PHEOCHROMOCYTOMA

PHEOCHROMOCYTOMA

Current Diagnosis

• Hypertension is the most common clinical sign.

• A triad of headaches, palpitations, and sweating, with or without hypertension, indicates the possibility of a pheochromocytoma.

• Biochemical diagnosis of pheochromocytoma should be based on the determination of plasma free or urine fractionated metanephrines.

• Localization of pheochromocytomas should consist of anatomic imaging, preferably computed tomography (CT) or magnetic resonance imaging (MRI), and specific functional imaging by positron emission tomography (PET).

• Cost-effective genetic screening guided by family history, clinical features, and a gene-specific biochemical phenotype should be performed on most patients. The identification of a causative mutation should lead to presymptomatic genetic testing in a patient’s relatives.

Current Therapy

• The optimal therapy for a pheochromocytoma is prompt surgical removal of the tumor.

• At least 1 to 2 weeks before the operation there should be adequate maintenance of blood pressure using mainly α-adrenoceptor blockers and possibly β-adrenoceptor blockers; less commonly, calcium channel blockers and metyrosine (Demser) may be used if indicated.

• For most pheochromocytomas, laparoscopy is the procedure of choice.

• Adrenal cortex–sparing surgery should be advocated in all patients with bilateral adrenal pheochromocytomas, if feasible.

• Clinical follow-up should be lifelong, especially in cases of an underlying germline mutation or with a large primary tumor greater than 4–5 cm.

• Management of metastatic tumors requires a multidisciplinary approach, in which pharmacologic treatment, targeted radiotherapy, chemotherapy, and surgery play an important role.

The 2004 WHO classification of endocrine tumors defines pheochromocytoma* as a tumor arising from catecholamine- producing chromaffin cells in the adrenal medulla. Closely related paragangliomas are divided into two groups: those arising from parasympathetic-associated tissues and those that arise from sympathetic-associated chromaffin tissue. Sympathetic paragangliomas were formerly designated as extra-adrenal pheochromocytomas. Pheochromocytomas and paragangliomas are characterized by the synthesis, metabolism, storage, and usually, but not always, secretion of catecholamines.

Parasympathetic paragangliomas are mainly located along the cranial and vagus nerves. Glomus or carotid body tumors, for example—head and neck paragangliomas—can be locally invasive but rarely develop metastases and are usually nonsecretory.

Sympathetic paragangliomas mainly arise in the abdomen from chromaffin tissue neighboring sympathetic ganglia. Less often, they originate from the pelvis and infrequently from the mediastinum (2%) and neck (1%). In the abdomen, they often derive from the organ of Zuckerkandl, a collection of chromaffin tissue around the origin of the inferior mesenteric artery (Figure 1).

FIGURE 1    Anatomic distribution of chromaffin tissue. (Adapted from Lack E: Tumors of the adrenal gland and extra-adrenal paraganglia. In Armed Forces Institute of Pathology: Atlas of Tumor Pathology. Washington, DC, Armed Forces Institute of Pathology, 1997, 261–267.)

Epidemiology

Pheochromocytomas can occur at any age, including in childhood, but most often they are detected in the fourth and fifth decades. There is no gender preference. In Western countries the prevalence of pheochromocytoma is estimated between 1:6500 and 1:2500, with an annual incidence of 3 to 8 cases per 1 million per year in the general population, although autopsies show a higher incidence. The pheochromocytoma-to-paraganglioma ratio is about 0.80 to 0.20.

About 35% are familial, and 3% to 50% are malignant, depending on their genetic background.

Genetics

There are no lifestyle-related risk factors that increase the risk of pheochromocytoma. However, the understanding of the role of genetics has dramatically increased over the last years. Up to 35% of pheochromocytomas are hereditary, and a significant number of patients (approximately 35%) with apparently sporadic tumors carry a germline mutation. Thus, gene mutations are the largest risk factor involved in the development of pheochromocytoma.

