Pheochromocytoma : Diagnosis, Localization, and Treatment

Pheochromocytoma

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Pheochromocytoma Diagnosis, Localization, and Treatment

Karel Pacak, MD, PhD, DSc National Institute of Child Health and Human Development NIH, Bethesda, USA

Jacques W. M. Lenders, MD, PhD Department of Internal Medicine Division of General Internal Medicine Radboud University Nijmegen Medical Center Nijmegen, The Netherlands

Graeme Eisenhofer, PhD National Institute of Neurological Disorders and Stroke NIH, Bethesda, USA

© 2007 Karel Pacak, Jacques W. M. Lenders and Graeme Eisenhofer Published by Blackwell Publishing Blackwell Publishing, Inc., 350 Main Street, Malden, MA 02148-5020, USA Blackwell Publishing Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK Blackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, Australia The right of the Authors to be identified as the Authors of this Work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. First published 1

2007

Library of Congress Cataloging-in-Publication Data Pacak, Karel. Pheochromocytoma : diagnosis, localization, and treatment / Karel Pacak, Jacques W. M. Lenders, Graeme Eisenhofer. p. ; cm. Includes index. ISBN: 978-1-4051-4950-1 1. Pheochromocytoma. I. Lenders, Jacques W. M. II. Eisenhofer, Graeme. III. Title. [DNLM : 1. Pheochromocytoma–diagnosis. 2. Diagnosis, differential. 3. Pheochromocytoma–genetics. 4. Pheochromocytoma–therapy. QZ 380 P113p 2007] RC280.A3P33 2007 616.99'445–dc22

2007000685

A catalogue record for this title is available from the British Library Set in 9/12, Stone serif by Charon Tec Ltd (A Macmillan Company), Chennai, India www.charontec.com Printed and bound in Singapore by Fabulous Printers Pte Ltd Commissioning Editor: Alison Brown Editorial Assistant: Jennifer Seward Development Editor: Adam Gilbert Production Controller: Debbie Wyer For further information on Blackwell Publishing, visit our website: http://www.blackwellpublishing.com The publisher’s policy is to use permanent paper from mills that operate a sustainable forestry policy, and which has been manufactured from pulp processed using acid-free and elementary chlorine-free practices. Furthermore, the publisher ensures that the text paper and cover board used have met acceptable environmental accreditation standards. Blackwell Publishing makes no representation, express or implied, that the drug dosages in this book are correct. Readers must therefore always check that any product mentioned in this publication is used in accordance with the prescribing information prepared by the manufacturers. The author and the publishers do not accept responsibility or legal liability for any errors in the text or for the misuse or misapplication of material in this book.

Contents 1

Introduction

1

2

Historical comments

3

3

Pathology

4

4

Clinical presentation of pheochromocytoma 4.1 Signs and Symptoms 4.2 Differential Diagnosis 4.3 Special Presentations 4.3.1 Diagnosis of Pheochromocytoma in Patients with an Incidentally Discovered Adrenal Mass 4.3.2 Pheochromocytoma as an Endocrine Emergency 4.3.2.1 Hypertensive Crisis 4.3.2.2 Hypotension and Shock 4.3.2.3 Multisystem Failure 4.3.2.4 Cardiac Emergencies 4.3.2.5 Acute Peripheral Ischemia 4.3.2.6 Pulmonary Emergencies 4.3.2.7 Gastrointestinal Emergencies 4.3.2.8 Nephrological Emergencies 4.3.2.9 Neurological Emergencies 4.3.3 Malignant Pheochromocytoma 4.3.4 Pheochromocytoma in Children 4.3.5 Pheochromocytoma in Pregnancy 4.3.6 Pseudopheochromocytoma 4.3.7 Factitious Pheochromocytoma

5

6

8 8 12 14 14 15 15 16 16 17 18 19 19 19 20 20 24 26 28 29

Current trends in genetics of pheochromocytoma 5.1 MEN Syndromes 5.1.1 Diagnostic Approaches 5.2 VHL Syndrome 5.3 NF Type 1 5.4 Succinate Dehydrogenase Gene Related Pheochromocytoma 5.5 Genetic Problems in Sporadic and Other Pheochromocytomas

30 30 33 34 36 37

Catecholamines and adrenergic receptors 6.1 Synthesis and Sources of Catecholamines 6.2 Synthesis of Catecholamines in Pheochromocytoma 6.3 Storage and Release of Catecholamines by the Sympathoadrenal System

41 41 43

38

45

vi

Contents

6.4

Uptake and Metabolism of Catecholamines Produced by the Sympathoadrenal System 6.5 Catecholamine Metabolism in Hepatomesenteric Organs 6.6 Catecholamines Metabolism and Release by Pheochromocytoma 6.7 Kinetics and Elimination of Catecholamines and Their Metabolites 6.8 Pharmacology of Catecholamine Systems: Implications for Pheochromocytoma 6.9 Physiology of Catecholamine Systems 6.9.1 Adrenal Medullary Hormone System 6.9.2 Peripheral Dopamine Systems 6.10 Adrenergic Receptors and Their Functions 6.11 Actions of the Catecholamines 7

8

9

Current trends in biochemical diagnosis of pheochromocytoma 7.1 Biochemical Tests of Catecholamine Excess 7.2 Measurement Methods 7.3 Reference Intervals 7.4 Initial Biochemical Testing 7.5 Follow-up Biochemical Testing 7.6 Collection and Storage of Plasma and Urine Specimens 7.7 Interferences from Diet and Drugs 7.8 Pharmacologic Tests 7.9 Additional Interpretative Considerations 7.10 Summary

46 51 54 58 60 60 60 62 64 69 72 72 74 76 78 81 84 85 88 91 91

Current trends in localization of pheochromocytoma 8.1 Anatomical Imaging of Pheochromocytoma 8.1.1 Computed Tomography 8.1.2 Magnetic Resonance Imaging 8.2 Functional Imaging of Pheochromocytoma 8.2.1 MIBG Scintigraphy 8.2.2 Positron Emission Tomography 8.2.3 Somatostatin Receptor Scintigraphy (Octreoscan) 8.2.4 Current Imaging Algorithm

93 94 94 96 97 99 100

Treatment of pheochromocytoma 9.1 Medical Therapy and Preparation for Surgery 9.2 Postoperative Management

109 110 112

105 108

10 Future trends and perspectives 10.1 Genomics in Pheochromocytoma Research 10.2 Proteomics in Pheochromocytoma Research 10.3 Future Therapeutic Modalities for Pheochromocytoma

114 114 115 118

References

120

Index

167

To our children Tomáš, Ruud, Koen, Anne, and Suzanne

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The glory of medicine is that it is constantly moving forward, that there is always more to learn. Dr. William J. Mayo, 1928

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CH APTE R 1

Introduction

Pheochromocytomas are rare but treacherous catecholamine-producing tumors, which if missed or not properly treated, will almost invariably prove fatal [1–6]. Prompt diagnosis is, therefore, essential for effective treatment, usually by surgical resection. The manifestations are diverse and the tumor can mimic a variety of conditions, often resulting in erroneous and delayed diagnosis [1, 7]. Therefore, not surprisingly pheochromocytoma earned the title “great mimic” [8]. The incidence of pheochromocytoma in autopsy studies is about 0.05–0.1% [9–14]. Autopsy studies have also shown that up to 50% of pheochromocytomas are unrecognized [12, 14]. Recent advances in biochemical diagnosis (the measurement of plasma free metanephrines), tumor localization (the use of positron emission tomography), surgical approaches (the use of laparoscopic adrenal-sparing surgery), and improved understanding of the pathophysiology and genetics of pheochromocytoma (the role of succinate dehydrogenase gene family or hypoxia and apoptosis pathways) are leading to earlier diagnosis and changes in management strategies and therapeutic options [1, 2, 5, 15–29]. Pheochromocytomas are most frequent in individuals between 40 and 50 years, with very slight predilection in females. The tumors occur in all races, but have been predominantly reported in caucasians [30]. Pheochromocytomas typically derive in about 85% of cases from adrenal medullary chromaffin tissue and in about 15% of cases from extra-adrenal chromaffin tissue [31]. Those arising from extra-adrenal tissue are commonly known as paragangliomas. The 2004 WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from catecholamine-producing chromaffin cells in the adrenal medulla – an intra-adrenal paraganglioma. Paragangliomas are divided into two groups: those that arise from parasympathetic-associated tissues (most commonly along cranial and vagus nerves; e.g. glomus or carotid body tumors) and those that arise from sympathetic-associated chromaffin tissue (often designated extra-adrenal pheochromocytomas). Extra-adrenal pheochromocytomas arise mainly from chromaffin tissue of sympathetic ganglia in the abdomen (in about 75%) [32, 33]. Extra-adrenal pheochromocytomas in the abdomen most commonly arise from a collection 1

2

Chapter 1

of chromaffin tissue around the origin of the inferior mesenteric artery (the organ of Zuckerkandl) or aortic bifurcation [1]. Both adrenal and extra-adrenal paragangliomas display similar histopathological characteristics. Less frequent sites of pheochromocytoma include kidney, urethra, prostate, spermatic cord, genital tract, and liver. Most pheochromocytomas arise sporadically, but based on recent reports up to 24% are familial [25, 34]. Up to 25% of patients with pheochromocytoma present with adrenal incidentaloma, whereas approximately 5% are diagnosed at surgery [22, 35–39]. In contrast to sporadic pheochromocytomas that are usually unifocal and unilateral, familial pheochromocytomas are often multifocal and bilateral [1, 4, 7, 15, 40]. Although metastases may be rare for adrenal (about 10%) and familial (less than 5%; except succinate dehydrogenase subunit B SDHB pheochromocytomas [32, 41], the prevalence is up to 36% for extra-adrenal abdominal pheochromocytomas [38, 40, 42–44]. Finally, up to 14% of intra-adrenal pheochromocytomas show local recurrence [22, 30, 45]. One study also showed that patients with mainly adrenal pheochromocytoma have an increased risk for developing other cancers (e.g. liver and biliary tract cancers, malignant melanoma, cervix carcinoma, and central nervous tumors) [46]. According to different reviews and statistics, pheochromocytomas account for approximately 0.05–0.6% of patients with any degree of sustained hypertension [1, 15, 47–49]. However, this probably accounts for only 50% of persons harboring the tumor, when it is considered that about half the patients with pheochromocytoma have only paroxysmal hypertension or are normotensive. Also, despite the low incidence of pheochromocytoma among patients with sustained hypertension, it must also be considered that the current prevalence of sustained hypertension in the adult population of Western countries is up to 30% [50–52]. Thus, the prevalence of pheochromocytoma can be estimated to lie between 1:4500 and 1:1700, with an annual incidence of detection three to eight cases per 1 million per year in the general population [53].

CH APTE R 2

Historical comments

Alfred Kohn, Professor of Histology at the Charles University in Prague, introduced the terms “chromaffin,” “chromaffin system,” “paraganglion,” and “paraganglionic cell” [54–58]. The name pheochromocytoma was proposed by Pick in 1912 [59] and comes from the Greek words phaios, dusky (brown), and chroma, color, and refers to the staining that occurs when the tumors are treated with chromium salts. The brown pigment of the chromaffin reaction is composed of oxidation products of epinephrine (adrenaline) or norepinephrine (noradrenaline) resulting in the generation of adrenochrome and noradrenochrome, respectively. The first diagnosis of pheochromocytoma was made in 1886 by Fränkel [60] who found bilateral tumors of the adrenal gland at autopsy in an 18-year-old girl who had died suddenly after collapse. Extraadrenal pheochromocytoma was first reported by Alezais and Peyron in 1908 [61]. Based on these findings they applied the term paraganglioma to describe the presence of extra-adrenal tumors arising in paraganglia. The first successful surgical removals of pheochromocytomas were by Roux in Switzerland in 1926 and by Mayo in the United States in 1927 [47, 62]. In 1936, epinephrine was isolated from a pheochromocytoma by Kelly et al. [63] but, it was not until 1946, that von Euler and his co-workers, and 1947, that Holtz and his co-workers reported independently the occurrence of norepinephrine in the body [64–66]. In 1949, Holton [67] first demonstrated the presence of norepinephrine in a pheochromocytoma. Early in the 1950s, von Euler showed that patients with pheochromocytoma had increased urine excretion of epinephrine, norepinephrine, or hydroxytyramine (metabolite of dopamine) [68]. Shortly thereafter, Lund together with Moller described elevated plasma concentrations of norepinephrine and epinephrine in patients with pheochromocytoma [69, 70]. In the late 1950s, Armstrong and co-workers were first in showing elevated urine excretion of vanillylmandelic acid in patients with pheochromocytoma [71]. In 1957, Axelrod and co-workers described O-methylation as the important pathways in catecholamine metabolism [72] and LaBrosse and co-workers for the first time demonstrated elevated urine excretion of normetanephrine (O-methylated metabolite of norepinephrine) in patients with pheochromocytoma [73].

3

CH A PTE R 3

Pathology

Sporadic pheochromocytomas are generally solitary, well-circumscribed, encapsulated tumors with characteristic histopathological features [74, 75] (Figure 3.1). They are usually located in the adrenal gland or in its immediate vicinity (Figure 3.2). However, the adrenal gland may not be in its expected place atop the kidney, but actually located anywhere superior, inferior, medial, lateral, dorsal, or ventral to the kidney. Thus, pheochromocytoma may still be considered intra-adrenal in origin, if the cortex of the adrenal is found in close relationship to the pheochromocytoma. Malignant tumors appear to be larger, contain more necrotic tissue, and are composed of smaller cells than benign adrenal pheochromocytomas [47, 76, 77]. However, it is impossible

Figure 3.1 Histopathology of sporadic pheochromocytoma (H&E, original magnification: 20⫻) that shows characteristic nests of pheochromocytoma cells with abundant, finely granular basophilic cytoplasm and vesicular nuclei with nucleoli. High vascularity of pheochromocytoma is reflected in the prominent capillary network (gray) seen throughout the tumor. Cytoplasm can also be amphophilic or eosinophilic and nuclei can vary in size and shape (not shown).

4

Pathology

5

to distinguish malignant from benign pheochromocytoma based on histopathological features, although capsular invasion, vascular penetration, the presence of atypical nuclei, pleomorphism, higher mitotic count, and mitosis exist in both types of pheochromocytoma; they are more common in malignant pheochromocytoma [74, 77–79]. The presence of metastatic lesions where chromaffin cells are normally absent (e.g. in liver, lungs, lymphatic nodes, and bones) are currently consistent with the diagnosis of malignant pheochromocytoma [47, 75, 80]. As described by Linnoila et al. [43] fewer neuropeptides are expressed in malignant than in benign pheochromocytoma cells. There are no differences in immunohistochemical expression of cathepsins, basic fibroblastic growth factor, c-met, collagenase between benign and malignant pheochromocytomas [81]. Clarke et al. [81] reported that MIB-1 appears to be a good indicator of metastatic pheochromocytoma’s potential with a specificity of 100% and a sensitivity of 50%. Recently, it has been shown that both telomerase activity and the catalytic subunit of telomerase (hTERT) are up-regulated in malignant, but not in benign pheochromocytomas [82, 83]. Currently, two scales are used to attempt to distinguish benign from malignant pheochromocytoma. The first one represents the so-called pheochromocytoma of the adrenal gland scaled score (PASS) [84] and the other one is based on the presence of immunohistochemical markers [85] (Tables 3.1 and 3.2). A PASS of ⭓4 has been suggested to identify tumors that are histologically malignant. However, about 1/3 of patients with identified “primary malignant tumors” using a PASS score do not develop metastatic lesions although all patients in whom metastatic tumors are found, a PASS score of these tumors is ⭓4. Widespread application of these scores with appropriate clinical follow-up in large prospective studies is needed to further validate these findings. Thus, there is currently no consensus on adoption of a formal scoring system; however, it is recommended that pathology

Figure 3.2 A small intra-adrenal pheochromocytoma.

6

Chapter 3

Table 3.1 Pheochromocytoma of the adrenal gland scoring scale Score if Present (Number of Points)

Feature Large nests or diffuse growth (⬎10% of tumor volume) Central (middle of large nests) or confluent tumor necrosis (not degenerative change) High cellularity Cellular monotony Tumor cell spindling (even if focal) Mitotic figures ⬎3/10 HPF Atypical mitotic figure(s) Extension into adipose tissue Vascular invasion Capsular invasion Profound nuclear pleomorphism Nuclear hyperchromasia Total score

2 2 2 2 2 2 2 2 1 1 1 1 20

HPF: high-power field. Adapted from Thompson [84].

Table 3.2 Immunohistochemical markers that may facilitate the evaluation of malignancy in pheochromocytomas

Marker Ki-67/Mib-1 c-erbB-2 Inhibin βB p53 bcl-2 VEGF Heparanase-1 Tenascin COX-2 S-100

Expression in Malignant Pheochromocytoma Increases Increases No difference Decreases Increases No difference Increases No difference Increases Increases Increases Increases Decreases

VEGF: vascular endothelial growth factor; COX-2: cyclooxygenase-2. Adapted from Salmenkivi [85].

reports conform to templates for minimal standard reporting endorsed by several pathology associations. The templates list the major elements of the proposed scoring systems and permit additional optional elements. The listing of potentially unfavorable findings will presumably flag a tumor for some type of follow-up, but the nature of the required follow-up remains unclear [86]. The most important immunohistochemical markers that facilitate the evaluation

Pathology (a)

7

(b)

Figure 3.3 Electron microscopy shows the presence of membrane-bound, dense-core, neurosecretory epinephrine (E)- and norepinephrine (NE)-containing granules in (a) multiple endocrine neoplasia type 2 (MEN-2)- and (b) von Hippel–Lindau (VHL)associated pheochromocytoma.

of malignancy in pheochromocytomas as introduced by Salmenkivi [85] are outlined in Table 3.2. Most pheochromocytomas range in size from 3 to 5cm [47, 74, 87]. Those that are larger than 5 cm have a higher potential to metastasize [40, 88, 89]. The chromaffin reaction, originally described by Henle in 1865, is a deepbrown color of the adrenal medulla that occurs after the tissue is placed in a dichromate solution [90]. The reaction is due to the oxidation of the catecholamines, epinephrine and norepinephrine, into adrenochrome pigments. When this pattern is well developed it mimics tumor cell nests or “zellballen,” seen also in parasympathetic paragangliomas in the head and neck. Another pattern consists of anastomosing cords of cells (trabecular). The third and most common pattern is a mixture of anastomosing cell cords and nests of cells (Figure 3.1) [74]. The tumor cells are usually polygonal with an intermediate amount of lightly colored eosinophilic granular cytoplasm. Cells may vary in size from small to large [91]. Nuclei are well demarcated and generally eccentric in location. Nuclear pleomorphism with enlargement and hyperchromatism may be seen [74], this is not diagnostic of malignancy. Occasionally, tumor cells resemble ganglion cells with rounded, eccentric nuclei, and prominent nucleoli. Electron microscopy reveals the presence of membrane-bound, densecore, neurosecretory epinephrine- and norepinephrine-containing granules 150–250nm in diameter (Figure 3.3) [74]. In most tumors, the predominant granule is the one associated with norepinephrine, while in the normal gland the predominant granule is the one associated with epinephrine [92]. Chromaffin cells have ability to synthesize and secrete various amines and certain hormones, that is adrenocorticotropic hormone (ACTH), chromogranins, neuropeptide Y, calcitonin, angiotensin-converting enzyme, renin, vasoactive intestinal polypeptide, adrenomedullin, renin, atrial natriuretic factor, angiotensin-converting enzyme, thyrotropin-releasing hormone, parathormone, insulin, gastrin, melatonin, galanin, bombesin, opioids, synaptophysin, and others have also been found in neuroendocrine neoplasms, including pheochromocytoma [93–100].

CH A PTE R 4

Clinical presentation of pheochromocytoma

4.1

Signs and Symptoms

The presence of pheochromocytoma is usually characterized by clinical signs and symptoms (Table 4.1) that result from hemodynamic and metabolic actions of circulating catecholamines, or less frequently other amines and co-secreted neuropeptides [5, 6, 47]. However, the severity of clinical symptoms does not always correlate with plasma catecholamine levels [36, 101]. Several clinical findings such as hypertension, headache, spontaneous sweating, palpitations, and the presence of pallor are highly suggestive of pheochromocytoma. If signs and symptoms are of paroxysmal nature, the suspicion of a pheochromocytoma is strengthened. Although headache, palpitations, and sweating are non-specific symptoms, their presence in patients with hypertension should arouse immediate suspicion of a pheochromocytoma [5, 15, 38, 53, 102–105]. Sustained or paroxysmal hypertension (equally present) is the most common and prominent clinical sign (85–90%) and if severe, it may result in an emergency situation requiring immediate medical attention and treatment. Some patients feature paroxysms that are superimposed on a background of sustained hypertension. Up to about 10% of the patients present with persistently normal blood pressure [15, 47, 106], but this proportion can be much higher in patients with adrenal incidentalomas or who undergo periodic screening for familial pheochromocytoma [34, 107–109]. Other factors that may impact on pheochromocytoma-associated changes in blood pressure include the nature of catecholamine secretion, adrenoreceptor downregulation due to consistently high levels of catecholamines, hypovolemia, and associated changes in sympathetic nerve function [110]. In some patients blood pressure may show huge short-term variability called “manic–depressive behavior” of blood pressure [1]. The diurnal blood pressure rhythm is disturbed as reflected by the lack of the typical nocturnal blood pressure dip [111, 112]. Hypertensive pheochromocytoma patients may have a decreased cardiac output [113]. Pheochromocytoma may also present with hypotension, particularly postural hypotension or alternating episodes of high and low blood pressure [15, 114, 115]. In 1949 orthostatic hypotension was described as an important clue to the diagnosis. It is usually accompanied by orthostatic tachycardia. 8

Clinical Presentation of Pheochromocytoma 9 Table 4.1 Clinical symptoms and signs characteristic of patients presenting with pheochromocytoma Symptoms

Percent

Headache Palpitations ⫾ tachycardia Diaphoresis Anxiety Nervousness Abdominal/chest pain Nausea Fatigue Dyspnea Dizziness Heat intolerance Pain/paresthesias Visual symptoms Constipation Diarrhea

70–90 50–70 60–70 20 35–40 20–50 26–43 15–40 11–19 3–11 13–15 Up to 11 3–21 10 6

Signs

Percent

Hypertension Sustained Paroxysmal Orthostatic hypotension Pallor Flushing Fever Hyperglycemia Vomiting Convulsions

90–100 50–60 50 12 30–60 18 Up to 66 42 26–43 3–5

Adapted from Ram and Fierro-Carrion [106], Manger and Gifford [47], and Werbel and Ober [832].

Our knowledge about the prevalence of orthostatic hypotension is incomplete. Prevalence data vary strongly (10–50%), probably because standing blood pressures are infrequently recorded. Possible mechanisms include a decreased intravascular volume due to the state of chronic vasoconstriction, and a attenuated increases in vascular resistance during standing due to desensitization of α-adrenergic receptors. Activation of presynaptic autoinhibitory α2-adrenergic receptors by high circulating catecholamines may also blunt sympathoneuronal release of norepinephrine irresponse to orthostasis. Hypotension is commonly seen in patients harboring tumors secreting predominantly epinephrine, dopamine, or other compounds causing vasodilation. Other causes of hypotension may include hypovolemia, abnormal autonomic reflexes, differential stimulation of α- and β-adrenergic receptors, intermittent secretion of catecholamines. Other typical cardiovascular complaints are palpitations and pallor. Palpitations are very common due to the effect of catecholamines (especially epinephrine) on cardiac β-adrenergic

10 Chapter 4

receptors. Pallor results from catecholamine-induced cutaneous vasoconstriction and is seen in about 25–30% of patients. Headache occurs in up to 90% of patients with pheochromocytoma [1, 47] usually as pounding headache, mostly occurring in paroxysmal attacks. Excessive generalized sweating occurs in approximately 60–70% patients presenting with pheochromocytoma [1, 7, 47]. Other complaints are dyspnea, weight loss despite normal appetite, warmth with or without heat intolerance (caused by catecholamine-induced glycogenolysis and lipolysis), and generalized weakness [114, 116]. In about 10% of patients with pheochromocytoma visual disturbances (e.g. blurred or so-called snowy vision, patchy loss of vision) occur during attacks due to the catecholamine effect on ocular muscles. Increased lacrimation and dilation of the pupils is also commonly present during attacks. Some patients present with new-onset and commonly more severe episodes of anxiety or panic attacks [114]. Less frequent clinical manifestations include fever of unknown origin (hypermetabolic state) and constipation, secondary to catecholamine-induced decrease in intestinal motility [100, 106]. About 10% patients say that they feel flushed [47, 87, 117]. Pheochromocytoma-induced metabolic or hemodynamic attacks may last from a few seconds to up to one or more hours with intervals between attacks varying widely and as infrequent as once every few months. Attacks sometimes occur at night and awaken the patient, and not infrequently the onset of attacks has been experienced in the early morning while in bed. A typical paroxysm is characterized by a sudden major increase in blood pressure; a severe headache, often pounding; profuse sweating over most of the body, especially the trunk; palpitations with tachycardia; prominent anxiety or a sense of doom; skin pallor; nausea, with or without emesis; and pain in the abdomen or chest [47, 87, 104, 118]. Pheochromocytoma associated with above-described attacks was uniquely described by Robinson as a “metabolic volcano” that remains quiescent and then suddenly erupts into such violent activity that the patient can die [119]. Unusual symptoms related to paroxysmal blood pressure elevations during diagnostic procedures (e.g. endoscopy, radiographical contrast agents), anesthesia, or ingestion of food or beverages containing tyramine (certain cheeses, beers, wines, bananas, chocolate) or synephrine (citrus fruit juice) should arouse immediate suspicion of pheochromocytoma. The use of certain drugs such as histamine, metoclopramide, ACTH, phenothiazine, methyldopa, monoamine oxidase inhibitors, tricyclic antidepressants, opiates, metoclopramide, glucagon, chemotherapy as well as cigarette smoking may also precipitatea hypertensive episode [47, 87, 120–126]. Moreover, micturition or bladder distension in the case of a pheochromocytoma of the urinary bladder (over half of the latter have painless hematuria) should promptly arouse a suspicion of the presence of this tumor [127]. In some situations episodic catecholamine secretion may be due to either intentional or accidental tumor manipulation coupled with an increase in intra-abdominal pressure from palpation, defecation, a fall, an automobile accident, or pregnancy [47, 87, 128]. Psychological stress alone and by itself does not usually precipitate a hypertensive crisis [47, 87, 128]. About 8–10% of patients may be completely asymptomatic usually

Clinical Presentation of Pheochromocytoma 11

due to a very small (less than 1cm) tumor associated with non-significant catecholamine secretion or tumor dedifferentiation characterized by the absence of catecholamine-synthesizing enzymes resulting in no production of catecholamines [15, 129]. Besides causing insulin resistance, pheochromocytoma may cause overt diabetes mellitus. The hyperglycemia is usually mild, occurs with the hypertensive episodes, is accompanied by a subnormal level of plasma insulin (due to α2-adrenergic inhibition of insulin release, epinephrine-induced inhibition of glucose uptake by skeletal muscle, α-adrenergic stimulation of hepatic glucose production, and β-adrenergic receptor desensitization) [36, 130–134]. It can, however, be sustained and severe enough to require insulin, even to present as diabetic ketoacidosis [135]. Recently a French study showed a higher prevalence of diabetes mellitus in patients with pheochromocytoma (about 35%), than in patients with primary hypertension. In young non-obese patients with diabetes mellitus, the predictive value of having a pheochromocytoma was 91% [136]. In addition, it has been shown that removal of a pheochromocytoma does improve insulin sensitivity [137]. Very rarely, a pheochromocytoma produces vasoactive intestinal peptide with resultant watery diarrhea, hypokalemia, and achlorhydria (Verner– Morrison syndrome) [138]. Interleukin-6 (IL-6) may cause fever and multiorgan failure in patients with pheochromocytoma with increased serum IL-6 and another with pheochromocytoma and Castleman’s disease (IL-6-mediated B-cell proliferation) since these conditions are reversed in each patient when the tumor is removed [139–142]. Hematological abnormalities usually include leukocytosis and elevated hematocrit [143]. Elevation of hematocrit is usually associated with normal red cell mass and mainly reflects diminished plasma volume [1] or rarely erythropoietin-secreting tumor [144, 145]). Some patients with pheochromocytoma are asymptomatic or have only minor signs and symptoms. Therefore, the diagnosis is easily missed, often with tragic consequences. Several studies of routine autopsies have indicated that the majority of pheochromocytomas are first discovered after death [12, 146]. A list of emergency situations characteristic for the presence of pheochromocytoma is described in Table 4.2. Estrogen, growth hormone, vitamin D, and accutane (Retinol A) administration have been shown to induce pheochromocytoma in experimental animals [147]. Whether these hormones contribute to the higher incidence of clinical pheochromocytoma or an increase in malignant potential is unknown. However, recently at least two patients receiving chronic accutane treatment were found to have pheochromocytoma (personal communications). In summary, the following patients should be evaluated for a pheochromocytoma: [148] anyone with the tetrad of hypertension, tachycardia, sweating, and pallor; [2] anyone with any other paroxysmal signs or symptoms; [3] anyone with a family history of pheochromocytoma; [4] anyone with an incidental adrenal mass; [148] anyone whose hypertension is associated with borderline increases in catecholamine production reflected by either elevated plasma or urine levels of catecholamines or metanephrines; [6] anyone whose blood pressure is poorly responsive to standard therapy; and [7] anyone who has had hypertension, tachycardia, or an arrhythmia in response to

12 Chapter 4 Table 4.2 Emergency situations related to catecholamine excess released from pheochromocytoma Clinical Setting

Symptoms

PMC

Hypertension and/or hypotension, multiple organ failure, temperature, 40⬚C, encephalopathy

Cardiovascular

Collapse Hypertensive crisis Upon induction of anesthesia Medication-induced or other mechanisms Shock or profound hypotension Acute heart failure Myocardial infarction Arrhythmia Cardiomyopathy Myocarditis Dissecting aortic aneurysm Limb ischemia, digital necrosis, or gangrene

Pulmonary

Acute pulmonary edema Adult respiratory distress syndrome

Abdominal

Abdominal bleeding Paralytic ileus Acute intestinal obstruction Severe enterocolitis and peritonitis Colon perforation Bowel ischemia with generalized peritonitis Mesenteric vascular occlusion Acute pancreatitis Cholecystitis Megacolon

Neurological

Hemiplegia Limb weakness

Renal

Acute renal failure Acute pyelonephritis Severe hematuria

Metabolic

Diabetic ketoacidosis Lactic acidosis

PMC: pheochromocytoma multisystem crisis. Adapted from Brouwer et al. [3].

anesthesia, surgery, or medications known to precipitate symptoms in patients with pheochromocytoma [110]. The rule of six “H”s (hypertension, headache, hyperhidrosis, heart consciousness, hypermetabolism, and hyperglycemia) can also be applied to patients with pheochromocytoma [149].

4.2

Differential Diagnosis

The differential diagnosis of pheochromocytoma includes a extensive list of conditions that may suggest the presence of the tumor (Table 4.3) [5, 47,

Clinical Presentation of Pheochromocytoma 13 Table 4.3 Differential diagnosis of pheochromocytoma Endocrine

Adrenal medullary hyperplasia Hyperthyroidism, thyroid storm Carcinoid Hypoglycemia (often due to the presence of insulinoma) Medullary thyroid carcinoma Mastocytosis Menopausal syndrome

Cardiovascular

Heart failure Arrhythmias Ischemic heart disease, angina pectoris Baroreflex failure Syncope Orthostatic hypotension Labile hypernoradrenergic essential hypertension Renovascular disease

Neurological

Migraine or cluster headaches Stroke Diencephalic autonomic epilepsy Meningioma POTS Guillain–Barré syndrome Encephalitis

Psychogenic

Anxiety or panic attacks Factitious use of drugs Somatization disorder Hyperventilation

Pharmacologic

Tricyclic antidepressant Cocaine Alcohol withdrawal Drugs stimulating adrenergic receptors Abrupt clonidine withdrawal Dopamine antagonists Monoamine oxidase inhibitors Ephedrine-containing drugs Factitious use of various drugs including catecholamines

Miscellaneous

Neuroblastoma, ganglioneuroma, ganglioneuroblastoma Acute intermittent porphyria Mastocytosis Unexplained flushing spells Recurrent idiopathic anaphylaxis Lead and mercury poisoning

POTS: postural orthostatic tachycardia syndrome. Adapted from Lenders et al. [5].

87, 128, 150]. Many of these conditions can be excluded readily on the basis of a thorough history and physical examination. The most common mimic is hyperadrenergic hypertension, characterized by tachycardia, sweating, anxiety, and an increased cardiac output [101, 151]. These patients frequently have

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increased levels of catecholamines in blood and urine and are best excluded by use of the clonidine suppression test, which shows that the excess catecholamines results from increased sympathetic nervous activity and are not due to a tumor (see below) [110]. Another frequent problem is differentiating patients with pheochromocytoma from those with anxiety or panic attacks. In this era, one must also be aware of drug-induced states that can resemble a pheochromocytoma, especially amphetamines or cocaine. Amphetamines produce CNS stimulation and increased release of catecholamines. Cocaine causes catecholamine release and also blocks catecholamine reuptake so that the actions of released catecholamines are increased and prolonged [152]. The individual who takes cocaine and releases large amounts of catecholamines into his or her circulation has also poisoned the only defense mechanism that protects the heart from the effects of these catecholamines. Ingestion of phencyclidine (PCP) or lysergic acid diethylamide can mimic a pheochromocytoma, as can the ingestion of tyramine-containing foods or indirect-acting amines when taking monoamine oxidase inhibitors [153]. Abrupt withdrawal of clonidine brings about a rebound of central sympathetic nerve stimulation and is associated with all the signs and symptoms of a pheochromocytoma, including elevated catecholamines in blood and urine [154]. This state responds readily to readministration of clonidine and a gradual stepwise elimination of the drug. In the very rare situations where a patient has typical symptoms of a pheochromocytoma with a strong inconsistency in laboratory results, one must consider the possibility of factitious pheochromocytoma due to intentional (self-) administration of catecholamines. In this rare situation, as in other cases of factitious illness, it is therefore important to be specifically informed about the profession of the patient or even about an association of the patient with someone in the medical profession. Proportionally larger elevations above the upper reference limits of normal of plasma norepinephrine or epinephrine are consistent with states of sympathoadrenomedullary activation such occurs in hypernoradrenergic and renovascular hypertension, congestive heart failure, panic disorder, dumping syndrome, and other conditions. In contrast, pheochromocytomas are more usually associated with proportionally large increases in normetanephrine and metanephrine than of the parent catecholamines. Although severe paroxysmal hypertension should always suspicion of pheochromocytoma, it can also reflect a clinical entity called pseudopheochromocytoma.

