Approach

The goal of treatment is to eliminate the dangerous effects of excessive catecholamine production by the tumor. Surgical resection is the mainstay of treatment.

Hypertensive crisis

A hypertensive crisis (systolic BP >250 mmHg) may occur on presentation of a pheochromocytoma or during surgical resection of the tumor if the patient has not received adequate preoperative medical therapy.

Treatment includes immediate alpha blockade with an alpha-1 blocker (e.g., terazosin, doxazosin, or prazosin) or with the nonselective alpha-blocker, phenoxybenzamine. Intravenous agents (nitroprusside, phentolamine, or nicardipine) are short-acting and titratable, and can be used first line.[64]​ Nitroprusside, phentolamine, or nicardipine can be added, as required, to an oral alpha-1 blocker prescribed in the initial management of hypertensive crisis.[43]

Clinical presentation will inform prescribing decisions. Consult a specialist when deciding on the most appropriate regimen.

Pretreatment alpha blockade

The first step in medical management is to block the effects of catecholamine excess by controlling hypertension and expanding intravascular volume.[1] This is achieved by first establishing adequate alpha blockade.[2][43]

Alpha-1 blockers (e.g., terazosin, doxazosin, or prazosin), or the nonselective alpha-blocker phenoxybenzamine, are recommended for initial pretreatment blockade.[2][43] These drugs lower BP by decreasing peripheral vascular resistance.[65]

Alpha-1 blockers have a shorter duration of action than phenoxybenzamine, making them particularly useful in the perioperative period. The dose of alpha-1 blocker can be rapidly titrated, avoiding postoperative hypotension. These drugs do not enhance the release of norepinephrine (noradrenaline) and therefore do not cause a reflex tachycardia.

Hydration and a high-salt diet (>5 g/day) are given for 7-14 days (or until the patient is stable) to offset the effects of catecholamine-induced volume contraction associated with alpha blockade.[43]

Consider adding a calcium-channel blocker or metyrosine

Dihydropyridine calcium-channel blockers can supplement alpha blockade if additional blood pressure control is required.[43] Monotherapy with calcium-channel blockers is not recommended, but may be an option if the patient is unable to tolerate alpha blockade.[2][43] Nifedipine and amlodipine are the most commonly recommended dihydropyridine calcium-channel blockers in the setting of perioperative pheochromocytoma BP control.[2]

Metyrosine can be used in conjunction with alpha blockade to stabilize blood pressure. Metyrosine, an inhibitor of tyrosine hydroxylase, inhibits catecholamine synthesis. In patients with pheochromocytomas, metyrosine can reduce the biosynthesis of catecholamines by 35% to 80%.[66]​ This is particularly useful in patients with very high circulating levels of catecholamines, which can be cytotoxic to myocardial cells.

Metyrosine also has a role in patients where tumor manipulation or destruction will be marked, such as patients with metastatic disease receiving chemotherapy.[67]​ It should be started 2 weeks prior to surgery. It can also be used when surgery is contraindicated.

Beta blockade after alpha blockade

Following adequate alpha blockade, which may take 3-4 days of therapy, beta blockade can be established to prevent and treat cardiac arrhythmia, as well as to manage hypertension.[2]

If beta blockade alone is used this can precipitate a hypertensive crisis due to unopposed alpha-adrenergic stimulation.[3] Combined alpha- and beta-adrenergic blockade is often used to control BP and prevent hypertensive crisis.

Benign pheochromocytoma

Surgical excision of the entire adrenal gland remains the mainstay of treatment for benign pheochromocytomas and is curative in more than 85% of cases.[68][69]​ The treatment of choice for pheochromocytoma ≤6 cm is laparoscopic adrenalectomy.[2]

Bilateral disease can be successfully treated with adrenal-sparing surgery.[70] Partial rather than total adrenalectomy should also be considered as first-line treatment for small adrenal tumors.[2][71]​ Removal is a high-risk surgical procedure requiring a skilled surgeon and anesthetic team. Complete excision is vital to prevent spread of the tumor and prevent other harmful effects of hypercatecholaminemia. Surgical complication rates are low; mortality rates of about 2% to 3% and morbidity rates of approximately 20% have been reported.[72]

Open adrenalectomy may be required to prevent rupture if the tumor is large (>6 cm), or to reduce local recurrence for invasive pheochromocytomas, or if malignancy is suspected.[2][73][74]

Paragangliomas are extra-adrenal tumors. They require specialized surgical approaches depending on the various locations of origin.[70]

Surgical risk

The patients at highest risk for complications include those with severe preoperative hypertension or high catecholamine secreting tumors, and those undergoing repeat surgical interventions.[73]

Much of the risk associated with surgery is attributable to the risk of evoking a massive uncontrolled release of catecholamines due to manipulation of the tumor during resection. Complications are less likely with medical optimization and the current practice of strict perioperative BP control and plasma volume expansion.

