Both PHEO and non–head-neck paraganglioma (PGL) are tumors of the sympathetic nervous system. Although they are similar tumors, they warrant distinction from each other to emphasize their differences in the following: (1) locations, (2) manifestations, (3) secretion profiles, (4) genetic syndromes, (5) difficulty of surgical resection, and (6) propensity to metastasize.
PHEOs are tumors that arise from the adrenal medulla, whereas non–head-neck PGLs arise from the ganglia of the sympathetic nervous system. PHEOs are more common (85%), and may be bilateral (17%). Patients with adrenal PHEOs are less likely to develop detectable metastases (11%) compared to PGLs (30%).
Among adult patients with hypertension, the prevalence of PHEO/PGL is between 0.2% and 0.6%. In children with hypertension, the prevalence of PHEO/PGL is about 1.7%. Nearly 5% of incidentally discovered adrenal masses are found to be PHEOs; about 9% of patients with such PHEOs are normotensive with normal tumor markers and atypical symptoms, particularly dizziness, or vertigo.
In the general population, PHEO and PGL tumors are diagnosed in about 2 to 8/million population yearly; nearly half of these present as an unexplained death. The National Cancer Registry in Sweden has reported that PHEOs/PGLs are discovered in about 2 patients/million people yearly. Autopsy series suggest a higher incidence, varying from about 250 cases/million to 1300 cases/million in a Mayo Clinic autopsy series. Retrospectively, 61% of PHEO/PGL tumors at autopsy occurred in patients who were known to have had hypertension; about 91% had the nonspecific symptoms associated with secretory PHEO/PGL tumors. In one autopsy study, a large number of patients with these tumors had nonclassic symptoms such as abdominal pain, vomiting, dyspnea, heart failure, hypotension, or sudden death (Table 11–6). Some patients have only intermittent hypertension or are not hypertensive at all, increasing the likelihood of missing the diagnosis. Considering these autopsy data, it is clear that the majority of PHEO/PGL tumors are not diagnosed during life. Tumors occur in both sexes and at any age. They are most commonly diagnosed in the fourth and fifth decades, but tend to present earlier in patients with germline mutations predisposing to PGL.
TABLE 11–6Causes of death in patients with unsuspected pheochromocytomas. |Favorite Table|Download (.pdf) TABLE 11–6 Causes of death in patients with unsuspected pheochromocytomas.
Dissecting aortic aneurysm
Acute respiratory distress syndrome
Pheochromocytomas are chromaffin tumors that arise from the adrenal medulla. They account for 90% of all PHEO/PGL tumors in adults and 70% in children. Adrenal PHEOs are usually unilateral (90%). Unilateral PHEOs occur more frequently in the right (65%) versus the left adrenal (35%). Right-sided PHEOs have been described as producing paroxysmal hypertension more often than sustained hypertension, whereas the opposite was true for tumors arising from the left adrenal. Adrenal PHEOs are bilateral in about 10% of adults and 35% of children. Bilateral PHEOs are particularly common (24% overall) in patients with familial pheochromocytoma syndromes caused by certain germline mutations (discussed later).
Basically, the adrenal medulla is a sympathetic ganglion whose neurons secrete neurotransmitters (epinephrine and norepinephrine) into capillaries instead of synapses. The adrenal medulla is surrounded by the adrenal cortex, with which it shares a portal system that bathes it in high concentrations of cortisol. Cortisol stimulates expression of the gene encoding PNMT, the enzyme that catalyzes the conversion of norepinephrine to epinephrine. Adrenal PHEOs nearly always secrete catecholamines with variable amounts of epinephrine as well as norepinephrine and their metanephrine metabolites. Metastases from adrenal PHEOs usually secrete only norepinephrine and its metabolite normetanephrine; they may rarely secrete epinephrine.
PHEOs are typically encapsulated by a true capsule or a pseudocapsule, the latter being the adrenal capsule. PHEOs are firm in texture. Hemorrhages that occur within a PHEO can give the tumor a mottled or dark red appearance. A few black PHEOs have been described, with the dark pigmentation believed to be due to an accumulation of neuromelanin, a catecholamine metabolite. Larger tumors frequently contain large areas of hemorrhagic necrosis that have undergone cystic degeneration; viable tumor may be found in the cyst wall. Calcifications are often present. PHEOs can invade adjacent organs, and tumors may extend into the adrenal vein and the vena cava, resulting in pulmonary tumor emboli. PHEOs vary tremendously in size, ranging from microscopic to 3600 g. The average PHEO weighs about 100 g and is 4.5 cm in diameter.
Sympathetic PGLs (non head-neck) arise from sympathetic ganglia (Figure 11–9). They account for about 10% of all PHEO/PGL tumors in adults and about 30% in children. About 75% are intra-abdominal where they are often mistaken for adrenal PHEOs. PGLs are sometimes nonsecretory and may be confused with other neuroendocrine tumors. They arise most commonly in the perinephric, periaortic, and bladder regions but often found in the chest (25%), arising in the anterior or posterior mediastinum or the heart. Pelvic PGLs may involve the bladder wall, obstruct the ureters, and metastasize to regional lymph nodes. About 36% to 60% of paragangliomas are functional, secreting norepinephrine and normetanephrine. Functional status is not known to affect survival. Nonfunctional PGLs can often concentrate metaiodobenzylguanidine (MIBG) or secrete normetanephrine and CgA. PGLs of the bladder can cause symptoms associated with micturition; such symptoms occur particularly after voiding large amounts of urine, as upon arising in the morning. Large perinephric tumors can cause renal artery stenosis and elevations in plasma renin activity. Vaginal tumors may cause dysfunctional vaginal bleeding. PGLs can rarely arise in central nervous system locations, including the sella turcica, petrous ridge, and pineal region. Cauda equina PGLs can cause increased intracranial pressure.
Left: Anatomic distribution of extra-adrenal chromaffin tissue in the newborn. Right: Locations of extra-adrenal PHEOs reported before 1965. (Reproduced with permission from Coupland R. The Natural History of the Chromaffin Cell. Longmans Green; 1965.)
PGLs commonly metastasize (30%-50%) and present with pain or a mass. They tend to metastasize to the liver, lungs, lymph nodes, and bone. PGLs can be locally invasive and may destroy adjacent vertebrae and cause spinal cord and nerve root compression. PGL metastases usually secrete norepinephrine and normetanephrine. They do not secrete epinephrine and therefore do not typically cause significant weight loss, hyperglycemia, anxiety, or tremor.
Head-neck paragangliomas (HNPGL) are nonchromaffin tumors of parasympathetic ganglia. HN-PGLs occur with an incidence of 10 to 33 cases/million persons. Unlike chromaffin sympathetic paragangliomas, only about 5% of these tumors secrete catecholamines. However, about 23% secrete dopamine, and serum dopamine levels can be a useful tumor marker for patients whose dopamine levels are elevated prior to surgical resection. Carotid body tumors (chemodectomas) are PGLs that arise near the carotid bifurcation. They usually present as a painless neck mass near the carotid that sometimes has a bruit. Carotid body tumors can injure the vagus or hypoglossal nerves and can metastasize. Jugulotympanic PGLs arise in the middle ear and cause tinnitus, hearing loss, and dizziness. The tumor may be seen as a reddish-blue colored pulsating mass behind an intact tympanic membrane (red drum) that blanches when pressure is applied with a pneumatic ear speculum (Brown sign). Glomus jugulare PGLs arise in the jugular foramen. They often cause tinnitus and hearing loss as well as compression of cranial nerves, resulting in dysphagia. Vagal PGLs are rare, usually presenting as a painless neck mass often associated with hoarseness or dysphagia. Head-neck PGLs can also arise in the larynx, nasal cavity, nasal sinuses, and thyroid gland. Head-neck PGLs themselves are of more interest to otolaryngologists than endocrinologists. But they may be seen along with sympathetic PHEO/PGL in familial PGL syndromes, particularly those with germline SDHD and SDHC mutations (discussed later).
Nonchromaffin HN-PGLs behave differently from sympathetic PHEO/PGLs, although they are embryologically related to chromaffin sympathetic PGLs and may arise concurrently with sympathetic PGLs in familial PGL syndromes. These tumors are less likely to be malignant, although their indolence can be deceiving; recurrence and metastases may not appear for many years. Metastases to local nodes, lungs, and bone can occur. Long-term surveillance for recurrence or metastases is recommended for all patients. These tumors can produce CgA, and preoperative determination of CgA is recommended to determine if it will be a good serum marker for tumor recurrence. About 45% of patients with HN-PGLs carry SDHx germline mutations. About 33% harbor SDHD mutations; about 9% have SDHB mutations; about 4% have SDHC mutations. Therefore, gene sequencing is strongly recommended for all patients with HN-PGLs. Individuals harboring such germline mutations are prone to multiple and bilateral HN-PGLs and must also be screened for PGL/PHEO tumors outside the neck (see Genetic Conditions Associated with Pheochromocytomas and Paragangliomas, discussed later).
Neuroblastomas, ganglioneuroblastomas, and ganglioneuromas are sympathetic nervous system tumors that are related to PHEOs and likewise arise from embryonal sympathogonia (see Figure 11–1). Neuroblastoma is the most common malignant disease of infancy and the third most common pediatric cancer, accounting for 15% of childhood cancer deaths.
Ganglioneuroblastomas are composed of a mixture of neuroblasts and more mature gangliocytes; these develop in older children and tend to run a more benign course. Ganglioneuromas are the most benign of these tumors and are composed of gangliocytes and mature stromal cells.
Despite catecholamine secretion, children with neuroblastomas tend to be more symptomatic from their primary tumor or metastases than from catecholamine secretion. Tumors tend to concentrate radiolabeled MIBG, making it a useful imaging and therapeutic agent. Treatment of malignant tumors consists of surgery, chemotherapy, external beam radiation to skeletal metastases, and high-dose 131I-MIBG therapy for patients with MIBG-avid tumors.
Screening for Pheochromocytomas and Paragangliomas
Hypertension is defined in adults as either a systolic blood pressure over 140 mm Hg or a diastolic blood pressure over 90 mm Hg. Hypertension is an extremely common condition, affecting about 20% of all American adults and over 50% of adults over 60 years of age. The incidence of PHEO/PGL is estimated to be less than 0.1% of the entire hypertensive population, but it is higher in certain subgroups whose hypertension is labile or severe. The risk for PHEO/PGL also appears to be higher in patients who have had cyanotic congenital heart disease, possibly due to stimulation of hypoxia-sensitive pathways in the adrenal medulla and paraganglia. Screening for PHEOs should be considered for such patients with severe hypertension and also for hypertensive patients with suspicious symptoms (eg, headaches, palpitations, sweating episodes, or unexplained bouts of abdominal or chest pains; Table 11–7).
TABLE 11–7Patients to be screened for pheochromocytoma and paraganglioma. |Favorite Table|Download (.pdf) TABLE 11–7 Patients to be screened for pheochromocytoma and paraganglioma.
Hypertension in youth
Hypertensive crisis or shock related to:
Drugs: decongestants, glucocorticoids, MAO inhibitors
Hypertensive patients with:
Symptoms listed in Table 11–14
Cyanotic congenital heart disease
Family history of PHEO/PGL or medullary thyroid carcinoma
Gastrointestinal stromal tumors (GIST)
Hypertension that is uncontrolled, severe, or markedly labile
Medullary thyroid carcinoma
Neurofibromatosis and other neurocutaneous syndromes
Personal history of prior PHEO/PGL
Renal cell carcinoma
Patients harboring germline mutations associated with PHEO or PGL
Radiologic evidence of an adrenal mass
Radiologic evidence of a mass in area of paraganglia
Genetic Conditions Associated with Pheochromocytomas and Paragangliomas
PHEOs and PGLs usually appear to occur sporadically, with only about 10% to 15% of affected patients readily giving a family history compatible with a familial germline mutation (Tables 11–8, 11–9, 11–10, 11–11, 11–12). However, 30% to 40% of patients with PHEO/PGL harbor a germline mutation predisposing to the tumor. This disparity is due to variable penetrance for PHEO/PGL, undiagnosed PHEO/PGL among family members with hypertension and sudden death, and patients’ incomplete knowledge of their family’s medical history. Mutations in multiple different genes have been demonstrated to predispose to familial PHEO/PGL (Table 11–8). Somatic mutations are common in sporadic PHEO/PGL. An underlying somatic mutation can be detected in 65% to 80% of all cases of PHEO/PGL.
TABLE 11–8Germline mutations predisposing to pheochromocytoma and paraganglioma.* |Favorite Table|Download (.pdf) TABLE 11–8 Germline mutations predisposing to pheochromocytoma and paraganglioma.*
VHL2: von Hippel Lindau Type 2
VHL Type 2A
VHL Type 2B
VHL Type 2C
EGLN2: Prolyl Hydroxylase Domain 1 (PHD1)
EGLN1: Prolyl Hydroxylase Domain 2 (PHD2)
EPAS1-HIF2A: Hypoxia-Inducible Factor-2α (HIF-2α)
SDHA: Succinate Dehydrogenase complex subunit A: PGL5**
SDHB: Succinate Dehydrogenase complex subunit B: PGL4**
SDHC: Succinate Dehydrogenase complex subunit C: PGL3**
SDHD: Succinate Dehydrogenase complex subunit D: PGL1**
SDAF2: Succinate Dehydrogenase Assembly Factor 2: PGL2**
MDH2: Malate Dehydrogenase 2
FH: Fumarate Hydratase
RET: Multiple Endocrine Neoplasia Type 2 (MEN 2)
NF-1: von Recklinghausen Neurofibromatosis 1
KIF1β: Kinesin Family member 1β
MAX: Myc-Associated factor X
TMEM127: Transmembrane protein 127
TABLE 11–9Suggested lifetime surveillance protocol for individuals with a VHL2 germline mutation. |Favorite Table|Download (.pdf) TABLE 11–9 Suggested lifetime surveillance protocol for individuals with a VHL2 germline mutation.
Patient self-monitors blood pressure regularly and reports hypertension or suspicious symptoms.
Age 10-15 years: Yearly retinal examination and blood pressure measurement; plasma free normetanephrine levels.
Age >15 years: Twice yearly physical examinations with blood pressure measurement; plasma free normetanephrine.
For suspicious symptoms and before major surgical procedures and pregnancy: biochemical screening for pheochromocytoma with plasma free normetanephrine.
Every 2 years: MRI scanning (with intravenous contrast) of the entire brain and spinal cord (VHL types 2A and 2B VHL); MRI scanning of the abdomen.
For abnormal biochemical screening: MRI or CT scan of the abdomen (nonionic contrast) with thin-section adrenal cuts; 123I-MIBG SPECT or 18F-FDA PET scan to confirm the identity of small masses.
TABLE 11–10Suggested lifetime surveillance protocol for individuals with a germline SDHB, SDHC, or paternally-inherited SDHD mutation. |Favorite Table|Download (.pdf) TABLE 11–10 Suggested lifetime surveillance protocol for individuals with a germline SDHB, SDHC, or paternally-inherited SDHD mutation.
Patient self-monitors blood pressure regularly and reports hypertension or suspicious symptoms.
Twice yearly: physical examination and blood pressure; plasma-fractionated free metanephrines and serum CgA.
Yearly: scanning with ultrasound of the neck, abdomen, and pelvis.
Every 3 years: MRI of the chest, abdomen, and pelvis to detect early PHEO/PGL and renal cell carcinoma (RCC).
MRI of the head and neck (SDHC, paternal SDHD mutations) to detect head-neck PGL and jugular tympanicum PGL.
For suspicious symptoms and before endoscopies, major surgical procedures, and pregnancy: complete biochemical screening for pheochromocytoma with fractionated plasma metanephrines and serum chromogranin A.
For patients with epigastric discomfort: upper endoscopy, due to incidence of gastrointestinal stromal tumors (GIST).
For patients with headache, amenorrhea, hypogonadism, or clinical suspicion for a pituitary adenoma: biochemical evaluation and MRI for pituitary adenoma.
For abnormal biochemical screening: MRI or CT scan (nonionic contrast) of the chest, abdomen, and pelvis or 18F-FDG-PET with CT fusion scan; to confirm ambiguous results: 123I-MIBG SPECT or 18F-FDA PET scan.
TABLE 11–11Suggested lifetime surveillance protocol for individuals carrying a RET proto-oncogene germline mutation. |Favorite Table|Download (.pdf) TABLE 11–11 Suggested lifetime surveillance protocol for individuals carrying a RET proto-oncogene germline mutation.
Patient self-monitors blood pressure regularly and reports hypertension or suspicious symptoms.
Twice yearly: physical examination with blood pressure and neck examination; plasma free metanephrine; serum calcium and albumin (serum PTH if RET codon 634 mutation); serum calcitonin (patients with intact thyroid or with medullary thyroid carcinoma).
Prophylactic thyroidectomy: by age 5 years for MEN 2A and by 6 months for codon 918 mutations (MEN 2B).
Yearly thyroid ultrasound for patients with an intact thyroid.
For rising or elevated serum calcitonin levels after thyroidectomy: close surveillance for medullary thyroid carcinoma is required. 18FDG-PET-CT fusion scans are particularly helpful.
For suspicious symptoms and before major surgical procedures and pregnancy: biochemical screening for pheochromocytoma with plasma free metanephrine.
For abnormal biochemical screening for pheochromocytoma: MRI or CT scan of the abdomen (nonionic contrast) with thin-section adrenal cuts; 123I-MIBG SPECT or 18F-FDA PET scan to confirm the identity of small masses.
TABLE 11–12Suggested lifetime surveillance protocol for individuals carrying a NF-1 gene mutation. |Favorite Table|Download (.pdf) TABLE 11–12 Suggested lifetime surveillance protocol for individuals carrying a NF-1 gene mutation.
Patient self-monitors blood pressure regularly and reports hypertension or suspicious symptoms.
Twice yearly: physical and neurologic examination and blood pressure, and a careful examination of the skin for development or growth of neurofibromas.
Yearly: CBC with WBC differential; plasma-fractionated free metanephrines; complete eye examination with visual fields.
Before major surgical procedures and pregnancy: plasma-fractionated free metanephrines to screen for pheochromocytoma.
For abnormal biochemical screening: MRI or CT scan of the abdomen (nonionic contrast); 123I-MIBG SPECT or 18F-FDA PET scan.
About 20% of patients with an apparently sporadic single PHEO/PGL and no known family history of PHEO/PGL can be shown to harbor a germline mutation, if extensive genetic testing is performed. Such unsuspected germline mutations are more prevalent in PGLs than in PHEOs. For example, about 9% of patients with apparently sporadic, unilateral PHEOs have been found to have von Hippel-Lindau (VHL) mutations. Genetic testing is advisable for all patients with a PHEO/PGL. Genetic testing is strongly recommended for patients with extra-adrenal paragangliomas or multifocal tumors, onset of symptoms before age 45 years, prior history of head-neck PGL, family history of PHEO/PGL or other tumors associated with MEN 2 or VHL. Genetic screening is also performed for patients with other manifestations of genetic syndromes noted later. Commercial genetic screening is available. Ambry Genetics offers a panel (PGLNext) that screens 12 genes for germline mutations and deletions that predispose to PHEO/PGL: FH, MAX, MEN 1, NF-1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, and VHL. Neurofibromatosis is usually diagnosed clinically without genetic testing, since the clinical manifestations of NF-1 are usually unmistakable and the NF-1 gene is very large and costly to sequence.
Known germline mutations that predispose to PHEO/PGL have been categorized into two clusters, according to their reputed common underlying mechanisms of tumorigenesis. Patients who harbor such germline mutations require close surveillance. Suggested lifetime surveillance protocols for patients with the most frequent germline mutations are presented in Tables 11–9 to 11–12.
Cluster 1 germline or somatic mutations involve genes that cause a pseudohypoxia signature that triggers an overabundance of hypoxia inducible factor (HIF), which promotes angiogenesis and cell division. Patients harboring mutations in this cluster might be sensitive to hypoxia. Individuals harboring SDHD germline mutations who live at high altitude have been shown to develop more PGLs that present earlier in life, compared to other affected members of their kindred living at sea level. However, it is not known whether altitude affects tumorigenesis in kindreds with other germline mutations. Whether other causes of chronic hypoxia (eg, sleep apnea, chronic obstructive pulmonary disease) might have a tumor-promoting effect upon these patients is also unknown. VHL disease is the most common condition associated with Cluster 1A mutations. Mutations in PHD1, PHD2, and HIF2A can also predispose to PHEO/PGL. Germline mutations in the gene Cluster 1B mutations encode proteins that are critical for oxidative metabolism in the tricarboxylic acid (TCA) cycle, also known as the citric acid cycle or Krebs cycle. These include mutations in the following: SDHA, SDHB, SDHC, SDHD, SHAF2, MDH2, and FH.
von Hippel-Lindau (VHL) 3p25.3 The VHL gene is a tumor suppressor gene that encodes two different proteins (pVHL) of 213 and 160 amino acids. Both gene products have a role in the degradation of the hypoxia-inducible factors (HIF-1α and HIF-2α) as follows: the pVHL proteins have an α domain that binds with the protein elongin. The β domain of pVHL is open to bind HIF that has been hydroxylated, a reaction that requires oxygen. This complex then binds ubiquitin that targets HIF for intracellular destruction by proteases. In this manner, well-oxygenated cells destroy HIF. Conversely, cells that are either oxygen-deprived or that lack functional pVHL cause an intracellular accumulation of HIF, a transcription factor that induces the production of vascular endothelial growth factor (VEGF), erythropoietin, erythropoietin receptor, glucose transporter-1, and platelet-derived growth factor-B; these proteins allow an adaptation to hypoxia, but, in excess, they are believed to enhance tumorigenesis.
A germline mutation in the VHL tumor suppressor gene has been identified in most families with VHL disease. About 60% of affected families have loss-of-function mutations (30% with truncated pVHL and 30% with large VHL gene deletions), resulting in type 1 VHL. About 40% have missense mutations, resulting in an amino acid substitution in pVHL, causing type 2 VHL (discussed later).
In patients with VHL disease, vascular tumors, particularly hemangioblastomas, renal cysts, and renal cell carcinomas, develop when there is a somatic second-hit on the wild-type allele in one cell; this can be caused by various spontaneous mutations (loss of heterozygosity) or promoter hypermethylation of the wild-type VHL allele. In these vascular tumors, a second-hit is usually necessary to cause sufficient accumulation of HIF to promote tumorigenesis. In contrast, PHEOs that develop in patients with type 2 VHL typically have a normal wild-type VHL allele. However, most VHL-associated PHEOs also demonstrate a somatic loss of chromosome 3 (94%) or chromosome 11 (86%).
Although certain VHL kindreds are predisposed to develop PHEOs, it is not the dominant tumor of this syndrome. PHEOs develop only in patients with type 2 VHL (discussed later), and these are different from sporadic PHEOs, in that they are less likely to be malignant, more likely to be bilateral, more likely to be asymptomatic, and and more likely to present at an earlier age. Adrenal medullary hyperplasia is not associated with PHEOs in VHL, in contrast to MEN 2. Although most VHL-associated PHEOs arise in the adrenal, extra-adrenal sympathetic PGLs sometimes occur and head-neck parasympathetic PGLs have been described. The mean age of presentation for a PHEO/PGL in type 2 VHL is 28 years; the youngest reported patient was 5 years old. In VHL disease, most PHEO/PGLs are relatively small (average 3.6 cm) and are characterized by a thick vascular tumor capsule.
The different types and subtypes of VHL are as follows:
Type 1 VHL—Affected members of families with type 1 VHL do not develop PHEOs. They tend to have loss-of-function VHL gene mutations, particularly gene deletions, frameshifts, or truncations.
Type 2 VHL—Affected members of families with type 2 VHL mutations are prone to develop PHEOs. These patients carry VHL missense mutations. Type 2 VHL may be divided into subtypes as follows:
Type 2A VHL—PHEOs, hemangioblastomas, low risk of renal cell carcinoma.
Type 2B VHL—PHEOs, hemangioblastomas, high risk of renal cell carcinoma.
Type 2C VHL—PHEOs, no hemangioblastomas, no renal cell carcinomas.
The prevalence of VHL is at least 1/36,000 persons. About 20% of cases are caused by de novo mutations and do not have a family history of VHL. VHL disease carriers are predisposed to multicentric hemangioblastomas in the retina (retinal angiomas), cerebellum, and spinal cord. Renal cysts and renal clear-cell carcinoma commonly develop.
