Pheochromocytoma

Introduction to Pheochromocytoma
Pheochromocytomas are rare tumors arising from the adrenal medulla. A fraction of them are hereditary, and the treatment is complicated due to the excess cathecholamines secreted by the tumor. An overview of diagnosis and treatment follows.

Pheochromocytoma – epidemiology and genetics
The annual incidence of this rare tumor is in Sweden about 2-8 per million. Slightly less than 10% are malignant, but the histopathological diagnosis is sometimes difficult. The classical symptoms include headache, palpitations, and hypertension caused by the increased production of cathecholamines (e.g. epinephrine and/or norepinephrine). The symptoms may occur in attacks, provoked by a stressful stimulus, with or without hypertension between attacks, or may present as a continuous hypertension being difficult to discriminate from essential hypertension. The tumor is usually less than 3 cm in diameter, and may be discovered by an MRI or CT scan performed for other reasons (adrenal incidentaloma), or in an investigation of e.g. refractory hypertension. The larger the tumor, the higher the likelihood of a malignant tumor. In case of metastastic disease the malignant diagnosis I obvious, but in many cases this is difficult. Histopathological hints for malignancy include vascular invasion, perineural growth etc. Some inherited cancer syndromes, like multiple endocrine neoplasia type II (MEN2), von Hippel-Lindau, and neurofibromatosis type I, are associated with pheochromocytoma. We therefore routinely offer patients genetic guidance, especially when diagnosed at an early age (<50 years).

Diagnosis of pheochromocytoma
The most sensitive methods for determination of pheochromocytoma are measurements of metanephrines in plasma, or fractionated metanephrines in 24-hour urine samples. Apart from regular CT and MRT, 11C-Hydroxyephedrine-PET (11C-HED-PET) may be used, being specific for tumors arising from the adrenal medulla. Scintigraphy with 131I-metaiodobenzylguanine (131I-MIBG, an epinephrine precursor) is another option, and radiolabeled somatostatin analog scintigraphy (Octreoscan) is positive in a subset of pheochromocytomas.

Treatment of pheochromocytoma
Surgery offers a good chance of a cure. It is imperative that the patient is pretreated with alpha receptor blockade, to avoid dangerous effects of large amounts of cathecholamines being released during surgery. Pretreatment, usually by Alfadil® in doses slowly increased to 4-32 mg/day, may last 1-6 weeks. Efficient treatment imply development of symptoms such as ortostatic hypotension and runny nose. Surgery for pheochromocytoma must be performed in close collaboration with experienced anesthesiologists who are well familiar with this condition. Most pheochromocytomas are operated with a laparoscopic technique (either lateral or retroperitoneal approach), but larger tumors may require open surgery.

Postoperatively the patient may need infusion of norepinephrine, and are surveilled at the postoperative department, usually overnight. Recovery after surgery is normally uneventful, and the patient may be discharged within 2-3 days after surgery.

Metastatic disease is usually treated with targeted radionuclide therapy. If there is a large uptake on the MIBG scintigraphy, a higher dose of 131I-MIBG can be given, resulting in a targeted destruction of tumor cells. If the tumors are Octreoscan positive, treatment with 177Lu-DOTA-Octreotate may be used. The multiple tyrosine kinase inhibitor sunitinib appears to have anti-tumor activity in pheochromocytoma, but this needs to be evaluated further in larger clinical trials.

At our center, we offer expertise in all aspects of the management of pheochromocytomas, including expert endocrine surgeons, anesthesiologists, endocrine pathologists and endocrine oncologists; genetic guidance; a PET center with 11C-HED-PET capability; a nuclear medicine unit with experience in 131I-MIBG and 177Lu-DOTA-Octreotate treatments. We all collaborate in a team effort to provide the best possible care for patients with this rare disease.

Pheochromocytoma in MEN-2
Pheochromocytomas in MEN 2 patients predominantly excrete epinephrine and metanephrine, and present an adrenergic biochemical phenotype. 
Annual biochemical screening and CT is done to exclude development of pheochromocytoma in patients with MEN 2. Unrecognized pheochromocytomas may cause significant morbidity and mortality during surgical procedures or pregnancy, and should always be excluded prior to thyroidectomy for medullary thyroid carcinoma.
Due to detection by screening ~50% or more of MEN-2 patients with pheochromocytoma have been asymptomatic at time of diagnosis. Patients with symptoms have had the common complaints of headache, palpitations, excessive sweating, and hypertension.

Adrenal surgery for pheochromocytoma in MEN-2
After unilateral adrenalectomy for pheochromocytoma in MEN 2 the risk for recurrent contralateral pheochromocytoma has been 33% during 5 years, and 50% during 11 years of follow-up. The contralateral tumors have developed especially in patients where the size of the primary tumor exceeded 5 cm.

When bilateral adrenalectomy has been required the patients can be managed with glucocorticoid and mineralocorticoid replacement, combined with dehydroepiandrosterone in females, to prevent osteoporosis and improve well-being. Addison crisis develops in 25-33% of patients, and almost half of them feel handicapped despite adequate substitution.

In order to avoid adrenal insufficiency, efforts have been made to preserve adrenal function by partial “cortical-saving” adrenalectomy for familial pheochromocytomas. The surgical procedure is always laparoscopic (or retroperitoneoscopic).