Chromaffin cells are derived from neuroectoderm and characterized by intense positive reaction of stored catecholamines with chromium salts, particularly potassium dichromate, giving a yellow-brown color on tissue sectioning.⁴¹ These cells are usually innervated by the preganglionic sympathetic nervous system and are capable of synthesizing and storing large quantities of catecholamines: adrenaline, noradrenaline, and epinephrine.⁴² The true chromaffin system, although closely associated with the sympathetic system, by itself comprises groups of cells topographically organized into the adrenal medulla, para-aortic bodies, paraganglia proper, carotid bodies, splanchnic nerves, prevertebral autonomic plexuses, and the small group of diffusely dispersed cells, paravertebral sympathetic ganglia. In essence chromaffin cells are distributed in almost all structures innervated by the autonomic sympathetic system, as described by Glenner and Grimley.⁷⁷ The discovery of the enterochromaffin system and the amine-storing mast cells of the gut, pancreas, and liver, which also demonstrated chromaffin affinity, led to the belief that chromaffin affinity was not necessarily restricted to the sympathetic system. However, the common feature underlying all these cells is their amine-handling properties; hence the acronym APUD, for amine precursor uptake and decarboxylation, was introduced by Pearse¹⁸² to categorize these cells. Currently about 40 different types of APUD cells have been identified, which constitute the modern diffuse neuroendocrine system of the human body.¹⁵⁶

Ever since the description of the formation of yellow-brown precipitate by reaction of catecholamine-producing tissues with chromic salts in 1902 by Kohn,¹¹⁷ the terms chromaffin reaction and chromaffin cells have been synonymous with the adrenal glands. However, works by Coupland⁴³ recognized the fact that chromaffin staining was also characteristic of paraganglionic cells, which did not secrete catecholamines. In fact, the presence of catecholamine is essential for the chromaffin reaction, implying that although some cells did not secrete catecholamines, they still synthesized and stored them in cytoplasmic granules. This has been confirmed by electron microscopy. Histologically, functioning and nonfunctional paragangliomas are indistinguishable, as they both synthesize catecholamines and hence are chromaffin-positive. The only distinguishing factor is the level of circulating and excretory catecholamines and their metabolites, as recognized by McEwan et al.¹⁴⁶ and Shapiro and Fig.²¹⁰ Microscopically, the characteristic nesting pattern of cells termed “Zellballen” is unique to paragangliomas (Fig. 198-1). By immunohistochemistry, paragangliomas are positive for chromogranin, S-100 protein, and leu-encephalin, but they are negative for keratin.¹⁵⁷ The presence of synaptophysin, chromogranin, and neuron-specific enolase in these cells indicates a neuroendocrine origin.^104,216 Occasionally melanotic pigmentation has been identified in pheochromocytomas⁸⁹ and cardiac paragangliomas,¹⁵³ supporting divergent differentiation from neural crest cells expressing both pheochromatous and melanocytic features.³⁵ The simultaneous expression of functional properties of two different types of neural crest cells in one tumor stresses the close relationship between all neural crest elements, as noted by Hofmann.⁹⁵

The clinical presentation of paragangliomas can be varied and ranges from local pressure symptoms, especially in the case of nonfunctional tumors, to symptoms related to the systemic effects of secreted catecholamines and their metabolites in functional tumors. In many instances, complications arising from hypercatecholaminemia are the primary reason medical attention is sought for these patients, which then uncovers an underlying functional paraganglioma.

