Pheochromocytomas and paragangliomas are catecholamine- producing tumors derived from the sympathetic or parasympathetic nervous system. These tumors may arise sporadically or be inherited as features of multiple endocrine neoplasia type 2 or several other pheochromocytoma-associated syndromes. The diagnosis of pheochromocytomas provides a potentially correctable cause of hypertension, and their removal can prevent hypertensive crises that can be lethal. The clinical presentation is variable, ranging from an adrenal incidentaloma to a patient in hypertensive crisis with associated cerebrovascular or cardiac complications.
Pheochromocytoma is estimated to occur in 2–8 of 1 million persons per year, and about 0.1% of hypertensive patients harbor a pheochromocytoma. Autopsy series reveal prevalence of 0.2%. The mean age at diagnosis is about 40 years, although the tumors can occur from early childhood until late in life. The "rule of tens" for pheochromocytomas states that about 10% are bilateral, 10% are extraadrenal, and 10% are malignant. However, these percentages are higher in the inherited syndromes.
Etiology and Pathogenesis
Pheochromocytomas and paragangliomas are well-vascularized tumors that arise from cells derived from the sympathetic (e.g., adrenal medulla) or parasympathetic (e.g., carotid body, glomus vagale) paraganglia (Fig. 343-1). The name pheochromocytoma reflects the black-colored staining caused by chromaffin oxidation of catecholamines. Although a variety of terms have been used to describe these tumors, most clinicians use the term pheochromocytoma to describe symptomatic catecholamine-producing tumors, including those in extraadrenal retroperitoneal, pelvic, and thoracic sites. The term paraganglioma is used to describe catecholamine-producing tumors in the head and neck. These tumors may secrete little or no catecholamines.
The paraganglial system and topographic sites (in red) of pheochromocytomas and paragangliomas. [Parts A,B, from WM Manger, RW Gifford: Clinical and experimental pheochromocytoma. Cambridge, Blackwell Science, 1996; Part C, from GG Glenner, PM Grimley: Tumors of the Extra-adrenal Paraganglion System (Including Chemoreceptors), Atlas of Tumor Pathology, 2nd Series, Fascicle 9. Washington, DC, AFIP, 1974.]
The etiology of sporadic pheochromocytomas and paragangliomas is unknown. However, about 25% of patients have an inherited condition, including germ-line mutations in the RET, VHL, NF1, SDHB, SDHC, SDHD, or SDHAF2 genes. Biallelic gene inactivation has been demonstrated for the VHL, NF1, and SDH genes, whereas RET mutations activate the receptor tyrosine kinase activity. SDH is an enzyme of the Krebs cycle and the mitochondrial respiratory chain. The VHL protein is a component of a ubiquitin E3 ligase. VHL mutations reduce protein degradation, resulting in upregulation of components involved in cell cycle progression, glucose metabolism, and oxygen sensing.
The clinical presentation is so variable that pheochromocytoma has been termed "the great masquerader" (Table 343-1). Among the presenting symptoms, episodes of palpitations, headaches, and profuse sweating are typical and constitute a classic triad. The presence of all three symptoms in association with hypertension makes pheochromocytoma a likely diagnosis. However, a pheochromocytoma can be asymptomatic for years, and some tumors grow to a considerable size before patients note symptoms.
Table 343-1 Clinical Features Associated with Pheochromocytoma |Favorite Table|Download (.pdf)
Table 343-1 Clinical Features Associated with Pheochromocytoma
|Palpitations and tachycardia|
|Hypertension, sustained or paroxysmal|
|Anxiety and panic attacks|
|Paradoxical response to antihypertensive drugs|
|Polyuria and polydipsia|
|Elevated blood sugar|
The dominant sign is hypertension. Classically, patients have episodic hypertension, but sustained hypertension is also common. Catecholamine crises can lead to heart failure, pulmonary edema, arrhythmias, and intracranial hemorrhage. During episodes of hormone release, which can occur at very divergent intervals, patients are anxious and pale, and they experience tachycardia and palpitations. These paroxysms generally last less than an hour and may be precipitated by surgery, positional changes, exercise, pregnancy, urination (particularly bladder pheochromocytomas), and various medications (e.g., tricyclic antidepressants, opiates, metoclopramide).