At present, at least 14 well-known susceptibility genes have been discovered that fall into two categories: major susceptibility genes and minor susceptibility genes. Major susceptibility genes represent about 85% to 90% of all hereditary tumors: the VHL gene, which causes von Hippel–Lindau syndrome; the RET gene, for multiple endocrine neoplasia (MEN) types 2A and 2B; the NF1 gene in neurofibromatosis type 1; and the SDHB and SDHD genes in familial paraganglioma syndromes. Minor susceptibility genes include SDHA, SDHC, SDH5/SDHAF2, MAX, TMEM127, EGLN1/PHD2, IDH1, KIF1Bβ and HIF2A (EPAS1), which represent 10% to 15% of hereditary tumors. The list of susceptibility genes is constantly growing, with recently reported genes having a very low incidence; therefore, some of their characteristics have not yet been fully elucidated. We expect more genes to be reported in connection with familial pheochromocytoma but their relevance must be confirmed. The characteristics of hereditary tumors are described in Table 1.

Table 1

Characteristics of Known Hereditary Pheochromocytomas

Note: An adrenergic phenotype represents either an increase only in metanephrine or both metanephrine and normetanephrine; a noradrenergic phenotype represents an increase only in normetanephrine; a mixed phenotype represents an increase in both metanephrine and normetanephrine.

Abbreviations: bHLHLZ = basic helix–loop–helix leucine zipper; HNPGL = head and neck paraganglioma; MEN = multiple endocrine neoplasia; NF =  neurofibromatosis;

PGL = paraganglioma; SDH = succinate dehydrogenase; VHL = von   Hippel–Lindau.

*  Seldom seen in children.

†  Our unpublished observations show lower  penetrance.

Pheochromocytomas can occur as part of several syndromes, which are associated with additional clinical conditions (Box 1). A recently described Pacak-Zhuang syndrome connects novel mutations in the gene-encoding hypoxia-inducible factor HIF2A (EPAS1) with paraganglioma, polycythemia, and somatostatinoma. Other rare syndromes that include pheochromocytomas are Carney triad and Carney–Stratakis syndrome, which are characterized by gastrointestinal stromal tumors and paragangliomas in SDHB and SDHD carriers. It is well established that renal cell carcinomas are also related to SDHB, SDHC, and SDHD gene mutations.

Box 1
Main Clinical Features of Syndromes Associated with Pheochromocytoma
von Hippel–Lindau Syndrome

Type 1 (No Pheochromocytoma)

Renal cell cysts and carcinomas

Retinal and CNS hemangioblastomas

Pancreatic neoplasms and cysts

Endolymphatic sac tumors

Epididymal cystadenomas

Type 2 (with Pheochromocytoma)

Type 2A: Retinal and CNS hemangioblastomas

•   Pheochromocytomas

•   Endolymphatic sac tumors

•   Epididymal cystadenomas

Type 2B: Renal cell cysts and carcinomas

•   Retinal and CNS hemangioblastomas

•   Pancreatic neoplasms and cysts

•   Pheochromocytomas

•   Endolymphatic sac tumors

•   Epididymal cystadenomas

Type 2 C: Pheochromocytomas only

Multiple Endocrine Neoplasia Type 2

Type 2A (medullary thyroid carcinoma)

•   Pheochromocytomas

•   Hyperparathyroidism

•   Cutaneous lichen amyloidosis

Type 2B (medullary thyroid carcinoma)

•   Pheochromocytomas

•   Multiple neuromas

•   Marfanoid habitus

FMTC: familial medullary thyroid carcinoma only

Neurofibromatosis Type 1

Multiple benign neurofibromas on skin and mucosa

Café au lait skin spots

Iris Lisch nodules

Learning disabilities

Skeletal abnormalities

Vascular disease

CNS tumors

Malignant peripheral nerve sheath tumors

Pheochromocytomas

Paraganglioma Syndromes

Head and neck tumors

•   Carotid-body tumors

•  Vagal, jugular, and tympanic paragangliomas

Abdominal and/or thoracic paragangliomas

Pheochromocytomas

Renal cell carcinoma (SDHB)

Gastrointestinal stromal tumor (SDHB and SDHD)

Gastrointestinal stromal tumor (SDHB and SDHD)

Pacak-Zhuang Syndrome

Multiple paragangliomas

Multiple somatostatinomas

Polycythemia

Abbreviations: CNS = central nervous system; SDH = succinate dehydrogenase.