Frequently the clinical presentations of these tumors are ill defined. Hypertension is the most common symptom in 82% of
cases with functioning paraganglioma, as noted by Goldstein.⁸² Indeed, paragangliomas may account for up to 0.5% of all cases of hypertension, and elevated blood pressure may be the only initial presentation of these tumors, as reported by Chao.³³ In one series of 236 patients with benign paragangliomas (of all locations), catecholamine hypersecretion was found in 40 of 128 screened patients (31%) and 38 were hypertensive.⁶⁰

In addition to hypertension, secretion of vasoactive catecholamines may lead to other symptoms of catecholamine excess, such as headache, palpitations, sweating, nausea, shortness of breath, weakness, myocardial infarction, flushing, weight loss, visual changes, stroke, coma, arrhythmias, and psychosis. Ventricular tachycardia can be a life-threatening initial presentation in functional paragangliomas, as reported by Michaels,¹⁵² Petit,¹⁸⁴ and Li.¹³³ Some types of cardiac paraganglia are believed to derive their blood supply from the coronary vasculature and may manifest as atypical angina or even myocardial ischemia.

Both sexes are equally affected. The peak incidence is in the third and fourth decades of life, as reported by Freier,⁶⁹ and children are occasionally affected, according to DiStefano⁴⁹ and Petit et al.¹⁸⁴

Workup of young patients with mediastinal paraganglioma should promptly include evaluation of the upper GI tract and chest wall to exclude the presence of Carney’s triad. First described in 1979 by Carney,³¹ the triad comprises gastric epithelioid leiomyosarcoma, functioning extra-adrenal paraganglioma, and pulmonary chondroma, with patients usually presenting in the second or third decade of life. As two of the three components of the triad are potentially lethal, it is essential that any young patient with a functioning paraganglioma be thoroughly evaluated for the presence of other tumors.^31,44

Confirmation of the diagnosis depends on the functionality of the tumor. Tissue diagnosis is best avoided in functional tumors, as this can precipitate a hypertensive crisis. In addition, most of these tumors are highly vascular and are liable to cause bleeding complications. In the presence of elevated catecholamines and anatomic localization of the tumor, functional studies may be utilized and a tissue diagnosis is generally not necessary. If tissue biopsy has been obtained, several markers help in establishing the diagnosis. Paragangliomas simultaneously coexpress catecholamines and different peptides. Pavai¹⁸¹ has suggested that the diagnosis is essentially confirmed by S-100 and chromogranin positivity. Chromogranin by itself has a low sensitivity, but neuron-specific enolase (NSE) and chromogranin together have a sensitivity that approaches 100%, as reported by Kliewer.¹¹⁵ It has been observed that undifferentiated tumors with malignant features are less likely to express characteristic tumor markers, whereas more differentiated tumors are more prone to express them. In addition paragangliomas express a variety of neuropeptides, the more common ones being metencephaline (73%–75%) and leu-encephaline (50%–76%),
as reported by Warren.²⁴⁴ Parasympathetic paragangliomas are usually chromaffin-negative.²

Several syndromes have been associated with paragangliomas, including neurofibromatosis type 1 (NF1), Von Hippel–Lindau disease (VHL), and hereditary paraganglioma syndromes 1 through 4 (PGL1–4). It is important to understand these syndromes, as a chromaffin-positive tumor may be the only manifestation of the underlying genetic mutation. Almost all of these associated syndromes are autosomal dominant.

Neurofibromatosis type 1 is an autosomal dominant disorder caused by inactivating mutations of neurofibromin, a tumor suppressor gene. Clinically it manifests itself with café au lait spots, axillary freckling, multiple neuromas, iris hamartomas (known as Lisch nodules) and chromaffin tumors. The majority of chromaffin tumors in these patients appear in the fourth decade of life. In many circumstances the diagnosis of NF1 is made during childhood, as the typical skin lesions precede the appearance of paragangliomas/pheochromocytomas. Hence the chance that NF1 could manifest as an apparent sporadic paraganglioma is quite rare, as reported by Gutmann.⁸⁷ Overall, extra-adrenal sympathetic paragangliomas are present in 6% of patients with NF1, the majority being benign, as noted by Walther.²⁴²

VHL disease is an autosomal dominant syndrome, clinically associated with both benign and malignant tumors: renal and testicular tumors and pancreatic cysts, islet cell tumors, retinal angiomatosis, cerebellar hemangioblastoma, chromaffin tumors, and renal cell carcinoma.⁹⁴ Some 50% of patients with VHL present with a catecholamine-producing tumor. About 2% of these are thoracic sympathetic paragangliomas. More than 90% of functional chromaffin tumors in patients with VHL are benign, with a higher incidence of malignant behavior quoted among paragangliomas of extra-adrenal origin.²⁴² These catecholamine-producing tumors in patients with VHL mutation may manifest as the first or only evidence of the disease.

