Endocrine-Related Cancer 14 (4) 935-956 DOI: 10.1677/ERC-07-0142
Copyright © 2007 by the Society for Endocrinology.
Pheochromocytoma: an update on genetics and management
Asterios Karagiannis,
Dimitri P Mikhailidis1,
Vasilios G Athyros and
Faidon Harsoulis
Division of Endocrinology, Second Propedeutic Department of Internal Medicine, Medical School, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece 1 Department of Clinical Biochemistry,, Royal Free University College Medical School, Royal Free Hospital, University College London (University of London), Pond Street, London NW3 2QG, UK
(Correspondence should be addressed to D P Mikhailidis; Email: mikhailidis{at}aol.com)
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Abstract
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Pheochromocytomas (PHEOs) are rare neoplasms that produce catecholamines and usually arise from the adrenal medulla and are considered to be an adrenal paraganglioma (PGL). Closely related tumors of extraadrenal sympathetic and parasympathetic paraganglia are classified as extraadrenal PGLs. Most PHEOs are sporadic, but a significant percentage (
25%) may be found in patients with germline mutations of genes predisposing to the development of von Hippel–Lindau disease, neurofibromatosis 1, multiple endocrine neoplasia type 1 (MEN1) and 2 (MEN2), and the PGL/PHEOs syndrome, based on the described mutations of the genes for succinate dehydrogenase subunit D (SDHD), B (SDHB), and C (SDHC). As one out of four PHEOs turns out to be a hereditary clinical entity, screening for genetic alterations is important, as it provides useful information for a rational diagnostic approach and management. This review discusses the genetics, the pathophysiology of hypertension, the clinical picture, the biochemical and imaging diagnosis, and the preferred therapeutic approach for PGLs/PHEOs. Furthermore, it emphasizes the need for genetic testing in cases with apparently sporadic PHEOs.
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Introduction
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The adrenal medulla and ganglia of the sympathetic nervous system (SNS) are derived from the embryonic neural crest. The endocrine cells of this sympathoadrenal system synthesize and secrete catecholamines and exhibit a characteristic histochemical (chromaffin) reaction when treated with oxidizing agents. Pheochromocytomas (PHEOs), according to the World Health Organization (2004) classification, are rare tumors arising from catecholamine-producing cells in the adrenal medulla – an intraadrenal paraganglioma (PGL). Adrenal and extraadrenal PGLs produce significant amounts of catecholamines and give rise to the well-known clinical picture of PHEOs. In contrast, the parasympathetic PGLs (mainly in head and neck) rarely produce significant amounts of catecholamines.
During the last few years, a considerable amount of new data, concerning the genetics of PHEO/PGL, have accumulated and changed the whole approach to such patients. It has been shown that in about 25% of cases, PHEO/PGLs develop secondary to germline mutations in any of five susceptibility genes (Dluhy 2002, Neumann et al. 2002, Amar et al. 2005a, Gimenez-Roqueplo et al. 2006, Pacak et al. 2007).
A classic PHEO, a solitary tumor of the adrenal medulla, reminds us of a ‘tip of an iceberg’ because this expression suggests that beyond a single tumor there is potentially a broader clinical picture awaiting exploration. This review summarizes the important relevant data related to this fascinating clinical entity.
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Prevalence
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The prevalence of PHEOs is not precisely known. Among the general population in Olmsted County, Minnesota, USA, a PHEO occurs in about 1 or 2 per 100 000 adults per year (Beard et al. 1983). This figure suggests that if 20% of the adult population is hypertensive, approximately five PHEOs would be expected among 100 000 hypertensives each year. In a large series of patients screened biochemically for suspicion of PHEO, the incidence has been reported to be as high as 1.9%, occurring equally in men and women (Smythe et al. 1992). On the other hand, a large number of patients with PHEO have nonclassic symptoms such as abdominal pain, vomiting, dyspnea, heart failure, hypotension, or sudden death, suggesting that the majority of PHEOs are not diagnosed during life (Sibal et al. 2006).
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Etiology–genetics
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Most PHEOs are sporadic and arise from chromaffin cells of the adrenal medulla, but in about 9–23% of cases tumors develop from extraadrenal chromaffin tissue and are then referred as PGLs (Bravo & Tagle 2003, Sibal et al. 2006). In children, multifocal and extraadrenal PHEOs are found in 30–43% of cases (Khafagi et al. 1991, Levine & DiGeorge 2000). Malignant PHEOs account for up to 26–35% of cases (Whalen et al. 1992, Mundschenk & Lehnert 1998) and the prevalence of malignancy in sporadic adrenal PHEOs is 9% (Bravo & Tagle 2003). About 10% of patients with PHEOs present with metastatic disease at the time of their initial work-up (Goldstein et al. 1999). Approximately up to 25% of patients with apparent sporadic PHEOs, without family history of the disease, may in fact be carriers of germline mutations predisposing to the development of neurofibromatosis 1 (NF1), von Hippel–Lindau (VHL), multiple endocrine neoplasia type 1 (MEN1) and 2 (MEN2), and the PHEO/PGL syndromes based on the described mutations of the genes for succinate dehydrogenase subunit D (SDHD), B (SDHB), and C (SDHC) (Baysal et al. 2000, Neumann et al. 2002, Amar et al. 2005a).