Adapted from Lenders JW, Eisenhofer G, Mannelli M, Pacak K: Phaeochromocytoma. Lancet 2005;366:665–675.

Genetic counseling is recommended for all patients with pheochromocytoma, but it would be neither appropriate nor cost- effective to test for each disease-causing gene in every patient with a pheochromocytoma. An algorithm that takes family history, clinical characteristics, and biochemical phenotype into consideration is shown in Figure 2. In cases of confirmation of a hereditary disorder, one should offer specific genetic tests and genetic counseling to the patient’s family members. Disease screening should be offered to presymptomatic relatives who have a diagnosed mutation, especially because familial syndromes are also associated with other types of tumors and early diagnosis improves the prognosis of these patients. If a genetic syndrome can be established by genetic diagnosis, patient management can be individually tailored based on the specific characteristics of the syndrome.

FIGURE 2    Suggested algorithm for genetic analysis in  patients affected by pheochromocytoma or paraganglioma. If both normetanephrine and methoxytyramine are elevated, follow the algorithm for methoxytyramine. If both normetanephrine and metanephrine are elevated, follow the algorithm for  metanephrine.

SDHAF2 mutation screening should be considered in patients who suffer exclusively from head and neck paragangliomas and who have familial antecedents, multiple tumors, or a very young age of onset and in whom the SDHB/C/D genes have been shown to be negative for mutations. In patients older than 50 years with benign adrenal tumors and no family history, consider TMEM127 testing. *In a patient with elevated normetanephrine in whom clinical features and investigations do not clearly indicate which gene to test, perform immunohistochemistry before proceeding with testing. Abbreviations: DA = dopamine; H/O = history of; MTY = methoxytyramine. (From Karasek D, Shah U, Frysak Z, et al. An update on the genetics of pheochromocytoma. J Hum Hypertens. 2012 May 31 27(3):141–147, 2013. doi: (https://doi.org/10.1038/jhh.2012.20.)

Presymptomatic genetic testing in minors can raise ethical and legal issues, partly owing to the potential emotional impact of the results and the difficulty of obtaining individual informed consent for the testing of minors. To address these issues, the criteria for proper genetic testing should include several steps (Box 2). The advent of next-generation sequencing methods has the potential to decrease the cost of sequencing and enable all patients with pheochromocytoma to be screened.

Box 2
Criteria for Proper Genetic Testing in Minors
Decision should be made by both parents after appropriate consultation with a geneticist.

Parents should be advised about how to inform their child about the hereditary disease and the reason for genetic testing.

The discussion of the most appropriate time for testing for each child should take into account the potential medical benefits and the minor’s schedule (school schedule, birthdays, etc.).

Periods of medical examinations or hospitalization for the carrier parent should be avoided where possible.

Adapted from Lahlou-Laforet K, Consoli SM, Jeunemaitre X, Gimenez-Roqueplo AP. Presymptomatic genetic testing in minors at risk of paraganglioma and pheochromocytoma: Our experience of oncogenetic multidisciplinary consultation. Horm Metab Res 2012;44:354– 358.

Clinical Manifestations

The signs and symptoms of pheochromocytoma are mostly the result of the hemodynamic and metabolic actions of the often inconsistent and disorderly secreted catecholamines on α- and β-adrenoceptors.

Most symptoms are nonspecific, including dyspnea, nausea, weakness, weight loss, visual disturbances, arrhythmias, and mental problems, but when a triad of headaches, palpitations, and sweating is accompanied by hypertension, pheochromocytoma should immediately be suspected. The typical episodic symptoms of catecholamine secretion seen in patients (e.g., palpitations, sweating, headache) may be caused by manipulation of the tumor, endoscopy, anesthesia, ingestion of food or beverages that contain tyramine, and certain medications. However, very often these symptoms occur spontaneously. Psychological stress does not seem to provoke a hypertensive crisis. Many patients have no symptoms or only minor ones. The diagnosis can therefore be easily missed. This is especially true in elderly patients.