The diagnosis is based on documentation of catecholamine excess by biochemical testing and localization of the tumor by imaging. Both are of equal importance, although measurement of catecholamines is traditionally the first step.
Pheochromocytomas and paragangliomas synthesize and store catecholamines, which include norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine. Elevated plasma and urinary levels of catecholamines and the methylated metabolites, metanephrines, are the cornerstone for the diagnosis. The hormonal activity of tumors fluctuates, resulting in considerable variation in serial catecholamine measurements. Thus, there is some value in obtaining tests during or soon after a symptomatic crisis. However, most tumors continuously leak O-methylated metabolites, which are detected by measurements of metanephrines.
Catecholamines and metanephrines can be measured by using different methods (e.g., high-performance liquid chromatography, enzyme-linked immunosorbent assay, and liquid chromatography/mass spectrometry). In a clinical context suspicious for pheochromocytoma, when values are increased three times the upper limit of normal, a pheochromocytoma is highly likely regardless of the assay used. However, as summarized in Table 343-2, the sensitivity and specificity of available biochemical tests vary greatly, and these differences are important in assessing patients with borderline elevations of different compounds. Urinary tests for vanillylmandelic acid (VMA), metanephrines (total or fractionated), and catecholamines are widely available and are used commonly for initial testing. Among these tests, the fractionated metanephrines and catecholamines are the most sensitive. Plasma tests are more convenient and include measurements of catecholamines and metanephrines. Measurements of plasma metanephrine are the most sensitive and are less susceptible to false-positive elevations from stress, including venipuncture. Although the incidence of false-positive test results has been reduced by the introduction of newer assays, physiologic stress responses and medications that increase catecholamines still can confound testing. Because the tumors are relatively rare, borderline elevations are likely to be false positives. In this circumstance, it is important to exclude diet or drug exposure (withdrawal of levodopa, sympathomimetics, diuretics, tricyclic antidepressants, alpha and beta blockers) that might cause false positives and then repeat testing or perform a clonidine suppression test (measurement of plasma metanephrines 3 h after oral administration of 300 μg of clonidine). Other pharmacologic tests, such as the phentolamine test and the glucagon provocation test, are of relatively low sensitivity and are not recommended.
Table 343-2 Biochemical and Imaging Methods Used for Pheochromocytoma and Paraganglioma Diagnosis |Favorite Table|Download (.pdf)
Table 343-2 Biochemical and Imaging Methods Used for Pheochromocytoma and Paraganglioma Diagnosis
|24-h urinary tests|
|Somatostatin receptor scintigraphy*||++||++|
|Dopa (dopamine) PET||+++||++++|
A variety of methods have been used to localize pheochromocytomas and paragangliomas (Table 343-2). CT and MRI are similar in sensitivity. CT should be performed with contrast. T2-weighted MRI with gadolinium contrast is optimal for detecting pheochromocytomas and is somewhat better than CT for imaging extra-adrenal pheochromocytomas and paragangliomas. About 5% of adrenal incidentalomas, which usually are detected by CT or MRI, prove to be pheochromocytomas after endocrinologic evaluation.
Tumors also can be localized by using radioactive tracers, including 131I- or 123I-metaiodobenzylguanidine (MIBG), 111In-somatostatin analogues, or 18F-dopa (or dopamine) positron emission tomography (PET). Because these agents exhibit selective uptake in paragangliomas, nuclear imaging is particularly useful in the hereditary syndromes.
When one is entertaining the possibility of a pheochromocytoma, other disorders to consider include essential hypertension, anxiety attacks, use of cocaine or amphetamines, mastocytosis or carcinoid syndrome (usually lacking hypertension), intracranial lesions, clonidine withdrawal, autonomic epilepsy, and factitious crises (usually from sympathomimetic amines). When an asymptomatic adrenal mass is identified, likely diagnoses other than pheochromocytoma include a nonfunctioning adrenal adenoma, aldosteronoma, and cortisol-producing adenoma (Cushing's syndrome).