4.3

Special Presentations

4.3.1 Diagnosis of Pheochromocytoma in Patients with an Incidentally Discovered Adrenal Mass The increasing use of radiological imaging modalities as standard procedures in modern medicine has led to recognition of incidentally discovered adrenal masses as a relatively common clinical problem, with a prevalence in the general population of up to 5% [35, 39, 155]. Although the majority of adrenal incidentalomas are benign non-hypersecretory cortical adenomas, an

Clinical Presentation of Pheochromocytoma 15

important minority represent pheochromocytomas, aldosteronomas, cases of cortical cancer, or Cushing’s syndrome. These tumors are pathological and require appropriate diagnosis and treatment. Pheochromocytomas are particularly life threatening, appearing in about 4.2% of adrenal incidentalomas [35, 39]. Pheochromocytomas found as incidentalomas often do not secrete large amounts of catecholamines and may present without hypertension or symptoms. Differentiation of pheochromocytoma from other adrenal tumors requires highly sensitive and specific biochemical tests and imaging modalities. Similar to other pheochromocytomas, the biochemical diagnosis of pheochromocytomas found as incidentalomas is preferably based on the measurement of plasma free metanephrines or urinary fractionated metanephrines. Functional imaging using preferably [123I]-metaiodobenzylguanidine (MIBG) scintigraphy is helpful and often indicated to further establish pheochromocytoma (see chapter on imaging procedures).

4.3.2

Pheochromocytoma as an Endocrine Emergency

Numerous reports in the literature exist of unusual presentations of benign or metastatic pheochromocytomas that require emergency intervention. These emergency situations are usually the result of organ-specific actions of catecholamines or are the consequence of complications related to tumor localization. Since symptoms related to tumor localization are non-specific and in management similar to that of any other tumor at such a location, those will not be discussed here.

4.3.2.1

Hypertensive Crisis

A hypertensive crisis is one of the most frequent emergency conditions of patients with a pheochromocytoma. The crisis can be accompanied by severe headaches, visual disturbances, cardiac arrhythmias, encephalopathy, acute myocardial infarction, congestive heart failure, or a cerebrovascular accident. Therefore, immediate and proper antihypertensive therapy is crucial. Phenoxybenzamine is the drug usually recommended for treatment of a hypertensive crisis due to pheochromocytoma should be based on administration of phentolamine (not recommended in the situation of overt heart failure or myocardial infarction because of the high risk of shock). This drug is usually given as an intravenous bolus of 2.5–5mg at 1mg/minute. If necessary, phentolamine’s short half-time allows this dose to be repeated every 5 minutes until hypertension is adequately controlled. Phentolamine can also be given as a continuous infusion (100mg of phentolamine in 500ml of 5% dextrose in water) with an infusion rate adjusted to the patient’s blood pressure during continuous blood pressure monitoring. Phentolamine, however, these days has limited availability. Intravenous infusion of vasodilatators such as nitroprusside, nicardipine or fenoldopam are more commonly available and now more often used for treatment of hypertensive crises [53, 114]. If hypertension is less severe, but still worrisome, treatment should include an α-adrenoceptor blocking agent that can be given orally, such as Doxazosin (starting dose of 4 mg, uptitrating to 16 mg/day). Successful management with oral and intravenous (perioperative) calcium channel blockers, such as

16 Chapter 4

nicardipine, as the sole medication has also been described [156]). However, not all calcium blockers are equally successful: diltiazem fails to prevent uncontrolled blood pressure during pheochromocytoma surgery [157], and verapamil may be associated with the development of pulmonary edema in the post-surgical period [158]. If tachycardia, arrhythmia, or angina is present, β-adrenoceptor blockers such as propranolol, esmolol, atenolol, or metoprolol are indicated only after appropriate α-adrenoceptor blockade [53]. There are several approaches to prevent hypertensive crisis, especially during situations when marked catecholamine release is anticipated (e.g. direct manipulation of tumor during an operation). For such situations patients must be prepared using pharmacologic blockade of adrenoceptors or catecholamine synthesis as described later.

4.3.2.2

Hypotension and Shock

Severe hypotension or shock is rarely seen in pheochromocytoma patients and may be preceded by a paroxysm of hypertension. In less than 2% of pheochromocytoma patients profound shock is the presenting manifestation [159]. In some patients there may be “pseudoshock”. In this situation peripheral blood pressure is unmeasurable due to extreme peripheral vasoconstriction, whereas central blood pressure is very high. In some patients who present with shock, there may be also severe abdominal pain, pulmonary edema, diaphoresis, and cyanosis [159]. In many patients that present with hypotension or shock, the tumor seems to predominantly secrete epinephrine [160–162]. The mechanisms that lead to hypotension and shock in patients with pheochromocytoma are incompletely understood. Intravascular hypovolemia (e.g. due to increased capillary permeability, vasodilation) and decreased cardiac output (e.g. due to systolic dysfunction as a consequence of downregulation of cardiac β-adrenoceptors, catecholamine cardiomyopathy, myocardial infarction) are the factors that most likely contribute to shock in pheochromocytoma [163]. Hypocalcemia may be an additional important pathogenic factor that decreases cardiac contractility and contributes to shock in patients with epinephrine secreting pheochromocytoma [164]. In cases of hemorrhagic necrosis in a large tumor, the abrupt cessation of catecholamine secretion may also contribute to sudden hypotension or shock.

4.3.2.3

Multisystem Failure

Pheochromocytoma may occasionally present as a multisystem crisis, defined as multiple organ failure with hypertension and/or hypotension, high fever, and encephalopathy [165]. If confused with septicemia, appropriate treatment may be delayed [166–171]. If patients with presumed septicemic shock are refractory to fluid and inotropic agents a pheochromocytoma should be suspected, in this situation immediate abdominal imaging is mandatory. If a tumor is located, emergency removal is indicated. Preferably the patient should be hemodynamically stabilized before going to surgery.

Clinical Presentation of Pheochromocytoma 17

4.3.2.4

Cardiac Emergencies

Patients with a pheochromocytoma may present with several cardiac emergency conditions, including arrhythmias, toxic cardiomyopathy, and myocardial infarction [172]. Arrhythmias Stimulation of β-adrenoceptors in patients with pheochromocytoma may cause severe arrhythmias due to catecholamine release from a tumor. Sinus tachycardia; is the most frequently observed arrhythmia; other arrhythmias include supraventricular [173], atrial fibrillation [174], nodal [175], broad complex [176], ventricular tachycardia [177–179], torsade de pointes [180], Wolff–Parkinson–White syndrome [181], and ventricular fibrillation [170, 182, 183]. In all situations where arrhythmia is accompanied by paroxysmal sweating, hypertension or anxiety, a pheochromocytoma should be considered. For rapid control of tachycardia due to atrial fibrillation or flutter, intravenous esmolol, a cardioselective, rapidly working but short-acting β1-blocker, esmolol can be used (0.5mg/kg intravenously over 1 minute), followed by an intravenous infusion at 0.1–0.3mg/kg/minute. Caution is warranted if α-blockade has not been achieved prior to the use of β-blockers since unopposed α-receptor stimulation can result in a hypertensive crisis [184]. Nevertheless, even in the absence of α-adrenergic blockade, esmolol treatment should be initiated. Ventricular arrhythmias may be treated with lidocaine [1]. Bradyarrhythmia and asystolic arrest are other presentations of pheochromocytoma [167, 185, 186]. These may result as a reflex response to a sudden paroxymal increase in blood pressure [186]. Rarely atrioventricular dissociation and bigeminy [173, 180], right bundle branch block [187], sick sinus syndrome [188] have been described in patients with pheochromocytoma. Treatment in these situations is similar to that of patients who do not have pheochromocytoma. Catecholamine-Induced Cardiomyopathy Catecholamine excess can also cause sterile myocarditis and cardiomyopathy [189]. Although catecholamine-induced dilating cardiomyopathy is most frequently reported [190–195], occasionally few patients may present with an obstructive hypertrophic catecholamine-induced cardiomyopathy [188, 196, 197]. Immediate treatment is required in cases of acute heart failure or pulmonary edema. The prognosis for patients with pheochromocytoma presenting with acute heart failure is poor, and death due to pulmonary edema may occur within 24 hours of the onset of such complaints [198]. When cardiomyopathy occurs without other typical pheochromocytoma symptoms, the diagnosis may be overlooked. If appropriate medication is initiated or the pheochromocytoma is removed, cardiac changes are reversible in most cases [199–202]. Sometimes improvement occurs shortly after treatment [192, 203, 204], while in other cases recovery is more slowly and can take over 2 years [197–202]. The mechanisms for catecholamine-induced myocarditis and cardiomyopathy have been studied extensively. The relative importance of the different

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factors contributing to myocardial injury is still debated. Apart from myocardial ischemia, direct toxic effects of catecholamine-oxidation products [205] and high intracellular levels of calcium in myocytes appear to contribute pivotally to the resultant myocardial injury. The high intracellular levels of calcium in myocytes may be due to increased permeability of the sarcolemmal membranes. The early lesions, pathologically characterized by small hemorrhages, edema, and infiltrating polymorphonuclear leukocytes, lymphocytes, and histocytes [201] are followed by focal degeneration [189, 206], ultimately resulting in progressive myocardial fibrosis [189]. Myocardial Ischemia and Myocardial Infarction Pheochromocytoma patients may present with symptoms suggestive of myocardial ischemia or myocardial infarction [182, 207]. Often, however, coronary blood vessels are devoid of critical stenoses. It is well known that catecholamines cause vasoconstriction of the coronary arteries while simultaneously increasing myocardial oxygen demand through stimulation of heart rate and cardiac contractility. Thus, the clinical presentation may be very similar to patients with myocardial ischemia and infarction due to coronary artery disease. Chest discomfort, tachycardia, sweating, and anxiousness are commonly shared symptoms. Electrocardiographic changes such as ST-segment elevation or depression [208], negative T-waves, and prolonged QT-interval (present in 7–35% of pheochromocytoma patients) are also similar [180, 209]. Can patients with a pheochromocytoma be distinguished from patients with coronary artery stenosis? In pheochromocytoma patients the cardiac complaints may be accompanied by other symptoms due to the high levels of catecholamines (e.g. severe hypertension, headache, profuse sweating, or intense pallor). A history of paroxysmal attacks is even more helpful. Furthermore, if coronary arteries appear normal at angiography and no changes over time can be observed in cardiac enzymes despite at severe initial presentation, a pheochromocytoma should strongly be suspected [179]. On the other hand, patients with severe cardiac ischemia or myocardial infarction may display high levels of plasma catecholamines due to intense stress-related sympathoadrenal activation. This situation may cause a chicken-or-egg discussion, leading to considerable confusion. In this context, it may be hard to rule out a pheochromocytoma reliably. Biochemical testing for pheochromocytoma should only be done if there is firm suspicion of a pheochromocytoma.

4.3.2.5

Acute Peripheral Ischemia

Sudden peripheral ischemia may be a presenting symptom in some patients, resulting in necrosis or gangrene [210–213]. It is important to establish the correct diagnosis since any surgery in a patient with unsuspected pheochromocytomas carries a high risk for morbidity and mortality. In most cases extreme vasoconstriction or diffuse arterial vasospasm induced by catecholamine overload is the cause. Some patients may already have a history of intermittent claudication [212, 214]. If no other typical symptoms of pheochromocytoma are present, catecholamine-induced vasospasms are invariably overlooked and patients may undergo extensive surgical procedures including amputation

Clinical Presentation of Pheochromocytoma 19

[198]. Occasional patients with catecholamine-induced arrhythmia experience arterial occlusion as a result of embolisms from cardiac thrombi [215]. Pheochromocytoma is sometimes found during the evaluation or emergency surgery for suspected ruptured aneurysms of the abdominal aorta [212]. Both dissecting and obstructive abdominal aortic aneurysm have been reported in pheochromocytoma patients [216, 217]. Acute peripheral ischemia or deep venous thrombosis may also represent increased coagulopathy that may occur in patients with metastatic pheochromocytoma, similar to other patients with cancer [218, 219].

4.3.2.6

Pulmonary Emergencies

Infrequently, pheochromocytoma manifests itself with pulmonary edema as the primary manifestation [162, 220]. Although pulmonary edema is of cardiogenic origin in most pheochromocytoma patients, non-cardiogenic pulmonary edema is also sometimes seen [162]. This is called neurogenic pulmonary edema because it is thought to be a direct effect of catecholamines on the pulmonary blood vessels involving a transient increase in pulmonary capillary pressure and an altered pulmonary capillary permeability [162, 182, 221].

4.3.2.7

Gastrointestinal Emergencies

Pheochromocytomas presenting with acute onset of abdominal symptoms are very challenging. Patients usually experience severe abdominal pain and vomiting and these symptoms can indicate hemorrhage of the tumor, which may lead to secretion of large amounts of catecholamines, causing hypertensive crisis [222–224], shock and rapid deterioration of the patient. Sometimes this may require emergency surgery or angiographic embolization to stop associated arterial bleeding [222]. Other abdominal catastrophes like severe bowel ischemia are the result of intense vasoconstriction due to prolonged catecholamine overload. High catecholamine levels in other patients appear to predominantly affect gastrointestinal motility by relaxation of the gastrointestinal muscles and contraction of both pyloric and ileo-cecal sphincters. Patients may present with intestinal pseudo-obstruction [225, 226], abdominal distension [227], severe paralytic ileus [210, 223, 228], dilated small bowel loops [229], megacolon [227, 230], ischemic enterocolitis [230, 231], volvulus or colonic rupture with fecal peritonitis [232]. Other more rare abdominal emergencies include acute cholecystitis [233, 234], acute pancreatitis [235], and ruptured aneurysm of the abdominal aorta [217].

4.3.2.8

Nephrological Emergencies

Acute renal failure is sporadically the presenting symptom of pheochromocytoma [236]. It may occur as a complication during the course of the disease [170, 187, 219, 237, 238] but is sometimes due to rhabdomyolysis leading to acute myoglobinuric renal failure [236]. The rhabdomyolysis is the consequence of severe vasoconstriction-mediated muscle ischemia. More seldom complications include renal infarction, as a consequence of renal ischemia

20 Chapter 4

due to (deep) systemic shock, vasoconstriction, or tumor compression of the renal artery [239]. In some patients hemodialysis is required [238].

4.3.2.9

Neurological Emergencies

Although cerebral hemorrhage and subarachnoidal bleeding have been described in patients during paroxysmal attacks of hypertension, most of the neurological symptoms seen in pheochromocytoma patients are the result of cerebrovascular accidents [215, 218, 240–246]. Hemiparesis, sometimes together with homonymous hemianopsy, is reported most frequently [242]. Cerebral bleeding may be accompanied by seizures [149, 241, 247, 248].

4.3.3

Malignant Pheochromocytoma

Malignant pheochromocytoma is established by the presence of metastases at sites where chromaffin cells are normally absent. Significant invasion of a tumor into surrounding organs or tissues may indicate a potential for malignancy but in itself does not provide a reliable indicator that a pheochromocytoma will metastasize. Pheochromocytoma metastasizes via hematogenous or lymphatic pathways; the most common metastatic sites are lymph nodes, bone, lung, and liver [36, 249–255]. Among all pheochromocytomas, the frequency of malignant pheochromocytomas ranges from 3% to 36% with a slight male predominance [38, 40, 42–44, 255]. About one-half of malignant tumors are found at initial presentation. The others develop after a median interval of 5.6 years after initial presentation of the initial tumor [252]. Two groups of patients can be distinguished based on the location of metastatic lesions. The first group represents short-term survivors with presence of metastatic lesions, especially in liver and lungs. Their survival is usually less than 2 years. The second group represents long-term survivors with the presence of bone metastatic lesions. Patients in this group can survive more than 20 years after the initial diagnosis. The overall 5-year survival rate varies between 20% and 60% with an average of about 35% [89, 256, 257]. The survival rate of patients with locally invasive disease and of those with distant metastatic lesions is about the same [40]. Recent advances in biochemical testing and nuclear imaging techniques have greatly improved our ability to diagnose and localize malignant pheochromocytoma at much earlier stages. Clinical manifestations of malignant pheochromocytoma are similar to those of the benign tumor. There are no characteristic symptom or groups of symptoms that would suggest a tentative diagnosis of malignancy [36, 249, 250, 252–255]. The most frequent manifestations are hypertension, headache, sweating and palpitations. Some patients have minimal symptoms despite markedly elevated catecholamine levels. This is most likely due to desensitization of adrenergic receptors by constant exposure to high concentrations of catecholamines. Patients can present with symptoms caused by local invasion of tumors into various organs. Similar to benign pheochromocytomas, malignant pheochromocytomas predominantly secrete NE [253, 258, 259]. In addition, increased dopamine production, is frequently associated with malignant pheochromocytomas. Various attempts have been made to develop ancillary criteria to distinguish malignant from benign pheochromocytomas before they develop metastases.

Clinical Presentation of Pheochromocytoma 21

Young age, extra-adrenal tumor location, large tumor size, and adrenal pheochromocytomas that fail to take up MIBG have all been associated with an increased likelihood of malignancy [89, 252–255, 259, 260]. Persistent postoperative arterial hypertension is also reported to be more common in malignant pheochromocytomas [89]. Conventional pathological features such as tumor necrosis, vascular or capsular invasion, nuclear atypia, and mitotic index do not consistently predict the malignant behavior of pheochromocytomas [89, 250, 252–255, 259]. More recently described features of malignant pheochromocytomas include increased activity of telomerase (the ribonucleoprotein enzyme that elongates chromosomal ends) or its catalytic subunit, increased expression of tenascin (an extracellular matrix glycoprotein), a high MIB-I score (a monoclonal antibody to Ki-67 antigen, as a nuclear proliferation marker), increased activity of cyclooxygenase-2, overexpression of p53, vascular endothelial growth factor, matrix metalloproteinases, and heparanase as well as loss of inhibin/activin β-subunit expression [82, 261–276] none of the above factors in either isolation or combination are capable of predicting with any certainty the aggressive potential of pheochronomocytoma in an individual patient at the time of tumor removal. Therefore, long-term follow-up of all patients with pheochromocytoma is mandatory. The localization of malignant pheochromocytoma follows the same steps as for benign pheochromocytoma. Malignant pheochromocytoma may lack expression of components of the cell membrane and vesicular transporter systems. In such a situation [18F]-dihydroxyphenylalanine, Octreoscan, or FDG PET may be more helpful than the use of a specific positron-emitting agents or MIBG scintigraphy [250, 277–286]. Successful management of malignant pheochromocytoma requires a multidisciplinary approach. Treatment is performed with the intention of possible cure for limited disease and palliation for advanced disease. The treatment regimen should be individualized to meet the goal of controlling endocrine activity, decreasing tumor burden, and alleviating local symptoms. Pharmacologic presurgical treatment of malignant pheochromocytoma is the same as for benign disease. For patients with limited disease, surgery may be the most appropriate modality of therapy [260]. However, for patients with multiple metastatic lesions, radical surgical resection is often impossible. Surgical procedures may also be associated with some complications including those related to significant catecholamine release during tumor manipulation. At present it is not clear whether surgery can prolong survival of such patients; more detailed, large, and prospective studies are needed. The rationale for surgical debulking is that the reduced tumor burden may allow for an improved response to radio- and chemotherapy. Decreased catecholamine levels may also leading to in symptomatic improvement. The current first-line systemic treatment for malignant pheochromocytoma is targeted radiotherapy using [131I]-MIBG [287, 288]. Since malignant pheochromocytomas are very rare tumors, experience with their treatment at any single medical center has been limited. In 1997, Loh summarized the worldwide published experience with [131I]-MIBG therapy [289]. The report summarized treatment of 116 patients with malignant pheochromocytoma,

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ages 12–76 years. Fifteen percent of patients were under the age of 18 years. Although the doses of radioactivity were modest, less than 300mCi in almost all instances, the treatment had some therapeutic effect in over 70% of the patients. In 30%, a partial but significant reduction in tumor volume occurred, but only five patients had complete responses. In 45%, a significant reduction in catecholamine levels occurred; and in 75%, there was significant improvement in the patient’s clinical condition or symptomatology. On average those who responded remained in a stable condition for average of 29 months and in some instances for as long as 8 years. Those who had complete responses were still in remission at the time their series were reported. Thirtythree percent of the initial responders, however, died of progressive disease. This compared to 45% of those who did not respond. Although these trials included patients with varying stages of disease and had different follow-up periods, they clearly showed that [131I]-MIBG therapy was effective for palliation and in a few instances gave complete and prolonged remissions. [131I]-MIBG therapy is used in MIBG positive tumors, especially those that are unresectable. The doses vary from as low as 50mCi up to 900mCi as a single dose (such high doses require bone marrow rescue) [289–291]. However, more often multiple doses around 200mCi at intervals of 3–6 months are used with the cumulative dose of up to about 2300mCi [291–300]. There is no clear relationship between tumor response and individual or cumulative dose. In fact, patients who have small tumors, located principally in soft tissue, are more likely to respond and consequently receive lower total amounts of radioactivity. [131I]-MIBG therapy is well tolerated, with minimal toxicity (if lower doses are used). Side effects may include nausea, mild bone marrow suppression, especially thrombocytopenia, mildly elevated liver enzymes, and some renal toxicity. Following intravenous administration, [131I]-MIBG rapidly accumulates in sympathetically innervated tissues such as the salivary glands, heart, liver, and spleen. [131I]-MIBG also accumulates in the adrenal medulla but since this tissue has a small volume, it is faintly visualized in up to 20% of patients. Ninety-eight percent of the administered [131I]-MIBG is excreted in the urine with fecal excretion being less up to only 2% of administered activity. In the first hour after administration, [131I]-MIBG rapidly leaves the vascular compartment. There is, however, an accumulation of activity in platelets and red blood cells. Thus, thrombocytopenia is usually seen few weeks later after MIBG is administered. Overall, only one-third of patients show partial response (less than 50% reduction of tumor mass) and improvement in symptoms and signs [289]. Using higher doses around 700mCi may result in better response but further studies are needed [290]. In 10% of patients, [131I]-MIBG therapy causes an exacerbation of pheochromocytoma symptoms – headache, palpitation, or diaphoresis – although symptoms are usually mild and resolve without treatment. Less frequently, mild orthostatic hypotension occurs requiring fluid therapy. Two-thirds of patients may experience mild nausea, anorexia, and vomiting for one to several days after therapy. These effects of radiation exposure it occurs mainly when the whole body dose is greater than 80 rad. Toxicity to the lungs, heart, or the autonomic nervous system has not been reported with [131I]-MIBG

Clinical Presentation of Pheochromocytoma 23

therapy. After administration of [131I]-MIBG a significant portion localizes in the liver and then rapidly clears. Increases in both bilirubin and transaminase have been observed in about 3% of patients. Occasionally pheochromocytoma patients with extensive metastases may developed mild hepatic failure. Patients will extensive carcinoid metastases and repetitive [131I]-MIBG therapies may present with severe liver failure resulting in death [300a]. Thus, there is concern that with very high doses of [131I]-MIBG, of over 12mCi/kg, liver failure may occur. Renal toxicity has not been found in adult pheochromocytoma patients; however, in children, mild reductions of renal function occur when the whole body radiation dose is 200 rad or greater. Similarly symptoms of radiation cystitis do not occur in adult patients with pheochromocytoma who void frequently after [131I]-MIBG therapy. Urinary bladder catheterization, however, is a common practice in children with neuroblastoma who receive very large doses. Adrenal cortical insufficiency has been reported in one pheochromocytoma patient after [131I]-MIBG therapy presumably because of radiation from activity that concentrates in the adrenal medulla. Therapeutic [131I]-MIBG contains up to 8% free iodide that would readily accumulate in the thyroid if not blocked by stable iodine or perchlorate. Even so, hypothyroidism is an occasional late complication (less than 1%). Thus, blockade is not totally protective, particularly when the doses of [131I]MIBG are very large. Patients who have MIBG-negative (or very weakly positive) metastatic pheochromocytoma or who do not respond to [131I]-MIBG therapy should be evaluated for possible radiation treatment using octreotide labeled with 111 indium or 90 yttrium. These two compounds are used in the treatment of neuroendocrine tumors, including pheochromocytoma, with some beneficial responses [280, 288]. The radiolabeled somatostatin analog is administered intravenously at intervals of 6 weeks for three to four cycles. However, the limited data using these radiopharmaceuticals are not encouraging since only a few patients responded and organ toxicity (especially kidney toxicity and bone marrow suppression) hampers the use of higher doses. Recently, the PET radiopharmaceutical [86Y]-Dotatoc has been reported to represent an option in treatment of somatostatin receptor positive pheochromocytomas [301]. Coupling chemotherapeutic agents to somatostatin analogs may provide another novel approach for delivery of specific antitumor therapy [280, 288]. In rapidly progressive metastatic pheochromocytoma, chemotherapy rather than MIBG therapy is recommended [302]. A combination of cyclophosphamide 750 mg/m2, vincristine 1.4mg/m2, and dacarbazine 600mg/m2 administered intravenous in 21-day cycles is used [303]. On average, however, only about one-third of patients show a partial tumor response, a 50% or more reduction in the size of metastases. In addition, up to two-thirds of the patients have some biochemical response, characterized by a reduction in plasma concentrations or urinary excretion of catecholamines and catecholamine metabolites. Chemotherapy stops when the patient shows either the development of new lesions or a 25% increase in the size of old lesions despite of continued treatment. A major reason for the development

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of resistance of malignant pheochromocytoma to treatment with the CVD regimen is induction of MDR-1 gene activity. Attempts to block the activity of this gene have, so far, been unsuccessful. Previous experimental studies demonstrated that under in vitro conditions cisplatin and doxorubicin led to an enhanced uptake of [131I]-MIBG in neuroendocrine tumors [304]. Similarly, in clinical studies the combination of [131I]-MIBG and chemotherapy was shown to result in improved update of [131I]-MIBG6 by malignant pheochromocytoma [291]. Patients with large tumor burdens may present with massive release of catecholamines within the first few hours after administration of the first course of chemotherapy [305]. A similar massive release of catecholamines was reported after chemotherapy with cyclophosphamide, vincristine, and prednisone in a patient with pheochromocytoma and lymphocytic lymphoma [306]. These instances of “catecholamine storm” are manifested by the sudden onset of either extreme tachycardia or severe hypertension, or both. Since they are not predictable, we generally advise that the first course of chemotherapy, in any patient, be administered in a hospital setting. It is important to intervene immediately with β-blockers if severe tachycardia occurs or with α-blockers if extreme hypertension develops, or a combination of α- and β-blockers. Unless this is done rapidly, patients may go into severe congestive heart failure with resultant decreases in cardiac ejection fraction to as low as 6–10% [305]. The catecholamine-stunned heart can respond with recovery within 7–10 days. External beam radiation is used for palliation of chronic pain and symptoms of local compression arising from pheochromocytoma metastases (usually for bone metastatic lesions) [307, 308]. However, no systemic effects on tumor burden or hormone levels are usually observed. Successful infarction of pheochromocytoma by embolization has been demonstrated in individual case reports [309, 310]. Radiofrequency ablation, cryotherapy, and percutaneous microwave coagulation have also been used for treatment of malignant pheochromocytoma [21, 311, 312].

4.3.4

Pheochromocytoma in Children

Although pheochromocytomas are the most common endocrine tumors in children, they account for only 5–10% of all pheochromocytomas with an incidence of 2/million/year [313, 314]. In children, pheochromocytomas are more frequently familial (9–50%), extra-adrenal (8–43%), bilateral adrenal (7–53%), and multifocal [7, 315–317]. Childhood pheochromocytomas peak at 10–13 years with a male predominance before puberty [315, 316, 318]. About 10–47% of pediatric pheochromocytomas are malignant [315, 316, 319–321] with reported mean survival rates of 73% at 3 years, 40–50% at 5 years, and about 30% at 10 years after diagnosis [289, 318, 321, 322]. Children also have a higher incidence of extra-adrenal pheochromocytomas, especially in the organ of Zuckerkandl and the urinary bladder. Recurrent pheochromocytomas may appear years after initial childhood diagnosis, emphasizing the importance of careful long-term follow-up [320]. In contrast to adult patients in whom sustained hypertension is found in only 50% of cases, more than 70–90% of children present with sustained

Clinical Presentation of Pheochromocytoma 25 Table 4.4 Signs and symptoms of pheochromocytoma in children Hypertension (less than 10% paroxysmal) Headache Sweating Palpitations Weight loss Pallor/flushing Nausea/emesis Polyuria/polydypsia Constipation

82% 81% 36–68% 34–45% 44% 11–36% 27–56% 25% 8%

Adapted from Reddy et al. [320], Manger and Gifford [47], [7], and Hume [318].

hypertension [314, 315, 320, 321, 323]. Pheochromocytoma is the underlying cause in 1–2% of cases of pediatric hypertension and should be considered after exclusion of the more common causes such as renal disease, renal artery stenosis, and coarctation of the aorta [316]. Pheochromocytomas secreting epinephrine may also present with hypotension, particularly postural hypotension [114, 115]. Sweating, visual problems, weight loss, nausea, and vomiting are more common in children than in adults [7, 324] as are polyuria and polydypsia (Table 4.4). In addition, children commonly present with palpitations, anxiety, and hyperglycemia [47]. Other signs of catecholamine excess are pallor and flushing [47]. As summarized by Manger and Gifford [47] occasionally some children present with a reddish blue mottling of the skin and puffy red and cyanotic appearance of the hands. Less frequent clinical manifestations include fever and constipation. Similar to adult patients, the presence of the triad of headache, palpitations, and sweating in children in combination with hypertension should arouse immediate suspicion of a pheochromocytoma. It should be also mentioned that in children or young adults various symptoms and signs (especially nausea, vomiting, headache, unusual sweating) occur at the end or shortly after exercise. Since neuroblastomas (the most common solid tumors in childhood), ganglioneuroblastomas, and ganglioneuromas can synthesize and excrete catecholamines and their metabolites, the differential diagnosis from a pheochromocytoma is somewhat difficult or, at times, impossible without histology. Other differential diagnoses of pheochromocytoma in children include coarctation of the aorta, and less commonly panic/anxiety disorders, “autonomic epilepsy,” cluster or migraine headache, hyperthyroidism, and side effects of medications or dietary supplements [323, 325]. Measurements of plasma free metanephrines under standardized conditions with the use of age and gender specific reference ranges are the biochemical test of choice for detecting childhood pheochromocytoma [326] (Figure 4.1). Genetic testing is mandatory in all children with a pheochromocytoma. A recent study found that succinate dehydrogenase complex II, subunit B, SDHB, mutations are common in children presenting with an extra-adrenal pheochromocytoma [327]. More than 90% of pheochromocytomas in children are localized in the abdomen, therefore, imaging studies

26 Chapter 4

should be directed to this part of the body. Although CT localizes about 95% of pheochromocytomas to avoid radiation exposure, MRI is the preferred imaging modality in children. MIBG scintigraphy is used to confirm that the tumor is indeed pheochromocytomas and to rule out metastatic disease. Treatment of childhood pheochromocytoma is similar to pheochromocytoma that occur in adult patients.

4.3.5

Pheochromocytoma in Pregnancy

Pheochromocytoma in pregnancy is extremely rare with a prevalence of 1 in 50,000 pregnancies. However, this situation demands special attention since it carries a high risk of morbidity and mortality if pheochromocytoma is unsuspected (40.3% maternal mortality and 56% fetal mortality). Both maternal and fetal mortality can be greatly reduced if the diagnosis is made antenatally [328–331]. In a more recent series, maternal mortality had fallen to 17% and even to 1% if the diagnosis was made antepartum [328]. Nevertheless, in two series it was found that pheochromocytoma remained unrecognized antepartum in 47–65% of patients [328, 329]. Hypertensive crisis due to pheochromocytoma in pregnancy is highly unpredictable [331]. Direct tumor stimulation leading to marked catecholamine release can occur as the result of examination, postural changes, pressure from the uterus, labor contractions, fetal movements, and tumor hemorrhage. Hypertensive crisis most frequently occur in the period surrounding delivery. Acute hypertensive crisis may manifest itself as severely elevated blood pressure, arrhythmia, or pulmonary edema. The deleterious effects for the fetus are due to the compromised maternal and placental circulation during a hypertensive crisis. The fetus is relatively protected from high maternal circulating catecholamines by placental enzymes responsible for the inactivation of catecholamines, thereby minimizing transfer of catecholamines from the maternal to the fetal circulation [332]. The clinical picture of hypertensive crisis in the pregnant patient can be easily mistaken for acute toxemia [7]. In contrast to acute toxemia, hypertension or hypertensive crisis can occur early in pregnancy (before the third trimester), be paroxysmal, or accompanied by postural hypotension; proteinuria or edema, however, are often absent [333, 334]. Biochemical diagnosis can be hindered if a patient is on methyldopa, which in some biochemical assays can result in a false-positive test result. Therefore, if pheochromocytoma is suspected, treatment with methyldopa should be suspended or delayed until after measurements of metanephrines have been carried out. Localization of a suspected pheochromocytoma is vital and best accomplished by MRI and/or ultrasonography. It is important to administer α-adrenergic blocking agents as soon as the diagnosis is confirmed. The agent of choice, as in other cases of pheochromocytoma, remains phenoxybenzamine. Placentar transfer of this drug, may lead to mild perinatal depression and transient hypotension in the newborn. Apart from this there have been no reports of other adverse fetal effects during a short-time period of 2-weeks presurgical treatment [335]. β-Blockers have been used to control tachycardia; however, atenolol may be associated with intrauterine growth retardation [328].