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Neurofibromatosis type 1 (NF1)
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PHEO constitutes a minor but established feature of NF1. This is an autosomal-dominant disorder, with a PHEO frequency estimated at 0.1–5.7% but rising to 20–50% in hypertensive patients with NF1 (Riccardi 1981, Zoller et al. 1997, Bausch et al. 2007). The clinical diagnosis of NF1 requires two of the following seven criteria (Gutmann et al. 1997): six or more café-au-lait spots; two or more cutaneous neurofibromas or a plexiform neurofibroma, inguinal, or axillary freckles; two or more benign iris hamartomas (Lish nodules); at least one optic-nerve glioma; dysplasia of sphenoid bone or pseudoarthrosis; and a first degree relative with NF1, according to the preceding criteria.
NF1 is caused by inactivating mutations of neurofibromin, a tumor suppressor gene, which encodes a GTPase-activating protein involved in the inhibition of Ras activity, which controls cellular growth and differentiation. The susceptibility gene, the NF1 gene, is localized to chromosome subband 17q11.2 (Gutmann et al. 1994). In most cases, PHEOs are benign (90%) and single (84%), followed by bilateral (10%) and sympathetic PGLs (6%; Walther et al. 1999a, Bausch et al. 2006). Most of them occur in adults and produce predominantly norepinephrine (NE) and therefore present with hypertension and noradrenergic symptomatology.
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VHL disease
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VHL is an autosomal-dominant disease with an incidence of 1 in 3600 births (Maher et al. 1991). PHEO develops in 20% of patients with VHL, with a mean age at onset in the second decade of life, although such tumors often occur even later. VHL is caused by mutations of the VHL gene localized to chromosome 3p25–26. A germline mutation in the VHL gene predisposes carriers to tumors in multiple organs (Lonser et al. 2003). The gene is a tumor suppressor that encodes a protein (pVHL) which is involved in blood vessel formation by regulating the activity of hypoxia inducible factor (HIF)-1
(Iliopoulos et al. 1996). This protein inhibits the accumulation of hypoxia-induced proteins through ubiquitin-mediated degradation of HIF-1, under conditions of normoxemia (Hes et al. 2003). In carriers of VHL gene mutations, the regulation of genes such as the vascular endothelial growth factor and other genes involved in cellular growth seems to be lost, predisposing the VHL carriers to both benign and malignant tumors in multiple organs. Loss of pVHL function reduces HIF degradation and increases vascular endothelial growth factor that leads to angiogenesis (Kaelin 2002). These tumors may include hemangioblastoma in the retina (also referred to as retinal angioma); cerebellum and spine; renal cell carcinoma (clear cell type); PHEO; islet tumors of the pancreas; endolymphatic sac tumors; and cysts and cystadenoma in the kidney, pancreas, epididymis, and broad ligament (Choyke et al. 1995). If present, metastases from renal cell carcinoma and neurological complications from cerebellar hemangioblastomas are the most common causes of death.
On the basis of its clinical expression, VHL disease has been divided into four subtypes with a central role for PHEO (Maher et al. 1996, Koch et al. 2002, Hes et al. 2003). Patients with VHL type 1 disease have loss of pVHL function, due to gene deletions or specific missense mutations and develop retinal or central nervous system hemangioblastomas and renal carcinoma, but they are not at risk for PHEO. Patients with type 2 disease have mainly specific missense mutations and develop hemangioblastoma and PHEO. They are also at low (type 2A) or high (type 2B) risk for renal cell carcinoma. A small percentage of patients with VHL (type 2C) will have only PHEO without the other tumors. In this type, the missense mutation has the gain of function effect causing PHEO, but these particular missense mutations do not substantially affect pVHL-mediated HIF degradation. Thus, even the loss of the second VHL gene would not lead to development of hemangioblastoma or renal cell carcinoma in patient with a type 2C mutation. Knowledge of the VHL mutation could tailor clinical attention and surveillance to the organs at risk and potentially reduce the psychological anxiety and the cost of unnecessary investigations.
PHEO may present as the first or only manifestation of VHL (VHL type 2C; Hes et al. 2003). Consequently, VHL carriers can present as apparently sporadic PHEO. VHL catecholamine-producing tumors are most commonly PHEOs (90%), although sympathetic PGLs have been described. Approximately half of PHEOs are bilateral and most produce NE (Eisenhofer et al. 1999, 2001b). There are uncommon examples of malignant catecholamine-producing tumors in VHL, frequently sympathetic PGLs (Pujol et al. 1995).