Complete tumor removal is the ultimate therapeutic goal. Preoperative patient preparation is essential for safe surgery. α-Adrenergic blockers (phenoxybenzamine) should be initiated at relatively low doses (e.g., 5–10 mg orally three times per day) and increased as tolerated every few days. Because patients are volume-constricted, liberal salt intake and hydration are necessary to avoid orthostasis. Adequate alpha blockade generally requires 7 days, with a typical final dose of 20–30 mg phenoxybenzamine three times per day. Oral prazosin or intravenous phentolamine can be used to manage paroxysms while awaiting adequate alpha blockade. Before surgery, blood pressure should be consistently below 160/90 mmHg, with moderate orthostasis. Beta blockers (e.g., 10 mg propranolol three to four times per day) can be added after starting alpha blockers and increased as needed if tachycardia persists. Other antihypertensives, such as calcium channel blockers or angiotensin-converting enzyme inhibitors, have been used when blood pressure is difficult to control with phenoxybenzamine alone.
Surgery should be performed by teams of anesthesiologists and surgeons with experience in the management of pheochromocytomas. Blood pressure can be labile during surgery, particularly at the onset of intubation or when the tumor is manipulated. Nitroprusside infusion is useful for intraoperative hypertensive crises, and hypotension usually responds to volume infusion. Although laparotomy was the traditional surgical approach, endoscopic surgery, using either a transperitoneal or a retroperitoneal approach, is associated with fewer complications, a faster recovery, and optimal cosmetic results. Atraumatic endoscopic surgery has become the method of choice. It may be possible to preserve the normal adrenal cortex, particularly in hereditary disorders in which bilateral pheochromocytomas are more likely. Extra-adrenal abdominal as well as most thoracic pheochromocytomas also can be removed endoscopically. Postoperatively, catecholamine normalization should be documented. An adrenocorticotropic hormone test should be used to exclude cortisol deficiency when bilateral adrenal cortex–sparing surgery is performed.
About 5–10% of pheochromocytomas and paragangliomas are malignant. The diagnosis of malignant pheochromocytoma is problematic. Typical histologic criteria of cellular atypia, presence of mitoses, and invasion of vessels or adjacent tissues do not reliably identify which tumors have the capacity to metastasize. Thus, the term malignant pheochromocytoma generally is restricted to tumors with distant metastases, most commonly found in lungs, bone, or liver, suggesting a vascular pathway of spread. Because hereditary syndromes are associated with multifocal tumor sites, these features should be anticipated in patients with germ-line mutations of RET, VHL, SDHD, or SDHB. However, distant metastases also occur in these syndromes, especially in carriers of SDHB mutations.
Treatment of malignant pheochromocytoma or paraganglioma is challenging. Options include tumor mass reduction, alpha blockers for symptoms, chemotherapy, and nuclear medicine radiotherapy. Averbuch's chemotherapy protocol includes dacarbazine (600 mg/m2 days 1 and 2), cyclophosphamide (750 mg/m2 day 1), and vincristine (1.4 mg/m2 day 1), repeated every 21 days for three to six cycles. Palliation (stable disease to shrinkage) is achieved in about one-half of patients. Other chemotherapeutic protocols remain in the experimental stage. An alternative is 131I-MIBG treatment using 200-mCi doses at monthly intervals over three to six cycles. The prognosis of metastatic pheochromocytoma or paraganglioma is variable, with a 5-year survival of 30–60%.
Pheochromocytoma in Pregnancy
Pheochromocytomas occasionally are diagnosed in pregnancy. Endoscopic removal, preferably in the forth to sixth month of gestation, is possible and can be followed by uneventful childbirth. Regular screening in families with inherited pheochromocytomas provides an opportunity to identify and remove asymptomatic tumors in women of reproductive age.
About 25–33% of patients with a pheochromocytoma or paraganglioma have an inherited syndrome. The mean age at diagnosis is about 15 years lower in patients with inherited syndromes compared with patients with sporadic tumors.
Neurofibromatosis type 1 (NF 1) was the first described pheochromocytoma-associated syndrome (Chap. 379). The NF1 gene functions as a tumor suppressor by regulating the Ras signaling cascade. Classic features of neurofibromatosis include multiple neurofibromas, café au lait spots, axillary freckling of the skin, and Lisch nodules of the iris (Fig. 343-2). Pheochromocytomas occur in only about 1% of these patients and are located predominantly in the adrenals. Malignant pheochromocytoma is not uncommon.
