The classical triad of pheochromocytoma presentation is paroxysmal sweating, hypertension, and headache. Hypertension is sustained in 50%, paroxysmal in 30%, and blood pressure is normal in 20% of patients. In rare cases when mainly epinephrine or dopamine is secreted, orthostatic hypertension may be the presenting symptom [43]. Further symptoms include weight loss, hyperglycemia, tachycardia or tachyarrhythmia, tremor, pallor, and flushing depending on which catecholamine is secreted. Other clues to the diagnosis are hypertension that is episodic (spells) or difficult to treat, glucose intolerance, nausea, palpitations, and problems with blood pressure in connection with induction of anesthesia, labor, abdominal examination, surgery, or other forms of stress. A pressor response to particular drugs can also suggest the presence of this tumor. These drugs include histamine, glucagon, droperidol, metoclopramide, tyramine (in food or wine), cytotoxic drugs, saralasin, tricyclic antidepressants and phenothiazines, cocaine, alcohol, ephedrine, ketamine, pancuronium, halothane, morphine, atracurium, and suxamethonium [1]. Intravenous contrast previously was considered a trigger, but recently published experience suggests otherwise [44]. Glucocorticoids can increase catecholamine synthesis in pheochromocytoma cells by inducing biosynthetic enzymes such as phenylethanolamine N-methyltransferase, tyrosine hydroxylase, and dopamine b-hydroxylase [10], which explains the time lag of several hours between the glucocorticoid administration and the onset of hypertension [44].

A sudden increase in sympathetic activity with both neuronal norepinephrine unloading and tumor catecholamine release can cause severe vasoconstriction which may lead to life-threatening pulmonary edema and dysrhythmias [41]. Mortality in pheochromocytoma is usually caused by a malignant hypertensive crisis with cerebrovascular accidents or dissecting aortic aneurysm, myocardial infarction, arrhythmias, heart failure, acute renal failure, or irreversible shock leading to multiple organ dysfunction. Pheochromocytoma cells may also release other peptides, some of which cause symptoms that cannot be controlled by adrenergic blockade only. Such secretory products include substance P, neuropeptide Y, enkephalins, somatostatin-corticotropin-releasing hormone, adrenocorticotropin hormone, atrial natriuretic peptide, vasointestinal peptide, parathormone, interleukin-1, interleukin-6, calcitonin gene-related peptide, and chromogranin A [41].

Provocation or suppression tests are not often used in modern practice. In the common clinical setting, measurement of 24-h urinary metanephrines may be best screening due to low likelihood of false positive results. In patients at high risk of having pheochromocytoma, measurements of fractionated plasma metanephrines may be preferable as its sensitivity approaches 100% [26, 29]. The introduction of HPLC (high-pressure liquid chromatography) methods has largely removed the problem of drug and dietary interference affecting the results [15].

It is important to first appreciate that under normal conditions, catecholamines released by nerve cells are mainly subject to neuronal reuptake [24]. Only minor amounts are metabolized or escape into circulation. The first step of metabolism (Fig. 8.2) is deamination, but in the adrenal medulla where catechol-O-methyltransferase (COMT) is present, methylation results in the formation of metanephrines. Other intermediate metabolites undergo conjugation to glucuronides and sulfates that are excreted in the urine.

Dopamine metabolism normally constitutes just a minor pathway (Fig. 8.3). A negative feedback mechanism regulates catecholamine synthesis via tyrosine hydroxylase in normal adrenal medullas but not in pheochromocytomas where the enzyme activity also is much higher.

In contrast to sympathetic nerves that contain monoamine oxidase (MAO), pheochromocytoma cells contain both MAO and high concentrations of membrane-bound COMT. The latter explains the abundance of methylated free metanephrines in plasma from these patients. The continuous intratumoral production of metanephrines makes possible the detection of pheochromocytomas in patients with normal plasma or urinary levels of catecholamines. In a recent review [45] and a report from an international symposium [46], it was suggested that screening with urine 24-h fractionated total metanephrines can be confirmed by analysis of plasma fractionated free metanephrines and plasma chromogranin A or the use of the clonidine suppression test.