Pheochromocytoma can also be discovered during preventive screening, as a result of signs and symptoms related to a mass effect of the tumor, and as incidental findings during imaging studies.

The primary clinical indicators for the diagnosis of pheochromocytoma are summarized in Box 3.

Box 3
Patients Who Should Be Evaluated for Pheochromocytoma or Paraganglioma
Anyone with a triad of headaches, sweating, and tachycardia, whether or not the subject has hypertension

Anyone with a known mutation of one of the susceptibility genes or a family history of pheochromocytoma and paraganglioma

Anyone with an incidental adrenal mass

Anyone whose blood pressure is poorly responsive to standard therapy

Anyone who has had hypertension, tachycardia, or arrhythmia in response to anesthesia, surgery, or medications known to precipitate symptoms in patients with pheochromocytoma and paraganglioma

Differential Diagnosis

Pheochromocytoma is often referred to as “the great mimic,” because it has signs and symptoms that are common in numerous other clinical conditions. As a result, this often leads to the misdiagnosis of pheochromocytoma. Consideration should be given to other conditions that are associated with sympathomedullary activation (e.g., hyperadrenergic hypertension, renovascular hypertension, panic disorders), because they mimic pheochromocytoma most closely. This overlap can be excluded by a normal response to the clonidine suppression test.

Biochemical Diagnosis

Missing a pheochromocytoma can have a fatal outcome. Therefore, tests with high sensitivity are needed to safely exclude a pheochromocytoma without using expensive and unnecessary biochemical follow-up or imaging studies.

Pheochromocytomas can secrete all, none, or any combination of catecholamines (epinephrine, norepinephrine, dopamine). After multiple studies at the National Institutes of Health (NIH), measurement of plasma free metanephrines (the O-methylated metabolites of parent catecholamines), which represent metabolism of catecholamines, but not their secretion, showed superior combined diagnostic sensitivity (98%) and specificity (92%) over all other tests.

Analysis of free metanephrines and metoxytyramine in plasma is currently the method of choice to both detect and exclude the disease. In addition, 24-h urine collections may be used. The decision to rule out pheochromocytoma should be based on normal values of these tests, respecting for age-adjusted reference ranges.

The conditions under which blood samples are collected can be crucial to the reliability and interpretations of test results. The optimal circumstances are noted in Box 4. Besides these conditions, numerous foods and medications can cause direct or indirect interference in the measurement of catecholamines and metanephrines. This should be kept in mind when interpreting a positive test result. Tricyclic antidepressants, phenoxybenzamine (Dibenzyline), acetaminophen, monoamine oxidase inhibitors, and other drugs interfere with test results. Tricyclic antidepressants and phenoxybenzamine lead to elevated norepinephrine and normetanephrine levels. Patients with chronic kidney disease, particularly those on dialysis, commonly have elevated plasma metanephrines, even in the absence of pheochromocytoma. Use of liquid chromatography tandem mass spectrometry (LCMS/MS) is the recommended detection method, because it can remove potentially interfering substances. It is also faster, cheaper, and more specific than other techniques.

Box 4
Optimal Conditions for Blood Collection of Plasma-Free Metanephrines or Catecholamines
Patient is supine for at least 15 minutes before sampling.

Samples are collected through a previously inserted IV to avoid stress associated with the needle stick.

Patient has abstained from nicotine and alcohol for at least 12 hours.

Patient has fasted overnight before blood sampling.

