of the inhibition of insulin secretion by catecholamines and the increased glycolysis, glycogenolysis, lipolysis, and ketogenesis, impaired glucose tolerance is common. Frank diabetes is unusual, but may be present and requires oral hypoglycemic drugs or insulin therapy. Hull (1986) has noted that close monitoring of blood glucose is mandatory throughout the preoperative, intraoperative, and postoperative periods.

Intraoperative Monitoring

The ability to promptly detect and respond appropriately to intraoperative disturbance of physiology is essential to successful surgery, as advised by one of us (BS) and Fig (1989), Bravo (1994), and Lewis (1994) and Shibata (1990) and their colleagues. This requires continuous monitoring of electrocardiography, intraarterial blood pressure, central venous pressure, pulmonary artery wedge pressure, urine output, and temperature. In addition, cutaneous oximetry, capnography, and electromyographic monitoring of neuromuscular blockade all may be helpful. Frequent intraoperative determinations of blood gases, blood sugar, and hematocrit also may be appropriate, as Desmonts and Marty (1984) and Hauss (1985), Shibata (1990), and Hoffman (1982) and their associates have noted.

GENERAL ANESTHETIC PRINCIPLES

Almost every conceivable anesthetic regimen has been reported to be both suitable and dangerous in the surgery of pheochromocytoma. Although certain problems occur in those patients in whom hypercatecholaminemia is present, nonfunctioning paragangliomas are not materially different from those of nonneurogenic lesions. Anesthetic management has been discussed by Desmonts and co-workers (1977), Desmonts and Marty (1984), Hull (1986), one of us (BS) and Fig (1989), and Hauss (1985), Lewis (1994), and Shibata (1990) and their colleagues, among others. In the presence of hypercatecholaminemia, premedication should probably not include atropine. A rapid and stress-free induction and intubation are essential in reducing the risks for anesthesia-induced pheochromocytoma crisis. Thiopentone is the most widely used induction agent, but fentanyl or alfentanil also may be used because, unlike other opiates, they do not cause histamine release, which may, in turn, trigger catecholamine release, as noted by Shibata and co-workers (1990). After induction, intubation is performed under direct laryngeal visualization.

The choice of muscle relaxant is controversial, because many drugs may, at least in theory, lead to complications, according to one of us (BS) and Fig (1989). Suxamethonium may stimulate sympathetic ganglia; tubocurarine and atracurium may release histamine; and pancuronium may discharge catecholamine stores. Vecuronium would appear to be the drug of choice, because it has no autonomic or catecholamine-discharging effects. A mixture of humidified oxygen and nitrous oxide is used as a vehicle for volatile anesthetics. Hypoxia may sensitize the

P.2776

myocardium to catecholamine-induced arrhythmia and must be avoided. Halothane may have a similar action, and thus isoflurane or enflurane may be preferred, as discussed by Desmonts and Marty (1984), Fay and Holzman (1983), Hull (1986), one of us (BS) and Fig (1989), as well as by Janeckzo (1977), and Shibata (1990) and their co-workers.

Despite preoperative -blockade, anesthesia and operative tumor manipulation may cause catecholamine release, which leads to marked hypertension, as emphasized by two of us (BS, MDG) (1987) and Shibata and associates (1990). Additional intraoperative -blockade thus may be required. The short-acting agent, phentolamine, has been widely used for this purpose, either as repeated boluses of 2 to 5 mg or as a continuous infusion. Cardiopulmonary bypass may help isolate the systemic circulation from such surges, as suggested by Shibata and co-workers (1990). Labetalol also has been used intraoperatively. These drugs may lead to hypotension when plasma catecholamine levels decrease after tumor isolation, as observed by Desmonts and Marty (1984) and Hoffman and colleagues (1982). It is now widely believed by Shibata (1990), Csansky-Treels (1976), El Naggar (1977), and Jones (1979) and their associates that nitroprusside, which has a short period of action on vascular smooth muscle, is the drug of choice for intraoperative control of hypertension. Anton and co-workers (1993) have reported on a patient unresponsive to nitroprusside but sensitive to phentolamine. It may occasionally be necessary to administer -blockers to control tachycardia and, although the greatest experience has been with propranolol, cardioselective -blockers may be superior and less liable to cause postoperative hypoglycemia. -blockers may be useful for control of supraventricular tachyarrhythmias. Amiodarone also has been used successfully for catecholamine-induced tachyarrhythmias. El Naggar (1977) and Hoffman (1982) and their colleagues report that ventricular ectopy or tachycardia usually responds to lidocaine.

Fluid Replacement

Physiologic saline or Ringer's lactate in quantities that are adjusted on the basis of central venous pressure, or Swan-Ganz measurements, are generally appropriate, as noted by one of us (BS) and Fig (1989) and by two of us (BS, MDG) (1991). Large volumes of glucose-containing fluids should be avoided in the early phases of surgery because of catecholamine-induced inhibition of insulin secretion and enhanced glycogenolysis. After catecholamine levels decrease, Chambers (1982) and Meeke (1985) and their co-workers observed that a risk of hypoglycemia exists, and glucose should be administered. Frequent monitoring of blood sugar levels is essential. Severe intraoperative blood loss is an ever-present danger, and adequate provision of packed red cells and fresh-frozen plasma is mandatory. Intraoperative blood salvage has been recommended, but the infusion of catecholamine-laden blood may cause hypertension.

Intraoperative Hypertensive Crises

According to Modlin (1979) and Yajima (1997) and their associates, as well as two of us (BS, MDG) (1991), intraoperative hypertensive crises in patients with known pheochromocytoma should be unusual because of the institution of preoperative -blockade and awareness of the risk on the part of the anesthesiologist. Wooster and Mitchell (1981), Mitra and co-workers (1995), and two of us (BS, MDG) (1991) have warned that the greatest danger lies in patients undergoing operation without a preoperative diagnosis having been made, undergoing operation for unrelated intercurrent surgical disease, or presenting in crisis caused by intratumoral hemorrhage or rupture.

Hypotension or Shock

Hypotension or shock may follow the surgical isolation of the tumor from the circulation, which results in a precipitous decrease in plasma catecholamines (half-life approximately 4 minutes) and thus of vascular tone, as reported by one of us (BS) and Fig (1989) and two of us (BS, MDG) (1991). This phenomenon, which may be combined with a contracted intravascular volume because of long-standing vasoconstriction, downregulation of adrenergic receptors, -blockade, and operative blood loss, leads to predictable hypotension. Preoperative -blockade and volume expansion can partly mitigate this, but rapid infusion of fluids is essential. At least two large-bore intravenous catheters are mandatory. The downregulation of -receptors and residual -adrenergic blockade render these patients resistant to the effects of pressor amines.

SURGERY OF INTRATHORACIC PHEOCHROMOCYTOMAS AND PARAGANGLIOMAS

General Principles

According to Hodgkinson (1980) and McNeill (1970) and their colleagues, fewer than 100 cases of intrathoracic pheochromocytomas have been reported. Symington and Goodall (1953) reported that the majority of the tumors have occurred in association with the sympathetic chain in the paravertebral sulci. Maier and Humphreys (1958) emphasized the increased vascularity of the overlying pleura and the appreciable bleeding that may occur even when the pleura is incised some distance from the mass. Judicious use of the electrocautery is helpful in lessening the amount of bleeding encountered.

P.2777

As with other endocrine tumors, the complete surgical extirpation of all pheochromocytoma deposits remains the only definitive curative therapy, as stressed by Herrera (1993), Lamy (1994), and Gomi (1994) and their co-workers, as well as by one of us (BS) and Fig (1989). Regardless of tumor location, a number of general principles apply. These include: (a) wide surgical exposure, (b) meticulous hemostasis, (c) minimal tumor manipulation before the early isolation and interruption of tumoral venous drainage to relieve catecholamine hypersecretion, and (d) removal of the tumor with capsule intact to reduce seeding into the operative field. The development of endoscopic, minimally invasive surgery has led to reports of successful laparoscopic adrenalectomies for a variety of lesions, including pheochromocytomas. Thorascopic surgery is increasingly used for a growing number of procedures and might be applicable to suitably selected paragangliomas, particularly of the paravertebral sulci. In the case of mediastinal lesions, the advantages of wide exposure probably outweigh those of the minimally invasive technique. Yajima and co-workers (1997) reported a case in which video-assisted minimally invasive resection of a posterior mediastinal pheochromocytoma had to be converted to open thoracotomy because of hypertensive crisis. It is possible that in the future more use will be made of minimally invasive procedures. In a case report of an endobronchial pheochromocytoma, Sandur and colleagues (1999) used neodymium:yttrium-aluminum-garnet (Nd:YAG) laser photoresection to ablate the tumor.

