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PHEOCHROMOCYTOMA |
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ML Kendrick, MD
,
JA van Heerden, MD
,
DR Farley, MD
, Mayo Clinic Rochester, Rochester, United States
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1. History 2. Epidemiology 3. Etiology/Pathogenesis 4. Pathology 5. Diagnosis 6. Preoperative management 7. Treatment 8. References |
1.
History
While Pick coined the term pheochromocytoma in 1912, Frankel described and reported the lethal effects of this neoplasm in 1886, demonstrating bilateral adrenal tumors in an 18-year-old patient who presented with hypertension and syncope. It was not until 1926 that the first successful surgical removal of such a tumor was performed by Roux in Lausanne, Switzerland. Charles Mayo, in the United States, repeated the feat a few months later. |
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;) Figure 1.a CT scan of a left pheochromocytoma |
Definition
Pheochromocytomas are catecholamine-secreting tumors that originate from chromaffin cells of the adrenal medulla. Catecholamine-secreting paragangliomas, also erroneously referred to as extra-adrenal pheochromocytomas, arise from chromaffin cells of the sympathetic ganglia. A pheochromocytoma, which derives its name from the Greek pheo (meaning “dusky”) and chroma (meaning “color”), is a rare, potentially lethal tumor that may generate signs mimicking many other diseases (eg, hyperthyroidism, diabetes mellitus, anxiety and panic attacks). The onus rests on the physician to suspect, confirm, localize, and resect these tumors, as they are a surgically curable cause of hypertension (with potentially lethal hypertensive paroxysms) and are malignant in 10% of patients.
1. History
2. Epidemiology
3. Etiology/Pathogenesis
4. Pathology
5. Diagnosis
6. Preoperative management
7. Treatment
8. References
2.
Epidemiology
While pheochromocytomas are rare (incidence 1:100 000), as many as 800 people in the US die every year from complications of their unsuspected occurrence (
Graham, 1951; Beard
et al.
, 1983
). Pheochromocytomas can occur in infants as well as in the elderly, but the incidence does increase with age. Pheochromocytoma has been described as the “tumor of 10%”, with extra-adrenal, childhood, multiple or bilateral, familial, and malignant tumors occurring in about 10% of patients. The familial association of pheochromocytomas with MEN II, von Hippel-Lindau disease, and other clinical syndromes is well described.
;) Figure 2 Familial and associated syndromes of patients with pheochromocytoma |
1. History
2. Epidemiology
3. Etiology/Pathogenesis
4. Pathology
5. Diagnosis
6. Preoperative management
7. Treatment
8. References
3.
Etiology/Pathogenesis
In the fifth week of fetal development, neuroblastic cells migrate from the thoracic neural crest primordium to form the primitive sympathetic chains and pre-aortic ganglia. These neuroblasts and their descendants are thought to be the precursors of neuroblastomas and ganglioneuromas. Some of these cells differentiate into endocrine cells referred to as chromaffin cells because they become brown in color when exposed to chromic salts. These cells migrate and invade the adrenal cortex, giving rise to the adrenal medulla. Small clusters of chromaffin cells also settle around the sympathetic ganglia, the vagus nerve, paraganglia of the carotid arteries, the arch of the aorta, and the abdominal aorta. Less common sites of extra-adrenal chromaffin tissue are the wall of the urinary bladder, the prostate, the hepatic and renal hila, and near the rectum and gonadal tissue. Catecholamine-secreting tumors can arise from any of these clusters of chromaffin cells.
;) Figure 3.a Proportion of adrenal vs. extra-adrenal pheochromocytoma ( Remine et al., 1974 ) |
Tumors in the head, neck, and paravagal region are usually non-functional, while those around the aorta, sympathetic chain, and visceral tumors (bladder or ovary) are secreting tumors.
;) Figure 3.b Distribution of catecholamine-secreting tumors ( Remine et al., 1974 ) |
1. History
2. Epidemiology
3. Etiology/Pathogenesis
4. Pathology
5. Diagnosis
6. Preoperative management
7. Treatment
8. References
4.
Pathology
Macroscopically, the tumors are typically encapsulated, and frequently cystic with areas of hemorrhage and necrosis.
;) Figure 4.a Macroscopic section of pheochromocytoma |
Microscopically, they are composed of nests or cords of polyhedral cells separated by a fibrovascular stroma.