Neurofibromatosis. A. MRI of bilateral adrenal pheochromocytoma. B. Cutaneous neurofibromas. C. Lisch nodules of the iris. D. Axillary freckling. (Part A from HPH Neumann et al: Keio J Med 54:15, 2005; with permission.)
The best-known pheochromocytoma-associated syndrome is the autosomal dominant disorder multiple endocrine neoplasia type 2A and type 2B (MEN 2A, MEN 2B) (Chap. 351). Both types of MEN 2 are caused by mutations in RET (REarranged during Transfection), which encodes a tyrosine kinase. The locations of RET mutations correlate with the severity of disease and the type of MEN 2 (Chap. 351). MEN 2A is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism; MEN 2B also includes MTC and pheochromocytoma, as well as multiple mucosal neuromas, marfanoid habitus, and other developmental disorders, though it typically lacks hyperparathyroidism. MTC is seen in virtually all patients with MEN 2, but pheochromocytoma occurs in only about 50% of these patients. Nearly all pheochromocytomas are benign and located in the adrenals, often bilateral (Fig. 343-3). Pheochromocytoma may be symptomatic before MTC. Prophylactic thyroidectomy is being performed in many carriers of RET mutations; pheochromocytomas should be excluded before any surgery in these patients.
Multiple endocrine neoplasia type 2. Multifocal medullary thyroid carcinoma shown by (A) MIBG scintigraphy and (B) operative specimen Arrows demonstrate the tumors; arrowheads show the tissue bridge of the cut specimen. Bilateral adrenal pheochromocytoma shown by (C) MIBG scintigraphy, (D) CT imaging, and (E) operative specimens. (From HPH Neumann et al: Keio J Med 54:15, 2005; with permission.)
Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disorder that predisposes to retinal and cerebellar hemangioblastomas, which also occur in the brainstem and spinal cord (Fig. 343-4). Other important features of VHL are clear cell renal carcinomas, pancreatic islet cell tumors, endolymphatic sac tumors (ELSTs) of the inner ear, cystadenomas of the epididymis and broad ligament, and multiple pancreatic or renal cysts.
Von Hippel-Lindau disease. Retinal angioma (A); hemangioblastomas of cerebellum are shown by MRI in (B) brainstem; (C and D) spinal cord; (E) bilateral pheochromocytomas and bilateral renal clear cell carcinomas; and (F) multiple pancreatic cysts. [Parts A and D from HPH Neumann et al: Adv Nephrol Necker Hosp 27:361, 1997. Copyright Elsevier. Part B from SH Morgan, J-P Grunfeld (eds): Inherited Disorders of the Kidney. Oxford, UK, Oxford University Press, 1998. Part F from HPH Neumann et al: Contrib Nephrol 136:193, 2001. Copyright S. Karger AG, Basel.]
The VHL gene encodes an E3 ubiquitin ligase that regulates expression of hypoxia-inducible factor-1 (HIF-1), among other genes. Loss of VHL is associated with increased expression of vascular endothelial growth factor (VEGF) that induces angiogenesis. Although the VHL gene can be inactivated by all types of mutations, patients with pheochromocytoma predominantly have missense mutations. About 20–30% of patients with VHL have pheochromocytomas, but in some families the incidence can reach 90%. The recognition of pheochromocytoma as a VHL-associated feature provides an opportunity to diagnose retinal, central nervous system, renal, and pancreatic tumors at a stage when effective treatment may still be possible
The paraganglioma syndromes (PGL) have been classified by genetic analyses of families with head and neck paragangliomas. The susceptibility genes encode subunits of the enzyme succinate dehydrogenase (SDH), a component in the Krebs cycle and the mitochondrial electron transport chain. SDH is formed by four subunits (A–D). Mutations of SDHB (PGL4), SDHC (PGL3), SDHD (PGL1), and SDHAF2 (PGL2) predispose to the paraganglioma syndromes. Mutations of SDHA do not predispose to paraganglioma tumors but instead cause Leigh's disease, a form of encephalopathy. The transmission of the disease in carriers of SDHB, SDHC, and SDHAF2 germ-line mutations is autosomal dominant. In contrast, in SDHD families, only the progeny of affected fathers develop tumors if they inherit the mutation. In a small number of patients with familial pheochromocytoma, a mutation has not been identified. PGL1 is most common, followed by PGL4; PGL2 and PGL3 are rare. Adrenal, extra-adrenal abdominal, and thoracic pheochromocytomas that are components of PGL1 and PGL4, are rare in PGL3, but absent in PGL2 (Fig. 343-5). About one-third of the patients with PGL4 develop metastases.