Pancreatic lesions occur in about 70% of patients with VHL. Such lesions are usually discovered incidentally and are usually multiple cysts or cystadenomas. Although such lesions are usually benign, they can cause pancreatitis or jaundice by obstruction of the pancreatic duct or the bile duct, respectively. Pancreatic neuroendocrine tumors (pNETs) occur in up to 17% of cases and are usually multiple. NETs have also arisen outside the pancreas in the duodenum and gallbladder. In VHL disease, NETs tend to occur at a relatively early age of about 35 years. They are usually nonfunctioning. However, they may secrete CgA, which can be a useful tumor marker. Such NETs are usually indolent, particularly those with a diameter under 3 cm and a doubling-time of over 500 days; such NETs are often followed clinically with scanning every 2 years. However, larger and more aggressive NETs are more likely to be malignant and are usually resected. Only 60% are visible with somatostatin receptor scintigraphy.
Other endocrine abnormalities have been described in VHL disease, including hyperparathyroidism and an aggressive pituitary adenoma that secreted both prolactin and growth hormone.
Endolymphatic sac tumors may occur, resulting in hearing loss, vertigo, or ataxia. Adnexal cystadenomas of probable mesonephric origin (APMO) are found in many women with VHL. APMOs may develop in the ovary, broad ligament, vagina, uterine cervix, and vulva. Equivalent epididymal cystadenomas occur in men with VHL.
Genetic testing for VHL disease should be done in children born to a parent with known VHL disease. If VHL disease is suspected, but the family’s VHL mutation is not known, the patient must be screened for point mutations by direct VHL gene sequencing of the entire coding region and splice junctions.
The clinical diagnosis of VHL disease is made when a patient with a known VHL gene mutation develops one tumor typical of VHL. In patients without a known family history of VHL, a presumptive diagnosis of VHL is made when they develop two or more hemangioblastomas or a hemangioblastoma in association with a PHEO or clear-cell renal carcinoma. Similarly, VHL disease should be suspected in patients with multiple VHL-associated tumors or one VHL-associated tumor that presents at a young age (<50 years for PHEO or hemangioblastoma; <30 years for clear-cell renal carcinoma). Such patients should have VHL gene sequencing.
In a French series of 36 patients with PHEOs and VHL disease, PHEOs were the presenting tumor in 53%. PHEOs tended to develop at an early age and were bilateral in 42%; concurrent PGLs were present in 11%. Three of the 36 patients had a malignant PHEO. In 18% of these patients with VHL disease, PHEO was the only known manifestation. Approximately 9% of patients with apparently sporadic, unilateral PHEO have been found to harbor a germline VHL mutation. In certain regions of Europe, the percentage is up to 20%, due to a founder effect for the Tyr98His black forest mutation that is more common in kindreds with German ancestry.
PHEOs in VHL disease exclusively produce norepinephrine. Therefore, the metabolite of norepinephrine (normetanephrine) is also produced in these tumors. Plasma free normetanephrine levels are usually elevated when patients with VHL disease develop a PHEO. Therefore, plasma free normetanephrine is the best screening test for patients who harbor a type 2 VHL gene missense mutation.
In patients with VHL, a major risk to life is the development of a renal cell carcinoma. When an abdominal computed tomography (CT) scan detects a solid renal lesion, it must be removed. Even simple cystic renal lesions are considered premalignant, and their removal is advisable if renal function can be preserved. If renal cysts are observed, they must be followed every 6 months with dynamic thin-section CT scanning to search for characteristics of malignancy: growth, wall irregularity, or septation. Individuals carrying a VHL mutation must have close medical surveillance. A surveillance protocol is recommended in Table 11–9.
Egg Laying Gene Nine (EGLN) These genes encode hypoxia-inducible factor—prolyl hydroxylase (HIF-PH) proteins (ie, prolyl hydroxylase domain [PHD] proteins). PHD proteins are enzymes that hydroxylate hypoxia-inducible factor (HIF), marking it for degredation by the VHL ubiquitination complex. Malfunction of PHD proteins causes an increase in HIF, predisposing to congenital erythrocytosis and formation of PHEO/PGL tumors. PHD proteins exist as three isoforms: PHD1, PHD2, and PHD3, which are encoded by the EGLN homolog genes: EGLN2, EGLN1, and EGLN3, respectively. PHEO/PGL tumors have been described in patients with germline mutations in EGLN2 and EGLN1. An additional mutation of the wild-type EGLN allele in an adrenal medulla or paraganglion is required to give rise to a sympathetic PHEO/PGL. In patients harboring EGLN germline mutations, available first-degree relatives have tested negative for the mutation, indicating that these may be early post-zygotic mutations. These gene mutations are different from VHL gene mutations, although both cause an increase in HIF, and provide an alternative mechanism for PHEO/PGL tumorigenesis.
EGLN2 19q13.2: This gene encodes the enzyme prolyl hydroxylase domain 1 (PHD1). Germline mutations in EGLN2 are rare. The index case was a woman who presented at age 6 with erythrocytosis (borderline elevated serum erythropoietin levels) that required phlebotomies at age 10, hypertension and a PHEO at age 14 that was resected but recurred and metastasized to a thoracic periaortic lymph node. At age 48, she was found to have contralateral PHEOs, an aortocaval PGL, a pelvic PGL, and a bladder PGL.
EGLN1 1q42.1: This gene encodes the enzyme prolyl hydroxylase domain 2 (PHD2). Germline mutations in EGLN1 are rare. The index case was a woman who presented at age 16 with erythrocytosis (borderline elevated serum erythropoietin levels) requiring phlebotomies. At age 39, she was found to have hypertension and a left PHEO and 2 PGLs in the left renal hilum. At age 60, a right PHEO and 3 periaortic PGLs were resected.
Endothelial PAS1 (EPAS1) aka Hypoxia Inducible Factor 2A (HIF2A) 2p21-p16 The EPAS1-HIF2A gene encodes the protein eponymously known as endothelial PAS domain-containing 1 (EPAS1) protein or hypoxia inducible factor 2α (HIF-2α). Rare mutations in EPAS1-HIF2A cause a syndrome of early PHEO/PGL, somatostatinomas, and erythrocytosis. Mutations causing constitutive activation and prolonged half-life of HIF-2α are typically somatic mutations found in sporadic PHEO/PGL tumor tissue. However, patients with EPAS1 constitutively activating germline mutations have been described. A familial PHEO/PGL syndrome has not been described with this gene. These appear to be post-zygotic germline mutations that affect only certain related tissues. The index case presented with erythrocytosis in early childhood and high serum erythropoietin levels. At age 35, he was found to have hypertension and a retroperitoneal PGL, followed by multiple additional PGLs with pulmonary and bone metastases. Other patients have been described with multiple PGLs being detected as early as age 14 years. Affected patients are also prone to develop duodenal or pancreatic somatostatinomas and retinal abnormalities with decreased visual acuity.
B. Cluster 1B Mutations: PHEO/PGL syndromes due to mutations involving the tricarboxylic acid cycle (TCA or Krebs cycle)
Certain kindreds have a proclivity to develop multicentric head-neck PGLs, sympathetic PGLs, and adrenal PHEOs. They are now also known to be prone to develop renal cell carcinomas and pituitary adenomas. These autosomal dominant syndromes were originally called familial PGL syndromes, although some patients develop adrenal PHEOs. Four of the familial PGL syndromes are caused by mutations in three of the four genes encoding mitochondrial complex II or a gene encoding their assembly into succinate dehydrogenase, which catalyzes the conversion of succinate to fumarate in the mitochondrial Krebs cycle (citric acid cycle) ultimately leading to oxidative phosphorylation and ATP generation. The resultant accumulation of intracellular succinate prevents the degradation of HIF; high intracellular levels of HIF stimulate cell division and angiogenesis, thereby promoting tumorigenesis. The responsible mutations occur in the genes encoding the following: SDH subunit B (SDHB, PGL 4), SDH subunit C (SDHC, PGL 3), SDH subunit D (SDHD, PGL 1), and succinate dehydrogenase complex assembly factor 2 (SDAF2, PGL 2). SDHB encodes a catalytic subunit, while SDHC and SDHD encode membrane-anchoring subunits involved in electron transport. SDHC and SDHD (paternal) have an autosomal dominant proclivity to develop PGLs; those with SDHB and SDHD mutations can also develop adrenal PHEOs. Overall, about 12% of patients with PGLs and PHEOs have been found to harbor one of these germline mutations.
These syndromes are caused by mutations in nuclear genes that encode 3 of the 4 subunits that comprise mitochondrial complex II (SDH) that oxidizes succinate to fumarate (Krebs cycle). The four subunits of the tetrameric SDH consist of a 70-kDa flavoprotein (SDHA), a 30-kDa iron-sulfur protein (SDHB), a 15-kDa subunit of cytochrome b (SDHC), and a 12-kDa subunit of cytochrome b (SDHD). SDHC and SDHD components of cytochrome b are integral mitochondrial membrane subunits anchoring the catalytic subunits SDHA and SDHB that are involved with the electron transport chain, transferring an electron to coenzyme Q (ubiquinone). SDH is essential for aerobic energy production and the TCA cycle. Genetic defects cause mitochondrial dysfunction making the cells functionally hypoxic. This leads to increased secretion of VEGF that is necessary for tumor growth. (SDHA germline mutations do not cause PGLs but rather cause Leigh syndrome, a fatal early-onset mitochondrial neurodegenerative disease.)
All patients with PGLs and PHEOs ideally should be tested for germline mutations in SDH; such testing is highly recommended for patients with neck PGLs (>15% have germline mutations), other PGLs (particularly multifocal PGLs or PHEOs), a family history of PGL or PHEO, and PGLs arising in patients with Dutch ancestry.
Carney-Stratakis syndrome: Some patients with loss-of-function mutations in SDHB, SDHC, or SDHD can develop the dyad of PGLs and gastric stromal sarcomas, which is known as Carney-Stratakis syndrome. Tumors present relatively early, with an average age of 24 years at diagnosis. Women and men are affected equally. The PGLs that develop in this syndrome are usually functional and develop in the abdomen, rather than head-neck region. In this syndrome, the condition is familial, and affected kindreds do not develop pulmonary chondromas, factors that distinguish it from Carney triad.
Succinate Dehydrogenase complex subunit A (SDHA) 5p15 SDHA germline mutations are usually lethal. SDHA mutations are more typically somatic mutations that have been found in sporadic paragangliomas. This is also known as PGL 5.
Succinate Dehydrogenase complex subunit B (SDHB) 1p36 SDHB germline mutations cause a familial PGL/PHEO syndrome known as PGL 4. Affected individuals are prone to develop PGLs all along the parasympathetic and sympathetic chains, from the neck to the pelvis, and can develop adrenal PHEOs as well; they are less prone to glomus tumors of the neck than individuals with SDHD mutations. Sympathetic PGLs that arise in patients with SDHB germline mutations are much more likely to be metastatic (35%) at the time of diagnosis than tumors seen in patients with SDHD germline mutations. In one kindred with a large SDHB exon 1 deletion, the phenotypic penetrance of PGL was 35% by age 40. There have been no clear genotype-phenotype correlations with different SDHB mutations. However, certain kindreds have a distinctly higher penetrance. Also, some point SDHB “mutations” may be relatively benign genetic polymorphisms rather than pathological mutations. Due to the rarity of these tumors, the precise penetrance for each SDHB mutation has not been fully determined. Other malignancies may also be more common in patients with SDHB mutations. In one series of 53 patients, renal cell carcinoma was detected in two patients. Pediatric neuroblastoma has been described in a child with an SDHB exon deletion.
Succinate Dehydrogenase complex subunit C (SDHC) 1q2 SDHC encodes a protein of the same name, also known as succinate dehydrogenase cytochrome b560 subunit, mitochondrial. The SDHC protein forms a transmembrane dimer with SDHD that anchors complex II (SDHB and SDHA) to the inner mitochondrial membrane. SDHB germline mutations cause a familial PGL/PHEO syndrome known as PGL 3. SDHC germline mutations predispose to parasympathetic HN-PGLs and sympathetic PGLs but not adrenal PHEOs. About 4% of patients with HN-PGLs harbor an SDHC germline mutation.
Succinate Dehydrogenase complex subunit D (SDHD) 11q23 The resultant protein is also known as succinate dehydrogenase (ubiquinone) cytochrome b small subunit, mitochondrial (CybS). SDHD germline mutations cause a familial PGL/PHEO syndrome known as PGL 1. Only patients with paternally inherited SDHD gene mutations are predisposed to develop PGLs and PHEOs. Affected individuals are particularly prone to develop parasympathetic HN-PGLs that do not typically secrete catecholamines. About 15% of patients with HN-PGLs harbor this germline mutation. Patients with SDHD mutations are more prone to develop renal cell carcinoma and can also develop Carney-Stratakis syndrome: gastrointestinal stromal cell tumors (GIST); such tumors have an additional acquired somatic SDHD mutation in their normal wild-type gene.
In kindreds with SDHD gene mutations, only paternal transmission of the mutated gene causes the susceptibility to PGLs and PHEOs; this phenomenon is known as maternal genomic imprinting, meaning that the maternally inherited mutant gene does not cause the syndrome in the mother’s offspring. A male who inherits an SDHD mutation from his mother does not express the phenotype (no PGLs) but can pass on the gene to his children, who can express the phenotype (PGL/PHEO). A female who inherits an SDHD mutation from her father develops PGL/PHEOs, but her children who inherit the SDHD mutation are not affected.
Individuals with SDHD germline mutations are particularly prone to develop HN-PGLs that arise from parasympathetic ganglia that are embryologically related to sympathetic paraganglia. These tumors do not usually secrete catecholamines and are known as nonchromaffin PGLs. Multicentric tumors have been reported in about 74% of PGL patients with SDHD mutations. About 50% of patients with seemingly isolated PHEOs and a germline SDHD mutation harbor a hidden PGL. Sympathetic PGLs and adrenal PHEOs (8%) also occur in affected individuals.
A founder SDHD mutation has been noted in families of Italian descent: Q109X. Three SDHD founder mutations have been discovered in families of Dutch ancestry: Leu95Pro, Asp92Tyr, and Asp92Tyr. An investigation of 243 family members with a paternally inherited Asp92Tyr mutation in SDHD reported the following. The risk of developing a PGL or PHEO was 54% by age 40 years, 68% by 60 years, and 87% by 70 years. Most patients had HN-PGLs, while some had sympathetic PGLs and 8% had PHEOs. Multiple tumors were found in 65%.
Malignancy appears to be uncommon in patients with SDHD-associated PGLs. However, malignant neck PGLs can be indolent, and metastases to neck nodes, lungs, and bones may not be clinically evident for many years. Therefore, lifelong surveillance is necessary (see Table 11–10).
Succinate Dehydrogenase complex Assembly Factor 2 (SDAF2) 11q12.2 This gene is also known as SDH5. Germline mutations in SDAF2 cause familial PGL syndrome type 2 (PGL 2). The SDAF2 gene is a member of a family of genes known as mitochondrial respiratory chain complex assembly factors. There appears to be maternal imprinting and only individuals with a paternally inherited mutated gene develop both PGLs and PHEOs. The most common mutation has been Gly78Arg.
Malate Dehydrogenase 2 (MDH2) 7cen-q22 The MDH2 gene encodes an enzyme of the TCA cycle. The index case for this germline mutation was a 55-year-old man who presented with multiple malignant PGLs.
Fumarate Hydratase (FH) 1q42.1 The FH gene encodes another enzyme in the TCA cycle. Germline FH mutations predispose to familial leiomyomatosis and renal cell carcinoma (FLRCC). Affected individuals develop cutaneous and uterine leiomyomatosis type 2 papillary renal cell carcinoma, and PGLs. About 40% of PGLs have presented with metastatic disease.
Cluster 2 germline or somatic mutations cause an overexpression of RAS/MAPK and P13K-AKT-mTOR signaling pathways. Cluster 2 mutations include the following: (1) RET proto-oncogene activating mutations (Multiple Endocrine Neoplasia Type 2A, MEN 2A and MEN 2B); (2) von Recklinghausen Neurofibromatosis Type 1 (NF-1); (3) KIF1β; (4) MAX; and (5) TMEM127.
RET proto-oncogene 10q11.2 RET is an abbreviation for the term “rearranged during transfection.” Germline activating mutations in the RET proto-oncogene give rise to multiple endocrine neoplasia type 2 (MEN 2A and MEN 2B).
The first description of PHEO was in a patient with MEN 2. In 1882, Felix Fränkel described PHEOs in an 18-year-old woman with bilateral adrenal tumors; genetic testing of four living relatives has revealed a germline mutation in the RET proto-oncogene.
The prevalence of MEN 2 has been estimated at 1 in 30,000. MEN 2 is an autosomal dominant disorder that causes a predisposition to medullary thyroid carcinoma, PHEO, duodenal or pancreatic somatostatinomas (rare), and other abnormalities described later. MEN 2 is caused by an activating mutation in the RET proto-oncogene on chromosome 10q11.2. RET consists of 21 exons that encode a transmembrane receptor tyrosine kinase that is expressed in neural crest tissues. The constitutive activation of RET causes hyperplasia in affected tissues, including the adrenal medulla. Additional mutation(s) are believed to be required for a PHEO to develop. The somatic loss of a tumor suppressor gene on chromosome 1p appears to be necessary for PHEO formation. Additionally, reduced expression of NF-1 has been reported in a minority of PHEOs arising in patients with MEN 2 mutations.
MEN 2 kindreds can be grouped into two distinct subtypes: MEN 2A (90%) and MEN 2B (10%). Patients with MEN 2A have various single amino acid missense mutations affecting the extracellular RET domain that cause RET homodimerization and constitutive activation of its tyrosine kinase. Patients with MEN 2B have a particular missense mutation (codon 918, exon 16) affecting the intracellular domain at the RET tyrosine kinase’s catalytic site, causing constitutive activation. In either subtype, PHEOs usually develop in the adrenals (96%); extra-adrenal paragangliomas are rare (4%). About 42% of patients with PHEO in MEN 2 have hypertension, usually paroxysmal. Overall, only about 53% exhibit symptoms of PHEO. Each specific type of mutation in the RET codon determines each kindred’s idiosyncrasies, such as the age at onset and the aggressiveness of medullary thyroid carcinoma.
A limited number of RET gene exons have been found to harbor mutations that are capable of causing constitutive activation of the tyrosine kinase. RET exons 10, 11, 13, 14, 15, and 16 are usually involved. Therefore, routine genetic screening searches for mutations only in these exons. If no mutation is found in these exons, the remaining 15 exons can be sequenced in a research laboratory. When an affected kindred’s RET mutation is already known, all first-degree relatives in the kindred should be screened for that specific mutation.
PHEOs arise in the adrenals, and extra-adrenal PGLs are uncommon in MEN 2. In patients with MEN 2, only about 4% of PHEOs are found to be metastatic, possibly because of earlier detection. When PHEOs develop in patients with MEN 2, they are bilateral in about two-thirds of cases; however, with close surveillance of affected kindreds, PHEOs are discovered earlier and are more likely to be unilateral. After a unilateral adrenalectomy for PHEO in a patient with MEN 2, a contralateral PHEO develops in about 50% of patients an average of 12 years after the first adrenalectomy. In patients with MEN 2, adrenal PHEOs produce norepinephrine and epinephrine (with its metabolite metanephrine). When screening for small PHEOs, plasma catecholamine concentrations may be normal, but plasma metanephrine concentrations are usually elevated, making plasma free metanephrines the screening test of choice for these patients. However, some PHEOs are detected only by a 24-hour urine determination for fractionated metanephrines, catecholamines, and creatinine.
MEN 2A (Sipple syndrome)—Patients with this genetic condition develop medullary thyroid carcinoma (95%-100%), hyperparathyroidism due to multiglandular hyperplasia (20%), and PHEO (50%; range 6%-100% depending on the kindred) or adrenal medullary hyperplasia. Patients with MEN 2A also have an increased incidence of cutaneous lichen amyloidosis and Hirschsprung disease.
Individuals belonging to an MEN 2A kindred should have genetic testing for RET proto-oncogene mutations by 5 years of age to determine if they carry the genetic mutation that will require prophylactic thyroidectomy and close surveillance for PHEO and hyperparathyroidism.
More than 85% of the mutations in MEN 2A families affect codon 634 in exon 11 of the RET proto-oncogene. PHEOs tend to present in middle age, often without hypertension. The exceptions are patients who harbor a RET C634R (arginine) germline mutation, in whom 59% develop bilateral PHEO by age 40 and who therefore require more intense surveillance for PHEO at an earlier age. Individuals with mutations in RET codon 630 also have a high incidence of PHEO. PHEOs also occur in most other kindreds with MEN 2A. Screening for PHEO should commence with the routine blood pressure measurements that are performed during examinations in childhood for medullary thyroid carcinoma and follow-up of hypothyroidism following thyroidectomy. At about age 15 years, affected individuals should commence yearly screening for PHEO with plasma free metanephrine determinations.
Certain RET mutations (codons 609, 768, V804M, and 891) rarely produce PHEOs. Less intense screening for PHEOs is required in patients with these mutations.
MEN 2B—Over 90% of patients with MEN 2B have a single amino acid substitution of methionine to threonine on codon 918 in exon 16 that affects the intracellular domain of tyrosine kinase. About 50% of such mutations are familial while the rest arise de novo as post-zygotic mutations and are sporadic. Patients with this genetic condition are prone to develop mucosal neuromas, PHEO, adrenal medullary hyperplasia, and aggressive medullary thyroid carcinoma. About 50% of affected patients develop all three manifestations of the syndrome. Mucosal neuromas tend to develop first and occur in most patients. They appear as small bumps on the tongue, lips and buccal mucosa, eyelids, cornea, and conjunctivae. The lips and eyelids may become diffusely thickened. Intestinal ganglioneuromatosis occurs and alters intestinal motility, causing diarrhea or constipation and occasionally megacolon. Affected individuals have a marfanoid habitus with associated spinal scoliosis or kyphosis, pectus excavatum, a high-arched foot and talipes equinovarus (club foot) deformities. In patients with MEN 2B, medullary thyroid carcinoma tends to be aggressive and occurs at an earlier age than in patients with MEN 2A. Members of kindred with MEN 2B should immediately have genetic testing for their family’s RET proto-oncogene mutation. If an individual is found to carry the family’s RET mutation, early prophylactic thyroidectomy is advisable. In kindreds with MEN 2B, infants are screened for the mutation at birth. For affected infants, prophylactic thyroidectomy is performed by 6 months of age.
All individuals carrying a RET proto-oncogene mutation require close lifetime medical surveillance (see Table 11–11). See Chapter 22, Multiple Endocrine Neoplasia.
Neurofibromatosis Type 1 (NF-1) 17q11.2 PHEOs are ultimately diagnosed in 0.1% to 5.7% of patients with von Recklinghausen neurofibromatosis type 1 (NF-1). Most of these PHEOs are not diagnosed during life, since the autopsy incidence of PHEO in NF-1 patients is 3.3% to 13%. PHEOs that develop in patients with NF-1 are similar to sporadic PHEOs: 84% have solitary adrenal tumors, 10% have bilateral adrenal tumors, 6% have extra-adrenal PGLs, and 12% have metastases or local invasion.
PHEOs are present in 20% to 50% of NF-1 patients with hypertension, and all NF-1 patients with hypertension must be screened for PHEO. It is prudent to screen all patients with NF-1 for PHEO yearly, with interval testing if hypertension or symptoms develop that are suggestive of PHEO (headache, perspiration, palpitations). Similarly, all patients with NF-1 should be screened for PHEO before major surgical procedures and pregnancy.
In patients with NF-1, PHEOs can present anytime during life, from infancy to old age, with a mean age of 42 years at diagnosis. These PHEOs can grow to large size. Although patients with PHEOs may develop hypertension, many patients are surprisingly asymptomatic despite increased catecholamine secretion. Patients with NF-1 are prone to develop vascular anomalies such as coarctation of the aorta and renal artery dysplasia, which can produce hypertension and mimic a PHEO.
von Recklinghausen disease is caused by a mutation in the NF-1 tumor suppressor gene mapped to chromosome 17q11.2. The NF-1 gene encodes a 2818 amino acid protein called neurofibromin, which inhibits Ras oncogene activity; loss of neurofibromin leads to Ras activation and tumor formation. It is a common autosomal dominant genetic disorder (although 50% of cases seem sporadic), with an approximate incidence of 300 to 400 cases per million population. Although genetic testing for NF-1 is available, the diagnosis is usually made clinically during childhood or adolescence.
