Pheochromocytoma

Pheochromocytomas are tumors that arise from chromaffin cells of the adrenal medulla. When such tumors arise at an extra-adrenal site, they are called paragangliomas, which can be located from the neck to the base of the pelvis (Fig. 4-1). These tumors have an incidence of one to two per 100,000 adults and represent a curable cause of hypertension in 0.1% to 1% of hypertensive patients.1,2 The malignancy rate is thought to be between 10% and 20%, though paragangliomas have a higher reported rate of malignancy, with over 50% reported malignant in some series.3,4 Pheochromocytomas may be familial in 10% of cases and are associated with a variety of other conditions including the syndromeof multiple endocrine neoplasia (MEN) type II-A,II-B, von Hippel–Lindau disease, and von Reckling-hausen’s disease.

The diagnosis and medical and surgical management of this condition have been evolving continuously since the first surgical resections of these lesions by C. H. Mayo in the United States and Roux in Europe.5,6 The nature of the biochemical pathways and the diagnostic urinary studies for catecholamines and their metabolites were established by Crout et al. in the early 1960s.7 The development of computed tomography in the 1970s provided an accurate, noninvasive method of imaging the adrenal glands and localizing these tumors,8 as has the later development of magnetic resonance imaging. Throughout the 1980s new medications and surgical techniques were developed to control intraoperative hemodynamics, which allowed a variety of surgical approaches including laparoscopy to be utilized for resection of these lesions.
DIAGNOSIS
Symptoms

Pheochromocytomas are rarely asymptomatic, though the symptoms may be varied and frequently mimic those of other conditions. Paroxysmal symp-toms (headache, diaphoresis, pallor, palpitations, andapprehension) are present in over 50% of patients. Hy-pertension, present in more than 90% of patients,may be paroxysmal in 25% to 50%. Other symptomsinclude nausea, trembling, weakness, epigastric pain, and syncope.
Biochemical
Pheochromocytoma or paraganglioma can be confirmed by demonstration of elevated urinary catecholamine levels (>100 µg total catecholamines per 24 hours overall, with epinephrine >20 µg and norepinephrine >80 µg, per 24 hours, respectively) or catecholamine degradation products such as metanephrines (>1.3 mg per 24 hours) and vanillymandelic acid (>6.5 mg per 24 hours); a value of >9.0 mg/24 hours determines over 90% of patients with pheochromocytomas.1 Total catecholamines, such as epinephrine, norepinephrine, and dopamine, can also be measured in the blood. Although urinary catecholamines have a higher specificity than plasma catecholamines, either may give misleadingresults because of other medical conditions (acute alco-holism, hypothyroidism, or volume depletion) or in-terfering medications. A combined free plasma norepinephrine and epinephrine level in excess of 950 pg/ml has a diagnostic sensitivity of 94% and a specificity of 97%. The radioenzymatic assay is sensitive to the circumstances in which the blood was collected, and this should be carefully controlled by having the patient in a fasting state and supine for at least 30 minutes before blood sampling through a large-bore needle placed at least 20 minutes beforehand to avoid a spurious catecholamine elevation caused by pain or apprehension. Baseline plasma norepinephrine and epinephrine levels of more than 2,000 pg/ml (norepinephrine >2,000pg/ml, epinephrine >200 pg/ml) indicate a pheochromocytoma. Failure of these levels to decline to less than 500 pg/ml after oral clonidine is also indicative of tumor.
Stimulation or provocation tests of patients suspected of this diagnosis can be extremely hazardous and are not recommended. Despite the reliance on diagnostic measurements of urinary catecholamines and their degradation products, newer agents have been tried to delineate borderline patients. Plasma catecholamines are measured after administration of clonidine or pentolinium tartrate. Patients with pheochromocytoma experience no significant decrease in circulating catecholamines with either agent, as opposed to normal patients, who do.
Imaging Techniques
A variety of imaging techniques are available for the detection of pheochromocytoma. Several decades ago, angiography and venography were the imaging techniques of choice. However, along with a low sensitivity, these modalities carried a significant morbidity and a risk of provoking a hypertensive crisis if the possibility of pheochromocytoma had not been considered.