Hereditary paragangliomas account for about 30% of cases of paragangliomas, highlighting the importance of family history in young patients who present with paragangliomas, as reported by Van Baars.²³⁷ Hereditary paragangliomas are characterized by an earlier age of onset and more severe form of disease. Four different loci have been implicated giving rise to hereditary paraganglioma syndromes PGL1 through PGL4: PGL1 on 11q23, PGL2 on 11q13, PGL3 on 1q21, and PGL4 on 1p36, as studied by Favier.⁶⁹ Hereditary paragangliomas are inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity. Until the year 2000, only two syndromes (VHL and NF1) were known to be associated with extra-adrenal paragangliomas. The recent identification of germline mutations in the SDH genes encoding succinate dehydrogenase in patients with familial paraganglioma has highlighted a primary role of mitochondrial deficiency in carcinogenesis, as reported by Eng.⁵⁹ The discovery of the first deleterious mutations in the SDHD gene for PGL1 by Baysal et al.¹⁸ and subsequent mutations in SDHC (PGL3) by Niemann¹⁶⁹ and SDHB (PGL4) by Astuti⁸ have resulted in significant changes in the counseling and genetic workup of patients with hereditary paragangliomas. Several mutations in these genes have subsequently been reported in patients with hereditary PGL and sporadic cases as well by Baysal.¹⁶ SDH gene mutations are also frequently encountered in patients with an apparently sporadic form of paragangliomas.

Most of the hereditary paraganglioma syndromes are associated with head and neck parasympathetic paragangliomas (chemodectomas) that usually remain nonfunctional. Only PGL1 and PGL4 have been found to be associated with functional types of sympathetic paragangliomas. PGL 3 mutations of succinate dehydrogenase Subunit C are associated with benign nonfunctional head and neck parasympathetic paragangliomas. So far there has been no association with functional sympathetic paragangliomas or pheochromocytomas as observed by Schiavi.²¹⁷ The causative gene for PGL2 remains to be identified. Currently this has been exclusively associated with parasympathetic nonfunctional paragangliomas of head and neck as reported by Baysal.¹⁷ The association with mediastinal tumors is rare.

MEN1 and MEN2 are commonly associated with pheochromocytomas but rarely with thoracic paragangliomas. Although MEN2 is associated with pheochromocytomas, the incidence of paragangliomas is very low, most of which have been in the periadrenal area or after the primary adrenal tumor has been resected. This has been attributed to ectopic rests of adrenal tissue or secondary to tumor recurrence or spillage as noted by Nilsson.¹⁷⁰ Hence, thoracic paragangliomas are almost never associated with MEN2 syndrome. Neumann et al.¹⁶⁴ and Gimenez-Roqueplo et al.⁷⁴ reported that about 50% of patients with extra-adrenal tumors were found to harbor germline mutations, most commonly of succinate dehydrogenase subunits B and D, thereby necessitating genetic testing as a part of the initial workup of patients presenting with functional paragangliomas. The presence of multicentric tumors and head and neck parasympathetic paragangliomas should also raise the possibility of underlying genetic syndrome, prompting early genetic counseling and testing.

Reports by Bauters¹⁴ and Neumann¹⁶⁴ have suggested that the likelihood of finding a hereditary basis for functional paragangliomas is increased when age of onset is young (≤18 years). About half of those presenting <20 years have hereditary disease. The first line of genetic testing for those with mediastinal paragangliomas should be for Von Hippel–Lindau germline, as the incidence is about 74% in patients <20 years of age. The next in line are SDHB and SDHD mutations. The incidence of germline mutation progressively decreases as the age of presentation increases. For patients >50 years who present with an apparently sporadic paraganglioma, the probability of having a VHL, SDHB, or SDHD mutation is <2%, making genetic testing unnecessary and difficult to justify.