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MEN1
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MEN1 is an autosomal-dominant syndrome characterized by primary hyperparathyroidism, pancreatic islet cell neoplasms, and pituitary adenomas caused by inactivating mutations of the MEN1 locus coding for the suppressor protein menin localized to chromosome 11q13. MEN1 is very rarely associated with PHEO, all unilateral, rarely malignant, and most characterized by hypertension and predominant NE production (Schussheim et al. 2001).
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MEN2
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MEN2 is an autosomal-dominant syndrome caused by activating mutations in the RET proto-oncogene located on chromosome 10q11.2, which encodes a transmembrane receptor tyrosine kinase involved in the regulation of cell proliferation and apoptosis, causing constitutive activation of the receptor. As a result of tissue-specific expression, calcitonin-producing parafollicular cells and adrenomedullary chromaffin cells initially undergo hyperplasia with a high rate of subsequent neoplastic transformation. MEN2A is characterized by medullary thyroid carcinoma (MTC), hyperparathyroidism, and PHEO. MEN2B is characterized by MTC, mucosal ganglioneuromas, and PHEOs (Gagel et al. 1988, Brandi et al. 2001). PHEO occurs in approximately half of gene carriers and is almost always located within the adrenal glands.
Bilateral PHEOs occur in approximately half of patients with MEN2 who have PHEO and are usually confined to the adrenal medulla; their development is frequently asynchronous, with separation by as much as 15 years (Recasens et al. 2007). PHEOs occur most commonly with codon 634 (MEN2A) or 918 (MEN2B) RET proto-oncogene mutations (Eng et al. 1996). Malignant PHEOs are uncommon, <5%, and are generally found in patients with large tumors (Chevinsky et al. 1990). The pattern of catecholamine production in MEN2 PHEO differs from that seen in other hereditary forms of PHEO. Epinephrine (E) is produced in disproportionately large amounts, resulting in an early clinical phenotype characterized by attacks of palpitations, nervousness, anxiety, and headaches rather than the more common patterns of hypertension seen with sporadic or other hereditary tumors (Hamilton et al. 1978, Gagel et al. 1988, Eisenhofer et al. 1999, Yip et al. 2003, Young & Abboud 2006).
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Paragangliomas (PGLs)
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PGLs are rare tumors that arise from chromaffin cells. They represent 10–18% of all chromaffin tissue-related tumors that are reported at a rate of 2–8 cases/million a year. According to their origin, they are classified as sympathetic or parasympathetic (Lack 1997).
Sympathetic PGLs
They are derived from the sympathetic chain and usually are located in the chest, abdomen, or pelvis. The clinical picture is a consequence of either the secretion of catecholamines or the size of the tumors with consequent impingement on other structures. The morphology of adrenal PHEOs and extraadrenal PGLs is usually very similar. The frequency of malignancy is much higher in sympathetic tumors with extraadrenal location.
Parasympathetic PGLs
They are tumors of the parasympathetic ganglia usually found in the head and neck region, arising from the cell nests located adjacent to blood vessels, such as the carotid body or the ganglion jugulare. Unlike PGLs in the abdomen, they are usually biochemically silent, and malignancy is seen in <10% of the cases (Lack 1997).
In a large series of 236 patients with 297 benign PGLs evaluated at the Mayo Clinic during 1978–1998, the mean age at diagnosis was 47±16 years (Erickson et al. 2001). Of the 297 PGLs, 205 were in the head and neck region and 92 were below the neck. They were discovered and diagnosed incidentally on imaging in 9% of patients. The most frequent PGLs in the neck were carotid body tumors, and those most common below the neck were abdominal periaortic–pericaval tumors. The most frequent symptoms for the patients with head and neck tumors were palpable neck mass (55%) and cranial nerve palsies (16%). The clinical presentations of these tumors were dominated by local mass effects (neck mass, tinnitus, and cranial nerve dysfunction) and only a small proportion (4%) was hyperfunctional. In patients with PGLs below the neck, one or more of the classic catecholamine excess pentad of headaches (26%), palpitations (21%), perspiration (25%), pallor (12%), and orthostasis (6%) were observed; hypertension was present in 64%. Their location were periaortic and pericaval, perirenal, mediastinal, intracardiac, pulmonary parencymal, intraspinal, sacral, duodenal, jejunal, pancreatic, or in the organ of Zuckerland, bladder, or prostate (Neumann et al. 2004, Benn et al. 2006). Retroperitoneal PGLs are most likely to be malignant and present with pain or a mass. They tend to metastasize to the lungs, lymph nodes, and bones or they can extend locally and may destroy adjacent vertebrae and can cause spinal compression (O'Riordain et al. 1996, Edström Elder et al. 2003). Disease-causing mutations in three genes (SDHB, SDHD, and SDHC) encoding-subunits of succinate dehydrogenase of mitochondrial complex II are responsible for most cases of familial PGLs. SDH has an important function in the Krebs cycle and the mitochondrial respiratory chain.