The most frequent initial diagnostic modality currently is the abdominal CT scan, which, as a result of its widespread usage, has led to a significant increase in the diagnosis of asymptomatic adrenal lesions. This test has an accuracy rate for diagnosis of pheochromocytomas of over 90% and can be performed in patients who have not previously undergone a blockade, although unenhanced CT has been recommended as the initial localizing study to avoid even the small risk of precipitating a hypertensive crisis during the intravenous injection of contrast medium.9 Computed tomography has largely replaced nephrotomography, ultrasonography, selective angiography, and venography with venous sampling. However, CT does not differentiate among adrenal lesions and benign and malignant disease.
Magnetic resonance imaging (MRI) appears to be as accurate as CT in identifying adrenal lesions and also has a characteristically bright, light bulb image on T2-weighted study (Fig. 4-2). It is also very useful in the detection of recurrent local tumors in patients with metal clips and may have indications in pregnant patients. Sagittal and coronal imaging can give excellent definition of the surrounding anatomic and vascular relationships.
An alternative in the search for residual or multiple pheochromocytoma is the meta-iodobenzylguanidine scan (131I-MIBG). This compound is taken up by adrenergic granules and adrenal medulla cells and causesvirtually no pharmacologic effects. Because MIBG is concentrated in catecholamine storage vesicles, it is quite specific for pheochromocytoma rather than just an adrenal mass: MIBG scans have a 78.4% sensitivity in primary sporadic lesions, 92.4% in malignant lesions, and 94.3% in familial cases, giving an overall 87.4% sensitivity with 99% specificity. Although it provides no anatomic detail, this test is extremely useful when CT and MRI findings are confusing (Fig. 4-3).

INDICATIONS FOR SURGERY
Indications for surgery are an adrenal mass or extra-adrenal mass that meets the biochemical criteria for a pheochromocytoma. Additional indications include a positive MIBG scan or MRI with borderline biochemical criteria.
ALTERNATIVE THERAPY
There is no acceptable alternative therapy to the management of pheochromocytoma except surgery. Alternative approaches to the adrenal would include laparoscopic surgery, though with the high perioperative risks associated with this procedure, open surgery is by far the preferred route. In pregnant patients, oral blocking agents may be utilized until the fetus has matured, and cesarean section and tumor excision can be safely performed as one procedure, avoiding the potential stress of vaginal delivery.
SURGICAL TECHNIQUE
Preoperative Management

The localization of a pheochromocytoma is essential in planning definitive therapy and is influenced by whether it is sporadic (80% solitary adrenal lesion) or familial (50% bilateral) and whether it occurs in children or in adults. Multiple or extra-adrenal lesions occur in 10% of cases in adults and up to 30% in children. Localization techniques usually involve one or more of the imaging techniques listed above.
Adequate preoperative pharmacologic blockade provides a smoother and safer procedure for the surgeon, patient, and anesthesiologist. Phenoxybenzamine hydrochloride is an a-adrenergic blocker with both postsynaptic (a1) and presynaptic (a2) blocking capabilities. An initial divided dose of 30 to 60 mg orally is commenced. The dose is increased by 10 to 20 mg per day until the blood pressure has stabilized (maximum 100 mg/day). Recently, newer blocking agents have become available that are more selective and avoid some of the associated side effects. Patients are usually adequately blocked when they complain of postural hypotension and nasal stuffiness.
b-Blockers protect against arrhythmias, control tachyphylaxis from a-blockers and permit a decrease in the amount of a-blocker necessary to control blood pressure. These agents should be used only after a-blockade has been established because, alone, they may precipitate a rise in total peripheral vascular resistance through unopposed a-adrenergic activity, and used only when cardiac arrhythmias are expected.
a-Methylparatyrosine has been utilized in addition to phenoxybenzamine and/or propranolol. This agent decreases the rate of catecholamine synthesis and is particularly useful in patients who are resistant to a-blockers or have multiple paragangliomas.