Once diagnosis of pheochromocytoma is confirmed by biochemical testing, imaging techniques are employed for tumor localization. Pheochromocytomas are typically large tumors (2–5 cm in diameter) and may contain areas of hemorrhage or necrosis. Tumors in hereditary syndromes tend to be smaller and bilateral. Most tumors are intra-abdominal and 90% originate within the adrenal gland [43]. CT scanning has good sensitivity (93–100%) for detection of adrenal pheochromocytomas, but sensitivity decreases for extra-adrenal tumors. MRI is superior to CT for detecting extra-adrenal tumors and is also used as method of choice in pregnant patients [13]. Functional imaging includes iodinated metaiodobenzylguanidine scanning (¹³¹I-MIBG) and ¹¹¹In-DTPA-octreotide somatostatin-receptor scintigraphy (SRS), but the method of choice currently is ¹²³I-MIBG scintigraphy [46] and the recent development of several positron emission tomography (PET) ligands [50]. Somatostatin receptor imaging might be considered as a supplement for MIBG scintigraphy in pheochromocytoma and paraganglioma patients with suspected metastatic disease [51]^.

Medical treatment is given mainly in line of preparation for surgery. Chemotherapy (e.g., cyclophosphamide, vincristine, and dacarbazine) is currently the treatment of choice for inoperable tumors [50]. Patients that show positive testing for somatostatin receptors and positive scintigraphy may benefit from targeted chemotherapy. Irradiation with radiolabeled MIBG was used for malignant tumors with or without metastases. Even with good initial regression of tumors, no long-lasting effects could be shown so far for either approach [16]. Metyrosine (α-methylparatyrosine) inhibits tyrosine hydroxylase and may decrease catecholamine synthesis by up to 80%. It is very effective but used mainly in malignant or inoperable cases because of the many side effects (sedative fatigue, anxiety, depression, extrapyramidal signs, and tremor).

The treatment of choice for adrenal tumor in general is surgical resection once the tumor has reached a certain size (>3–5 cm), becomes symptomatic, or if imaging, genetic testing, or history is suspicious for malignancy [52]. For secreting pheochromocytomas, less invasive techniques like arterial embolization, chemoembolization, cryotherapy, and radiofrequency ablation are normally not considered safe to use, as catecholamine release and its circulatory effects may be difficult to predict and control. Traditionally, open surgery was performed, but since the first report of laparoscopic adrenalectomy for pheochromocytoma in 1992, practices have changed. Several studies have shown that the two techniques are comparable with regards to intraoperative hemodynamic changes, but the postoperative recovery is faster for the laparoscopic approach [53–55]. In many centers, laparoscopic adrenalectomy is the preferred technique for pheochromocytomas and all other benign tumors of up to a size of 6–8 cm [56–59] or bigger [60]. An Italian Registry, with 833 patients undergoing surgery since 2000, concluded that the main risk factors for the occurrence of complications during laparoscopic adrenalectomy appear to be surgical inexperience, the age and BMI of the patient, and the size and nature of the tumor [61]. One recommendation was that laparoscopic removal of these tumors should be undertaken only in high-volume specialty centers by surgical teams with the appropriate training and experience with adrenalectomies [62]. Laparoscopic adrenalectomy has been compared with the posterior retroperitoneoscopic technique in a study on 46 patients. It was concluded that both methods are safe but that the retroperitoneoscopic approach decreased operative times, blood loss, and postoperative length of stay [63]. The two different approaches for retroperitoneoscopic adrenalectomy have also been compared, and both the lateral and posterior techniques have a similar perioperative outcome when patients are selected for each option on predefined criteria [64]. Adrenocortical-sparing surgery may be performed using laparoscopy in patients with hereditary forms of pheochromocytoma [65].

The laparoscopic technique has also been used with success in patients that presented with malignant hypertension and acute heart failure. A release of norepinephrine was elicited by pneumoperitoneum but hypertension could be controlled safely even in this type of patients [66]. However, there are also reports of pneumoperitoneum causing massive norepinephrine release leading to acute heart failure despite treatment with α₁-, β-, and calcium channel blockers [67].

