Alexis D. Smith
Douglas J. Turner
Presentation
A 52-year-old male with a history of poorly controlled hypertension is referred for evaluation of a 4.5-cm left adrenal mass. The mass was incidentally discovered during routine trauma computed tomography (CT) scans following a minor motor vehicle accident. History is significant for episodic headaches with blurry vision and occasional epistaxis, but he denies any chest pain, palpitations, shortness of breath, or diaphoresis. He denies any history of recent weight gain or loss. He has no personal history of cancer. He states his father died of sudden cardiac arrest in his 50s; his mother is alive and otherwise healthy. His antihypertensive regimen is currently nicardipine, lisinopril, metoprolol, and hydrochlorothiazide (HCTZ). On examination, blood pressure was 192/106 mm Hg; heart rate, 102 beats per minute; body mass index, 29. The remainder of his physical examination was normal.
Differential Diagnosis
Incidental discovery of adrenal masses is increasingly common. This is largely due to the widespread use of thoracic and abdominal cross-sectional imaging. Adrenal incidentalomas are present in up to 4% to 5% of all CT scans. In adults, an adrenal mass can represent an extensive differential diagnosis (Table 1). In order to determine the appropriate treatment of the mass, both biochemical testing and high-resolution imaging should be employed to differentiate between biochemically functional versus nonfunctional tumors and malignant versus benign tumors.
TABLE 1. Differential Diagnoses for Adrenal Incidentalomas
Workup
The patient subsequently undergoes initial evaluation of his adrenal incidentaloma with biochemical testing. Morning and 24-hour urinary cortisol levels are within normal limits. Additionally, plasma aldosterone: renin ratio is <20. Serum electrolytes are within normal limits. Subsequent 24-hour urinary-fractionated metanephrines and plasma-free metanephrines return elevated at 1,800 nmol/24 h and 2.6 nmol/L, respectively. This biochemical profile confirms the diagnosis of pheochromocytoma. The patient then undergoes an adrenal-protocol CT scan for localization of the tumor that demonstrates a 4.5-cm left heterogeneous adrenal mass with a 60% contrast washout after 15 minutes (Figures 1 and 2).
FIGURE 1 • Computed tomography (CT) scan of left pheochromocytoma.
FIGURE 2 • Magnetic resonance imaging (MRI) of left pheochromocytoma.
Discussion
Pheochromocytomas are catecholamine-producing neuroendocrine tumors derived from chromaffin cells of the adrenal medulla. Pheochromocytomas are rare, with a reported incidence of 2 to 8 per million individuals, occurring in 0.1% to 0.5% of hypertensive patients and in approximately 5% of patients with documented adrenal incidentalomas. However, the potentially lethal cardiovascular complications related to high levels of circulating catecholamines mandate biochemical testing in those found to have an adrenal incidentaloma as well as in patients with severe, episodic, or refractory hypertension. Historically, pheochromocytoma has been coined the “10% tumor” meaning that approximately 10% of cases are malignant, 10% extra-adrenal, 10% bilateral, and 10% associated with hereditary tumor syndromes. However, recent literature has demonstrated that those approximations largely underestimate the incidence of hereditary pheochromocytoma and paragangliomas (PG). Some studies have shown that up to 24% of cases are associated with familial tumor syndromes, including multiple endocrine neoplasia (MEN) types 2A and 2B, von Hippel–Lindau disease (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis, Sturge-Weber syndrome, and the familial pheochromocytoma–paraganglioma (PGL) syndrome.
Sporadic pheochromocytoma is most commonly diagnosed between the ages of 40 and 50, whereas hereditary types are usually diagnosed earlier, most often before 40 years of age. The classic triad of symptoms consists of paroxysmal hypertension, palpitations, and sweating. However, the true clinical presentation varies greatly, and it is often termed a great mimicker of many other clinical conditions. Hypertension, tachycardia, pallor, headache, and anxiety usually dominate the clinical presentation. Paroxysmal signs and symptoms are a hallmark of the clinical presentation and are due to the episodic nature of catecholamine release from the tumor. Extra-adrenal pheochromocytomas are termed PG and can be located anywhere along the sympathetic nervous system, but are most commonly found at the organ of Zuckerkandl.