Preoperative preparation also requires intravenous fluid replacement to ensure adequate hydration because many patients will have a depleted intravascular volume. Unless active fluid expansion is planned, the pharmacologic blockade should be of at least 2 weeks’ duration in order to allow the patient’s own homeostatic mechanisms to compensate for the recently expanded intravascular space. Crystalloids and in some cases blood transfusions may be required to accommodate the expanded intravascular volume produced by blockade, and an extra fluid load of 1 to 2 liters should be administered the night before surgery.
Anesthesia
The primary focus of anesthetic management of a pheochromocytoma patient is hemodynamic control. Close monitoring of the blood pressure, EKG, urinary output, and central venous pressure is essential in all phases of the procedure. An arterial line and Swan–Ganz catheter are frequently utilized. Sodium pentobarbital is usually used for induction, and virtually all inhalational agents have been administered for maintenance of anesthesia; these are usually combined with the neuromuscular blocking agents succinylcholine, d-tubocurarine, or pancuronium. The two inhalational agents of choice appear to be enflurane and isoflurane, with the latter decreasing myocardial contractility but being more resistant to metabolism and consequently less toxic. Either agent can also be combined with phentolamine or nitroprusside to control hypertension. Intraoperative arrhythmias can be controlled with either lidocaine or propranolol, although they frequently resolve following blood pressure normalization. Following interruption of the venous drainage of a pheochromocytoma, profound hypotension may ensue, and the surgeon should inform the anesthesiologist before performing this maneuver. Volume replacement is the treatment of choice, which may be augmented by the addition of vasopressors (Levophed) if necessary until the situation stabilizes.
Surgical Approach
There are numerous approaches to the adrenal gland, and the appropriate choice of access is governed by the size, multiplicity, and site of the lesion and the underlying pathology. In situations where a paraganglioma is a possibility, a midline abdominal incision allows a full assessment of the abdomen, retroperitoneum, and pelvis. The one essential is a detailed knowledge of the surgical anatomy of the adrenal glands (Fig. 4-4 and Fig. 4-5). Other factors such as the body habitus of the patient and the preference and experience of the surgeon must also be considered. Therefore, in view of all these variables, it is apparent that each case should be approached individually, with account taken of the various preferred guidelines for individual diseases.
The left adrenal gland is supplied by multiple small arteries superiorly originating from the inferior phrenic artery. Medially, multiple arteries arise directly from the aorta. Inferiorly, a constant artery arises either directly from the aorta just above the left renal artery or from the proximal renal artery itself. The venous drainage of the left gland is mainly through the inferior adrenal vein, which drains into the superior aspect of the left renal vein, usually just lateral to the aorta. There are virtually no blood vessels entering or draining the lateral aspect of the left adrenal under normal circumstances. Gerota’s fascia can be dissected anteriorly off the posterior aspect of the pancreas and the splenic vein and artery. If an anterior approach is used, the splenorenal ligaments must be divided, and the colon reflected medially, before Gerota’s fascia can be dissected, following which the spleen and pancreas can be elevated superiorly to expose the underlying anterior surface of the adrenal gland. A virtually avascular plane also exists posteriorly between Gerota’s fascia and the paraspinous muscles such that the gland can be mobilized from the surrounding structures before its blood supply.
The right adrenal gland is supplied superiorly by branches of the inferior phrenic artery that are often obscured by the overlying liver and inferior vena cava. Medially, small direct branches from the aorta course beneath the vena cava, and inferiorly a fairly constant branch of the proximal renal artery enters the gland. The venous drainage is again mainly through one vessel, which is short and enters directly into the vena cava just below the hepatic veins. Securing this vein is perhaps the most challenging aspect of adrenal surgery, as it is nearly always higher and shorter than expected, and adjacent vascular and fascial structures may have to be divided beforehand. In cases involving a large right-sided tumor, following reflection of the colon and duodenum it is not unusual to have to divide the caudate lobe veins entering directly into the vena cava in order to gain adequate exposure anteriorly. Once again, there are relatively avascular planes anteriorly, posteriorly, and laterally. Care should be exercised when freeing the inferior aspect of the gland, which can have vascular attachment to the upper pole of the kidney.