Middle Visceral Compartment Mediastinal Lesions

Until relatively recently, reports of middle mediastinal pheochromocytomas have been extremely rare. Nagant de Deuchaisnes and co-workers (1960) described one such tumor arising in the aorticopulmonary window, and Peiper and Golestan (1963) discussed one involving the aortic arch. The occurrence of cardiac pheochromocytomas has been even less frequent; less than 50 cases have been reported. Wilson and associates (1974) resected a pheochromocytoma of the left atrial wall through a right thoracotomy without cardiopulmonary bypass, and although this patient was prepared preoperatively with - and -adrenergic blockers, marked intraoperative hypertension with systolic pressures above 300 mm Hg occurred as the tumor was mobilized. Besterman and colleagues (1974) approached a 5 8 cm tumor arising from the superior aspect of the left atrium above the pulmonary veins through a median sternotomy while using cardiopulmonary bypass. Enucleation of the tumor resulted in thinning out of the atrial wall, which required division of the aorta and pulmonary artery for adequate exposure and repair of the atrial wall. A malignant cardiac pheochromocytoma in a 76-year-old woman who died of chronic hypertension, congestive heart failure, and diffuse metastatic disease was reported by Voci and co-workers (1982). Others have reported intracardiac pheochromocytomas, Meunier and colleagues (2001) in the interatrial septum, and Brown (2002), Hartgrink (2001) and Dresler (1998) and their colleagues in atrial tissues. Hodgson and associates (1984) described another case; the location of the tumor proved elusive in life and the lesion was only found at postmortem examination, while Heindel and colleagues (2002) reported a case of clinically silent intracardiac pheochromocytoma that was treated successfully.

Development at the University of Michigan of the radiopharmaceutical ¹³¹I-MIBG by Sisson and co-workers (1981, 1984a) permitted scintigraphic localization of pheochromocytomas. In combination with contrast-enhanced CT, the MIBG scan has localized intrapericardial pheochromocytomas in an increasing number of patients at the University of Michigan through the methods described by Glazer and associates (1984) and one of us (BS) (1984a) and co-workers. Five of these patients have undergone resection of these tumors and were reported by one of us (MBO) and associates (1985). The sudden surge in cardiac pheochromocytomas encountered at our institution and by others is a direct result of improved imaging technology and ability to localize these lesions and suggests that they will be encountered even more frequently in the future as a surgically correctable cause of hypertension, as reported by Abad (1992), Herrera (1993), Chang (1991), Lamy (1994), Gomi (1994), Corbi (1990), Aravot (1992), David (1986), Dunn (1986), Feltynowski (1990), Hodgson (1984), Kawasuji (1989), Lee (1990), Peiffert (1990), and Velilla Marco (1991) and their co-workers, as well as by Chatal and Charbonnel (1985), Heufelder and Hofbauer (1996), and by Dresler (1998), Meunier (2001), Hartgrink (2001), Brown (2002) and Heindel (2002) and their colleagues.

When preoperative scanning and radiographic studies localize the tumor to the middle mediastinum, the surgeon is basically dealing with a cardiac tumor, the origin of which is either the coronary paraganglia or the visceral autonomic paraganglia of the atrium or interatrial septum, as noted by Lee (1990), Herrera (1993), one of us (MBO) (1985), Cane (1996), and Hodgson (1984) and associates. Those tumors arising from the left atrium may be approached through a posterolateral thoracotomy using femoral artery and caval cannulation for institution of cardiopulmonary bypass. In general, as noted by Gopalakrishnan and co-workers (1978) and many other groups, a median sternotomy provides wider exposure and access to lesions of the anterior surface of the heart, aortic arch, and aorticopulmonary window (see Fig. 191-11). One gross characteristic of these tumors has particular surgical significance: Pheochromocytomas are soft, fleshy tumors that are easily compressed and flattened within the pericardium, as reported by Feltynowski (1990) and Fisher (1985) and their colleagues. As pointed out by Besterman (1974), Hui (1987), and Chang (1991) and their co-workers, as well as by our group, if the unsuspecting surgeon is performing an exploration of the chest in search of a pheochromocytoma that has been localized to the mediastinum by scanning or selective venous sampling, the

P.2778

surgeon may not detect the tumor unless the pericardium is opened and the heart inspected directly (see Fig. 191-2). Lee (1990) and Kawasuji (1989) and their associates reported resection of pheochromocytomas arising from the interatrial septum.

Shimoyama and co-workers (1987) and others stress that these tumors must not be approached like abdominal or paravertebral pheochromocytomas with the expectation that they shell out from adjacent tissues. A plane of dissection between the atrial wall and the tumor may be established if the neoplasm is near the surface of the myocardium. However, a safer, more adequate resection may involve the full thickness of the tumor-containing atrial wall and pericardial patch replacement, as described by Cane (1996), Gomi (1994), and Kawasuji (1989) and their colleagues. Those tumors arising from the atrial wall may lack a complete capsule and may demonstrate histologic evidence of myocardial infiltration by paraganglioma cells (Fig. 191-14). Attempts to dissect the tumor away from the atrial wall may thus result in untoward bleeding that requires resection of the thinned-out myocardium and patching with pericardium, autologous, human banked tissue, or bovine or prosthetic material to achieve satisfactory hemostasis, as recorded by Shimoyama (1987), Gomi (1994), and Kawasuji (1989) and their co-workers. Where the right ventricular infundibulum and pulmonary trunk were involved, an en bloc resection with aortic homograft implantation was required in the report of Casanova and associates (1996). A small but significant fraction of lesions is unresectable, as recorded by Abad (1992) and Herrera (1993) and their co-workers. Although some of these tumors may be removed without resorting to cardiopulmonary bypass, this technique, as noted by Levi (1982), one of us (MBO) (1985), Shimoyama (1987), Lamy (1994), Chang (1991), and Peiffert (1990) and their colleagues, particularly when combined with cardioplegia, greatly aids tumor dissection. This is especially true when the lesion is closely adherent to the cardiac atria, or where the origin of the coronary arteries is involved and resection of a segment of involved vessel or myocardial revascularization, or both, may be required, as pointed out by one of us (MBO) (1985), David (1986), Jebara (1992), Stowers (1987), Saad (1983), and Lee (1990) and associates. Postoperative myocardial infarction can occur in the face of coronary artery or coronary sinus involvement, as reported by David (1986) and one of us (MBO) (1985) and colleagues. Some lesions may be paraesophageal and found in the aorticopulmonary window, as observed by Lacquet and Moulijn (1976) and Lacquet and co-workers (1977). Despite adequate preoperative preparation with - and -adrenergic blockers, serious intraoperative hypertension and arrhythmias are typically induced by manipulating these cardiac tumors and discharging their vasoactive hormones directly into the systemic circulation. However, once cardiopulmonary bypass and cardioplegia have been established so that the heart is isolated from the systemic circulation, safe direct dissection is feasible. The ability to better control the blood pressure, tissue perfusion, and circulating volume while the patient is on bypass is a further advantage, given the potential for cardiovascular instability during the removal of these lesions, as noted by one of us (MBO) and associates (1985), by Fitzgerald (1995), Saad (1983), and Kawasuji (1989), and by Rote (1977), Shimoyama (1987), Peiffert (1990), Gomi (1994), and Williams (1994) and their associates. Severe life-threatening hemorrhage remains an ever-present danger during the resection of these highly vascular tumors and results in significant mortality, as stressed by one of us (MBO) (1985), and by Awoke and Perlstein (1985), as well as by Williams (1994) and Saad (1983) and their colleagues.

Fig. 191-14. Photomicrograph of same tumor shown in Fig. 191-2. In this field, nests of paraganglioma cells (arrows) have infiltrated into cardiac tissue and are intimately associated with myocardial fibers. Lack of a complete capsule around this tumor precluded shelling it out. Full-thickness resection of the left atrial wall with pericardial patching was required for its complete removal. From Orringer MB, et al: Surgical treatment of cardiac pheochromocytomas. J Thorac Cardiovasc Surg 89:753, 1985. With permission.