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PGL–SDHD
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PGL–SDHD is an autosomal-dominant syndrome characterized by familial and isolated head and neck parasympathetic PGLs and less frequently by sympathetic PGLs and PHEOs, caused by mutations in SDHD gene located on chromosome 11q21–23 (Baysal et al. 1997, Baysal et al. 2002, Benn et al. 2006). Head and neck PGLs are generally regarded as benign tumors but can extend into the skull. In addition, SDHD mutation carriers should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal PHEOs (Benn et al. 2006). The hereditary nature of the disease may be masked by maternal imprinting of SDHD, resulting in only paternal transmission of SDHD-associated disease (Baysal et al. 2002), although recently a different mechanism has been proposed to account for exclusive paternal transmission (Hensen et al. 2004). PHEOs may be unilateral or bilateral and the mean age of diagnosis is 43 years.
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PGL–SDHB
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PGL–SDHB is an autosomal-dominant syndrome characterized by sympathetic extraadrenal PGLs and malignant disease (Brouwers et al. 2006, Timmers et al. 2007a,b). The syndrome is caused by inactivating mutations in the tumor suppressor SDHB gene located on chromosome 1p35–36 (Astuti et al. 2001). These mutations cause mitochondrial complex II destabilization and may activate the hypoxic/angiogenic pathway predisposing to tumor formation, with a very strong association with a malignant intra- or extraadrenal phenotype. Malignant PHEOs are reported in 35% in these patients (Neumann et al. 2004). In a series of 44 patients with malignant PGLs, SDHB mutations were found in 30% and nearly one-third had metastases originating from an adrenal primary tumor and two-thirds from an extraadrenal tumor. The latter patients had a frequency of SDHB mutations of 48%. This high frequency of SDHB mutations justifies the priority for SDHB germline mutations testing in these patients (Brouwers et al. 2006).
In another recent study of 29 patients with SDHB-related abdominal or thoracic PGLs, the mean age of diagnosis was 33.7±15.7 years, 76% had hypertension and 90% lacked a family history of PGL. All primary tumors, but one, originated from extraadrenal locations. Symptoms were related to tumor mass effect rather to catecholamine excess and the predominant biochemical phenotype consisted of hypersecretion of NE/dopamine, with 10% of tumors being silent (Timmers et al. 2007b). Therefore, SDHB mutation in a patient with single initial tumor is a prognostic factor for malignancy (Havekes et al. 2007). In families with SDHB mutations, maternal imprinting has not been noted. There is also an increased risk for renal cell carcinoma and papillary thyroid cancer (Schiavi et al. 2005).
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Other PGLs
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A PGL caused by mutations in SDHC gene located on chromosome 1q21 has been described as an autosomal-dominant syndrome, without maternal imprinting. It is characterized by benign and seldom multifocal head and neck parasympathetic PGL (Schiavi et al. 2005). Another autosomal-dominant syndrome with familial head and neck parasympathetic PGLs has been described exclusively in children of fathers carrying the gene which was mapped to chromosome 11q13.1 but not identified yet (Mariman et al. 1995, Baysal et al. 1997).
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Genetic testing
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Hereditary catecholamine-producing PHEOs and PGLs can be caused by germline mutations in any of the five above-described genes and mutation testing is now routinely available for the four of the above genes. Extensive clinical experience demonstrates that germline mutations are responsible for about 25% of cases instead of 10% thought to be hereditary previously (Dluhy 2002). Most importantly, 7.5–27% of tumors without an obvious syndrome or family history result from otherwise unsuspected germline mutations in one of these four genes. Despite these high figures of unsuspected germline mutations, most experts agree that testing must be restricted to patients who fulfill several clinical criteria (Amar et al. 2005a, Gimenez-Roqueplo et al. 2006, Jimenez et al. 2006 Pacak et al. 2007).
Family history
Familial PHEOs/PGLs syndromes are inherited in an autosomal-dominant manner; thus, an affected individual has a one in two (50%) chance of passing on the mutation to each child. A family history may be found in patients with VHL-, MEN2-, NF1-, and SDHD-related syndromes. In families with SDHD mutation, inheritance is complicated by the maternal imprinting phenomenon. It must be reminded that carriers of the SDHB or SDHD gene mutations do not necessarily have evidence of tumors. Those mutations have an age-related penetrance, and the lifetime risk of developing PGLs approaches 100% by the age of 70 years (Benn et al. 2006). In the absence of any family history, sudden deaths should be recorded, bearing in mind that 50% of catecholamine-producing tumors remain undiagnosed until death.
Age in presentation
Hereditary tumors usually occur at a younger age than sporadic tumors, but the age range is wide being 5–69 years for the mutation carriers and 4–81 years in the group of patients with no identified tumors (Gimenez-Roqueplo et al. 2006). Genetic testing is more necessary in young adults, especially for VHL disease, as 36% of PHEOs/PGLs in children occur secondary to germline mutations (Barontini et al. 2006).