Small well-localized adrenal lesions may be approached by either a posterior, modified posterior, or flank approach. Larger lesions including pheochromocytomas, both single and multiple, may be approached by either an abdominal or thoracoabdominal incision. These latter two options are dealt with below, and the other approaches are described elsewhere in this section.
Thoracoabdominal and Transabdominal Approaches
The thoracoabdominal eighth, ninth, or tenth intercostal approach is the incision preferentially utilized for large right-sided pheochromocytomas.10 This approach offers the advantage of excellent adrenal exposure and an opportunity to palpate the thoracic sympathetic chain in the case of a rare associated paraganglioma metastasis. The peritoneal cavity may be widely opened for laparotomy, and in cases in which the contralateral gland must be explored, the incision is extended, though closure may be tedious. There is usually less requirement for this incision, with its extrapulmonary morbidity, when dealing with left-sided lesions. There is generally less vascularity to deal with, especially on the superior, lateral, and posterior aspects of the tumor, and the pancreas and spleen can be mobilized away from the lesion with ease.
The patient is placed in a semioblique position on a bean bag that is rolled to elevate the relevant flank and hemithorax. For this description the lesion is assumed to be right-sided, but the approach is similar for left-sided lesions. The right arm is then draped across the chest over a Mayo stand with careful padding and positioning to avoid a stretch or pressure injury. The left axilla is protected with a pad. The pelvis should lie almost parallel, with the contralateral knee flexed 90 degrees and lying under the straight ipsilateral leg, with padding between the two gFigure 4-6). The table is then hyperextended, and the patient is fixed in position with adhesive tape. The incision is made in the eighth, ninth, or tenth intercostal space at the angle of the rib and extended across the costal margin to curve inferiorly to the midpoint of the opposite rectus muscle. Once the latisimus dorsi, posterior inferior serratus, and the external oblique have been divided, the internal oblique is divided on the upper border of the rib itself, which need not be resected; the costvertebral ligament is divided, allowing the rib to swing down after division of the intercostal muscles. The pleura is then carefully entered, and the lung protected by a padded retractor. The diaphragm with overlying pleura will then be visualized and should be divided at the periphery about 2 cm from the chest wall in a circumferential pattern from anterior to posterior to allow for later reconstruction and to avoid damage to the phrenic nerve.
Heavy scissors are used to divide the costochondral junction, the peritoneum is opened, and the underlying liver can then be retracted upward. Because this incision is usually employed in large pheochromocytomas, the right triangular and coronary ligaments are divided, thus mobilizing the right lobe of the liver, which can be further retracted upward, providing excellent exposure of the suprarenal vena cava and the adjoining right adrenal vein. A fixed retractor (either Omnitract or Bookwalter) is preferred for this procedure. With the liver well protected and retracted into the chest, the posterior peritoneum lateral to the right colon is incised, and the incision is carried up along the vena cava to the level of the retracted liver edge (at the level of the hepatic veins) (Fig. 4-7). The right colon and duodenum are mobilized medially, and the kidney is gently retracted downward to bring the adrenal into view. The attachment of the kidney to the adrenal should be preserved until the gland has been completely mobilized, as this facilitates exposure and prevents direct manipulation of the tumor. At this point care must be exercised to avoid trauma to the small veins draining directly into the vena cava from the caudate lobe. If necessary, these veins may be divided between Adson clamps and sutured below the clamps with 5-0 Proline. At this point, full retraction is instituted to expose the entire operative field.