Cardiac Transplantation

Pheochromocytomas arising from the atria, aorticopulmonary window, and similar sites, if large, and involving pulmonary veins, pulmonary arteries, or coronary arteries, may be nonresectable or resectable only with severe operative risk. Cooley (1985), Goldstein (1995), and Jeevanadam (1995) and their co-workers have suggested that in this situation, as with other nonresectable primary cardiac tumors, consideration may be given to cardiac transplantation. A particularly careful body-wide search for second primary lesions and, most especially, metastatic disease is essential. Goldstein (1995) and Jeevanadam (1995) and their associates

P.2779

recommend that this should include meticulous review of all anatomic imaging modalities, a conventional bone scan, and whole-body screening scintigraphy with ¹²³I-MIBG, or, if unavailable, ¹³¹I-MIBG or ¹¹¹In-DTPA-octreotide, or both, or PET scanning. Should occult metastases be present after cardiac transplantation, these may conceivably progress rapidly in the face of the immunosuppression required to prevent transplant rejection.

Paravertebral Lesions

Tumors arising in the paravertebral sulci are approached through a posterolateral thoracotomy, and cases have been recorded by Cueto and co-workers (1965), Edmunds (1966), McLeish and Adler (1955), and Pampari and Lacerenza (1958) and others. Like the nonchromaffin paragangliomas, pheochromocytomas are soft, vascular, and reddish brown. The majority are benign, and when located in the paravertebral sulci, they readily shell out, just as is the case when they are removed from the abdomen. Peiper and Golestan (1963) and Ogawa and associates (1982), as well as others, noted that they are, in general, more readily removed than are middle mediastinal lesions. The exception to this is when a portion of the tumor invades one or more neural foramina. These lesions may then impinge on the spinal nerve roots, and even enter the extradural space of the spinal canal with resultant cord compression syndromes, which was reported by Ogawa (1982) and Noorda (1996) and their colleagues. Removal of these lesions may involve resection of appropriate portions of the bony walls of the neural foramen of the vertebral column; their approach is discussed in Chapter 190.

Anterior Mediastinal Lesions

Anterior mediastinal paragangliomas are exceptionally rare and lie within or in close proximity to the thymus, as described by Moran (1997) and Blandino (1992) and their co-workers. They may derive a blood supply from the internal mammary artery, according to Imafuku and co-workers (1986). Although their removal may be achieved through a cervical collar incision if they lie high in the upper mediastinum, for most of these tumors, which are large, low, or highly vascular, a sternotomy is safer and the preferred approach.

Intravascular Tumor

Abdominal primary tumors may invade the inferior vena cava, and intravascular extension into the thorax and even into the right atrium and ventricle may occur, as reported by Hartgrink and co-workers (2001). Local invasion of the vena cava has been reported. Sharma (1993) and Rote (1977) and their colleagues pointed out that the removal of such lesions may require extracorporeal circulation.

Pulmonary Tumors

Primary paragangliomas of the lung itself occur rarely, arise from the pulmonary visceral paraganglia, and present primarily as solitary pulmonary nodules, as reported by Skodt (1995) and Petit (2000) and their co-workers.

POSTOPERATIVE MANAGEMENT

Before the advent of modern anesthesia and postoperative intensive care of patients with pheochromocytomas, successful tumor resection was all too often followed by catastrophic and frequently lethal complications, as documented by Desmonts and associates (1977), Levine and McDonald (1984), and Bravo (1994), as well as by Freier (1980), Modlin (1979), and van Heerden (1982) and their co-workers. The close monitoring of cardiovascular and other vital functions performed intraoperatively should be continued while any doubt exists as to the stability of the patient, typically for 24 to 72 hours. A number of postoperative problems deserve special attention.

Postoperative Volume Status and Hypotension

The problem of hypotension after the decrease in plasma catecholamines that begins intraoperatively continues in the postoperative period, and vigorous fluid replacement guided by the central venous or pulmonary artery wedge pressure is indicated. The possibility of ongoing internal bleeding also must be considered seriously, as emphasized by Williams (1994) and Saad and co-workers (1983), as well as by one of us (MBO) (1985) and our associates. Myocardial infarction may complicate resection of lesions involving the coronary arteries, as noted by David and co-workers (1986). The risk of hypoglycemia may persist for some days, and Meeke and co-workers (1985) advise that glucose-containing fluids are indicated.

Residual Hypertension

Levine and McDonald (1984), van den Broek and de Graef (1978), and Bravo (1994), as well as Modlin (1979) and Herrera (1993) and their colleagues and ourselves, have observed that in most cases removal of the source of catecholamine hypersecretion leads to immediate relief of hypertension and the paroxysmal symptoms and signs of pheochromocytoma. Catecholamine measurements do not return completely to normal for 1 to 2 weeks because of the increased stores of tumor-derived catecholamines in the sympathetic nervous system. In perhaps one third of patients,

P.2780

some degree of residual hypertension remains, even after complete return of catecholamine levels to normal. This is invariably much less severe than before tumor resection and is not labile. Modlin and co-workers (1979) suggest that this probably results from microvascular damage to the kidney from the pheochromocytoma-induced hypertension. Scott (1982), as well as one of us (BS) and co-workers (1984b) and Maurea and colleagues (1993), warned that failure of blood pressure to decrease promptly to normal or near normal levels must strongly suggest the presence of residual tumor, incomplete resection, occult metastases, or second primary tumors. This phenomenon is well illustrated in Fig. 191-10. The recurrence of hypertension after a period of normality must similarly raise the possibility of recurrent or metastatic disease or the asynchronous development of a second primary lesion. Because all of these phenomena may occur after long latent periods, life-long follow-up is warranted. We believe that follow-up should involve a clinical history and physical examination at yearly intervals. Patients should be questioned specifically as to the recurrence of symptoms similar to those at the initial presentation and for the occurrence of bone pain. Blood pressure and pulse should be measured with the patient supine and standing. Screening biochemical studies in the form of a 12-hour overnight urine collection for catecholamines and metanephrines, or those tests that are locally available and found to be reliable, are warranted also. It is not justifiable to routinely obtain medical imaging procedures, other than chest radiography, if the history, physical examination, and screening biochemistries reveal no abnormality, but they should be performed promptly if any abnormalities are present, as pointed out by one of us (BS) and associates (1984b) and by Maurea and co-workers (1993).

SCREENING OF FAMILY MEMBERS AT RISK

A detailed family history is required in all patients with pheochromocytomas, as suggested by Bravo (1994). The neurocristopathic syndromes that predispose patients to these tumors are inherited as autosomal-dominant disorders and include MEN type 2a, Sipple's syndrome type 2b, neurofibromatosis, von Hippel-Lindau disease, and isolated familial pheochromocytoma, and Valk and co-workers (1981) advised a thorough investigation of first-degree relatives in the presence of these syndromes. We, as well as Glowniak (1985) and Timmis (1981) and their associates, stress that it is important to recognize that early in the development of these familial pheochromocytomas, symptoms, signs, and biochemical abnormalities may be subtle. Molecular biology, through the development of specific genetic probes to screen family members at risk, provides highly sensitive means of early diagnosis before development of symptoms and signs in these syndromes, as reported by Atuk (1998) and Bender (1997) and their colleagues. These tests make diagnosis possible at birth or even prenatally.

MANAGEMENT OF MALIGNANT DISEASE

Malignant extraadrenal pheochromocytomas are rare. Although only 10% of all pheochromocytomas are malignant, the incidence of malignancy in extraadrenal pheochromocytomas is 20% to 50%, as reported in the literature by Modlin (1979), Valk (1981), Scott (1982), Lack (1980), and Herrera (1993) and their associates, as well as by Bravo (1994). Because malignant pheochromocytomas are histologically, biochemically, and immunocytochemically similar to the benign form, the definitive diagnosis of malignancy is made on the basis of demonstrated distant metastatic disease, as noted by Kennedy and co-workers (1961) and one of us (BS) and colleagues (1984b). Scott and associates (1982) have emphasized that surgery has an important role in the treatment of malignant pheochromocytoma, some cures having been obtained with complete resections of solitary and limited metastases. Gitles and Mahoney (1977) have suggested that initial wide resection and lymphadenectomy may prolong survival. Because the tumor is to some degree radiosensitive, it also has been suggested by Cohen and Israel (1989) that irradiation might be a reasonable initial treatment when combined with resection, because local tumor recurrence of malignant pheochromocytomas is common. Cohen and Israel (1989) and Drasin (1978) also point out that although multiple chemotherapeutic regimens have been used for malignant pheochromocytomas, the rarity of these lesions means that experience with their management at any institution or with any particular regimen is rather limited, and many publications on the subject consist of small series or single case reports from which it is difficult to draw meaningful conclusions about the efficacy of treatment. Averbuch and colleagues (1988) have shown that a typical combined chemotherapy protocol for neuroblastoma (i.e., vincristine, cyclophosphamide, and dacarbazine) also can be moderately efficacious in malignant pheochromocytoma (see Chemotherapy, later in this chapter).