Paraganglioma syndrome. PGL1, a patient with incomplete resection of a left carotid body tumor and the SDHD W5X mutation. A. 18F-dopa positron emission tomography demonstrating tumor uptake in the right jugular glomus, the right carotid body, the left carotid body, the left coronary glomus, and the right adrenal gland. Note the physiologic accumulation of the radiopharmaceutical agent in the kidneys, liver, gallbladder, renal pelvis, and urinary bladder. B and C. CT angiography with three-dimensional reconstruction. Arrows point to the paraganglial tumors. (From S Hoegerle et al: Eur J Nucl Med Mol Imaging 30:689, 2003; with permission.)
Familial pheochromocytoma (FP) has been attributed to hereditary, exclusively adrenal tumors in patients with germline mutations in the TMEM127 gene.
Guidelines for Genetic Screening in Patients with Pheochromocytoma or Paraganglioma
In addition to family history, general features suggesting an inherited syndrome include young age, multifocal tumors, extra-adrenal tumors, and malignant tumors (Fig. 343-6). Because of the relatively high prevalence of familial syndromes among patients who present with pheochromocytoma or paraganglioma, it is useful to identify germline mutations even in patients without a known family history. A first step is to search for clinical features of inherited syndromes and to perform an in-depth, multigenerational family history. Each of these syndromes exhibits autosomal dominant transmission with variable penetrance, but a proband with a mother affected by paraganglial tumors is not predisposed to PLG1 (SDHD mutation carrier). Cutaneous neurofibromas, café au lait spots, and axillary freckling suggest neurofibromatosis. Germ-line mutations in NF1 have not been reported in patients with sporadic pheochromocytomas. Thus, NF1 testing does not have to be performed in the absence of other clinical features of neurofibromatosis. A personal or family history of medullary thyroid cancer or elevation of serum calcitonin strongly suggest MEN 2 and should prompt testing for RET mutations. A history of visual impairment, or tumors of the cerebellum, kidney, brainstem, or spinal cord, suggests the possibility of VHL. A personal and/or family history for head and neck paraganglioma suggests PGL1 or PGL4.
Mutation distribution in the RET, VHL, NF1, SDHB, and SDHD genes. A. Correlation with age. The bars depict the frequency of sporadic or various inherited forms of pheochromocytoma in different age groups. The inherited disorders are much more common among younger individuals presenting with pheochromocytoma. Germ-line mutations according to (B) multiple, (C) extraadrenal retroperitoneal, (D) thoracic, and (E) malignant pheochromocytomas (Data from the Freiburg International Pheochromocytoma and Paraganglioma Registry in 2009.)
A single adrenal pheochromocytoma in a patient with an otherwise unremarkable history may still be associated with mutations of VHL, RET, SDHB, or SDHD (in decreasing order of frequency). Two-thirds of extra-adrenal tumors are associated with one of these syndromes, and multifocal tumors occur with decreasing frequency in carriers of RET, SDHD, VHL, and SDHB mutations. About 30% of head and neck paragangliomas are associated with germ-line mutations of one of the SDH subunit genes (particularly SDHD) and are rare in carriers of VHL and RET mutations.
Once the underlying syndrome is diagnosed, the benefit of genetic testing can be extended to relatives. For this purpose, it is necessary to identify the germ-line mutation in the proband and, after genetic counseling, perform DNA sequence analyses of the responsible gene in relatives to determine whether they are affected (Chap. 63). Other family members may benefit from biochemical screening for paraganglial tumors in individuals who carry a germ-line mutation.