;) Figure 4.b Histology section of pheochromocytoma |
Although nuclear pleomorphism and other findings suggestive of malignancy are present in some tumors, malignancy is determined clinically based on the presence of local invasion or more accurately and more commonly by metastatic disease. Metastases, however, must be distinguished from multifocal tumors originating in other chromaffin cell sites.
Malignant tumors occur in 7-15% of patients with pheochromocytoma ( Remine et al. , 1974 ). Metastases usually occur (in decreasing order) in the bone, regional lymph nodes, liver, lung, or brain.
;) Figure 4.c Vertebral metastasis of pheochromocytoma |
;) Figure 4.d Liver metastasis of pheochromocytoma |
1. History
2. Epidemiology
3. Etiology/Pathogenesis
4. Pathology
5. Diagnosis
6. Preoperative management
7. Treatment
8. References
5.
Diagnosis
;) Figure 5 Algorithm for the diagnosis and localization of pheochromocytoma |
5.1. Hypertension
Hypertension is the hallmark clinical finding and is detected in 60-100% of patients with pheochromocytoma; hypertension may be paroxysmal (50%) or sustained (50%) ( Remine et al. , 1974 ). Importantly, of all hypertensive patients, a pheochromocytoma is present in only 0.1%, and in contrast to essential hypertension, 70% of patients exhibit orthostatic hypotension. Episodic symptoms may occur as paroxysms, which can be spontaneous or precipitated by postural change, anxiety, medications, exercise, or maneuvers that increase intra-abdominal pressure. Patients may also present with symptoms of headache, diaphoresis, or palpitations. On occasion, the diagnosis of pheochromocytoma is suspected during medical intervention because of hemodynamic instability during angiography, childbirth, or an operative procedure.
;) Figure 5.1.a Clinical presentation |
Whereas epinephrine accounts for about 80-85% of normal adrenal medullary catecholamine production, most pheochromocytomas secrete an excess of norepinephrine and epinephrine. The less common pure epinephrine-secreting tumors are frequently associated with hypotension and shock after alpha-blockade due to the beta-adrenergic effects of epinephrine, and the inherent hypovolemic state of all patients with a pheochromocytoma ( Young, 1997; Walther et al. , 1999 ).
;) Figure 5.1.b Synthesis of catecholamines |
5.2. Urinary catecholamines
All hypertensive patients with pheochromocytoma secrete excessive catecholamines. Measurement of fractionated urinary catecholamines (epinephrine, norepinephrine, and dopamine over 12-24 hours) identifies this disorder in >95% of patients. Addition of the analysis of urinary metanephrines and vanillylmandelic acid (VMA) increase the diagnostic accuracy to >99%. Measurement of plasma catecholamines is not as sensitive as 24-hour urinary measurements and adds little information. Plasma metanephrines, however, are sensitive and are increasingly used.
;) Figure 5.2 Metabolism of catecholamines |
5.3. Pharmacologic provocation tests
Pharmacologic provocation tests such as histamine or glucagons are potentially dangerous and are largely of historic interest. In the rare patient where clinical suspicion of pheochromocytoma exists yet catecholamine levels are normal or indeterminate, the clonidine suppression test may be used. Clonidine, an alpha-2 agonist, will suppress mildly elevated levels of catecholamines in normal individuals, but does not suppress the autonomous production of catecholamines in patients with pheochromocytoma. Although many medications may alter catecholamines and their metabolite levels, tricyclic antidepressants and labetalol are among the most common.5.4. Radiography/imaging studies
Rarely, adrenal neoplasms are suspected on radiographs obtained for evaluation of abdominal or back pain.
;) Figure 5.4.a CT scan: Calcified left adrenal pheochromocytoma |
;) Figure 5.4.b Radiograph: Calcified left adrenal pheochromocytoma |
With the increased use of abdominal imaging for other diseases, unexpected adrenal tumors (“incidentalomas”) are increasingly identified. It is imperative to investigate such patients for pheochromocytoma.
;) Figure 5.4.c CT scan: Right adrenal pheochromocytoma |
5.5. CT scans
Modern spiral computed tomography (CT) from diaphragm to pelvis with thin sectioning (3 mm) accurately identifies most unilateral or bilateral pheochromocytomas and extra-adrenal paraganglioma. Nearly 98% of catecholamine-secreting neoplasms are intra-abdominal, and roughly 90% of tumors that do secrete excess catecholamines lie within the adrenal gland(s).