Besides the initial biochemical tests, which can exclude the disease, follow-up tests are required to establish the diagnosis. This is necessary because although the initial tests are specific, the diagnosis of pheochromocytoma is so rare that there are many false-positive results. Options for biochemical follow-up testing are repeated plasma or urinary metanephrine tests, additional sampling for plasma free or urinary fractionated catecholamines, and the clonidine (Catapres) suppression test. Biochemical follow-up testing is not necessary for patients with increases above four times the upper reference limit (URL) of plasma free metanephrines, which are almost always diagnostic for the presence of pheochromocytoma. The previously used glucagon stimulation test should be abandoned, because this test is insufficiently sensitive and can lead to hypertensive complications.

With the increasing proportion of familial tumors, it is important to highlight their different catecholamine profiles. The biochemical profile of a tumor can help guide genetic testing, as reflected in the genetic testing algorithm depicted in Figure 2. Biochemical measurements can also help identify metastatic tumors; a recent study introduced the O-methylated metabolite of dopamine, plasma methoxytyramine, as the most accurate biomarker for discriminating between patients with and without metastases. Several previous studies suggested that increased dopamine could have prognostic significance for metastatic pheochromocytomas, but later methoxytyramine was shown to be a more sensitive biomarker of a tumor’s dopamine production than either plasma or urinary dopamine.

Based on these findings, an algorithm for biochemical diagnosis was designed and is shown in Figure 3.

FIGURE 3    Algorithm for biochemical diagnosis. *It has been  reported that venlafaxine (a serotonin–norepinephrine reuptake inhibitor) can cause an increase of more than four times the URL of normetanephrine. Abbreviations: MIBG = meta-iodobenzylguanidine; MRI = magnetic resonance imaging; PET = positron  emission tomography; URL = upper reference limit.

Localization of Pheochromocytoma

Imaging studies to locate pheochromocytoma should be initiated once there is clear biochemical evidence. For optimal results, anatomic imaging studies such as CT or MRI should be combined with high- specificity functional imaging studies. Computed tomography (CT) rather than magnetic resonance imaging (MRI) was suggested as the first-choice imaging modality because of its excellent spatial resolution of the thorax, abdomen, and pelvis. Use of MRI (T2- weighted) is recommended in patients with metastatic pheochromocytoma, for detection of skull base and neck paragangliomas in patients with surgical clips, in patients with an allergy to CT contrast and for patients in whom radiation exposure should be limited (children, pregnant women, patients with known germline mutations, and those with recent excessive radiation exposure).

Initial imaging should be focused on the adrenals. Negative imaging of the adrenals should be followed by CT or MRI scans of the abdomen and pelvis, where paragangliomas are most commonly located. If these scans are negative, chest and neck images should be obtained. Ultrasound is not recommended to localize pheochromocytoma. Exceptions include children and pregnant women when MRI is not available.

After anatomic imaging, which lacks the specificity to indisputably identify a mass as a pheochromocytoma, functional imaging methods can confirm a tumor as a pheochromocytoma. Functional imaging also detects most cases of metastatic and multifocal disease. They include 123I-MIBG scintigraphy, PET, and somatostatin receptor scintigraphy (Octreoscan), which is not recommended for hereditary tumors. PET scanning is preferred for comprehensive localization of metastatic disease. The most commonly used radiopharmaceuticals in PET scanning are 18F-fluorodopamine (18F-FDA), 18F-3,4- dihydroxyphenylalanine (18F-FDOPA), and 18F-fluorodeoxyglucose (18F-FDG) and recently intoduced 68Ga-DOTATATE. Different circumstances require different radiopharmaceuticals (Figure 4). The 18F-FDOPA PET scan is recommended as the initial imaging modality for head and neck paragangliomas, and the 68Ga-DOTATATE or 18F- FDG PET scan is recommended for metastatic SDHB-related pheochromocytomas. The use of 123I-MIBG scintigraphy in patients with known metastatic pheochromocytoma should be limited to the evaluation of whether a patient qualifies for 131I-MIBG treatment. A combined PET–MRI scan has been introduced and might represent a novel advantageous imaging modality.