Hypertension is the primary underlying feature of catechola- mine-secreting paragangliomas. The presence of severe and symptomatic paroxysmal hypertension should always generate suspicion of a catecholamine-secreting pheochromocytoma, as noted by Goldstein.⁸¹ Not all patients with a functioning paraganglioma will necessarily present with paroxysmal episodes, as many patients have persistent hypertension without episodic increases in blood pressure. In addition, there have been reports
of patients with functioning paragangliomas without clinical evidence of hypertension. Catecholamine-producing tumors may arise in the adrenal medulla (pheochromocytomas) or in extra-adrenal chromaffin cells (secreting paragangliomas). The estimated overall prevalence (based on autopsy studies) is 0.05% to 0.12%,⁵ and an estimated prevalence in unselected patients with hypertension is 0.2% to 0.6%.¹⁵⁵ Hence it is important to suspect, confirm, localize, and resect these tumors, because the hypertension associated with pheochromocytoma is curable, and these patients are at risk for a lethal paroxysm.

Functional paragangliomas may secrete either norepi- nephrine or epinephrine but predominantly release norepi- nephrine. Rarely, they may secrete dopa and/or dopamine. Approximately half of patients have permanent hypertension, the rest suffer from paroxysmal hypertension, and there is no clear reason as to why patients may present in one form or the other, as noted by Reisch.¹⁹⁶ Paroxysms may occur on a background of sustained hypertension, whereas others can have normal blood pressure between paroxysms, as reported by Lenders.¹³⁰ The frequency of paroxysms is quite varied: 75% of affected patients suffer from attacks weekly, others several times per day or just once every few months. Paroxysms occur suddenly and unexpectedly. In 80%, they last <1 hour, then subside gradually and lead to exhaustion.¹⁴¹ The attacks are characterized by headache (50%), sweating (50%), and palpitations (50%–60%). However, recent studies showed that this classic triad occurs more rarely (15%–24%) than usually assumed, as observed by Baguet.¹¹ Even hypertension appears to be less frequent (60%–70%) than stated in earlier studies by Mannelli.¹⁴² Normotensive courses are more frequent in familial pheochromocytomas, as observed by Plouin.¹⁸⁶

Because catecholamines can inhibit peristalsis, functional paragangliomas may be associated with severe constipation, pseudo-obstruction, or ileus, as reported by Murakami.¹⁶⁰

Mesenteric artery vasoconstriction due to hypercatecholaminemia may result in ischemic enterocolitis with intestinal necrosis. Because thoracic paragangliomas are rare tumors, most of the complications reported in the literature pertain to excessive catecholamine secretion from adrenal pheochromocytomas. These systemic effects, however, hold true for functional paragangliomas anywhere in the body. Bowel perforation,¹⁰⁷ stroke, dilated cardiomyopathy,¹³⁴ sick sinus syndrome,⁸⁵ and a variety of other complications from catecholamine secretion have been reported. The intense vasoconstriction also leads to volume contraction and hemoconcentration, which has an important bearing on the preoperative management of patients with catecholamine-secreting tumors. In any case of sustained paroxysmal hypertension or paradoxical hypertension despite antihypertensive therapy, especially during therapy with beta-blockers, the diagnosis of pheochromocytoma has to be kept in mind and ruled out. New onset of hypertension under tricyclic antidepressive medication, severe symptomatic hypotension when starting therapy with alpha blockers, or severe retinopathy in newly diagnosed hypertension may suggest functional catecholamine-producing tumor.