Patients with NF-1 mutations can present in childhood with optic gliomas that impair vision or in adolescence with plexiform neurofibromas. Patients develop visible subcutaneous neurofibromas and schwannomas of cranial and vertebral nerve roots. Skeletal abnormalities are common. Hypothalamic hamartomas may occur and cause precocious puberty. Iris hamartomas may occur and are known as Lisch nodules. NF-1 patients have an increased risk of developing other tumors, especially malignant peripheral nerve sheath tumors and leukemia (particularly juvenile chronic myelogenous leukemia). Affected patients can also develop pancreatic somatostatinomas. Patients may also have freckles in their axillae and skin folds. Multiple cutaneous pigmented café au lait spots develop and grow in size and number with age; most patients ultimately develop more than six spots (smooth bordered) measuring more than 1.5 cm in diameter.
Individuals carrying an NF-1 mutation must have lifetime medical surveillance (see Table 11–12).
Kinesin Factor 1B (KIF1B) 1p36 KIF1B is a gene that is believed to synthesize a proapoptotic factor for sympathetic cell precursors. The gene is located on 1p36, where gene deletions have been noted in neural crest tumors. Rare mutations in KIF1B have been associated with PHEOs, PGLs, and neuroblastomas, as well as other tumors that are not of neural crest origin. These tumors are transcriptionally related to NF-1 and RET tumors.
Myc-Associated factor X (MAX) 14q23 Germline mutations in the MAX gene predispose to PHEO/PGL. These rare mutations appear to arise from differential paternal transmission in this syndrome. About two-thirds of cases have been found to have multiple tumors or bilateral adrenal tumors that are synchronous or metachronous; such tumors display loss of heterozygosity in the wild-type MAX allele. About 10% to 37% of such tumors have metastasized by the time they are discovered.
Transmembrane protein 127 (TMEM127) 2q11.2 This gene encodes a tumor suppressor protein that controls a signaling pathway (mTORC1) that promotes cell proliferation and survival. Individuals with rare TMEM127 germline mutations are prone to develop renal cell carcinomas and PHEOs/PGLs; such tumors have been found to have a second somatic mutation in TMEM127, resulting in loss of heterozygosity. Affected individuals usually present between ages 42-54 years, older than patients in some other familial PHEO/PGL syndromes. They usually develop adrenal PHEOs that are benign. About one-third of cases have bilateral adrenal PHEOs when discovered. However, secretory PGLs and HN-PGLs have been reported. Only about 25% of patients with TMEM127 germline mutations give a family history of PHEO, so 75% appear to be “sporadic.” TMEM127 germline mutations are found in about 2% of all patients with PHEO/PGL. No other tumors have been definitely associated with germline TMEM127 mutations.
Other genetic syndromes associated with PHEO or PGL:
Carney-Stratakis syndrome This familial syndrome is autosomal dominant and almost always associated with a detectable germline mutation in SDHB, SDHC, or SDHD. Both sexes are affected equally. Affected patients develop PHEO/PGL and gastrointestinal stromal cell tumors (GIST); such tumors have an additional acquired somatic SDHx mutation in their normal wild-type gene. The syndrome is also known as GIST-PGL dyad. This syndrome is not associated with pulmonary chondromas.
Carney triad Multicentric paragangliomas occur in patients with Carney triad. About 150 cases have been reported worldwide. About 10% of affected patients have been found to harbor germline mutations in SDHA, SDHB, or SDHC genes. However, for the remaining patients, the precise underlying genetic defect is unknown. This condition is not usually familial. Affected individuals are usually young women who develop malignant but indolent GISTs (leiomyosarcomas), pulmonary chondromas, and PHEO/PGLs. Only one-fifth of reported cases have had all three tumors, while most patients have had two of the three tumors, usually gastric sarcomas and pulmonary chondromas. Other tumors can develop in this syndrome, including ganglioneuromas, neuroblastomas, adrenocortical adenomas (12%), and esophageal leiomyomas. Women account for 86% of the cases. Tumors tend to develop early in life, with an average age of 21 years at diagnosis. This tumor syndrome is distinct from Carney-Stratakis syndrome (discussed earlier).
Beckwith-Wiedemann syndrome PHEOs have been reported in patients with Beckwith-Wiedemann syndrome and may be bilateral. Affected individuals also have other abnormalities, particularly neonatal hypoglycemia, omphalocele, umbilical hernia, macroglossia, and gigantism, and they are prone to develop malignancies.
Other genetic tumor syndromes that may possibly predispose to PHEO/PGL:
ATM (Ataxia-Telangiectasia Mutated gene) Homozygotes have ataxia-telangiectasia, immunodeficiency with respiratory infections, and an increased risk for breast cancer and lymphoid malignancies. At least one patient with an ATM germline mutation has developed a PHEO/PGL (author’s experience).
SETD2 (Su[var], Enhancer of zeste, Trithorax-Domain containing 2) Germline loss-of-function mutations in the SETD2 gene predispose to renal cell carcinoma and childhood brain gliomas. At least one patient with an SETD2 germline mutation has developed a PHEO/PGL (author’s experience).
Somatic Mutations in PHEO and PGL
Somatic mutations have been found in nearly 50% of PHEO/PGLs. Somatic activating HRAS gene mutations have been found only in sporadic PHEO/PGL tumor tissue. The many different germline mutations that cause familial syndromes also occur as somatic mutations in sporadic PHEO/PGL tumors: (1) Activating somatic mutations in RET and HIF2; (2) Loss-of-function somatic mutations are predominantly seen for NF-1, and somatic mutations in VHL, SDHB, SDHD, and MAX are less common. Somatic mutations have also been described for EPAS1. Somatic mutations in other genes have been reported in only a few PHEO/PGLs: MEN 1, EGLN1, EGLN2, MDH2, and IDH1. Other somatic mutations have been described in sporadic PHEO/PGL, but their role in tumorigenesis is uncertain: TP53, ATRX, and BRAF.
Physiology of PHEO and PGL
PHEOs are tumors that arise from the adrenal medulla, whereas non–head-neck PGLs arise from sympathetic nerve ganglia. Although some PHEOs/PGLs do not secrete catecholamines, most synthesize catecholamines at increased rates that may be up to 27 times the synthetic rate of the normal adrenal medulla (Figure 11–10). The persistent hypersecretion of catecholamines by most PHEOs/PGLs is probably due to lack of feedback inhibition at the level of tyrosine hydroxylase. Catecholamines are produced in quantities that greatly exceed the vesicular storage capacity and accumulate in the cytoplasm. Such catecholamines and their metabolites (metanephrine and normetanephrine) diffuse out of the PHEO/PGL tumor cells into the circulation.
Plasma norepinephrine and epinephrine levels in venous samples of blood from a patient with a secretory left perinephric PGL. Note that the level of epinephrine is very high in the left adrenal vein sample, distinguishing it from the drainage of the PGL that secretes norepinephrine into the left renal vein. Note the relatively normal peripheral levels of epinephrine (seen in the iliac vein or the superior vena cava). Such venous sampling is no longer required for diagnosis and localization of PHEO or PGL.
In contrast to the normal adrenal medulla, most adrenal PHEOs produce more norepinephrine than epinephrine, while many produce both hormones. Some PHEOs produce epinephrine almost exclusively. Most PGLs produce mostly norepinephrine with some dopamine and no epinephrine. PGLs that produce large amounts of dopamine tend to be metastatic. Some PGLs secrete no catecholamines or metanephrines.
Serum levels of catecholamines correlate only modestly with tumor size. On average, large tumors secrete more catecholamines than smaller tumors. However, large tumors are much more variable in their secretion of tumor markers. This may be due to the fact that larger tumors tend to develop hemorrhagic necrosis and cysts that are not functional. Additionally, about 20% of large, malignant PGLs are less differentiated and are nonsecretory.
Severe hypertensive episodes occur in most patients with PHEOs and secretory PGLs. Exocytosis of catecholamines from the PHEO can play a role in such paroxysms, but most PHEOs have minor sympathetic innervation. Instead, hypertensive crises are often caused by spontaneous hemorrhages within the tumor or by pressure on the tumor causing the release of blood from venous sinusoids that are rich in catecholamines. Thus, catecholamines can be released by physical stimuli such as bending or twisting or by micturition in patients with bladder PGLs. Of course, surgical manipulation of such tumors releases catecholamines and can cause life-threatening hypertensive crises.
Chronically high circulating levels of catecholamines may cause normal sympathetic axons to become saturated with catecholamines due to active catecholamine neuronal uptake. This may account for the paroxysms of hypertension that are triggered by pain, emotional upset, intubation, anesthesia, or surgical skin incisions. Adrenergic catecholamine saturation may also explain the elevations in plasma and urine catecholamines that can occur for 10 days or longer after a successful surgical resection of a PHEO/PGL.
Secretion of Other Peptides by PHEOs and PGLs
Although PHEOs/PGLs secrete mainly catecholamines and their metabolites, they also secrete many other peptide hormones, many of which contribute to a patient’s clinical symptoms (Table 11–13). Secretion of parathyroid hormone–related peptide (PTHrP) can cause hypercalcemia. Ectopic ACTH production can cause Cushing syndrome. Erythropoietin secretion can cause erythrocytosis. Leukocytosis is frequently seen in patients with PHEO, probably caused by cytokine release from the tumor. Interleukin-6 secretion can cause fevers and acute respiratory distress syndrome (ARDS).
TABLE 11–13Other proteins and peptides that may be secreted by pheochromocytomas and paragangliomas, in addition to catecholamines and metanephrines.a |Favorite Table|Download (.pdf) TABLE 11–13 Other proteins and peptides that may be secreted by pheochromocytomas and paragangliomas, in addition to catecholamines and metanephrines.a
Atrial natriuretic factor
Parathyroid hormone–related peptide
Tumor necrosis factor alpha (TNFα, cachexin)
Vasoactive intestinal polypeptide
Chromogranin A: Chromogranins are acidic single-chain glycoproteins that are found in neurosecretory granules. They have been categorized into three classes: chromogranins A (CgA), CgB (secretogranin I), and CgC (secretogranin II). In humans, the gene for CgA is on chromosome 14 and encodes a molecule with 431 to 445 amino acids. CgA molecules aggregate with low pH or high calcium concentrations and promote the formation of secretory vesicles and the concentration of hormones within these vesicles.
CgA also acts as a prohormone. It is cleaved by endopeptidases into smaller peptides. CgA is the prohormone for the amino terminal fragments vasostatin I (CgA 1-76) and vasostatin II (CgA 1-115), which appear to inhibit vasoconstriction. CgA is also the prohormone for catestatin (CgA 352-372), which blocks acetylcholine receptors and thus inhibits adrenosympathetic activity.
Most PHEO/PGL tumors secrete CgA, and serum CgA levels may be assayed as a tumor marker for PHEO. However, CgA is not unique to the adrenal medulla. It is produced in neuroendocrine cells outside the adrenal medulla that secrete peptide hormones. CgA is found in the pituitary gland, parathyroid gland, central nervous system, and pancreatic islet cells.
Neuropeptide Y (NPY): Many PHEOs secrete significant amounts of NPY. The molecule is a 36 amino acid peptide (see primary sequence, discussed later) that is found in neurosecretory granules and is secreted along with catecholamines. It is a very potent nonadrenergic vasoconstrictor that contributes to hypertension in some patients with PHEO.
NPY acts on G protein–coupled receptors, which belong to the pancreatic polypeptide family of cell-surface receptors called peptide YY (PYY). Six subtypes of these receptors have been identified (Y1R-Y6R). NPY has particular affinity for the Y1-R, Y2-R, Y3-R, and Y5-R receptors. Some PYY receptors are found in vascular smooth muscle and mediate NPY-induced vasoconstriction. Other PYY receptors are found on the pheochromocytes themselves and mediate NPY’s autocrine effects: NPY appears to inhibit catecholamine synthesis via Y3R, a receptor which blocks L-type Ca2+ channels. It inhibits catecholamine release via Y2R, a receptor that blocks N-type Ca2+ channels.
NPY also has paracrine effects, stimulating endothelial cell proliferation and angiogenesis that may foster tumor growth. Patients with essential hypertension have normal levels of NPY. However, in a series of eight patients with PHEO, NPY levels were elevated 2- to 465-fold above the normal reference range. In another series, 59% of adrenal PHEOs were found to secrete NPY during surgical resection; high serum levels of NPY were observed to correlate with vascular resistance, independent of norepinephrine. NPY appears to contribute to hypertension and left ventricular hypertrophy in most patients with PHEO. In contrast, few PGLs secrete NPY.
Adrenomedullin (AM): It was originally isolated from a PHEO, thus its misleading name. Although AM is produced by the adrenal medulla, it is also produced in the adrenal cortex (zona glomerulosa). It is produced by so many other tissues that the adrenal gland is actually a minor source for circulating AM.
AM is a 52 amino acid peptide cleavage product of a prohormone, preproadrenomedullin, encoded on chromosome 11. AM has some homology with calcitonin gene–related peptide (CGRP), and exerts its effects as a ligand for CGRP1 receptors and specific AM receptors. Ligand binding to the G protein–coupled receptors causes adenylate cyclase activation and an elevation of cellular cAMP levels.
AM is a pluripotent hormone. In the adrenal, AM appears to suppress aldosterone secretion. It is also secreted by the heart, lung, kidney, and brain as well as vascular endothelium, where it causes vasodilation. AM is also a natriuretic peptide and is secreted by the heart in congestive heart failure. AM is expressed in PHEOs and a variety of other tumors, where it appears to stimulate tumor growth, reduce apoptosis, and suppress the immune response to the tumor.
Neuron-specific enolase (NSE): It is a neuroendocrine glycolytic enzyme. Serum levels of NSE have been reported to be normal in patients with benign PHEO but are elevated in about half of patients with malignant PHEOs. Therefore, an elevated serum level of NSE may increase the likelihood that a given PHEO is malignant.
Manifestations of PHEO and PGL
More than one-third of PHEOs and sympathetic PGLs cause death prior to diagnosis (Table 11–14). Death usually results from a fatal cardiac dysrhythmia, myocardial infarction, stroke, cardiomyopathy, ARDS, or multisystem crisis. Adult patients with a secretory PHEO/PGL usually have paroxysmal symptoms, which may last minutes or hours; symptoms usually begin abruptly and subside slowly. The particular constellation of symptoms varies considerably among patients. One cause for the differences in symptoms is the variable production of epinephrine and norepinephrine by these tumors. PHEOs that produce epinephrine tend to cause paroxysmal β-adrenergic manifestations, particularly anxiety, tremor, diaphoresis, tachycardia, palpitations, and hyperglycemia. Epinephrine and cytokine secretion can cause pulmonary edema and ARDS. PGLs do not secrete epinephrine but most secrete norepinephrine that causes hypertension. PGLs are more likely to metastasize.
TABLE 11–14Clinical manifestations of pheochromocytoma and paraganglioma. |Favorite Table|Download (.pdf) TABLE 11–14 Clinical manifestations of pheochromocytoma and paraganglioma.
|Blood pressure ||Hypertension: severe or mild, paroxysmal or sustained; orthostasis; hypotension/shock; normotension |
|Vasospasm ||Cyanosis, Raynaud syndrome, gangrene; severe radial artery vasospasm with thready pulse; falsely low blood pressure by radial artery transducer |
|Multisystem crisis ||Severe hypertension/hypotension, fever, encephalopathy, ARDS, renal failure, hepatic failure, death |
|Cardiovascular ||Palpitations, dysrhythmias, chest pain, acute coronary syndrome, cardiomyopathy, heart failure, cardiac paragangliomas |
|Gastrointestinal ||Abdominal pain, nausea, vomiting, weight loss, intestinal ischemia; pancreatitis, cholecystitis, jaundice; rupture of abdominal aneurysm; constipation, toxic megacolon |
|Metabolic ||Hyperglycemia/diabetes; lactic acidosis; fevers |
|Neurologic ||Headache, paresthesias, numbness, dizziness, CVA, TIA, hemiplegia, hemianopsia, seizures, hemorrhagic stroke; skull metastases may impinge on brain structures, optic nerve, or other cranial nerves; spinal metastases may impinge on cord or nerve roots |
|Pulmonary ||Dyspnea; hypoxia from ARDS |
|Psychiatric ||Anxiety (attacks or constant); depression; chronic fatigue; psychosis |
|Renal ||Renal insufficiency, nephrotic syndrome, malignant nephrosclerosis; large tumors often involve the kidneys and renal vessels |
|Skin ||Apocrine sweating during paroxysms, drenching sweats as attack subsides; eczema; mottled cyanosis during paroxysm |
|Ectopic hormone production ||ACTH (Cushing syndrome); VIP (Verner-Morrison syndrome); PTHrP (hypercalcemia) |
|Children ||More commonly have sustained hypertension, diaphoresis, visual changes, polyuria/polydipsia, seizures, edematous or cyanotic hands; more commonly harbor germline mutations, multiple tumors, and paragangliomas |
|Women ||More symptomatic than men: more frequent headache, weight loss, numbness, dizziness, tremor, anxiety, and fatigue |
|Pregnancy ||Hypertension mimicking eclampsia; hypertensive multisystem crisis during vaginal delivery; postpartum shock or fever; high mortality |
|General laboratory ||Leukocytosis, erythrocytosis, eosinophilia |
|Associated tumors ||Renal cell carcinoma, hemangioblastoma, gastric sarcoma, pulmonary chondroma, pituitary adenoma, papillary thyroid cancer |
Manifestations and their approximate incidence include hypertension (90%), headaches (80%), diaphoresis (70%), and palpitations or tachycardia (60%). Other common symptoms include episodic anxiety (60%), tremor (40%), abdominal or chest pain (35%), pallor (30%), and nausea or vomiting (30%). Hyperglycemia occurs in about 30% but is usually asymptomatic; diabetic ketoacidosis has been reported but is very rare. Patients may also experience fever (28%), fatigue (25%), flushing (18%), and dyspnea (15%). Change in bowel habits occurs frequently with either constipation (13%) or diarrhea (6%). Visual changes occur in 12% with either transient blurring or field loss during attacks; metastases to the orbit or skull base may directly impinge on the optic nerve (see Table 11–14).
Triggers for paroxysms: Episodic paroxysms may not recur for months or may recur many times daily. Each patient tends to have a different pattern of symptoms, with the frequency or severity of episodes usually increasing over time. Attacks can occur spontaneously or may occur with bladder catheterization, anesthesia, or surgery. Acute attacks may also be triggered by eating foods containing tyramine: aged cheeses, meats, fish, beer, wine, chocolate, or bananas. Hypertensive crises can also be triggered by certain drugs: radiocontrast media (especially ionic type), MAO inhibitors, tricyclic antidepressants, sympathomimetics, decongestants, glucagon, chemotherapy, glucocorticoids (prednisone, dexamethasone), ACTH, opiates, metoclopramide, nicotine, and cocaine. Phenothiazines have been reported to cause shock and pulmonary edema in patients with PHEO.
Paroxysms can be induced by seemingly benign activities such as bending, rolling over in bed, exertion, abdominal palpation, or micturition (with bladder paragangliomas). There is an amazing inter-individual variability in the manifestations of PHEO/PGLs. Most patients have dramatic symptoms, but other patients with incidentally discovered secretory PHEOs are completely asymptomatic. Patients who develop PHEOs as part of MEN 2 or VHL disease are especially prone to be normotensive and asymptomatic.
Blood pressure: Hypertensive crisis is the quintessential manifestation of PHEO/PGL. Blood pressure that exceeds 200/120 mm Hg is an immediate threat to life, being associated with encephalopathy or stroke, cardiac ischemia or infarction, pulmonary edema, aortic dissection, rhabdomyolysis, lactic acidosis, and renal insufficiency.
Definition of hypertension: In adults, hypertension is considered to be present when blood pressure exceeds 140 mm Hg systolic or 90 mm Hg diastolic. In children, blood pressure increases with age, such that maximal normal ranges are age dependent; hypertension is considered to be present when blood pressure measurements exceed the following: younger than 6 months, 110/60 mm Hg; 3 years, 112/80 mm Hg; 5 years, 115/84 mm Hg; 10 years, 130/90 mm Hg; and 15 years, 138/90 mm Hg.
Presentation of hypertension: Hypertension is present in 90% of patients in whom a PHEO/PGL is diagnosed. Hypertension occurs primarily from the secretion of norepinephrine. Epinephrine secretion variably increases blood pressure. Also, PHEO/PGLs often secrete neuropeptide Y that is a potent vasoconstrictor. Some tumors may grow so large that they impinge upon the renal artery, causing increased renin production and secondary renovascular hypertension. Blood pressure patterns vary among patients with PHEOs. Adults most commonly have sustained but variable hypertension, with severe hypertension during symptomatic episodes. Paroxysms of severe hypertension occur in about 50% of adults and in about 8% of children with PHEO. Other patients may be completely normotensive, may be normotensive between paroxysms, or may have stable sustained hypertension.
Hypertension can be mild or severe and resistant to treatment. Severe hypertension may be noted during induction of anesthesia for unrelated surgeries. Although hypertension usually accompanies paroxysmal symptoms and may be elicited by the earlier activities, this is not always the case.
Orthostasis: Patients with sustained hypertension frequently exhibit orthostatic changes in blood pressure, often with orthostatic tachycardia. Patients may complain of orthostatic faintness. Blood pressure may drop, even to hypotensive levels, after the patient arises from a supine position and stands for 3 minutes; such orthostasis, especially when accompanied by a rise in heart rate, is suggestive of PHEO. Epinephrine secretion from a PHEO may cause episodic hypotension and even syncope.
Hypotension and shock: Although hypertension is usually the key symptom in PHEO/PGL patients, hypotension and shock can occur. Some PHEOs produce purely epinephrine that can produce mild hypertension from alpha stimulation but can also produce hypotension from predominantly β-stimulated vasodilation. After an especially intense and prolonged attack of hypertension, shock may ultimately occur. This may be due to loss of vascular tone, low plasma volume, arrhythmias, or cardiac damage. Spontaneous necrosis within a PHEO can lead to severe hypotension when norepinephrine levels suddenly drop. Similarly, surgical resection of a PHEO/PGL often precipitates sudden and severe intraoperative hypotension, particularly in the presence of α-blockade and other antihypertensives. Cardiogenic shock can occur as a result of cardiac ischemia or infarction as well as catecholamine cardiomyopathy (see Cardiac Manifestations, discussed later).
Peripheral vasospasm and gangrene: Vasoconstriction is responsible for the pallor and mottled cyanosis that can occur with paroxysms of hypertension. Raynaud phenomenon can occur. Peripheral pulses may become thready or even nonpalpable during paroxysms. Catheters inserted into the radial artery and connected to continuous blood pressure monitoring transducers can give misleadingly low-pressure readings during paroxysms of vasospasm, a condition known as pseudoshock. Prolonged severe peripheral vasospasm has rarely caused gangrene of the skin, fingers, or toes. Reflex vasodilation usually follows an attack and can cause facial flushing.
Multisystem crisis: Massive release of catecholamines and cytokines from PHEO/PGL tumors can occur spontaneously during tumor necrosis or can be triggered by any of the factors noted earlier. This can cause multisystem crisis that can be the presenting manifestation of PHEO/PGL, with hypertension or hypotension, high fever, encephalopathy, cardiomyopathy with heart failure, ARDS, renal failure, hepatic injury, and death. Multisystem crisis resembles septic shock, so the diagnosis of PHEO may be missed entirely.
Cardiac manifestations: The heart is affected in most patients with PHEO/PGL, either directly from excessive catecholamines or indirectly from hypertension. Palpitations are one of the most frequent complaints.
Dysrhythmias: Tachycardia or dysrhythmias occur in about 60% of patients with PHEO/PGL. Patients may note palpitations, described variably as episodes of excessive heart pounding at rest or a fluttering sensation, during which they may become lightheaded. Supraventricular tachycardia is common, particularly in patients with an epinephrine-secreting adrenal PHEO. The heart rate will often increase when standing. There can be an initial tachycardia during a paroxysm, followed by a reflex bradycardia. Atrial fibrillation may occur. Other dysrhythmias described with PHEO/PGL include nodal tachycardia, torsades de pointes, sick sinus syndrome, and Wolff-Parkinson-White (WPW) syndrome. Atrioventricular dissociation can occur and right bundle branch block has been reported. Ventricular tachycardia or ventricular fibrillation can occur suddenly and is a common cause of death.
Acute coronary syndrome (ACS): During a paroxysm, severe coronary vasospasm can cause myocardial ischemia or infarction, even in the absence of coronary atherosclerosis. This typically occurs simultaneously with increased myocardial oxygen demand caused by catecholamine-induced increases in heart rate and contractility. Patients may experience crushing chest pain or pressure with referred pain, usually to the jaw or the left shoulder or arm. Acute heart failure may occur along with severe hypotension or shock.
