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Diagnosis and Treatment of Pheochromocytoma

Definition

Pheochromocytoma is a rare, potentially malignant tumor of the adrenal medulla with the production of catecholamines, causing arterial hypertension and hypertonic crisis.

Epidemiology

Pheochromocytomas cause less than 1% of arterial hypertension. Incidence 0,2/100.000. Peak age 30–50 years.

Etiology and Pathology of Pheochromocytoma

Etiology:

Most pheochromocytomas arise from the chromaffin cells of the adrenal medulla. However, 10–20% are located extraadrenally, e.g., in the paravertebral ganglia and the ganglia of abdominal organs.

Malignancy:

Sporadic pheochromocytoma is malignant in 10%, familial pheochromocytoma in 25%. The assessment of malignancy by histologic criteria is complex. Using the PASS score (pheochromocytoma of the adrenal gland scale score), malignant potential can be estimated using the following criteria (points in parentheses): Vascular invasion (1), capsular invasion (1), nuclear pleomorphism (1), hyperchromasia of the nucleus (1), infiltration of adjacent adipose tissue (2), necrosis (2), large cell nests or diffuse growth (2), spindle-shaped tumor cells (2), cellular uniformity (2), increased or atypical mitoses (2). A PASS score of more than 6 points suggests a malignant potential of pheochromocytoma (Thompson et al., 2002). Other risk factors for malignancy include tumor size greater than 5 cm and a Ki-67 index greater than 3%.

Familial pheochromocytoma:

All patients with pheochromocytoma should be screened for the following entities for early diagnosis of other carcinomas:

• MEN (multiple endocrine neoplasia) type IIa (Sipple disease): medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism.
• MEN type IIb (Gorlin disease): medullary thyroid carcinoma, pheochromocytoma, ganglioneuromatosis (intestine, neurofibromas), and marfanoid habitus.
• Hippel-Lindau syndrome
• Neurofibromatosis: risk of 1–2% for pheochromocytoma.
• Paraganglioma-pheochromocytoma syndrome: occurrence of paragangliomas (paravertebral tumors from the skull base to the pelvis), pheochromocytomas, and other tumors such as renal cell carcinoma and papillary thyroid carcinoma.

Signs and Symptoms of Pheochromocytoma

Typically, paroxysmal attacks (15–90 min), triggers are exercise, massage, micturition, sex, food (wine, cheese), sneezing, coughing, and pregnancy. The following symptoms characterize the attacks:

• Arterial hypertension, hypertensive crises.
• Tachycardia, palpitations. Hypotension is also possible
• Sweating, fever
• Abdominal pain
• Tremor, headache, anxiety

Other possible symptoms are weight loss, weakness, and pain.

Diagnosis of Pheochromocytoma

Laboratory tests:

Typical findings include leukocytosis, hyperglycemia, glucosuria, hyperlipidemia, and elevated serum concentrations of metanephrine and normetanephrine. If one of the catecholamine metabolism products is elevated 2–3 times over the normal value, pheochromocytoma or paraganglioma is likely.

24-hour urine collection:

Pheochromocytoma causes elevated concentrations of the catecholamines epinephrine and norepinephrine and their breakdown products metanephrine and normetanephrine. Metanephrines have the highest sensitivity. The collection container must be acidified at the beginning of collection. If a value is above 2–3 times the norm, then a pheochromocytoma/paraganglioma is likely. See section adrenal incidentaloma for further hormone testing and differential diagnosis.

Clonidine suppression test:

Clonidine acts as a central sympatholytic and (if the regulatory circuit is intact) reduces catecholamine concentrations. A clonidine suppression test should be performed in patients with borderline elevated concentrations of catecholamines or metanephrines. The test is started with an intravenous cannula and bed rest. Basal measurement of serum catechol amines and serum metanephrines is done in the supine position. After 300 μg clonidine orally, elevated concentrations should decrease by at least 50% to exclude pheochromocytoma. Side effect: severe drop in blood pressure with clonidine; close monitoring of vital signs is necessary.

CT or MRI of the abdomen:

Pheochromocytoma presents on T1-weighted sequences with hypointensity and on T2 weighted sequences with hyperintensity (light bulb sign).

MIBG scintigraphy:

MIBG scintigraphy with ¹²³iodine or ¹³¹iodine labeled metaiodobenzylguanidine (MIBG) can identify ectopic (extraadrenal) pheochromocytomas or metastases.

PET:

PET with ¹⁸F labeled L-DOPA (FDOPA) as a tracer shows promising results in staging of pheochromocytomas and paragangliomas.

Treatment of Pheochromocytoma

Preoperative catecholamine blockade:

α-blocker phenoxybenzamine 10~mg 1-0-1. Dosage is slowly increased by 20 mg/d until hypertension is under control. 40–100 mg/d is usually sufficient.

A β-blocker (e.g., propranolol) may be given only after prior α-blockade and is indicated only for arrhythmias and lack of blood pressure control. The dosage of propranolol is 20-40 mg 1-1-1.

Adrenalectomy:

The standard approach for adrenalectomy is transabdominal for large tumors; otherwise, a generous lumbar approach (if necessary, with resection of the 11th rib) is used. Circular dissection of the organ without major manipulation of the tumor (non-touch technique) is important, as a hypertensive crisis may be precipitated. See section adrenalectomy for surgical technique and complications. Laparoscopic adrenalectomy is increasingly becoming a new standard for (small) pheochromocytomas.

Metastatic tumor stage:

Blood pressure control is possible with the above-mentioned catecholamine blockade. Resection of the primary tumor and metastases should be attempted if possible. Other therapeutic options include radionuclide therapy with 177Lu-Dotatate or iodine-131-MIBG and chemotherapy (e.g., cyclophosphamide, vincristine, and dacarbazine).

References

Lehnert u.a. 2002 LEHNERT, H. ; HAHN, K. ; DRALLE, H.: Benignes und malignes Phäochromozytom.
In: Internist (Berl)
43 (2002), Nr. 2, S. 196, 199–209

J. W. M. Lenders et al., “Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.,” The Journal of clinical endocrinology and metabolism, vol. 99, no. 6, pp. 1915–1942, Jun. 2014, doi: 10.1210/jc.2014-1498.

Parenti, G.; Zampetti, B.; Rapizzi, E.; Ercolino, T.; Giachè, V. & Mannelli, M. Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma.
J Oncol, 2012, 2012, 872713.

Thompson, L. D. R. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases.
Am J Surg Pathol, 2002, 26, 551-566

  Deutsche Version: Diagnose und Therapie des Phäochromozytoms