In addition to a catecholamine excess, pheochromocytomas have been found to secrete neuropeptide Y or chromogranin A. Rarely, they may release vasointestinal peptide, serotonin, calcitonin, parathyroid hormone–related protein, adrenocorticotropic hormone (ACTH), neuron-specific enolase, or interleukin-6, as noted by Yeo.²⁵² Production of vasoactive intestinal polypeptide by functional chromaffin tumors is extremely rare. Since the first report in 1975 by Loehy et al.,¹³⁷ only 16 cases of adrenal pheochromocytoma associated with the watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome have been reported, as summarized by Ikuta.⁹⁷ Some of these presentations have not been reported yet for thoracic functional paragangliomas because these are unusual manifestations in an extremely rare tumor to begin with. Excessive insulin production is extremely rare, as reported by Fujino⁷¹ and Uysal.²³⁶ Although erythropoietin has not been directly implicated, refractory polycythemia has been reported by Imai.⁹⁹ Terada²³¹ and associates demonstrated a lack of elevation in erythropoietin levels in patients with functioning paragangliomas, favoring the volume contraction theory as the more likely cause of polycythemia. Systemic amyloidosis was reported by Rey¹⁹⁷ and hypercalcemia due to parathormone related peptide production was reported by Loh.¹³⁸ A wide range of peptide hormones may be present within the tumor and identified by immunohistochemistry without necessarily giving rise to clinical syndromes, as reported by Shapiro and Fig.²¹⁰

As Smit and associates²²¹ reported, functional paragangliomas may, in addition to the effects of catecholamine hypersecretion, exert local pressure effects, whereas nonsecreting paragangliomas present only with local mass effects. 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 tumor interrupts the thoracocervical sympathetic outflow. Lesions arising close to the coronary arteries may compress them and cause angina. 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. Left atrial tumors are associated with compressive symptoms obstructing pulmonary venous inflow into the left atrium.

The overall frequency of malignancy in adrenal paragangliomas had been reported to be 10%. Extra-adrenal primary tumors appear to have a greater metastatic potential than adrenal medullary tumors, as pointed out by Shapiro²¹¹ and Bravo.²⁶ The most common metastatic sites for chromaffin-cell tumors are local lymph nodes, bone (50%), liver (50%), and lung (30%), as reported by Bravo²⁶ and Loh et al.¹³⁹ Malignant lesions have a propensity to spread to bone, as noted by Shapiro et al.,²¹⁰ Scharf,²⁰⁵ and Lamy¹²⁷ and their colleagues, where the deposits may cause bone pain and pathologic fractures, but they are often asymptomatic, as reported by Heindel and colleagues.⁹¹ Rarely,
metastases to brain, skin, or serous cavities have been described. Metastases may become clinically evident after long latent intervals following apparent cure; thus lifelong follow-up is recommended. Persistent postoperative symptoms in patients with chromaffin-cell tumors in the absence of radiologically evident residual tumor may suggest the presence of occult metastases.¹⁰³

The histologic findings do not permit definite diagnosis of malignancy in chromaffin-cell tumors; this still remains a controversial topic. Several possible correlates have been suggested, such as tumor weight >80 g and high tumor concentration of dopamine by John et al.,¹⁰³ tumor size >5 cm (75% prevalence of malignancy) by Goldstein et al.,⁸¹ or the presence of confluent tumor necrosis (a common feature in larger tumors). None of these, however, can conclusively predict malignant behavior.

When there is recurrence of disease, biochemical evidence of excess catecholamine production usually precedes the clinical manifestations of catecholamine excess.²⁴⁶ Detection of malignant characteristics primarily relies on follow-up, as there are no reliable biochemical, clinical, or histologic features that reliably predict malignancy, as noted by Pommier.¹⁸⁷ Invasion of surrounding tissues, spread to lymphatics, and presence of metastatic disease are the only definitive predictors of malignancy, as described by Sandur,²⁰⁴ Whalen,²⁴⁷ and Goldfarb.⁷⁸ Although none of these are diagnostic, the presence of nuclear atypia, vascular invasion, or tumor necrosis may suggest a malignant potential, as highlighted by Shapiro.²¹¹ The absence of these histologic findings does not exclude malignancy, as seemingly benign lesions may metastasize widely, with the only proof of malignancy dependent on the unequivocal presence of metastatic disease or local infiltration of surrounding structures.