Diagnosis and Treatment
All patients with suspected pheochromocytoma should undergo biochemical testing followed by high-resolution imaging for tumor localization and determination of the extent of disease. The preferred method of choice for biochemical assays remains a controversial topic. No current consensus exists on the best screening test and no prospective studies comparing test regimens have been published. However, current literature favors the measurement of plasma-free metanephrines and/or urinary-fractionated metanephrines as the most sensitive tests available for screening and diagnosis. However, these tests lack high specificity, and the common occurrence of false-positive results can be attributed to external stressors as well as drug and dietary interferences related to catecholamine measurements. Some common interfering substances include coffee, nicotine, labetalol, tricyclic antidepressants, and monoamine oxidase inhibitors. A clonidine suppression test may be utilized to confirm diagnosis in those patients with equivocal results. Fine needle aspiration has no role in the diagnosis of PCC and should be avoided due to the risk of precipitation of a hypertensive crisis.
Once a biochemical diagnosis has been confirmed, tumor localization should be initiated in order to guide treatment planning. A CT scan of the abdomen, including pelvis (to below the level of the aortic bifurcation), is currently an appropriate initial imaging study with a >95% sensitivity for detecting adrenal pheochromocytoma.4 Magnetic resonance imaging (MRI) is considered equally efficacious and is the procedure of choice in pregnancy and childhood. A major advantage of MRI is the lack of exposure to both radiation and iodinated contrast, which has the potential to elicit a hypertensive crisis in patients. Since no certain histologic criteria that distinguish benign from malignant tumors exist, a critical step in the radiologic evaluation is determination of malignancy, extra-adrenal extension, or bilateral disease. Malignancy is reported in 9% of sporadic pheochromocytoma and as high as 33% with extra-adrenal tumors. Tumors that secrete only dopamine have also been noted to be at increased risk of malignancy. Therefore, functional imaging in the form of metaiodobenzylguanidine (MIBG) scanning is warranted if there exists a high probability of malignancy noted by the presence of local invasion, metastases, adrenal lesions >5 cm, and contrast washout of <40% in 15 minutes on cross-sectional imaging.
Special Preoperative Considerations
Surgical resection is the only effective treatment for pheochromocytoma. Due to the high concentration of circulating catecholamines, cardiovascular lability is a frequent complicating factor during resection of these tumors. The likelihood of surgical success directly correlates to the degree of preoperative medical management. The goals of this regimen include correction of hypertension, restoration of intravascular volume, and control of dysrhythmias. The foundation of this regimen is alpha blockade, most typically phenoxybenzamine, a long-acting nonselective alpha antagonist initially dosed at 10 mg/d or twice daily with incremental increases to attain appropriate blood pressure control. A subsequent beta-blocker is added after adequate alpha blockade for heart rate control secondary to reflex tachycardia associated with alpha-blockade or for tachyarrhythmias. Monotherapy or initiation of therapy with a beta-blocker should be avoided due to the risk of a hypertensive crisis in the absence of β2-adrenergic vasodilation. Calcium channel blockers may be utilized as a third agent for persistent hypertension. Some institutions prefer the use of shorter-acting selective alpha1-blockers, such as prazosin, doxazosin, or terazosin, secondary to their avoidance of reflex tachycardia. However, no prospective head-to-head comparison trial has been done and phenoxybenzamine remains the mainstay for alpha blockade.
In addition to adequate preoperative blood pressure control, patients should be instructed about the importance of increased fluid and salt intake prior to surgery in order to assist with repletion of intravascular volume, which is low due to the vasoconstriction from high levels of circulating catecholamines.
Surgical Approach
Laparoscopic Adrenalectomy
The principles of successful surgical resection of a pheochromocytoma are minimizing tumor manipulation, avoidance of tumor spillage, complete extirpation of the tumor, early ligation of the adrenal vein, and close coordination with the anesthesiology team for tight control of intraoperative hemodynamics (Table 2). Traditionally, an open approach was utilized due to the theory of an increased risk of catecholamine surge with insufflation and tumor manipulation during laparoscopic adrenalectomy. However, over the past decade, laparoscopy has evolved as the standard of care for surgical resection of pheochromocytoma.