Locally recurrent (see Fig. 191-7) or surgically seeded lesions present almost identical management problems, as do frankly malignant disease, because they are rarely curable with further surgical intervention. Surgical debulking, when this can be performed without undue risk or morbidity, may make subsequent medical management easier. When lesions are not amenable to surgery, or if the patient cannot be made fit for surgery, embolization of the blood supply of the tumor may be attempted, as suggested by Timmis and co-workers (1981). The limited experience with this technique has been primarily with abdominal lesions, but thoracic lesions also might be amenable; however, this may put the normal coronary supply to the myocardium at risk. Successful embolization is followed by ischemic necrosis of the highly vascular tumor, which may be followed by massive catecholamine release and hypertensive crisis; hence, close monitoring and adequate -blockade are mandatory.

P.2781

An adequate analgesic program to control pain associated with the tumor is essential. The pain usually arises from skeletal metastases. Initially, nonsteroidal antiinflammatory drugs may suffice, but adequate doses of narcotics given sufficiently frequently to prevent breakthrough pain are usually required. We have found sustained-release oral morphine to be especially useful. Because narcotics may exacerbate the constipation caused by hypercatecholaminemia, the use of appropriate laxatives is helpful.

The natural history of malignant lesions is highly variable, and a significant fraction of patients with widespread metastases may survive for many years with a good quality of life. Examples of this have been observed by one of us (BS) and co-workers (1984b) and by Sisson and associates (1981), as well as by van den Broek and de Graeff (1978). Averbuch (1988), Herrera (1993), and Scott (1982) and their colleagues report that the overall 5-year mortality rate is approximately 50%.

Pharmacologic Management

Pharmacologic management similar to that described for preoperative preparation remains the cornerstone of therapy, as noted by one of us (BS) and Fig (1989) and Bravo (1994). Adequate doses of phenoxybenzamine supplemented by -blockers or -methylparatyrosine, or both, can control the effects of hypercatecholaminemia, which in the past frequently led to premature morbidity and mortality from stroke or cardiac or renal failure. In addition, appropriate medical management of heart failure and diabetes may be important in maintaining the best possible quality of life.

Chemotherapy

Because of the rarity of these lesions, until recently, the experience with chemotherapy, as noted by Drasin (1978), was limited to case reports and small series, and the general consensus was that chemotherapy was usually ineffective for malignant pheochromocytomas. Feldman (1983) has reported a favorable response to streptozotocin. Averbuch (1988) and Keiser (1985) and their associates treated malignant pheochromocytomas with a first-line neuroblastoma protocol of 21-day cycles of cyclophosphamide, vincristine, and dacarbazine, reasoning that this regimen might be an effective therapy because of the close embryologic similarities between the two neoplasms. Tumor shrinkage was achieved in 57% and biochemical remission in 79% of cases treated. This was achieved with only modest toxicity. Recently, Naoi and colleagues (2003) reported a favorable result with this chemotherapy regimen in a patient with widespread metastases from a malignant pheochromocytoma.

External Beam Radiation Therapy

Local therapy with 3,000 to 5,000 cGy may palliate painful bone metastases if not too widespread, as reported by one of us (BS) and Fig (1989) and Bravo (1994). The response of soft tissue metastases and locally recurrent tumor is less clear-cut, but responses may be achieved, which have been reported by Drasin (1978), as well as by Scott and co-workers (1982).

¹³¹I-Metaiodobenzylguanidine Therapy

After the observation that tracer doses of ¹³¹I-MIBG are avidly accumulated and retained by malignant pheochromocytoma and nonfunctioning paraganglioma deposits (see Fig. 191-7), experimental therapy with activities of MIBG calculated to deliver therapeutic absorbed radiation doses to tumor deposits has been attempted. This modality has been restricted to highly selected patients with the greatest tumoral MIBG avidity. In this setting, Sisson (2002) and one of us (BS) (1987, 1995, 1996) and his colleagues (1984b, 1991, 1995a, 2001), as well as Janeckzo (1997), Cornford (1992), Baulieu (1988, 1991), Sisson (1984b), and Khafagi (1987) and their associates, have noted that partial responses have been achieved in a significant minority of patients. Initial positive responses may be followed by subsequent relapses that are unresponsive to MIBG. The results of dosimetric calculations by one of us (BS) (1987, 1996), as well as by one of us (BLS) and colleagues (1988) and Sisson and associates (1984b, 1987) suggest that doses of ¹³¹I-MIBG of 100 to 250 mCi may deliver in excess of 2,000 cGy to the tumor and only 50 to 200 cGy to blood, bone marrow, and the whole body. In a recent review by Sisson (2002) in more than 100 patients treated with ¹³¹I-MIBG in doses ranging from 3.7 to 18.5 GBq (100 to <500 mCi), partial responses were seen in about one third of the patients. Complete remission was unusual, and recurrence with progression occurred within 2 years. Furthermore, the combination of ¹³¹I-MIBG with chemotherapy had little additional benefit.

Other Radiopharmaceutical Therapy

Large doses of ¹¹¹In-DTPA octreotide (150 mCi) administered on multiple occasions have been used experimentally for the therapy of carcinoids and similar neuroendocrine tumors and could conceivably be used to treat nonresectable or metastatic intrathoracic pheochromocytomas, according to Hoefnagel (1994, 1995) and Lamberts and co-workers (1991). Subsequently, yttrium 90 (⁹⁰Y)-labeled octreotide has been developed for such therapy by Hoefnagel (1994, 1995). Finally, according to Robinson (1990), widespread painful skeletal metastases might be palliated by means of strontium chloride 89,

P.2782

samarium 153-ethylenediaminetetramethylene phosphonic acid, ¹¹⁷mSn-DTPA, and other bone-seeking radiopharmaceuticals.

REFERENCES

Abad C, et al: Primary cardiac paraganglioma. Case report and review of surgically treated cases. J Cardiovasc Surg 33:768, 1992.

Allison DJ, et al: Role of venous sampling in locating a pheochromocytoma. BMJ 286:1122, 1983.

Anton AH, et al: An atrial pheochromocytoma-induced hypertensive crisis resistant to nitroprusside. Int J Clin Pharmacol Ther Toxicol 31:89, 1993.

Aravot DJ, et al: Location, localization and surgical treatment of cardiac pheochromocytoma. Am J Cardiol 69:283, 1992.

Argos MD, et al: Gastric leiomyoblastoma associated with extraadrenal paraganglioma and pulmonary chondroma: a new case of Carney's trial. J Pediatr Surg 28:1545, 1993.

Ashley DJ, Evans CJ: Intrathoracic carotid body tumour (chemodectoma). Thorax 21:184, 1966.

Atuk NO, et al: Pheochromocytoma in von Hippel Lindau disease: clinical presentation and mutational analysis in a large multigenerational kindred. J Clin Endocrinol Metab 83:117, 1998.

Averbuch SD, et al: Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 109:267, 1988.

Awoke S, Perlstein RS: Dopamine- and norepinephrine-secreting intrapericardial pheochromocytoma in a normotensive patient. South Med J 78:994, 1985.

Banzo J, et al: Functioning intrapericardial paraganglioma diagnosed by I-123 MIBG imaging. Clin Nucl Med 16:860, 1991.

Basoglu T, et al: The usefulness of cardio-vascular visualization in the localization of mediastinal pheochromocytomas with I-131-MIBG. Ann Nucl Med 10:135, 1996.

Baulieu JL, et al: Therapeutic effectiveness of iodine-131 MIBG metastases of a nonsecreting paraganglioma. J Nucl Med 29:2008, 1988.