FIGURE 4    Recommended imaging studies for the localization  of pheochromocytoma. 2, second choice; 3, third choice. Abbreviations: CT = computed tomography; 18 F-FDA = 18 F-fluorodopamine; 18 F- FDOPA = 18 F-3,4-dihydroxyphenylalanine; 18 F-FDG = 18 F- fluorodeoxyglucose; HNPGL = head and neck  paraganglioma; MIBG = meta-iodobenzylguanidine; MRI = magnetic resonance imaging; PET = positron emission  tomography.

The algorithm described in Figure 4 provides the basis for diagnostic localization of pheochromocytoma.

If all tests return negative, it is advised to repeat noninvasive localization after 2 to 6 months.

Treatment

The optimal therapy for a pheochromocytoma is prompt surgical removal of the tumor, because an unresected tumor represents a time bomb waiting to explode with a lethal hypertensive crisis. In patients with extensive or metastatic disease, surgery can reduce the hormone secretion and prevent critical anatomic complications, such as urinary tract or cord compression or cardiac obstruction. Safe surgical removal requires the efforts of a team made up of an internist, an anesthesiologist, and a surgeon, preferably in a center experienced with this demanding surgery.

Medical Therapy and Preparation for Surgery

The goal of preoperative medical treatment is to control hypertension, maintain stable blood pressure during surgery, minimize adverse effects during anesthesia, and reduce other clinical signs and symptoms caused by high plasma levels of catecholamines.

As soon as the diagnosis is made, blood pressure should be adequately treated for at least 2 weeks before the operation. With satisfactory pretreatment, perioperative mortality has fallen to less than 3%. α-Adrenergic blockade is the basis of medical management and preoperative preparation. The most commonly used nonselective α-adrenoceptor blocker is phenoxybenzamine (Dibenzyline), which is also used for nonhypertensive patients. Other possibilities include α- blocking agents such as prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura). Though these have a shorter duration of action and more often cause hypotension when initially administered for preoperative blood-pressure control, postoperative hypotension is more often seen with phenoxybenzamine. In addition to α-blockers, one can use β-blockers (especially when cardiac tachy- and other arrhythmias occur) and calcium-channel blockers such as nicardipine (Cardene). α-Methyl-l-tyrosine or metyrosine (Demser) has limited use as a premedication. Diuretics should be avoided.

β-Blockers should never be used until α-adrenoceptor blockers have been administered for at least 2 to 3 days, because this can result in severe hypertensive crisis in patients with pheochromocytoma, which is believed to result from inhibition of β2-adrenoceptor–mediated vasodilation (in the presence of catecholamine stimulation of incomplete α-adrenoceptor blockage). It might be presumed that cardioselective β1-adrenoceptor–blocking drugs might be administered without adverse effect. Indeed, almost all adverse reactions to β-blockers in pheochromocytoma patients have involved nonselective β-blockers. Therefore, cardioselective β-blockers, such as atenolol (Tenormin), esmolol (Brevibloc), and metoprolol, (Lopressor) are favored over nonselective blockers for the management of patients with pheochromocytoma. Nevertheless, because of incomplete specificity and likelihood of some actions on β2-adrenoceptors, even β- blockers deemed to be cardioselective should only be administered to patients with pheochromocytoma once there is adequate control of blood pressure by α-adrenoceptor blockade or other means.

Patients can be recommended a salt- and fluid-rich diet. A proposed algorithm for preoperative treatment is given in Figure 5.

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FIGURE 5    Current recommended preoperative treatment  algorithms in patients with pheochromocytoma. Abbreviations: BP = blood pressure; HR = heart rate. (Adapted from Pacak K: Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 2007;92:4069–4079.)

Operative and Postoperative Management

After extensive preoperative preparation, surgery should be performed by an experienced surgical and anesthesiology team.

To ensure adequate preoperative preparation, several criteria have been proposed. First, targeted blood pressure should be below 140/90 mm Hg for at least 24 hours. Orthostatic hypotension should be present, but not below 80/45 mm Hg. In some cases, Doppler or conventional echocardiography are indicated in addition to ECG to detect the presence of cardiomyopathy or coronary artery disease. In patients with a large left adrenal pheochromocytoma, splenectomy is likely; therefore, vaccinations against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis should be given preoperatively.