Clinical Presentation of Pheochromocytoma 27 Plasma norepinephrine concentration (nmol/l)

Plasma normetanephrine concentration (nmol/l) 0.56

2.70

0.42 1.80 0.28 0.90 0.14 0

0 Children

Children

Adults

Plasma epinephrine concentration (nmol/l) 0.70

Adults

Plasma metanephrine concentration (nmol/l) 0.52

0.56

0.39

0.42 0.26 0.28 0.13

0.14 0

0 Children

Adults

Children

Adults

Figure 4.1 Reference ranges for plasma concentrations of catecholamines and free metanephrines in healthy children (n ⴝ 86; mean age 12 years) compared to healthy normotensive adults (n ⴝ 175; mean age 36 years). Horizontal lines show median values and boxes the 95% confidence intervals as calculated from logarithmically transformed data. Adapted from Weise et al. [326].

Maternal hypertensive crisis is always very dangerous for the fetus, commonly resulting in utero-placental insufficiency, early separation of the placenta, or fetal death [332]. In situations of hypertensive crisis intravenous phentolamine, as a bolus of 1–5mg or as a continuous infusion of 1mg/ minute, can be used to control blood pressure. As a final resort, sodium nitroprusside may be used, but this has to be infused at a rate of less than 1 µg/kg/ minute to avoid fetal cyanide toxicity [336]. If the patient is in the first two trimesters, then the tumor should be removed as soon as the patient has been adequately prepared with β-blockers. Recently, this has been accomplished laparoscopically [337]. In most instances, the fetus will remain undisturbed, but a spontaneous abortion is likely. In the third trimester, it is appropriate for the patient to be treated with α-blockers and carefully monitored until the fetus reaches sufficient maturity to be viable.

28 Chapter 4

At that point, a cesarean section should be performed, as vaginal delivery is extremely hazardous [47, 87, 338]. The tumor can be removed in the same operation. Anesthetic management is critical during cesarean section and removal of the tumor, whether done at the same time or in sequence [339]. However, if uncontrolled hypertension, hemorrhage, or other emergency occurs, the tumor should be removed immediately [47, 87]. Magnesium sulfate has been used to control hypertensive emergencies during labor and during resection of the tumor in pregnant patients with pheochromocytoma [340]. The efficacy of the drug can be severely limited in some patients if an adequate blood level of magnesium can not be achieved due to pre-existing hypomagnesemia. Labor and vaginal delivery should be avoided since this may stimulate catecholamine secretion by the tumor with severe hypertensive crisis, even in the presence adrenergic blockade.

4.3.6

Pseudopheochromocytoma

Although severe paroxymal hypertension should always arouse suspicion of pheochromocytoma, it can also reflect clinical entity called pseudopheochromocytoma. Thus, pseudopheochromocytoma refers to the large majority of individuals with severe paroxysmal hypertension, whether normotensive or hypertensive between episodes, in whom pheochromocytoma has been ruled out [341, 342]. The clinical picture resembles closely that of a pheochromocytoma and poses a frequently encountered clinical dilemma. This is particularly the case when spells of abrupt onset and severe hypertension (blood pressure higher than 200/110 mmHg) have been demonstrated. Recent evidence indicated that pseudopheochromocytoma is a heterogeneous clinical condition subdivided into a primary and a secondary forms. In contrast to the primary form, secondary form is associated with various pathologies (e.g. hypoglycemia, obstructive sleep disorder, epilepsy, baroreceptor failure), medications, or drug abuse (Table 4.3). The most common clinical characteristics of this syndrome as in many cases be attributable to a short-term activation of the sympathetic nervous system. Paroxysmal hypertension is usually associated with tachycardia, palpitations, nervousness, tremor, weakness, excessive sweating, pounding headache, feeling hot, facial paleness, or rarely redness. In contrast to pheochromocytoma, patients with pseudopheochromocytoma more often but not consistently present with panic attacks or anxiety, flushing, nausea, and polyuria [341–343]. All these symptoms well resemble a syndrome described by Page [344] and simulate the symptoms caused by diencephalic stimulation. Equally interesting is also Page’s observation that “an attack is brought on by excitement” and that the syndrome has a clear predominance in women. Another important feature distinctive from pheochromocytoma are the circumstances under which the episode occurs. In pheochromocytoma, symptoms are usually unprovoked, while in pseudopheochromocytoma they usually follow some identifiable events. It is important, therefore, in questioning these patients, to search for specific provocative factors that may have precipitated these episodes. Similar to pheochromocytoma, episodes may last from few minutes to several hours and may occur daily or once every few months.

Clinical Presentation of Pheochromocytoma 29

Between episodes blood pressure is normal or may be mildly elevated. Pseudopheochromocytoma is usually successfully treated by antihypertensive and psychopharmacologic drugs or psychotherapy.

4.3.7

Factitious Pheochromocytoma

Factitious disorders are characterized by the intentional production of physical symptoms as a means of assuming the sick role [345]. Malingering is characterized by intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives (e.g. avoid work, obtain drugs). Patients with these disorders present a significant challenge to health care workers and often have poor outcomes resulting in prolonged illness, unnecessary surgeries and even, on occasion, death [346]. Munchausen’s syndrome is the term designated for a chronic factitious disorder with physical symptomatology [347]. In such a situation repeated chronic injections of epinephrine or [348] prompt a diagnostic evaluation for a pheochromocytoma. Because catecholamines are metabolized to free metanephrines within pheochromocytoma tumor cells, a process independent of catecholamine release, measurements of plasma free metanephrines can be helpful to differentiate factitious from real pheochromocytoma [349]. In patients with pheochromocytoma plasma levels of metanephrines are elevated between cardiovascular attacks whereas in patients with factitious pheochromocytoma plasma levels of metanephrines are normal. Furthermore, during cardiovascular attacks, plasma levels of metanephrines are only very mildly elevated (up to 5%) above the baseline level in patients with factitious pheochromocytoma in contrast to those who harbor the tumor.

CH A PTE R 5

Current trends in genetics of pheochromocytoma

According to studies examining the frequency at known germline mutations in patients with pheochromocytoma, up to 24% of tumors are inherited [25, 34, 128, 150, 350, 351]. Hereditary pheochromocytoma and paraganglioma are associated with multiple endocrine neoplasia type 2 (MEN-2A or MEN2B), von Recklinghausen’s neurofibromatosis type 1 (NF-1), von Hippel– Lindau (VHL) syndrome, and familial paraganglioma (PG) due to germline mutations of genes encoding succinate dehydrogenase (SDH) subunits B, C, and D (Table 5.1). In general, the traits are inherited in an autosomal dominant pattern.

5.1

MEN Syndromes

MEN-2 is an autosomal dominantly inherited syndrome (Sipple’s syndrome) characterized by predisposition to pheochromocytoma, medullary thyroid carcinoma and hyperparathyroidism (352). The syndrome affects about 1 in 40,000 individuals. The gene responsible for MEN-2 is the RET proto-oncogene located on chromosome 10q11.2 (353). RET consists of 21 exons with 6 so-called hot spot exons (exons 10, 11, 13, 14, 15, 16) in which mutations are identified in 97% of patients with MEN-2. The RET gene encodes a receptor tyrosine kinase expressed primarily in neural crest and urogenital precursor cells. The ret receptor tyrosine kinase is activated by four related neurotophic factors including glial cell line-derived neurotrophic factor (GDNF), neurturin, artemin and persephin. These ligands bind to glycosylphosphatidylinositol of α-adrenergic receptors (354, 355). RET plays an important role in normal gastrointestinal neuronal and kidney development as exemplified by the RET knockout mouse which has a Hirschprung-like phenotype and renal cyst or agenesis (356, 357). In additional to pheochromocytoma, expression of RET has also been detected in other neural crest-derived tumors such as neuroblastoma and medullary thyroid carcinomas. As an oncogene, activation of RET leads to hyperplasia of target cells in vivo. Subsequent secondary events then lead to tumor formation [358–361]. It has been proposed that in addition to other events, RET protein accumulation 30

Current Trends in Genetics of Pheochromocytoma 31 Table 5.1 Familial pheochromocytoma Syndrome MEN syndromes MEN-2A (Sipple’s syndrome)

MEN-2B

Genetic Abnormalities

Phenotypic Abnormalities

Chromosome 10 (10q11.2) RET proto-oncogene mutations affect tyrosine kinase ligand-binding domain

Medullary carcinoma of the thyroid Hyperparathyroidism

Chromosome 10 (10q11.2) RET proto-oncogene mutations affect tyrosine kinase catalytic site

Medullary carcinoma of the thyroid Mucosal neuromas Intestinal ganglioneuroma Megacolon Marfanoid habitus

Neuroectodermal syndromes Neurofibromatosis Chromosome 17 (17q11) type I (NF-I; mutations affect von Recklinghausen’s NF-1, tumor suppressor gene disease) Cerebelloretinal hemangioblastomatosis (VHL syndrome) type 2

Chromosome 3 (3p25–26) missense mutations affect VHL, tumor suppressor gene

Succinate dehydrogenase gene family syndromes SDHB (Paraganglioma/ Chromosome 1 (1p36) missense, PG/type 4) nonsense, frameshift

Peripheral neurofibromas

Retinal angiomas Cerebellar and spinal cord hemangioblastomas Renal cell cancer Pancreatic, renal, epididymal, and endolymphatic cysts/tumors

Adrenal or extra-adrenal often metastatic; parasympathetic paraganglioma pheochromoctyoma

SDHC PG type 3

Chromosome 1 (1q21)

Parasympathetic paraganglioma

SDHD PG type 1

Chromosome 11 (11q23) missense, nonsense, frameshift mutations paternal transmission

Parasympathetic paragang lioma, adrenal or extra-adrenal pheochromocytoma

secondary to absent or reduced VHL protein, may then cause transformation of selected chromaffin cells to pheochromocytoma [362]. Further studies are needed to clarify whether such somatic VHL gene alterations in MEN-2associated tumors play a role in early or late tumorigenesis or rather in tumor progression. A pheochromocytoma often develops if further mutational events e.g. deletion of tumor suppressor gene on the short arm of chromosome 1 (1p) occur [363]. Loss of chromosome 1p has been identified in all patients with

32 Chapter 5 Table 5.2 Signs and symptoms of pheochromocytoma in patients with MEN-2, VHL syndrome and sporadic pheochromocytoma

Hypertension Symptoms (total) Headache Diaphoresis Palpitations Anxiety

MEN-2 (n ⴝ 19)

VHL (n ⴝ 31)

Sporadic (n ⴝ 37)

42% 53% 32% 32% 37% 21%

19% 32% 26% 23% 19% 16%

90% 90% 92% 70% 73% 60%

Adapted from Pacak et al. [390].

MEN-2-associated pheochromocytomas [364]. Lui et al. [365] found also loss of 11p in two of five MEN-2-related pheochromocytomas. Interestingly, the chromosomal area 1p may play a role in the development of neuroblastoma [366]. A responsible corresponding gene for neuroblastoma, however, has not yet been identified [367]. Reduced NF1 expression was found in 5 of 14 MEN-2-related pheochromocytomas, suggesting a possible role of the NF1 gene and the ras pathway in tumor formation [368]. Pheochromocytoma (about 70% are bilateral) develops on a background of adrenomedullary hyperplasia and becomes manifest in about 50% of patients with MEN-2 [350, 359i, 362]. The peak age is around 40 years but children as young as 10 years can be affected [369, 370]. Annual surveillance of patients with MEN-2 starting at age 6 years is recommended [350, 371]. Patients with MEN-2-related pheochromocytoma often lack hypertension or symptoms (occurs only in about 50%) (Table 5.2). As with most epinephrine-producing pheochromocytomas hypertension when present is usually paroxysmal. MEN-2-related pheochromocytomas are almost always intra-adrenal, often bilateral and they are rarely malignant (
5%) [107, 109, 372]. Due to the rarity of the condition, there are no adequate data to reliably assess survival of MEN-2 patients with malignant pheochromocytoma. In children with MEN2B-associated pheochromocytomas, a higher risk of malignancy compared to MEN-2A or sporadic disease is found [316]. Germline RET mutations in MEN-2B patients affect the tyrosine kinase catalytic site in the intracellular domain of the protein [373–376]. More than 94% of unrelated patients have a single methionine to threonine substitution at codon 918 in exon 16 of RET, corresponding to the tyrosine kinase domain [373–376]. MEN-2B patients have pheochromocytoma, medullary carcinoma of the thyroid, ganglioneuromatosis, multiple mucosal neuromas of eyelids, lips, and tongue, and some connective tissue disorders that include marfanoid habitus, scoliosis, kyphosis, pectus excavatum, slipped femoral epiphysis, and pes cavus [352, 356, 377]. Various crossover syndromes have been reported in which pheochromocytoma has been associated with characteristics of MEN-1, MEN-2A, MEN-2B, von Recklinghausen’s NF, VHL, and the Zollinger–Ellison syndrome [378]. It

Current Trends in Genetics of Pheochromocytoma 33

has been proposed that the combination of NF, duodenal carcinoid, and pheochromocytoma constitutes a neuroendocrine syndrome that is separate from the combination of VHL, islet cell tumor, and pheochromocytoma [379]. MEN-1 (Wermer’s syndrome) consists of hyperparathyroidism, pituitary adenomas, and pancreatic islet cell tumors [380, 381]. Pheochromocytoma is not usually part of this complex; however, the occurrence of pheochromocytoma and pancreatic islet cell tumors has been reported in some families [382, 383]. Often the islet cell tumors were non-functional.

5.1.1

Diagnostic Approaches

Genetic screening for RET mutations is recommended in all subjects where there is clinical suspicion of familial pheochromocytoma (e.g. bilateral pheochromocytomas, family history of pheochromocytoma, or medullary thyroid cancer) but only after consideration of the relative livelihood of other underlying mutations [371]. Since it has been recently shown that up to 24% of patients with apparently sporadic non-syndromic pheochromocytoma may be carriers of predisposing germline mutations, it has been suggested that genetic screening (including RET mutation testing) should also be done in patients where there is no clinical evidence of a hereditary basis [34], especially in subjects aged 50 years and younger. Once a germline mutation is identified it is proposed that biochemical screening for pheochromocytoma should be carried out at yearly intervals from age 10 (for codons 630, 634, 918) and 20 (for codons 609, 611, 618, 620, 790, 791, 804, 891) years, respectively [384]. Many pheochromocytomas discovered during routine screening in MEN-2 patients are small and clinically silent. Furthermore, pheochromocytomas in MEN-2 patients often secrete both epinephrine and norepinephrine episodically (but metabolize them continuously to metanephrines), so that measurements of catecholamines in urine or plasma may yield normal results despite the presence of a tumor. Therefore, the first choice for biochemical diagnosis are the measurements of plasma free metanephrines or urinary fractionated metanephrines. The sensitivity of measurements of plasma metanephrines for the detection of pheochromocytoma in patients with MEN-2 is very high (almost 100%) and better than that of any other biochemical test (Table 5.3) [19, 385–387]. In patients with exclusively normetanephrine-producing pheochromocytomas, MEN-2 can be excluded. Where increases in plasma metanephrines are insufficient to conclusively prove the tumor, a plasma normetanephrine to norepinephrine ratio above 0.52 or a metanephrine to epinephrine ratio above 4.2 can provide further confirmatory evidence of pheochromocytoma in up to 30% of patients [388]. In selected cases with equivocal baseline results, the implementation of dynamic testing using clonidine suppression or glucagon stimulation tests may verify the presence of a pheochromocytoma. The caveat is that the glucagon test has not been validated for responses of epinephrine. Furthermore, although responses of plasma normetanephrine to clonidine are useful (norepinephrine responses are much less reliable) [388], no appreciable responses of metanephrine are noted, which is particularly crucial to MEN-2-related pheochromocytoma.

34 Chapter 5 Table 5.3 Sensitivity of biochemical tests in patients with MEN-2, VHL syndrome, and sporadic pheochromocytoma

Number of subjects Male/female Mean age  SD (years) Plasma-free normetanephrine Plasma-free metanephrine Plasma norepinephrine Plasma epinephrine Urinary normetanephrine Urinary metanephrine Urinary norepinephrine Urinary epinephrine Urinary vanillylmandelic acid

MEN-2

VHL

Sporadic

35 16/19 41.0  12.2 86% 100% 41% 44% 100% 95% 52% 58% 63%

56 31/23 47.3  16.0 96% 11% 71% 4% 95% 14% 78% 2% 36%

169 86/83 41.3  15.8 98% 60% 82% 43% 94% 54% 82% 38% 77%

Adapted from Pacak et al. [390] and Lenders et al. [19].

Anatomical imaging modalities computed tomography (CT) or magnetic resonance imaging (MRI) provide the first choice for the localization of MEN-2-related pheochromocytoma. Functional imaging modalities are largely confirmatory but can be useful to rule out bilateral adrenal disease, to evaluate patients with recurrent pheochromocytoma, to assess patients with distorted anatomy from previous surgery, and also in those patients with equivocal biochemical data despite high suspicion for the presence of pheochromocytoma. Currently, the functional imaging test of first choice is scintigraphy with [123I]-metaiodobenzylguanidine (MIBG) [389, 390]. When MIBG scintigraphy is negative, positron emission tomography (PET) studies should be performed using specific ligands such as [18F]-fluorodopamine ([18F]-DA), [18F]-dihydroxyphenylalanine ([18F]-DOPA), [11C]-epinephrine, or [11C]-hydroxyephedrine. If these are also negative, non-specific modalities, such as somatostatin receptor scintigraphy or PET with [18F]-fluorodeoxyglucose (FDG), should follow (Table 5.4) [390].

5.2

VHL Syndrome

In 1895 Eugene von Hippel described a patient with retinal angiomas [391]. In 1926 Arvid Lindau observed retinal and central nervous system angiomatous lesions [392] and a year later their association with kidney and pancreatic cysts [393]. The term “von Hippel-Lindau syndrome” was subsequently introduced by Melmon and Rosen [394]. VHL syndrome affects about 1 in 36,000 individuals [395]. The syndrome is caused by mutations in chromosome 3 (3p25/26), that encodes the VHL tumor suppressor gene [396–398]. Up to 9% of unselected, apparently sporadic pheochromocytomas have VHL gene mutations. As many as 23% of patients do not have positive family history, but present as de novo cases [399–403]. The mutated VHL gene product leads to up-regulation of various genes involved in hypoxia cascade,

Current Trends in Genetics of Pheochromocytoma 35 Table 5.4 Established or preferred tests for the genetic assessment, biochemical diagnosis and localization of MEN-2-related pheochromocytoma Genetic • RET mutations in all patients with MEN-2 or in their relatives Biochemical Plasma Urine

Imaging Anatomical imaging Functional imaging

• • • •

Free metanephrine and normetanephrine Epinephrine, norepinephrine Fractionated metanephrines Epinephrine, norepinephrine

• CT (preferred) or MRI of adrenals • Particularly useful if pheochromocytoma is larger than 5cm or if there is suspicion of metastatic disease • Scintigraphy with [123I]-MIBG is currently the first choice • PET with [18F]-fluorodopamine or [18F]-fluorodihydroxyphenylalanine (second choice because although they have the same sensitivity as [123I]-MIBG they are not widely available) • PET with [18F]-FDG or somatostatin receptor scintigraphy (only if imaging with e.g. [18F]-fluorodopamine or [123I]-MIBG is negative)

Adapted from Pacak et al. [390].

and with consequent increases in angiogenesis and changes in the extracellular matrix and regulation of the cell cycle [404–412]. The disease has been divided into two types based on genotype–phenotype correlations. Type 1 involves mainly large deletions or mutations and expresses the full phenotype of vascular lesions of the retina (retinal angiomas or hemangioblastomas), cysts or solid tumors in the brain or spinal cord, pancreatic, renal, and splenic cysts, solid pancreatic tumors (rarely adenocarcinomas), renal cell carcinoma, epididymal cystadenoma, and endolymphatic sac tumors, but no pheochromocytoma. Type 2 involves missense mutations, pheochromocytoma, and the full phenotype [403, 413, 414]. Type 2 disease is subdivided into low (type 2A) or high (type 2B) risk for pheochromocytoma. Type 2C patients present only with pheochromocytoma [415–417]. Patients are frequently asymptomatic when they present with other aspects of this disease. At present, metastases from renal cell carcinoma and neurological complications from cerebellar hemangioblastomas are the most common causes of death of VHL patients. This syndrome is quite variable in terms of the different organ systems involved and the extent of involvement from patient to patient and from family to family. Overall less than 30% of patients with VHL germline mutations develop pheochromocytoma with a mean age at diagnosis of 30 years [418]. Pheochromocytomas in VHL syndrome typically develop according to Knudson’s two-hit model, including the an inherited germline VHL mutation, and additional loss of function of the wild-type allele. The exact mechanisms of tumorigenesis in VHL-associated pheochromocytoma remain unknown. It appears that not all cells with biallelic inactivation of VHL become tumors, and that the time point of the second hit during cell development and other factors may determine the fate of affected

36 Chapter 5

cell [419]. None of these tumors had somatic mutations in the MEN1 gene at 11q13 or the SDHD gene at 11q23. Reduced NF1 expression was found in 1 of 2 VHL-related pheochromocytomas [420–421]. Regarding chromosomal changes, loss of heterozygosity of chromosome 3p, at which the VHL gene is located, were also found in about 60% of sporadic pheochromocytomas [420]. Several studies also found loss of chromosome 11 in most and 1p in some patients with VHL-related pheochromocytoma [364, 365]. Pheochromocytomas occuring as the part of the VHL syndrome have an exclusively noradrenergic phenotype reflecting the predominant production of norepinephrine [386] (Tables 5.2 and 5.3). These tumors are mainly located intra-adrenally; in about 50% of patients the tumors are bilateral; the incidence of metastases is less than about 7%. Very rarely pheochromocytoma is found in extra-adrenal locations [418]. Since the tumors do not express glucagon receptors, the glucagon test is not used for the detection of these tumors. These tumors when found based on periodic annual screening or during searches for other tumors that are part of this syndrome are usually small and often fail to be detected by nuclear imaging methods. Furthermore, about 80% of pheochromocytomas found in VHL patients during screening are asymptomatic and are not associated with hypertension. Low sensitivity of specific nuclear imaging methods may reflect relative lack of storage granules or reduced expression of the membrane norepinephrine or vesicular monoamine transporters [422, 422a]. Therefore, it is not surprising that MIBG scintigraphy often fails to localize VHL-related adrenal pheochromocytomas [423, 424]. Our preliminary data suggest that 6-[18F]fluorodopamine PET is a more sensitive imaging method than MIBG scintigraphy (unpublished observations). Screening for pheochromocytoma is recommended in all VHL patients starting at age 5 years [425].

5.3

NF Type 1

NF is divided into two types: NF-1 has neurofibromas of peripheral nerves, while NF-2 has central neurofibromas. Pheochromocytoma is not associated with NF-2. NF-1 known as von Recklinghausen’s disease is a common genetic autosomal dominant disorder occurring in 1 per 3000–4000 individuals [426]. This genetic disorder is characterized by typical findings such as café-au-lait macules (at least five macules need to be present), neurofibromas, lisch nodules (iris hamartomas), optic gliomas, and axillary and inguinal freckling [368, 427, 428]. NF-1 patients also have increased incidence of various tumors including those that are malignant (malignant peripheral nerve sheath tumor) and chronic myelogenous leukemia [368, 425, 428]. The association of NF-1 with pheochromocytoma is less than 1–2% but about 5% of patients with pheochromocytoma have NF [429–433]. However, from autopsy studies, NF1-related pheochromocytomas are present in up to 13% patients [425]. The mean age at the diagnosis is 42 years [434]. Slightly over 20% of patients are asymptomatic [434]. The NF-1 gene located on chromosome 17(17q11) encodes the protein, neurofibromin. Mutations including inactivation of this tumor suppressor

Current Trends in Genetics of Pheochromocytoma 37

gene and its protein [435] result in activation of Ras followed by cellular proliferation [436]. Similar mutations introduced into the NF-1 gene in mice lead to pheochromocytoma, which is otherwise rare in these animals [437]. About 50% of all cases of NF1 are sporadic and represent de novo mutations, most likely a result of paternal germ cell mutations [438]. The NF-1 gene is very large consisting of 51 exons [439]. Therefore, although genetic testing for mutations of NF-1 gene is available, the diagnosis is usually made based on specific clinical presentation [425]. Pheochromocytoma in patients with NF1 is rarely seen in children since it usually occurs at a later age (around 50 years). Only 10% of NF1 patients are diagnosed with bilateral and multifocal pheochromocytomas and less than 6% of patients have metastatic pheochromocytoma [434]. The incidence of pheochromocytomas in NF-1 is relatively low compared to other hereditary syndromes and routine screening of such patients is not generally recommended. However, if a patient with NF-1 has hypertension, then a pheochromocytoma should be considered and excluded [431]. Thus, screening for pheochromocytoma on a yearly basis is recommended for any NF1 patient with hypertension or if any other suggestive symptoms of catecholamine excess are present [368, 425, 428]. Since NF-1-related pheochromocytomas produce metanephrine and normetanephrine levels both norepinephrine and epinephrine, diagnosis is based on findings of elevated plasma or urine. The algorithm for the localization of NF-1-related pheochromocytomas is the same as for other adrenal pheochromocytomas.

5.4 Succinate Dehydrogenase Gene Related Pheochromocytoma Recently, pheochromocytoma susceptibility has been associated with germline mutations of the succinate dehydrogenase gene family (SDH) [440–443, 444, 445]. There are four SDH genes. The SDHD gene (paraganglioma 1 gene) is located on chromosome 11q23 and encodes a small subunit of cytochrome b. The SDHB gene (paraganglioma 4 gene) is located on chromosome 1p35 and its product is iron–sulfur protein. The SDHC gene (paraganglioma 3 gene) is located on chromosome 1q23 and encodes a large subunit of cytochrome b. The SDHA gene is located on chromosome 5p15 and encodes a flavoprotein. The iron–sulfur protein and flavoprotein are anchored to the mitochondrial inner membrane. The SDH genes encode the four subunits of mitochondrial complex II linked to the electron transport chain and the Krebs cycle. Specifically, complex II catalyzes oxidation of succinate to fumarate (SDH) and transfers released electrons via flavin adenine dinucleotide and iron–sulfur clusters of SDHB to ubiquinone (coenzyme Q ) [425, 443, 446]. Coenzyme Q interacts with cytochrome b to allow transferring electrons between mitochondrial complexes I/II to mitochondrial complex III. Thus, dysfunction of the mitochondrial complex II results in malfunction of the oxygen sensory apparatus followed by the continuous activation of hypoxia pathways (so-called oxygensensing hypothesis) [443, 446–448]. Since mitochondria are involved in

38 Chapter 5

apoptosis by releasing toxic proteins that participate in caspase activation, it has been proposed that SDH mutations cause inhibition of apoptosis resulting in pheochromocytoma formation (so-called apoptosis hypothesis) [443, 446, 449]. Mutations of 3 of the 4 SDH genes are associated with the presence of familial and non-familial extra-adrenal and rarely adrenal pheochromocytomas (SDHB, SDHD) and parasympathetic paragangliomas (SDHB, SDHC, SDHD) [25, 26, 28, 29, 34, 447, 450–452]. Frameshift, missense, and nonsense mutations have been identified for variants in the SDH gene family. In recent studies it has been found that about 4–12% of sporadic pheochromocytomas [34, 449] have either SDHD or SDHB mutations. None of patients included in these studies had SDHC mutations. Recently, large germline deletions of mitochondrial complex II subunits SDHB and SDHD have been described as well [453]. Currently, there is a strong association of SDHD and SDHB mutations with the presence of extra-adrenal multifocal pheochromocytomas [425, 442, 450]. Furthermore, SDHB mutations are suggested to be associated with metastatic pheochromocytoma, often in younger patients [25, 447, 454]. SDHD mutations follow a paternal transmission (maternal imprinting) [455, 456]. The penetrance of SDH genes is currently unknown but some data suggest some at-risk carriers might remain unaffected [446]. Furthermore, differences among affected subjects in terms of different age of the initial diagnosis, multiple vs solitary tumors, abdominal vs extra-abdominal tumors may reflect various expressivity of SDH genes. Recently, it has been suggested that all patients younger than 50 years with either solitary extra-adrenal or multifocal pheochromocytoma should undergo genetic testing to search for the SDH gene mutations [34, 425]. Preliminary results suggest that these tumors secrete norepinephrine or dopamine [29]. It has also been suggested that these patients have periodic follow-up including yearly measurement of plasma free metanephrines [425]. There are some considerations how to take some measures to prevent the development of SDH-related pheochromocytoma. Whether migration of carriers of SDHX mutations to lower altitudes or supplementation of elemental iron or fumarate could be useful to prevent the development of pheochromocytomas in these patients is unknown [443].

5.5 Genetic Problems in Sporadic and Other Pheochromocytomas Genetic analyses of DNA from sporadic pheochromocytomas have yielded variable results: with up to 20% RET mutations (half MEN-2A and half MEN-2B) in some series and up to 20% VHL mutations in others [350, 417, 457]. In another study, 45% of sporadic adrenal pheochromocytomas had loss of heterozygosity at the VHL gene locus, but no genetic abnormalities were found in sporadic extra-adrenal pheochromocytomas [458]. Using comparative genomic hybridization various chromosomal losses and gains were described and suggested to be involved in the pathogenesis of sporadic and malignant pheochromocytoma [364, 458–463]. In the study of

Current Trends in Genetics of Pheochromocytoma 39

Dannenberg et al. [459] the most frequently observed changes in sporadic pheochromocytomas, were losses in the chromosomes 1p11–p32 (86%), 3q (54%), 6q (35%), 3p, 17p (31% each), 11q (28%) regions, and gains of chromosomes 9q (38%) and 17q (31%) regions. No differences were identified between adrenal and extra-adrenal pheochromocytomas. Malignancy was strongly associated with deletions of chromosomes 6q (60% vs 21% of benign tumors) and 17p (50% vs 21%). It has been suggested that tumor suppressor genes on chromosomes 1p and 3q could be involved in early tumorigenesis, and deletions of chromosomes 6q and 17p in progression to malignancy [459, 464]. The analysis of adrenal and extra-adrenal abdominal pheochromocytomas revealed significantly more frequent 11cen–q13 gain in malignant tumors [464, 465]. Gain of 11q13 was previously found to be associated with metastatic behavior of various tumors [466] perhaps reflecting higher malignant potential of extra-adrenal vs adrenal abdominal pheochromocytomas. Recently, loss of 8p22/23 was found in 62% of pheochromocytomas including all malignant cases, suggesting that this region contains candidate genes involved in pathogenesis of the tumor [464]. Finally, loss of the chromosome 11p14/15 containing IGF2 gene was suggested to be involved in the pathogenesis of VHL-related pheochromocytoma [467]. However, the main drawback of comparative genomic hybridization, the relatively low resolution, will be overcome by the advent of genome-wide and chromosome arm-specific DNA microarrays, which offer much higher resolution and can pinpoint chromosomal areas of interest for further detailed studies. Recently, the involvement of metastasis suppressor genes in the pathogenesis of malignant pheochromocytoma has been introduced by Ohta et al. [468]. In that study, 11 metastasis suppressor genes were studied and 6 of them (nm23-H1, TIMP-4, BRMS-1, TXNIP, CRSP-3, and E-Cad ) were found to be significantly down-regulated. The four genes (nm23-H1, TIMP-4, CRSP-3, and E-Cad) with the best P-value were used to define a rule of classifying pheochromocytomas either benign or malignant. A non-linear rule using median malignant value as a threshold was used to distinguish malignant from benign samples. The sample was classified as malignant when at least one of mRNA levels of these four genes was below the median malignant value threshold. Samples were classified as benign if the expression level of all 4 genes was above the median malignant valve. No malignant tumors, but 12% of benign tumors were misclassified. In the clinical situation this translates into reasonable sensitivity, but suboptimal specificity. Pheochromocytoma may also occur as part of Carney’s triad, that is, gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal pheochromocytoma [469]. The syndrome is very rare; less than 30 cases have been reported, and only 25% of patients manifest all three parts of the triad. It occurs sporadically and is clearly non-familial [470]. The panel of experts at the 1st International Symposium on Pheochromocytoma agreed that although there is now a reasonable argument for more widespread genetic testing, it is neither appropriate nor currently costeffective to test every disease-causing gene in every patient with a pheochromocytoma or paraganglioma [86]. The decision on which genes to test requires careful consideration of numerous factors. First, a detailed medical

40 Chapter 5

and family history may be particularly important; in the absence of family history of pheochromocytoma or paraganglioma, descriptions of sudden death due to incompletely explained cardiovascular events in family members may suggest an increased likelihood of hereditary tumor. Typical clinical manifestations that are part of a syndrome that includes the presence of pheochromocytoma or paraganglioma in patients or other family members might also point to a particular disease-causing gene. Findings that at least 36% of pheochromocytomas or paragangliomas in children occur secondary to germline mutations underscore the potential importance of genetic testing in pediatric patients with these tumors [471]. Young adults with apparently sporadic tumors are likely to harbor occult germline mutations more often than elderly patients with these tumors; however, advanced age at presentation does not preclude familial disease. Tumor location, the presence of metastases, and the type of catecholamine produced by tumors represent important information in choosing an appropriate genetic test. For example, testing for SDHD and SDHB gene mutations in patients with extra-adrenal tumors can particularly be revealing; furthermore, because SDHB mutations carry a high risk for malignant disease, testing for such mutations in patients with metastases, especially from an extra-adrenal paraganglioma, is particularly warranted [25, 28, 29, 451, 452]. In contrast to the above situations, malignant disease and extra-adrenal tumors are rare in MEN-2 so that testing for RET mutations is unlikely to be rewarding.

CH APTE R 6

Catecholamines and adrenergic receptors

Pheochromocytomas are neuroendocrine tumors arising from chromaffin cells and characterized by excessive production of catecholamines. Diagnosis of these tumors therefore depends critically on several biochemical tests involving measurements of plasma and urinary catecholamines or catecholamine metabolites. All these tests have limitations and some have different utilities or are better than others for confirming or excluding pheochromocytoma. Understanding the utility and limitations of biochemical tests for diagnosis of pheochromocytoma and interpretation of test results can benefit from an understanding of catecholamine release and metabolism. This is not restricted to knowledge of the sources of catecholamines and the pathways of their metabolism, but more importantly requires an appreciation of how catecholamines are metabolized before and after entry into the bloodstream and among different cells and tissues, including sympathetic neurons and chromaffin cells. Also important to interpretation of biochemical test results is an understanding of how catecholamines are released, metabolized, and eliminated from the body in disorders or disease states where differential diagnosis of pheochromocytoma is difficult. Potential confounding influences of medications that affect the disposition of catecholamines are other variables that often require consideration during interpretation of biochemical test results.