Baulieu JL, et al: ¹³¹I-metaiodobenzylguanidine treatment of a malignant paraganglioma. J Nucl Biol Med 35:313, 1991.

Bender BU, et al: Functioning thoracic paraganglioma: association with von Hippel Lindau syndrome. J Clin Endocrinol Metab 82:3356, 1997.

Besterman E, Bromley LL, Peart WS: An intrapericardial phaeochromocytoma. Br Heart J 36:318, 1974.

Bird DJ, Seiler MW: Aorticopulmonary paraganglioma (aortic body tumor): report of a case. Ultrastruct Pathol 15:475, 1991.

Bjork VO, et al: Malignant intrathoracic pheochromocytoma with lung metastases and raised noradrenaline concentration in superior vena cava blood. Acta Chir Scand 116:411, 1959.

Blandino A, et al: Unusual malignant paraganglioma of the anterior mediastinum: CT and MR findings. Eur J Radiol 15:1, 1992.

Bravo EL: Evolving concepts in the pathophysiology, diagnosis, and treatment of pheochromocytoma. Endocr Rev 15:356, 1994.

Bravo EL: Pheochromocytoma. Cardiol Rev 10: 44, 2002.

Bravo EL, Gifford RW Jr: Current concepts. Pheochromocytoma: diagnosis, localization and management. N Engl J Med 311:1298, 1984.

Brown IE, et al: Case 3 2002. Pheochromocytoma presenting as a right intra-atrial mass. J Cardiothorac Vasc Anesth 16: 370, 2002.

Bundi RS: Chemodectomas. Clin Radiol 25:293, 1974.

Cane ME, et al: Paraganglioma of the interatrial septum. Ann Thorac Surg 61:1845, 1996.

Carney JA: The triad of gastric epithelioid leiomyosarcoma, functioning extra-adrenal paraganglioma, and pulmonary chondroma. Cancer 43: 374, 1979.

Casanova J, et al: Intrapericardial paraganglioma. Eur J Cardiothorac Surg 10:287, 1996.

Chambers S, et al: Hypoglycaemia following removal of phaeochromocytoma: case report and review of the literature. Postgrad Med J 58:503, 1982.

Chang CH, et al: Intrapericardial pheochromocytoma. Ann Thorac Surg 51:661 1991.

Chatal JF, Charbonnel B: Comparison of iodobenzylguanidine imaging with computed tomography in locating pheochromocytoma. J Clin Endocrinol Metab 61:769, 1985.

Cohen PS, Israel MA: Biology and treatment of thoracic tumors of neural crest origin. In Roth JA, Ruckdeschel JC, Weisenburger TH (eds): Thoracic Oncology. Philadelphia: WB Saunders, 1989, pp. 520 540.

Conti VR, Saydjari R, Amparo EG: Paraganglioma of the heart. The value of magnetic resonance imaging in the preoperative evaluation. Chest 90:604, 1986.

Cooley DA, et al: Human cardiac explanation and autotransplantation: application in a patient with a large cardiac pheochromocytoma. Tex Heart Inst J 12:171, 1985.

Corbi P, et al: Benign tumors of the heart (excluding myxoma). Experience with 9 surgically treated cases. Ann Cardiol Angeiol (Paris) 39:433, 1990.

Cornford EJ, Wastie ML, Morgan DA: Malignant paraganglioma of the mediastinum: a further diagnostic and therapeutic use of radiolabeled MIBG. Br J Radiol 65:75, 1992.

Csansky-Treels JC, et al: Effects of sodium nitroprusside during excision of pheochromocytoma. Anesthesia 31:60, 1976.

Cueto JC, McFee AS, Bernstein EF: Intrathoracic pheochromocytoma: report of a case. Dis Chest 48:539, 1965.

Cueto-Garcia L, et al: Two-dimensional echocardiographic detection of mediastinal pheochromocytoma. Chest 87:834, 1985.

David TE, et al: Pheochromocytoma of the heart. Ann Thorac Surg 41:98, 1986.

Deoreo GA Jr, et al: Preoperative blood transfusion in the safe surgical management of pheochromocytoma: a review of 40 cases. J Urol 111:715, 1974.

Desmonts JM, Marty J: Anaesthetic management of patients with phaeochromocytoma. Br J Anaesth 56:781, 1984.

Desmonts JM, et al: Anaesthetic management of patients with phaeochromocytoma. A review of 102 cases. Br J Anaesth 49:991, 1977.

Di Stefano A, et al: Intrapericardial chemodectoma. Description of the first known case in a child. Minerva Pediatr 35:789, 1983.

Downs AR, Schloemperlen CB: Intrathoracic pheochromocytoma. Can J Surg 9:180, 1966.

Drasin H: Treatment of malignant pheochromocytoma. West J Med 128: 106, 1978.

Dresler C, et al: Intrapericardial pheochromocytoma. Thorac Cardiovasc Surg 46: 100, 1998.

Drucker EA, et al: Mediastinal paraganglioma: radiologic evaluation of an unusual vascular tumor. AJR 148:521, 1987.

Dunn GD, et al: Functioning middle mediastinal paraganglioma (phaeochromocytoma) associated with intercarotid paragangliomas. Lancet 1:1061, 1986.

Edmunds LH: Mediastinal pheochromocytoma. Ann Thorac Surg 2:742, 1966.

El Naggar M, Suerte E, Rosenthal E: Sodium nitroprusside and lidocaine in the anaesthetic management of pheochromocytoma. Can Anaesth Soc J 24:353, 1977.

Engelman K, Hammond WG: Adrenaline production by an intrathoracic phaeochromocytoma. Lancet 1:609, 1968.

Falke THM, et al: Magnetic resonance imaging of functioning paragangliomas. Magn Reson Q 6:35, 1990.

Fay ML, Holzman RS: Isoflurane for resection of pheochromocytomas. Anesth Analg 62:955, 1983.

Feldman JM: Treatment of metastatic pheochromocytoma with streptozocin. Arch Intern Med 143:1799, 1983.

Feltynowski T, et al: Intrapericardial pheochromocytoma: a case report. Cor Vasa 32:145, 1990.

Fisher MR, Higgins CB, Andereck W: MR imaging of an intrapericardial pheochromocytoma. J Comput Assist Tomogr 9:1103, 1985.

Fitzgerald PJ, et al: Intracardiac pheochromocytoma with dual coronary blood supply: case report and literature review. Cardiovasc Surg 3:557, 1995.

Francis IR, et al: Complementary roles of CT scanning and ¹³¹I-MIBG scintigraphy in diagnosing pheochromocytoma. AJR 141:719, 1983.

Freier DT, Eckhauser FE, Harrison TS: Pheochromocytoma: a persistently problematic and still potentially lethal disease. Arch Surg 115:388, 1980.

Geisler F, et al: A case of pheochromocytoma with cardiac localization. Review of the literature. Presse Med 14:1024, 1985.

P.2783

Gellad F, Whitley J, Shamsuddin AKM: Silent malignant intrathoracic pheochromocytoma. South Med J 73:513, 1980.

Gitles RF, Mahoney EM: Pheochromocytoma. Urol Clin North Am 4:239, 1977.

Glazer GM, et al: Computed tomography of pericardial masses: further observations and comparisons with echocardiography. J Comput Assist Tomogr 8:895, 1984.

Glenner GG, Grimley PM: Tumors of the extra-adrenal paraganglion system (including chemoreceptors). In Firminger HI (ed): Atlas of Tumor Pathology. Washington, DC: Armed Forces Institute of Pathology, 1974, p. 13.

Glowniak JV, et al: Familial extra-adrenal pheochromocytoma: a new syndrome. Arch Intern Med 145:257, 1985.

Goldstein DJ, et al: Experience with heart transplantation for cardiac tumors. J Heart Lung Transplant 14:382, 1995.

Gomi T, et al: Cardiac pheochromocytoma. A case report and review of the literature. Jpn Heart J 35:117, 1994.

Gopalakrishnan R, et al: Cardiac paraganglioma (chemodectoma). A case report and review of the literature. J Thorac Cardiovasc Surg 76:183, 1978.

Grace MP, et al: Aorticopulmonary paraganglioma and gastric leiomyoblastoma in a young woman. Am J Med 70:1288, 1981.