An experienced anesthesiologist should be aware of potential catecholamine release either as a side effect of the drugs used or as a result of tumor manipulation during the surgery.

A minimally invasive approach is the accepted standard for small, noninvasive, nonmetastatic pheochromocytomas and retroperitoneal paragangliomas, because of its significant postoperative benefits.

Locoregional invasion is difficult to establish preoperatively; therefore it has been recommended that potentially invasive tumors should be initially explored by laparoscopy or retroperitoneoscopy followed by conversion to open surgery in cases of critical adhesion. To prevent permanent glucocorticoid deficiency in patients with bilateral pheochromocytomas, adrenal cortex–sparing surgery is advocated.

There are multiple potential hazardous events and situations during surgery, including anesthesia induction, tumor manipulation, hypotension, and hypoglycemia. The treatment of hypotension with pressor agents is not recommended, especially when long-acting β- blockers or metyrosine have been used; these paralyze the vascular bed in a dilated state. Instead, volume replacement is the treatment of choice.

Postoperative hypertension can indicate incomplete tumor resection. However, during the first 24 hours after surgery, hypertension is most likely attributed to pain, volume overload, or autonomic instability, all of which are treated symptomatically. If hypertension persists, any attempts to collect specimens for biochemical evidence of an incompletely resected tumor should be delayed for at least 5 to 7 days after surgery to ensure that the large increases in both plasma and urinary catecholamines produced by surgery have dissipated.

Close monitoring of blood glucose in the postoperative period is recommended, because its level can be decreased due to decreased glucose production and increased glucose utilization in the absence of the previous catecholamine excess and persistence of α-adrenoceptor blockers.

If the patient is hypotensive, hemorrhage should be excluded first; however, the most likely cause of hypotension is the prolonged effect of the α-adrenoceptor blockers in the presence of reduced plasma catecholamine levels.

Hypertensive Crisis

The most dangerous complication of pheochromocytoma is the occurrence of a hypertensive crisis. Hypertensive crisis can manifest as a severe headache, visual disturbances, acute myocardial infarction, congestive heart failure, or a cerebrovascular accident. It is treated with an intravenous bolus of 5 mg phentolamine (Regitine), a reversible nonselective α-adrenergic antagonist. Phentolamine has a very short half-life, and therefore the same dose can be repeated every 2 minutes until hypertension is adequately controlled. Phentolamine can also be given as a continuous infusion. Continuous intravenous infusion of sodium nitroprusside (Nitropress) or, in some cases, oral or sublingual nifedipine (Procardia),1 can also be given to control hypertension.

Malignant Pheochromocytoma

Malignant pheochromocytoma is established only by the presence of metastases at sites where chromaffin cells are normally absent.

Paragangliomas are malignant more commonly than pheochromocytomas (25% vs. 7%).

Pheochromocytoma metastasizes via hematogenous or lymphatic routes, and the most common metastatic sites are lymph nodes, bones, lung, and liver. About one half of malignant tumors are found at original presentation, and the other half develop at a median interval of 5.6 years, but they can be delayed up to 24 years. Based on the localization of the metastatic lesions, there are short-term and long- term survivors.

Up to 50% of malignant pheochromocytomas develop because of a germline mutation. SDHB mutations with the presence of pheochromocytoma represent about 70% or even more of the risk of malignancy (both in children and adults). Currently, there are several other independent factors of malignancy, including extra-adrenal localization (paragangliomas), the size of the primary tumor (larger than 5 cm), and high methoxytyramine level. Owing to the substantial amounts of methoxytyramine produced by a significant portion of metastatic pheochromocytomas, this measurement should also offer utility in patient management as a surrogate biomarker to assess tumor burden, disease progression, and response to treatment.

Malignant disease is often complicated by clinical manifestations of catecholamine excess and is invariably fatal. The 5-year survival probability after the diagnosis of the first metastasis is reported to be 36% in SDHB carriers and 67% in the absence of this mutation.