;) Figure 5.5.a CT scan: Large right adrenal pheochromocytoma with cystic component |
;) Figure 5.5.b CT scan: Right adrenal pheochromocytoma with cystic component |
;) Figure 5.5.c CT scan: Right pararenal paraganglioma |
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5.6. MRI
Magnetic resonance imaging (MRI) is also very sensitive in identifying both adrenal and extra-adrenal tumors with enhancement of pheochromocytoma on T2-weighted images. MRI negates the need for contrast enhancement of CT, thus avoiding the potential hypertensive crisis precipitated by contrast injection.
;) Figure 5.6.a MRI: Right adrenal pheochromocytoma |
;) Figure 5.6.b MRI: Locally invasive malignant paraganglioma on T2-weighted MRI |
;) Figure 5.6.c MRI: Right adrenal pheochromocytoma |
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Equivocal CT or MRI studies, or associated familial syndromes [eg multiple endocrine neoplasia (MEN II) or von Hippel-Lindau] should prompt meta-iodobenzylguanidine (MIBG) scanning. MIBG is a physiologic analog of norepinephrine and is taken up and stored in neurosecretory granules (123) or (131). MIBG is useful in imaging the adrenal medulla as well as in the detection of extra-adrenal, metastatic, or recurrent sites of disease or when whole-body imaging is important.
;) Figure 5.6.d MIBG scan demonstrating right paraspinal paraganglioma |
1. History
2. Epidemiology
3. Etiology/Pathogenesis
4. Pathology
5. Diagnosis
6. Preoperative management
7. Treatment
8. References
6.
Preoperative management
Preoperative pharmacologic preparation lowers morbidity and mortality by minimizing intraoperative hemodynamic instability and is imperative in all patients undergoing elective surgical intervention. Figure 6 shows a standard preoperative preparation of patients with pheochromocytoma. A variety of regimens (eg, prazosin, labetalol, calcium channel blockers, and methyronsine) have been used successfully.
;) Figure 6 Classic preoperative preparation for patients with pheochromocytoma |
The most common agent of choice today remains the long-acting alpha-adrenergic blocker phenoxybenzamine. Phenoxybenzamine should be commenced at least 7 days prior to the operation. The initial oral dose is 10 mg twice daily and is increased by 10-20 mg/day, titrated to the onset of nasal congestion and orthostatic hypotension. Patients should be encouraged to take fluids and salt liberally to help replace their deleted intravascular volume.
The use of beta-blockers (eg, propanolol 10 mg qd) is somewhat controversial but is largely indicated to minimize tachyarrhythmias. Asthma and cardiac failure are absolute contraindications to the use of beta-blockers. In addition, they should not be used without prior alpha-blockade, as unopposed vasoconstriction can lead to potentially catastrophic hypertension.
1. History
2. Epidemiology
3. Etiology/Pathogenesis
4. Pathology
5. Diagnosis
6. Preoperative management
7. Treatment
8. References
7.
Treatment
The mainstay of treatment of pheochromocytomas and catecholamine-secreting paragangliomas is surgical resection. Non-surgical treatment however, is occasionally necessary in patients who are not operative candidates (such as those with metastatic disease or severe co-morbidities). Use of alpha-methyl-penta-tyrosine, an inhibitor of catecholamine synthesis, can reduce circulating levels by as much as 50%, offering some symptomatic control.
;) Figure 7 MIBG scan showing multiple metastases |
1. History
2. Epidemiology
3. Etiology/Pathogenesis
4. Pathology
5. Diagnosis
6. Preoperative management
7. Treatment
8. References
8.
References
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Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 1983;58:802-4.
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Graham JB. Pheochromocytoma and hypertension: An analysis of 207 cases. Int Abstr Surg 1951; 92:105-121.
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Remine WH, Chong GC, Van Heerden JA, Sheps SG, Harrison EG, Jr. Current management of pheochromocytoma. Ann Surg 1974;179:740-8.
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Walther MM, Keiser HR, Linehan WM. Pheochromocytoma: evaluation, diagnosis, and treatment. World J Urol 1999;17:35-9.
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Young WF, Jr. Pheochromocytoma and primary aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am 1997;26:801-27.