It can be difficult to distinguish ACS due to coronary stenosis/thrombosis from ACS due to a PHEO. Changes in the electrocardiogram and serum levels of troponin and creatine kinase-MB (CK-MB) are the same for both conditions. Patients with coronary disease can have tachycardia, cardiomyopathy, hypertension, dysrhythmias, diaphoresis, anxiety, and increased plasma catecholamine levels. However, patients with PHEO usually do not have critical coronary artery stenosis on coronary angiogram and usually have severe hypertension, headache, and other paroxysmal symptoms.
Cardiomyopathy: Left ventricular hypertrophy and hypertensive cardiomyopathy can occur in patients with chronic hypertension from a PHEO/PGL. High levels of catecholamines can also directly cause myocarditis and a dilated cardiomyopathy. This is known as catecholamine cardiomyopathy. Takotsubo cardiomyopathy is the term used to describe asymmetric cardiac contractility with apical and midventricular akinesis or dyskinesis with hyperkinesis at the base. Other patterns of cardiac hypokinesis can occur. Most patients with catecholamine cardiomyopathy develop pulmonary edema and die. However, full recovery from cardiomyopathy may occur after treatment and surgical resection of a PHEO/PGL. In some patients, myocardial scarring and fibrosis lead to irreversible cardiomyopathy and heart failure. Fatal Takotsubo cardiomyopathy has been reported after dobutamine stress echocardiography.
There can be multiple causes of cardiomyopathy in patients with PHEO/PGL: hypertensive, ischemic, and catecholamine. The underlying pathophysiology of catecholamine cardiomyopathy appears to involve high levels of intracellular calcium in cardiac myocytes. Postmortem histopathology typically reveals intracardiac hemorrhages, edema, and concentrations of lymphocytes and leukocytes in cardiac muscle with areas of myocardial fibrosis.
Cardiac PGLs: These are rare tumors that arise at the base of the heart near the trunks of the aortic and pulmonary arteries and may be asymptomatic or cause hypertension and palpitations. They typically involve the left atrium or interatrial groove and often protrude into the atrium, resembling an atrial myxoma. Cardiac PGLs often have an invasive intramural component, making tumor resection difficult.
Diaphoresis and fever: During a paroxysm, sweating usually occurs initially from apocrine glands, affecting the palms, axillae, head, and shoulders. Reflex thermoregulatory eccrine sweating occurs later in an attack, dissipating the heat that was acquired during the prolonged vasoconstriction that occurred during the paroxysm. This can cause drenching sweats, usually as a paroxysm subsides. Patients with PHEO commonly develop fevers that may be mild or severe, even as high as 41°C. Up to 70% of patients have unexplained low-grade elevations in temperature of 0.5°C or more. Such fevers have been attributed to the secretion of interleukin-6 and respond to nonsteroidal anti-inflammatory drug therapy.
Gastrointestinal manifestations: Many patients with PHEO/PGL exhibit gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and constipation. Most patients lose some weight, even if appetite is preserved. More severe weight loss (>10% of basal weight) occurs in about 15% of patients overall and in 41% of those with sustained and prolonged hypertension. Abdominal pain may be due to splanchnic vasoconstriction (intestinal angina) and prolonged vasospasm can cause ischemic enterocolitis. Vasospasm can rarely cause ischemic gangrene of the bowel. Pain may also be caused by the growth of a large intra-abdominal tumor. Intestinal motility disorders are also common. Catecholamines relax gastrointestinal smooth muscle while increasing contraction of the pyloric and ileocecal sphincters. Constipation is common, and abdominal distention and even toxic megacolon can occur. Other abdominal emergencies can be seen with PHEO, including the rupture of an aortic aneurysm, acute cholecystitis, and acute pancreatitis.
Neurologic manifestations: Headache is a common manifestation during an acute paroxysm. Patients frequently complain of paresthesia, numbness, or dizziness. Affected patients have an increase risk of experiencing a cerebrovascular accident (CVA) or transient ischemic attack (TIA). Hemiplegia can occur, sometimes with homonymous hemianopsia, and may be transient or permanent. Although most CVAs are ischemic in origin, hemorrhagic stroke can also occur during hypertensive paroxysms. Rupture of the internal carotid artery into the cavernous sinus can occur, causing a third nerve palsy. Some patients develop confusion or even psychosis during paroxysms. Paresthesias can occur.
Pulmonary manifestations: Patients may complain of dyspnea during a paroxysm. Patients with catecholamine cardiomyopathy may also present with dyspnea. Some patients develop ARDS, which can develop acutely or over several days. This is a life-threatening condition but may be self-limited during an attack. PHEO/PGL can produce ARDS that may be mistaken for pneumonia, pulmonary edema, pulmonary emboli, or congestive heart failure. It is hypothesized that ARDS may be caused by interleukin-6 produced by the tumor. Congestive heart failure may also cause pulmonary edema and can be distinguished from ARDS by echocardiogram.
Renal manifestations: Some degree of renal insufficiency is common in patients with PHEO. Hypertensive nephrosclerosis occurs in patients with a long history of severe hypertension. Nephrotic syndrome may occur with significant proteinuria, possibly due to secretion of interleukin-6 by the tumor. Malignant nephrosclerosis can occur with severe hypertension damaging renal arterioles, resulting in rapidly progressive renal failure. Large PHEOs and perirenal PGLs can impinge upon the renal artery, causing increased renin production and a Goldblatt kidney, resulting in renovascular hypertension that is additive to norepinephrine-induced hypertension. The tumor may directly invade the renal vein and extend into the inferior vena cava, causing pulmonary emboli and an increased risk of lower extremity deep vein thrombosis. Severe hypertensive paroxysms can cause muscle ischemic damage and rhabdomyolysis with release of myoglobin that causes myoglobinuric renal failure. Acute tubular necrosis can occur after a severe hypotensive episode.
Ectopic hormone production: PHEOs can rarely produce ACTH that stimulates the adrenal cortex to produce excessive cortisol, resulting in Cushing syndrome. Tumors can also produce VIP that can cause watery diarrhea, hypokalemia, and achlorhydria, the WHDA (Verner-Morrison) syndrome. Some tumors produce PTHrP that causes hypercalcemia. Although PHEOs can secrete renin directly, elevated plasma renin levels are usually derived from the juxtaglomerular apparatus, whose β1 receptors are stimulated by both epinephrine and norepinephrine.
Manifestations in children: The symptoms of PHEO/PGL in children are different from those in adults. Over 80% of children exhibit hypertension that is usually sustained and less frequently (10%) paroxysmal. Children are more prone to diaphoresis and visual changes. Children are more likely to have paroxysms of nausea, vomiting, and headache, which often occur after exertion. They are also prone to weight loss, polydipsia, polyuria, and convulsions. Affected children may also exhibit reddish-blue mottled skin along with edematous and cyanotic-appearing hands, a symptom rarely seen in adults. Children are more likely to have multiple tumors and extra-adrenal PGLs. In one series, 39% of affected children had bilateral adrenal PHEOs, an adrenal PHEO plus a PGL, or multiple PGLs; a single PGL occurred in an additional 14% of children. Affected children often have genetic conditions associated with PHEOs/PGLs. Thus, they may harbor the other tumors associated with these conditions. All affected children should be considered for genetic testing for germline mutations or deletions predisposing to PHEO/PGL (see Table 11–8).
Manifestations in women: There are sex differences in PHEO/PGL symptomatology, with women tending to be more symptomatic than men. Women report significantly more headache (80% vs 52%), weight change (88% vs 43%), numbness (57% vs 24%), dizziness (83% vs 39%), tremor (64% vs 33%), anxiety (85% vs 50%), and changes in energy level (89% vs 64%).
Manifestations in pregnancy: A PHEO/PGL during pregnancy can cause sustained hypertension or paroxysmal hypertension that is typically mistaken for eclampsia. Hypertensive paroxysms tend to occur more frequently as the uterus enlarges, triggered by direct pressure upon the tumor by shifts in position or movement of the fetus. Hypertensive crisis typically occurs at the time of vaginal delivery and is commonly associated with cardiac arrhythmia, ARDS, and death. Postpartum women may develop shock or fever that can mimic uterine rupture, amniotic fluid embolus, or infection (puerperal sepsis). A tumor that is unrecognized carries a grave prognosis, with a reported 40% maternal mortality and a 56% fetal mortality. If the diagnosis of PHEO is made before delivery, the maternal mortality rate drops to about 10% (see Pregnancy and Pheochromocytoma, discussed later).
Manifestations of malignancy: Metastases occur in about 11% of adrenal PHEOs and 30% to 50% of sympathetic PGLs. Since histopathology cannot distinguish whether a given PHEO is malignant, the term malignant is dependent upon whether metastases are detectable at presentation (50%) or months to years later (50%). Metastases are usually (80%) functional and can cause recurrent hypertension and symptoms many months or years after an operation that had been thought to be curative (see Metastatic Pheochromocytoma and Paraganglioma, discussed later).
Normotension despite high plasma levels of norepinephrine: Interestingly, about 14% of patients with PHEO/PGL have no hypertension despite having chronically elevated serum norepinephrine levels. This phenomenon has been variably called desensitization, tolerance, or tachyphylaxis.
Patients can be genetically prone to adrenergic desensitization. Adrenergic desensitization is caused by adrenergic receptors undergoing sequestration, down-regulation, or phosphorylation. Adrenergic desensitization appears to be one cause of the cardiovascular collapse that can occur abruptly following the surgical removal of a PHEO/PGL in some patients.
Desensitization does not account for all patients who are normotensive in the face of elevated serum levels of norepinephrine, because some such patients can still have hypertensive responses to norepinephrine. Secretion of epinephrine can have a hypotensive effect and may account, at least in part, for this phenomenon. Some patients are homozygous for certain polymorphisms of β2-adrenergic receptors that allow continued β2-adrenergic-mediated vasodilation, thus counteracting the pressor effects of circulating epinephrine and norepinephrine caused by stimulation of vascular α1-adrenergic receptors.
Cosecretion of dopamine may reduce blood pressure through a central nervous system action. Also, cosecretion of dopamine may directly dilate mesenteric and renal vessels and thus modulate the effects of norepinephrine.
Biochemical Testing for Pheochromocytoma
No single test is absolutely sensitive and specific for PHEO. Plasma-fractionated free metanephrines or urinary 24-hour fractionated metanephrines have a sensitivity of about 97%. Sensitivities of other tests are somewhat lower: urinary norepinephrine 93%, plasma norepinephrine 92%, urinary VMA 90%, plasma epinephrine 67%, urinary epinephrine 64%, and plasma dopamine 63%. However, some malignant tumors secrete only dopamine and no catecholamines and no metanephrines at all. Also, the determination of plasma catecholamines-metanephrine ratios can be of value in discriminating false-positive from true-positive results (discussed later). Therefore, assays for plasma catecholamines, dopamine, and serum chromogranin A are often warranted.
PHEO/PGLs are deadly tumors and missing the diagnosis can be disastrous, so screening tests must be very sensitive. The secretion of catecholamines can be paroxysmal, with low secretion rates between paroxysms. In contrast, the secretion of metanephrine or normetanephrine metabolites is relatively high and constant. Tumors secrete metanephrines in their unconjugated (free) form. Thus, plasma-fractionated free metanephrines is the single most sensitive screening tests for these tumors. Urinary 24-hour fractionated metanephrines has a similar sensitivity but the collection is less convenient. Some rare tumors (usually malignant) have a defect in the conversion of dopamine to norepinephrine by DBH, such that serum dopamine levels are very high while catecholamines are normal or mildly elevated and metanephrines are totally normal. Additionally, some paragangliomas secrete no catecholamines or metanephrines but do secrete CgA.
The establishment of normal reference ranges is problematic for catecholamines and metanephrines, since levels vary with sex, age, and medical conditions:
Sex Women have lower plasma epinephrine and metanephrine levels than men; their urinary excretion of catecholamines and metanephrines is also lower. Women also have lower 24-hour urine metanephrine and normetanephrine than do men. However, such sex differences disappear when normalized to creatinine excretion.
Age Children, especially boys, normally have somewhat higher levels of plasma epinephrine and metanephrine than do adults. For boys ages 5 to 17 years, the upper limit of normal (ULN) for plasma free metanephrine is less than 57 pg/mL (0.52 nmol/L) and the ULN for plasma free normetanephrine is 97 pg/mL (0.53 nmol/L). For girls ages 5 to 17 years, the ULN for plasma free metanephrine is 0.37 nmol/L and the ULN for plasma free normetanephrine is 77 pg/mL (0.42 pmol/L). Conversely, children’s average 24-hour urine epinephrine and norepinephrine excretion rates are lower than those of adults and increase through childhood as weight increases. Therefore, using ratios of catecholamines to creatinine and metanephrines to creatinine best assesses children’s 24-hour urine tests.
Commonly, the adult plasma free metanephrine ULN is reported to be 57 pg/mL (0.31 nmol/L), with the adult plasma free normetanephrine ULN reported to be 148 pg/mL (0.75 nmol/L). However, reference ranges vary greatly between laboratories. The reported ULN for plasma free metanephrine ranges from 55 pg/mL to 85.6 pg/mL (0.30-0.47 nmol/L), and the reported ULN for plasma free normetanephrine ranges from 110 to 200 pg/mL (0.56-1.02 nmol/L). Plasma norepinephrine and normetanephrine levels increase with advancing age. For patients over age 65, the plasma-fractionated free normetanephrine ULN should be considered 200 pg/mL (1.02 nmol/L).
Medical conditions On average, hospitalized patients and those with essential hypertension have higher levels of catecholamines and metanephrines (plasma and urine) than do matched nonhospitalized and normotensive individuals. Therefore, many laboratories have separate reference ranges for hypertensives and nonhypertensives.
Patients with illness, trauma, or sleep apnea have increased excretion of both catecholamines and metanephrines. Patients with renal failure on dialysis have elevated levels of plasma catecholamines (58%), plasma free metanephrines (25%), and plasma total (deconjugated) metanephrines (100%). Patients with partial renal insufficiency also have misleadingly elevated levels of plasma catecholamines (32%), plasma free metanephrines (26%), and plasma total metanephrines (50%). Thus, in patients with renal failure, the best screening test is plasma free metanephrines, but the test still lacks specificity when elevated. Serum CgA levels are also elevated in renal insufficiency.
Misleading elevations of at least one metanephrine or catecholamine determination occur in 10% to 20% of tested individuals without PHEO/PGL. These elevations are typically less than 50% above the maximum normal and often normalize on retesting. Patients with PHEOs usually have elevations of metanephrines or catecholamines that are more than three times normal. In one large series, a false-positive elevation in at least one test occurred in 22% and marked elevations in at least one test occurred in 3.5% of patients with no PHEO. False-positive test results were judged to have occurred from physiologic variation (33%), laboratory errors (29%), or drug interference (21%).
Plasma normetanephrines reflect disease activity in patients with secretory PGLs or metastases. Normal ranges for plasma metanephrines in children are different from those of adults and have been reported by Weise et al, 2002. Plasma normetanephrine levels typically increase with age; about 16% of older patients being evaluated for PHEO/PGL have levels above the published normal range for young adults (false positives); only 3% of young adults have false-positive plasma normetanephrine concentrations. Stimulation tests are not recommended (discussed later).
A. Metanephrines and catecholamines
Plasma-fractionated free metanephrines
The most sensitive and simple screening test for PHEO/PGL is an assay for plasma-fractionated (metanephrine and normetanephrine) free metanephrines. This assay is particularly useful to screen patients for secretory PHEO/PGL (see Table 11–7). For younger children, plasma testing is particularly preferred over urine testing due to the relative ease of collection. This assay’s sensitivity pertains to secretory PHEO/PGL. However, some tumors, particularly PGLs, may not secrete any metanephrines. So to screen for a PGL in a normotensive patient with a suspicious mass, it is recommended that plasma dopamine and serum CgA also be tested, since some PGLs secrete purely dopamine or only CgA (discussed later).
In the United States, most reference laboratory assays for metanephrines employ high-pressure liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS). This test is 97% sensitive. The 3% of affected patients with PHEO/PGL with normal plasma-fractionated free metanephrines usually have very small tumors, nonsecreting tumors, or dopamine-secreting tumors such that they are not hypertensive. Although MS/MS reduces drug interference that can be a problem with assays that employ HPLC with electrochemical detection (ECD), the test is only 87% specific for PHEO/PGL in a referred patient population.
Patient preparation: In order to reduce the chance of false-positive testing, patients having plasma-fractionated free metanephrines determinations by tandem mass spectroscopy (MS/MS) should observe the following precautions: No decongestants, amphetamines, MAO inhibitors, or cocaine for at least 7 days before testing. The patient must not have any current stressful illness or be in withdrawal from alcohol, narcotics, or clonidine. There must be full recovery from any postoperative pain. The patient should have no local anesthetics (lidocaine) or acetaminophen for 24 hours before blood draw. Overnight fasting is preferred (water permitted). Patients should avoid coffee (including decaffeinated coffee) tea, tobacco, and strenuous exercise on the day of the blood draw. The patients being screened should be relaxed and ideally resting supine for at least 15 minutes prior to the blood draw; if that is not possible in an outpatient laboratory, the patient should at least sit quietly for a minimum of 15 minutes before the blood draw.
Since the test’s specificity is much lower than its sensitivity, most patients with levels above the reference range do not harbor a tumor. This is particularly true when plasma levels are less than three times higher than the upper limit of the reference range. Conversely, it is extremely likely that a patient harbors a PHEO when the plasma free metanephrine is above 220 pg/mL (1.2 nmol/L) or the plasma free normetanephrine is above 430 pg/mL (2.2 nmol/L). Patients with abnormally high plasma-fractionated metanephrines usually need to have the test repeated under controlled conditions (see Patient Preparation, discussed earlier), along with a 24-hour urine collection for fractionated metanephrines, catecholamines, and creatinine (discussed later).
Normally, about 90% of circulating metanephrine and about 50% of circulating normetanephrine originate directly from the adrenal medulla. The term total metanephrines refers to both normetanephrine and metanephrine. There are two circulating forms of normetanephrine and metanephrines: free and sulfate-conjugated metanephrines. The free metanephrines produced in the adrenal medulla and paraganglia are sulfate-conjugated by intestinal tissue; the sulfated form represents 97% of circulating metanephrines. Only 3% of total circulating metanephrine is free. Plasma metanephrine levels are sometimes measured after a deconjugation step, such that both free and conjugated metanephrines are measured; this assay is termed deconjugated metanephrines and reflects mostly the sulfate-conjugated species. The plasma free metanephrines assay is superior to the total (deconjugated) metanephrine assay.
The sensitivity of the plasma free metanephrines is due to the tumor’s continuous secretion of metanephrines. Catecholamines in secretory vesicles exist in a dynamic equilibrium with the surrounding cytoplasm, with catecholamine uptake into the vesicles being balanced by their leakage into the cytoplasm. In the cytoplasm, the enzyme COMT converts epinephrine to metanephrine and converts norepinephrine to normetanephrine. The catecholamine metabolites then leak out of the cell continuously to become free metanephrines. While catecholamines are secreted in bursts associated with exocytosis of neurosecretory vesicles, free metanephrines are produced continuously. This eliminates the need to catch a paroxysmal hypertensive event. Plasma free metanephrine levels are within the reference range in 75% of patients on dialysis and 74% of patients with renal insufficiency. In contrast, plasma deconjugated metanephrines are within the reference range in 0% of patients on dialysis and in 50% of patients with renal insufficiency.
Factors causing misleading plasma free fractionated metanephrine levels
Smoking can elevate plasma free metanephrine assays. The patient must not smoke for at least 4 hours before collection (Table 11–15). Coffee increases plasma normetanephrine by 20% and food consumption increases it by 8%; but they have no effect upon plasma metanephrine levels. Sympathomimetics such as decongestants and amphetamine derivatives should be discontinued for at least 7 days before the test. Other drugs that can misleading elevate plasma free metanephrines include local anesthetics, cocaine, lidocaine, halothane anesthesia, and MAO inhibitors. Acetaminophen is one of the few medications that can actually interfere with the MS/MS assay. Conditions that increase plasma metanephrine and normetanephrine levels include any severe physical stress such as acute illness or narcotic or alcohol withdrawal, anxiety, sleep apnea, renal failure, and essential hypertension. Physical exercise raises plasma free metanephrine and normetanephrine by over 80%. There can be seasonal variations in plasma normetanephrine levels, with 20% higher levels during winter being reported in Germany and the Netherlands.
TABLE 11–15Factors that can cause misleading catecholamine or metanephrine results.a |Favorite Table|Download (.pdf) TABLE 11–15 Factors that can cause misleading catecholamine or metanephrine results.a
|Drugs ||Foods ||Conditions |
Contrast media (meglumine acetrizoate, meglumine diatrizoate)e
Ephedrine & Epinephrinec
Monoamine oxidase inhibitorsf
Serotonin-norepinephrine reuptake inhibitors (SSNRI): venlafaxine, desvenlafaxine, duloxetine, levomilnacipranc
Age (children & elderly)f
Amyotrophic lateral sclerosisc
Drug withdrawal (narcotic, alcohol, clonidine)c,f
Myocardial infarction (acute)c
Assumption of a supine resting position reduces plasma metanephrine by an average of 34% and reduces normetanephrine by 19%, compared to standing at rest. Blood samples should ideally be drawn from an indwelling heparin-locked intravenous line while the patient is fasting and resting supine. However, it is not usually practical for patients to rest supine for prolonged periods in outpatient laboratories, so patients are advised to sit quietly for at least 15 minutes prior to the blood draw. Blood should be centrifuged immediately and stored at 4°C to improve stability.
In patients with adrenal PHEO, over 90% of circulating metanephrine originates from the tumor, while variable percentages of circulating normetanephrine originate from the tumor. Patients with elevated plasma metanephrine or epinephrine are likely to have an adrenal PHEO, since PGLs do not ordinarily secrete epinephrine or metanephrine. Metastases from epinephrine-secreting adrenal PHEOs may sometimes continue to secrete epinephrine and its metabolite metanephrine.
24-Hour urine-fractionated metanephrines
This assay, which measures the sum of both conjugated and free urinary metanephrines, rivals plasma free metanephrines in sensitivity. In the United States, most reference laboratories employ tandem mass spectrometry (MS/MS), which eliminates interference from most drugs and foods. Urinary metanephrines are rather stable compounds, so it is not necessary to collect the specimen with acid preservative. Conversely, acid preservative (used for collection of urinary catecholamines) does not adversely affect metanephrines. Urine fractionated 24-hour metanephrines are useful to confirm high plasma levels or to help rule-out a PHEO/PGL in patients with marginal elevations in plasma-fractionated metanephrines. The disadvantages of 24-hour urine collections include: (1) the inconvenience to the patient; (2) the likelihood that there will be an error in the patient’s collection or in the laboratory’s handling of the specimen; (3) the lower specificity for urinary fractionated metanephrines (69%) compared to plasma-fractionated free metanephrines (89%); (4) the inaccuracy for patients with renal failure (see Appendix for normal reference ranges for 24-hour metanephrines).
Like plasma-fractionated metanephrines, urinary metanephrines are much more sensitive than they are specific. Most patients with elevated levels of fractionated metanephrines do not harbor a PHEO if their levels are less than three times the upper limit of the reference range. Conversely, patients are very likely to have a pheochromocytoma if the 24-hour urine metanephrine excretion is above 600 μg/d (3.0 μmol/d) or normetanephrine excretion is above 1500 μg/d (8.2 μmol/d).
As with plasma metanephrines, patients with a definitely elevated urinary metanephrine are likely to harbor an adrenal PHEO, since PGLs rarely secrete epinephrine or metanephrine.
Misleading elevations in plasma catecholamines commonly occur from the stress of having the phlebotomy. Normal plasma levels of catecholamines are listed in the Appendix. In patients with PHEO/PGL, plasma concentrations of norepinephrine do not correlate well with blood pressure.
Although plasma metanephrines are more sensitive than plasma catecholamines for detecting a PHEO, plasma catecholamines are of value in helping distinguish true-positive from false-positive results. In normal individuals, about 100% of circulating epinephrine originates from the adrenal medulla, while over 90% of circulating norepinephrine originates from peripheral sympathetic synapses. In both normals and those with PHEOs, plasma norepinephrine levels fluctuate with the degree of peripheral sympathetic activation and both epinephrine and norepinephrine levels can increase during PHEO paroxysms. In patients with PHEOs, the tumor’s production of metanephrine metabolites is rather constant and relatively unrelated to peripheral sympathetic activity or a tumor’s paroxysmal catecholamine secretion. Patients with false-positive test results due to sympathetic activation tend to have the following pattern: a higher percentage increase of plasma norepinephrine above the upper limit of the reference range compared to plasma normetanephrine; a higher percentage increase of plasma epinephrine above the upper limit of the reference range compared to plasma metanephrine. Plasma dopamine should be assayed in normotensive patients with a mass that is suspicious for a PGL, since some PGLs secrete only dopamine.
