Approach Considerations
Treatment of pheochromocytoma is with surgical removal. Schedule surgical removal only after successful pharmacotherapy to block the effects of catecholamine excess. Blockade of the alpha-adrenergic receptors in the preoperative phase is widely recommended, with additional beta-receptor blockade to treat cardiac dysrhythmias. Perform procedures in a hospital with the capability for intensive intraoperative and postoperative monitoring and therapy.
During a hypertensive crisis, immediately institute alpha-blockade with phentolamine. Nitroprusside also should be used for uncontrolled hypertension.
For further blood pressure control, initiate beta-blockade (esmolol-labetalol). Beta-blockade that is initiated without prior alpha-blockade can further exacerbate hypertension. As vasoconstriction is relieved, use vigorous fluid resuscitation to maintain a normal blood pressure.
Ventricular tachyarrhythmias can be treated with lidocaine and amiodarone.
The outcome in malignant pheochromocytoma appears to be related to the tumor quantity and the aggressiveness of the therapy. Chemotherapy and radiotherapy have been used, but their value is questionable. The long-term survival rate in patients with untreated malignant or unresectable tumors is unclear. Because of the rarity of the condition, no randomized clinical trials concerning the treatment of malignant pheochromocytoma have been performed.
The course of pheochromocytoma may be adversely affected by drugs or diagnostic studies that affect catecholamine metabolism. Severe and fatal crises have been induced by opiates, histamine, corticotropin, saralasin, glucagon, metoclopramide, and pancuronium.
Cold medicines and decongestants that contain sympathomimetic amines can worsen symptoms. Drugs that block the neuronal uptake of catecholamines, such as guanethidine and tricyclic antidepressants, may enhance the physiological effects of circulating catecholamines.
Inpatient care is necessary if the patient with pheochromocytoma has episodes of sustained hypertension or life-threatening paroxysms. Close monitoring is required, making an intensive care unit the most suitable place for admission. In this setting, the patient is prepared for surgical removal of the tumor.
Obtain consultations as needed for comorbid conditions and their definitive treatment (eg, pediatric surgeon, oncologist, cardiologist, ophthalmologist, endocrinologist).
Surgical Removal
Surgery to remove pheochromocytomas is a high-risk procedure because of several reasons. Substantial comorbidity must be expected, including catecholamine-induced myocardiopathy. Intraoperative manipulation of the tumor may induce excessive catecholamine excretion, resulting in a life-threatening hypertensive crisis. Hypotensive crisis may occur because of a postoperative drop of catecholamines.
Preoperative blockade of alpha-1 receptors has been used to reduce the risk of hypertensive episodes. Drugs such as urapidil have been shown to produce a significant reduction in hypertensive peaks. [38]
Transabdominal surgery has been the traditional approach; it allows early ligation of the adrenal vein to minimize systemic catecholamine release during manipulation. This approach also facilitates exploration of the sympathetic chain for multifocality.
Other options include a subcostal or posterior extraperitoneal approach that offers rapid recovery and avoids the risk of transperitoneal surgery (adhesions, bowel obstruction). Alternatively, a laparoscopic adrenalectomy, which has been shown to be a useful technique in patients with tumors smaller than 7 cm and a body mass index of less than 45 kg/m, [39] can be considered; tumors as large as 11 cm have been successfully removed. The contraindications to laparoscopy include evidence of soft-tissue or vascular extra-adrenal extension.
Guidelines for the surgical removal of adrenal masses in pediatric patients has been published in the Journal of Laparoendoscopic & Advanced Surgical Techniques. [40]
A large, multicenter review of children who had undergone laparoscopic adrenalectomy at 12 institutions over a 10-year period identified 140 patients (50% males). Of those patients, 54.3% had left lesions, 42.1% had right lesions, and 3.6% had bilateral lesions. Mean operative time was 130.2 ±63.5 minutes. The most common pathology was neuroblastoma (27.9%), followed by pheochromocytomas (21.4%), ganglioneuromas (15.7%), and adenomas (14.3%). Only 9.9% of the cases required an open surgery. A blood transfusion was required in only 2 cases. At 18 months (median follow-up), only one local recurrence was reported, which was in a patient with a pheochromocytoma. [41]
Bilateral tumors develop in children with multiple endocrine neoplasia type 2 and pheochromocytoma. Bilateral adrenalectomy has been recommended at presentation in these patients.
Careful and intensive monitoring of the patient's status throughout the perioperative period is imperative. Hypotension that develops after tumor removal reflects reversal of the volume-contracted state and should respond to judicious replacement of fluids. Some patients may develop pulmonary edema, possibly as a result of impaired myocardial function and the inability to tolerate intravenous fluids.
When the tumor is removed, the blood pressure usually falls to approximately 90/60 mm Hg. Lack of a fall in pressure at the time of tumor removal indicates the presence of additional tumor tissue.