Postoperatively, the sudden decrease in catecholamine levels can lead to hypotension and hypoglycemia. Hypoglycemia may occur secondary to loss of the catecholamine-suppressed insulin secretion postoperatively. Treatment involves intravenous glucose replacement.[75]

After the pheochromocytoma is removed, catecholamine secretion usually returns to normal within 1 week.[Figure caption and citation for the preceding image starts]: Left laparoscopic adrenalectomy: (A) macroscopic examination, 6 cm tumor; (B) microscopic examination: neoplasm of the adrenal medulla with eosinophilic cytoplasm of large cells with positive fine granular chromogranin A; (C) round and oval nucleus and sustentacular cells S100+; (D) pheochromocytomaAlface MM et al. BMJ Case Rep. 2015 Aug 4;2015:bcr2015211184; used with permission [Citation ends].com.bmj.content.model.Caption@5ffd33f0

Metastatic pheochromocytoma

Malignant or metastatic pheochromocytomas represent 10% of all catecholamine-secreting tumors. The diagnosis is based on local invasion of surrounding tissues or distant metastases.

As in benign disease, surgical removal/debulking to improve symptoms is the primary therapy; however, this may not be possible if the tumor has extensive local or metastatic spread.[76] Hypertension can be controlled with a combination of alpha- and beta-adrenergic blockade as well as calcium-channel blockers if needed.

Chemotherapy is given to all patients with metastatic disease after surgery.[61]​ Nonsurgical candidates with metastatic pheochromocytoma may also receive chemotherapy. Chemotherapy regimens usually consist of cyclophosphamide, vincristine, and dacarbazine.​[43][61]​​[77] Temozolomide, an alkylating drug and an alternative to dacarbazine, can be used as monotherapy or in combination with other antineoplastic drugs in patients with malignant pheochromocytomas and SDHB mutations.[78][79]

The radiopharmaceutical, iobenguane I-131 (also known as I-131 metaiodobenzylguanidine [MIBG]), may be considered if I-123 MIBG scintigraphy was positive.

Painful skeletal metastases can be treated with external beam radiation therapy.[80]​ Radiofrequency ablation of hepatic and bone metastases may also be effective.[61][81]

Unresectable tumor

Patients with unresectable tumors have a:

  • malignant tumor with extensive local or metastatic spread that could not be removed by surgery, or

  • benign tumor and who is not a surgical candidate for other medical reasons (i.e., a patient who is a high surgical risk because of heart failure).

Long-term BP control in patients with unresectable tumors can be achieved with alpha and beta blockade, as well as calcium-channel blockers if needed.

Symptomatic patients with unresectable tumors have been treated with chemotherapy regimens (usually consisting of CVD) and/or iobenguane I-131 (also known as I-131 MIBG).[43][82] However, iobenguane I-131 based treatment is less likely to achieve complete response.[83]

In cases of malignant pheochromocytomas refractory to both radiation therapy and chemotherapy, enrollment in a clinical trial is suggested and other treatment options, such as tyrosine kinase inhibitors (e.g., sunitinib), peptide receptor radionuclide therapy (lutetium Lu 177 dotatate also known as 177Lu-DOTATATE), immunotherapy (e.g., pembrolizumab), and hypoxia-inducible factor 2 alpha inhibitors (e.g., belzutifan), considered on a case-by-case basis.[27][43][49][84]

External beam radiation therapy (EBRT) at doses greater than 40 Gy has been shown to provide local tumor control and relief of symptoms at both soft tissue sites of metastases and painful bone metastases.​​[80][85]

Patient with hereditary pheochromocytoma

There is evidence in favor of cortical-sparing adrenalectomy in patients with hereditary pheochromocytomas.[70] This method can avoid the need for lifelong corticosteroid therapy. However, patients need to be monitored postoperatively for local recurrence.[86] 

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