Plasma catecholamines are of limited value in patients on dialysis and in those with renal insufficiency. About 58% of dialysis patients have plasma catecholamines above the normal reference range; about 32% of renal insufficiency patients have catecholamines above the normal reference range.
Most assays for plasma catecholamines currently employ HPLC with ECD; assays using tandem mass spectrometry (MS/MS) have not become generally available.
Urine-fractionated catecholamines and dopamine
Adult normal maximal urinary concentrations for catecholamines and their metabolites are listed in the Appendix. A single 24-hour urine specimen is collected for fractionated catecholamines, fractionated metanephrines, dopamine, and creatinine. The container is acidified with 10 to 25 mL of 6 N HCl for preservation of the catecholamines; the acid does not interfere with metanephrine and creatinine assays. The acid preservative may be omitted for children for safety reasons, in which case the specimen should be kept cold and processed immediately. The laboratory requisition form should request that assays for fractionated catecholamines, fractionated metanephrines, and creatinine be performed on the same specimen. Urinary dopamine determination is not a sensitive test for PHEOs. However, in patients with established PHEOs, a normal urine dopamine is fairly predictive of benignity, whereas elevated urine dopamine excretion is seen in both benign and malignant PHEOs.
Single-void (spot) urine specimens
can be collected on first morning void or following a paroxysm. No acid preservative is used on single-void specimens, because it dilutes the specimen and is not required. For single-void collections, patients are instructed to void and discard the urine immediately at the onset of a paroxysm and then collect the next voided urine. The laboratory requisition should request spot urine for total metanephrines and creatinine concentrations. It is prudent to contact the laboratory directly and explain that the specimen is meant to be a single-void urine and not a 24-hour specimen, else the specimen may be rejected. Patients with PHEOs generally excrete over 2.2 μg total metanephrine/mg creatinine.
Some tumors (mostly PGLs) fail to secrete catecholamines or metanephrines. Serum CgA is a useful test to diagnose and monitor such nonsecretory tumors. CgA may be determined by immunoradiometric assays. The serum CgA assay has become useful for the diagnosis of PHEO. However, CgA undergoes extensive tumor-specific cleavages so that only certain serum assays are useful for clinical diagnosis.
Serum CgA levels have a circadian rhythm in normal individuals, with lowest levels found at 8 am and higher levels in the afternoon and at 11 pm. CgA levels are not elevated in essential hypertension. CgA is also secreted from extra-adrenal sympathetic nerves. Serum CgA levels are elevated in the great majority of patients with PHEOs. The serum levels of CgA correlate with tumor mass, making CgA a useful tumor marker. However, smaller tumors may not be diagnosed. Serum CgA levels tend to be particularly elevated in patients with metastatic PHEO.
Serum CgA can be elevated even in patients with biochemically silent tumors. In patients with normal renal function, serum CgA has a sensitivity of 83% to 90% and a specificity of 96% for diagnosis of these tumors. However, the usefulness of serum CgA levels is negated by any degree of renal failure because of its excretion by the kidneys; even mild azotemia causes serum levels to be elevated. However, in patients with normal renal function, a high serum level of CgA along with high urine or plasma catecholamines or metanephrines is virtually diagnostic of PHEO.
Since CgA is also cosecreted with gastrin, serum CgA levels are also elevated in conditions with elevated serum gastrin: atrophic gastritis, pernicious anemia, postvagotomy, gastrinoma, gastric carcinoma, carcinoid tumor, and small cell lung carcinoma. CgA levels are elevated in about 60% of patients taking proton pump inhibitors (PPIs), but not H2 blockers. Serum CgA levels rise variably after meals, so blood for CgA should be drawn after an overnight fast or repeated fasting if a nonfasting level is elevated. False-positive testing has also occurred in patients with inflammatory bowel disease, liver disease, hepatocellular carcinoma, prostate cancer, pituitary tumors, rheumatoid arthritis, and stress. False-positives have been reported to be due to heterophile antibody interference with the assay. Serum CgA levels can also be elevated without any discernable cause.
C. Suppression and stimulation testing
Glucagon stimulation testing is no longer used since it can cause dangerous hypertension.
Clonidine suppression test: This test may help distinguish patients with PHEO from normals with elevated normetanephrine levels. Clonidine is a central α2 adrenergic blocker that suppresses the release of norepinephrine at sympathetic nerve synapses, thereby reducing circulating levels of norepinephrine and its metabolite, normetanephrine. In contrast, in patients with PHEO, most circulating normetanephrine is derived from continuous leakage from the tumor, such that clonidine is less able to suppress it. This test is most accurate when free normetanephrine is assayed, rather than norepinephrine.
To perform the clonidine suppression test, the patient must be fasting overnight and avoid smoking or interfering medications such as phenoxybenzamine, β-adrenergic blockers, tricyclic anti-depressants and diuretics for at least 48 hours. An indwelling venous catheter is inserted, and the patient should remain recumbent. Thirty minutes later, blood is drawn for baseline plasma free normetanephrine. Clonidine is then given orally in a dose of 0.3 mg; 3 hours afterward, blood is again drawn for plasma free normetanephrine.
In a study of 49 normals without PHEO, clonidine suppressed plasma normetanephrine levels more than 40% or to below 112 pg/mL in 100%. However, clonidine failed to suppress normetanephrine in 46 of 48 patients with PHEO. Despite the potential helpfulness of the clonidine suppression test, it cannot be completely relied upon. Unnecessary surgeries have been performed on the basis of misleading clonidine suppression testing.
D. Other laboratory tests
Urine VMA Urinary VMA determinations have an overall diagnostic sensitivity for PHEO of only about 63% and do not improve the sensitivity or specificity of other tests for the diagnosis of PHEO. However, some centers have traditionally used a combination of 24-hour urinary VMA, metanephrine, and creatinine determinations with good results. VMA is stable for 5 days at room temperature; 6 N HCl is used to preserve urine specimens that are stored for longer than 5 days before analysis. Before urine collections for VMA testing, patients must avoid salicylates, caffeine, phenothiazines, and antihypertensive drugs for 72 hours. Coffee, tea, chocolate, bananas, and vanilla must also be avoided. Normal ranges for VMA vary by age (see Appendix).
Plasma renin activity Levels of plasma renin activity are not typically suppressed in patients with PHEO/PGL because catecholamines stimulate renin release, and some tumors may secrete renin ectopically.
Other tests Patients with PHEO/PGL are frequently found to have an increased white blood count with a high absolute neutrophil count. Counts as high as 23,600/μL have been reported. Marked eosinophilia may sometimes occur. Hyperglycemia is noted in about 35% of patients with PHEO, but frank diabetes mellitus is uncommon. The erythrocyte sedimentation rate is elevated in some patients. Hypercalcemia is common and may be caused by bone metastases or tumoral secretion of PTHrP. Hypocalcemia occurs rarely. Erythrocytosis sometimes occurs, usually due to volume contraction and rarely due to ectopic secretion of erythropoietin.
Factors That May Cause Misleading Biochemical Testing for PHEO
Several different methods may be employed for assay of urine and plasma catecholamines and metanephrines (Table 11–15). Each assay uses different methods and internal standards. Most assays for catecholamines now employ HPLC with ECD. Such assays can be affected by interference from a diverse range of drugs and foods. These substances cause unusual shapes in the peaks on the chromatogram. Not all of these assays are the same, and the potential for interference depends on the particular method employed. Therefore, it is best to check with the reference laboratory that runs the test or provides the test kit.
Certain radiopaque contrast media, including those that contain meglumine acetrizoate or meglumine diatrizoate (eg, Renografin, Hypaque-M, Renovist, Cardiografin, Urografin, and Conray), can falsely lower urinary metanephrine determinations in some assays for up to 12 hours following administration. However, diatrizoate sodium is an intravenous contrast agent that does not cause such interference and should be requested if a CT scan must be performed prior to testing for metanephrines. Many other drugs cause interference in the older fluorometric assays for VMA and metanephrines. Tandem mass spectrometry for metanephrines virtually eliminates direct drug interference in the assay.
Even while using HPLC-ECD assay techniques, certain foods can cause misleading results in assays for catecholamines and metanephrines (see Table 11–15). Coffee (even if decaffeinated) contains substances that can be converted into a catechol metabolite (dihydrocaffeic acid) that may cause confusing peaks on HPLC. Caffeine inhibits the action of adenosine; one action of adenosine is to inhibit the release of catecholamines. Heavy caffeine consumption causes a persistent elevation in norepinephrine production and raises blood pressure an average of 4 mm Hg systolic. Bananas contain considerable amounts of tyrosine, which can be converted to dopamine by the central nervous system; dopamine is then converted to epinephrine and norepinephrine. Dietary peppers contain 3-methoxy-4-hydroxybenzylamine (MHBA), a compound that can interfere with the internal standard used in some assays for metanephrines.
Any severe stress can elicit increased production of catecholamines and metanephrines. Urinary excretion of catecholamines and metanephrines is reduced in renal failure.
Differential Diagnosis of Pheochromocytoma and Paraganglioma
PHEOs and PGLs have such protean manifestations that many conditions enter into the differential diagnosis (Table 11–16). Essential hypertension is extremely common, and it is not practical to screen for PHEO in all patients with elevated blood pressure. However, PHEO should enter the differential diagnosis for any hypertensive patient having blood pressures above 180 mm Hg systolic and for any hypertensive patient who has one of the following symptoms: headaches, palpitations, sweating episodes, or unexplained bouts of abdominal or chest pains.
TABLE 11–16Differential diagnosis of pheochromocytoma. |Favorite Table|Download (.pdf) TABLE 11–16 Differential diagnosis of pheochromocytoma.
Acute intermittent porphyria
Hypertensive crisis associated with:
Acute pulmonary edema
Hypertensive crisis of MAO inhibitors
Hypogonadal hot flushes
Migraine and cluster headache
Sympathomimetic drug ingestion
Toxemia (eclampsia) of pregnancy
Anxiety (panic) attacks begin abruptly and can be associated with tachycardia, tachypnea, and chest discomfort, symptoms that are commonly seen with PHEOs. However, patients with panic attacks are more likely to have a precipitating social situation, tend to be exhausted for more than 2 hours following an attack, live in dread of the next attack, and often change their activities to avoid situations that might trigger anxiety.
Renal artery stenosis and renal parenchymal disease can cause increased secretion of renin resulting in severe hypertension. However, a detectable serum renin level does not exclude PHEO, because catecholamines can stimulate renin secretion, and PHEOs can secrete renin ectopically. Furthermore, large PHEOs and PGLs arising near the renal hilum can occlude the renal artery, causing concomitant renovascular hypertension.
Hypogonadism can cause vasomotor instability in both women and men; attacks of flushing, sweating, and palpitations can mimic symptoms seen with PHEO. Factitious symptoms may be caused by surreptitious self-administration of various drugs such as epinephrine. Hyperthyroidism can cause heat intolerance, sweating, palpitations, and systolic hypertension with a widened pulse pressure. Carcinoid syndrome causes flushing during attacks but usually without pallor, hypertension, palpitations, or diaphoresis.
Obstructive sleep apnea can cause systemic hypertension; recurrent nocturnal hypoxia results in repeated episodes of stressful arousal that cause bursts of secretion of catecholamines, particularly epinephrine. Sleep apnea has been reported to cause misleading increases in the urinary excretion of catecholamines.
Patients with erythromelalgia can have episodic hypertension, but it is associated with flushing of the face and legs during the attack; patients with PHEO typically have facial pallor during attacks. With erythromelalgia, patients have painful erythema and swelling in the legs that is relieved by application of ice; such symptoms are not characteristic of PHEO.
Patients who have intermittent bizarre symptoms may have their blood pressure and pulse checked during a symptomatic episode with a home blood pressure meter or an ambulatory blood pressure monitor. Those who are normotensive during an attack are not likely to harbor a PHEO.
PHEOs and PGLs often present with abdominal pain and vomiting. Such symptoms are similar to those of an intra-abdominal emergency, particularly in the presence of leukocytosis and fever, which can also be seen with PHEOs. Abdominal pain usually prompts a CT scan of the abdomen, which generally shows the PHEO or PGL. Even after detection on CT scan, PHEOs and juxtarenal PGLs may be mistaken for renal carcinoma. Large left-sided PHEOs are often mistaken for carcinoma of the tail of the pancreas.
Neuroblastoma is the most common extra-cranial solid malignancy of childhood. It is also the most common malignancy in infants under 18 months old. Neuroblastomas are derived from the embryonic neural crest of the peripheral sympathetic nervous system. They most often arise in the adrenal gland, but can also develop in sympathetic nerve ganglia near the cervical or thoracic vertebrae or in the pelvis. They metastasize to bones, lymph nodes, liver, and skin. Symptoms depend upon the age of the patient, site of origin, degree of metastatic involvement, and the systemic response to the tumor. Infants usually present with localized disease (Stage 1 or 2) or with a special disseminated pattern of disease (Stage 4S—infants with metastatic disease to liver and/or skin) associated with a favorable outcome. In contrast, most children over 1 year of age present with advanced disease (Stage 3 or 4). Unfavorable biologic features include amplification of myelomatosis viral-related oncogene, neuroblastoma (MYCN), deletion or loss of heterozygosity of chromosome 1p or 11q and gains at 17q. Favorable biologic features include hyperdiploidy and overexpression of the gene encoding the nerve growth factor receptor, tyrosine kinase A (TrkA). About 85% of affected children secrete excessive catecholamines—but rarely in sufficient amounts to cause symptomatic hypertension or the paroxysms typical of PHEOs. Most neuroblastomas concentrate 123I-MIBG but they can be distinguished from PHEOs and PGLs by clinical and histologic criteria.
Localization Studies for Pheochromocytoma
There are several available imaging modalities for PHEO/PGL, each having unique sensitivity and specificity. There is no single imaging study that is 100% sensitive and specific. Generally, when a PHEO or PGL is suspected, the initial diagnosis is best made biochemically. The initial localization scan is with CT or MRI of the abdomen and pelvis, which will detect about 95% of these tumors. However, since PGLs can arise in the chest, further scanning of the chest may be required. Diagnostic confirmation that the tumor is a PHEO or PGL may be done with either 123I-MIBG or 18F-FDA positron emission tomography (PET) scanning; unfortunately, these scans are only 78% sensitive for these tumors. Scanning with 18F-FDG or 18F-FDA PET is more sensitive for detecting metastases than is 123I-MIBG.
After a PHEO has been diagnosed by clinical and biochemical criteria, hypertension must first be controlled (discussed later), because intravenous contrast can precipitate a hypertensive crisis (Figure 11–11). The PHEO must then be localized. It is useful to perform an initial nonenhanced (without intravenous contrast) CT of the adrenals because the density of an adrenal tumor can be better approximated without intravenous contrast. An adrenal mass with a density of less than 10 Hounsfield units (HU) is unlikely to be a PHEO. CT scanning of the entire abdomen (from the diaphragm through the pelvis) is obtained with intravenous nonionic contrast-enhanced and delayed contrast-enhanced imaging. Thin-section (2-5 mm) cuts should be obtained through the adrenals with an adrenal protocol that specifically looks for a vascular tumor blush and determines rate of contrast washout. PHEOs tend to have a tumor blush and slower contrast washout than adrenocortical adenomas. Hypertensive crises have been provoked in patients with PHEO/PGL who receive intravenous contrast. Ionic intravenous contrast frequently triggers hypertension, while nonionic intravenous contrast infrequently triggers hypertension. Therefore, all patients with suspected PHEO/PGL should have hypertension controlled before receiving intravenous CT contrast, and nonionic contrast is strongly preferred. Care must be taken in patients with contrast allergy, since glucocorticoids that are typically given by protocol to such patients can precipitate hypertensive crisis in patients with secretory PHEO/PGL. Glucagon should not be used during a CT because it may provoke a hypertensive crisis.
Left infrarenal PGL shown by CT scanning. The diagram on the right identifies many of the visible structures.
If no mass is discovered, 123I-MIBG imaging may be obtained or the CT scan may be extended into the chest in search of a PGL—or both procedures may be employed. The great majority of PHEOs are over 2 cm in diameter, well within the resolution capacity of the CT scan.
The overall sensitivity of CT scanning for an adrenal PHEO is about 90%—and over 95% for PHEOs that are over 0.5 cm in diameter. However, CT scanning is less sensitive for the detection of small adrenal PHEOs or adrenal medullary hyperplasia; this becomes an important issue in patients with MEN 2 or VHL disease. CT is also less sensitive for detecting extra-adrenal PGLs and early recurrent tumors in the adrenal surgical bed. CT will not detect small metastases or some metastases that strictly involve the bone marrow without osteoclastic activity. Metal surgical clips pose problem for CT scanning, causing distortion artifact and reducing the resolution of the scan.
B. Magnetic resonance imaging
MRI is useful in the diagnosis of adrenal PHEOs, PGLs, and metastatic disease. It may be used with or without gadolinium contrast. However, intravenous gadolinium contrast does not cause hypertensive crisis and improves resolution for metastases, particularly hepatic metastases. MRI scanning with intravenous gadolinium contrast is also useful for patients with a known allergy to intravenous iodinated CT contrast agents. MRI is the scanning technique of choice in children and during pregnancy, because it involves no radiation exposure. Since MRI scanning delivers no radiation, it is preferred for serially scanning patients known to harbor a gene mutation predisposing them to PHEO/PGL.
MRI can help determine whether an adrenal mass is a PHEO when biochemical studies are inconclusive. On MRI T1-weighted images, PHEOs have a dull signal (due to lack of fat cells), similar to kidney and muscle, distinguishing it from adrenal cortical adenomas, which contain fat and therefore have an intensely bright signal on T1-weighted images. The hypervascularity of PHEOs makes them appear bright on MRI T2-weighted images, without signal loss on opposed phase imaging. However, other adrenal malignancies, adrenal adenomas, and hemorrhages can also appear bright on MRI T2-weighted images. Therefore, MRI scanning cannot definitively identify an adrenal mass as a PHEO. MRI of the abdomen has a sensitivity of about 95% for adrenal PHEOs over 0.5 cm in diameter. Like CT scanning, MRI is less sensitive for the detection of extra-adrenal PGLs, metastatic disease, and recurrent small tumors in the adrenal surgical bed. MRI is helpful in visualizing PGLs that are intracardiac, juxtacardiac, or juxtavascular; MRI is particularly important for patients with PGLs adjacent to the vena cava or renal vein to detect vascular invasion. MRI is superior to CT in visualizing PGLs of the bladder wall. MRI can visualize some metastases to bone suspected on 123I-MIBG imaging or PET scanning. Another advantage of MRI scanning is that retained internal metallic surgical clips do not cause the distorting reflection artifacts that occur with CT scanning.
The disadvantages of MRI scanning include expense and its inability to crisply image lungs (due to movement artifact). Also, morbidly obese patients may not be able to fit into a standard helical MRI scanner; open MRI scanners can be used but are generally less sensitive. Claustrophobic patients require a sedative before the scan or an open MRI. Patients with internal pacemakers or defibrillators may not have MRI scans; nor may patients with implanted neural stimulators, cochlear implants, Swan-Ganz catheters, insulin pumps, cerebral aneurysm clips, ocular metallic foreign bodies, or retained metal shrapnel or bullets. Patients with retained surgical clips, artificial heart valves and joints may have MRI imaging; the spine may be imaged in patients with spinal hardware, but the imaging can be distorted.
C. Metaiodobenzylguanidine scanning
MIBG is a guanidine derivative that resembles norepinephrine and is actively transported into adrenal medullary cells via the norepinephrine transporter system, selectively accumulating in neurosecretory granules (Figure 11–12 and Table 11–17). Unlike norepinephrine, MIBG has low affinity for catecholamine receptors and is not metabolized.
123I-metaiodobenzylguanidine (123I-MIBG) scan of a woman with a large left PHEO. Normal 123I-MIBG uptake is seen in the liver, salivary glands, and heart. 123I-MIBG is renally excreted and is visible in the bladder.
TABLE 11–17Drugs that potentially inhibit MIBG uptake by pheochromocytomas and paragangliomas. Inhibition can persist up to 2 weeks. |Favorite Table|Download (.pdf) TABLE 11–17 Drugs that potentially inhibit MIBG uptake by pheochromocytomas and paragangliomas. Inhibition can persist up to 2 weeks.
Antidepressant inhibitors of norepinephrine reuptake: bupropion, clomipramine, desvenlafaxine, duloxetine, levomilnacipran, mirtazapine, tricyclic drugs, venlafaxine
Antiemetics: metoclopramide, prochlorperazine, promethazine
Antipsychotics: phenothiazines, haloperidol, thiothixene
Amphetamines: amphetamine, dextroamphetamine, lisdexamfetamine, methamphetamine
Anorexic diet medications: benzphetamine, diethylpropion, phendimetrazine, phentermine, sibutramine
Antihypertensive: labetalol (2-6 weeks)
CNS stimulants: cocaine, methylphenidate, dexmethylphenidate
Decongestants (oral, nasal, ophthalmic): pseudoephedrine, ephedrine, phenylpropanolamine, naphazoline, oxymetazoline, propylhexedrine, tetrahydrozoline, xylometazoline
Herbal therapies: ephedra (ma huang), St. John’s Wort, yohimbine
Monoamine oxidase inhibitors (MAOi): isocarboxazid, linezolid, phenelzine, selegiline, tranylcypromine
Scintigraphy using 123I-MIBG or 131I-MIBG is useful for determining whether an adrenal mass is a PHEO, for imaging occult PGLs, and for confirming whether a certain extra-adrenal mass is a PGL or neuroblastoma. MIBG scanning is also useful for screening patients for metastases. MIBG uptake can often be seen in apparently nonfunctioning PHEOs.
The isotope that is preferable for precise imaging is 123I-MIBG, because 123I emits γ radiation at lower energy (159 keV) than does 131I (364 keV). The lower-energy γ emissions allow crisper images with 123I-MIBG scanning as well as single photon emission computed tomography (SPECT). 123I-MIBG SPECT scanning is more sensitive than 123I-MIBG planar imaging for detecting small metastases and has the advantage of being able to do the scanning on the day following injection of the isotope. SPECT scanning with 123I-MIBG can be combined with CT to produce a three-dimensional fusion scan; the resultant combined images can help distinguish whether a given mass has 123I-MIBG uptake.
123I-MIBG scanning has an overall sensitivity of 82% and a specificity of 82% for PHEOs and PGLs combined. The sensitivity of 123I-MIBG scanning is 88% for primary adrenal PHEOs and 67% for PGLs, with an overall sensitivity of 78% for primary PHEO/PGL tumors. The sensitivity of 123I-MIBG scanning for metastases is lower at only 57%. Scanning with 123I-MIBG is more sensitive for PHEOs that are benign, unilateral, adrenal, capsule-invasive, and sporadic. Scanning with 123I-MIBG is less sensitive for bilateral, malignant, extra-adrenal, noninvasive, and MEN 2-related or VHL-related PHEOs.
To block the thyroid’s uptake of free radioiodine, saturated solution of potassium iodide, five drops orally three times daily, is given before the injection and daily for 4 days after 123I-MIBG and for 7 days after 131I-MIBG. Scanning is performed 24 to 48 hours after 123I-MIBG infusion and 48 to 72 hours after 131I-MIBG infusion.
False-negative MIBG scans are seen in about 15% of cases of either benign or malignant PHEO. False-negative scans can occur in patients who have taken certain drugs (eg, tricyclic antidepressants or cyclobenzaprine) within 6 weeks. Other drugs that can cause false-negative scans when taken within 2 weeks include amphetamines, phenylpropanolamine, haloperidol, phenothiazines, nasal decongestants, cocaine, and diet pills. Labetalol reduces MIBG uptake, but the scan can still be done, albeit with suboptimal sensitivity (Table 11–17). When plasma norepinephrine levels are over 500 pg/mL (3 nmol/L), cardiac visualization is reduced on 18F-dopamine PET scanning. This phenomenon is believed due to competitive inhibition of uptake-1 by high levels of circulating norepinephrine. Therefore, it is likely that very high endogenous norepinephrine levels may reduce the sensitivity of 123I-MIBG scanning as well as PET scanning that employs 18F-DA or 19F-DOPA because these compounds are transported into PHEOs, PGLs, and their metastases by the same uptake mechanism.