Gross BH, Glazer GM, Francis IR: CT of intracardiac and intrapericardial masses. AJR 140:903, 1983.

Gross MD, Shapiro B: Scintigraphic studies in adrenal hypertension. Semin Nucl Med 19:122, 1989.

Hamilton BH, et al: Intrapericardial paragangliomas (pheochromocytomas): imaging features. AJR 168:109, 1997.

Hanson MW, et al: Iodine-131-labeled meta-iodobenzylguanidine scintigraphy and biochemical analyses in suspected pheochromocytoma. Arch Intern Med 151:1397, 1991.

Haouzi A, et al: Cardiac pheochromocytoma. Failure of classic non-invasive diagnostic methods. Arch Mal Coeur Vaiss 82:97, 1989.

Hartgrink HH, et al: Primary pheochromocytoma extending into the right atrium: report of a case and review of the literature. Eur J Surg Oncol 27: 115,2001.

Hauss GM, Van Aken H, Lawin P: Anesthetic management in patients with pheochromocytoma. Cardiology 72(suppl 1):174, 1985.

Heindel SW, et al: A patient with intracardiac masses and an undiagnosed pheochromocytoma. J Cardiothorac Vasc Anesth 16: 338, 2002.

Herrera MF, et al: Mediastinal paraganglioma: a surgical experience. Ann Thorac Surg 56:1096, 1993.

Heufelder AE, Hofbauer LC: Greetings from below the aortic arch: the paradigm of cardiac paraganglioma. J Clin Endocrinol Metab 81:891, 1996.

Hodgkinson DJ, et al: Extra-adrenal intrathoracic functioning paraganglioma (pheochromocytoma) in childhood. Mayo Clin Proc 55:271, 1980.

Hodgson SF, et al: Catecholamine-secreting paraganglioma of the interatrial septum. Am J Med 77:157, 1984.

Hoefnagel CA: Metaiodobenzylguanidine and somatostatin in oncology: role in the management of neural crest tumours. Eur J Nucl Med 21:561, 1994.

Hoefnagel CA: MIBG and radiolabeled octreotide in neuroendocrine tumors. Q J Nucl Med 39:137, 1995.

Hoffman RW, Gardner DW, Mitchell FL: Intrathoracic and multiple abdominal pheochromocytomas in von Hippel-Lindau disease. Arch Intern Med 142:1962, 1982.

Hui G, McAllister HA, Angelini P: Left atrial paraganglioma: report of a case and review of the literature. Am Heart J 113:1230, 1987.

Hull CJ: Phaeochromocytoma. Diagnosis, preoperative preparation and anesthetic management. Br J Anaesth 58:1453, 1986.

Imafuku T, et al: Intrapericardial pheochromocytoma: a case report and review of the literature. Nippon Naibunpi Gakkai Zasshi 62:1266, 1986.

Janeckzo GF, et al: Enflurane anesthesia for surgical removal of pheochromocytoma. Anesth Analg 56:62, 1977.

Jebara VA, et al: Cardiac pheochromocytomas. Ann Thorac Surg 53:356, 1992.

Jeevanadam V, et al: Surgical management of cardiac pheochromocytoma. Resection versus transplantation. Ann Surg 22:415, 1995.

Johnson TL, et al: Cardiac paragangliomas: a clinicopathological and immunohistochemical study of four cases. Am J Surg Pathol 9:827, 1985.

Jones DH, et al: Selective venous sampling in the diagnosis and localization of pheochromocytoma. Clin Endocrinol (Oxf) 10:179, 1979.

Jonsson A, et al: Cardiac pheochromocytoma. J Intern Med 236:93, 1994.

Kalff V, et al: The spectrum of pheochromocytoma in hypertensive patients with neurofibromatosis. Arch Intern Med 142:2092, 1982.

Kao PF, et al: Using 131I-MIBG and 99mTc-MDP bone scan for localization of rare extra-adrenal pheochromocytomas: report of 2 cases. J Formos Med Assoc 91(suppl 4):283, 1992.

Kawasuji M, Matsunaga Y, Iwa T: Cardiac phaeochromocytoma of the interatrial septum. Eur J Cardiothorac Surg 3:175, 1989.

Keiser HR, et al: Treatment of malignant pheochromocytoma with combination chemotherapy. Hypertension 7(3 part 2):118, 1985.

Kennedy JS, Symington T, Woodger BA: Chemical and histochemical observations in benign and malignant pheochromocytomas. J Pathol Bacteriol 81:409, 1961.

Khafagi F, et al: Localization and treatment of familial malignant nonfunctional paraganglioma with iodine-131-MIBG: report of two cases. J Nucl Med 28:528, 1987.

Khafagi FA, et al: Labetalol reduces iodine-131 MIBG uptake by pheochromocytoma and normal tissues. J Nucl Med 30:481, 1989.

Kocak S, Aydintug S, Canakci N: Alpha blockade in preoperative preparation of patients with pheochromocytomas. Int Surg 78: 191, 2002.

Krenning EP, et al: Somatostatin receptor scintigraphy with 111-In-D-ThA-D-Phe and 123-I-TyrJ-octreotide: The Rotterdam experience with more than 1000 patients. Eur J Nucl Med 20:716, 1993.

Krenning EP, et al: Somatostatin receptor scintigraphy. Nucl Med Ann 1995:1, 1995.

Kwekkeboom DJ, et al: Octreotide scintigraphy for the detection of paragangliomas. J Nucl Med 34:873, 1993

Lack EE, et al: Extra-adrenal paragangliomas of the retroperitoneum. A clinicopathologic study of 12 tumors. Am J Surg Pathol 4:109, 1980.

Lacquet LK, Moulijn AC: Mediastinal chemodectoma. Acta Chir Belg 75:435, 1976.

Lacquet LK, et al: Intrathoracic chemodectoma with multiple localisations. Thorax 32:203, 1977.

Lamberts SWJ, Krenning EP, Reubi JC: The role of somatostatin and its analogs in the diagnosis and treatment of tumors. Endocr Rev 12:450, 1991.

Lamy AL, et al: Anterior and middle mediastinum paraganglioma: complete resection is the treatment of choice. Ann Thorac Surg 57:249, 1994

Lee HH, et al: Cardiac pheochromocytoma originating in the interatrial septum. Chest 97:760, 1990.

Lenders JW, et al: Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 123:101, 1995.

Leung A, et al: Specificity of radioiodinated MIBG for neural crest tumors in childhood. J Nucl Med 38:1352, 1997.

Levi B, Cain AS, Dorzab WE: Coronary paraganglioma. Clin Cardiol 5:505, 1982.

Levine SN, McDonald JC: The evaluation and management of pheochromocytomas. Adv Surg 17:281, 1984.

Lewis IH, et al: Case 2 1994: management of a cardiac pheochromocytoma in two patients. J Cardiothorac Vasc Anesth 8:223, 1994.

Lloyd RV, et al: An immunohistochemical study of pheochromocytomas. Arch Pathol Lab Med 108:541, 1984.

Lynn MD, et al: Portrayal of pheochromocytoma and normal human adrenal medulla by ^123Iiodobenzylguanidine: concise communication. J Nucl Med 25:436, 1984.

Lynn MD, et al: Pheochromocytoma and the normal adrenal medulla: improved visualization with I-123 MIBG scintigraphy. Radiology 156: 789, 1985.

MacDougall IC, et al: Overnight clonidine suppression test in the diagnosis and exclusion of pheochromocytoma. Am J Med 84:993, 1988.

Mader MT, Poulton TB, White RD: Malignant tumors of the heart and great vessels: MR imaging appearance. Radiographics 17:145, 1997.

Maier HC, Humphreys GH II: Intrathoracic pheochromocytoma. J Thorac Surg 36:625, 1958.

Mandak JS, et al: Echocardiography in the evaluation of cardiac pheochromocytoma. Am Heart J 132:1063, 1996.

Manger WIM, Gifford RW Jr: Pheochromocytoma. New York: Springer-Verlag, 1977, pp. 31 42.

Manger WIM, Gifford RW Jr: Hypertension secondary to pheochromocytoma. Bull NY Acad Med 58:139, 1982.

P.2784

Mangner TJ, et al: Metabolism of iodine-131 metaiodobenzylguanidine in patients with metastatic pheochromocytoma: concise communication. J Nucl Med 27:37, 1986.