6.1

Synthesis and Sources of Catecholamines

The rate-limiting step in catecholamine biosynthesis involves conversion of tyrosine to 3,4-dihydroxyphenylalanine (L-dopa) by the enzyme, tyrosine hydroxylase (Figure 6.1) [472]. Sources of catecholamines are therefore principally dependent on the presence of this enzyme, which is largely confined to dopaminergic and noradrenergic neurons of the central nervous system (CNS), and to sympathetic nerves and adrenal and extra-adrenal chromaffin cells in the periphery. Other sites of catecholamine synthesis include certain non-neuronal cells of the gastrointestinal tract and kidneys. Tyrosine hydroxylase belongs to a small family of monooxygenases, that additionally include tryptophan hydroxylase and phenylalanine hydroxylase, all these enzymes require tetrahydrobiopterin as a substrate to drive the 41

42 Chapter 6 NH2 HO COOH

L-Tyrosine

Chromaffin cell cytoplasm TH HO

NH2

HO

COOH

L-DOPA

L-AADC

HO

NH2

HO

Dopamine

Norepinephrine chromaffin granule DBH HO

OH

NH2

Norepinephrine

HO

Epinephrine chromaffin granule PNMT HO

OH N

HO

H CH3

Epinephrine

Figure 6.1 The catecholamine biosynthetic pathway in an adrenal chromaffin cell. TH: tyrosine hydroxylase; L-AADC: L-aromatic amino acid decarboxylase; DBH: dopamine β-hydroxylase; PNMT: phenylethanolamine N-methyltransferase.

hydroxylation reaction [473]. Conversion of L-dopa to dopamine is catalyzed by aromatic-L-amino acid decarboxylase, an enzyme with a wide tissue distribution and broad substrate specificity for aromatic amino acids. The enzyme requires pyridoxal-5-phosphate as a cofactor. The dopamine formed in the cytoplasm by aromatic-L-amino acid decarboxylase is transported into vesicular storage granules where the amine is available for exocytotic release as the principal neurotransmitter of CNS dopaminergic neurons. The dopamine formed in noradrenergic neurons and adrenal chromaffin cells is further converted to norepinephrine by dopamine β-hydroxylase, a copper-containing enzyme that requires molecular oxygen and ascorbic acid for activity. The enzyme has a unique presence in vesicular storage granules,

Catecholamines and Adrenergic Receptors 43

either bound to the vesicular membrane or present in the soluble matrix core. The noradrenergic neurochemical phenotype of central noradrenergic neurons and peripheral sympathetic nerves depends on both translocation of dopamine into storage granules and the presence of dopamine β-hydroxylase. The additional presence of phenylethanolamine N-methyltransferase (PNMT) in adrenal medullary chromaffin cells leads to further conversion of norepinephrine to epinephrine. Since PNMT is a cytosolic enzyme, this step depends on leakage of norepinephrine from vesicular storage granules into the cell cytoplasm and the transfer of a methyl group from S-adenosylmethionine to norepinephrine, thereby forming epinephrine. Epinephrine is then translocated into chromaffin granules where the amine is stored awaiting release. Conversion of tyrosine to L-dopa by tyrosine hydroxylase represents a pivotal point for regulating synthesis and maintaining stores of catecholamines in response to changes in catecholamine turnover associated with variations in exocytotic release. Rapid activation of tyrosine hydroxylase is achieved by phosphorylation of serine residues at the regulatory domain, under the control of multiple Ca2
- and cAMP-dependent pathways influenced by changes in nerve activity and actions of peptides and other coactivators [474, 475]. Feedback inhibition by catecholamines provides a further mechanism for short-term regulation of enzyme activity. Long-term regulation involves induction of synthesis of the enzyme at the transcriptional level.

6.2 Synthesis of Catecholamines in Pheochromocytoma Although all pheochromocytomas produce catecholamines, they show considerable variation in catecholamine content, depending on expression of biosynthetic enzymes [476–480]. Most pheochromocytomas produce predominantly norepinephrine, many produce both norepinephrine and epinephrine, and more rarely others produce predominantly epinephrine. Dopamine, which is usually efficiently converted to norepinephrine, is therefore a minor component. However, some cases of paragangliomas have been identified that produce mainly dopamine [481–483]. Activities of tyrosine hydroxylase, L-aromatic amino acid decarboxylase, and dopamine β-hydroxylase are generally higher in pheochromocytoma than normal adrenal medullary tissue, which may account for catecholamine overproduction in these tumors [484–486]. Among different pheochromocytomas, activities of tyrosine hydroxylase are high in tumors from patients with multiple neoplasia type 2 and low in those from von Hippel–Lindau patients or patients with non-functional tumors (Figure 6.2) [479, 480]. Tumors from the former patients have high contents of catecholamines and those from the latter patients low contents. The above differences not only influence the clinical presentation of patients with pheochromocytoma, but also biochemical test results. Differences in PNMT expression and epinephrine production among tumors also contribute to variations in presenting symptoms [487]. Patients with epinephrine-secreting pheochromocytomas often show episodic symptoms

44 Chapter 6 VHL

MEN-2

1 2 3 4 5 6 1 2 3 4 5 6

kDa 208

∗

110 40

49

(a) MEN-2

VHL

1 2 3 4 5 6 1 2 3 4 5 6

kDa 49 35 23

Tumor catecholamines (µmol/g)

79

Epinephrine

∗

30

20

10

0

(c)

Norepinephrine

VHL

MEN-2

(b) Figure 6.2 Western blots showing expression of tyrosine hydroxylase (a) and phenylethanolamine N-methyltransferase (b) in pheochromocytomas from patients with von Hippel–Lindau (VHL) syndrome compared to tumors from patients with multiple endocrine neoplasia type 2 (MEN-2). The resulting differences in tumor contents of norepinephrine and epinephrine are shown in panel (c).

with palpitations, anxiety, hyperglycemia, and pulmonary edema presenting more frequently than in patients with tumors that secrete mainly norepinephrine [125, 477, 487, 488]. Expression of PNMT is controlled by glucocorticoid receptor-mediated mechanisms, acting in concert with several transcription factors [489, 490]. Local availability of steroids may explain why adrenal pheochromocytomas often produce epinephrine, whereas extra-adrenal tumors typically lack PNMT and produce predominantly norepinephrine [478]. Pheochromocytomas in von Hippel–Lindau syndrome produce almost exclusively norepinephrine, regardless of location, whereas those in patients with multiple endocrine neoplasia type 2 produce norepinephrine and significant quantities of epinephrine (Figure 6.2) [386, 387, 491, 492, 493]. Pheochromocytomas in the two hereditary syndromes can therefore be distinguished by the pattern of catecholamine metabolites in plasma or urine [386, 387]. Whether different tumor phenotypes reflect mutation-dependent differences in expression of genes or development from different types of chromaffin cells is not established. In metastatic pheochromocytoma, for example, the tumors often have a primitive phenotype that may reflect either loss of expression of genes (i.e. dedifferentiation) or development from chromaffin cells arrested at an early stage of development. Norepinephrine is usually the predominant catecholamine produced [293, 494], but more importantly metastatic pheochromocytomas are often characterized by high tissue, plasma and urinary levels of (dihydroxyphenylalanine (L-dopa)) and dopamine [89, 482, 495–497]. Elevations in plasma or urinary L-dopa and dopamine are not in themselves particularly sensitive or specific markers of benign or metastatic pheochromocytoma. However, when accompanied by elevations in plasma

Catecholamines and Adrenergic Receptors 45

norepinephrine or other clinical evidence of pheochromocytoma, such elevations should arouse immediate suspicion of metastatic disease.

6.3 Storage and Release of Catecholamines by the Sympathoadrenal System Storage of catecholamines in vesicular granules is facilitated by two vesicular monoamine transporters, VMAT-1 and VMAT-2, both of which are expressed in adrenal chromaffin cells, but only VMAT-2 in sympathetic neurons [498]. Both VMAT-1 and VMAT-2 have a wide specificity for different monoamine substrates. The driving force for vesicular monoamine transport is provided by an ATPdependent vesicular membrane proton pump that maintains an H
electrochemical gradient between cytoplasm and granule matrix [499]. Disruption of this gradient in situations of energy depletion and lowered intracellular pH, such as occurs with ischemia, anoxia, or cyanide poisoning, result in a rapid and massive loss of monoamines from storage vesicles into the neuronal cytoplasm. Contrary to usual depictions, vesicular stores of catecholamines do not exist in a static state simply waiting for a signal for exocytotic release. Rather, vesicular stores of monoamines exist in a highly dynamic equilibrium with the surrounding cytoplasm, with passive outward leakage of monoamines into the cytoplasm counterbalanced by inward active transport under the control of vesicular monoamine transporters (Figure 6.3). The magnitude and highly dynamic nature of this process can be appreciated by consideration of the effects of the drug, reserpine, which blocks the ability of vesicular monoamine transporters to move monoamines from the cytoplasm into vesicles. Leakage of monoamines from vesicles is then no longer counterbalanced by vesicular translocation and stores of monoamines are rapidly depleted. Monoamines share the acid environment of the storage granule matrix with ATP, peptides, and proteins, the most well known of which are the chromogranins [500]. The chromogranins are ubiquitous components of

Synthesis

MAO Leakage

Loss due to intraneuronal deamination

Release

Sequestration Reuptake

Loss due to extraneuronal metabolism or escape to blood

Figure 6.3 Model of a sympathetic nerve varicosity illustrating the dynamic nature of vesicular-axoplasmic exchange of transmitter and the contribution of this to catecholamine turnover. Loss of transmitter due to intraneuronal deamination by monoamine oxidase (MAO) makes a much larger contribution to turnover than loss due to extraneuronal metabolism or escape into the bloodstream, and is primarily driven under baseline conditions by leakage of transmitter from storage vesicles.

46 Chapter 6

secretory vesicles and their widespread presence among endocrine tissues has led to their measurement in plasma as useful, albeit relatively non-specific markers of neuroendocrine tumors, including pheochromocytomas, but most importantly, carcinoid tumors [501]. Catecholamines are stored in different types of vesicular granules that vary in size and types of protein and peptide components, the specific functions of which are incompletely understood. In the adrenal medulla there are two populations of chromaffin cells with morphologically distinct vesicles that preferentially store either norepinephrine or epinephrine and which release the two catecholamines differentially in response to different stimuli [502]. In sympathetic nerves there are large and small dense-core vesicles, the latter believed to be formed by retrieval of membranes of large dense-core vesicles after exocytosis [503]. This may occur as part of the process of synaptic vesicle recycling, where endocytosis and refilling of vesicles with neurotransmitter follows exocytosis. The process of exocytosis occurs at specialized locations on nerve endings or sympathetic varicosities dictated by the cell-surface expression of specialized docking proteins that interact with other proteins on the surface of secretory vesicles [504]. The process is stimulated by an influx of Ca2
, which in neurons is primarily controlled by nerve impulse-mediated membrane depolarization, and in adrenal medullary cells by acetylcholine release from innervating splanchnic nerves. The wide range of voltage-, receptor-, G-protein-, and second messenger-operated Ca2
channels provides numerous points for regulation of Ca2
-triggered exocytosis. In this way a variety of peptides, neurotransmitters, and humoral factors provide additional mechanisms for stimulation of exocytosis or may act to modulate nerve impulse-stimulated release of monoamines. Dopamine and norepinephrine also modulate their own release through occupation of autoreceptors. The mechanisms regulating monoamine release are closely coordinated to also regulate the enzymes responsible for synthesis of the released monoamines, thereby ensuring that there is appropriate replenishment of the amines lost due to exocytosis [505]. Neuronal release of catecholamines may also occur by calcium-independent non-exocytotic processes involving increased loss of monoamines from storage vesicles into the cytoplasm and reversal of the normal inward carrier-mediated transport to outward transport of monoamines into the extracellular environment. Examples of this process include the release of catecholamines induced by tyramine and amphetamine. Excessive release of catecholamines that accompanies hypoxic ischemia in part occurs by a similar mechanism.

6.4 Uptake and Metabolism of Catecholamines Produced by the Sympathoadrenal System Since the enzymes responsible for metabolism of catecholamines have intracellular locations the primary mechanism limiting the lifespan of catecholamines in the extracellular space is uptake by active transport, not metabolism by enzymes [422]. Uptake is facilitated by transporters that

Catecholamines and Adrenergic Receptors 47

belong to two large families of proteins with mainly neuronal or extraneuronal locations. Neuronal uptake of catecholamines involves the dopamine transporter at dopaminergic neurons, and the norepinephrine transporter at noradrenergic neurons. These same transporters are also present at some non-neuronal locations, including adrenal chromaffin cells, endothelial cells of the lungs, and specialized cells of the gastrointestinal tract. However, most uptake of catecholamines at non-neuronal locations is facilitated by a second set of proteins belonging to the organic cation transporter family. These latter transporters are expressed exclusively at extraneuronal locations and act on a broader range of substrates than the plasma membrane monoamine transporters expressed at neuronal locations. The neuronal monoamine transporters provide the principal mechanism for rapid termination of the signal in neuronal transmission, whereas the transporters at extraneuronal locations are more important for limiting the spread of the signal and for clearance of catecholamines from the bloodstream. For the norepinephrine released by sympathetic nerves about 90% is removed back into nerves by neuronal uptake, 5% is removed by extraneuronal uptake, and 5% escapes these processes to enter the bloodstream (Figure 6.4). In contrast, for the epinephrine released directly into the bloodstream from the adrenals about 90% is removed by extraneuronal monoamine transport processes, particularly important in the liver. The presence of these highly active transport processes means that monoamines are rapidly cleared from the bloodstream with a circulatory half-life of less than 2 minutes. In addition to terminating the actions of released monoamines, the plasma membrane monoamine transporters present at neuronal locations

2540 (87%)

2870

Sympathetic varicosity Extraneuronal cell

138 (5%)

Bloodstream

228

(8%)

Figure 6.4 Model showing the relative amounts of norepinephrine released by the sympathetic nervous system that are removed by neuronal and extraneuronal uptake. Values show the relative rates of each process and the proportions (values in parentheses) of neuronal released norepinephrine removed by neuronal and extraneuronal uptake and the amount that escapes these processes to diffuse into the circulation.

48 Chapter 6

function in sequence with vesicular monoamine transporters to recycle catecholamines for re-release. In this way, most of the norepinephrine released and recaptured by sympathetic nerves is sequestered back into storage vesicles, thereby substantially reducing the requirements for synthesis of new transmitter. Plasma membrane monoamine transporters also function as part of metabolizing systems, requiring the additional actions of enzymes for irreversible inactivation of the released amines. For both neuronal and extraneuronal metabolizing systems, inactivation of catecholamines occurs in a series arrangement with uptake followed by metabolism. Metabolism of catecholamines occurs by a multiplicity of pathways catalyzed by an array of enzymes resulting in a wide variety of metabolites (Figure 6.5) [506]. Deamination of catecholamines by monoamine oxidase (MAO) yields reactive aldehyde intermediate metabolites that are further metabolized to either deaminated acids by aldehyde dehydrogenase, or to deaminated alcohols by aldehyde or aldose reductase. The aldehyde intermediate formed from dopamine is a good substrate for aldehyde dehydrogenase, but not aldehyde or aldose reductase. In contrast, the aldehyde intermediates formed from the β-hydroxylated catecholamines, norepinephrine and epinephrine, are good substrates for aldehyde or aldose reductase, but poor substrates for aldehyde dehydrogenase. Therefore, norepinephrine and epinephrine are both preferentially deaminated to 3,4-dihydroxyphenylglycol (DHPG), the alcohol metabolite. Deamination to the deaminated acid metabolite, 3,4-dihydroxymandelic acid (DHMA), is not a favored pathway. Catechol-O-methyltransferase (COMT) is responsible for the second major pathway of catecholamine metabolism, catalyzing O-methylation of dopamine to methoxytyramine, norepinephrine to normetanephrine, and epinephrine to metanephrine. COMT is not present in monoamine-producing neurons, which contain exclusively MAO, but is present along with MAO in most extraneuronal tissues. The membrane-bound isoform of COMT, which has high affinity for catecholamines, is especially abundant in adrenal chromaffin cells. As a result of the above and other differences in the expression of metabolizing enzymes, catecholamines produced at neuronal and adrenal medullary locations follow different neuronal and extraneuronal pathways of metabolism (Figure 6.6). Neuronal pathways are quantitatively far more important than extraneuronal pathways for metabolism of the catecholamines synthesized at neuronal locations, such as the norepinephrine produced in sympathetic nerves (Figure 6.6). The reasons for this are 2-fold. First, much more norepinephrine released by sympathetic nerves is removed by neuronal uptake than by extraneuronal uptake. Second, under resting conditions much more of the norepinephrine metabolized intraneuronally is derived from transmitter leaking from storage vesicles than from transmitter recaptured after exocytotic release. Thus, most of the norepinephrine produced in the body is metabolized initially to DHPG, mainly from transmitter deaminated intraneuronally after leakage from storage vesicles or after release and reuptake. Most circulating DHPG is derived from sympathetic nerves and much smaller amounts from the brain (5%) and adrenals (7%).

Dopamine HO

Norepinephrine

NH2 MAO AR HO

COMT NH2

MAO HO

HO Methoxytyramine

DOPAC

HO

H3CO C OH

COMT AR ADH H3CO MAO C OH HO MOPET H H

C AD O OH

AD COMT H3CO

AD C

HO HVA

ADH

O

OH

AR HO

OH NH2

MAO

HO Normetanephrine HO HO

AD OH C

ADH

MAO OH

H3CO

DHPGH H AR H

COMT OH

DHMAO OH

COMT OH H N CH3

Metanephrine MAO

AR C-OH

MAO HO

AD

AR

C OH HO

HO

MAO

OH H N CH3

MHPGH H ADH

AD COMT H CO 3

OH

AD

C

HO O VMA

MAO

AD

OH

Figure 6.5 Pathways of metabolism of catecholamines. Enzymes responsible for each pathway are shown at the head of arrows. Solid arrows indicate the major pathways whereas dotted arrows indicate pathways of negligible importance. Pathways of sulfate conjugation – which are particularly important for metabolism of dopamine, normetanephrine, metanephrine, 3-methoxytyramine, and 3-methoxy-4-hydroxyphenylglycol are not shown. DBH: dopamine β-hydroxylase; PNMT, phenylethanolamine N-methyltransferase; MAO, monoamine oxidase; COMT: catechol-O-methyltransferase; AR: aldose or aldehyde reductase; AD: aldehyde dehydrogenase; ADH: alcohol dehydrogenase; DOPET: 3,4-dihydroxyphenylethanol; DOPAC: 3,4dihydroxyphenylacetic acid; DHPG, 3,4-dihydroxyphenylglycol; MOPET: 3-methoxy-4-hydroxyphenylethanol; HVA: homovanillic acid; MHPG: 3-methoxy-4hydroxyphenylglycol; VMA: vanillylmandelic acid.

Catecholamines and Adrenergic Receptors 49

HO

HO PNMT

MAO

COMT

DOPET H H

MAO

AD

HO

OH NH2

HO

HO

H3CO

HO

DBH

Epinephrine

50 Chapter 6

NE

E

Extraneuronal Adrenal tissues chromaffin cells COMT COMT

Sympathetic nerves MAO DHPG

MN

NMN

MN

COMT MAO

MHPG ADH Liver

VMA

SULTIA3

SULTIA3

Gut MHPG-SO4

NMN-SO4 MN-SO4

Circulatory clearance by kidneys

Urinary excretion Figure 6.6 The main pathways for metabolism of the norepinephrine and epinephrine derived from sympathoneuronal or adrenal medullary sources. Deamination in sympathetic nerves (white) is the major pathway of catecholamine metabolism and involves intraneuronal deamination of norepinephrine leaking from storage granules or of norepinephrine recaptured after release by sympathetic nerves. Metabolism in adrenal chromaffin cells (black) involves O-methylation of catecholamines leaking from storage granules into the cytoplasm of adrenal medullary cells. The extraneuronal pathway (gray) is a relatively minor pathway of metabolism of catecholamines released from sympathetic nerves or the adrenal medulla, but is important for further processing of metabolites produced in sympathetic nerves and adrenal chromaffin cells. The free metanephrines produced in extraneuronal tissues or adrenal chromaffin cells are either further metabolized by deamination or sulfate conjugation. NE: norepinephrine; E: epinephrine; MN: metanephrine; NMN: normetanephrine; MHPG: 3-methoxy-4-hydroxyphenylglycol; VMA: vanillylmandelic acid; MHPG-SO4: 3-methoxy-4-hydroxyphenylglycol sulfate; NMN-SO4: normetanephrine sulfate; MN-SO4: metanephrine sulfate; ADH: alcohol dehydrogenase; SULT1A3: phenolsulfotransferase type 1A3.

Catecholamines and Adrenergic Receptors 51

DHPG is further O-methylated by COMT in non-neuronal tissues to 3-methoxy-4-hydroxyphenylglycol (MHPG), a metabolite also produced to a limited extent by deamination of normetanephrine and metanephrine (Figure 6.6). Compared to DHPG, the latter O-methylated metabolites are produced in small amounts, and only at extraneuronal locations, with the single largest source representing adrenal chromaffin cells, accounting for over 90% of circulating metanephrine and 24–40% of circulating normetanephrine [507]. Within the adrenals, normetanephrine and metanephrine are produced similar to DHPG in sympathetic nerves, from norepinephrine and epinephrine leaking from storage granules into the chromaffin cell cytoplasm. The MHPG produced from DHPG and metanephrines is either conjugated or metabolized to vanillylmandelic acid (VMA) by the sequential actions of alcohol dehydrogenase and aldehyde dehydrogenase. The former enzyme is localized largely to the liver. Thus, at least 90% of the VMA formed in the body is produced in the liver, mainly from hepatic uptake and metabolism of circulating DHPG and MHPG [508]. In contrast to production of VMA, production of homovanillic acid (HVA) from dopamine depends mainly on O-methylation of the deaminated metabolite of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and to a lesser extent on deamination of methoxytyramine, the O-methylated metabolite of dopamine. As a result HVA is formed in multiple tissues, with about 30% of circulating and urinary HVA arising from mesenteric organs and up to 20% from the brain. With the exception of VMA, all the catecholamines and their metabolites are metabolized to sulfate conjugates by a specific sulfotransferase isoenzyme (phenolsulfotransferase type 1A3, SULT1A3). In humans, a single amino acid substitution confers the enzyme with particularly high affinity for dopamine and the O-methylated metabolites of catecholamines, including normetanephrine, metanephrine, and methoxytyramine. The SULT1A3 isoenzyme is found in high concentrations in gastrointestinal tissues, which therefore represent a major source of sulfate conjugates. In humans, VMA and the sulfate and glucuronide conjugates of MHPG represent the main end-products of norepinephrine and epinephrine metabolism. HVA and the conjugates of HVA are the main metabolic end-products of dopamine metabolism. These end-products and the other conjugates are eliminated mainly by urinary excretion. As a result, their circulatory clearance is slow and plasma concentrations high relative to those of the precursor amines.

6.5 Catecholamine Metabolism in Hepatomesenteric Organs The unique and substantial contributions of hepatomesenteric organs to the total body production and metabolism of catecholamines have important implications for interpretation of biochemical tests used to diagnose pheochromocytoma. Mesenteric organs, including the gastrointestinal tract, spleen, and pancreas, are responsible for about half of all the dopamine and norepinephrine produced in the body [508–510]. Concentrations of dopamine, norepinephrine,

52 Chapter 6

and their deaminated and O-methylated metabolites are therefore much higher in the portal venous outflow than in the arterial inflow of mesenteric organs. Importantly, however, most of the catecholamines and their metabolites produced by mesenteric organs and other tissues of the body are efficiently extracted by the liver (Figure 6.7) [508, 509]. The liver therefore makes a substantial contribution to the circulatory clearance of not only catecholamines, but also the metanephrines and the deaminated catecholamine metabolites, DHPG, DOPAC, and MHPG. In humans, the pattern of catecholamine metabolites produced by hepatomesenteric organs is additionally influenced by localization to the liver of alcohol dehydrogenase [511] and to the gastrointestinal tract of monoamine-preferring sulfotransferase [512]. Alcohol dehydrogenase is important in catecholamine metabolism for converting MHPG to VMA [511, 513, 514]. VMA is produced almost exclusively in the liver from the intrahepatic metabolism of norepinephrine, epinephrine, normetanephrine, metanephrine, DHPG, and MHPG extracted from the circulation (Figure 6.7) [508]. In humans, VMA is therefore the major end-product of norepinephrine and epinephrine metabolism. The substantial production of VMA from circulating DHPG and MHPG, most of which is derived from neuronal norepinephrine metabolism, explains why VMA is a relatively insensitive marker for pheochromocytoma compared with the catecholamines and metanephrines [38, 387, 515]. SULT1A3 is the sulfotransferase isoenzyme responsible for sulfate conjugation of monoamines [516]. The enzyme prefers catechols to phenols, and although it can sulfate all three endogenous catecholamines, dopamine represents a particularly good substrate [517]. Given the substantial production of dopamine in gastrointestinal tissues, the presence of SULT1A3 in these tissues is teleologically appropriate. The enzyme therefore provides a major pathway for metabolism of gastrointestinal dopamine, so that the substantial quantities of dopamine sulfate present in plasma and urine are almost exclusively derived from the gastrointestinal tract [518]. In addition to sulfation of catecholamines, SULT1A3 also utilizes various catecholamine metabolites as substrates (Figure 6.7). MHPG is extensively sulfate conjugated within the gastrointestinal tract from the substantial amount of norepinephrine produced and metabolized within these tissues [508]. The metanephrines (normetanephrine, metanephrine, and methoxytyramine) are particularly good substrates of SULT1A3. Although most metanephrine sulfate is derived from circulating free metanephrine produced originally in adrenal chromaffin cells, this is not the situation for normetanephrine sulfate. Analogous to production of MHPG sulfate, substantial quantities of normetanephrine sulfate are derived from the norepinephrine produced and metabolized to normetanephrine locally in the gastrointestinal tract and other extra-adrenal sites. Thus, in patients with pheochromocytoma, percent increases above normal in plasma concentrations of total (sulfate-conjugated plus free) normetanephrine are lower than percent increases in free normetanephrine [519]. These findings imply that plasma concentrations of free normetanephrine may provide a more sensitive marker of pheochromocytoma than plasma concentrations of total normetanephrine.

Catecholamines and Adrenergic Receptors 53 Sympathetic nerves

Bloodstream

MAO

DHPG

NE Adrenal medulla NE NE

NE EPI

NE

NE

EPI

EPI

EPI

COMT COMT MN NMN MAO

MN

MN

NMN

NMN MAO

MHPG Extraneuronal tissues

NE

SULT1A3

DHPG MHPG NMN

Mesenteric organs Substantial production of NE in sympathetic nerves and local metabolism, including sulfate conjugation by SULT1A3

Hepatic extraction of MHPG, DHPG, NE, EPI, NMN, MN and conversion to VMA Liver VMA Sulfate conjugates Elimination by kidneys VMA

Urine MHPG-SO4 NMN-SO4 MN-SO4

Relative amounts excreted

NE

EPI

Figure 6.7 The regional pathways of norepinephrine and epinephrine metabolism. Most norepinephrine is released and metabolized within sympathetic nerves, including up to a half produced in sympathetic nerves of mesenteric organs. Sulfate conjugation of catecholamines and catecholamine metabolites, particularly MHPG, occurs mainly in mesenteric organs, whereas production of VMA occurs mainly in the liver. NE: norepinephrine; EPI: epinephrine; NMN: normetanephrine; MN: metanephrine; NMN-SO4: normetanephrine sulfate; MN-SO4: metanephrine sulfate; MHPG-SO4: 3-methoxy-4-hydroxyphenylglycol sulfate, DHPG: 3,4-dihydroxyphenylglycol, VMA: vanillylmandelic acid, COMT: catechol-O-methyltransferase, MAO: monoamine oxidase.

54 Chapter 6

Importantly, rather than metabolism of endogenous catecholamines, the primary function of SULT1A3 is probably conjugation and inactivation of dietary xenobiotics. As shown by substantial increases in plasma concentrations of sulfate-conjugated catecholamines and metabolites after meals, this function includes inactivation of monoamines present in food [512, 520–522]. Thus, the variable contribution of diet to production of sulfate-conjugated metanephrines may contribute to poorer specificity of tests of total (conjugated plus free) than of free metanephrines.

6.6 Catecholamine Metabolism and Release by Pheochromocytoma

LIVER AD MD

PHEO 6

PHEO 5

PHEO 4

PHEO 3

PHEO 2

STD PHEO 1

Unlike sympathetic neurons, where MAO-A is the sole catecholamine metabolizing enzyme, metabolism of catecholamines in adrenal medullary chromaffin and pheochromocytoma tumor cells involves both MAO and COMT [484, 485, 523]. However, unlike most extraneuronal tissues such as the liver, where soluble COMT is the principal isoenzyme, in adrenal medullary chromaffin cells and pheochromocytoma tumor cells, membrane-bound COMT is the principal enzyme (Figure 6.8) [523, 524]. The presence of mainly membrane-bound COMT in chromaffin cells represents an important and teleologically appropriate distinction, since this isoenzyme has a much higher affinity for catecholamines than the soluble form of COMT [525, 526]. The profile of catecholamine metabolites produced by adrenal medullary chromaffin and pheochromocytoma tumor cells therefore importantly includes the O-methylated metabolites, normetanephrine, metanephrine [509, 524, 527, 528]. Although some DHPG is produced by the adrenal medulla, most is O-methylated to MHPG [523]. Since intraneuronal metabolism is the main source of deaminated catecholamine metabolites, the overall contribution of the adrenal medulla to circulating DHPG and MHPG is minor. In contrast, at least 90% of circulating metanephrine and up to 40%

kDa

30 22

MB S

Figure 6.8 Western blot analysis of membrane-bound and soluble forms of COMT in samples from 6 pheochromocytomas (PHEO 1–6), 1 sample of human liver, and 1 sample of normal human adrenal medulla (AD MD). The positions of membrane-bound COMT (MB) and soluble COMT (S) polypeptides are depicted on the right and molecular mass standards on the left. The amount of total protein used was 12 µg for each sample. COMT: catechol-O-methyltransferase.

Catecholamines and Adrenergic Receptors 55

of normetanephrine are formed from epinephrine and norepinephrine within the adrenals [509, 528]. This makes the adrenal medulla the single largest source of both normetanephrine and metanephrine in the body, exceeding the contribution of the liver [509]. Similarly, in patients with pheochromocytoma, over 94% of the elevated plasma concentrations of metanephrines are derived from metabolism of catecholamines by the COMT within pheochromocytoma tumor cells and not by actions of extra-adrenal COMT on catecholamines released into the circulation [524]. This finding agrees with the observations of Crout and Sjoerdsma [476] who concluded that most of the increased levels of catecholamine metabolites in patients with pheochromocytoma were produced within tumors and not after the release of catecholamines from tumors. In patients with pheochromocytoma, percent increments above normal in plasma concentrations of free metanephrines are larger than percent increments in catecholamines [387, 519, 529]. The differences in percent increments and test sensitivities for norepinephrine and normetanephrine are explained in part by the larger 24–40% normal contribution of the adrenals to circulating normetanephrine than the 7% contribution to circulating norepinephrine [509]. To double plasma norepinephrine from normal concentrations (e.g. 50% of the upper reference limit) to the upper reference limit would require 14.3-fold (100/7) more norepinephrine than the adrenals 7% contribution, whereas with a 24% contribution of the adrenals to circulating normetanephrine, only a 4.2-fold (100/24) increase would be necessary to raise normetanephrine to the upper reference limit (Figure 6.9). The above explanation assumes that catecholamines are metabolized and released by pheochromocytoma tumor cells similarly to normal adrenal chromaffin cells. Such an explanation, however, cannot explain findings in patients with pheochromocytoma of larger relative increases in plasma concentrations of free metanephrine than of epinephrine, both of which are derived to similar extents from the adrenal medulla [509]. While catecholamines appear to be metabolized continously in adrenal medullary chromaffin cells and pheochromocytoma tumor cells, a continuos process catecholamine secretion is not [524]. Thus, despite considerably and consistently elevated plasma metanephrines, some patients with pheochromocytoma have entirely normal plasma or urinary catecholamines or show elevations in plasma catecholamines only during paroxysmal attacks (Figure 6.10). Some of these cases may be explained by the presence of so-called non-functional or silent tumors that do not secrete significant amounts of catecholamines, but which nevertheless synthesize and metabolize catecholamines to metanephrines. Other cases may be explained by episodically secreting tumors, that between episodes do not secrete catecholamines but which continuously metabolize catecholamines to metanephrines. The continuous production of metanephrines within normal adrenal medullary or pheochromocytoma tumor cells is explained by the dependence of this process on catecholamines leaking from chromaffin granules into the cell cytoplasm. This process is analogous to the situation mentioned elsewhere in sympathetic nerves (Figure 6.4) and also occurs independently of exocytotic catecholamine release. Thus, during a paroxysmal attack or episodic secretion associated with large increases in catecholamine release from a

56 Chapter 6 Bloodstream Sympathetic nerve Varicosity NE NE

Adrenal medullary chromaffin cell 930

70 NE (1000)

NE

NE

COMT 76 NMN

24

NE COMT

(NMN) (100)

NMN

Extraneuronal cell 1000 NE (2000)

NE

NE

343 NMN (443)

NMN

COMT

Pheochromocytoma tumor cell Figure 6.9 Mathematical explanation for the superior sensitivity of plasmafree normetanephrine (NMN) than norepinephrine (NE) for detection of pheochromocytoma. Values at the head of upper most arrows show the relative amounts of norepinephrine and normetanephrine in the bloodstream that are derived from sympathetic nerves and the adrenal medulla. Values in parentheses show total amounts derived from both sources (upper values) or from the additional contribution of a pheochromocytoma (lower values). Values at the head of lower arrows show relative amounts of norepinephrine and normetanephrine derived from a pheochromocytoma that would be required to double plasma concentrations of norepinephrine, assuming similar proportional production as in adrenal medullary cells. Due to the larger proportion of circulating normetanephrine (24%) than norepinephrine (7%) derived from the adrenal medulla a similar proportional 14.3fold increase in normetanephrine (343/24) and norepinephrine (1000/70) from this source would cause a larger percent increase in plasma normetanephrine than in norepinephrine concentrations (4.4- vs 2-fold). NF: norepinephrine, NMN: normetanephrine, COMT: catechol-O-methyltransferase.

pheochromocytoma, plasma concentrations of metanephrines show only small increases (Figure 6.10). Similarly, tumor manipulation during surgery results in much smaller increases in plasma-free metanephrines than in plasma catecholamines [529].