False-positive MIBG scans occur infrequently. Following 123I-MIBG, some uptake in a normal adrenal medulla is seen in 32% to 75% of patients at 24 hours. Following 131I-MIBG, uptake in a normal adrenal medulla is seen in 16% of normals at 48 hours. Adrenal uptake is often asymmetric and can be misinterpreted as showing a tumor. MIBG has renal excretion, so the renal pelvis and bladder are usually visualized on scanning and must be distinguished from tumor. If a patient is being evaluated for a bladder mass (to exclude a PGL), a bladder catheter may be inserted and the bladder flushed with saline to distinguish tumor from renal excretion of isotope. Urine contamination with 123I-MIBG can also cause a false-positive scan. False-positive results have been reported with adrenal carcinomas and infections such as actinomycosis. The salivary glands are typically visualized since they are richly innervated. The heart, liver, and spleen normally take up some 123I-MIBG. Some isotope is excreted in the stool, and intracolonic collections can be mistaken for tumor. When there is doubt about whether an area of uptake is a tumor, scanning can be repeated the next day, preceded by a laxative if required.
D. Positron emission tomography
PET scanning can be performed shortly after the intravenous infusion of short-lived isotopes that are tagged to a compound that is preferentially absorbed by tumor tissue (Figure 11–13).
18F-deoxyglucose (18FDG) PET/CT fusion scan. Patient had a retroperitoneal PGL that was resected. 18FDG-PET/CT fusion scan shows a large metastasis involving the left acetabulum and inferior pubic ramus. The metastasis had negligible 123I-MIBG uptake. A metastasis causing L4 compression had been treated previously with radiation therapy.
PET scanning has certain advantages over MIBG scanning. PET scanning can be done almost immediately. This gives it some advantage over MIBG scanning, which must be delayed for 24 to 48 hours after the injection to allow dissipation of background radiation. PET scanning does not require pretreatment with iodine to protect the thyroid, as is necessary with MIBG scanning. However, PET scanning is very expensive. The isotope 18F has a half-life of just 2 hours and must be produced in a cyclotron, so 18F-FDG or 18F-FDA PET scanning is practical only at medical centers that have a cyclotron nearby.
PET scanning with 18F-FDG Deoxyglucose (DG) is absorbed by tissues with active metabolism, including tumors. For PET scanning, DG is tagged with 18F to produce fluorodeoxyglucose, or 18F-FDG. This scan is widely available as a fusion scan with CT, 18F-FDG PET/CT. This scan’s sensitivity is 88% for nonmetastatic PHEO/PGL and 76% for metastatic PHEO/PGL. The sensitivity of 18F-FDG-PET/CT is lower for indolent tumors and for patients who are diabetic or who are not fasting before the scan. 18F-FDG-PET localizes in other tissues with a high metabolic rate, including areas of inflammation, brown fat, shivering muscles, but such areas of PET uptake can be distinguished from tumors by the lack of a CT correlate. However, 18F-FDG-PET/CT detects other tumors besides PHEO/PGL and is, therefore, less specific for PHEO/PGL than is 18F-FDA-PET or 123I-MIBG scanning. 18F-FDG/CT scanning is usually performed without CT contrast, such that it misses certain tumors, particularly indolent PGL/PHEO metastases to liver, where the hepatic metastases may be invisible on both 18F-FDG scanning as well as noncontrast CT scanning.
PET scanning with 18F-FDA PET scanning may also be performed using radioisotope-tagged dopamine: 6-[18F] fluorodopamine (18F-FDA-PET). This scan is more specific for PGL and metastatic PHEO than is 18F-FDG-PET/CT, because dopamine is a substrate for the norepinephrine transporter in tumor tissue. The sensitivity of 18F-FDA-PET is 78% for nonmetastatic PHEO/PGL and 76% for metastatic PHEO/PGL. It is not widely available, but is generally more sensitive than 123I-MIBG scanning, particularly in patients who harbor VHL or MEN 2 germline mutations. It is particularly useful for detecting other neuroendocrine tumors and PHEO/PGL metastases that are not visualized by scanning with 123I-MIBG or 18F-FDG and for tumors and metastases in patients with VHL disease.
E. Somatostatin receptor (SSTR) imaging SSTRs
are cell-surface G protein–coupled receptors, and there are five subtypes. About 70% of PHEOs express SSTRs, particularly types 2 and 4. SSTR imaging detects some metastases not visible on MIBG scanning, and vice versa. SSTR imaging has been reported to detect a cardiac PGL that was not visible on MIBG scanning.
111In-octreotide: Octreotide is a stable 8 amino acid analog of somatostatin with a high affinity for type 2 receptors. For imaging, octreotide is coupled with 111In-diaminetriaminepentacetate (DTPA). 111In has a half-life of 2.8 days and γ emissions of 173 keV and 247 keV. Scanning with 111In-labeled octreotide, known as SSTR imaging (SRI), has a sensitivity of only 25% for adrenal PHEOs and juxtarenal PGLs. This low sensitivity is due to high uptake of 111In-octreotide by the kidneys as well as renal excretion. However, 111In-octreotide detects 87% of PHEO metastases and is also a sensitive technique for detecting PGLs of the head and neck (chemodectomas). 111In-octreotide has physiologic uptake in the kidneys, thyroid, pituitary, salivary glands, gallbladder, bowels, spleen, liver, and mammary glands. Infection and recent surgery sites can also have misleading uptake of 111In-octreotide.
68Ga-DOTATATE-PET: This scans employs a somatostatin congener with increased affinity for SSTRs. It is tagged with 68Ga, a positron emitter, to allow PET scanning; when fused with a simultaneous CT scan; this provides exceptional sensitivity and clarity in the fusion scan. This scan is proving to be superior to all imaging modalities, particular for detecting PHEO/PGL metastases in patients with SDHB germline mutations.
On transabdominal ultrasound, an adrenal PHEO typically appears as a well-defined mass. Large PHEOs tend to develop internal hemorrhagic necrotic cysts, making the tumor appear heterogenous. Transabdominal ultrasound is most sensitive in slender individuals, in whom 85% of adrenal PHEOs can be visualized. However, ultrasound lacks specificity, such that a PHEO is not distinguishable from an adrenal adenoma or a mass in the superior pole of a kidney. Likewise, a left adrenal PHEO may be mistaken for a pancreatic tail tumor, and a right adrenal PHEO may be mistaken for a hepatic mass. Ultrasound may be used for initial imaging for PHEO in pregnant women, infants, and young children, although MRI is superior. Ultrasound is also useful for imaging and surveillance of neck PGLs. Ultrasound examinations have also been performed endoscopically, from the stomach and duodenum, with a longitudinal sector array, yielding sensitive detection of small adrenal PHEOs, lymphangitic metastases, and local recurrences. For pelvic and bladder PGLs, pelvic transvaginal ultrasound is very helpful for tumor localization and surveillance.
INCIDENTALLY DISCOVERED ADRENAL MASSES
Clinically unapparent adrenal nodules are discovered incidentally on about 4% of all abdominal CT or MRI scans that are performed for unrelated reasons (see Computed Tomography, discussed earlier.) Such nodules are known as adrenal incidentalomas. The incidence of adrenal nodules increases with age, being about 3% in middle-age and rising to about 10% in the sixth and seventh decades of life. Most such nodules are small, benign adrenal adenomas, with densities below 10 HU on noncontrast CT. However, PHEOs can produce nonspecific symptoms of abdominal pain, nausea, and weight loss, for which CT scans may be performed. PHEOs account for about 4% of incidentally discovered adrenal masses. In the United States nearly half of the PHEOs diagnosed during life are detected incidentally on an abdominal or chest CT scan performed for other reasons. Therefore, most patients with adrenal nodules, even normotensives, should be screened for PHEO with plasma-fractionated free metanephrines. However, such testing is not mandatory for normotensives whose adrenal nodule has all of the following characteristics: (1) density on unenhanced CT less than or equal to 10 Hounsfeld Units (HU); (2) size less than or equal to 3 cm; (3) morphology not suspicious. A problem arises with metanephrines that are marginally elevated. Such patients with metanephrines that are one to two times higher than the reference range’s ULN have about a 30% chance of harboring a PHEO. Those with metanephrines more than twice the ULN have a very high risk of having a PHEO. For apparently nonfunctioning adrenal nodules, it is generally reasonable to observe those that are under 3 cm in maximum diameter. Nonfunctioning nodules that are 3 to 5 cm in maximum diameter require especially close surveillance. Adrenal nodules that are over 5 cm in diameter are generally resected, except for obvious myelolipomas. When a PHEO has been ruled out, patients with an adrenal nodule may be screened for hyperaldosteronism and Cushing syndrome. Of note, hypertensive crisis has been described in patients with PHEO/PGL undergoing the high-dose dexamethasone suppression (DST) test, but not the low-dose DST.
Adrenal Percutaneous Fine-Needle Aspiration (FNA) Cytology
Most PHEO/PGLs can be readily diagnosed on the basis of their clinical, biochemical, and radiologic presentation. FNA cytology is not usually required for the diagnosis of a PHEO/PGL. However, some PHEO/PGLs are discovered incidentally on abdominal CT or ultrasound and may be clinically or biochemically silent. Although there may be a temptation to biopsy such masses, patients with a suspicious adrenal or retroperitoneal mass require testing for PHEO/PGL before any biopsy. There is a 70% risk of complications after percutaneous FNA of PHEO/PGLs. Such complications include: increased difficulty in the tumor’s resection (41%), severe hypertension (15%), hematoma (30%), severe pain (25%), and incorrect or inadequate biopsy (25%). FNA cytology can be misinterpreted as a different primary malignancy or a metastasis from another malignancy; this potential for confusion is due to the fact that PHEO/PGLs are rare tumors and have pleomorphic and hyperchromic nuclei. Large left-sided PHEOs have been misdiagnosed as carcinoma of the tail of the pancreas based on CT scanning and FNA cytology. Percutaneous FNA can also disrupt the PHEO capsule and cause seeding of the tumor within the peritoneum.
Medical Management of Patients with Pheochromocytoma and Paraganglioma
Patients need to be treated with oral antihypertensives and stabilized hemodynamically prior to surgery. Patients receiving increasing doses of antihypertensive medications should have daily measurements of blood pressure and pulse rate in the lying, sitting, and standing positions. Additionally, patients are taught to determine their own blood pressure and pulse rate regularly and during any paroxysmal symptoms. Most clinicians gradually increase antihypertensive medications over 2 or more weeks. However, prolonged preoperative preparation has not proven more effective for preventing intraoperative hypertension than shorter preparation periods. Some hypertensive patients have been admitted emergently for hypertension control and hydration, stabilized, and operated on successfully with intravenous infusion of a vasodilator drug (eg, nicardipine, nitroprusside, nitroglycerin; discussed later). Ideally, the blood pressure should be reduced to an average of 130/85 mm Hg (sitting) or less prior to surgery, while avoiding symptomatic orthostasis. Normotensive patients with PHEO/PGL who have documented increased plasma catecholamine levels are usually prepared for surgery with careful titration of α-blockade and/or calcium channel blockade. However, some normotensive patients, particularly those with PGLs, have truly nonsecreting tumors with completely normal plasma levels of catecholamines and metanephrines; such patients may not require any preoperative antihypertensive preparation, unless they have a clinical history of intermittent hypertension. Similarly, normotensive patients with PGLs secreting only dopamine do not require preoperative antihypertensive medication.
The type of preoperative medical preparation varies by region. In the USA, α-blockade is predominantly used. In Europe, about half the patients receive either nonselective α-adrenergic blockade (phenoxybenzamine) or selective α1-adrenergic blockade (prazosin); about half receive calcium channel blockade (CCB), usually with nicardipine. Perioperative morbidity is the same with either type of medical preparation. The choice between preoperative α-blockade versus CCB (or a combination of both) is usually determined by local protocols and consultation between the endocrinologist, surgeon, and anesthesiologist and by the individual patient’s reaction to the medication.
A. Alpha-adrenergic blockers
Alpha-adrenergic blockers have historically been used for most patients with PHEO in preparation for surgical resection. Phenoxybenzamine (10-mg capsules) is an oral nonselective α-blocker that is the most commonly used α-blocking agent. It has a long half-life of about 24 hours. Patients with mild hypertension may be given phenoxybenzamine at a starting dosage of 10 mg once daily, while those with more severe hypertension may receive a starting dosage of 10 mg twice daily. The dose of phenoxybenzamine may be increased by 10 mg every 2 days until the blood pressure falls to an average of 130/85 mm Hg sitting or until symptomatic orthostatic hypotension occurs. Patients who have been normotensive between paroxysms are particularly prone to develop hypotension with phenoxybenzamine. Phenoxybenzamine does not block the synthesis of catecholamines; in fact, the synthesis of catecholamines and metanephrines tends to increase during α-blockade. Therapy with phenoxybenzamine increases the heart rate but decreases the frequency of ventricular arrhythmias. Patients are encouraged to hydrate themselves well. Patients must be monitored daily for symptomatic orthostatic hypotension. Certain adverse effects are common, including dry mouth, headache, diplopia, inhibition of ejaculation, and nasal congestion. Nasal decongestants should not be used if urinary catecholamine determinations or 123I-MIBG scanning is planned, but antihistamines are acceptable. Phenoxybenzamine is not usually well tolerated as chronic therapy for hypertension in patients with unresectable or metastatic PHEO, and such patients are better treated with calcium channel blockers (discussed later), sometimes together with low-dose α-blockade.
Phenoxybenzamine crosses the placenta and accumulates to levels that are 60% higher in the fetus than in the maternal circulation; this can cause hypotension and respiratory depression in the newborn for several days following birth. Most patients require 30 to 60 mg/d, but the dosage is sometimes escalated to as high as 200 mg/d. However, phenoxybenzamine has a long half-life and excessive α-blockade with phenoxybenzamine can cause prolonged postoperative hypotension. Furthermore, excessive α-blockade may deny a critical surgical indicator (ie, a drop in blood pressure after complete resection of the tumor and aggravation of hypertension during palpation of the abdomen in case of multiple tumors or metastases).
Selective α1-adrenergic blockers cause relatively less reflex tachycardia and orthostasis, compared to phenoxybenzamine. They also tend to cause less ejaculatory disturbance in men, which is a consideration with long-term use. Doxazosin is selective α1-adrenergic blocker with a half-life of about 22 hours. It is effective in the medical management of PHEO/PGL when given orally in doses of 2 to 16 mg daily. In one series, there was no difference in hemodynamic instability during surgery in patients pretreated with doxazosin versus phenoxybenzamine. Terazosin is a selective α1-adrenergic blocker with a half-life of about 12 hours. Although its usual indication is for benign prostatic hypertrophy, it has been used as an antihypertensive for patients with PHEO/PGL; the starting dose is 1 mg daily with subsequent doses being given twice daily and titrated upward every 2 days to a dose where hypertension is controlled or to a maximum of 10 mg every 12 hours. Prazosin is a short-acting selective α1-adrenergic blocker. Due to its shorter half-life of only 3 hours, prazosin must be given every 8 to 12 hours. The starting dose of prazosin is 0.5 mg every 12 hours, increasing up to 10 mg twice or three times daily, if necessary. Patients treated with prazosin have experienced less postoperative hypotension, due to the drug’s short half-life. Prazosin is particularly useful as a perioperative medication for pregnant women with PHEO/PGL who undergo a cesarean section (discussed later). Urapidil is an intravenous α1-adrenergic blocker that has been used for in-hospital control of hypertension prior to surgical resection of PHEOs/PGLs. Urapidil has been successfully administered at constant intravenous infusion rates of 5 mg/h for the first day, increasing (if necessary) to 10 mg/h on the second day, and to 15 mg/h on the third day. In one study, urapidil therapy achieved preoperative hypertension control more rapidly (compared to phenozybenzamine), without any change in clinical outcomes.
Labetalol and carvedilol are combined selective α1-adrenergic blocker and nonselective β-adrenergic blocking drugs with half-lives of about 6.5 and 8 hours, respectively. They should not be used as the initial medication for treating hypertension in patients with PHEO/PGL, due to their unpredictable initial effects, sometimes causing an initial increase in blood pressure due to their nonselective β-blockade. Labetalol also can cause misleading elevations in catecholamine determinations in some assays, and inhibits MIBG uptake into PHEO/PGLs. However, labetalol has proven useful for some patients with metastatic or unresectable PHEO/PGL, especially after other medical therapy has failed. Labetalol is initiated at doses of 100 mg orally every 12 hours, titrating the dose upward every 2 days until the patient is normotensive or to a maximum of 1200 mg every 12 hours.
B. Calcium-channel blockers (CCBs)
Dihydropyridine CCBs are usually excellent antihypertensive agents for patients with PHEO/PGLs. However, they tend to reduce cardiac output and are not preferred for patients with congestive heart failure. Otherwise, CCBs are particularly useful for patients in whom α-blockers have caused adverse reactions, such as orthostatic hypotension or excessive fatigue. CCBs may be added to α-blockers to prepare patients for surgery. Patients who are normotensive between paroxysms are less likely to become hypotensive with CCBs compared to α-blockers. Patients with angina from coronary vasospasm are also best treated with CCBs. Perioperative fluid requirements have been lower among patients who were pretreated with CCBs instead of α-blockers. In a French series, 70 patients with PHEO were successfully prepared for surgery using oral CCBs (usually nicardipine). Nicardipine may be given in doses of 20 to 40 mg orally every 8 hours; nicardipine is also available as a sustained-release preparation that may be given in doses of 30 to 60 mg orally every 12 hours. Patients tend to tolerate CCBs better than α-blockers, such that CCBs are usually preferred for patients with PHEO/PGL who require long-term therapy due to recurrent or metastatic disease. However, some patients prefer α-blockade.
Nifedipine is a calcium channel blocker that is administered as an extended-release (ER) preparation in doses of 30 to 90 mg orally once or twice daily. The half-life of the ER preparation is 7 hours, so twice-daily dosing is preferred. For hypertensive paroxysms (systolic BP persistently above 170 mm Hg), nifedipine 10 mg (chewed pierced capsule) is usually a fast and effective treatment. Chewed nifedipine is generally safe for use by patients with PHEO, who may self-administer the drug at home during paroxysms but only with close blood pressure monitoring. In one small study, nifedipine therapy appeared to improve the uptake of MIBG into PHEOs in 4 of 8 patients at scanning doses. Nifedipine might possibly reduce the growth of PHEO/PGL and metastases, because in vitro nifedipine added to cultured PHEO cells reduces their mitotic index and proliferation. However, the effect of nifedipine on PHEO/PGL tumor growth has not been studied in patients.
Amlodipine may also be used for patients with PHEO/PGL in doses of 10 to 20 mg daily, but has a long half-life of 30 to 50 hours. There is little experience with other non-dihydropyridine CCBs (nimodipine, nisoldipine, isradipine, felodipine) for treating patients with PHEO/PGL.
Intravenous dihydropyridine CCBs are useful for hypertensive crisis, particularly during surgery. Nicardipine and clevidipine are both available as intravenous preparations (see Surgical Management of Pheochromocytoma and Paraganglioma, discussed later.)
Non-dihydropyridine CCBs are reported to be less effective for patients with PHEO. Verapamil has been used in a sustained-release preparation, but has been reported to be associated with postoperative pulmonary edema after PHEO resection. Diltiazem provides inadequate intraoperative blood pressure control.
C. Beta-adrenergic blockers
These agents are generally not prescribed for patients with PHEO/PGL tumors until treatment has been started with antihypertensive medications such as α-adrenergic blockers or CCBs. Beta-adrenergic blockade should then be used for treatment of β-adrenergic symptoms such as flushing, pounding heart, or tachycardia. It is important to institute α-blockade first, because blocking vasodilating β2 receptors without also blocking vasoconstricting α1 receptors can lead to hypertensive crisis if serum norepinephrine levels are high.
Nonselective β-blockers block both β1- and β2-adrenergic receptors. The inhibition of vasodilating arterial β2 receptors causes unopposed vasoconstrictive α-adrenergic stimulation that aggravates hypertension. Therefore, nonselective β-blockers should ordinarily not be administered to patients with PHEO/PGL. Nonselective β-blockers include: nadolol, pindolol, propranolol, and timolol. Labetalol and carvedilol are different nonselective β-blockers that additionally block α1 receptors.
Selective β-blockers specifically block β1-adrenergic receptors at low doses. This leads to a rather selective reduction in heart rate without unopposed α-receptor dependent hypertension. However, at higher doses, these β-blockers also block β2-adrenergic receptors and can cause a paradoxical worsening of hypertension. Selective β-blockers include: metoprolol succinate ER, atenolol, betaxolol, bisoprolol, nebivolol, and esmolol. Nebivolol has vasodilating activity through enhancement of nitric oxide release. Esmolol is the preferred intravenous preparation.
D. Angiotensin-converting enzyme inhibitors
ACE inhibitors have successfully treated hypertension in patients with PHEO/PGL, but not as the sole agent. Angiotensin receptor blockers have also been successfully added to multidrug antihypertensive therapy. Catecholamines stimulate renin production. In turn, renin stimulates the production of angiotensin I, which is converted by ACE to angiotensin II; this can be blocked by ACE inhibitors. Furthermore, PHEOs have been demonstrated to have angiotensin II-binding sites. ACE inhibitors are contraindicated in pregnancy (discussed later).
E. Metyrosine (`-methyl-para-tyrosine)
Metyrosine inhibits the enzyme tyrosine hydroxylase, which catalyzes the first reaction in catecholamine biosynthesis. Because of its potential side effects, it is usually used only to treat hypertension in patients with metastatic PHEO. Metyrosine is administered orally as 250-mg capsules, beginning with one every 6 hours; the dose is titrated upward every 3 to 4 days according to blood pressure response and side effects. Most patients can tolerate 2 g/d, but higher doses usually cause side effects. The maximum dosage is 4 g/d. Catecholamine excretion is usually reduced by 35% to 80%. Preoperative treatment with metyrosine tends to reduce intraoperative hypertension and arrhythmias; however, postoperative hypotension is likely to be more severe for several days. Side effects of metyrosine include sedation, psychiatric disturbance, extrapyramidal symptoms, and potentiation of sedatives and phenothiazines. Crystalluria and urolithiasis can occur, so adequate hydration is mandatory. Metyrosine does not inhibit MIBG uptake by the tumor, allowing concurrent 123I-MIBG scanning or treatment with high-dose 131I-MIBG.
Octreotide has not been formally studied or approved for use in patients with PHEO/PGL. However, octreotide (100 μg subcutaneously three times daily) has been reported to reduce hypertensive episodes and catecholamine excretion in a man with PHEO whose hypertensive paroxysms were uncontrolled using other means. Octreotide therapy has been observed to reduce bone pain in a woman with a malignant PGL whose skeletal metastases were avid for 111In-labeled octreotide. Octreotide therapy is usually begun at a dose of 50 to 100 μg injected subcutaneously every 8 hours. Side effects are common and may include nausea, vomiting, abdominal pain, and dizziness. If the drug is tolerated, the dose can be titrated upward to a maximum of 1500 μg daily. Octreotide LAR can be given as subcutaneous injections in doses of 10 to 40 mg every 4 weeks.
Vigorous exercise, particularly involving bending or heavy lifting, can aggravate hypertension in some individuals with PHEO/PGL, so mild exertion or rest is best during preparation for surgery. Emotional stress can provoke hypertensive attacks, so arguments and stressful situations are best avoided.
Intravenous tyramine causes hypertension in most patients with PHEO/PGL. While dietary tyramine has not been studied in patients with secretory PHEO/PGL, it is known that dietary tyramine can provoke hypertensive crisis in patients taking MAO inhibitor antidepressants. Therefore, although strict dietary precautions are not required, it is reasonable for patients with a known secretory PHEO/PGL to avoid consuming large amounts of foods with high tyramine content during preparation for surgery such as red wine, tap beers, aged dairy products, aged meats, fermented or pickled fish, liver, protein extracts, overripe fruit, soybeans, tofu, fava bean pods, bean pastes, brewer’s yeast pills, marmite, and vegemite.