TABLE 2. Key Technical Steps and Potential Pitfalls for Laparoscopic Adrenalectomy
Although multiple approaches to an adrenalectomy have been described, our institution prefers the laparoscopic lateral transabdominal approach. Following induction of general anesthesia and placement of appropriate hemodynamic monitoring devices, the patient is placed in the lateral decubitus position and the operating table is flexed at the waist to optimize the space between the lower ribs and the iliac crest. A Veress needle is used to establish pneumoperitoneum. Three ports (four for right sided lesions) are placed between the midclavicular line anteriorly and the midaxillary line laterally, two finger widths below the costal margin. The abdomen is inspected for hepatic or peritoneal metastases. For a right adrenalectomy, the right triangular ligament is divided and the liver is mobilized from the diaphragm, retracting it cephalad with a fan or snake retractor; it is important to be able to visualize the IVC. It is rarely necessary to mobilize the hepatic flexure or duodenum. The adrenal gland is identified on the superomedial aspect of the kidney, and the right adrenal vein is identified at its junction with the IVC. Early identification and ligation of the adrenal vein is paramount. It is double clipped on the IVC aspect and divided sharply with endoscopic scissors. Division of the adrenal vein may also be accomplished with a vascular stapler. The vein is often on the posterior aspect of the vena cava, and occasionally there are accessory adrenal veins that require clipping. Hemostasis is difficult to achieve when the vein is injured, and retraction of the vein into the surrounding tissue may result in large-volume blood loss mandating conversion to an open procedure. The remaining arterial branches and soft tissue attachments are then divided hemostatically. The specimen is placed in an endoretrieval bag and brought through one of the port sites.
For a left laparoscopic adrenalectomy, patient positioning and port insertion are approached in a similar manner, although three ports often suffice on the left side. The retroperitoneum is opened by dividing the splenocolic ligament. The splenic flexure is mobilized. The lateral attachments of the spleen and the tail of the pancreas are divided for their medial mobilization. The adrenal gland is identified superior to the kidney under the mobilized pancreas and spleen. The left adrenal vein is identified when it emerges from the inferomedial aspect of the gland near to where it empties into the left renal vein. It is double clipped on the renal vein aspect and sharply divided. Any accessory adrenal veins should be handled in a similar manner.
Special Intraoperative Considerations
Hemodynamic fluctuations are a common intraoperative occurrence during resection of a PCC. Open communication with the anesthesia team is a critical component of surgical success. During induction of anesthesia, insufflation with carbon dioxide and tumor manipulation prior to ligation of the adrenal vein, the patient often experiences severe hypertension and tachyarrhythmias requiring intravenous medications such as nitroprusside, nicardipine, or esmolol. The anesthesiologists should be notified prior to ligation of the adrenal gland in order to anticipate and prepare for a precipitous drop in blood pressure following abrupt cessation of the catecholamine source with large-volume fluid resuscitation and vasoactive pressor support.
Postoperative Care
Postoperatively, patients require monitoring for hypotension and hypoglycemia. The average stay for patients following an uncomplicated laparoscopic adrenalectomy is approximately 2 days. Follow-up between 3 and 6 months is necessary to obtain a baseline plasma metanephrine level or 24-hour urine metanephrine level. Levels should be monitored every 3 months during the first year and then annually for at least 5 years. No consensus exists for extent of postoperative follow-up; however, the fact that recurrences and metastases may occur up to 20 years after curative resection argues for indefinite follow-up in sporadic PCC. Patients diagnosed with hereditary PCC should undergo yearly follow-up for their lifetime.
TAKE HOME POINTS
· Pheochromocytoma continues to be a rare catecholamine-producing neuroendocrine tumor responsible for a surgically correctable cause of hypertension.
· The incidence of hereditary pheochromocytoma is underestimated with recent studies demonstrating up to a 24% association with familial tumor syndromes including MEN2a, MEN2b, NF1, and VHL syndromes.
· Plasma metanephrine levels (sensitivity of 99%) can biochemically confirm the diagnosis and CT scans are utilized for tumor localization.
· Laparoscopic adrenalectomy has evolved as the standard of care for surgical resection of a pheochromocytoma.
· Surgical resection is the treatment of choice for malignant pheochromocytoma with curative intent for local disease and palliation in more advanced disease.
Case Conclusion
The patient underwent a successful laparoscopic left adrenalectomy without any postoperative pressor requirement or intensive care unit admission. He was subsequently discharged to home on postoperative day 2. Surveillance plasma metanephrine taken 3 months following the operation was within normal limits. The patient opted for genetic testing secondary to his father’s history of sudden cardiac death, but this test returned negative for any germline mutations.
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