Tumor location – metastases
Patients with SDHB/SDHD gene mutations commonly present with extraadrenal often multifocal disease. SDHB gene mutations carry a high risk of malignant disease and therefore testing for such mutations is warranted and identification of a mutation in the SDHB gene is a high risk factor for malignancy. In contrast, malignant disease and extraadrenal tumors are rare in MEN2, so testing for RET gene mutations is not rewarding; furthermore, it is inappropriate to test for RET gene mutations in tumors characterized by an increase in urinary or plasma NE but not E. This differs from PHEOs in VHL syndrome which do not produce significant amounts of E (Table 1).
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Pathophysiology of hypertension
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PHEO, even if they do not secrete, synthesize catecholamines at increased rates that may be up to 27 times the synthetic rate of the normal adrenal medulla. This persistent overproduction is due to lack of feedback inhibition on tyrosine hydroxylase. Catecholamines are then produced in quantities that greatly exceed the vesicular storage capacity and accumulate in the cytoplasm. Catecholamines in the cytoplasm are subject to intracellular metabolism; the excess catecholamines and their metabolites diffuse out of the PHEO cells into the circulation (Fitzerald & Goldfren 2004). In contrast to the normal adrenal medulla, PHEO cells ordinarily contain more NE than E. The PHEO of the adrenal medulla in adults contain both catecholamines, whereas the extraadrenal PGLs rarely secrete E.
Traditionally, the hypertension of PHEO has been thought to result solely from the action of circulating catecholamines on cardiovascular circulating receptors. The activity of the SNS was thought to be normal or depressed reflexly because of baroreceptor resetting, and neurally released NE was considered of minor physiological importance in comparison with the effects of markedly elevated plasma catecholamine levels. However, clinical and experimental studies suggest that the SNS is intact, markedly enhanced and that SNS function is integral to the maintenance of elevated blood pressure (BP) in this form of catecholamine-induced hypertension (Langer et al. 1980, Johnson et al. 1983). The elevation of sympathetic activity during elevation of circulating catecholamines is postulated to be due to loading of sympathetic vesicles with catecholamines, increased sympathetic neuronal impulse frequency, and selective desensitization of presynaptic 2-adrenergic receptors, which results in enhanced release of neuronal NE during nerve stimulation. Therefore, because of enhanced SNS activity and excessive stores of NE in sympathetic nerve terminals, any direct or reflexly mediated stimulus to the SNS could release excessive quantities of NE into the synaptic cleft and produce a hypertensive crisis. The easier access of NE released from the postganglionic neuron at its receptor site on effector cells can result in marked symptoms with relatively small increments in circulating NE. These findings account for the observation that spontaneous or evoked crises in BP can occur without additional increases in the elevated plasma catecholamine levels and that BP may be normal despite high circulating catecholamine levels. This may account for the paroxysms of hypertension that are triggered by pain, emotional upset, intubation, anesthesia, or surgical skin incision and explain the elevations in serum and urine catecholamines that can occur for 10 days or longer after a successful surgical resection of PHEO (Bravo et al. 1990, Bravo & Tagle 2003).
Many PHEOs secrete significant amounts of neuropeptide Y (NPY) along with NE. NPY has potent direct and indirect cardiovascular effects. It increases coronary and peripheral vascular resistance independently of -adrenergic mechanisms by interacting with vascular G-protein-coupled receptors (O'Hare & Schwartz 1989). In some vascular beds, NPY has no direct vasoconstrictor effects but potentiates NE-induced vasoconstriction (Macho et al. 1989). NPY appears to contribute to hypertension in most patients with PHEO. In contrast, few PGLs secrete NPY (deS Senanayake et al. 1995). PHEOs secrete many other peptides, many of which contribute to clinical symptoms, such as PTHrP (hypercalcemia), adrenocorticotrophin (ACTH; Cushing's syndrome), erythropoietin (erythrocytosis), and IL-6 (fever). Most PHEOs secrete chromogranin A which can be assayed as a tumor marker, and many secrete other peptides which have not been documented to produce clinical manifestations (Grossrubatscher et al. 2006).