Maurea S, et al: Iodine-131-metaiodobenzylguanidine scintigraphy in preoperative and postoperative evaluation of paragangliomas: comparison with CT and MRI. J Nucl Med 34:173, 1993.

McEwan AJ, et al: Radio-iodobenzylguanidine for the scintigraphic location and therapy of adrenergic tumors. Semin Nucl Med 15:132, 1985.

McLeish GR, Adler D: A case of intrathoracic pheochromocytoma with hypertension. Acta Med Scand 152:135, 1955.

McNeill AD, Groden BM, Neville AM: Intrathoracic phaeochromocytoma. Br J Surg 57:457, 1970.

Meeke RI, O'Keefe JD, Gafney JD: Phaeochromocytoma removal and postoperative hypoglycaemia. Anesthesia 40:1093, 1985.

Meunier JP, et al: Cardiac pheochromocytoma. Ann Thorac Surg 71: 712, 2001.

Mitra S, et al: Anesthetic hazards in a previously unsuspected case of posterior paraganglioma. Anesth Analg 81:1097, 1995.

Modlin IM, et al: Phaeochromocytomas in 72 patients: clinical and diagnostic features, treatment and long term results. Br J Surg 66:456, 1979.

Moncada R, et al: Diagnostic role of computed tomography in pericardial heart disease: congenital defects, thickening, neoplasms, and effusion. Am Heart J 103:263, 1982.

Moran CA, et al: Pigmented extraadrenal paragangliomas. A clinicopathologic and immunohistochemical study of five cases. Cancer 79:398, 1997.

Muros MA, et al: ¹¹¹In-pentetreotide scintigraphy is superior to ¹²³I-MIBG scintigraphy in the diagnosis and location of chemodectoma. Nucl Med Commun 19:735, 1998.

Nagant de Deuchaisnes C, et al: Pheochromocytomes extra-surrenaliens multiples avec dystrophic d'Albright et hamangiomes cutanes. Schweiz Med Wochenschr 33:886, 1960.

Nakajo M, et al: The normal and abnormal distribution of the adrenomedullary imaging agent m(I-131) iodobenzylguanidine (131-I-MIBG) in man: evaluation by scintigraphy. J Nucl Med 24:672, 1983a.

Nakajo M, et al: Inverse relationship between cardiac accumulation of meta 131-I-iodobenzylguanidine (I-131-MIBG) and circulating catecholamines in suspected pheochromocytomas. J Nucl Med 24:1127, 1983b.

Naoi Y, et al: A case of metastatic pheochromocytoma with remarkable response to combination of cyclophosphamide, vincristine and dacarbazine. Gan To Kagaku Ryoho 30: 145, 2003.

Navaratnarajah M, White DC: Labetalol and pheochromocytoma. Br J Anaesth 56:1179, 1984.

Neumann DR, et al: Malignant pheochromocytoma of the anterior mediastinum: PET findings with (18F) FDG and Rb-82. J Comput Assist Tomogr 20:312, 1996.

Nicholson JP Jr, et al: Pheochromocytoma and prazosin. Ann Intern Med 99:477, 1983.

Noorda RJ, et al: Non-functioning malignant paraganglioma of the posterior mediastinum with spinal cord compression. A case report. Spine 21:1703, 1996.

Ogawa J, et al: Functioning paraganglioma in the posterior mediastinum. Ann Thorac Surg 33:507, 1982.

Olsen WL, et al: MR imaging of paragangliomas. AJR 148:201, 1987.

Olson JL, Salyer WR: Mediastinal paragangliomas (aortic body tumor): a report of four cases and a review of the literature. Cancer 41:2405, 1978.

Orenstein HH, Green GE, Kancheria PL: Aortocoronary paraganglioma. Anatomic relationship of left coronary artery to paraganglia of aorta. NY State J Med 84:33, 1984.

Orr LA, et al: Gadolinium utilization in the MR evaluation of cardiac paraganglioma. Clin Imaging 21:404, 1997.

Orringer MB, et al: Surgical treatment of cardiac pheochromocytomas. J Thorac Cardiovasc Surg 89:753, 1985.

Pacak K, et al: Diagnostic localization of pheochromocytoma: the coming age of positron emission tomography. Ann NY Acad Sci 970: 170, 2002.

Palubinskas AJ, Roizen MF, Conte FA: Localization of functioning pheochromocytomas by venous sampling and radioenzymatic analysis. Radiology 136:495, 1980.

Pampari D, Lacerenza C: Intrathoracic pheochromocytoma. J Thorac Surg 36:174, 1958.

Pantanowitz D, Sareli P: Multiple malignant paragangliomas. A case report. S Afr Med J 76:441, 1989.

Peiffert B, et al: Retrocardiac pheochromocytoma associated with a double carotid site. Diagnostic and therapeutic discussion. Ann Chir 44:611, 1990.

Peiper JH, Golestan C: Intrathorakales pheochromozytom. Thorax Chir 10:517, 1963.

Petit T, et al: Thoracic pheochromocytoma revealed by ventricular tachycardia. Clinical case and review of the literature. Eur J Pediatr Surg 10: 42, 2000.

Pickering TG, et al: Pheochromocytoma of the heart Am J Cardiol 86: 1288, 2000.

Pinaud M, et al: Preoperative acute volume loading in patients with pheochromocytoma. Crit Care Med 13:460, 1985.

Plouin PF, Menard J, Corvol P: Hypertensive crisis in patient with phaeochromocytoma given metoclopramide. Lancet 2:1357, 1976.

Quint LE, et al: Pheochromocytoma and paraganglioma: comparison of MR imaging with CT and I-131 MIBG scintigraphy. Radiology 165:89, 1987.

Robinson RG: Systemic radioisotopic therapy of primary and metastatic bone cancer. J Nucl Med 31:1326, 1990.

Robinson RG, et al: Childhood pheochromocytoma, treatment with alpha methyl tyrosine for resistant hypertension. J Pediatr 91:143, 1977.

Rote AR, Flint LD, Ellis FH Jr: Intracaval recurrence of pheochromocytoma extending into right atrium: surgical management using extracorporeal circulation. N Engl J Med 296:1269, 1977.

Routh A, et al: Malignant chemodectoma of the posterior mediastinum. South Med J 75:879, 1982.

Rutegard L, Granstrand M, Aberg J: Intracaval paraganglioma causing superior vena cava syndrome. Eur J Cardiothorac Surg 6:337, 1992.

Saad MF, et al: Intrapericardial pheochromocytoma. Am J Med 75:371, 1983.

Sahin-Akyar G, et al: Magnetic resonance imaging findings of a nonfunctional mediastinal paraganglioma with an unusual presentation. Eur Radiol 7:1114, 1997.

Sandur S, et al: Thoracic involvement with pheochromocytoma: a review. Chest 115: 511, 1999.

Scharf Y, et al: Prolonged survival in malignant pheochromocytoma of the organ of Zuckerkandl with pharmacological treatment. Cancer 31:746, 1973.

Scott HW Jr, et al: Clinical experience with malignant pheochromocytomas. Surg Gynecol Obstet 154:801, 1982.

Shapiro B: MIBG in the diagnosis and therapy of neuroblastoma and pheochromocytoma. In Cattaruzi E, Englaro E, Geatti O (eds): Proceedings of the International Symposium on Recent Advances in Nuclear Medicine. Udine, Italy, October 2 3, 1987. Italy: Surin Biomedica, 1987, p. 11.

Shapiro B: Ten years of experience with MIBG applications and the potential of new radiolabeled peptides: a personal overview and concluding remarks. Q J Nucl Med 39:150, 1995.

Shapiro B: Radiopharmaceutical diagnosis and therapy of sympatho-medullary disorders. Ann Nucl Med 10:9, 1996.

Shapiro B, Fig LM: Management of pheochromocytoma. Endocrinol Metab Clin North Am 18:443, 1989.

Shapiro B, Gross MD: Radiochemistry, biochemistry and kinetics of ¹³¹I-MIBG and ¹²³I-MIBG: clinical implications of the use of ¹²³I-MIBG. Med Pediatr Oncol 15:170, 1987.

Shapiro B, Gross MD: Endocrine crises. Pheochromocytoma. Crit Care Clin 7:1, 1991.

Shapiro B, Gross MD, Shulkin BL: Radioisotope diagnosis and therapy of malignant pheochromocytomas. Trends Endocrinol Metab 12:469, 2001.