Sustained norepinephrine release over months or years will lead to hypertrophic cardiomyopathy in 20–30% of patients, the condition being at least partially reversible by the use of adrenergic blockade and tumor removal. Patients may present with symptoms ranging from palpitations and nonspecific electrocardiogram (ECG) – changes to severe dysrhythmias and congestive heart failure. The myocardial dysfunction may be secondary to activation (or down regulation) of adrenoreceptors, coronary vasospasm, or relative ischemia due to hypertrophy and increased myocardial oxygen demands [8]. Even young patients are at risk of developing myocardial ischemia or sustaining a myocardial infarction [68]. Microscopy shows interstitial edema, hemorrhage, and inflammatory infiltrates. The criteria for myocarditis are normally not met. The myocytes show contraction-band necrosis, and later fibrosis and calcification may follow [6]. Intracellular calcium overload appears to be the main abnormality involved [69]. Catecholamines have been shown [70] to influence the extracellular matrix with collagen deposition and subsequent fibrosis in the arterial wall and in the myocardium. These morpho-functional changes can be emphasized by ultrasound imaging. A total of 15 patients were included (hypertension in 10) in a recent study [71]. All but one had a normal left ventricular ejection fraction, however, with a depressed systolic strain rate detected by tissue Doppler echocardiography and an increased risk of intraoperative collapse.

With tailored vasoactive support, congestive heart failure may resolve within a week, and the cardiomyopathy will to some extent reverse over a few months [13, 72–74]. In one case report [48], pretreatment leads to a dramatic reversal of catecholamine-induced cardiomyopathy in less than 2 weeks, i.e., even before resection of the tumor.

Takotsubo cardiomyopathy (“broken-heart syndrome” or “stress-cardiomyopathy”) is an increasingly recognized clinical syndrome of transient left ventricular dysfunction, commonly with apical ballooning. An inverted-Takotsubo contractile pattern is now increasingly associated with pheochromocytoma [75].

Patients presenting with Takotsubo type heart failure should not be administered inotropic agents [76] because of the integral adrenergic mechanism in the pathophysiology of the syndrome. An initial proper treatment could be implantation of an intra-aortic balloon pump counterpulsation to avoid administration of inotropic agents. Further, medications like β-blockers can be used to attenuate the exaggerated stress reaction and carvedilol as α- and β-blocking agent, might be especially useful in patients with Takotsubo syndrome. Also calcium sensitizing medications such as levosimendan could be of use to counter the calcium overload.

For any patient with VHL or MEN II A/B presenting for surgery, the diagnosis of pheochromocytoma should be suspected even if the patient is asymptomatic. Additionally, patients who have had pheochromocytoma previously resected, and are returning for surgery, should be screened for recurrences and/or for pheochromocytoma on the unresected side [77]. While extra-adrenal pheochromocytomas are rare in MEN, such tumors should be part of the screening for VHL patients. Examination should aim to uncover any signs of pheochromocytoma sequelae.

The presence of symptomatic cardiac dysfunction will have an impact on both selection and duration of pretreatment and intraoperative management. If catecholamine secretion remains uncontrolled, a life-threatening crisis may develop [78]. The pressor effect will cause end-organ damage such as hypertensive encephalopathy and worsening cardiomyopathy. Since the introduction of aggressive antihypertensive treatment, this crisis is far less commonly seen, but during surgery and other tumor interventions, one should always be prepared to manage acute episodes of hypertension [6]. The events of greatest concern are anesthesia induction, insufflation of pneumoperitoneum, tumor manipulation, and loss of endogenous catecholamine stimulation upon tumor ligation in combination with residual α₁-adrenergic blockade after tumor removal. Tumor manipulation is the main risk factor during adrenalectomy since large amounts of catecholamines are released to the circulation with plasma concentration in some patients exceeding normal values by a factor of more than 1,000. Although specific anesthetic drugs have been recommended, the most important factors still are optimal preoperative preparation, gentle induction of anesthesia, and good communication between the surgeon and anesthesiologist. Virtually, all anesthetic drugs and techniques (including isoflurane, sevoflurane, sufentanil, remifentanil, fentanyl, and regional anesthesia) have been used with satisfactory result [1].

No controlled, randomized, prospective clinical studies have investigated the value of pretreatment with adrenergic receptor blocking drugs. It is often forgotten that the use of phenoxybenzamine in the original publication [18] was for 3 days only prior to surgery. These α-blocking drugs probably reduce the incidence of hypertensive crisis, the wide blood pressure fluctuations during manipulation of the tumor and the myocardial dysfunction that occur perioperatively. The reduction in perioperative mortality (from ~50% to the current 0–3%) is often used as an indirect proof of its efficacy. The α-adrenergic receptor blockade restores plasma volume by counteracting the vasoconstrictive effects of high levels of norepinephrine. For patients who exhibit ST-T changes on electrocardiogram (ECG), long-term (1–6 months) preoperative α-adrenergic receptor blockade has produced ECG normalization and clinical resolution of catecholamine-induced cardiomyopathy [79]. The optimal duration of preoperative therapy with phenoxybenzamine has not been studied. Criteria for the treatment have been recommended [1]. Accordingly, one should aim at a blood pressure of not higher than 165/90 mmHg and with an orthostatic hypotensive response present. The ECG should be free of related ST-T changes that are not permanent and of frequent premature ventricular contractions or symptomatic dysrhythmias.