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Clinical picture
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The clinical picture is characterized by diverse manifestations reflecting the variations of hormone secretion, the patterns of release, and the individual-to-individual differences in catecholamine sensitivities (Eisenhofer et al. 2004, Amar et al. 2005b, Reisch et al. 2006, Sibal et al. 2006). As mentioned before, there is no correlation between circulating levels of catecholamines and hypertension. Plasma catecholamines were increased in periods of normotension in some patients and sudden increases in BP may not be encountered with further elevations in plasma catecholamines. In general, the hypertension is paroxysmal in 48% of patients, persisted in 29%, and 13% have normal BP (Bravo et al. 1979). NE-secreting tumors are usually associated with sustained hypertension. Tumors that secrete large amounts of E together with NE are associated with episodic hypertension. Pure E-producing tumors can produce hypotension rather than hypertension (Fitzgerald & Goldfren 2004). Large (50 g) cystic PHEOs are often asymptomatic because the secreted catecholamines are metabolized within the tumor, and only a small amount of free catecholamines is released into circulation. Symptoms typically include a sudden rise of BP with concurrent episodes of headache (80%), diaphoresis (70%), and palpitations (60%). The episodes usually last minutes or hours; symptoms usually begin abruptly and subside shortly. These 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 of severity of episodes usually increasing over time. In one study, this symptomatic triad was found to have a sensitivity of 90.9% and specificity of 93.8% (Plouin et al. 1981). Other symptoms may include anxiety (50%), a sense of dread, tremor, or paresthesias. However, about 8% of patients may be completely asymptomatic, usually those with familial forms of the disease or with large, cystic tumors (Kudva et al. 1999). Approximately 5% of adrenal incidentalomas have proved to be PHEOs and diagnosis relies on imaging phenotype and measurement of fractionated metanephrines and catecholamines in 24 h urine (Young 2007). The ‘typical’ clinical signs and symptoms occur more frequently in patients with benign tumors. Abdominal pain and dorsalgia occur more frequently in malignant PHEOs and short history and extraadrenal localization are suspicious for malignancy (Glodny et al. 2001). High preoperative 24-h urinary dopamine levels, high tumor weight, elevated tumor dopamine concentration, and postoperative persistent arterial hypertension are factors that increase the likelihood of malignant PHEO (Houbert et al. 1999).
Attacks can occur spontaneously or may occur with bladder catheterization, anesthesia, and surgery. Attacks can be induced by seemingly benign activities, such as bending, rolling over in bed, exertion, abdominal palpation, or micturition (with bladder PGLs). Other disorders can dominate the clinical picture such as hypercalcemia, Cushing's syndrome, thyroid carcinoma, diabetes mellitus, or acute abdomen (Yip et al. 2003). Cardiovascular episodes, such as shock, myocarditis, dilated cardiomyopathy, cardiac arrhythmias, pulmonary edema, and heart failure, and neurological disorders, such as altered mental status, stroke, seizures, focal neurological signs, and symptoms, may also dominate the clinical picture and be the main cause of death (Sutton et al. 1981, Sibal et al. 2006). The administration of nonselective β-blocker therapy without preceding -blockade in a patient with PHEO may precipitate a crisis with hemodynamic collapse (Sloand & Thompson 1984). The opposite phenomenon has been described in an interesting case report. The administration of unopposed -blockade induced a state of β-adrenergic overstimulation with tachycardia, diastolic dysfunction, diffuse edema, and hypotension with peripheral vasodilation. The patient responded to small doses of 5 mg propranolol (Kantorovich & Pacak 2005).
A percentage of patients with PHEOs may present with minor or no signs and symptoms and some patients remain undiagnosed despite advances in diagnostic techniques. Elderly patients appear to present a special diagnostic challenge. A contributory factor to the delay in the antemortem diagnosis of PHEOs in the elderly may be a decrease in baroreceptor function with age, or concomitant diseases, the signs and symptoms of which can confound the diagnosis.
Patients with sustained hypertension usually exhibit episodes of orthostatic hypotension and even syncope, which are due to vasomotor receptor desensitization or diminished intravascular volume. Patients with tumors secreting E may present with sinus tachycardia and peripheral vasoconstriction; the radial pulse can become thready or even nonpaplable during a hypertensive crisis. Vasoconstriction is also responsible for the pallor and mottled cyanosis that can occur with paroxysms of hypertension. Reflex vasodilatation usually follows an attack of hypertension and can cause facial flushing. After an 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. In malignant PHEOs, metastases are usually functional and can cause recurrent hypertension and symptoms, many months or years after surgery that was thought to be curative. Metastases can cause a variety of problems as space-occupying lesions (Bouloux 2002, Bravo 2004). PHEOs or secreting PGLs may recur after initial surgery. The risk of recurrence is fairly high and these patients should be followed up indefinitely. The risk is higher in younger patients, with larger tumors and was more likely to have familial disease or bilateral extraadrenal or right-sided tumors (Amar et al. 2005b). On the other hand, no recurrence was found in 71 patients with benign tumors followed up for 144 months (Edström Elder et al. 2003).
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Biochemical diagnosis
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The optimal approach to biochemical confirmation of catecholamine-secreting tumors is debatable. When performed under appropriate clinical settings, currently available tests can establish the diagnosis in more than 95% of cases. Given that PHEOs are a heterogeneous group of hormone-secreting tumors with variable metabolism, it is prudent to recommend that for a high diagnostic accuracy, multiple tests should be performed. The combination of different tests may increase sensitivity and specificity. Readily available biochemical tests include 24-h urinary catecholamines (NE and E) and vanillyl-mandelic acid (VMA), 24-h urinary total and fractionated metanephrines (normetanephrine and metanephrine), plasma concentrations of NE and E, and plasma concentrations of free metanephrines.