Surgical Management of Pheochromocytoma and Paraganglioma
A. Perioperative preparation
Prior to surgery, patients should be reasonably normotensive on medication, with an average blood pressure of 130/85 mm Hg or less, without symptomatic orthostasis (discussed earlier). They should also be well hydrated. It is ideal for patients to be admitted for administration of intravenous fluids at least 1 day prior to surgery; however, this is rarely done due to cost considerations. Patients may predonate blood for autologous transfusion. The transfusion of two units of blood within 12 hours before surgery reduces the risk of postoperative hypotension. Blood pressure must be monitored continuously during surgery. This requires placement of an arterial line, preferably in a large artery that is not prone to spasm (eg, femoral artery). A central venous pressure line helps determine the volume of fluid replacement. For certain high-risk patients with congestive heart failure or coronary artery disease, a pulmonary artery (Swan-Ganz) line may be inserted preoperatively to further optimize fluid replacement. Constant electrocardiographic monitoring is mandatory. Severe hypertension can occur—even in fully blocked patients—during bladder catheterization, intubation, or surgical incision. During laparoscopic surgery, catecholamine release is typically stimulated by pneumoperitoneum and by tumor manipulation. However, laparoscopic procedures cause less fluctuation of catecholamine levels and blood pressure than do open surgeries. All antihypertensive medications (discussed later) that might be required should be available and should be in the operating room well in advance.
Arterial embolization of the tumor can be performed immediately prior to surgery. This may be beneficial to the surgeon, particularly for the open resection of very large PGLs that tend to be extremely vascular and difficult to resect, due to blood loss and venous oozing. Embolization of neck PGLs is an established intervention. Secretory PGLs can also be embolized preoperatively. An experienced interventional radiologist must perform such embolizations with full monitoring and an anesthesia team in attendance.
The major problem during surgery for PHEO/PGL is hemodynamic instability. Serious blood pressure variations are more common in patients whose blood pressure has not been adequately controlled preoperatively. Intraoperative hemodynamic instability is also more common in patients with higher plasma norepinephrine levels and larger tumor size.
B. Antihypertensive and antiarrhythmic drugs
Calcium channel blockers These are effective therapies for intraoperative hypertension. They can cause reflex tachycardia that can be controlled with intravenous β-blockers (eg, esmolol). Nicardipine is administered as an intravenous infusion, starting at a dose of 5 mg/h and increasing by 2.5 mg/h every 5 to 15 minutes up to 15 mg/h. Nicardipine was successfully used as the sole intraoperative vasodilating agent in one French series of 70 patients and in another series of 19 patients. Its half-life is 9 hours. Clevidipine has a shorter half-life of 1 to 15 minutes. It is available for intravenous infusion at a dose of 1 to 2 mg/h, doubling the dose after 90 seconds, then increasing in smaller increments at longer intervals (5-10 minutes) up to 4 to 6 mg/h or a maximum of 16 mg/h.
Phentolamine It is a parenteral α-adrenergic blocker that has a short half-life of 19 minutes. It can be given intravenously in bolus doses, starting with a trial dose of 2.5 mg, followed by 5 mg (children, 1-3 mg) and repeating in doses of 5 to 15 mg as needed for blood pressure control. Phentolamine may also be given by intravenous infusion at a rate of 0.5 to 1 mg/min. Side effects include hypotension, tachycardia, cardiac arrhythmias, nasal stuffiness, nausea, and vomiting.
Nitroprusside It is given by intravenous infusion and is an effective drug for managing hypertensive episodes; advantages include widespread familiarity with its use and its short half-life of 2 minutes. Nitroprusside is initiated at 0.25 to 0.3 μg/kg/min and titrated for the desired effect. The maximum infusion rate is 10 μg/kg/min for 10 minutes. High infusion rates should not be given for prolonged periods; long-duration (over 6 hours) nitroprusside infusion rates above 2 μg/kg/min cause cyanide accumulation and toxicity. Cyanide toxicity causes metabolic acidosis and an increase in venous oxygen saturation (>90%) in severe cases. If cyanide toxicity is suspected, the nitroprusside infusion must be stopped or slowed. In the United States, there are two different cyanide antidote kits available. (1) The conventional kit contains amyl nitrite, sodium nitrite, and thiosulfate. Administer an amyl nitrite crushed ampule at the end of the endotracheal tube or under the patient’s nose and give 10 mL 3% sodium nitrite intravenously. Also administer 25% sodium thiosulfate solution (50 mL) intravenously. (2) Additionally, hydroxocobalamin (Cyanokit) is available for intravenous administration at a dose of 5 g (children, 70 mg/kg). Coadministration of sodium thiosulfate (1 g/100 mg nitroprusside) prevents cyanide accumulation. Nitroprusside must be administered cautiously, since it can cause precipitous and profound hypotension, resulting in irreversible ischemic injuries.
Nitroglycerin It is given by intravenous infusion and is effective therapy for perioperative hypertension. Nitroglycerin infusions are initiated at 5 μg/min and increased by 5 μg/min every 3 to 5 minutes until target blood pressure is achieved or a dose of 20 μg/min is reached; if the response has been insufficient, the dose can be increased by 10 to 20 μg/min every 5 minutes to a maximum of 100 μg/min. Because nitroglycerin adheres to polyvinyl chloride tubing, non-PVC infusion sets must be used. Nitroglycerin infusions can cause headache and hypotension. Methemoglobinemia has occurred during prolonged high-dose infusions and is manifested by cyanosis in the presence of a normal arterial pO2. The therapy for methemoglobinemia consists of immediately stopping the nitroglycerin and giving methylene blue, 1 to 2 mg/kg intravenously.
Beta-blockers Atrial tachyarrhythmias may be treated with intravenous atenolol in 1-mg boluses or by constant intravenous infusion of esmolol, a short-acting β-blocker. Esmolol is given as an initial dose of 500 μg/kg intravenously over 1 minute, then continued at 50 μg/kg/min. If required, the infusion rate may be increased by 50 μg/kg/min every 4 minutes.
Magnesium sulfate It is useful for suppressing ventricular arrhythmias and also for managing hypertension during resection of a PHEO/PGL, particularly during pregnancy. Magnesium sulfate may be given as a 4-g intravenous bolus, followed by 3 to 20 mg/min IV infusion.
Lidocaine It may be used to treat cardiac ventricular arrhythmias. In adults, lidocaine is administered with a loading dose of 150 to 200 mg over about 15 minutes, or as a series of smaller boluses. This is followed by a maintenance infusion of 2 to 4 mg/min in order to achieve a therapeutic plasma level of 2 to 6 μg/mL.
Drugs to avoid Atropine should not be used as preoperative medication for patients with PHEOs because it can precipitate arrhythmias and severe hypertension. Metoclopramide, glucagon, and glucocorticoids can also precipitate a hypertensive crisis. MAO inhibitor antidepressants can provoke hypertensive crisis by blocking the metabolism of catecholamines. Other medications that can elicit hypertensive crisis include decongestants (eg, pseudoephedrine), epinephrine, amphetamines and amphetamine derivatives, and cocaine. Labetalol is not recommended for preoperative or intraoperative management of PHEOs because it may aggravate post-resection hypotension. It can also paradoxically aggravate hypertension early in the course of treatment, because its β-blocking effect may occur initially, allowing a brief period of unopposed α-receptor stimulation. Labetalol also inhibits MIBG uptake and causes misleading elevations in catecholamine determinations in certain assays. Diazoxide has been ineffective against hypertension caused by PHEO/PGL.
Anesthetic agents such as intravenous propofol, enflurane, isoflurane, sufentanil, alfentanil, and nitrous oxide appear to be safe and effective. Atropine should not be used. Muscle relaxants with the least hypertensive effect should be employed (eg, vecuronium). Intraoperative hypertension can be managed by increasing the depth of anesthesia and by intravenous vasodilators for blood pressures over 160/90 mm Hg. Serum catecholamine levels drop sharply after adrenal vein ligation and profound hypotension can occur suddenly after resection of a PHEO. Therefore, it is prudent to stop the vasodilator infusion just prior to adrenal vein ligation.
Perioperative mortality is about 2.4% overall, but morbidity rates of up to 24% have been reported. Surgical complications do occur and include splenectomy, which is more common with open abdominal exploration than with laparoscopic surgery. Reported surgical complication rates have been higher in patients with severe hypertension and in patients having reoperations. Surgical morbidity and mortality risks can be minimized by adequate preoperative preparation, accurate tumor localization, and meticulous intraoperative care.
Laparoscopy Most PHEOs can be resected laparoscopically, which has become the procedure of choice for removing most adrenal neoplasms that are under 6 cm in diameter. Adrenal laparoscopic surgery is usually performed through four subcostal ports of 10 to 12 mm. Laparoscopic surgery is widely used now that preoperative localization of the tumor is possible. However, tumors that are invasive or over 6 cm in diameter are more difficult to resect laparoscopically and may require open surgery. For larger PHEOs/PGLs, a lateral laparoscopic approach can be used, because it affords greater opportunity to explore the abdomen and inspect the liver for metastases. For patients with a small adrenal PHEO and for those who have had prior abdominal surgery, a posterior laparoscopic approach may be preferred.
The laparoscope allows unsurpassed magnified views of the PHEO and its vasculature. PHEOs are bagged to reduce the risk of fragmentation and spread of tumor cells within the peritoneum or at the port site. Larger tumors can be removed through laparoscopic incisions that can be widened for the surgeon’s hand (laparoscopic-assisted adrenalectomy). With laparoscopic surgery, hypotensive episodes are less frequent and less severe. Laparoscopic adrenalectomy has other advantages compared with open adrenalectomy: less postoperative pain, faster return to oral foods, and shorter hospital stays (median 3 days vs 7 days for the open approach). This approach is the least invasive for the patient, who can usually begin eating and ambulating the next day. The laparoscopic approach may be used during pregnancy. The technique has also been used successfully for certain extra-adrenal PGLs. Surgical-related mortality has been reduced to 3% at referral centers.
Needlescopic adrenalectomy This procedure uses three subcostal ports of 3 mm, with a larger umbilical port for tumor removal. In one series of 15 patients, this technique reduced surgical times and recovery time compared with the standard laparoscopic approach. However, more extensive experience with this technique is required.
Adrenal cortex-sparing surgery All patients undergoing bilateral total adrenalectomies require life-long glucocorticoid and mineralocorticoid hormone replacement. To avoid adrenal insufficiency, patients with bilateral PHEOs and those with unilateral PHEOs but with highly penetrant familial PHEO/PGL syndromes (especially MEN 2 and VHL) who are at high risk for developing a contralateral PHEO, have had successful laparoscopic partial adrenalectomy during resection of small adrenal PHEOs, sparing some of the adrenal cortex. Such adrenal-sparing surgery is difficult and risks a local recurrence of the PHEO, especially in patients with MEN2.
Open laparotomy Open laparotomy is indicated for patients with particularly large PHEOs or PGLs, or for those with intra-abdominal metastases that require debulking. Large vascular PGLs can be considered for preoperative arterial embolization, but its efficacy is uncertain. An open anterior midline or subcostal approach usually yields adequate exposure. For patients with PGLs of the urinary bladder, a partial cystectomy can sometimes be curative. Other patients with larger bladder PGLs require a total cystectomy and construction of a diverting ureteroenterostomy if the tumor has not been fully resected. For patients with a curative total cystectomy, construction of a new ileal neobladder is possible.
Immediately following removal of a secretory PHEO/PGL, intravenous 5% dextrose should be infused at a constant rate of about 100 mL/h to prevent postoperative hypoglycemia that is otherwise frequently encountered.
F. Therapy for shock occurring after PHEO/PGL resection
Severe shock and cardiovascular collapse can occur immediately following ligation of the adrenal vein during resection of a PHEO, particularly in patients having norepinephrine-secreting tumors. Such hypotension may be due to desensitization of α1-adrenergic receptors, persistence of antihypertensives, and low plasma volume. Preoperative preparation with CCBs or α-blockade plus intravenous hydration or blood transfusions reduces the risk of shock. Intravenous antihypertensives are held just prior to ligation of the adrenal vein. Treatment of shock consists of large volumes of intravenous saline or colloid. Intravenous norepinephrine is sometimes required in very high doses. In cases of post-resection catecholamine-resistant hypotension, intravenous low dose vasopressin administration may be efficacious, given as boluses of 0.08 U, followed by an intravenous continuous vasopressin infusion of 1.6 U/h.
PHEO/PGLs occur in about 1 in every 50,000 pregnancies and are often unrecognized antepartum. Such unsuspected PHEO/PGLs result in a maternal mortality of 40% and a fetal mortality of 56%. However, if the diagnosis is made antepartum, the mortality is much lower. Hypertension is often misdiagnosed as eclampsia or preeclampsia. Hypertensive crisis usually occurs during labor and can be associated with cardiac dysrhythmias or ARDS. Although maternal catecholamines do not cross the placenta, maternal hypertensive crisis is very dangerous for the fetus, causing uteroplacental insufficiency and fetal death.
Pregnant hypertensive patients are often treated with methyldopa that can cause false-positive testing for catecholamines by older fluorometric methodologies, but not by HPLC. Methyldopa does not cause interference with plasma or urine metanephrine measurements performed with MS/MS. Labetalol is often used to treat pregnant hypertensive women, but its use with PHEO/PGL is discouraged (discussed earlier).
During pregnancy, the localization of a PHEO in pregnancy is best done with MRI. As soon as a PHEO is diagnosed, α-blockade is commenced. Phenoxybenzamine is usually used. However, phenoxybenzamine crosses the placenta and accumulates in the fetus. After 26 days of maternal phenoxybenzamine therapy, cord blood levels in the newborn are 60% higher than the mother’s serum levels. Therefore, some perinatal depression and hypotension may occur in newborns of mothers receiving phenoxybenzamine. Prazosin has an advantage for maternal treatment near term, since it is a short-acting selective α1-adrenergic blocker and causes less newborn hypotension, compared to longer acting α-adrenergic blockers. However, chronic use of prazosin increases the risk of fetal demise. The starting dose of prazosin is 0.5 mg/d orally, increasing up to 10 mg orally twice daily if necessary.
There has been little experience with the use of CCBs to treat hypertension in pregnant women with PHEO. However, CCBs can be safely added to α-blockers during pregnancy and are not teratogenic in the first trimester. Therefore, nifedipine or nicardipine may be used to supplement or replace α-blockade as needed.
If possible, β-blockade should not be used at all during pregnancy. Propranolol crosses the placenta and can cause intrauterine growth restriction. Newborns of mothers taking propranolol at delivery exhibit bradycardia, respiratory depression, and hypoglycemia. Therefore, β-blockers should ideally be discontinued 48 hours prior to expected delivery. During delivery, serious atrial tachyarrhythmias should be controlled by a short infusion of esmolol, a β-blocker with a very short half-life.
Angiotensin converting enzyme (ACE) inhibitors should not be used during pregnancy, since their use in the second and third trimesters has been associated with fetal malformations, including skull hypoplasia, renal failure, limb and craniofacial deformation, lung hypoplasia, intrauterine growth retardation, patent ductus arteriosus, and death.
During the first 6 months of pregnancy, it is often possible to treat a woman with α-blockade, followed by laparoscopic resection of the tumor. Although the fetus usually survives, spontaneous abortion is common, despite a successful resection of the tumor. If a PHEO is not discovered until the last trimester, treatment consists of α-blockade followed by elective cesarean delivery as early as feasible. Intravenous magnesium sulfate is a useful antihypertensive during surgery. Intravenous CCBs may be used to treat patients with hypertensive crisis caused by PHEO in pregnancy. The tumor is resected after the cesarean delivery. In the presence of an active PHEO, vaginal delivery should never be allowed, since life-threatening hypertensive crisis will predictably occur.
Pheochromocytoma-Induced Life-Threatening Complications: Cardiomyopathy, ARDS, and Multisystem Crisis
Life-threatening complications can occur in patients with PHEO/PGL in an idiosyncratic fashion and are not necessarily associated with hypertension.
Cardiomyopathy and attendant serious cardiac dysrhythmias often occur in patients with PHEO/PGL. It is also known as “catecholamine cardiomyopathy.” Heart failure and shock can occur and can sometimes present with reverse ventricular activity, also known as “Takatsubo cardiomyopathy.” “Takatsubo” is a Japanese term for a traditional octopus fishing pot, which the heart may resemble on imaging studies. Affected patients can present with life-threatening ventricular arrhythmias, cardiac rupture, systemic embolism, or shock due to cardiac pump failure. Serum BNP can be very high. The etiology for cardiomyopathy in PHEO/PGL has been ascribed to catecholamines, although circulating cytokines may also be contributory. Acute cardiomyopathy is potentially reversible after the tumor is removed or the patient is stabilized. Therefore, every effort must be made to salvage these patients, who may require mechanical circulatory support (MCS).
ARDS occurs in patients with PHEO/PGL and is not associated with unusually severe hypertension or particularly high plasma catecholamine levels, compared to other PHEO/PGLs. ARDS is more apt to occur in patients with proteinuria that may serve as a marker for patients at risk. Proteinuria and ARDS itself may be due to tumoral secretion of certain cytokines in the setting of catecholamine excess. ARDS can occur spontaneously, after major surgery, and after therapy with high-activity 131I-MIBG in patients with metastatic disease. ARDS may accompany cardiomyopathy and can be mistaken for congestive heart failure or pneumonia. Most patients require intubation and respirator-assisted breathing with high oxygen supplementation. Some patients may require extracorporeal membrane oxygenation (ECMO). ARDS may progress to multisystem crisis.
Multisystem crisis can have manifestations such as ARDS, renal failure, hepatic failure, rhabdomyolysis, cardiomyopathy, shock, and disseminated intravascular coagulation. Multisystem crisis can occur spontaneously or following the administration of glucagon or corticosteroids. It can also occur following unrelated surgery or therapy with 131I-MIBG. The mortality rate is extremely high despite intensive care. It has been hypothesized that ARDS and multiorgan crisis may be due to increased circulating cytokines, in addition to catecholamines.
Pathology of PHEO and PGL
On histopathology, PHEOs are extremely vascular tumors with neurosecretory granules. Central necrosis is often present. The cells may be arranged in nests (zellballen pattern), anastomosing cords (trabecular pattern), or a combination of both. Cells vary in size with pleomorphic and eccentric nuclei that are often large and bizarre in appearance. The cells exhibit immunofluorescence staining for CgA and synaptophysin.
No single characteristic of PHEO or PGL can determine whether a given tumor is malignant. Therefore, the definition of malignancy is based upon whether metastases are present. Metastases must be distinguished from additional PGLs by their location (liver, lung, bone) where sympathetic paraganglia are rare. Metastases must also be distinguished from intraperitoneal seeding, a phenomenon known as pheochromocytomatosis. Metastases can vary in virulence from relatively indolent to extremely aggressive (see discussion on malignant PHEO later).
Overall, about 26% of these tumors arise in patients with identifiable germline mutations. Individuals with no known family history of these tumors have about a 17% risk of harboring a known germline mutation. About 18% of cases develop in children. The earlier a tumor presents, the more likely that individual harbors a germline mutation (see discussion on genetics of PHEO and PGL, earlier).
Adrenal PHEOs and PGLs appear very similar on microscopy. PGLs are often large and arise near the adrenal, making the distinction particularly difficult based upon preoperative localization scans. But it is important to distinguish these two tumors because PGLs are more likely to metastasize. One way to distinguish these tumors preoperatively is to evaluate their secretions. Tumors that secrete epinephrine (or its metabolite, metanephrine) are predictably adrenal PHEO. However, tumors that secrete strictly norepinephrine (or its metabolite normetanephrine) may be either PHEO or PGL. Intraoperatively, the surgeon may be able to identify the adrenal gland as separate from the tumor. On pathology, it is often possible to visualize the adrenal cortex lying in close proximity to the PHEO or even arising out of the adrenal medulla. An intact adrenal gland may be included in the surgical specimen, indicating that the tumor was a juxta-adrenal PGL. On microscopy, PGLs may have visible nerve ganglia.
Composite PHEOs are rare tumors that exhibit histopathologic features of both PHEO and neuroblastoma. Such tumors have generally not recurred and have not exhibited N-myc amplification, which distinguishes them from typical neuroblastomas. Therefore, composite PHEO are considered to be a histological variant of PHEOs.
Metastatic Pheochromocytoma and Paraganglioma
No PHEO or PGL should be labeled benign (Table 11–18). Histopathology cannot reliably determine whether a given tumor has metastasized. Such metastases can be microscopic and indolent, eluding detection with the most sensitive scanning and biochemical screening. Therefore, it is best to think of these tumors as either having detectable metastases (metastatic PHEO) or having no detectable metastases.
TABLE 11–18Distribution of metastases in 50 cases of metastatic pheochromocytoma and paraganglioma. |Favorite Table|Download (.pdf) TABLE 11–18 Distribution of metastases in 50 cases of metastatic pheochromocytoma and paraganglioma.
|Region of Metastasis ||Percentage |
Abdomen (nodes, peritoneum, local recurrence)
Pelvis (soft tissue)
Mediastinum and lung hila
Lymph nodes (extra-abdominal) especially supraclavicular and inguinal
Location: Metastases are evident at the time of diagnosis in about 10% of patients with an adrenal PHEO. Another 5% to 10% are found to have metastatic disease or local recurrence within 20 years. Extra-adrenal PGLs commonly metastasize. In a Mayo Clinic series of PGLs, 15% had local invasion and 21% had detectable distant metastases at the time of initial surgery, with an overall 36% risk of local or distant metastasis.
Genetics: The risk for detectable metastases is high for PHEOs/PGLs that arise in patients harboring a SDHB germline mutation, with this mutation being found in about 40% of metastatic PHEOs/PGLs. PHEOs/PGLs that arise in patients with NF-1 germline mutations have a 12% risk of metastasis. PHEOs that arise in patients with VHL or RET germline mutations have a low (<5%) risk of metastasis.
It is conceivable that all PHEOs and PGLs metastasize as single cells but that such cells will only grow if certain genes are down-regulated and other genes are up-regulated. This concept is supported by genome-wide expression profiling of PHEO/PGLs. These profiles have identified candidate genes that are differentially expressed in tumors with detectable metastases versus those with no detectable metastases. Gene expression arrays of PHEOs/PGLs with detectable metastases have demonstrated that 5 genes are differentially up-regulated in these tumors.
Research in malignant PHEO/PGL has been hampered by the absence of a viable human cell line. However, a highly malignant mouse PHEO model has been developed in which a gene expression array has demonstrated the up-regulation of 8 genes and the down-regulation of 38 genes.
Other predictors of malignancy: The risk of PHEO/PGL recurrence is higher if there is extensive local invasion. One surgical observation is that tumors that are “stickier” and more difficult to dissect from adjacent tissue are more likely to recur or metastasize. Tumors are also more likely to metastasize if they are larger than 5 cm diameter, although about 20% of metastatic primary tumors have been smaller than 5 cm diameter. Primary PHEOs/PGLs as small as 1 cm diameter have been documented to metastasize. Tumors are also more likely to metastasize if they contain high levels of Ki-67, a protein expressed in proliferating cells that can be detected by the monoclonal antibody MIB-1 and quantified as a high MIB-1 score. Metastatic PHEOs/PGLs also have increased activity of telomerase. Tumors with high c-myc gene expression are more likely to be malignant. In one series, 50% of patients with malignant PHEO were found to have high serum levels of NSE, but in none of 13 patients in another series with benign PHEOs.
The differential diagnosis for apparent metastases includes, multicentric PGLs, second PHEOs, false-positive scanning, and intraperitoneal seeding of tumor (pheochromocytomatosis). Patients with familial forms of PHEO/PGL may develop other tumors associated with their mutation: medullary thyroid cancer (RET), renal cell cancer (VHL, SDHx), pituitary adenoma, GIST, pulmonary chondroma (SDHx). Other non-PHEO/PGL malignancies also appear to be more common. A series of 110 Swedish patients with PHEO/PGL, treated surgically, showed an unexpectedly high relative risk for developing non-PHEO/PGL malignancies (RR ≅ 2.0). Therefore, additional tumors should not be presumed to be metastases unless they have uptake on 123I-MIBG or 18FDA-PET scanning. Suspicious lesions without such uptake should be considered for biopsy.
Sites of metastasis (Table 11–18): Metastases from PHEOs or PGLs typically involve bones (82%), liver (30%), lungs (36%), lymph nodes, the contralateral adrenal, and sometimes muscle. The bones most frequently involved include vertebrae, pelvis and ischium, clavicles, cranium, proximal femurs, and humeri. Tibia, radius, and ulna are occasionally involved. Patients with metastases and an SDHB mutation have a higher prevalence of metastases involving long bones compared to those without the mutation. PHEO/PGL metastases have a proclivity for the skull where they may form a dumbbell-type lesion, sometimes being palpable as a soft cyst-like bump; they also may grow inside the skull to impinge upon the brain. Prevertebral PGLs may destroy adjacent vertebrae, and spinal cord compression may occur. Most bone metastases affect the cortical bone; they may be indolent, but are often osteolytic and cause progressive bone destruction. Other bone metastases primarily involve trabecular bone and marrow; such metastases are usually visible on MRI but may be invisible on CT. Metastases to lymph nodes outside the abdomen are most frequent in the supraclavicular and inguinal regions. Metastases to muscle are usually indolent. These tumors have not been reported to metastasize to brain, although metastases to the cranium and skull base may impinge upon the brain, pituitary, and cranial nerves.