Catecholamines and Adrenergic Receptors 57 Plasma Normetanephrine Plasma Norepinephrine 4 4 (pmol/ml) (pmol/ml) 3

3

2

2

1

1

0 1

2

3

0

1

2

Day 2

3 Day

Plasma metanephrine (pmol/ml)

2 Plasma epinephrine (pmol/ml)

1

1

0

0 1

2

3 Day

1

2

3 Day

Figure 6.10 Plasma concentrations of metanephrines (left panels) and catecholamines (right panels) over a 3-day period involving repeated blood sampling in a patient with an adrenal pheochromocytoma. Dotted horizontal lines show upper reference limits for each analyte. Plasma concentrations of normetanephrine, and particularly metanephrine, are consistently elevated. In contrast, plasma concentrations of norepinephrine and epinephrine vary widely and are generally within normal limits.

A consequence of the considerable variation in catecholamine release in patients with pheochromocytoma is that plasma concentrations or urinary excretion of catecholamines are poorly correlated with tumor size [476, 524]. In contrast, due to metabolism of catecholamines within tumors and the independence of this process on catecholamine release, urinary excretion or plasma concentrations of metanephrines show strong positive correlations with tumor size (Figure 6.11) [387, 524, 530]. Because of the substantial intra-adrenal production of metanephrines little of these metabolites (6% for metanephrine and 2% for normetanephrine) are formed from metabolism of catecholamines after their release into the circulation [509, 528]. Thus, although intravenous infusion of catecholamines causes much larger proportional increases in plasma concentrations or urinary outputs of metanephrines compared to other metabolites, these increases are small compared to those of plasma and urinary catecholamine [531, 532]. Importantly, the substantial intra-adrenal production of metanephrines means that plasma concentrations of normetanephrine, and particularly metanephrine, are relatively insensitive markers of increased norepinephrine release by nerves or increased epinephrine release from the adrenals. The metabolites show very little response to increases in sympathoadrenal activity associated with increases in plasma catecholamines [524, 528, 529]. Thus, conditions of sympathoadrenal activation, such as may occur in hypernoradrenergic hypertension or other disorders, may be distinguished from

58 Chapter 6 1000

r  0.81, P  0.001

Urinary metanephrines (mol/day)

Plasma free metanephrines (nmol/L)

1000

100

10

1

.1 2

3

4

5

6

7

8

10

9 10 11 12

1000

0

2

(b)

Mean tumor diameter (cm)

100

10

r  0.47, P  0.001 1

4

6

8

10

12

Mean tumor diameter (cm) 100

r  0.52, P  0.001

Urinary catecholamines (mol/day)

1

(a)

Plasma catecholamines (nmol/L)

100

1 0

r  0.54, P  0.001

10

1

r  0.46, P  0.001 0.1

0

(c)

r 0.77, P  0.001

2

4

6

8

Mean tumor diameter (cm)

10

12

0

(d)

2

4

6

8

10

12

Mean tumor diameter (cm)

Figure 6.11 Relationships of tumor diameter with plasma concentrations of free metanephrines (a) or catecholamines (c), and urinary outputs of deconjugated metanephrines (b) or catecholamines (d). Data for plasma or urinary metanephrines and catecholamines are shown using a logarithmic scale and represent summed plasma concentrations or urinary outputs of normetanephrine and metanephrine (a and b) or norepinephrine and epinephrine (c and d). Data for adrenergic tumors (䊉) and noradrenergic tumors (䊊) are shown separately. Multiple linear regression analysis indicated significantly different (P  0.001) relationships of tumor diameter with plasma or urinary catecholamines for patients with noradrenergic (dashed regression lines) and adrenergic tumors (solid regression lines).

pheochromocytoma by proportionately different elevations of plasma catecholamines than metanephrines.

6.7 Kinetics and Elimination of Catecholamines and Their Metabolites The major route of elimination of catecholamines and their metabolites from the body is by urinary excretion. However, as discussed above, the catecholamines and their O-methylated and deaminated metabolites are largely metabolized before renal elimination to sulfate conjugates or to VMA and HVA. These end-products of catecholamine metabolism are more efficiently handled for elimination by the kidneys than the precursor metabolites, and

Catecholamines and Adrenergic Receptors 59

thus represent the main catecholamine metabolites present in urine [533]. The circulatory clearance of VMA, HVA, and the sulfate conjugates is therefore almost exclusively dependent on renal extraction, whereas the clearance of catecholamines and their deaminated and O-methylated metabolites is dependent mainly on uptake and metabolism by other organs and tissues, such as the liver. Due to active uptake by tissues and organs throughout the body, the circulatory clearance of catecholamines is extremely rapid at about 2 liters/minute [534]. Similar to catecholamines, the free metanephrines are also efficiently extracted from the circulation by extraneuronal uptake in tissues and organs throughout the body [509, 535]. Thus, the circulatory clearances and plasma half-lives of free normetanephrine and metanephrine are similar to those of their catecholamine precursors [509, 536]. The deaminated metabolite of norepinephrine and epinephrine, DHPG, freely diffuses across membranes and is also rapidly cleared from the circulation [534, 537]. Similarly, MHPG is efficiently cleared from the circulation, mainly by hepatic extraction, so that the circulatory clearance of this metabolite is also relatively rapid [537]. In contrast to the above, since circulatory clearances of HVA, VMA, and the sulfate conjugates depend exclusively on renal extraction, the plasma half-lives of these metabolites are relatively long and their clearances from the bloodstream slow [538–540]. As a result, plasma concentrations of VMA, HVA, and sulfate conjugates are much higher than those of their precursor metabolites, so that differences in concentrations do not accurately reflect relative rates of production. For example, the 25-fold higher plasma concentrations of metanephrine sulfate than of free metanephrine [528] reflect the much lower plasma clearance of sulfate conjugated than of free metanephrine, not any difference in rates of production of the two metabolites. Since circulatory clearances of VMA, HVA, and sulfate-conjugated catecholamines and metabolites of catecholamines are directly and crucially dependent on renal function, plasma levels of these metabolites are dramatically increased in renal failure [541–545]. In contrast, plasma concentrations of free catecholamines, metanephrines, DHPG, and MHPG are little or only mildly increased in renal failure, dependent on the degree of sympathoadrenal activation [542, 545]. Since the presence of a pheochromocytoma can directly contribute to renal artery stenosis or renal failure [187, 236, 237, 546–548], differential diagnosis of pheochromocytoma in these disorders is important. However, such patients, and particularly those with renal failure, represent a diagnostic challenge [544, 549]. In anuric patients or those on hemodialysis urine collections may be impossible or inappropriate. Even in less severely affected patients impaired renal function may render the results of 24-hour urine testing difficult to interpret [550]. As outlined above, impaired renal function results in dramatic increases in plasma concentrations of VMA and sulfate-conjugated metanephrines, rendering these tests invalid [551, 552]. Moreover, sympathetic overactivity is a feature of both renal failure and renal artery stenosis [553, 554], further complicating interpretation of catecholamine or catecholamine metabolite measurements. Since the circulatory clearance of plasma-free metanephrines is independent of renal function,

60 Chapter 6

measurements of these metabolites in plasma may represent the best test for differential diagnosis of pheochromocytoma in patients with renal failure.

6.8 Pharmacology of Catecholamine Systems: Implications for Pheochromocytoma Administration of catecholamine metabolic precursors and drugs that block catecholamine biosynthetic pathways has several therapeutic uses. Alphamethyl-L-tyrosine or metyrosine (Demser) is an analog of tyrosine that inhibits tyrosine hydroxylase, thereby decreasing catecholamine stores. The drug is used to control high blood pressure in patients with pheochromocytoma, particularly those with extensive metastatic disease, or pre-operatively, in patients with large or highly active tumors. Alpha-methyl-L-dopa (Aldomet) is an analog of L-dopa and a pro-drug that is converted to alpha-methyl-dopamine and alpha-methyl-norepinephrine. The antihypertensive actions of the agent appear to result from CNS-mediated inhibition of sympathetic outflow. L-dopa is used to treat Parkinson’s disease and is usually co-administered with an inhibitor of peripheral L-aromatic amino acid decarboxylase, such as carbidopa or beserazide. The latter agents increase delivery of L-dopa to the CNS, thereby facilitating formation of dopamine at sites of dopaminergic neurodegeneration. All the above agents have potential for significant interference with measurements of catecholamines and catecholamine metabolites in biological fluids. Importantly, patterns of catecholamine metabolites formed by neuronal and extraneuronal pathways can be markedly influenced by certain drugs. Antidepressants are a common problem and the neuronal uptake blocking actions of tricyclics are particularly troublesome to interpretation of biochemical tests for pheochromocytoma. By blocking neuronal reuptake, these drugs not only can increase the amount of norepinephrine escaping into plasma, but can also decrease plasma concentrations of deaminated metabolites, such as DHPG, and increase O-methylated metabolites, such as normetanephrine. Similarly, MAO inhibitors cause a decrease in deaminated metabolites and an increase in O-methylated metabolites [555]. Both tricyclics and MAO inhibitors can also cause blood pressure disturbances. These clinical signs together with accompanying changes in catecholamines and metabolites can lead to a false impression of an underlying pheochromocytoma, a medication-induced pseudopheochromocytoma [556, 557]. Alternatively, in patients with pheochromocytoma these drugs can exacerbate the effects of a tumor or precipitate a potentially dangerous hypertensive crisis [126, 558–563]. Confounding influences of medications should therefore always be considered during the diagnostic work-up of a patient with suspected pheochromocytoma.

6.9 6.9.1

Physiology of Catecholamine Systems Adrenal Medullary Hormonal System

Although often considered a part of the sympathetic nervous system, the adrenal medulla produces and secretes a different catecholamine, epinephrine, with different functions from the norepinephrine secreted by sympathetic

Catecholamines and Adrenergic Receptors 61

nerves. The adrenal medulla and sympathetic nerves are also regulated separately, often in divergent directions in response to different forms of stress. This makes it appropriate to consider both systems separately. The human adrenal medulla produces mainly epinephrine, which as a hormone, is secreted directly into the bloodstream to act on cells distant from sites of release. Both epinephrine and norepinephrine have overlapping but also different effects on α- and β-adrenergic receptors. In particular, epinephrine has more potent effects on β2-adrenoceptors than norepinephrine, while norepinephrine is a more potent β1-adrenoceptor agonist than epinephrine. Epinephrine is also a more potent α-adrenoceptor agonist than norepinephrine. However, the proximity of sites of norepinephrine and epinephrine release to adrenoceptors and resulting concentrations at effector sites are also important determinants of adrenoceptor-mediated responses to the two catecholamines. Due to the above differences, epinephrine exerts its effects on different populations of adrenoceptors than norepinephrine. As a circulating hormone, epinephrine acts potently on β2-adrenergic receptors of the skeletal muscle vasculature causing vasodilation. In contrast, norepinephrine released locally within the vasculature causes α1-adrenoceptor-mediated vasoconstriction. Increases in circulating epinephrine during stress may contribute to skeletal muscle vasodilatory responses, but appear to play little role in other cardiovascular changes, including increases in heart rate. Thus, despite the potent hemodynamic actions of epinephrine, the adrenal medulla appears to play a minimal role in cardiovascular regulation compared to sympathetic nerves. Epinephrine released from the adrenals is more important as a metabolic than as a hemodynamic-regulatory hormone [564]. In particular, epinephrine stimulates lipolysis, ketogenesis, thermogenesis, and glycolysis and raises plasma glucose levels by stimulating glycogenolysis and gluconeogenesis. Epinephrine also has potent effects on pulmonary function, causing β2-adrenoceptor-mediated dilation of airways. Circulating norepinephrine, in minor part derived from the adrenal medulla and functioning as a hormone, may have additional metabolic actions, but appears to have little importance for cardiovascular regulation compared to the higher concentrations of the amine at sympathoneuroeffector sites. Despite the apparent importance of the adrenal medulla in homeostasis, particularly regulation of metabolism, the medulla in contrast to the adrenal cortex is not vital for survival. Studies in adrenalectomized subjects show that both hemodynamic and glucose-counter-regulatory responses to insulin-hypoglycemia, exercise, and other manipulations remain intact despite absence of epinephrine responses [565, 566]. This contrasts with the severe disturbances of blood pressure regulation accompanying loss of sympathetic nerves. Compared to the sympathetic nervous system, the adrenal medulla makes a relatively minor contribution to the overall production and turnover of catecholamines (Table 6.1). However, because PNMT is expressed mainly in adrenal chromaffin cells, over 90% of circulating epinephrine is derived from the adrenal medulla. This contrasts with circulating norepinephrine, over 90% of which is derived from sympathetic nerves.

62 Chapter 6 Table 6.1 Contribution of the adrenals to circulating catecholamines and metabolites Adrenals (pmol/minute)

Total body (pmol/minute)

Adrenal contribution (%)

Catecholamines Epinephrine Norepinephrine Dopamine

979 274 6

1075 3953 290*

91 7 2

Metabolites Metanephrine Normetanephrine DHPG DOPAC

449 91 665 300

494 392 13,964 4120*

91 23 5 7

Values represent rates of release into the bloodstream. *Estimates are those for mesenteric organs only and therefore are underestimates of release into the bloodstream from all tissues of the body (total body).

Apart from catecholamines, adrenal medullary chromaffin cells produce, store, and secrete a wide array of neuropeptides and proteins. Peptides include enkephalins, β-endorphin, neuropeptide Y, substance P, vasoactive intestinal peptide, neurotensin, galanin, atrial natriuretic peptide, pituitary adenylate cyclase-activating peptide, adrenomedullin, and corticotrophin. These peptides are secreted together with the catecholamines and may be involved in local, autocrine, or paracrine regulation of adrenal medullary and cortical function. The major soluble proteins within chromaffin vesicles belong to the family of granins, which consist of several secretory acidic glycoproteins, the major representative being chromogranin A.

6.9.2

Peripheral Dopamine Systems

Dopamine is usually thought of as a neurotransmitter in the brain or as an intermediate in the production of norepinephrine and epinephrine in the periphery. It has been presumed that these sources account for the large amounts of dopamine and dopamine metabolites excreted in urine. The contribution of the brain to circulating levels and urinary excretion of dopamine metabolites is, however, now known to be relatively minor. Also, in sympathetic nerves and the adrenal medulla most dopamine is converted to norepinephrine. Therefore, other sources and functions of dopamine in the periphery must be considered. Emerging evidence suggests the presence of a third peripheral catecholamine system, in which dopamine functions not as a neurotransmitter or circulating hormone, but as an autocrine or paracrine substance [567]. In the kidneys, dopamine is now an established autocrine/paracrine effector substance contributing to the regulation of sodium excretion [568]. Unlike neuronal catecholamine systems, production of dopamine in the kidneys is largely independent of local synthesis of L-dopa by tyrosine hydroxylase. Thus, renal denervation does not affect urinary dopamine excretion. Instead, production of dopamine in the kidneys depends mainly on proximal tubular

Catecholamines and Adrenergic Receptors 63

cell uptake of L-dopa from the circulation. The L-dopa is then converted to dopamine by aromatic amino acid decarboxylase, the activity of which is up-regulated by a high-salt diet and down-regulated by a low-salt diet. The presence of a renal dopamine paracrine/autocrine system explains the considerable amounts of free dopamine excreted in the urine [569]. Most derives from renal uptake and decarboxylation of circulating L-dopa and reflects the plasma levels of this amino acid and the function of the renal dopamine paracrine/autocrine system. Although the kidneys represent the major source of urinary free dopamine, this source does not account for the larger amounts of excreted dopamine metabolites, such as HVA and dopamine sulfate. Findings of large arterial to portal venous increases in plasma concentrations of dopamine and its metabolites have indicated that substantial amounts of dopamine are produced in the gastrointestinal tract and other mesenteric organs [510]. The substantial production and metabolism of dopamine in the human gastrointestinal tract appear to reflect functions of dopamine as an enteric neuromodulator or paracrine/autocrine substance. Dopamine and dopamine receptor agonists stimulate bicarbonate secretion and protect against ulcer formation, whereas dopamine antagonists augment secretion of gastric acid and promote ulcer development [570]. Dopamine also appears to influence gastrointestinal motility, sodium transport, and gastric and intestinal submucosal blood flow. In the pancreas, dopamine may modulate secretion of digestive enzymes and bicarbonate. Morphological studies have demonstrated the presence of cells in the gastrointestinal tract that contain dopamine and express components of dopamine signaling pathways, including catecholamine biosynthetic enzymes and specific dopamine receptors and transporters [571]. In the stomach, tyrosine hydroxylase is expressed in epithelial cells, including acid-secreting parietal cells. In the small intestine, cells of the lamina propria, including immune cells, also express tyrosine hydroxylase. The enzyme is additionally found in pancreatic exocrine cells. The high rates of dopamine production by mesenteric organs cannot be accounted for by local extraction and decarboxylation of circulating L-dopa. Thus, unlike the kidneys, where dopamine is produced mainly from circulating L-dopa, in the gastrointestinal tract, production of dopamine requires the presence of tyrosine hydroxylase or other sources of L-dopa. Consumption of food increases plasma concentrations of L-dopa, dopamine, and dopamine metabolites, particularly dopamine sulfate, indicating that dietary constituents may also represent an important source of peripheral dopamine [512]. Such a source does not, however, account for the substantial amounts of dopamine produced in peripheral tissues outside the digestive tract, or of that produced in digestive tissues of fasting individuals. In particular, plasma concentrations of both L-dopa and dopamine sulfate remain high even after a 3-day fast. It is now clear that dopamine sulfate is mainly produced in the gastrointestinal tract from both dietary and locally synthesized dopamine. This is consistent with findings that the gastrointestinal tract contains high concentrations of the sulfotransferase isoenzyme, SULT1A3. Production of sulfate conjugates in the digestive tract appears to provide an

64 Chapter 6

enzymatic “gut-blood barrier,” for detoxifying dietary biogenic amines and delimiting physiological effects of locally produced dopamine.

6.10

Adrenergic Receptors and Their Functions

It is important to understand the concept of specific receptors to explain different cardiovascular responses to the catecholamines. In 1948 Ahlquist [572] divided adrenergic receptors into α and β types based on the rank order of potency of the various catecholamines in different vascular beds. Subsequent classification into α1, α2, β1, β2, β3, dopamine D1-, and D2-adrenergic receptors has been based on ligand-binding studies and responses to synthetic agonists and antagonists (Table 6.2) [573–576]. α1-adrenergic receptors are postsynaptic and located on effector tissues such as vascular smooth muscle. Stimulation causes vasoconstriction and an increase in blood pressure, while stimulation of other α1-receptors can cause pupillary dilation, intestinal relaxation, and uterine contraction (Table 6.3). The classic α1-agonist is phenylephrine and the classic α1-antagonist is prazosin. α1-adrenergic effects are mediated through the phosphoinositols with increases in cytosolic calcium concentration [577]. Some α2-receptors are located presynaptically and stimulation inhibits norepinephrine secretion, while others on vascular smooth muscle are postsynaptic and extrasynaptic and stimulation causes vasoconstriction (Table 6.3) [578, 579]. Classic α2-agonists include clonidine, methyldopa, and guanabenz. Their central α2-agonist action in the brain suppresses sympathetic outflow and thereby reduces blood pressure, which is the basis for their pharmacologic use. The classic α2-antagonist, yohimbine, leads to increases in plasma norepinephrine, as well as heightened CNS arousal. Alpha2-adrenergic effects are mediated by inhibition of adenylate cyclase and activation of potassium channels [577]. Beta1-adrenergic receptors have more diverse functions and stimulation of those in the heart causes positive inotropic and chronotropic actions, while stimulation of β1-receptors elsewhere causes lipolysis in fat cells, and increased renin secretion in the kidney (Table 6.3). The classic β1-agonist is dobutamine and selective β1-antagonists are metoprolol and atenolol. β2-receptors, when stimulated, cause bronchodilation; vasodilation in some blood vessels, especially those in skeletal muscle; glycogenolysis; uterine and intestinal smooth muscle relaxation; and an increased release of norepinephrine from sympathetic nerves. Typical β2-agonists include metaproterenol, albuterol, terbutaline, and isoetharine. Propranolol, alprenolol, nadolol, and timolol are antagonists at both β1- and β2-adrenergic receptors. Both β1- and β2-adrenergic effects are mediated via activation of adenylate cyclase [573]. While dopamine has weak agonist activity at α- and β-adrenergic receptors, there are also specific dopamine receptors. D1-receptors are found mainly in coronary, renal, mesenteric, and cerebral vascular beds. Stimulation of these receptors causes vasodilation [580, 581]. Stimulation of D1-receptors in the kidney produces diuresis and natriuresis. Low doses of dopamine are often used for this therapeutic goal [582]. As dopamine doses are increased, both β1- and α-receptors are stimulated, causing vasoconstriction and an increase in blood pressure. D2-receptors are presynaptic on sympathetic nerve endings

Table 6.2 Comparison of the effects of intravenous infusion of epinephrine and norepinephrine in humans Agonists

Antagonists

Tissue

Responses

α1

Epi  NE  Iso Phenylephrine

Prazosin

Vascular smooth muscle Genitourinary smooth muscle Liver Intestinal smooth muscle Heart

Contraction Contraction Glycogenolysis; gluconeogenesis Hyperpolarization and relaxation Increased contractile force; arrhythmias

α2

Epi  NE  Iso Clonidine

Yohimbine

Pancreatic islets (β cells) Platelets Nerve terminals Vascular smooth muscle

Decreased insulin secretion Aggregation Decreased release of NE Contraction

β1

Iso  Epi  NE Dobutamine

Metoprolol CGP 20712A

Heart

Increased force and rate of contraction and AV nodal conduction velocity Increased renin secretion

Juxtaglomerular cells β2

β3

Iso  Epi  NE

Iso  NE  Epi BRL 37344

ICI 118551

ICI 118551 CGP 20712A

Epi: epinephrine; NE: norepinephrine; Iso: isoproterenol; AV: atrioventricular. Adapted from Pacak et al. [833].

Smooth muscle (vascular, bronchial, gastrointestinal, and genitourinary) Skeletal muscle Liver

Relaxation Glycogenolysis; uptake of K
Glycogenolysis; gluconeogenesis

Adipose tissue

Lipolysis

Catecholamines and Adrenergic Receptors 65

Receptor

Table 6.3

Adrenergic receptors mediated responses of effector organs

Receptor type*

Responsesa

Responsesa

α1

Contraction (mydriasis)

 Relaxation for far vision


 Contraction (miosis)


Contraction for near vision




Increase in heart rate

Increase in contractility and conduction velocity

Increase in automaticity and conduction velocity


Increase in automaticity and conduction velocity


Increase in contractility, conduction velocity, automaticity, and rate of idioventricular pacemakers




Decrease in heart rate; vagal arrest


Decrease in contractility, shortened AP duration


Decrease in conduction velocity; AV block


Little effect

Constriction
; dilations

Constriction


Constriction

; dilations

Constriction (slight) Constriction
; dilations Constriction


; dilations
Constriction


Constriction


; dilations


Constriction
Dilation Dilation
Dilation Dilation  Dilation



Eye Radial muscle, iris Sphincter muscle, iris Ciliary muscle

β2

Heart SA node Atria

β1, β2 β1, β2

AV node

β1, β2

His-Purkinje system

β1, β2

Ventricles

β1, β2

Arterioles Coronary Skin and mucosa Skeletal muscle Cerebral Pulmonary Abdominal viscera Salivary glands Renal

α1, α2; β2 α1, α2 α; β2 α1 α1; β2 α1; β2 α1, α2 α1, α2; β1, β2

Slight decrease in contractility

(Continued)

Chapter 6

Effector organs

66

Cholinergic impulses

Adrenergic impulses

Table 6.3

(Continued) Cholinergic impulses

Adrenergic impulses Receptor type*

Responsesa

Responsesa

Veins (systemic)

α1, α2; β2

Constriction

; dilations





Lung Tracheal and bronchial muscle Bronchial glands

β2 α1; β2

Relaxation
Decreased secretion; increased secretion

Contraction

Stimulation




α1, α2; β2 β1

Decrease (usually)
Contraction (usually)
Inhibition (?)

Increase

Relaxation (usually)
Stimulation




Intestine Motility and tone Sphincters Secretion

α1, α2; β1, β2 α1 α2

Decrease
Contraction (usually)
Inhibition

Increase


Relaxation (usually)
Stimulation



Gall bladder and ducts

β2

Relaxation


Contraction


Kidney Renin secretion

α1; β1

Decrease
; increase





Urinary bladder Detrusor Trigone and sphincter

β2 α1

Relaxation (usually)
Contraction



Contraction


Relaxation



Ureter Motility and tone

α1

Increase

Increase (?)

Uterus

α1; β2

Pregnant: contraction (α1); relaxation (β2); nonpregnant: relaxation (β2)

Variable

Stomach Motility and tone Sphincters Secretion

Catecholamines and Adrenergic Receptors 67

Effector organs

Ejaculation



Erection




Skin Pilomotor muscles Sweat glands

α1 α1

Contraction

Localized secretion


 Generalized secretion




Spleen capsule

α1; β2

Contraction


; relaxation






Secretion of epinephrine and norepinephrine (primarily nicotinic and secondarily muscarinic) 

Adrenal medulla

Skeletal muscle

β2

Increased contractility; glycogenolysis; K
uptake

Liver

α1; β2

Glycogenolysis and gluconeogenesis




α α2 β2

Decreased secretion
Decreased secretion


Increased secretion


Secretion

 

Pancreas Acini Islets (β cells) Fat cells

α2; β1, (β3)

Lipolysis


(thermogenesis)



Salivary glands

α1 β

K
and water secretion
Amylase secretion


K
and water secretion




Lacrimal glands

α

Secretion


Secretion






Secretion



Nasopharyngeal glands Pineal gland

β

Melatonin synthesis



Posterior pituitary

β1

Antidiuretic hormone secretion



SA: sinoatrial; AV: atrioventricular. Adapted from Pacak et al. [833]. *: Indicates that a designation of subtype is not provided, the nature of the subtype has not been determined unequivocally. a : Responses are designated 1
to 3
to provide an approximate indication of the importance of adrenergic and cholinergic nerve activity in the control of the various organs and functions listed.

Chapter 6

α1

68

Sex organs, male

Catecholamines and Adrenergic Receptors 69

and stimulation inhibits release of norepinephrine. Other D2-receptors are present on sympathetic ganglia and their stimulation inhibits ganglionic transmission, while others in the brain cause emesis and inhibit prolactin release [583]. Bromocriptine, apomorphine, and lergotrile are specific D2agonists, while haloperidol and domperidone are specific D2-antagonists. Both D1 and D2 effects are mediated by adenylate cyclase, D1 via interaction with Gs-regulatory protein and D2 via interaction with Gi [582–584]. When high levels of catecholamines persist, desensitization may occur by two mechanisms: [A] internalization of receptors, reducing the number on the cell surface, and [B] decreased binding affinity of the catecholamine to the receptor [585]. Such receptor down-regulation may explain partially why some patients with pheochromocytoma are only moderately hypertensive despite high plasma levels of catecholamines.

6.11

Actions of the Catecholamines

Catecholamines affect nearly every tissue and organ in the body. Their release by sympathetic nerves and the adrenal medulla has important regulatory functions in helping the body adjust from moment to moment during both rest and stress. The human adrenal medulla produces mainly epinephrine, which as a hormone, is secreted directly into the bloodstream to act on cells distant from sites of release. The postganglionic sympathetic nerves that innervate blood vessels, the heart, and other tissues secrete norepinephrine, which as a neurotransmitter, acts close to sites of release. The release of norepinephrine by sympathetic nerves and epinephrine from the adrenal medulla can be both generalized and diffused throughout the body or patterned and localized to a specific organ or tissue. Thus, catecholamines increase heart rate, blood pressure, myocardial contractility, and conduction velocity in the heart (Table 6.4) [586]. They bring about constriction in most vascular beds, but produce relaxation of tracheal and bronchial muscles, and may either increase or decrease bronchial secretion. Catecholamines tend to decrease intestinal motility and tone and also to inhibit secretion. Graded adrenergic activity stimulates renin secretion in the kidney and relaxation in the gall bladder, as well as relaxation of the detrusor muscle of the urinary bladder. Some of the overall effects on the circulation include sodium retention due to direct tubular effects, as well as enhanced renin production and activity of the renin–angiotensin–aldosterone system. There are also α2-adrenergic receptor-mediated increases in platelet aggregation, and shunting of blood toward the cardiopulmonary region with stimulation of low-pressure cardiac baroreceptors [586, 587]. The two catecholamines have somewhat different effects on α- and β-adrenergic receptors (Table 6.2). In particular, epinephrine has much more potent effects on β2-adrenoceptors than norepinephrine. Compared to norepinephrine, epinephrine also demonstrates greater or equal affinity for α1- and α2-receptors, but less potency for β1-receptors. Due to the above differences, epinephrine exerts its effects on different populations of adrenoceptors than norepinephrine (Tables 6.2 and 6.3). As a circulating hormone,

70 Chapter 6 Table 6.4 Various effects of intravenously administered epinephrine and norepinephrine in humans Effects

Epinephrine

Norepinephrine

Cardiac Stroke volume Heart rate Cardiac output Arrhythmias Coronary blood flow
















0, 







Blood pressure Systolic Diastolic Mean arterial Mean pulmonary





, 0, 















Peripheral circulation Total peripheral resistance Cerebellar blood flow Muscle blood flow Cutaneous blood flow Renal blood flow Splanchnic blood flow





 






0,  0,    0, 

Metabolic effects Oxygen consumption Blood glucose Blood lactic acid











0,  0,
0,


Adapted from Pacak et al. [833].
 represent increase on decrease, respectively. 0 represents no change.

epinephrine acts potently on β2-adrenergic receptors of the skeletal muscle vasculature causing vasodilation. In contrast, norepinephrine released locally within the vasculature causes α1-adrenoceptor-mediated vasoconstriction. This and the chronotrophic and inotrophic effects of neurally released norepinephrine mediated by way of cardiac β1-adrenoceptors reflect a primary and critical function of the sympathoneural system in cardiovascular regulation, particularly maintenance of blood pressure. Under normal physiological conditions, epinephrine appears to be more important as a metabolic than as a hemodynamic-regulatory hormone [564, 588]. Metabolic effects of epinephrine include hyperglycemia, hyperlipidemia, thermogenesis, increased oxygen consumption, and hypokalemia. The hyperglycemic response to epinephrine is due to a series of actions, which include stimulation of hepatic glycogen phosphorylase, inhibition of glycogen synthase, stimulation of gluconeogenesis, inhibition of insulin secretion, and stimulation of glucagon release [589, 590]. Epinephrine also has potent effects on pulmonary function, causing β2-adrenoceptor-mediated dilation of airways [591]. The stimulation of β3-adrenoceptors is associated with increased lipolysis [592]. Most of the above actions of epinephrine occur at threshold plasma concentrations well within the physiological range.

Catecholamines and Adrenergic Receptors 71

Sweating of the palms of the hands and certain other sites, commonly referred to as adrenergic sweating, is due to α-adrenergic stimulation of apocrine glands. Eccrine glands are innervated by both noradrenergic and cholinergic nerves. They can thus respond to both adrenergic and cholinergic stimulation. Catecholamines diffusely inhibit gut motility and in some patients this can lead to hypodynamic ileus or “pseudo-obstruction.” Most endocrine organs are also affected by catecholamines. Thus, stimulation of α-adrenergic receptors tends to decrease the secretion of most preformed hormones, whereas stimulation of β-adrenergic receptors tends to stimulate release of preformed hormones. This includes insulin by the acinar cells of the pancreas, melatonin from the pineal, and antidiuretic hormone from the posterior pituitary. Beta-adrenergic stimulation in the eye increases the production of aqueous humor, while β-blockade diminishes secretion and is treatment for one type of glaucoma.

CH A PTE R 7

Current trends in biochemical diagnosis of pheochromocytoma

Biochemical evidence of excessive catecholamine production is a crucial step in the diagnosis of pheochromocytoma. This step requires measurements of the catecholamines, norepinephrine and epinephrine, or catecholamine metabolites in urine or plasma. There are, however, several limitations to these biochemical methods for diagnosis of pheochromocytoma. Pheochromocytomas often secrete catecholamines episodically. Between episodes, plasma concentrations or urinary excretion of catecholamines may be normal. Also, sometimes pheochromocytomas do not secrete catecholamines in amounts sufficient to produce either a positive test result or the typical clinical signs and symptoms of the tumor. Additionally, catecholamines are normally produced by sympathetic nerves and the adrenal medulla, so that high catecholamine levels are not specific to pheochromocytoma and may accompany a variety of other conditions or disease states. Appropriate implementation and interpretation of biochemical tests used for diagnosis of pheochromocytoma not only can benefit from an understanding of catecholamine release and metabolism, but also requires up-to-date knowledge about different measurement methods and their clinical utility for diagnosis of these life-threatening tumors.