When bilateral adrenal tumors are found and both adrenals are removed, adrenocortical lifelong steroid replacement is required. Significant morbidity is associated with bilateral adrenalectomy. Because of these risks, some clinicians have recommended adrenal-sparing surgery in patients who have bilateral tumors or who are at particular risk for a metachronous contralateral tumor.
Treatment of Unresectable Disease
Chemotherapy and radiotherapy have been of questionable value in patients with unresectable disease. Unresectable disease may be rendered resectable by intensive chemotherapy. Chemotherapy currently has a response rate of approximately 50%.
Unless chemotherapy allows surgical removal of the entire tumor, it is not usually curative. However, chemotherapy offers good palliation (for years) in a significant number of patients. On the other hand, if the treatment is fairly aggressive, palliation therapy (pain, catecholamine excess) may be long term (years).
A long-term study of 18 patients with a diagnosis of malignant pheochromocytoma or paraganglioma who were treated with combination chemotherapy reported a complete response rate of 11% and a partial response rate of 44%. The regimen used was cyclophosphamide at 750 mg/m2, vincristine at 1.4 mg/m2, and dacarbazine at 600 mg/m2 on day 1 and dacarbazine at 600 mg/m2 on day 2, every 21-28 days. [42] The treatment was well tolerated, with only grade I and II toxicities.
In this 22-year follow-up, no difference in overall survival was observed between patients whose tumors objectively shrank and those with stable or progressive disease. All patients with tumors scored as responding reported improvement in their symptoms related to excessive catecholamine release and had objective improvements in blood pressure. Median survival was 3.8 years for patients whose tumors responded to therapy and 1.8 years for patients whose tumors did not respond.
Over the past decade, substantial progress has been made in clinical, biochemical, and radiographic diagnosis of pheochromocytomas. Approximately 50% of patients with malignant pheochromocytomas and sympathetic paragangliomas have been found to carry hereditary germline mutations in the succinate dehydrogenase subunit B gene (SDHB), and antiangiogenic agents such as sunitinib have been found to potentially play a role in the treatment of malignant disease, especially in patients with SDHB mutations.
In some patients, treatment with sunitinib (Sutent; previously known as SU11248) has been associated with partial radiographic response, disease stabilization, decreased fluorodeoxyglucose uptake on positron emission tomography, and improved blood pressure control. [43, 44, 45, 46] Sunitinib inhibits cellular signaling by targeting multiple receptor tyrosine kinases, such as platelet-derived growth factor receptors, and vascular endothelial growth factor receptors, which play a role in both tumor angiogenesis and tumor cell proliferation.
The best established strategy is iodine 131I-metaiodobenzylguanidine (MIBG) therapy, which is well tolerated. MIBG is specifically taken up by chromaffin cells. MIBG can induce remission for a limited period in a significant proportion of patients.
Iobenguane I 131 was approved by the FDA in July 2018 for iobenguane scan–positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma in patients aged 12 years or older who require systemic anticancer therapy. Efficacy was shown in a single-arm, open-label, phase 2 clinical trial (n=68) conducted under a special protocol assessment with the FDA. The study met the primary endpoint, with 17 (25%) of the 68 evaluable patients experiencing a 50% or greater reduction of all antihypertensive medication for at least 6 months. Overall tumor response was achieved in 15 (22%). [47]
Octreotide as a single agent seems to be largely ineffective. The value of radiation therapy in patients with malignant pheochromocytoma is debatable.
Long-Term Monitoring
All patients should undergo catecholamines measurements approximately 1 week postoperation to confirm a cure. Long-term follow-up is required because of the possibility of metachronous recurrence. levels of catecholamines should be measured yearly until the likelihood of recurrence is very low (>5 y).
Patients with germline mutation and no evidence of active illness should have continued follow-up for pheochromocytoma.
In some patients, long-term medical management is necessary because of disseminated malignancy or some other intercurrent illness that makes surgery inappropriate. Most tumors grow slowly, and the manifestations of catecholamine excess can be controlled by adrenergic blocking agents in conjunction with metyrosine, which reduces catecholamine biosynthesis by the tumor.
Pheochromocytoma usually recurs in the retroperitoneum or appears as metastatic deposits in bone, lung, or liver. Recurrence can be found years after the initial surgery. Radiation therapy is usually not effective but may be of value for control of metastatic disease in bone. Limited success has been reported with combination therapy consisting of cyclophosphamide, vincristine, and dacarbazine. As an alternative, high doses of 131I-MIBG can be used repeatedly.
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Axial, T2-weighted MRI scan showing large left suprarenal mass of high signal intensity on a T2-weighted image. The mass is a pheochromocytoma.
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Abdominal CT scan demonstrating left suprarenal mass of soft tissue attenuation representing a paraganglioma.