In many countries, there is still dogmatic insistence on the use of phenoxybenzamine for at least 2 weeks preoperatively, although many experts find a shorter treatment period adequate. The length of treatment can be tailored to the patient’s condition [3]. A few days of treatment to allow reregulation of adrenergic receptors is sufficient for some, whereas prolonged treatment may be necessary to facilitate myocardial remodeling in case of severe hypertrophy of the heart or cardiac dysfunction. Some authors concluded that advances in anesthetic and monitoring techniques and the availability of fast-acting drugs capable of correcting sudden changes in cardiovascular variables have eliminated the need for the use of phenoxybenzamine or other drugs to produce profound and long-lasting α-blockade [20, 21]. In one study [80], patients who were treated with phenoxybenzamine for more than 10 days did not have better perioperative stability than patients who had treatment for less than a week. Nor did the degree of postural hypotension after pretreatment predict operative stability.

A study evaluated the predictive value of preoperative high systolic arterial pressure (SAP) on intra- and postoperative hemodynamic instability in 96 patients undergoing laparoscopic adrenalectomy for pheochromocytoma [81]. It was concluded that for most patients scheduled for laparoscopic pheochromocytoma removal, surgery can be carried out even without systematic preoperative arterial pressure normalization. Some patients, however, must receive hypotensive drugs before surgery to control various hypertension-associated organ dysfunctions such as left ventricular failure or neurological deficit of central origin, or symptoms such as headache or tinnitus. The data from this relatively large series do not support the concept of consistent preoperative SAP normalization. A prospective adequately powered study is mandatory for confirmation of these data [81]. A recent study of 59 patients compared the intraoperative hemodynamics in normotensive pheochromocytoma patients undergoing tumor resection with or without preoperative a-blockade. The authors concluded that pretreatment had no benefit in maintaining intraoperative hemodynamic stability in patients with normotensive pheochromocytoma, and there was an increased use of vasoactive drugs and colloid infusions in the pretreated group [82].

Alternative drugs should be considered for pretreatment of patients with congestive heart failure in whom α-adrenergic blockade leads to tachycardia and β-adrenergic blockade diminishes cardiac performance [13]. In a report of two complicated cases, it is pointed out how important it is that the anesthesiologist carefully monitors the endpoints of the patient’s pretreatment and alerts the team of potential cardiovascular risk factors that may impact the intraoperative course [83]. In these reports, the patients had large pheochromocytomas, preoperatively insufficiently controlled blood pressure, and/or myocardial dysfunction. The use of β-adrenergic blockade prior to surgery might also have increased the patient’s vulnerability to untoward events later on, including intractable hypotension, bradycardia, and asystolic cardiac arrest. Preoperatively it was noted that cardiac compromise secondary to volume overload occurred, and intraoperatively massive doses of exogenous catecholamines were needed post-ligation.

Author’s opinion on preoperative optimization is expressed in Table 8.2 and is supported in the current literature [84]. This prospective follow-up study of 35 pheochromocytoma patients systematically documents the reversibility of cardiovascular dysfunction. In the study were used serial assessments with ECHO, tissue Doppler imaging (TDI) and serum N-terminal pro-brain natriuretic peptide (NTpro-BNP) to evaluate cardiac function. Seven of the 35 pheochromocytoma patients (20%) were found to have significant LV systolic dysfunction (as defined by LVEF <45%, MPI (Doppler-derived performance index) >0.4, s-NTpro-BNP >500 pg/mL). Normalization ensued within 3 months in most cases.

Subtle myocardial damage is common in pheochromocytoma patients, and it can be detected by using biomarkers and/or tissue Doppler imaging despite an absence of overt LV dysfunction. Even if the clinical relevance of the combination of normal ECHO and positive other markers is still unclear, it may be assumed, however, that detailed cardiac evaluation may help tailoring preoperative optimization and thereby reducing perioperative morbidity.