7.1

Biochemical Tests of Catecholamine Excess

The biochemical tests of catecholamine excess most commonly used for diagnosis of pheochromocytoma include measurements of urinary and plasma catecholamines, urinary VMA, and urinary metanephrines (Table 7.1). Measurements of plasma concentrations of metanephrines represent a more recently developed test. Another biochemical test sometimes used for diagnosis of these tumors involves measurements of plasma concentrations of chromogranin A, an acidic protein contained in secretory granules that is coreleased with the catecholamines. Most of the above analytes occur in different forms. Catecholamines and metanephrines are present in plasma and urine in free and conjugated forms, while VMA is present almost exclusively in the free form. In humans, conjugation of catecholamines and metanephrines occurs predominantly by sulfation catalyzed by SULT1A3, located in high concentrations in the 72

Current Trends in Biochemical Diagnosis of Pheochromocytoma 73 Table 7.1 Biochemical tests of catecholamine excess Biochemical Test Urine tests Catecholamines Fractionated metanephrines Total metanephrines

Analytes Measured

Form Measured

Norepinephrine, epinephrine, and dopamine Normetanephrine and metanephrine Single measurement as combined sum

Free

Norepinephrine, epinephrine, and dopamine Normetanephrine and metanephrine Normetanephrine and metanephrine

Free

VMA Blood tests Catecholamines Free metanephrines Deconjugated metanephrines

Sum of conjugated plus free Sum of conjugated plus free Free

Free Sum of conjugated plus free

VMA: vanillylmandelic acid

gastrointestinal tract. The catecholamines are usually measured in the free form, while metanephrines can be measured in either the free form or after a deconjugation step that liberates free from the conjugated metabolites (Figure 7.1). Furthermore, the metanephrines can be measured as either total metanephrines, representing the combined sum of normetanephrine and metanephrine, or as fractionated metanephrines, representing individual measurements of normetanephrine and metanephrine. The particular form (i.e. free, deconjugated, total, fractionated) measured depends partly on the method of measurement and also on the quantities normally present in the sample matrix. The latter varies widely among different analytes. Plasma concentrations are dependent on both rates of entry into and clearance from the circulation. Similar to the parent catecholamines, the free metanephrines are cleared from the bloodstream extremely rapidly by active uptake processes and have short circulatory half-lives. Both catecholamines and free metanephrines are therefore present in plasma in picomolar to low nanomolar concentrations. In contrast, sulfate-conjugated metanephrines are cleared from the circulation slowly and almost exclusively by renal elimination. Thus, despite lower rates of production, the sulfate-conjugated metanephrines are present in plasma at 20- to 40-fold higher concentrations than those of their precursors, the free metanephrines. Quantities of urinary analytes mainly reflect overall rates of production, but also depend on the importance of renal elimination for their circulatory clearance. VMA, as the main end-product of catecholamine metabolism, is cleared exclusively by renal elimination and is present in urine in very high quantities, making its measurement relatively simple. The conjugated metanephrines are also end-products of catecholamine metabolism that are cleared exclusively by renal elimination. In contrast, the free metanephrines, like their catecholamine precursors, are cleared mainly by active uptake and metabolism in nonrenal tissues. Thus, quantities of sulfate-conjugated metanephrines are present

74 Chapter 7 Norepinephrine OH

Epinephrine OH

CH CH2

NH2

H

CH CH2

N

PNMT OH

CH3

Free catecholamines

OH

OH

OH

COMT Normetanephrine

Metanephrine OH

OH CH CH2

NH2

OCH3 OH

H N

CH CH2

CH3

OCH3 OH

Total metanephrines

SULTIA3 Normetanephrine sulfate

Metanephrine sulfate OH

OH CH CH2

NH2

H

CH CH2

N CH3

Sulfate-conjugated metanephrines

OCH3

OCH3 OSO3

Free metanephrines

OSO3

Figure 7.1 The pathways of metabolism of catecholamines to free and sulfateconjugated metanephrines. PNMT: phenylethanolamine N-methyltransferase; COMT: catechol-O-methyltransferase; SULT1A3: monoamine-preferring sulfotransferase.

in urine in a greater excess than the free metanephrines making the deconjugated metabolites more simple to measure.

7.2

Measurement Methods

The first chemical assays of urinary and plasma catecholamines involved fluorometric methods, that utilized production of fluorescent trihydroxyindole products or reaction of oxidized catecholamines with ethylenediamine to produce fluorescence in the visible spectrum [593–595]. These methods, however, had poor sensitivity and selectivity and were quickly replaced in the 1970s by radioenzymatic assays, which allowed separate measurements of norepinephrine, epinephrine, and dopamine at low concentrations suitable for small samples of plasma [596, 597]. Although the radioenzymatic assay remains a valuable and sensitive method in many research laboratories, the requirement for radioactive isotopes and the expense, complexity, and laborious nature of the method represent technical disadvantages that limit use of this assay in the routine clinical laboratory. High-performance liquid chromatography (HPLC), coupled with electrochemical or fluorometric detection, now provides the most widely used assay method for measurements of urinary or plasma catecholamines in the routine clinical laboratory [598–600]. Once the capital costs of equipment

Current Trends in Biochemical Diagnosis of Pheochromocytoma 75

are covered and trained staff are in place, the technique can provide reliable, reproducible, and relatively rapid measurements of large numbers of samples at minimal cost per sample. Problems with interference from drugs or dietary constituents are relatively easy to identify by careful inspection of chromatograms. Consistent sources of interference are usually remedied by simple changes to chromatographic conditions. A large number of different HPLC methodologies have been described. All require some kind of pre-analytical extraction step to concentrate (plasma) and clean up (plasma and urine) the sample. Most usually this involves extraction onto alumina, based on the method originally developed for the first fluorometric assays [601]. In contrast to the catecholamines, measurements of urinary metanephrines and VMA are still based in many routine laboratories on the early spectrophotometric assays developed by Pisano, Crout, and others in the late 1950s and early 1960s [602, 603]. Despite subsequent development of a variety of pre-analytical clean-up and extraction procedures, these assays remain susceptible to analytical interference. They are also restricted to measurements in urine. Another limitation for spectrophotometric or fluorometric assays of urinary metanephrines is that these methods do not allow separate (fractionated) measurements of normetanephrine and metanephrine. Tests of urinary total metanephrines, as measured by outmoded spectrophotometric assays, are best ignored by clinicians and abandoned by analytical laboratories in favor of measurement methods that incorporate a chromatographic step to fractionate normetanephrine and metanephrine and allow their separate measurement. Since significant numbers of pheochromocytomas produce mainly or solely only one of the two metabolites, separate measurements help to ensure that small or mild increases in one metabolite are not diluted by the normal levels of the other. Additionally, the chromatographic step provides an additional level of selectivity, thereby minimizing analytical interference. Although HPLC with electrochemical detection provides the most commonly available measurement method for urinary fractionated metanephrines, newer methods involving mass spectrometry are likely to offer further improvement. These methods, including gas chromatography– mass spectrometry and liquid chromatography–tandem mass spectrometry [604–606], should provide higher analytical specificity than HPLC methods, and with continuing improvements in instrumentation and cost should become more widely applicable for diagnostic purposes. Accurate measurement of the low levels of free normetanephrine in plasma was first achieved using a radioenzymatic assay that involved N-methylation of the metabolite with 3UCH-S-adenosylmethionine to form 3UCH-labeled metanephrine [607]. This method, however, allowed quantification of only normetanephrine and therefore had limited clinical utility. HPLC assays that allowed measurement of both plasma normetanephrine and metanephrine were developed subsequently, first for levels of deconjugated metabolites [551], and later for the much lower levels of the free metabolites [608]. It remains to be determined which test, plasma-free or deconjugated metanephrines, offers the better method for diagnosis of pheochromocytoma. In the interim, it is important to consider that the free metanephrines represent

76 Chapter 7

largely different metabolites from the deconjugated metanephrines usually measured in urine and in some laboratories, in plasma.

7.3

Reference Intervals

Interpretation of a biochemical test result as normal or abnormal depends on availability of valid reference intervals, usually determined from the 95% confidence intervals of results in a reference population of individuals without the disease for which the diagnosis is sought. The establishment of reference intervals using the 95% confidence intervals must be expected, by definition, to result in a certain percentage of false-positive results. For tests of a single analyte, such as VMA, it can be expected that at least 2.5% of patients without pheochromocytoma will have values for the analyte above the upper reference limits and 2.5% below the lower reference limits. Up to a 5% incidence of false-positive results might be expected for tests of pairs of analytes, such as norepinephrine and epinephrine in tests of urinary or plasma catecholamines or normetanephrine and metanephrine in tests of plasma-free or urinary fractionated metanephrines. False-positive rates usually, however, tend to be higher than expected, this likely due to reduced control over sampling conditions and sources of interference or differences in clinical characteristics of reference and patient populations. Use of appropriately matched reference populations can be important for effective diagnosis of pheochromocytoma among different populations of patients tested for the tumor (Figure 7.2). Urinary and plasma levels of catecholamines and metanephrines show different ranges in hypertensives or hospitalized patients compared to normotensive healthy volunteers [598, 609, 610, 611], children compared to adults [326, 598, 612], and males compared to females [528, 613]. Also, levels of catecholamines and metanephrines in 24-hour urine specimens and plasma are not normally distributed [519, 610]. Normalization of distributions, usually achievable by logarithmic transformation, is therefore required for establishment of valid reference ranges. Alternatively, a non-parametric method is appropriate. Patients with hypertension tend to have higher plasma and 24-hour urinary levels of catecholamines and metanephrines than normotensives [528, 609, 614, 615]. Use of reference ranges established in hypertensive rather than normotensive populations therefore minimizes the likelihood of false-positive results in patients tested for pheochromocytoma because of signs and symptoms. However, these same reference ranges are not necessarily appropriate for patients with pheochromocytoma who are normotensive and asymptomatic and tested for the tumor because of a hereditary predisposition or a finding of an adrenal incidentaloma. In some of these patients the tumor may be too small to produce large enough amounts of catecholamines or catecholamine metabolites for a positive test result using reference ranges established in hypertensive or hospital patient populations. For these patient populations, use of reference ranges established in normotensive healthy volunteers minimizes the potentially disastrous consequences of a false-negative test result. Reference ranges for plasma and urinary catecholamines and catecholamine metabolites also differ according to gender and age. Females have lower plasma

Current Trends in Biochemical Diagnosis of Pheochromocytoma 77 Normotensives (n = 175) 90

60

80

2.76

50

70

40

60 50

30

40

20

30 20

10

10 0 (a)

0.46

0

1

2

3

5

4

7

6

0 0.25

0.5

1.0

2.0

4.0

8.0

Hypertensives (n = 110) 35

30

30

25

25

0.60

4.21

20

20 15

15

10

10

5

5 0 0

1

2

3

4

(b)

6

5

7

0 0.25

Normotensives (n = 175)

1.0

0.10

70

35

60

30

50

25

40

20

30

15

20

10

10

5

0 (c)

0.5

2.0

8.0

4.0

Plasma norepinephrine (nmol/l)

0 0.4 0.2 Hypertensives (n = 110) 35

0.6

0.8

1.0

0 0.063 30

30

0.125

0.55

0.25

0.5

0.13

1.0 0.77

25

25

20

20 15 15 10

10

5

5 0 0 (d)

0.2

0.4

0.6

0.8

1.0

0 0.063

0.125

0.25

0.5

1.0

Plasma normetanephrine (nmol/l)

Figure 7.2 Frequency distributions for plasma norepinephrine (a and b) and plasmafree normetanephrine (c and d) in healthy normotensive volunteers (a and c) compared to patients with essential hypertension (b and d). Distributions shown in the panels on the right have been normalized by logarithmic transformation. The 95% confidence intervals (indicated by the vertical dashed lines) were estimated using the normalized distributions. Note that distributions in hypertensives show a shift to higher plasma concentrations compared to distributions in normotensives leading to correspondingly higher, lower and upper reference limits in hypertensives than normotensives.

78 Chapter 7

concentrations of epinephrine and metanephrine than males [528]. Similarly, 24-hour urinary outputs of catecholamines and metanephrines are lower in women than men [613, 616]; for epinephrine this difference remains significant when values are normalized for creatinine excretion [613]. Plasma levels of norepinephrine and normetanephrine increase with advancing age in adults, whereas plasma levels of epinephrine and metanephrine are little affected [528]. Age-related increases in 24-hour urinary outputs of norepinephrine and normetanephrine have also been reported [615, 616], but not consistently by all studies [613]. In general, the influences of age and gender on adult reference ranges are minor and perhaps only relevant to consider in patients with borderline normal or abnormal biochemical test results. Of greater importance than the age- and gender-related differences in adults are the much larger differences in plasma concentrations and urinary outputs of catecholamines and their metabolites in children compared to adults. Children have a smaller range in plasma concentrations of norepinephrine and normetanephrine, and a larger range and significantly higher plasma concentrations of epinephrine and metanephrine [326]. As in adults, girls have lower plasma concentrations of epinephrine and metanephrine than boys. In contrast, 24hour urinary outputs of norepinephrine and epinephrine are consistently lower in children than in adults, with values increasing throughout childhood, apparently a reflection of increases in body weight [598, 617]. Because of the above dynamic changes throughout childhood, and also due to the difficulty of obtaining complete urine collections, a standard practice for biochemical testing in children is to normalize excretion of catecholamines and metanephrines to that of creatinine. When this is done, ratios of urinary catecholamines or metanephrines to creatinine show a decrease with age through childhood [612, 617, 618]. It is therefore imperative that age-appropriate reference ranges be used when biochemical testing for pheochromocytoma is carried out in children. Another patient population where the usual reference ranges are often invalid and where diagnosis of pheochromocytoma can prove particularly difficult involves patients with renal failure [544, 549, 619]. In end-stage renal failure, urine collections may be impossible, and even in less severely affected patients results of 24-hour urine testing difficult to interpret [550]. Impaired renal function results in dramatic increases in plasma concentrations of VMA and sulfate-conjugated metanephrines, rendering these tests invalid [551, 552]. In contrast, since the circulatory clearance of plasma catecholamines and free metanephrines is largely independent of renal function, measurements of these analytes in plasma represent the most appropriate tests for diagnosis of pheochromocytoma in renal failure [619]. Nevertheless, plasma levels of catecholamines and free metanephrines tend to be elevated more in patients with renal failure than in normal and hypertensive populations. Also, dietary and medication-associated interferences with chromatographic analysis tend to be much more pronounced in patients with renal failure, making it difficult to obtain reliable results.

7.4

Initial Biochemical Testing

Missing a pheochromocytoma can have deadly consequences. Therefore, one of the most important considerations in the choice of an initial biochemical

Current Trends in Biochemical Diagnosis of Pheochromocytoma 79

test is a high level of reliability that the test will provide a positive result in that rare patient with the tumor. Such a test also provides confidence that a negative result reliably excludes the tumor, thereby avoiding the need for multiple or repeat biochemical tests or even costly and unnecessary imaging studies to rule out the tumor. Therefore, the initial work-up of a patient with suspected pheochromocytoma should include a suitably sensitive biochemical test. Catecholamine secretion by pheochromocytomas can be episodic, or in patients who are asymptomatic, negligible in nature. Thus, measurements of urinary or plasma catecholamines do not provide reliable biochemical tests for detection of the tumor. This is particularly problematic during screening for pheochromocytoma in patients with a predisposing hereditary condition, where 26–29% of tumors can be expected to be associated with normal urinary excretion or plasma concentrations of catecholamines [387]. Because of the intermittent nature of catecholamine secretion it has been recommended that urine or blood samples are best collected when the patient is hypertensive. Hypertension, however, can be present in some patients independent of catecholamine release by a tumor. Thus, normal catecholamines in a patient with hypertension do not exclude pheochromocytoma. Another more commonly prescribed practice is to include measurements of catecholamine metabolites in the initial panel of biochemical tests. Because metanephrines are produced continuously within pheochromocytoma tumor cells and largely independent of catecholamine release, these measurements obviate any need for collection of blood or urine samples during hypertensive episodes. To minimize false-positive results, it is now our recommendation that such samples should always be collected in the quiescent state. For sampling blood, patients should be resting comfortably supine for at least 20 minutes before sampling. Because production of metanephrines within pheochromocytoma tumor cells depends on O-methylation of catecholamines continuously leaking from storage vesicles, it has been proposed that measurements of these metabolites should provide a superior diagnostic test than measurements of the parent amines [524]. Consistent with these concepts it has now been established by four independent groups of investigators that measurements of plasma metanephrines provide superior diagnostic sensitivity over measurements of plasma or urinary catecholamines for detection of pheochromocytoma [18, 19, 387, 493, 529, 611]. Several studies involving measurements of urinary fractionated metanephrines have similarly indicated that these tests provide superior diagnostic sensitivity over urinary or plasma catecholamines, urinary VMA, or total metanephrines, the latter measured as the combined sum of normetanephrine and metanephrine by early spectrophotometric methods [19, 620–623]. Taken together, the weight of accumulating evidence clearly indicates that measurements of fractionated metanephrines (i.e. normetanephrine and metanephrine measured separately) in urine or plasma provide superior diagnostic sensitivity over urinary or plasma measurements of catecholamines and other catecholamine metabolites. In the largest of the above studies, involving over 200 patients with pheochromocytoma and more than 600 patients in whom the tumor was excluded, measurements of plasma-free metanephrines and urinary fractionated metanephrines provided the most highly sensitive diagnostic tests, urinary

80 Chapter 7 1.0

0.8 0.6

0.4

0.2

0.0 0.0 (a)

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True-positive rate (sensitivity)

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0.4 0.2

0.0 0.0

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0.4

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False-positive rate (1-specificity)

Figure 7.3 Receiver operating characteristic curves illustrating relationships between rates of true-positive test results (test sensitivity) and rates of false-positive test results (1-specificity) calculated at different upper reference limits for each of the tests. Curves for plasma-free metanephrines (䊉) are shown in all panels (a) and (b). Comparisons with plasma catecholamines (䊏), urinary catecholamines (䉭), and urinary VMA (䉱) are shown in panel (a) and those with urinary fractionated metanephrines (䊊) and urinary total metanephrines (ⵧ) are shown in panel (b). Note that at higher upper reference limits, rates of true-positive test results decrease (sensitivity decreases), whereas rates of false-positive test results increase (specificity increases).

and plasma catecholamines offered intermediate diagnostic sensitivity, while urinary total metanephrines and VMA offered the least sensitivity [19]. Analysis of receiver operating characteristic curves showed that, at equivalent levels of sensitivity, the specificity of plasma-free metanephrines was higher than that of all other tests; furthermore at equivalent levels of specificity, the sensitivity of plasma-free metanephrines was also higher than that of all other tests, even when the latter were combined (Figure 7.3). Due to the above considerations, a now widely endorsed recommendation is that initial biochemical testing should include measurements of plasma-free or urinary fractionated metanephrines [86, 624]. Both tests offer similarly high diagnostic sensitivity so that a negative result for either test appears equally effective for excluding pheochromocytoma. However, because of differences in specificity, tests of plasma-free metanephrines may exclude pheochromocytoma in more patients without the tumor than do tests of urinary fractionated metanephrines. Nevertheless, any differences in overall diagnostic accuracy of plasma compared to urinary fractionated metanephrines are relatively small compared to differences of either test of metanephrines with tests of plasma or urinary catecholamines. Choice of either plasma or urinary fractionated metanephrines may benefit from consideration of additional factors as outlined in Table 7.2. While measurements of plasma or urinary metanephrines may fail to detect some tumors that synthesize only small amounts of catecholamines or exclusively dopamine, patients with such tumors have an atypical clinical presentation that can benefit from consideration of other testing strategies. Urinary dopamine is mainly derived from renal extraction of circulating L-dopa and local conversion to dopamine by aromatic amino acid

Current Trends in Biochemical Diagnosis of Pheochromocytoma 81 Table 7.2 Relative advantages and disadvantages of measurements of urinary fractionated and plasma-free metanephrines for diagnosis of pheochromocytoma Urinary Fractionated Metanephrines

Plasma-Free Metanephrines

Well established widely available test

Relatively new test with increasing availability

Urinary concentrations (200–2000nmol) make analysis relatively easy

Plasma concentrations (0.1–0.5nmol) can make analysis difficult

Easy for clinicians to implement with minimal expenditure of time and effort

Blood collections requires some time and effort by medical staff

Twenty-four-hour collections can be inconvenient for patients

Blood sampling relatively more convenient for patients

Potential problems with reliability of incomplete timed urine collections

Collection and handling of blood samples can be carried out reliably

Difficult to control for daily life influences on sympathoadrenal function or diet

Influences of diet and sympathoadrenal function more easily controlled for

In children 24-hour collections are difficult with results difficult to interpret without ageappropriate reference intervals

In children blood sampling may be stressful, but results are more easily interpreted without age-appropriate reference intervals

Test not useful in patients with renal failure

Test can be used in patients with renal failure

decarboxylase [625]. Thus, measurements of plasma dopamine or its O-methylated metabolite, methoxytyramine (which may be measured in urinary and plasma assays of metanephrines), provide better methods for detecting dopamine-producing tumors than measurements of urinary dopamine [626]. With a mind to the above exceptions, the decision to rule out pheochromocytoma should be primarily based on findings of negative test results for measurements of normetanephrine and metanephrine.

7.5

Follow-up Biochemical Testing

Follow-up biochemical testing should usually only be necessary in patients with positive results of initial tests of plasma-free or urinary fractionated metanephrines. Exceptions include patients at high risk for pheochromocytoma because of a hereditary syndrome or a prior history of the tumor, all of who should undergo periodic screening. In these patients, and occasionally others with adrenal incidentalomas, the tumors may be too small to produce signs and symptoms or a positive result by any available biochemical test. In these patients positive results likely will follow enlargement of tumors. Due to the large numbers of patients tested for pheochromocytoma and the rarity of the tumor, false-positive results can be expected to outnumber true-positive results, even for tests with reasonably high specificity. Thus, the likelihood of pheochromocytoma in a patient with a positive result is usually low. Follow-up tests are invariably required to unequivocally confirm or exclude the tumor, the extent and nature of this requiring informed and sound clinical decision-making. Judging the likelihood of a pheochromocytoma from a single positive test result should, however, first take into account the degree of initial clinical suspicion or pre-test probability of the tumor, which impacts upon the post-test probability of a tumor (Figure 7.4).

82 Chapter 7

Plasma metanephrine (nmol/l)

100

Increasing probability of a tumor

10

1

1.20

0.31 0.1

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Increasing probability 2.19 of a tumor

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1

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Urinary normetanephrine (µmol/day)

Figure 7.4 Scatterplots showing the distributions for plasma concentrations (a) or urinary outputs (b) of normetanephrine vs metanephrine in patients with confirmed pheochromocytoma or paraganglioma (ⵧ) compared to patients in whom tumors were excluded (䊉). The horizontal dashed lines illustrate the upper reference limits for plasma concentrations of normetanephrine and metanephrine (0.61 and 0.31nmol/l) in panel (a) and urinary outputs of normetanephrine and metanephrine in panel (b) (1.7 and 0.7µmol/day) used to determine whether results are negative or positive (binary approach to test interpretation). With some exceptions, a tumor may be excluded when both normetanephrine and metanephrine fall below those upper limits. Exceptions include patients with tumors that produce only dopamine where diagnosis may be based on isolated elevations of methoxytyramine (metabolite of dopamine) or patients with very small or microscopic tumors (
1 cm diameter), and no other biochemical evidence or signs or symptoms of catecholamine excess. The gray areas beyond upper limits indicate areas where positive results are of insufficient magnitude to allow false-positive and true-positive results to be reliably distinguished, but where the probability of a tumor increases with increasing magnitude of the result (continuous approach to test interpretation). Beyond the boundary of gray areas the probability of a tumor approaches 100%.

Current Trends in Biochemical Diagnosis of Pheochromocytoma 83

The extent of increase of a positive test result is crucially important to judging the likelihood of a pheochromocytoma. Most patients with the tumor have increases in plasma or urinary metanephrines well in excess of those more commonly encountered as false-positive results in patients without the tumor. Increases in plasma concentrations of normetanephrine above 400 ng/l (2.2 nmol/l) or of metanephrine above 236ng/l (1.2nmol/l) are extremely rare in patients without pheochromocytoma, but occur in about 80% of patients with the tumor [19]. Similarly, increases in urinary outputs of normetanephrine above 1500µg/day (8.2µmol/day) or of metanephrine above 600µg/day (3.0µmol/day) are rare in patients without pheochromocytoma, but occur in about 70% of patients with the tumor. Provided biochemical test results are accurate, the likelihood of pheochromocytoma in such patient is so high that the immediate task is to locate the tumor. When there is concern about the analytical accuracy of a positive plasma test result, this can be checked by a follow-up urinary test, and vice versa when there is concern about an initial urinary test result. Such follow-up testing may be particularly prudent in patients with milder increases in plasma-free or urinary fractionated metanephrines, where the post-test probability of pheochromocytoma remains low, and where subtle analytical interferences can be difficult for the testing laboratory to recognize. A similar pattern of increases in urinary compared to plasma normetanephrine and metanephrine not only helps confirm accuracy of results, but also increases the likelihood of a pheochromocytoma. Additional sampling for plasma catecholamines in combination with plasmafree metanephrines or urinary catecholamines in combination with urinary fractionated metanephrines can provide further useful information to help distinguish true-positive from false-positive results [385]. Because free metanephrines are produced continuously within pheochromocytoma tumor cells by a process that is independent of catecholamine release, patients with truepositive results usually have larger percent increases of plasma metanephrines above the upper reference limits than percent increases of the parent catecholamines. Conversely, because substantial amounts of metanephrine (90%) and normetanephrine (26–40%) are normally produced within adrenal medullary cells independently of catecholamine release, increases in metanephrines during sympathoadrenal activation are smaller than increases in catecholamines. Thus, patients with false-positive results due to sympathoadrenal activation usually have larger percent increases of plasma norepinephrine than of plasma normetanephrine or of plasma epinephrine than of metanephrine. Because of relatively poor diagnostic sensitivity, measurements of urinary VMA or of urinary “total” metanephrines – where deconjugated normetanephrine and metanephrine are measured spectrophotometrically as a combined sum – are of limited value for detecting or excluding pheochromocytoma. Such tests rarely provide useful diagnostic information beyond that of measurements of plasma or urinary fractionated metanephrines, where normetanephrine and metanephrine are measured separately. Exceptions include metastases confined to the liver or mesenteric organs where the vascular drainage from the tumors enters the liver, the main site in the body for formation of VMA from catecholamines and catecholamine metabolites.

84 Chapter 7

Before follow-up testing is implemented some consideration should be given to sources of false-positive results, including accompanying medical conditions, inappropriate sampling conditions, dietary influences, and medications likely to directly interfere with analytical results or increase levels of normetanephrine or metanephrine.

7.6 Collection and Storage of Plasma and Urine Specimens The conditions under which plasma or urine samples are collected can be crucial to the reliability and interpretation of test results. Many clinicians prefer 24-hour collections of urine over blood sampling since the former avoids many of the rigid sampling conditions associated with blood collections and is more convenient for clinical staff to implement. However, 24-hour collections of urine are not always easily, conveniently, or reliably collected by patients, particularly pediatric patients. Also, influences of diet and sympathoadrenal activation associated with physical activity or changes in posture are not as easily controlled for as they are for blood collections. To minimize sympathoadrenal activation – associated with venipuncture or upright posture – that may obscure tumor-related increases in catecholamines, blood samples should be collected via a previously inserted intravenous line with patients supine for at least 20 minutes before sampling. Plasma levels of free metanephrines, although less responsive than catecholamines, nevertheless are cleared rapidly from the circulation, have extremely short plasma half-lives, and show similar rapid directional changes in response to changes in sympathoadrenal activity as their catecholamine precursors [524, 528]. Therefore, until established otherwise blood collected for measurements of plasma-free metanephrines should be collected under the same conditions as that for measurements of catecholamines. Pheochromocytomas often secrete catecholamines episodically so that between episodes plasma levels or urinary outputs of catecholamines can be normal. Because of this, some investigators advocate collection of blood samples during paroxysmal attacks or collection of urine samples after attacks. Importantly, however, pheochromocytoma tumor cells contain high concentrations of membrane-bound COMT, the particular enzyme isoform that preferentially converts catecholamines to free metanephrines [258, 524]. The catecholamines in chromaffin granules exist in a highly dynamic equilibrium with the surrounding cytoplasm, vesicular translocation balancing vesicular leakage of catecholamines and both processes occurring continuously and independent of catecholamine exocytotic release. This and the presence of COMT in the cytoplasm means that the free metanephrines are produced continuously within pheochromocytoma tumor cells from catecholamines leaking from storage vesicles. Thus, there is absolutely no need to time collection of blood or urine samples to coincide with paroxysmal attacks when measurements involve the metanephrines. To minimize the possibility of false-positive results it is best to sample between attacks with patients relaxed and resting comfortably supine.

Current Trends in Biochemical Diagnosis of Pheochromocytoma 85

Due to possible errors resulting from incomplete 24-hour urine collections or uncontrolled influences of physical activity some investigators advocate spot or overnight urine collections [627–629]. Correction for differences in duration of collection is achieved by normalizing catecholamine or catecholamine metabolite excretion against urinary creatinine excretion. Additional considerations for urine collected under these conditions include dietary protein, muscle mass, level of physical activity, and time of day, all of which impact creatinine excretion and may further confound interpretation of results [630–633]. Studies on the stability catecholamines in urine and plasma have yielded mixed results with variable recommendations on appropriate preservatives and methods of collection [634–640]. There is now, however, general agreement that elaborate earlier recommended techniques for sample preservation are unnecessary. Variable findings may be explained in part by two processes with opposing effects on levels of free amines: (1) autooxidation, particularly at alkaline pH and (2) deconjugation, particularly at low pH. The general recommendation is that catecholamines in urine samples are best preserved with HCl to maintain urine at low pH. To further minimize autooxidation and deconjugation, urine specimens are best kept on ice or refrigerated immediately after collection and aliquots stored frozen at 80ºC. Similarly blood samples are best collected into tubes containing heparin or ethylenediamine terraacetic acid (EDTA) as an anticoagulant and stored on ice before centrifugation at 4ºC and separation of plasma for further storage at 80ºC.

7.7

Interferences from Diet and Drugs

Dietary constituents or drugs can either cause direct analytical interference with assays or influence the physiological processes that determine plasma and urinary levels of catecholamines and catecholamine metabolites (Table 7.3). In the former circumstances, the interference can be highly variable depending on the particular measurement method. In the latter circumstances, interference is usually of a more general nature and independent of the measurement method. Dietary constituents represent a common source of direct analytical interference with assays of catecholamines and their metabolites. Examples include caffeic acid and its derivative dihydrocaffeic acid, which are found in coffee, including decaffeinated coffee. As catechols, these compounds bind to alumina, and can interfere with HPLC assays of catecholamines that incorporate an alumina extraction step [641]. Caffeic acid and dihydrocaffeic acid are structurally unrelated to caffeine; the latter not a direct source of analytical interference. However, caffeine can increase circulating catecholamines secondary to its stimulant properties. Other dietary sources of general interference include cereals, which can cause large increases in plasma levels and urinary excretion of dopamine and dopamine metabolites and smaller increases in other catecholamines [518, 522], and amine rich foods such as cheeses and bananas [520, 521, 642]. There are many other as yet unidentified dietary constituents that may influence assay results. The simplest way to avoid these sources of false-positive results is by sampling in the fasted state. Spectrophotometric or fluorometric assays of urinary catecholamines, metanephrines, and VMA are particularly prone to direct analytical interference

86 Chapter 7 Table 7.3 Medications that may cause physiologically mediated false-positive elevations of plasma and urinary catecholamines or metanephrines Catecholamines Metanephrines NE

E

NMN

MN

Tricyclic antidepressants Amitriptyline (Elavil), Imipramine (Topfranil), Nortriptyline (Aventyl)









α-blockers (non-selective) Phenoxybenzamine (Dibenzyline)









α-blockers (α1-selective) Doxazosin (Cardura), Terazosin (Hytrin), Prazosin (Minipress)









β-blockers Atenolol (Tenormin), Metoprolol (Lopressor), Propranolol (Inderal), Labetalol (Normadyne)*









Calcium channel antagonists Nifedipine (Procardia), Amlodipine (Norvasc), Diltiazem (Cardizem), Verapamil









Vasodilators Hydralazine (Apresoline), Isosorbide (Isordil, Dilatrate), Minoxidil (Loniten)





Unknown

Monoamine oxidase inhibitors Phenelzine (Nardil), tranylcypromine (Parnate), Selegiline (Eldepryl)









Sympathomimetics Ephedrine, Pseudoephedrine (Sudafed), Amphetamines, Albuterol (Proventil)









Stimulants Caffeine (coffee*, tea), Nicotine (tobacco), Theophylline





Unknown

 

 

Unknown Unknown 

Miscellaneous Levodopa, Carbidopa (Sinemet)* Cocaine Acetaminophen*

NE: norepinephrine; E: epinephrine; NMN: normetanephrine; MN: metanephrine. : substantial increase; : moderate increase; : mild increase if any; : little or no increase. *A drug that can also cause direct analytical interference with some methods. Adapted from Pacak et al. [833].

by medications, including several antihypertensives. Perhaps best known amongst these is interference by labetalol and its metabolites [643–645]. Labetalol can also cause spurious elevations of plasma epinephrine, as determined by some HPLC assays [646], but in general is not a significant problem for most HPLC assays, including those for urinary fractionated or plasma-free metanephrines. Among the latter assays, significant sources of interference

Current Trends in Biochemical Diagnosis of Pheochromocytoma 87

include the anxiolytic agent, buspirone, which can cause spurious elevations of urinary metanephrine [647], and acetaminophen, which can result in falsepositive elevations of plasma-free normetanephrine [608]. Problems with acetaminophen are, however, easily remedied by simple changes to extraction or chromatographic procedures [648]. Development of new drugs, variations in assay techniques, and continuing improvements in analytical procedures make it often difficult to identify which directly interfering medications should be avoided for a given analytical test. More readily identifiable and generalized sources of interference that are independent of the particular assay method tend to be associated with drugs that have primary actions on catecholamine systems. Due to the importance of these systems as therapeutic targets, such drugs represent a relatively common source of false-positive results. Tricyclic antidepressants in particular are a major source of false-positive results for measurements of norepinephrine and normetanephrine in plasma or urine [19, 385]. Presumably this is due to the primary actions of these agents to inhibit monoamine reuptake, which after chronic administration overrides the other action of these drugs to suppress sympathetic outflow, resulting in increased escape of norepinephrine from sympathetic nerve terminals into the bloodstream [649, 650]. These complex actions may also be responsible for the blood pressure disturbances that can accompany use of tricyclic antidepressants [651], and which may contribute to initial suspicion of pheochromocytoma. Phenoxybenzamine (dibenzyline) represents another major source of falsepositive results [19, 385]. Presumably the drug elevates norepinephrine and normetanephrine by attenuating α2-adrenoceptor-mediated feedback inhibition of norepinephrine release, possibly combined with reflexive sympathetic activation. The latter mechanism may also be responsible for elevations of plasma or urinary norepinephrine that can accompany use of other antihypertensives, such as calcium channel blockers. Decreased circulatory clearance associated with decreases in cardiac output or regional blood flow may also contribute to increased levels of catecholamines and metabolites after other vasoactive agents or adrenergic blockers, such as propranolol [652]. In general, however, the latter agents represent relatively minor sources of falsepositive test results with minimal influences on levels of catecholamines and metabolites. Withdrawing these medications may therefore not be justified unless an equivocal result has been obtained and repeat testing is necessary. Other medications that can cause significant interference, but which are less commonly encountered during testing for pheochromocytoma, include levodopa, sinemet, α-methyldopa (Aldomet), and MAO inhibitors. Levodopa, which is used alone or in combination with carbidopa (sinemet) for the treatment of Parkinson’s disease, is an alumina-extractable catechol and the direct precursor of dopamine. The drug can therefore interfere directly with catecholamine assays and is also converted by catecholamine synthesizing and metabolizing enzymes to catecholamine products and metabolites with additional interfering actions [653, 654]. Similarly, the antihypertensive agent, α-methyldopa, is metabolized by catecholamine biosynthetic and metabolizing enzymes to α-methyldopamine, α-methylnorepinephrine, and

88 Chapter 7

other products which in some but not all assays can result in significant interference [655, 656]. Because active cellular uptake and not metabolism is the main determinant of catecholamine clearance, inhibitors of monoamine oxidase have little effect on plasma or urinary catecholamines [422]. However, by blocking the main pathway for catabolism of the O-methylated catecholamine metabolites, monoamine oxidase inhibitors can cause substantial increases in plasma levels and urinary excretion of normetanephrine and metanephrine [555, 657].