In pheochromocytomas, it is essential that the blood supply be isolated as soon as possible, with the adrenal vein ligated with either silver clips or 2-0 silk sutures. In cases where the vein lies far superior, extensive dissection and division of the arterial supply medially and inferiorly may be necessary to allow safe and satisfactory exposure of the vein. When there are large tumors extending medially below the vena cava, mobilization of the vena cava with division of the relevant lumbar veins, if necessary, facilitates exposure and ligation of the medial vessels between vascular clips. The vena cava can be retracted by passing vascular tapes below it to provide the necessary medial traction. If the tumor is confined to the adrenal gland, the remaining lateral and inferior attachments of the gland are mobilized and divided to complete the adrenalectomy.
An alternative approach to large pheochromocytomas is the anterior transperitoneal approach. This approach also allows early vascular control and provides the opportunity for a thorough laparotomy. The optimal approach involves a bilateral subcostal or chevron incision. A midline incision is used only when an extra-adrenal pheochromocytoma is suspected in either the pelvis or retroperitoneum. This approach is particularly suitable for left-sided large pheochromocytomas.
A number of approaches are available to expose the left adrenal gland. Exploration through the lesser sac or the avascular plane in the transverse mesocolon is ideal for small tumors. However, for large tumors, following laparotomy, the posterior peritoneum lateral to the left colon is incised, and the incision is extended to include the lienorenal ligament. Splenic injury is a risk during this maneuver. Once again, a fixed ring retractor is optimal in this procedure. The initial dissection involves exposure of the left adrenal vein, which is easier to approach on this side and is ligated at its entry into the renal vein with 2-0 silk ligatures. The anterior and posterior adrenal planes are then developed, and the spleen and pancreas are gently retracted superiorly. The left colon and duodenum are reflected medially. Leaving the distal ligature long permits the ligated adrenal vein to be utilized to provide retraction to facilitate ligation of the inferior adrenal artery (Fig. 4-8). The gland is then mobilized with gentle blunt dissection on its lateral and posterior margins. Downward traction on the kidney facilitates exposure of the superior vascular ligaments, which may be tied with 3-0 silk or ligated with vascular clips. Lateral traction is then employed to expose the medial arteries and lymphatic vessels, which are ligated. Finally, the remaining inferior attachments are divided, and the adrenal gland is removed (Fig. 4-9, Fig. 4-10 and Fig.4-11).
The adrenal fossa is carefully inspected for bleeding and, after electrocautery, packed while the surrounding viscera are carefully examined. Persistent oozing may be controlled with Surgicel or Gelfoam. The incisions are closed in a standard fashion, with no drainage utilized. Nasogastric suction may be employed for 48 hours to minimize postoperative distention.
Postoperative Care and Specific Complications
In the recovery room, vital signs and mental status are closely monitored. Patients with a flank, posterior, or thoracoabdominal incision should have a chest radiograph to rule out a pneumothorax or document proper positioning of a chest tube. Pain control is a major contributing factor to reduce atelectasis and promote early ambulation. Intensive care monitoring for the initial 24-hour period is prudent following removal of a pheochromocytoma.
OUTCOMES
Complications

Specific complications seen during both the intra- and postoperative period include profound hemodynamic instability, which requires precise monitoring and adequate preoperative preparation. Postoperatively, large boluses of intravenous fluids with pressor support may be necessary to maintain stability. Vasospasm sufficient to reduce enteral blood flow may be encountered and should be considered along with possible neurologic complications in inadequately blocked or unrecognized cases.
When dealing with large lesions, the surgeon needs to bear in mind that the renal vascular anatomy may be distorted and out of position, putting it at risk of inadvertent injury. Significant hemorrhage secondary to vena caval or renal vein lacerations may occur and require repair with 4-0 or 5-0 Proline once adequate control has been established. Left-sided lesions may be associated with pancreatic or splenic injuries resulting in postoperative bleeding and hypotension (which may be attributed to metabolic causes) or a fistula. In cases where such an injury has occurred, placement of a drain may be prudent.
Results
The Lahey Clinic reported a 0% mortality in 62 patients treated for pheochromocytoma and a 25% postoperative morbidity rate in the 41 patients whose records were available.11 However, overall, convalescence of patients undergoing adrenal surgery is reasonably benign.

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