Metastases usually secrete norepinephrine and normetanephrine. Some metastases secrete predominantly dopamine. Metastases rarely secrete epinephrine or metanephrine, with the exception of some metastases from epinephrine-secreting adrenal PHEOs. About 20% of sympathetic PGLs and their metastases do not secrete catecholamines or metanephrines, but most continue to secrete CgA, which becomes a valuable tumor marker.
Assessing the growth rate of PHEO/PGL metastases: Treatment can be tailored to the tumor’s rate of growth. Knowledge of the growth rate of a patient’s metastases may be obtained through close biochemical surveillance and serial volumetric imaging with CT or MRI. Patients who are asymptomatic with a few indolent osseous metastases may elect to receive bisphosphonate therapy and delay life-threatening chemotherapy or radioisotope therapy, as long as they remain under close surveillance. Even patients with a symptomatic osteolytic metastasis may elect to receive targeted therapy rather than systemic treatment if their overall tumor burden is low.
Surveillance: Malignancy is determined only by the presence of metastases. MRI or CT scanning may not detect small metastases within their field and will certainly not visualize metastases outside their field. The various radiolabeled imaging scans can also be negative in the presence of metastases. Therefore, following the resection of an apparently benign PHEO or PGL, long-term surveillance is required, since metastases may not become clinically apparent for years or decades.
Biochemical surveillance: Patients should be followed with repeated determinations for the tumor markers that were highest prior to resection of their primary PHEO/PGL. Repeat postoperative testing should be postponed until at least 2 to 4 weeks postoperative, and the patient is fully recovered from surgery. Unfortunately, some patients with unsuspected PHEO/PGL have incomplete or no preoperative testing prior to the surgical resection of their primary tumor. Biochemical screening for recurrence or metastases in such patients is best done with plasma-fractionated free metanephrines and fractionated catecholamines (with dopamine), along with a fasting serum CgA. While this survey of tumor markers is sensitive for PHEO/PGL recurrence, false-positive testing occurs commonly. When a PHEO/PGL tumor marker is only marginally elevated, the test should be repeated. Interpretation of elevated tumor markers should be done cautiously with the knowledge that adrenal PHEOs usually secrete both norepinephrine and epinephrine, and their metastases may sometimes continue to produce epinephrine, but more commonly produce norepinephrine and its metabolite normetanephrine. Extra-adrenal PGLs ordinarily produce only norepinephrine and normetanephrine and sometimes only CgA; their metastases do likewise. When such tumor markers are consistently elevated, repeat scanning is certainly warranted.
Scan surveillance: It must be kept in mind that scan surveillance is useful to detect not only recurrent or metastatic PHEO/PGL, but also to detect other malignancies to which these patients are prone. Unfortunately, the long-term repetitive use of any CT or radionuclide scan delivers excessive cumulative radiation exposure to the patient, increasing their lifetime risk of additional non-PHEO/PGL malignancies. Therefore, a reasonable combination of modalities must be used, relying upon biochemical surveillance for secretory sympathetic PHEO/PGLs (discussed earlier). Neck ultrasound is useful for nonsecretory HN-PGLs, but will not detect a jugulotympanic PGL. MRI is useful for detecting recurrent or de novo HN-PGLs. MRI is also useful for general scanning, but scanning the entire chest, abdomen, and pelvis usually requires a prolonged time in the scanner; it can also be problematic to obtain insurance preauthorization and to schedule a full-body MRI. Rapid full-body MRI has been developed and is available in certain tertiary referral centers. Rapid full-body MRI reduces the time for each image cut from several seconds to milliseconds. However, it is a screening scan, rather than diagnostic procedure and can miss smaller tumors. Also, full body MRI does not typically cover the extremities and does not detect metastases to the extremities.
Radionuclide scanning is advantageous in that the entire body may be included in the scan. Some kind of radionuclide scanning is indicated for patients with biochemical or clinical evidence of recurrent or metastatic PHEO/PGL. However, no radionuclide scan is 100% sensitive. PHEO/PGL metastases have variable avidity for 123I-MIBG. Even when the primary tumor is avid for 123I-MIBG, some or all of the metastases may not be visible on 123I-MIBG scanning. This low sensitivity (57%) is seen for metastases that are deficient in norepinephrine transporter (NET) expression. In a given individual, some metastases may be avid for 123I-MIBG, while others show virtually no uptake. When patients have a recurrence or progression of metastases after 131I-MIBG therapy, metastases with less MIBG-avid may emerge or progress in size. When 123I-MIBG imaging is negative, metastases may be detected with MRI or CT scanning. Metabolically active PHEO/PGL metastases are usually visible with 18F-FDG-PET scanning, which has the additional advantage of being a whole-body scan with a sensitivity of about 76% for metastases. 18F-FDA-PET has a sensitivity of about 78% for metastases. Somatostatin receptor scintigraphy or 68Ga-DOTATATE-PET, will often detect metastases that are not visible with other scans.
Treatment for Patients with Recurrent or Metastatic PHEO and PGL
Patients with recurrent or metastatic PHEO/PGL must have individualized therapy and surveillance. They are usually considered for surgery, with the goal of either surgical cure or at least debulking. Some small metastases can be quite indolent, such that certain asymptomatic patients with a low and indolent tumor burden may be followed closely without treatment or treatment with less toxic modalities, such as denosumab or zoledronic acid for osseous metastases, and directed external beam radiation therapy for larger osteolytic metastases. In one series of 90 patients with metastatic PHEO/PGL, 9% had progression-free survival at 5 years.
A. General considerations
In vitro studies have found that cultured PHEO cells are protected from cytotoxic insult by amitriptyline and fluoxetine, possibly through up-regulation of superoxide dismutase. Therefore, patients being treated for metastatic PHEO/PGL should probably not take tricyclic antidepressants or selective serotonin reuptake inhibitors, although there have been no clinical studies of their effect on survival. A clinical study of kindreds with SDHD germline mutations noted that individuals with this mutation who lived at higher elevations developed more PGLs earlier than their affected relatives living at sea level (the Netherlands). Therefore, it is possible that residing at higher altitude may stimulate the development of PHEO/PGL among patients harboring SDHD germline mutations and perhaps other cluster 1 germline mutations with underlying pseudohypoxia (see Table 11–8). There is concern that chronic recurrent hypoxia from sleep apnea can trigger catecholamine release and might also stimulate tumor growth in susceptible patients with cluster 1 germline mutations. Therefore, screening for sleep apnea should be considered for affected patients who snore or have other risks for sleep apnea.
It is usually best to resect the primary tumor as well as large metastases. This is especially true of secretory tumors that are causing hypertension and other symptoms that can be life-threatening. Even lung metastases may be resected. However, the decision about whether to resect metastases is a difficult one and must be based upon very thorough staging of the patient’s tumor. Of course, when resecting secretory metastases, preoperative preparation is mandatory, and hypertension must be adequately controlled.
Due to the rarity of PHEO/PGL, there have been no large-scale clinical trials comparing available chemotherapies. However, there have been small series of patients and case reports from which to derive recommendations. Although chemotherapy can achieve remissions, no durable long-term remissions have been reported, such that lifetime chemotherapy is required. Therefore, when selecting chemotherapy, it is important to select a regimen that the patient can tolerate long term with a reasonable quality of life. Temozolomide is usually tolerated best. However, for aggressive metastases, it is best to induce a remission with either a tyrosine kinase inhibitor or cyclophosphamide, vincristine, and dacarbazine (CVD) combined chemotherapy (discussed later).
Temozolomide (TMZ): TMZ carries the advantage of either oral or intravenous administration on a daily basis for just 5 days monthly. Patients usually tolerate TMZ better than other chemotherapeutic regimens for long-term tumor suppression. However, TMZ causes nausea, and patients require prophylactic ondansetron and other supportive therapy during their treatment week. TMZ has reasonable anti-tumor effect in patients with metastatic PHEO/PGL, particularly those with SDHB germline mutations. In one study of 15 patients with metastatic PHEO/PGL (10 with SDHB germline mutations), treated with a mean dose of TMZ of 172 mg/m2 daily for 5 days monthly, partial responses (PR) were observed in 5 patients, stable disease (SD) in 7 patients, and progressive disease (PD) in 3 patients. All 5 patients experiencing a PR had an SDHB mutation. If most metastases remain stable, the patient may continue TMZ, while limited break-through metastases are treated surgically or with external beam radiation therapy.
Cyclophosphamide, vincristine, dacarbazine (CVD): Combined chemotherapy with CVD is usually given intravenously over 2 days and the cycles repeated every 3 to 4 weeks, indefinitely. After controlling symptoms of catecholamine excess, cycles of CVD are administered as follows: cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, and dacarbazine 600 mg/m2 on day 1, followed by dacarbazine 600 mg/m2 on day 2. The doses are adjusted according to the response and toxicity in each patient.
In a meta-analysis of 50 patients with metastatic PHEO/PGL treated with CVD, the tumor-size response rates have been: CR 4%; PR 37%; SD 14%; PD 45%. Catecholamine response rates have been: CR 14%; PR 40%; SD 20%; PD 26%.
When CVD chemotherapy is stopped, the tumors usually recur. Many patients cannot tolerate such a long-term regimen, due to fatigue, cytopenias, neuropathy, and other adverse reactions. However, some patients tolerate it reasonably well and may experience a complete biochemical remission. Once in remission, CVD cycles are continued at increased intervals, but not stopped.
Sunitinib: Partial remissions in metastatic PHEO have been reported with sunitinib, a tyrosine kinase inhibitor. Sunitinib is administered orally, usually in a dose of 50 mg daily in cycles of 4 weeks on, then 2 weeks off. However, a lower dose of 37.5 mg daily is also being used, since patients tend to tolerate the lower dosage better, and tumor growth has sometimes been documented during off weeks with the cycled regimen. The dosage may be adjusted in 12.5-mg increments according to response and toxicity. Sunitinib is metabolized in the liver by CYP3A4, so dose adjustments should be made for patients taking the wide variety of drugs that are inhibitors or inducers of CYP3A4. Sunitinib can cause serious adverse reactions, including heart failure, cardiac arrhythmias, marrow suppression, pancreatitis, hypo- or hyperthyroidism, nephrotic syndrome, and rhabdomyolysis with acute renal failure. Patients treated with sunitinib also commonly experience nausea, vomiting, diarrhea, hypertension, skin discoloration, mucositis, asthenia, dyspnea, myalgias, and arthralgias.
Adjuvant statin therapy: Certain lipophilic statins (lovastatin, fluvastatin, and simvastatin) inhibit the growth and migration of mouse PHEO cells and the more aggressive mouse PHEO tissue-derived cells in vitro. The effect appears to be mediated through inhibition of mitogen-activated kinase (MAPK) pathway. The MAPK pathway appears to play a role in certain human PHEO/PGL tumors with mutations in K-RAS, RET, NF-1, and SDHB. Although oral administration of these statins would not achieve adequate tumor levels to cause tumor cell apoptosis, the use of these statins is a promising therapeutic option as an adjuvant to chemotherapy. However, there have been no clinical trials to indicate whether this effect is clinically significant.
Potential therapeutic targets: ATP synthase (ATP5B) is an enzyme complex that is intracellular in most normal cells but is found on the surface of SDHB-associated PGLs and may promote tumor cell survival. Inhibition of tumoral ATP synthase with anti-ATP synthase antibodies and drugs that inhibit ATP synthase (eg, resveratrol) are possible future therapies against metastatic PHEO/PGL.
Triptolide, an inhibitor of nuclear factor-kappaB (NF-κB) increases the expression of norepinephrine transporter (NET) in PHEO cells and has increased the uptake of MIBG into mouse PHEO cells in vitro. Triptolide has also reduced the tumor burden in a metastatic PHEO animal model. Triptolide has serious clinical adverse effects; a better-tolerated prodrug (minnelide) is in early clinical trials for patients with metastatic GI tumors.
D. Bisphosphonates or denosumab
No controlled clinical trials have assessed the efficacy of bisphosphonates or denosumab against osteolytic bone metastases from PGLs and PHEOs. However, bisphosphonates and denosumab have demonstrated effectiveness in other osteolytic solid tumors to reduce skeletal-related adverse events. Zoledronic acid is usually administered in doses of 4 to 5 mg every 1 to 2 months as an intravenous infusion to patients with osteolytic bone metastases. Patients unable to tolerate zoledronic acid may tolerate intravenous pamidronate. Denosumab is administered subcutaneously at initial doses of 60 mg every 1 to 2 months for patients with osteolytic bone metastases. Long-term therapy with either agent is associated with an increased risk for atypical subtrochanteric (chalk stick) femoral fractures, aseptic necrosis of the jaw, and metatarsal stress fractures.
When administered to patients with symptomatic spinal or cranial PHEO/PGL metastases, radiation therapy can reduce pain and produce neurologic improvement. Although conventional radiation therapy is usually administered, gamma knife can be given to smaller symptomatic bone metastases and to jugulotympanic PGLs. Conventional radiation therapy to large primary tumors or intra-abdominal metastases is not advisable, because it is usually ineffective and causes morbidity such as radiation enteritis and a proclivity to later surgical complications such as wound dehiscence, infections, and fistulas. However, small recurrent tumors can be treated with CyberKnife stereotactic radiosurgery. Surgical debulking of large abdominal or thoracic tumors (or other therapies) is usually preferable to radiation therapy. Radiation therapy to tumors reduces their uptake of 131I-MIBG.
F. Arterial embolization and radiofrequency ablation
Before arterial embolization or radiofrequency ablation, patients with secretory PHEO/PGL must be fully prepared such that their blood pressure is near normal as described earlier. Pretreatment includes α-blockade and/or other measures such as β-blockade, CCBs, or metyrosine. Patients are monitored with arterial blood pressure transducers and given a central line before endotracheal general anesthesia. Anesthesia standby is necessary in case severe hypertension occurs, and it becomes necessary to administer intravenous antihypertensive drugs.
Arterial embolization has been used on rare occasions to reduce blood flow to PGLs and PHEOs, either in preparation for surgery or for inoperable cases. These tumors are usually very vascular and preoperative embolization may reduce intraoperative hemorrhage. Also, embolizing the tumor’s blood supply may slow its growth. However, there have been no controlled clinical trials as to its effectiveness. A major potential risk of embolization is that of PHEO crisis. However, embolization has been used successfully on secretory tumors where the patient has been fully prepared with α-blockade and/or other measures. Localization arteriograms should use nonionic contrast.
Radiofrequency (RF) thermal ablation has been used successfully for patients with metastatic PHEO/PGL, particularly for liver and bone metastases. Most reported RF ablations of bone metastases have targeted rib or ischial/pelvic lesions. Before RF ablations, the RF electrode(s) is guided into the tumor with ultrasound or CT guidance. Single electrodes may be used for small lesions, while metastases over 2.5 cm diameter usually require triple parallel cluster needle electrodes.
G. 131I-metaiodobenzylguanidine (131I-MIBG)
131I-MIBG is a treatment option for patients with metastatic or unresectable PHEO or PGL whose tumors are avid for the isotope (Figure 11–14). Benzylguanidine is a false neurotransmitter that resembles norepinephrine and is preferentially absorbed by PHEO/PGL tumors that express surface norepinephrine transporter 1 (NET 1) activity; it is tagged with 131I to produce 131I-MIBG. Only about 60% of metastatic or recurrent unresectable PHEO/PGLs have sufficient avidity for MIBG for 131I-MIBG therapy to be potentially efficacious. Nonsecretory PHEO/PGLs frequently have sufficient MIBG to allow treatment. Pretreatment with nifedipine increased MIBG retention in 4/8 patients in one report. Some patients with good uptake of MIBG on diagnostic scanning have disappointingly poor uptake of large therapeutic doses of 131I-MIBG, possibly caused by competitive inhibition by large amounts of nonradioactive (“carrier added”) 127I-MIBG that are present in most current formulations of 131I-MIBG. A “no-carrier-added” formulation of 131I-MIBG has been developed and is in clinical trials. Minnelide, a prodrug for an inhibitor of NF-κB has the potential for possibly increasing MIBG uptake into PHEO/PGL tumors (discussed later). Responses to 131I-MIBG therapy occur over several months and continued decreases in tumor markers and tumor size may be observed for up to a year following therapy.
Posttherapy scan 1 week after administration of 500 mCi 131I-MIBG. Patient is a 22-year-old woman with a large unresectable PHEO in the left adrenal that has central hemorrhagic necrosis. There are widespread metastases to liver and bones. A metastasis to the left orbit has caused optic nerve compression and a visual field defect. A large metastasis to the left pelvis has caused pain and required prior external beam radiation therapy. A. Anterior image; B. Posterior image.
Protocol: Treatment protocols vary among institutions. Most currently employ repeated low-activity therapies of 100 to 250 mCi (3.7-9.25 GBq) or intermediate activity therapies of 250 to 500 mCi (9.25-18.5 GBq). High-activity 131I-MIBG therapies over 500 mCi (18.5 GBq) have been employed for metastatic PHEO/PGL, but pose increased risks. 131I-MIBG is administered intravenously over 30 to 90 minutes via a peripheral or central venous catheter. Following therapy with 131I-MIBG, once background radiation has dissipated, a posttreatment whole-body scan is obtained.
Before and after 131I-MIBG therapy, patients with an intact thyroid are premedicated with oral potassium iodide to reduce the risk of thyroid damage that could be caused by free 131I generated through metabolism of 131I-MIBG. The best-tolerated oral potassium iodide preparation is ThyroShield. Patients are all pretreated with non-phenothiazine antiemetics such as ondansetron; they remain hospitalized in lead-shielded rooms with radiation safety precautions until the emitted gamma radiation declines to acceptable levels, which usually requires about 4 to 9 days, depending upon the amount of activity infused and its uptake and retention by PHEO/PGL tumors. Repeated treatments may be required.
Responses: Complete remission (CR) or partial remission (PR), defined by RECIST (Response Evaluation Criteria in Solid Tumors), occur in about 22% of patients treated with 131I-MIBG, while an additional 35% have minor responses (improvement in symptoms, tumor markers, and tumor size not meeting RECIST criteria for a PR); another 8% have stable disease (SD), at least temporarily. About one-third of patients fail to respond at all to 131I-MIBG and experience progressive disease (PD) within a year after therapy. 131I-MIBG therapy may improve 5-year survival, but controlled clinical trials are lacking.
Adverse reactions: Intermediate or high-activity 131I-MIBG therapy predictably causes immediate lymphocytopenia, followed by some degree of platelet and neutrophil suppression that commences about 2.5 to 4 weeks after therapy. Therefore, patients must be observed and treated for any thrush or inguinal candidiasis and complete blood counts with platelet counts must be monitored after therapy. Platelet transfusions, red blood cell transfusions, or filgrastim may be required. High-activity therapy with 131I-MIBG greater than 500 mCi (18.5 GBq) risks prolonged bone marrow suppression, requiring pretreatment peripheral blood stem cell harvesting with cryopreservation. High-activity 131I-MIBG also increases radiation exposure to hospital personnel and is especially problematic if the patient develops complications and requires care in an intensive care unit without lead shielding.
Other adverse reactions to 131I-MIBG therapy include nausea, occasional sialadenitis, transient hair loss, hypogonadism, and infertility. Also, ARDS and multisystem crisis have occurred in rare patients with proteinuria (a marker for this complication) after 131I-MIBG therapy with activities greater than or equal to 500 mCi (18.5 GBq). Patients with PHEO/PGL who have any degree of proteinuria are at increased risk for ARDS and multisystem crisis, either spontaneously or after 131I-MIBG or other procedures. Patients with metastatic PHEO/PGL and proteinuria may be treated with repeated low-activity 131I-MIBG therapies. Patients treated with 131I-MIBG have an increased lifetime risk of second malignancies, particularly myelodysplastic syndrome (MDS) and leukemia. MDS and leukemia have occurred about 5 to 7 years after 131I-MIBG, particularly in patients who have received cumulative activities greater than or equal to 1000 mCi (37 GBq).
The mortality rate for patients undergoing PHEO/PGL resection has dropped to under 3% due to improved medical preparation and surgical technique. Laparoscopic resections have reduced perioperative morbidity and shortened the length of hospitalization. However, even after complete resection of the PHEO/PGL, hypertension persists or recurs in 25% of patients. Recurrent hypertension is an indication for reevaluation for PHEO.
Following surgical resection of a PHEO/PGL without detectable metastases, patients have a 5-year survival rate of 96%. Risk factors for death from PHEO/PGL include tumor size over 5 cm, metastatic disease, and local tumor invasion. However, the long-term mortality rate is much higher than expected. In a Swedish long-term outcome study of 121 patients with PHEO/PGL, there was no perioperative mortality, but 50% of patients remained hypertensive postoperatively. Of the 121 patients, 42 died during an observation period averaging 15 years, versus an expected 24 deaths in an age-matched control population. Thus, their relative risk of mortality was increased 78% (RR 1.78). Of the 42 patients who died, 20 deaths were due to cardiovascular disease, 6 from associated neuroectodermal tumors, 5 from other malignancies,7 from unrelated causes, and 4 from malignant PHEO/PGL.
Metastases are variably aggressive, between patients and within a given patient. Some metastases are quite indolent and may present clinically one or two decades after resection of the primary tumor. However, other metastases are exceptionally aggressive. Asymptomatic patients with only a few bone metastases tend to have the best prognosis, while those with a heavy burden of liver and lung metastases tend to have the most malignant disease.
Patients with metastatic PHEO/PGL who have appropriate surveillance and treatment now have average overall survival rates as follows: 5-year survival, 77%; 10-year survival, 62%; 20-year survival, 39%. SDHB germline mutations are found in about 81% of children with metastatic PHEOs/PGLs, compared to about 49% of adults. Genetics affects prognosis. Adults SDHB germline mutations tend to fare worse than patients with metastases from sporadic PHEO/PGL. However, children with metastatic PHEO/PGL associated with SDHB germline mutations tend to fare better than their adult counterparts.
PHEO and PGL: Postoperative Long-Term Surveillance
A preoperative 123I-MIBG scan or other radionuclide scan (discussed earlier) is recommended for all patients with PHEO/PGL. Postoperative scanning is recommended for patients when there is any doubt about complete resection of an adrenal PHEO and for any patients with PGL or multiple tumors. The postoperative scan is usually obtained several months after surgery.
All patients with PHEOs/PGLs require lifetime postoperative surveillance. They require aggressive treatment of all cardiovascular risk factors, due to their increased long-term risk of death from cardiovascular causes. Additionally, patients should be tested for familial genetic syndromes and appropriately screened for associated malignancies (see Genetic Conditions Associated with Pheochromocytomas and Paragangliomas, see Tables 11–8 through 11–12). Persistent symptoms or hypertension can signify recurrence at the surgical site, seeding of the peritoneum, a contralateral PHEO, a PGL, or possibly metastatic disease. About 10% of adrenal PHEOs have metastasized at the time of diagnosis or soon postoperatively. However, occult metastatic disease is detected up to 20 years later in another 5%. Up to 35% of sympathetic PGLs have metastases at the time of diagnosis, particularly in patients harboring SDHB or fumarate hydratase (FH) germline mutations. Other patients develop multiple recurrent intra-abdominal tumors (pheochromocytomatosis) probably caused by tumor seeding that may occur spontaneously from the original tumor or during surgery.
Patients with secretory tumors are usually followed with plasma-fractionated free metanephrine determinations. Plasma-fractionated catecholamines and dopamine may also be obtained if they were predominantly secreted by the primary tumor. Serum CgA is a useful tumor marker for patients with PHEOs/PGLs whose primary tumor secreted CgA and whose renal function is normal; elevated and rising levels of CgA usually indicate tumor recurrence or metastases (see CgA, discussed earlier). The type of biochemical follow-up is tailored to the individual patient. The first determination of postoperative plasma-fractionated free metanephrines is obtained at least 2 weeks after surgery, because catecholamine excretion often remains high for up to 10 days after successful surgery. Testing is obtained quarterly during the first year following surgery, then semiannually for at least 5 years. After 5 years, lifetime routine yearly physical examinations and biochemical screening are recommended, with immediate evaluation for recurrent PHEO/PGL if suspicious symptoms recur. For hypertensive patients, weekly home blood pressure monitoring is recommended for the first year postoperatively and monthly thereafter. A rising blood pressure or recurrence of symptoms should trigger a full workup for recurrent or metastatic PHEO/PGL.