7.8

Pharmacologic Tests

Various pharmacologic tests have been used over the years in an attempt to improve the diagnostic accuracy for pheochromocytoma. This was especially true years ago when the assays for catecholamines and their metabolites were new, crude, and frequently undependable. However, provocative tests are inherently dangerous. In light of the much improved quality of present assays, the use of these pharmacologic procedures has been greatly reduced. On the other hand, suppression tests may be useful and bear minimal risk. Clonidine (Catapres) is now the drug used most often in suppression tests to identify a pheochromocytoma. It is a centrally acting α2-adrenergic agonist that suppresses central sympathetic nervous outflow, resulting normally in results in lower levels of plasma catecholamines. Blood is drawn for plasma catecholamines before and 3 hours after the oral administration of clonidine 0.3 mg/70 kg body weight. Tricyclic antidepressants and diuretics are reported to compromise reliability of the test [36]. Therefore, these medications should be withdrawn before testing. Profound hypotensive responses to clonidine can be troublesome in some patients taking antihypertensive medications. Plasma catecholamine levels will decrease if they are under normal physiological control, whereas in patients with pheochromocytoma, plasma catecholamines will not decrease. The clonidine suppression test is safe, but unreliable in patients with normal or only mildly increased plasma catecholamine levels [658–660]. In such patients there may be normal suppression of plasma norepinephrine after clonidine despite the presence of a pheochromocytoma. Presumably, normal suppression occurs because much of the norepinephrine is derived from sympathetic nerves and remains responsive to clonidine. The clonidine suppression test is therefore recommended for patients with plasma catecholamine levels over 5.9 nmol/l (1000 pg/ml), with a normal response defined as a fall to within the normal range [102]. This recommendation makes it problematic to use the clonidine suppression test in patients with normal or only mildly elevated plasma catecholamine levels, which is particularly troublesome, since such patients represent those in whom it is most difficult to conclusively diagnose pheochromocytoma. Additional measurements of plasma normetanephrine before and after clonidine provide a method to overcome the above limitation in patients with elevated plasma concentrations of normetanephrine, but normal or mildly elevated plasma concentrations of norepinephrine [385]. A decrease of plasma levels of normetanephrine of more than 40% or to below 0.61nmol/l (112 pg/ml)

Current Trends in Biochemical Diagnosis of Pheochromocytoma 89

was present in all patients without pheochromocytoma, indicating a diagnostic specificity of 100%. This was similar to that for norepinephrine (specificity  98%), where pheochromocytoma could be excluded by a decrease of norepinephrine of more than 50% or a level of norepinephrine after clonidine below 2.94nmol/l (498pg/ml). For patients with pheochromocytoma, only 2 out of 48 had plasma levels of normetanephrine that fell by more than 40% or to below 0.61nmol/l (112pg/ml) after clonidine. This indicated a diagnostic sensitivity for normetanephrine responses to clonidine of 98%, a substantial improvement over the sensitivity of only 67% for norepinephrine responses. Thus, the clonidine suppression test combined with measurements of plasma normetanephrine provides an efficient and reasonably reliable method for distinguishing false-positive from true-positive elevations of plasma normetanephrine. As noted above, provocative tests are inherently dangerous and rarely called for. If appropriate precautions are taken, a provocation test can provide useful diagnostic information with minimal risk in a patient who is on no medications or in one who is receiving α-adrenergic blockers. Glucagon is the drug usually used as it is the safest and most specific of the provocative tests. It is given in a dose of 1.0 mg, as an IV bolus. Blood for plasma catecholamines should be drawn before and 2 minutes after the drug is injected. Blood pressure and heart rate should be monitored every 60 seconds and phentolamine must always be at hand for the treatment of any episodes of severe hypertension. Only about 20% of patients with proven pheochromocytoma will have elevations in systolic blood pressure exceeding 200mmHg, so that phentolamine is required. If it is apparent that the blood pressure is beginning to rise rapidly, one can inject all 5mg from an ampule of phentolamine acutely IV and this will usually rapidly and completely block the hypertensive episode. In general, by the time the effect of the phentolamine is gone, the effect of the excess catecholamines released will also have dissipated. If the tumor secretes significant amounts of epinephrine, then a significant tachycardia may occur. This is usually very transient and the patient may need only reassurance, but if it is more severe, propranolol can be given IV. A positive test result is usually defined as an increase in plasma norepinephrine of greater than 3-fold or to more than 2000pg/ml [103]. The test has high diagnostic specificity but limited sensitivity. With consideration of the importance of high diagnostic sensitivity, our recommendation is that initial biochemical testing should include measurements of plasma-free metanephrines,or where this test is not available, measurements of urinary fractionated metanephrines as the next best test (Figure 7.5). Both tests offer similarly high diagnostic sensitivity so that a negative result for either test appears equally effective for excluding pheochromocytoma. However, because of differences in specificity, tests of plasma-free metanephrines exclude pheochromocytoma in more patients without the tumor than do tests of urinary fractionated metanephrines. Additional measurements of urinary or plasma catecholamines may also be carried out, but in our experience are unlikely to lead to detection of additional tumors not indicated by elevated levels of normetanephrine or metanephrine. Exceptions include rare tumors that produce exclusively dopamine [626]. With a mind to the above exception, the

90 Chapter 7 Clinical suspicion for pheochromocytoma

Plasma-free metanephrines

ⴚ

ⴙ

Excluded

Possible

Moderate increase (4ⴛ )

Possible

Confirmed

Rule out drug effect

Clonidine suppression test (Plasma-free normetanephrine) ⴚ

Excluded

ⴙ

Confirmed

Localization Figure 7.5 Algorithm for biochemical diagnosis of pheochromocytoma. We currently recommend HPLC measurements of plasma-free normetanephrine and metanephrine levels as the initial biochemical test. In medical centers where measurements of plasma-free metanephrines are not available, we recommend that initial biochemical tests for exclusion of a pheochromocytoma should include HPLC measurements of 24-hour urinary normetanephrine and metanephrine followed by measurements of plasma or urinary catecholamines in cases of positive test results. If plasma concentrations of either free normetanephrine or metanephrine are about 4 times above the upper reference limit, the diagnosis of pheochromocytoma is confirmed biochemically and no other biochemical tests are necessary. In patients with an elevation of plasma-free normetanephrine or metanephrine between the value of 4 times above the upper reference limit, and the upper reference limit, it may be unclear whether the increase is due to sympathetic activation or catecholamine production a tumor. After interference from various drugs is excluded, clonidine suppression test coupled with measurement of plasma-free normetanephrine should be performed.

Current Trends in Biochemical Diagnosis of Pheochromocytoma 91

decision to rule out pheochromocytoma should be primarily based on findings of negative test results for measurements of normetanephrine and metanephrine.

7.9

Additional Interpretative Considerations

Pheochromocytomas differ considerably in rates of catecholamine synthesis, turnover, release, and types of catecholamines and metabolites produced. These differences may explain variations in presenting signs and symptoms and can also provide useful information about the tumor, including the adrenal or extra-adrenal location, the underlying mutation, tumor size, and presence of metastatic disease. Adrenal pheochromocytomas may produce near exclusively norepinephrine or both norepinephrine and epinephrine. In contrast, extra-adrenal pheochromocytomas almost invariably produce exclusively norepinephrine [661]. Differences in plasma concentrations or urinary outputs of normetanephrine and metanephrine reflect underlying differences in tumor catecholamine phenotype better than do differences in plasma or urinary norepinephrine and epinephrine. Thus, patients with increases in only normetanephrine may have tumors with an adrenal or extra-adrenal location, whereas those with additional or exclusive increases in metanephrine are likely to have a tumor with an adrenal location. Exceptions to the above rule have been described in patients with recurrence or spread from a primary epinephrine-producing tumor with an adrenal location [662]. Pheochromocytomas that produce mainly epinephrine (and hence also produce large amounts of metanephrine) tend to present more often with alternating hypertension and hypotension and to be more paroxysmal in nature than those that produce exclusively norepinephrine [487, 663]. Patients with tumors that secrete large amounts of epinephrine may also present with signs and symptoms such as hyperglycemia, dyspnea, and pulmonary edema that reflect the potent actions of epinephrine on glucose metabolism and pulmonary physiology [125, 488]. A consequence of the considerable variation in catecholamine release among patients with pheochromocytoma is that plasma concentrations or urinary excretion of catecholamines are poorly correlated with tumor size [476, 524]. In contrast, due to metabolism of catecholamines within tumors and the independence of this process on catecholamine release, urinary excretion or plasma concentrations of metanephrines show strong positive correlations with tumor size and can be useful in judging the extent and progression of disease [387, 530].

7.10

Summary

Improved understanding about catecholamine release and metabolism and advances in methodologies for measurements of catecholamines and their metabolites have made biochemical diagnosis of pheochromocytoma more reliable and efficient than ever before. In particular, development of new methods for measurements of plasma-free metanephrines and recognition that these

92 Chapter 7

metabolites are produced within pheochromocytomas independently of any variations in catecholamine release are transforming how these treacherous tumors are detected. These advances have occurred in pace with others in molecular diagnosis and imaging that have allowed improved identification of patients at risk for the tumor because of hereditary factors or the finding of adrenal incidentaloma. In such patients, conventional biochemical tests are often insufficiently sensitive for reliable detection of pheochromocytoma and the newer methods help to avoid the potentially disastrous consequences of a missed diagnosis. The largest group of patients where pheochromocytoma must be considered remain those where clinical suspicion is based on signs and symptoms and where conventional biochemical tests are usually sufficiently sensitive to diagnose the tumor. However, even in this group use of plasma free metanephrines minimizes the likelihood of missing the tumor and is likely to offers a more efficient and cost-effective approach for biochemical diagnosis than use of conventional tests. Due to imperfect diagnostic specificity of all biochemical tests and the low prevalence of pheochromocytoma among patients tested for the tumor, high numbers of false-positive results remain a diagnostic dilemma that often require extensive and costly follow-up tests, and in many cases instigate unnecessary attempts to localize a suspected tumor. Further improvements in biochemical diagnosis are required to definitively confirm or exclude pheochromocytoma in every patient with a positive test result.

CH APTE R 8

Current trends in localization of pheochromocytoma

The localization of pheochromocytoma or paraganglioma should only be initiated once the clinical evidence for the tumor is reasonably compelling [86]. The finding of a mass in an adrenal gland does not prove that the mass is a pheochromocytoma – it only proves that there is a mass in the adrenal. In like manner, failure to find a mass in either adrenal gland does not prove that the patient does not have a pheochromocytoma. A detailed history and careful physical examination may yield vital clues as to the location of a pheochromocytoma, as in the case of postmicturition hypertension secondary to a pheochromocytoma of the urinary bladder. Overall pheochromocytomas located in the adrenal gland are identified more easily than those at extra-adrenal tissues. The usual focus is the adrenal gland as a main source of catecholamine production. Although appropriate imaging techniques are usually chosen to locate tumors in the adrenal gland, there can be confusion about what algorithm to follow and what technique to choose for the detection of extra-adrenal pheochromocytoma [389, 664]. Furthermore, it is not often considered that about 12–24% of patients with apparent sporadic pheochromocytoma may in fact be carriers of germline mutations, some of which involve a predisposition for extra-adrenal and even multiple pheochromocytomas [34, 452]. Similarly, it may not be recognised that malignant pheochromocytomas can be present in upto or more than 36% of patients with certain mutation [32, 40, 44, 252, 256, 303, 665], and that about 10% of patients with pheochromocytoma present with metastatic disease at the time of their initial work-up [288, 300]. After initial failed surgery, patients with metastatic pheochromocytoma are commonly re-evaluated using metaiodobenzylguanidine (MIBG) scintigraphy – a modality that should actually be performed before surgery to confirm that a tumor was indeed a pheochromocytoma, or to rule out metastatic disease or the presence of multiple tumors [389, 664, 666]. Ruling out metastatic pheochromocytoma before initial surgery can be useful since the detection of other lesions may affect the treatment plan and follow-up. There is some debate about whether functional imaging should be used as a second step after computed tomography (CT) or magnetic resonance imaging (MRI) to confirm that the tumor is indeed a pheochromocytoma [389,

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664, 667]. Several important considerations impact the choice of additional functional imaging studies. First, although pheochromocytomas are most often localized in the adrenal gland, this gland is also the site of many benign tumors (e.g. adenomas); in the general population between 5% and 10% may be expected to have such masses with increase in prevalance with advancing age. Second, about 50% of adrenal pheochromocytomas produce near exclusively norepinephrine, this representing the same pattern as in extraadrenal pheochromocytomas. Thus, whereas production of epinephrine (best detected by an increase in metanephrine) indicates an adrenal location, exclusive production of nor-epinephrine (best indicated by increases of normetanephrine with normal metanephrine) may reflect either an adrenal or extra-adrenal location. Third, about 10% of patients have metastatic pheochromocytoma at initial diagnosis; those with primary tumors larger than 5 cm are at particular risk. Fourth, in patients with previous surgeries (especially in the abdomen) the presence of post-surgical tissue changes (e.g. tissue fibrosis, adhesions) and surgical clips often precludes correct localization of recurrent or metastatic pheochromocytomas using CT or MRI. Fifth, up to 24% of pheochromocytomas are familial and these tumors are often multiple. Based on the above we advise additional use of functional imaging studies for localization of most cases of biochemically-proven pheochromocytoma. Exceptions may include small (less than 5cm) adrenal masses associated with elevations of plasma or urine metanephrine (practically all epinephrine-producing pheochromocytomas are found in the adrenal gland or are recurrences of previously resected adrenal tumors).

8.1 8.1.1

Anatomical Imaging of Pheochromocytoma Computed Tomography

CT of the abdomen, either with or without contrast, provides an appropriate initial method of localizing pheochromocytoma. This imaging technique is easy, widely available, and relatively inexpensive. CT can be used to localize adrenal tumors 1cm or larger and extra-adrenal tumors 2cm or larger (sensitivity about 90–95% but specificity is only about 70%) (Figure 8.1) [668–672]. CT densitometry can be used to differentiate adrenal adenomas from metastases [673–675]. Specifically, a homogenous mass with a density measurement of less than 10HU on an unenhanced CT is most probably an adenoma [675], whereas if the mass is inhomogeneous and/or has a density measurement of 10 HU or more, the diagnosis is uncertain. Although an adenoma is the most common possibility, a metastasis should be strongly considered. For cases with inconclusive clinical and biochemical results, further imaging assessment can be done using a washout technique after administration of contrast medium [674, 676]. Small 1–2 cm pheochromocytomas are usually homogeneous in appearance, with soft-tissue density and showing uniform enhancement with contrast [677]. Larger pheochromocytomas may undergo hemorrhage and can be inhomogeneous, with areas of low density seen following tumor necrosis [677–680]. Since most pheochromocytomas are located in the abdomen,

Current Trends in Localization of Pheochromocytoma 95

Figure 8.1 Abdominal CT that shows pheochromocytoma (arrow) in the right adrenal gland (5–6 cm in maximum diameter). Adapted from Ilias and Pacak [389].

CT of the abdomen should be done first, followed by chest and neck imaging if the abdominal CT is negative. Spiral CT is preferred for small thoracic tumors [681–685]. The advantages of CT in the localization of pheochromocytoma are the moderate cost and high sensitivity, at 85% to 94% if the pheochromocytoma is located in the adrenal gland [254, 671, 686, 687]. Sensitivity for detecting extra-adrenal, metastatic, or recurrent pheochromocytoma is around 90% before surgery [38, 668, 686]. The sensitivity of CT may decrease to around 77% due to postoperative changes [389, 662, 668]. For lesions limited to the adrenal glands, unenhanced CT followed by contrast-enhanced and delayed contrast-enhanced CT imaging yields a sensitivity of 98% [676, 688]. CT shows the structures surrounding a pheochromocytoma and permits exact localization of the tumor; however, intra-abdominal foreign bodies such as surgical clips may distort imaging findings [662, 689, 690]. In some patients with pheochromocytoma, CT may be negative or have equivocal findings while MRI examinations are positive [691, 692]. These cases are rare, especially in patients with no history of previous surgery. Traditionally, ␣-adrenergic and possibly also ␤-adrenergic receptor antagonist administration is advised for patients with biochemically-proven pheochromocytoma in order to safely give ionic monomeric intravenous contrast for enhanced CT examination [677, 693, 694]. However, no rise in plasma catecholamines was observed in 10 patients with pheochromocytoma who were given ioexol, a non-ionic contrast medium intravenously [693]. Thus, even contrast-enhanced CT most likely does not pose a significant risk of a hypertensive crisis. Nevertheless, more detailed studies are necessary to set proper guidelines on whether to use adrenergic blockade in pheochromocytoma patients undergoing CT examination.

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Figure 8.2 Abdominal T2-weighted MRI scans that show cystic pheochromocytoma (arrow) in the left adrenal gland (5–6cm in maximum diameter). Adapted from Ilias and Pacak [389].

If a high-quality – unenhanced and delayed enhanced – CT is done and the pheochromocytoma is localized, there should be no need to proceed to MRI. Rather the next step is to functional imaging to confirm that a tumor is indeed pheochromocytoma and to rule out metastatic disease. If the CT is negative, MRI should be performed. MRI should be substituted for CT in children, pregnant patients, and in situations where the radiation exposure must be minimized [695]. The disadvantage of CT is that it may fail to localize recurrent pheochromocytomas due to postoperative anatomical changes and the presence of surgical clips. Since extra-adrenal pheochromocytomas are located most commonly in the abdomen we suggest that CT of the abdomen, including pelvis, be done first. This should be followed by chest and neck imaging if abdominal CT is negative. Spiral CT is preferred for small thoracic tumors [40, 680, 696, 697].

8.1.2

Magnetic Resonance Imaging

MRI with or without gadolinium enhancement is a very reliable method that may identify more than 95% of tumors. MRI is superior to CT for detecting extra-adrenal tumors [668, 669, 672, 698, 699]. On MRI T1-sequences, pheochromocytomas have a signal like that of the liver, kidney, and muscle, and can be differentiated with ease from adipose tissue. Chemical shift MRI characterizes adrenal masses based on the presence of fat in benign adenomas and the absence of fat in pheochromocytoma, metastases, hemorrhagic pseudocysts, or malignant tumors. The hypervascularity of pheochromocytoma makes them appear characteristically bright, with a high signal on T2-sequence and no signal loss on opposed-phase images (Figure 8.2) [698]. More particularly, almost all pheochromocytomas have a more intense signal than that of the liver or muscle and often more intense than fat on

Current Trends in Localization of Pheochromocytoma 97

T2-weighted images [678]. However, such intense signals can be elicited by hemorrhages or hematomas, adenomas and carcinomas, so an overlap with pheochromocytoma must be considered and specific additional imaging is needed to confirm that the tumor is pheochromocytoma [700–702]. Atypical pheochromocytomas may show medium signal quality on T2-weighted images and an inhomogeneous appearance, especially if they are cystic. Advantages of MRI imaging of pheochromocytoma include high sensitivity for detecting adrenal disease (93–100%) and the lack of exposure to ionizing radiation [685, 687, 703]. MRI is a good imaging modality for the detection of intracardiac, juxtacardiac, and juxtavascular pheochromocytomas, because cardiac and respiratory motion-induced artifacts are minimal and the use of T2-sequences enables better differentiation from surrounding tissues. MRI can be carried out with or without use of intravenous contrast agents (such agents nevertheless are safe and do not cause release of catecholamines); thus no preparation with adrenergic blockade is necessary [704]. MRI offers the possibility of multiplanar imaging and of superior assessment of the relationship between a tumor and its surrounding vessels (the great vessels in particular) compared to CT, rendering this modality of utmost importance in the evaluation of patients with pheochromocytoma in these areas, and especially to rule out vessel invasion. However, its overall sensitivity for detection of extra-adrenal, metastatic, or recurrent pheochromocytoma is lower compared to that of adrenal disease. Overall specificity of MRI is about 70% [670, 671]. MRI should be used as the initial imaging procedure when there is pregnancy or allergy to the contrast materials used for CT scans and in children [316, 705]. However, MRI is more expensive than CT.

8.2

Functional Imaging of Pheochromocytoma

Anatomical imaging studies have inadequate specificity for pheochromocytoma and more specific imaging modalities are needed to confirm that a tumor is indeed a pheochromocytoma. This need is currently filled by functional imaging modalities using various radiopharmaceuticals. However, all functional imaging methods are hampered by the excretion of radioisotopes in urine, thus lowering their ability to localize pheochromocytoma close to the kidneys, the head of the pancreas, or the urinary bladder [706]. Functional imaging studies (enabled by the presence of the specific cell membrane and vesicular catecholamine transport systems in pheochromocytoma cells) include [123I]- or [131I]-MIBG scintigraphy, 6-[18F]-fluorodopamine, [18F]-dihydroxyphenylalanine ([18F]-DOPA), [11C]-hydroxyephedrine, and [11C]epinephrine positron emission tomography (PET) (Table 8.1) [16, 17, 283–285, 288, 662, 707–709]. These modalities are able to confirm that a tumor is a pheochromocytoma and can detect most cases of metastatic disease. However, malignant pheochromocytomas often have a relatively undifferentiated phenotype and may not express specific neurotransmitter transporters – leading to the inability to accumulate these isotopes. [18F]Fluorodeoxyglucose (FDG) PET scanning or somatostatin receptor scintigraphy (Octreoscan) may be required for the next step in the imaging algorithm [281, 389].

98 Chapter 8 Table 8.1 Radioligands used for functional imaging Uptake and Imaging Mechanism

Imaging Technique

I]-MIBG

Norepinephrine analog; actively transported into neurosecretory granules via catecholamine transporter systems

Planar, SPECT

13

[131I]-MIBG

Norepinephrine analog; actively transported into neurosecretory granules via catecholamine transporter systems

Planar

196

[11C]-epinephrine

Catecholamine; actively transported into neurosecretory granules via catecholamine transporter system

PET

0.34

[11C]hydroxyephedrine

Catecholamine analog; actively transported into neurosecretory granules via catecholamine transporter systems

PET

0.34

[11C]-DOPA

Catecholamine precursor; converted to [11C]-dopamine and then actively transported into neurosecretory granules

PET

0.34

[18F]-DA

Catecholamine; actively transported into neurosecretory granules via cell membrane norepinephrine transporter system

PET

1.83

[18F]-DOPA

Catecholamine precursor; converted to [18F]-dopamine and then actively transported into neurosecretory granules

PET

1.83

[18F]-FDG

Glucose analog; uptake and initial intracellular metabolism as of glucose via GLUT transporter system

PET

1.83

[123I]-Tyr3-DTPAoctreotide

Somatostatin analog acting on somatostatin cellular membrane receptors; undergoes receptor-mediated endocytosis but because of its polarity does not cross the lysosomal and cell membranes

Planar, SPECT

13

[111In]-DTPAoctreotide

Somatostatin analog acting on somatostatin cellular membrane receptors; undergoes receptor-mediated endocytosis but because of its polarity does not cross the lysosomal and cell membranes

Planar, SPECT

68

Radioligand [

123

DOPA: dihydroxyphenylalanine; DA: dopamine. For other abbreviations refer to text. Adapted from Ilias et al. [664].

T 1/2 (hour)

Current Trends in Localization of Pheochromocytoma 99

8.2.1 MIBG Scintigraphy MIBG is an aralkylguanidine which resembles norepinephrine. Radioactive labeling is done with iodine isotopes [131I] and [123I] at the meta-position of the benzoic ring. Like norepinephrine, MIBG is taken into sympathomedullary tissues mainly by a noradrenergic transporter system and into storage granules through a vesicular transporter system. MIBG is thus accumulated within adrenergic tissues. However, MIBG does not show any appreciable binding to adrenergic receptors and is minimally metabolized. The plasma membrane and vesicular monoamine transporters can be influenced by numerous drugs. [131I] has a long half-life (8.2 days) and emits high-energy gamma radiation (364 keV). For imaging, [131I]-MIBG is administered intravenously at doses ranging from 0.5 to 1.0mCi (18.5–37MBq) or 0.5mCi (18.5MBq)/ 1.7m2 [389]. [123I] has a shorter half-life (13 hours) and lower-energy gamma rays (159keV) compared to [131I]. [123I]-MIBG is administered intravenously at doses ranging from 3mCi in children to 10mCi in adults [389, 710, 711]. The absorbed radiation dose from 10mCi [370MBq] of [123I]-MIBG approaches that of 0.5mCi (18.5MBq) of [131I]-MIBG [711]. Both [123I]- and [131I]-MIBG require a saturated solution of potassium iodine (SSKI, 100 mg twice a day for 4 or 7 days, respectively) to be used to block thyroid gland accumulation of free [123/131I]. It should be noted that [123/131I]-MIBG is normally accumulated in the myocardium, spleen, liver, urinary bladder, lungs, and salivary glands, large intestine, and cerebellum. Moreover, the normal adrenal gland may show MIBG uptake (in as many as 75% of patients) [710, 712]. Some of the MIBG is taken up by platelets. Thrombocytopenia may occur but usually only if with higher treatment doses of [131I]-MIBG. There is also a slight risk of decreased thyroid function, as seen in experimental conditions with rats [713] and in children receiving larger doses of [131I]-MIBG for therapy of neuroendocrine tumors [714, 715]. The study is relatively expensive and the patient must usually be scanned at 24 hours and again at either 48 or 72 hours after injection of the radioisotope to determine whether images that appear on the early scan are physiological and will fade or are tumors and will persist or increase in intensity on the later scan. MIBG labeled with [131I] provides negative results in up to one-third of patients with proven pheochromocytomas. Much better sensitivity is, however, available with MIBG labeled with [123I] and it offers improved sensitivity [288, 672, 709, 716, 717]. Recently, a new scoring system, based on different uptakes of [123I]-MIBG by an organ/tissue, has been introduced (liver uptake was used as a reference; uptake more intense than in liver was classified as positive) [709]. This approach indicated high specificity (100%), sensitivity (91.5%), and accuracy (94%) in the diagnostic localization of adrenal or extra-adrenal sporadic or familial pheochromocytoma. Another advantage of [123I] over [131I] labeled MIBG is its additional utility for imaging by single photon emission computed tomography (SPECT). The agent also has a shorter half-life compared to [131I]-MIBG (13 hours vs 8.2 days), so that higher doses can be used [288]. The accumulation of MIBG can be decreased by several types of drugs A: agents that deplete catecholamine

100 Chapter 8 Table 8.2 Interfering pharmaceuticals that may affect [131I]-MIBG uptake by tumors and alternative therapy or non-interfering pharmaceuticals that can be used if necessary

Interfering Pharmaceuticals

Length of Time Pharmaceutical Must Be Discontinued Before [131I]-MIBG Therapy

Mechanisms of Interference

Labetalol Reserpine Calcium channel blockers Tricyclic antidepressants Phenylephrine Pseudoephedrine Phenylpropanolamine Ephedrine Atypical antidepressants

72 hours 21 days 72 hours 21 days 48 hours 48 hours 48 hours 48 hours 21 days

MIBG uptake inhibition MIBG storage depletion MIBG uptake inhibition MIBG storage depletion MIBG storage depletion MIBG storage depletion MIBG storage depletion MIBG storage depletion MIBG uptake inhibition

Adapted from Solanki et al. [718].

stores, such as sympathomimetics, reserpine, B: agents that inhibit cell catecholamine transporters, including cocaine and tricyclic antidepressants C: and other drugs such as calcium channel blockers and certain ␣- and ␤-adrenergic receptor blockers (Table 8.2) [718]. It is suggested that most of these drugs be withheld for about 2 weeks before undergoing MIBG scintigraphy. [131I]- and [123I]-MIBG scintigraphy has been used extensively in the workup of patients with pheochromocytoma (Figure 8.3) [672, 709, 719–723]. With [123I]-MIBG, SPECT is usually carried out [724]. [123I]-MIBG is particularly useful in detecting recurrent or metastatic pheochromocytoma, tumors with fibrosis, those in unusual locations, or in areas with distorted anatomy (Figure 8.4) [288, 721, 725, 726]. [131I]-MIBG scintigraphy has a sensitivity ranging from 77% to 90% and a high specificity (95–100%) for pheochromocytoma [36, 280, 722, 723]. Likewise, [123I]-MIBG scintigraphy has a sensitivity ranging from 83% to 100% and a high specificity (95–100%) for pheochromocytoma [280, 717, 727]. In the clinical setting, for most – but not all – patients, a negative result on [131I]- or [123I]-MIBG scintigraphy excludes a diagnosis of pheochromocytoma, while abnormal uptake on [131I]- or [123I]-MIBG scintigraphy usually confirms the presence of pheochromocytoma. Rarely, false-positive [131I]-MIBG examinations have been reported in cases of adrenal carcinoma [728], liver hemangioma [729], and in infectious lesions such as actinomycosis [730]. False-negative MIBG examinations may be expected with pheochromocytomas that have undergone necrosis or with dedifferentiated pheochromocytomas. Fusion imaging techniques of [123I]-MIBG SPECT with CT/MRI, although not yet in widespread use, hold great diagnostic potential in the evaluation of patients with pheochromocytoma [722].

8.2.2

Positron Emission Tomography

PET offers the advantage of assessment of physiological and pathophysiological processes: cellular metabolism, tissue perfusion, and DNA and protein

Current Trends in Localization of Pheochromocytoma 101

Figure 8.3 [123I]-MIBG scintigraphy that shows right adrenal pheochromocytoma (arrow).

Figure 8.4 [123I]-MIBG scintigraphy that shows metastatic pheochromocytoma (arrows show some lesions but not all).

synthesis, and, relevant to endocrine oncology, local synthesis, uptake, storage, and receptors for hormones. Functional imaging aids initial preoperative staging, diagnostic evaluation of suspicious lesions, identification of metastatic or recurrent tumors, refining prognosis, and deciding on and predicting responses to therapy [731]. PET scanning offers better resolution than SPECT due to the relatively intense radioactivity and coincidence detection, which increases signal-tonoise ratios. The duration of scanning is also relatively short. Thus, PET enables quantitative assessments of amounts of radioactivity in different tissues over time (“time–activity curves”). PET imaging is done within minutes or hours after injection of short-lived positron emitting agents. Low radiation exposure and superior spatial resolution are among the advantages of PET, while cost and limited availability of the radiopharmaceuticals and PET equipment (including cyclotron) still prohibit more widespread use. Most PET radiopharmaceuticals used for the detection of pheochromocytoma enter the pheochromocytoma cell using the cell membrane norepinephrine transporter. Dopamine is a better substrate for the norepinephrine transporter than most other amines, including norepinephrine. Thus, a labeled analog of dopamine should be useful as a scintigraphic imaging agent. In a series of 28 patients with known pheochromocytoma 6-[18F]-fluorodopamine

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Liver

Liver Pancreas

Pancreas

Tumor Kidney

(a)

Kidney

(b) 18

Figure 8.5 6-[ F]-fluorodopamine PET scan (transaxial view) (a) before and (b) after adrenalectomy for a large left adrenal pheochromocytoma (large arrow). Adapted from Pacak et al. [2].

PET scans were positive and localized adrenal and extra-adrenal pheochromocytomas in all (Figures 8.5 and 8.6) [16]. In another study [732], it has been showed that in patients with metastatic pheochromocytoma, 6-[18F]fluorodopamine PET localized pheochromocytoma in all patients and showed a large number of foci that were not imaged with [131I]-MIBG scintigraphy. Thus, 6-[18F]-fluorodopamine PET was found to be a superior imaging method in patients with metastatic pheochromocytoma (Figure 8.7). Furthermore, current use of new PET/CT devices is a new promising avenue in more accurate diagnostic localization of various tumors including pheochromocytoma (Figure 8.8). More recently, however, we have identified several pheochromocytomas that were negative on 6-[18F]-fluorodopamine PET scans [281]. All these pheochromocytomas also had negative [131I]- or [123I]-MIBG scintigraphy. Our preliminary data suggest that negative 6-[18F]-fluorodopamine PET scans reflect the lack of the cell membrane norepinephrine transporter system or catecholamine storage vesicles (unpublished observations). PET [11C]-hydroxyephedrine, [11C]-epinephrine, and [18F]-dihydroxyphenylalanine, [283–285, 288, 707, 733, 734] are other PET imaging agents. However, these agents have all been shown to have a limited diagnostic yield due to their less than perfect sensitivity and/or specificity. This could be partly due to their limited affinity for both cell membrane and vesicular norepinephrine transporter systems as well as short half-life of [11C] radiopharmaceuticals (20 minutes), which renders the implementation of whole-body scans difficult. The use of the maximal standard uptake value to distinguish adrenal pheochromocytoma from the normal adrenal gland has been recently introduced [284]. [18F]-dihydroxyphenylalanine is a precursor of dopamine and has also been used in patients with pheochromocytoma. The normal adrenals do not show

Current Trends in Localization of Pheochromocytoma 103

Liver

Right kidney

Left kidney Left ureter L iv er

Kid ney

Urinary bladder

Ur et er

Figure 8.6 6-[18F]-fluorodopamine PET scan in a patient with a primary pheochromocytoma in urinary bladder (filled arrow head) and a small lymphatic node metastasis (open arrow head).