As the distinction between malignant and benign tumors still remains difficult, there is a pressing necessity to identify markers that can reliably predict tumors with malignant potential. As pointed out by Herrera et al.,⁹² DNA ploidy correlates poorly with malignant potential. Kumaki et al.¹¹⁹ have suggested MIB-1 immunostaining as a useful adjunctive marker to predict malignant behavior in pheochromocytomas and paragangliomas. Recent molecular studies have shown that the prevalence of malignancy among paragangliomas is higher; especially those associated with succinate dehydrogenase subunit B gene mutations, as pointed by Chrisoulidou.³⁶ Genetic profiling of tumor cells has recently been proposed by Thouennon et al.²³² as a method of distinguishing malignant adrenal pheochromocytomas. Lower expression of key genes encoding peptide processing and activation factors—such as neuroserpin, glutaminyl-peptide cyclotransferase, peptidylglycine alpha-amidating mono-oxygenase—has been associated with greater malignant potential. The gamma-tubulin gene, which encodes a constituent of centrosomes, has been noted to be significantly overexpressed in malignant pheochromocytomas, while the genetic expression of occludin, a major component of junctions, is repressed in malignant tumors, suggesting a possible diminution of cell-to-cell contacts and an increased permeability in malignant adrenal pheochromocytomas. These findings are yet to be further explored in the realm of extra-adrenal paragangliomas. For all practical purposes paragangliomas are to be regarded as malignant and surgical principles are heavily reliant on this fact. The only absolute criterion for malignancy, however, is the presence of metastases to sites where chromaffin tissue is not usually found. The lack of firm predictors of malignancy coupled with the variable course of this rare disease makes lifelong follow-up of patients with chromaffin-cell tumors mandatory.

All patients with suspected functional paragangliomas should undergo biochemical testing. This includes patients with suggestive paroxysmal signs or symptoms; those with recent, therapy-resistant, or volatile hypertension; and those with a hereditary predisposition for a paraganglioma. Because of the low prevalence of these tumors, biochemical screening for the tumor in asymptomatic patients with hypertension is not indicated.

Two important factors guiding biochemical diagnosis are (a) to investigate signs and symptoms that suggest the presence of a functional paraganglioma and (b) to determine catecholamine hypersecretion in patients presenting with a mediastinal mass suspicious of a paraganglioma.

Nonfunctioning paragangliomas are unlikely to be diagnosed with biochemical testing unless a tissue sample is obtained that reveals the presence of chromaffin-positive cytoplasmic granules. The best screening tests for initial assessment of functioning chromaffin-cell tumors are the measurement of plasma free and urinary fractionated metanephrines, as reported by Lenders.¹²⁹ Extra-adrenal chromaffin tumors are more likely to produce norepinephrine, as noted by van der Harst.²³⁸ Plasma analysis for diagnosis includes measurement of catecholamines, norepinephrine and epinephrine, and free metanephrines, normetanephrine, and metanephrine. Urinary measurements include metanephrine, normetanephrine, and vanillyl mandelic acid (VMA). Based on work by Lenders,¹²⁹ sensitivities are highest for measurements of plasma free metanephrines (99%), followed closely by urinary fractionated metanephrines (97%). When used in combination, sensitivities of both the above tests considerably exceeded those for urinary catecholamines at 86%, plasma catecholamines at 84%, and urinary total metanephrines at 77%. The highest specificities were 95% for tests of urinary VMA and 93% for tests of urinary total metanephrines. Specificities of all tests were higher in patients tested for hereditary chromaffin tumors than for sporadic tumors. To minimize the risk of missing a patient with paraganglioma, clinicians often use multiple biochemical tests during the initial diagnostic workup of patients with suspected tumors. Plasma free metanephrines constitute the best test for excluding or confirming functional paragangliomas and should be the test of first choice for diagnosis of the tumor. A negative test result virtually excludes functioning chromaffin tumors. In many cases the diagnosis is usually accomplished fairly easily as the levels are remarkably elevated and the task of localization becomes more of a challenge. The molecular basis of metanephrine measurement is that chromaffin-cell tumors contain catechol-O-methyl-transferase, which metabolizes adrenaline and noradrenaline to metanephrine and normetanephrine respectively. However, one must be cognizant of the fact measurement of metanephrines may fail to identify tumors that secrete small amounts of catecholamines and those that exclusively produce dopamine, as pointed by Eisenhofer et al.⁵⁵