Whereas levels of free catecholamines are increased by even minimal anxiety and stress, levels of metanephrines are much less affected. Therefore, plasma catecholamines and metanephrines must be measured in a supine patient at rest for at least 20 min after insertion of an indwelling cannula in the forearm (Lenders et al. 2002, Eisenhofer et al. 2003) or in a seated ambulatory patient by standard venipuncture (Sawka et al. 2003). However, measurement of plasma metanephrines in blood samples collected from patients in the supine position preserves the high diagnostic sensitivity of the test (Lenders et al. 2007).
Urinary free catecholamines and metabolites
To detect the presence of a PHEO, 24 h urinary free NE and E and their metabolites (normetanephrine, metanephrine, and VMA) are commonly assayed. The demonstration of urinary NE >170 µg/24 h, of urinary E more than 35 µg/24 h, urinary total metanephrines at least 1.8 mg/24 h, and urinary VMA at least 11.0 mg/24 h makes the diagnosis highly probable (Bravo & Tagle 2003, Kudva et al. 2003). Large cystic tumors may release mainly metabolized catecholamines into the circulation as reflected by a relatively high ratio of metabolites to free catecholamines in urine (Crout & Sjoerdsma 1964).
Plasma catecholamines
The majority of patients with hormonally active PHEOs have elevated plasma levels of both NE and E, many exclusively NE and a much smaller proportion exclusively E. These differences in plasma catecholamine levels reflect differences in the expression of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts NE to E (Feldman et al. 1979). In a large series of 93 patients with either adrenal (n=80) or extraadrenal (n=13) PHEO, only three patients had plasma NE values that fell within the 95% upper confidence limits for values obtained in 104 patients with essential hypertension (i.e., 811 pg/ml). None had values that fell within the 95% upper confidence limits for gender- and age-matched 58 normotensive subjects (i.e., 402 pg/ml; Lenders et al. 1993). However, 30% of patients with adrenal and 62% of patients with extraadrenal PHEOs had plasma E values below the 95% upper confidence limits obtained in 104 patients with essential hypertension (i.e., 135 pg/ml; Lenders et al. 1993).
BP must be recorded during plasma sampling for catecholamine measurements. PHEO cannot be excluded if normal plasma catecholamine values are obtained when the patient is normotensive and asymptomatic. However, normal plasma catecholamine levels in a hypertensive and symptomatic patient make the diagnosis of a PHEO highly unlikely.
Plasma metanephrines
Newer techniques, such as liquid chromatography, allow the separate measurement of normetanephrine, the O-methylated metabolite of NE, and metanephrine, the O-methylated metabolite of E. Most methods also allow additional measurements of methoxytyramine, the O-methylated metabolite of dopamine (Eisenhofer et al. 2005). Measurements of the fractionated metabolites, although they are not widely available, are superior to measurements of total metanephrines in that they allow better detection of tumors that produce predominantly or only one of the three O-methylated metabolites (Eisenhofer 2003, Rosano et al. 1991, Gardet et al. 2001, Václavík et al. 2007).
PHEOs contain considerable amounts of the membrane-bound form of catechol-O-methyltransferase (COMT), resulting in local metabolism of catecholamines to free metanephrines (Eisenhofer et al. 1998). It has been shown that over 90% of circulating metanephrine and between 23 and 40% of circulating normetanephrine are produced by the metabolism of the parent catecholamines within the adrenal glands (Eisenhofer et al. 1995a,b). This makes the adrenals the single largest tissue source of circulating metanephrines in the body, with production surpassing by far that of metanephrines by the liver (Eisenhofer et al. 1995a).
In a large series of 208 patients with PHEOs, 23% had normal plasma NE concentrations compared with only 4% with normal levels of normetanephrine (Eisenhofer et al. 2003). Similarly, 68% of patients had normal plasma concentrations of E compared with only 47% with normal levels of metanephrine. Plasma levels of normetanephrine <112 pg/ml and of metanephrine <61 pg/ml virtually exclude PHEO. With plasma concentrations of normetanephrine above 400 pg/ml or of metanephrine above 236 pg/ml, the probability of PHEO is so high that the immediate task is to locate the tumor. When intermediate values are obtained, further investigation with pharmacologic tests is needed.
In another study, only 1 of 33 patients with PHEO had normal levels of both normetanephrine and metanephrine, a patient with a dopamine-secreting PGL (Sawka et al. 2003). Such tumors are extremely rare and are usually found as extraadrenal PGLs. Predominance of dopamine and relative lack of production of the other catecholamines in such tumors are due to deficiency in tumor cells of dopamine-β-hydroxylase, the enzyme that converts dopamine to NE (Eisenhofer et al. 2005).