Successful management of malignant pheochromocytoma requires a multidisciplinary approach, where pharmacologic treatment, targeted radiotherapy, chemotherapy, and surgery can all play a part. While external-beam radiation has been used for inoperable tumors or for symptom palliation, especially in the treatment of bone lesions, surgical debulking is considered the mainstay of palliative treatment.

About 30% of patients receiving CVD (cyclophosphamide1, vincristine1, and dacarbazine1) exhibit clinical benefits; this number is much higher in patients with SDHB-related malignant tumors (about 70%–80%). Limited documented experience with other chemotherapeutic regimes is available. Somatostatin analogues can be used as an alternative option (for example, DOTATATE). Nowadays, a lot is expected from the novel molecular targeted therapies. In fact, some therapies have already been tested in clinical settings with new possible targets emerging, especially in HIF genes, the mTOR pathway and Hsp90. Individualized treatment should be performed with the intention to cure limited disease and achieve palliation for advanced disease. Figure 6 shows a proposed algorithm for the treatment of metastatic pheochromocytoma.

FIGURE 6    Treatment algorithm for metastatic  pheochromocytoma. Asterisk indicates that the risk of side effects from therapy exceeds the chance of benefit. Abbreviations: CVD = cyclophosphamide, vincristine, and dacarbazine [chemotherapy]; MIBG =  meta-iodobenzylguanidine.

(Adapted from Adjallé R, Plouin PF, Pacak K, Lehnert H: Treatment of malignant pheochromocytoma. Horm Metab Res 2009;41:687-896.)

Prognosis and Monitoring

The long-term survival of patients after successful removal of a benign pheochromocytoma is essentially the same as that of age-adjusted normal subjects. Findings from a large study with a long-term follow- up showed a recurrence rate of 17%, with half the patients showing signs of malignant disease. Recurrences occur more often in patients with extra-adrenal disease and in patients with a hereditary disorder.

At least 25% of patients remain hypertensive after treatment, but this is usually easily controlled with medication.

Clinical follow-up should be lifelong for all patients, but especially in those with an underlying hereditary disorder. The frequency of checkups, once a year or more often, and the kind of diagnostic measurements, only biochemical tests or also imaging studies, should depend on the characteristics of the pheochromocytoma. Follow-up must be more intensive in patients with hereditary and malignant pheochromocytoma.

References

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15.   Lenders J.W., Duh Q.Y., Eisenhofer G., Gimenez-Roqueplo A.P., Grebe S.K., Murad M.H., et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metabol. 2014;99(6):1915–1942.

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17.   Lenders J.W., Pacak K., Huynh T.T., et al. Low sensitivity of glucagon provocative testing for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2010;95:238–245.

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22.  Neumann H.P., Bausch B., McWhinney S.R., et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–1466.

23.     Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92:4069–4079.

24.    Pacak K., Eisenhofer G., Ahlman H., et al. Pheochromocytoma: Recommendations for clinical practice from the First International Symposium, October 2005. Nat Clin Pract Endocrinol Metab. 2007;3:92–102.

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26.     Pasini B., McWhinney S.R., Bei T., et al. Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008;16:79–88.

27.     Renard J., Clerici T., Licker M., Triponez F. Pheochromocytoma and abdominal paraganglioma. J Visc Surg. 2011;148:e409–416.

28.  Timmers H.J., Chen C.C., Carrasquillo J.A., et al. Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography. J Natl Cancer Inst. 2012;104:700–708.

29.  Timmers H.J., Gimenez-Roqueplo A.P., Mannelli M., Pacak K. Clinical aspects of SDHx-related pheochromocytoma and paraganglioma. Endocr Relat Cancer. 2009;16:391–400.

30.  Welander J., Soderkvist P., Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer. 2011;18:R253–76.

31.      Zhuang Z., et al. Somatic Hif-2α gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med.  2012;367:922–930.

For the purpose of this chapter, the term pheochromocytoma also refers to paraganglioma unless otherwise specified.

1  Not FDA approved for this  indication.

1  Not FDA approved for this  indication.

KNOWLEDGE BASE
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