In dopamine-secreting tumors, measurement of plasma dopamine or its O-methylated metabolite, methoxytyramine, provides higher diagnostic accuracy than urinary dopamine. To minimize false positive results, medications known to interfere
with catecholamine metabolism (tricyclic antidepressants, phenoxybenzamine, and labetalol) should be avoided if possible, as noted by Eisenhofer et al.⁵⁶ Obtaining blood samples from seated rather than supine patients may be more practical for phlebotomists, but the sympathoadrenal activating effects of upright posture may compromise the diagnostic accuracy of measurements of plasma metanephrines. Use of reference intervals established from samples obtained from seated patients results in threefold increase in false-negative test results and loss of diagnostic sensitivity. Blood samples for diagnosis of chromaffin-secreting tumors should be obtained only with patients in the supine position.

Biochemical studies are inadequate to either predict malignancy or distinguish benign from malignant lesions, as noted by Ahlman.³ Plasma chromogranin A (CgA) has also been used for the diagnosis and prediction of malignant behavior in chromaffin-cell tumors by O’Connor,¹⁷² and neuron-specific enolase has been advocated as a screening marker for malignant behavior by Oishi and Sato.¹⁷⁵ A direct relation of ACTH overexpression and malignant behavior was reported by Moreno et al.¹⁵⁹ Other measurements, such as platelet norepinephrine measurements, have a sensitivity of 93%, as reported by Guller et al.⁸⁶ Platelet measures have the presumed advantage of maintaining a fairly consistent level over a period of time despite rapid fluctuation in plasma concentration of catecholamine derivatives.

Plasma norepinephrine concentrations typically are high and fail to decrease normally by 3 hours after oral administration of 300 μg of clonidine, which decreases the release of norepi- nephrine from sympathetic nerve endings but not from tumors. The failure of clonidine to suppress norepinephrine levels therefore is a positive, or abnormal, result. The clonidine suppression test, first described by Bravo in 1981,²⁵ is accepted as a diagnostic test in patients with elevated baseline norepinephrine levels. However, the clonidine suppression test is not specific enough when it is used as a single test. False-positive and false-negative results have been obtained from clonidine suppression testing, since some patients without catecholamine-secreting tumors can fail to suppress plasma norepinephrine levels after clonidine administration, and some with paragangliomas can have normal levels of norepinephrine after a clonidine suppression test, as pointed out by Grossman.⁸⁵

Several stimulation tests have been proposed in the diagnostic evaluation of functional chromaffin tumors, including pressor responses to sympathomimetic agents and glucagons. These can produce dangerous increases in pressure in patients with functional tumors; hence stimulation tests involving measurements of pressor responses are no longer recommended.

Preoperative localization is essential in the management of paragangliomas of the thorax. Surgical planning and determination of operative approach is heavily dependent on precise anatomic localization and relationship of the tumor to the surrounding structures.²¹³ Two types of imaging are utilized for functional paragangliomas: (a) anatomic imaging to locate the extent of the tumor and relation to surrounding structures and (b) functional imaging, which is utilized as screening for metastatic disease, staging, workup, and for localizing the tumor in patients with biochemically confirmed diagnosis.

Anatomic imaging can include a variety of tests, such as computed tomography (CT), magnetic resonance imaging (MRI), transthoracic echocardiography, transesophageal echocardiography, and chest radiography with barium swallow.

Functional studies include metaiodobenzylguanidine (MIBG) scans and somatostatin receptor scintigraphy. The choice of test depends on the clinical presentation, location and functional status of the tumor.