A multicenter cohort study examined the sensitivity and specificity of several biochemical tests in 214 patients with proven PHEOs (138 sporadic, 48 VHL, 23 MEN2, 3 NF1) and in 644 patients in whom the diagnosis was suspected but excluded (Lenders et al. 2002). In this study, the sensitivity of plasma free metanephrines was clearly superior to plasma catecholamines (99 vs 92% in sporadic PHEOs, and 97 vs 69% in hereditary PHEOs). The specificity of free metanephrines was also better in hereditary PHEOs (96 vs 89%), but was relatively low (82%), although superior to plasma catecholamines (72%). Test sensitivity for urinary fractionated metanephrines was similar to plasma free metanephrines, but lacked specificity for both hereditary (82%) and sporadic (45%) disease. In sporadic PHEOs, urinary catecholamines had excellent sensitivity (97%) and total metanephrines the best specificity (89%). The combination of different tests did not improve the diagnostic yield beyond that of a single test of plasma free metanephrines. The advantage of plasma metanephrines is that they are continuously produced and released by the tumor, in contrast with plasma catecholamines which are released intermittently. The above results have led the authors to recommend against the use of multiple biochemical tests to exclude PHEO in favor of a single test of plasma free metanephrines (Fig. 1).
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Figure 1 Algorithm for the biochemical and imaging diagnosis of pheo/PGL. Pheo, pheochromocytoma; PGL, paraganglioma; CT, computed tomography; MRI, magnetic resonance imaging; MIBG, metaiodobenzylguanidine; PET, positron emission tomography.
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The combination of resting plasma catecholamines (NE plus E) at least 2000 pg/ml and urinary metanephrines (normetanephrine plus metanephrine) at least 1.8 mg/24 h has a diagnostic accuracy close to 98% in both sporadic and hereditary PHEOs (Bravo & Tagle 2003). Assays for plasma catecholamines and urinary metanephrines have the lowest false-negative rates (7%), and assays of urinary NE and E the next higher (14%). Urinary VMA measurements have high false-negative rates (41%) and should not be used for screening purposes (Bravo & Tagle 2003). However, all four tests have excellent specificity when elevated. When available, the measurement of plasma free metanephrines should be performed, especially when hereditary PHEO is suspected. However, whether the measurement of plasma free metanephrines should be the sole diagnostic test for PHEO remains to be determined.
Serum chromogranin-A (CgA)
CgA has been suggested as an alternative diagnostic test to catecholamines for the detection of PHEO, because neither its secretion nor its measurement is influenced by drugs commonly used for the treatment of hypertension in PHEO patients. However, mild degrees of renal impairment can lead to significant increases in serum concentration of CgA, because the kidneys play a major role in its clearance. Therefore, although CgA is relatively sensitive (86%) in the diagnosis of PHEO, it has poor diagnostic specificity. When combined with elevated plasma catecholamines in patients with creatinine clearance of at least 80 ml/min, its diagnostic specificity increases to 98% (Canale & Bravo 1994, d'Herbomez et al. 2007).
Clinical situations and medication-associated false-positive results
When testing for PHEO, some consideration should be given to possible causes of false-positive results, including clinical situations, medications, inappropriate sampling conditions, and diet (Table 2). Biochemical testing for PHEO should ideally be carried out after discontinuation of medications known to influence catecholamine levels and their metabolites or interfere directly with biochemical analyses. Tricyclic antidepressants are the established cause of false-positive results, probably due to the inhibition of NE reuptake (Esler et al. 1991, Veith et al. 1994, Young 1997). Phenoxybenzamine (POB), a nonspecific -adrenoreceptor blocker commonly used in the treatment of patients with PHEO, may lead in high rates of false-positive results (Eisenhofer et al. 2003). False-positive elevations of plasma metanephrines and catecholamines with selective 1-adrenoreceptor blockers, such as doxazosin, are not a problem (Eisenhofer et al. 2003), while with calcium channel blockers appear restricted to NE, an effect most likely due to the reflexive sympathetic activation occurring with the short-acting agents (Wenzel et al. 1997).
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Table 2 Disorders that may increase both plasma and urinary catecholamines metabolites to levels often seen in pheochromocytoma
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Drugs that inhibit central sympathetic outflow, such as clonidine, methyldopa, and bromocriptine, decrease plasma catecholamines in normal and hypertensive subjects, but have little effect on the excessive catecholamine secretion by PHEO. Labetalol can increase plasma catecholamines and urinary metanephrines determined by HPLC (high pressure liquid chromatography) to values seen in PHEO (Feldman 1987). Acetaminophen can cause spurious increases in plasma free metanephrines. In addition, a urinary metabolite of buspirone, an anxiolytic drug, is artificially measured as metanephrine, resulting in marked increase in measured metanephrine excretion (Cook et al. 1995).
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Pharmacologic tests
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Abstract
Introduction