Shapiro B, Sisson JC: Atlas of Nuclear Medicine. Philadelphia: JB Lippincott, 1988, p. 72.

Shapiro B, Sisson JC, Beierwaltes WH: Experience with the use of 131-I-metaiodobenzylguanidine for locating pheochromocytomas. In Raymond C (ed): Nuclear Medicine and Biology. Proceedings of the Third World Congress of Nuclear Medicine and Biology. Vol. 2. Paris: Pergamon, 1982, p. 1265.

Shapiro B, et al: The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 87:814, 1984a.

Shapiro B, et al: Malignant phaeochromocytoma: clinical, biochemical and scintigraphic characterization. Clin Endocrinol 20:189, 1984b.

Shapiro B, et al: 131-I-metaiodobenzylguanidine (MIBG) adrenal medullary scintigraphy: interventional studies. In Spencer RP (ed): Interventional Nuclear Medicine. New York: Grune & Stratton, 1984c.

P.2785

Shapiro B, et al: Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases. J Nucl Med 267:576, 1985.

Shapiro B, et al: Radiopharmaceutical therapy of malignant pheochromocytoma with ¹³¹I-metaiodobenzylguanidine: results from ten years of experience. J Nucl Biol Med 35:269, 1991.

Shapiro B, et al: Metaiodobenzylguanidine therapy of neuroendocrine tumors. Q J Nucl Med 39:55, 1995a.

Shapiro B, et al: The current status of meta-iodobenzylguanidine and related agents for the diagnosis of neuro-endocrine tumors. Q J Nucl Med 39:3, 1995b.

Sharma SK, Sharma S, Mukhopadhyay S: Mediastinal paraganglioma presenting as an intracardiac mass with superior vena cava obstruction. Thorax 48:1181, 1993.

Shibata K, et al: Anesthetic management for resection of cardiac pheochromocytoma. Masui 39:639, 1990.

Shields TW: Primary tumors and cysts of the mediastinum. In Shields TW (ed): General Thoracic Surgery. 3rd Ed. Philadelphia: Lea & Febiger, 1989, p. 1096.

Shimoyama Y, Kawada K, Imamura H: A functioning intrapericardial paraganglioma (pheochromocytoma). Br Heart J 57:380, 1987.

Shirkoda A, Wallace S: Computed tomography of juxtacardiac pheochromocytoma. J Comput Tomogr 8:207, 1984.

Shulkin BL, Shapiro B: Current concepts on the use of MIBG in children. J Nucl Med 39:679, 1998.

Shulkin BL, et al: Primary extra-adrenal pheochromocytoma: positive 123I-MIBG imaging with negative 131I-MIBG imaging. Clin Nucl Med 11:851, 1986.

Shulkin BL, et al: Conjugate view gamma camera method for estimating tumor uptake of iodine-131-metaiodobenzylguanidine. J Nucl Med 29:542, 1988.

Shulkin B, et al: PET scanning with hydroxyephedrine: an approach to the localization of pheochromocytoma. J Nucl Med 33:1125, 1992.

Shulkin BL, et al: Pheochromocytomas that do not accumulate metaiodobenzylguanidine: localization with PET and administration of FDG. Radiology 186:711, 1993.

Sisson JC: Radiopharmaceutical treatment of pheochromoctomas. Ann NY Acad Sci 970: 54, 2002.

Sisson JC, et al: Scintigraphic localization of pheochromocytoma. N Engl J Med 305:12, 1981.

Sisson JC, et al: Locating pheochromocytomas by scintigraphy using 131-I-metaiodobenzylguanidine. CA Cancer J Clin 34:86, 1984a.

Sisson JC, et al: Radiopharmaceutical treatment of malignant pheochromocytoma. J Nucl Med 25:197, 1984b.

Sisson JC, et al: Acute toxicity of therapeutic 131-I-MIBG relates more to whole body than to blood radiation dosimetry. J Nucl Med 23:618, 1987.

Skodt V, Jacobsen GK, Helsted M: Primary paraganglioma of the lung. Report of two cases and review of the literature. APMIS 103:597, 1995.

Smit AS, et al: Meta ^I-131iodobenzylguanidine uptake in a nonsecreting paraganglioma. J Nucl Med 25:984, 1984.

Spizarny DL, Rebner M, Gross BH: CT evaluation of enhancing mediastinal masses. J Comp Assist Tomogr 11:990, 1987.

Stowers SA, et al: Cardiac pheochromocytoma involving the left main coronary artery presenting with exertional angina. Am Heart J 114:423, 1987.

Symington T, Goodall AL: Studies in pheochromocytoma. Glasgow Med J 34:75, 1953.

Tcherdakoff PH, Y et al: Bipolar pheochromocytoma: thoracic and renal pedicle localization in a child. J Urol Nephrol (Paris) 80:766, 1974.

Tenenbaum F, et al: Comparison of radiolabeled octreotide and meta-iodobenzylguanidine (MIBG) scintigraphy in malignant pheochromocytoma. J Nucl Med 36:1, 1995.

Timmis JB, Brown MJ, Allison DJ: Therapeutic embolization of phaeochromocytoma. Br J Radiol 54:420, 1981.

Tobes MC, et al: Effect of uptake-one inhibitors on the uptake of norepinephrine and metaiodobenzylguanidine. J Nucl Med 26:897, 1985.

Valk TW, et al: Spectrum of pheochromocytoma in multiple endocrine neoplasia: a scintigraphic portrayal using I-131-metaiodobenzylguanidine. Ann Intern Med 94:762, 1981.

van den Broek PJ, de Graeff J: Prolonged survival in a patient with pulmonary metastases of a malignant pheochromocytoma. Neth J Med 21:245, 1978.

van Gils APG, et al: MR imaging and MIBG scintigraphy of pheochromocytomas and extraadrenal functioning paragangliomas. Radiographics 11:37, 1991.

van Heerden JA, et al: Pheochromocytoma: current status and changing trends. Surgery 91:367, 1982.

Van Vliet PD, Burchell HB, Titus JL: Focal myocarditis associated with pheochromocytoma. N Engl J Med 274:1102, 1966.

Velilla Marco J, et al: Intrapericardial pheochromocytoma. An Med Interna 8:238, 1991.

Vinik AI, Shapiro B, Thompson NW: Plasma gut hormone levels in 37 patients with pheochromocytomas. World J Surg 10:593, 1986.

Voci V, Olson H, Beilin L: A malignant primary cardiac pheochromocytoma. Surg Rounds 9:88, 1982.

Von Moll L, et al: Iodine-131-MIBG scintigraphy of neuroendocrine tumors other than pheochromocytoma and neuroblastoma. J Nucl Med 28:979, 1987.

Weissman AF, et al: Multiple chemodectomas: carotid body tumor masked by salivary gland uptake on I-123 MIBG scintigraphy. Clin Nucl Med 19:527, 1994.

Williams KS, Temeck BK, Pass HI: Intrapericardial pheochromocytoma complicated by massive intraoperative hemorrhage. South Med J 87:1164, 1994.

Wilson AC, et al: An unusual case of intrathoracic phaeochromocytoma. Aust N Z J Surg 44:27, 1974.

Wooster L, Mitchell RI: Unsuspected phaeochromocytoma presenting during surgery. Can Anaesth Soc J 28:471, 1981.

Yajima H, et al: A case of asymptomatic posterior mediastinal pheochromocytoma diagnosed during the procedure of video-assisted thoracic surgery. J Jpn Assoc Thorac Surg 45:155, 1997.

Young MJ, et al: Biochemical tests for pheochromocytoma: strategies in hypertensive patients. J Gen Intern Med 4:273, 1989.

Zagar L, Han R, Mitrovic S: Meta-^131Iiodobenzylguanidine in the scintigraphic evaluations of neural crest tumors. Q J Nucl Med 39:13, 1995.

Reading References

Cha R, et al: Cardiac paraganglioma in New Jersey. NJ Med 94:35, 1997.

Hoefnagel CA, et al: Radionuclide diagnosis and therapy of neural crest tumors using iodine-131 metaiodobenzylguanidine. J Nucl Med 28:308, 1987.

Nevodnik VI, Kornilov BE: Rare combination of multiple primary neoplasms of the heart and adrenal gland. Vrachebnoe Delo 7:46, 1981.