Figure 8.7 6-[18F]-fluorodopamine PET scan in a patient with a large primary pheochromocytoma in abdomen (filled arrow head) and multiple bony metastases (open arrow head).

[18F]-dihydroxyphenylalanine uptake. [18F]-dihydroxyphenylalanine was used in a study of 14 patients with benign adrenal pheochromocytoma and a small number of patients (n ⫽ 3) with extra-adrenal but not metastatic pheochromocytoma [283]. In the former group, all tumors were localized with [18F]-dihydroxyphenylalanine PET, while in the latter group [18F]-dihydroxyphenylalanine PET imaging was concordant with MRI results in 1 of the 3 patients and imaged a tumor that was not seen with [131I]-MIBG scintigraphy [283]. In a recent study of 10 patients with glomus tumors these tumors arise from the paraganglionic tissue of the head and neck), 11 of the 15 presumed tumors diagnosed by [18F]-dihydroxyphenylalanine PET were confirmed by MRI [282]. Compared to other radiopharmaceuticals 6-[18F]-fluorodopamine PET offers several advantages as a functional imaging agent in pheochromocytoma. First, 6[18F]-fluorodopamine PET results in a lower total cumulative radiation dose than [131I]-MIBG [711, 735, 736]; the latter also necessitates thyroid blocking with administration of iodine. Moreover, PET scanning is carried out immediately

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(b)

(a)

Figure 8.8 6-[18F]-fluorodopamine (a) PET scan, (b) CT scan, and (c) fused 6-[18F]-fluorodopamine PET/CT scan in a patient with a left adrenal pheochromocytoma (arrow).

(c)

after administration of 6-[18F]-fluorodopamine, as opposed to the 24–48-hour delay necessary for [131I]-MIBG scanning, and yields tomographic images as opposed to the planar images. 6-[18F]-fluorodopamine is also more specific for pheochromocytoma than other amines such as dihydroxyphenylalanine, because the latter are taken up as amines by all body cells and are converted to dopamine. A major disadvantage of 6-[18F]-fluorodopamine PET scanning is, however, that this agent is currently available only at few clinical centers. Furthermore, further studies are needed to compare [123I]-MIBG with 6-[18F]-fluorodopamine. Increased glucose metabolism characterizes various malignant tumors, thus the uptake of glucose labeled with [18F]-fluoride can be useful in the imaging of these tumors. Uptake of FDG by cancer cells is based on an increased metabolic rate of glucose [737]. Several case reports and articles have shown that FDG successfully localizes pheochromocytoma with a variable sensitivity [284, 707, 738, 739]. Shulkin et al. [707] demonstrated that it has a higher sensitivity for metastatic (82%) than benign pheochromocytoma (58%). However, as in all tumors, FDG is non-specific, and Shulkin et al. also showed that in benign pheochromocytoma, while FDG localized 58% of the cases, MIBG localized 83%. In contrast, in malignant pheochromocytoma, FDG localized 82% whereas MIBG localized 88% [707]. In that series, they had four pheochromocytomas that did not accumulate MIBG but did accumulate FDG. Malignant pheochromocytomas may accumulate FDG more avidly compared to benign pheochromocytomas due to their dedifferentiation associated with

Current Trends in Localization of Pheochromocytoma 105

loss of specific transporters or storage vesicles. Recently, we hypothesized that such dedifferentiation would be especially prevalent in aggressive cases of malignant pheochromocytoma. We described several cases of metastatic pheochromocytoma that demonstrated discordant imaging results when more lesions were found using FDG than 6-[18F]-fluorodopamine PET or MIBG scintigraphy [281]. Nevertheless FDG cannot distinguish malignant from benign disease. It should be noted that the use of FDG is not recommended in the initial diagnostic localization of pheochromocytoma. This radiopharmaceutical is non-specific for this tumor. However, it can be useful in those patients in whom other imaging modalities are negative and in rapidly growing metastatic pheochromocytoma that is becoming undifferentiated losing the property to accumulate more specific agents [281, 389]. Overall advantages of PET are that it can be done within minutes or hours after injection of short-lived positron emitting agents, there is a low radiation exposure, and superior spatial resolution. Cost and limited availability of the radiopharmaceuticals and PET equipment still prohibit more widespread use of this imaging modality.

8.2.3 Somatostatin Receptor Scintigraphy (Octreoscan) Up to 73% of pheochromocytoma cells express somatostatin receptors in vitro [740]. Octreotide is an 8-amino-acid-long peptidic analog of somatostatin that is metabolically stable and has highest affinity for subtype-2 somatostatin receptors, high affinity for subtype-5 receptors, moderate affinity for subtype-3 receptors, and no affinity for the subtype-1 and -4 receptors of somatostatin [741]. [111In]-diethylenetriamine pentaacetic acid (DTPA), with a half-life of 2.8 days and gamma-ray emissions of 173 and 247keV, is usually used for labeling octreotide. Octreotide is given intravenously at doses of 3–6mCi [111–222MBq] and scintigraphic views are obtained at 4, 24, and 48 hours, as needed. SPECT imaging should be performed. Octreotide is predominantly (85%) cleared by the kidneys within 24 hours [742, 743]. Sites of physiological uptake include the mammary glands, liver, spleen, kidneys, bowel, gall bladder, pituitary, thyroid, and salivary glands [742–745]. Infections, inflammation, and recent surgery cause false-positive results [746, 747]. Inflamed joints in patients with arthritis also show increased octreotide uptake [288]. Somatostatin receptor scintigraphy (SRS) imaging (with either [123I]-Tyr3DTPA-octreotide or [111In]-DTPA-octreotide) has been used in patients with pheochromocytoma [278, 279, 748–752]. However, the interpretation of SRS is hampered by the normal presence of somatostatin receptors in a wide range of tissues as well as in inflammatory sites. Another drawback to imaging of intra-adrenal pheochromocytoma with SRS is the significant degree of octreotide uptake seen in the kidneys [753, 754] which reduces the scintigraphic sensitivity of [111In]-DTPA-octreotide for small tumors in the peri-renal region [753, 754]. Although the infusion of amino acid solutions such as lysine and arginine can lower renal uptake, this technique is not yet widely implemented [755]. Metastatic pheochromocytomas may show either loss or gain of somatostatin receptors [748, 756] and, consequently, negative or positive [111In]-DTPA-octreotide studies, can also be expected in these patients.

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Only a few reports have compared [123/131I]-MIBG with SRS in the same patients with pheochromocytoma [277, 279, 280, 751, 752]. Published reports have not found SRS to be helpful in the localization of primary pheochromocytomas [280], with SRS studies being negative in most patients (66–75%) with benign pheochromocytoma (despite positive [123I]- or [131I]-MIBG studies) [280, 668]. Malignant/metastatic pheochromocytomas are better detected with SRS compared to [123I]-MIBG scintigraphy (finding 87% vs 57% of lesions) [280]. Scans MIBG as well as 6-[18F]-fluorodopamine can sometimes be negative in patients with malignant pheochromocytoma, possibly because of decreased expression of the cell membrane norepinephrine transporter ([757, 758], In such cases, SRS should be performed to localize pheochromocytoma, since in various tumor tissues increased somatostatin receptor expression is frequently inversely related to the degree of differentiation [759]. Tables 8.3 and 8.4 summarize results of various functional imaging modalities in the localization of adrenal as well as extra-adrenal pheochromocytomas. In situations when the presence of pheochromocytoma or paraganglioma is biochemically proven but the tumor cannot be localized (e.g. anatomical

Table 8.3 Overview of selected results of functional imaging for pheochromocytoma Radioligand Proven utility [123I]-MIBG

Proven utility [11C]hydroxyephedrine Proven utility [18F]-DA

Proven utility [18F]-DOPA Moderate utility [18F]-FDG

Utility

References

Only recently has become more available in the United States In 75 patients with benign or malignant pheochromocytoma sensitivity of detection was almost 90%

[719]

In 10 patients sensitivity was 90% In 19 patients sensitivity was 90% and specificity 100%

[834] [708]

In 18 patients with metastatic pheochromocytoma, was compared to [131I]-MIBG and found to be a superior functional imaging modality: it localized pheochromocytomas in all patients and showed a large number of foci that were not imaged with [131I]-MIBG scintigraphy Is comparable to [123I]-MIBG scintigraphy in imaging adrenal and/or benign pheochromocytomas

[732]

100% sensitivity and specificity in 14 patients with 17 tumors

[283]

Had 72% sensitivity in localizing adrenal or metastatic pheochromocytomas (n ⫽ 29) Pheochromocytomas (n ⫽ 2) had a median standard [18F]-FDG uptake value (SUV) of

[707]

[280]

[Pacak et al., unpublished data]

[835] (Continued)

Current Trends in Localization of Pheochromocytoma 107 Table 8.3 (Continued) Radioligand

Utility

References

3.0, which was slightly higher than that of functioning adrenal adenomas (n ⫽ 7; median SUV ⫽ 2.3) and higher than that of non-functioning adrenal adenomas (n ⫽ 3; median SUV ⫽ 1.7) Selectively useful [111In]-DTPAoctreotide

Positive for tumors larger than 1cm that expressed somatostatin receptor type 2A (n ⫽ 25) but also for a subset of tumors (n ⫽ 6) that expressed somatostatin receptor type 3 (which were confined to the plasma membrane) Differences in the imaging of benign adrenal or metastatic pheochromocytoma have been noted. In a study of 32 patients with adrenal disease and 8 with metastatic, the sensitivity of SRS was 25% and 88%, respectively

[836]

[280]

DOPA: dihydroxyphenylalanine; DA: dopamine; SUV: standard uptabe value. For other abbreviations refer to text. Adapted from Ilias et al. [664].

Table 8.4 Overview of selected results from functional imaging for paraganglioma Radioligand

Utility

References

Moderate utility [123I]-MIBG

In 35 patients had 71% sensitivity

[837]

Is superior to [123I]-MIBG scintigraphy in imaging paragangliomas

[Pacak et al., unpublished data]

In 10 patients with mutations of the succinate dehydrogenase subunit D gene (which entails a predisposition for paragangliomas and pheochromocytomas) it showed more tumors than MRI

[282]

Proven utility [18F]-DA Proven utility [18F]-DOPA

[18F]-FDG

Further evaluation pending Shows uptake but the accumulated experience gathered is rather limited to case reports and small case series

Proven utility [123I]-Tyr3-DTPA- 90–94% sensitivity in 86 patients octreotide [111In]-DTPAoctreotide

Proven utility Sensitivity was 100% in 31 patients Useful and reliable for the localization of head and neck tumors that are at least 1cm in diameter with 97% sensitivity and 82% specificity in 60 patients

[838–840]

[749, 841–843]

[844] [845, 846]

DOPA: dihydroxyphenylalanine; DA: dopamine. For other abbreviations refer to text. Adapted from Ilias et al. [664].

108 Chapter 8 Biochemically proven pheochromocytoma

CT/MRI

[123I]- MIBG or 6-[18F]-fluorodopamine

⫹

⫺

[18F]-fluorodopamine, FDG, or Octreoscan

Pheochromocytoma localized

Therapy

⫹

⫺

Observation and repeat diagnostic biochemical work-up in 2–6 months

Figure 8.9 Diagnostic localization of pheochromocytoma.

changes due to previous surgery, unusual locations) venous sampling for catecholamines and metanephrines may be helpful [86, 662].

8.2.4

Current Imaging Algorithm

In summary, the strategies outlined above provide the basis for diagnostic localization of pheochromocytoma as described in Figure 8.9 despite the fact that a generally accepted and cost-effective approach for the diagnostic localization of pheochromocytoma is yet to be established. In patients with biochemically-proven pheochromocytoma, we propose the use of anatomical imaging methods (either CT or MRI) for initial imaging of the adrenals. In some cases, as in children or in pregnancy, MRI is preferred but U/S may also be considered. Negative imaging of the adrenals should be followed by abdomen, chest, and neck CT or MRI scans. Except for adrenal epinephrine-secreting tumors less than 5cm in diameter, the presence of pheochromocytoma should always be ruled out or confirmed with functional imaging (even if CT and MRI are negative but pheochromocytoma is biochemically proven). The functional imaging test of choice is [123I]-MIBG, or if this is not possible, [131I]-MIBG. If the MIBG scan is negative, PET studies should be performed with specific ligands, preferably 6-[18F]-fluorodopamine. If these are also negative, the patient most probably has a poorly differentiated tumor (commonly malignant pheochromocytoma), and scintigraphy with less or nonspecific ligands such as [18F]-dihydroxyphenylalanine, Octreoscan, or FDG PET should be carried out. Venous catheter studies may be also helpful to localize a tumor.

CH APTE R 9

Treatment of pheochromocytoma

The optimal therapy for a pheochromocytoma is prompt surgical removal of the tumor since an unresected tumor represents a time bomb waiting to explode with a potentially lethal hypertensive crisis [47]. Safe surgical removal requires the efforts of a team made up of an internist, an anesthesiologist, and a surgeon, preferably all with previous experience with pheochromocytoma. During the last decade laparoscopic surgery has become widely accepted as the first choice for removal of abdominal (especially adrenal) pheochromocytoma [760–772]. Patients undergoing this surgical procedure have a more rapid recovery and less morbidity compared to those who undergo classic open surgery. Previously constraints for the laparoscopic procedure included tumor size (6–9cm), multifocal tumors, and suspicion of malignant disease requiring en bloc resection. However, today even tumors larger than 9cm, multifocal tumors, as well as those that are malignant (except those that invade adjacent structures) can be removed by this technique. In cases of bilateral adrenal involvement (e.g. in patients with von Hippel–Lindau (VHL) or multiple endocrine neoplasia type 2 (MEN-2) syndrome), an adrenal cortex-sparing laparoscopic procedure (subtotal or partial adrenalectomy, adrenocortical function-preserving surgery) is often recommended to save the adrenal cortex and prevent permanent glucocorticoid deficiency that would require lifetime glucocorticoid and mineralocorticoid replacement [768, 773]. However, decisions concerning this procedure must be always balanced with the likelihood of recurrent disease in the adrenal remnant (a new tumor can develop due to genetic predisposition). The risk of the tumor recurrence is up to 30% within 7–10 years of initial resection [768, 773–775]. Even when some adrenal cortical tissue is left in place, some patients may still present with adrenocortical insufficiency requiring glucocorticoid replacement. Operative mortality is less than 1% provided there is appropriate medical preparation and procedures are performed by a skilled surgeon and an experienced anesthesiologist [765, 766, 776]. Subtotal adrenalectomy may also be considered in patients with sporadic unilateral pheochromocytomas in whom the contralateral adrenal gland was previously removed or damaged during previous surgery.

109

110 Chapter 9

9.1

Medical Therapy and Preparation for Surgery

Preoperative medical treatment is directed at controlling hypertension, including hypertensive crises during the removal of pheochromocytoma, maintaining stable blood pressure during surgery and minimizing adverse effects during anesthesia [5, 88, 777–780]. Maintenance of adequate blood pressure control for 2 weeks before the operation is an important aspect of management once a tumor is diagnosed. Treatment is most often initiated with the non-competitive α-adrenoceptor blocker, phenoxybenzamine. The initial dose of this long-acting drug is usually 10 mg twice a day, increased until the clinical manifestations are controlled or side effects appear. Mostly a total daily dose of 1mg/kg is sufficient. Some patients may require much larger doses and the dosage may be increased in increments of 10–20mg every 2–3 days. If the drug is given in too high an initial dosage, the patient may be prone to postural hypotension. As the correct dose is approached, paroxysmal hypertensive episodes will be brought under control, and when the right dose is achieved the patient should be normotensive. Other α-adrenoceptor blocking agents of use include prazosin (minipress), terazosin (hytrin), and doxazosin (cardura) [781, 782]. All three are specific α1-adrenergic antagonists; all have the potential for severe postural hypotension immediately after the first dose, which should therefore be given just as the patient is ready to climb into bed. Thereafter, the dosage can be increased as needed. Prazosin is administered in doses of 2–5mg 2 or 3 times a day, while terazosin is given in doses of 2–5mg once daily, and doxazosin in doses of 2–8 mg once daily. Labetalol (normodyne or trandate), a drug with both α- and β-antagonistic activity, may also be used in a dosage of 100–600 mg twice daily [783–785]. The advantages of labetalol are that an α- and a β-blocker are given simultaneously and both oral and intravenous formulations of the drug are readily available. However, with labetalol, one is forced to use a fixed ratio of α- to β-antagonistic activity (about 1:7). This often means that more slowing of the heart occurs, rather than control of hypertension, when what usually is needed is a drug with an α to β ratio of 4:1 or more. It is usually better to use the amounts needed of individual α- and β-blockers. Large doses of any of these drugs may be necessary to control blood pressure. If the blood pressure is controlled and the patient given a normal or high salt diet, the patient’s diminished blood volume will be restored to normal. As normal blood volume is restored, the degree of postural hypotension decreases. β-adrenergic blocking agents are only needed when significant tachycardia or a catecholamine-induced arrhythmia occurs. A β-blocker should never be used in the absence of an α-blocker since the former will exacerbate epinephrine-induced vasoconstriction by blocking its vasodilator component. This will make hypertensive episodes worse in subjects on a β-blocker alone. Metyrosine (Demser) is, in our experience, a valuable drug in the treatment of patients with pheochromocytoma; but it is rarely used elsewhere. The drug competitively inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis [786]. Thus, it facilitates blood pressure control

Treatment of Pheochromocytoma 111

both before and during surgery, especially during the induction of anesthesia and surgical manipulation of the tumor when extensive sympathetic activation or catecholamine release may occur. Treatment is started at a dosage of 250 mg orally every 6–8 hours and thereafter the dose is increased by 250– 500 mg every 2–3 days or as necessary up to a total dose of 1.5–4.0 g/day. The drug is a substituted amino acid (i.e. α-methyl-L-tyrosine) and therefore it readily crosses the blood–brain barrier. Thus, it inhibits catecholamine synthesis in the brain as well as in the periphery and frequently causes sedation and rarely causes extrapyramidal signs (e.g. parkinsonism) in older patients. These symptoms are reversed rapidly when the dosage is lowered or the drug is discontinued. If dreaming abnormalities are reported by the patient, then the dosage should be reduced to the previous lower dose for 1 or 2 days or until the abnormality disappears. Then the dosage should be increased more slowly until the desired effects are reached. Demser has side effects of diarrhea and crystalluria, especially with doses higher than 4 g/day. Various calcium channel blockers have been used to control blood pressure both before and during surgery [15, 36, 787]. In our experience, if both metyrosine and α-antagonists are used, the blood pressure of the patient is much less labile both during anesthesia and surgery, intraoperative blood loss is reduced, and less volume replacement is required during surgery, than if only α-antagonists are used [788]. It is our custom to administer 1mg/kg of dibenzyline and 0.5–0.75 g of metyrosine orally at midnight on the evening before surgery. Hypertensive crises that can manifest as severe headache, visual disturbances, acute myocardial infarction (due to either myocarditis or coronary spasm), congestive heart failure followed by acute cardiogenic pulmonary edema, or cerebrovascular accident (due to enhanced coagulation or vasospasm) are appropriately treated with an intravenous bolus of 5mg phentolamine (Regitine). Phentolamine has a very short half-time; therefore if necessary, the same dose can be repeated every 2 minutes until hypertension is adequately controlled or phentolamine is given as a continuous infusion (100 mg of phentolamine in 500ml of 5% dextrose in water). Only rarely pheochromocytoma be resistant will a patient with to Regitine [7]. A continuous intravenous infusion of sodium nitroprusside (preparation similar to phentolamine) or in some cases nifedipine (10mg orally or sublingually) can also be used to control hypertension. Due attention should also be given to the possibility that some drugs, such as tricyclic antidepressants, metoclopramide, and naloxone, can cause hypertensive crisis in patients with pheochromocytoma. In patients with clinical manifestations due to β-adrenoceptor stimulation (e.g. tachycardia or arrhythmias, angina, nervousness, etc.), β-adrenergic receptor blockers (such as propranolol, atenolol, or metoprolol) are indicated. β-adrenoceptor blockers, however, should never be employed before α-adrenoceptor blockers are administered since unopposed stimulation of α-adrenoceptors and loss of β-adrenoceptor-mediated vasodilation may cause a serious and life-threatening elevation of blood pressure. Labetalol, a combined αand β-adrenoceptor blocker, is not appropriate since in some patients it may cause hypertension, perhaps by its greater, effect antogonistic on β- than

112 Chapter 9

α-adrenoceptors [789]. It should be noted that both α- and β-adrenoceptor blockers may cause slight elevations of plasma-free metanephrines levels [385]. The most troublesome drug is phenoxybenzamine, which can lead to substantial increases in plasma and urinary norepinephrine, normelanephrine, and VMA. In contrast, calcium channel blockers also used to control hypertension and tachycardia in patients with pheochromocytoma do not affect plasma metanephrine levels. As suggested by Bravo, high-risk patients should have α-adrenergic blockade for surgery. If control of blood pressure is a problem, the addition of a calcium channel blocker may help reduce elevated blood pressure to reasonable levels obviating the need to increase the dosage of αblockers [36]. For patients with intermittent hypertension, the use of calcium channel blockers may be recommended since during normotensive period these drugs do not cause hypotension or orthostatic hypotension [790]. At our institution we usually start with phenoxybenzamine and metyrosine at least 2 weeks before surgery. The patient is admitted the day before surgery. Then at midnight phenoxybenzamine and metyrosine are given (usually 1mg/ kg and 500mg p.o., respectively) and the patient is kept in bed with rails up.

9.2

Postoperative Management

Volume replacement is the treatment of choice if hypotension should occur either during surgery (i.e. after the tumor is removed) or in the postoperative period. The use of pressor agents is ill advised, especially if long-acting α-blockers have been used. In this situation high doses of drugs may be necessary. Control of postoperative hypotension is even more imperative if both metyrosine and dibenzyline are used preoperatively. This is because the former inhibits catecholamine synthesis by both the tumor and the sympathetic nervous system, while the latter blocks the action of any catecholamines that are synthesized. In this situation, the vascular bed is effectively paralyzed in a dilated state. Therefore, the best means to control blood pressure is by adequate volume replacement. For intravascular volume expansion the volume of fluid required is frequently large: about 2–3 l of normal saline the day before surgery and about 0.5–1.5 times the patient’s total blood volume during the first 24–48 hours after removal of the tumor [790]. This is because the half-lives of both metyrosine and phenoxybenzamine are approximately 12 hours, and thus it takes nearly three half-lives or 36 hours for the sympathetic nervous system to resume autoregulation. When this occurs, the renal output begins to increase and the blood pressure and heart rate remain stable. It is at this time that normal replacement volumes can be used (i.e. 125ml/hour). If the last dose of medication was administered on the midnight before surgery, autoregulation usually occurs at about noon on the first postoperative day. Both the type and the amount of fluid replacement needed are readily determined by observation of the blood pressure, heart rate, central venous pressure, and urinary output. It is not unusual for patients to show a 10–12% increase in body weight by the time the diuresis begins. Postoperative hypertension may mean that some tumor tissue was not resected or the patient may have coexisting essential hypertension.

Treatment of Pheochromocytoma 113

Additional rare causes of postoperative hypertension can be accidental ligation of a renal artery or renal failure [103]. However, during the first 24 hours after surgery, hypertension is most likely attributed to pain, volume overload, or autonomic instability [117]. These are all readily treated symptomatically. If hypertension persists in a patient even after he or she has returned to dry weight, the coexistence of essential hypertension is still the most likely diagnosis. Postoperative hypotension reflects volume depletion, drug effect, or adrenocortical insufficiency. Severe, transient hypoglycemia with central nervous system manifestations and sometimes coma may occur within 2 hours following operation [1]. Hypoglycemia results from increased insulin secretion. α-blockers can augment it by reducing inhibition of catecholamines on insulin secretion. β-blockers can impair recovery from hypoglycemia by reducing gluconeogenesis and glycogenolysis, and can mask symptoms and signs associated with low blood sugar (e.g. substantially reduce tachycardia, sweating) [1]. If hypoglycemia develops, infusion with 5% dextrose should be immediately implemented. Postoperative hypotension, decreased appetite, fever, hypoglycemia, and unusual weakness may suggest hypocortisolism or Addisonian crisis. Therefore, plasma and urinary cortisol levels should be measured. This is mainly important in patients in whom adrenal cortex-sparing surgery was performed during resection of tumors in both adrenal glands or in patients in whom adrenal pheochromocytoma was previously removed and adrenal cortex-sparing surgery was performed on the contralateral side. Any attempt to collect specimens for biochemical evidence of a residual tumor should be delayed at least 7 days post surgery to be certain of minimal post-surgical stress effects on the sympatho-adrenal system. We normally suggest collecting a blood sample when the patient is seen by the surgeon 4– 6 weeks post operation. Repeat measurements should be made if symptoms reappear, or approximately yearly. The long-term survival of patients after successful removal of a benign pheochromocytoma is essentially the same as that of age-adjusted normals [791]. Approximately 20–25% of patients remain hypertensive, but this is usually easily controlled with medication [128, 792].

CH A PTE R 1 0

Future trends and perspectives

Currently there is no cure for malignant pheochromocytoma and no reliable prognostic or histopathological diagnostic markers of malignancy exist. Thus, establishing the pathways of tumorigenesis and malignancy in pheochromocytoma represents an important objective that can take advantage of the well-characterized functional nature and genetic background of these tumors and the wealth of information available about chromaffin cell biology. Establishing the pathways of tumorigenesis will facilitate the search for new molecular and genetic markers for diagnosis and targets for treatment of malignant pheochromocytoma. Those markers can then be used for the development of new and improved treatments for metastatic pheochromocytoma. However, due to the rarity of this tumor, large and well-conducted clinical studies that would provide sufficient clinical as well as pathological material are very rare. Future coordinated participation of different medical centers and research institutions, clinicians and investigators from diverse fields seems especially important for progress. From this initiative new and improved clinical algorithms in genetics, diagnosis, treatment, and imaging of sporadic and familial pheochromocytomas may be introduced. It is our view that the most important step toward this success is the application of new genomics and pooteomic-based tools that will identify the pathways involved in the development of pheochromocytoma. From this will come the identification of molecular markers for diagnosis (especially in early stage), prognosis (especially long-term prognosis to develop malignant or recurrent tumor), and targets for new therapeutic options (especially for malignant tumors).

10.1

Genomics in Pheochromocytoma Research

Currently, there remain some familial pheochromocytoma syndromes for which the primary genetic defect is unknown. Also, the genetic basis of the majority of sporadic pheochromocytomas remains largely uncharacterized. Somatic mutations in the genes involved in hereditary pheochromocytoma occur only infrequently in sporadic tumors [402, 793]. By genome-wide scan analysis it now appears that a novel locus in chromosome 2 might account for some remaining cases of familial pheochromocytoma [794]. From a preliminary 114

Future Trends and Perspectives 115

pilot series of tumors, somatic mutations at this same locus may also be responsible for a significant number of cases of sporadic pheochromocytoma. Microarray technology has been utilized recently in identifying and comparing simultaneously the expression of a large number of genes between normal and tumor tissues. This resulted in the identification of crucial genes implicated in tumorigenesis including metastatic potential of various tumors [795–800]. Recently, a cDNA microarray study to compare gene expression profiles in multiple endocrine neoplasia type 2A (MEN-2A)- and von Hippel–Lindau (VHL)-associated pheochromocytomas was conducted [410, 801]. An important group of genes related to hypoxia-driven pathways in VHL tumors was identified (Figures 10.1 and 10.2). Increased expression of many other genes we also observed that have been shown in other studies to be over-expressed in malignant compared with benign pheochromocytomas [264, 265, 406, 802–804]. However, as described earlier in this book, VHL pheochromocytomas have a low rate of malignancy. Thus, the commonalities of gene expression in malignant and VHL-associated pheochromocytomas appear instead to reflect the biochemical phenotype common to these tumors. Malignant and VHL-associated pheochromocytomas produce predominantly norepinephrine and usually have an exclusively noradrenergic biochemical phenotype, whereas MEN-2 tumors produce both epinephrine and norepinephrine [386, 388]. Sporadic, VHL, and malignant pheochromocytomas with a noradrenergic phenotype all show increased expression of the gene for endothelial PAS domain protein 1 (hypoxia-inducible factor 2α, HIF-2α) compared with benign hereditary and sporadic tumors that produce epinephrine [410]. However, it should be pointed out that microarrays are subject to certain limitations [805]. They may not always effectively discriminate between gene clusters with a high degree of sequence homology. Furthermore, they may not indicate to show small variations in gene expression or changes in important but weakly expressed genes [806]. Finally, microarrays usually require 5–25 µg for reliable gene detection, and RNA amplification may cause expression bias. Therefore, microarray results should be confirmed using the quantitative real-time polymerase chain reaction (QRT-PCR) technique [807]. Nevertheless, microarrays studies are well suited for future experiments to screen a large number of genes in order to select those that might be the most important key players in pathogenesis of pheochromocytoma including malignant potential.

10.2

Proteomics in Pheochromocytoma Research

Due to differential splicing and translation as well as post-translation modifications, our 40,000 genes may generate around 1 million distinguishable functional entities at the protein level [808]. Furthermore, in contrast to the genome, the dynamic nature of the proteome allows us to monitor changes in the state of cells and tissues over time [808]. This brings an important advantage to detect and monitor proteome changes before, during, and after therapy, and track pathogenetic mechanisms of a disease including cancer.

*

EPAS-1/HIF-2α Ets-1

pHIF

PDGF-A

GLUT1† † Hexokinase 2 Glucose

utilization

pHIF degradation

* VEGF

PlGF

Angiopoietin 2 Adrenomedullin

PDGFR-B

VEGFR-2

Tie-1

Neuropilin-1

Semaphorin 3F

Matrix metalloproteinase 2 TIMP3 †

VE-cadherin

Matrix metalloproteinase 19

†

†

*

RAMP-3

*

H-cadherin

*

† N-cadherin * Cadherin 19, type 2

Tenascin C

RAMP-2

CYR61

†

TIMP1

*

*

Plexin-D1

CTGF

signaling

Calcitonin receptor like receptor

Stanniocalcin 1

PECAM 1

Integrin α5 Integrin α1 † Integrin α7 * †

†

Fibromodulin † Microfibrillar-associated protein 3 †

Plakoglobin Laminin α2 † Thrombomodulin Perlecan * Glypican 3 Tetranectin Laminin ß2 Notch-3 * † † Laminin γ3 † Fibulin-2 † Glypican 5 † * Adlican † Ephrin-B2 Ephrin-B3 Jagged 1 * Cyclooxygenase 1 Cyclooxygenase 2 Collagen, type I α2 † † † Tensin 2 Matrix Gla protein Ankyrin 3 Phosphatidic acid phosphatase 2b Annexin A1 Basement membrane † † Collagen, type III α1 solubilization Gelsolin Annexin A11 Tropomyosin 2 † Interleukin 4 receptor † Collagen, type IV α1 Collagen, type IV α2 * Endothelial cell detachment † Smoothelin Annexin A13 Collagen, type V α2 Collagen, type V α3 * Cell migration Angiomotin like 2 † Cytoskeletal rearrangement Collagen, type VI α2 † Collagen, type VI α3 † Cell adhesion Aquaporin 1 * Collagen, type VIII α1 † Ficolin-3 † Proliferation † Collagen, type XIV α1 Cell– cell signaling Vasopermeability Collagen, type XV α1 † Alpha2-macroglobulin ADAMTS1 *

Tenascin XB

†

VCAM 1

Cell survival Extracellular matrix reorganization/resynthesis Vessel tube formation

Figure 10.1 A selection of 85 genes more highly expressed in VHL than MEN 2 tumors. The selection represents genes known to be involved in hypoxia or vascular endothelial growth factor signaling pathways or with established functions in angiogenesis, cell migration, adhesion, proliferation, and survival, cell–cell interaction, vascular permeability, and extracellular matrix reorganization. The black arrows indicate connections between genes known to be induced by an upstream signaling protein (e.g. VEGF, CYR61) or transcription factor (e.g. EPAS-1/HIF-2α, Ets-1). The gray arrows show pathways regulating amounts of HIF-1α or -2α protein. The asterisks indicate genes that are more highly expressed in sporadic noradrenergic than adrenergic tumors. The daggers indicate a gene showing no difference in expression of these two groups of tumors. VEGF: vascular endothelial growth factor; EPAS: endothelial PAS domain protein. Adapted from Eisenhofer et al. [410].

116 Chapter 10

pVHL/ubiquitin-ligase complex HIFprolylhydroxylase 3

Future Trends and Perspectives 117 VHL (369 genes, 261 with known function)

MEN-2 (129 genes, 77 with known function)

Extracellular matrix

Cytoskeleton

Apoptosis

Lipid metabolism

ATP-binding biosynthesis

Translation regulation/protein transport

Glucose metabolism

Signal transduction

Ion transport

Cell proliferation

Angiogenesis

Transcription factor/regulation

Nucleotide and nucleic acid metabolism Cell cycle

Figure 10.2 Pie charts showing the functional analysis. The functional analysis of differentially expressed genes in VHL vs MEN-2 tumors (top). Functions of genes for VHL tumors represent those with higher expression in VHL than MEN-2 tumors, whereas functions of genes in MEN-2 tumors are those with higher expression in MEN-2 than VHL tumors. Functions were established based on the annotation provided by the Gene Ontology database (http://www.geneontology.org) and are shown only for genes with known functions. Adapted from Eisenhofer et al. [410].

In recent years, new developments have made proteomic technologies such as two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry (MS), highly applicable to tumor biomarker discovery. For the analysis of complex protein samples MS has evolved as the method of choice [809, 810]. Matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) MS and surface enhanced laser desorption ionization timeof-flight (SELDI-TOF) MS, alone or in tandem with other proteomics techniques, have successfully identified numerous biomarkers in diseases such as breast cancer, rheumatoid arthritis, and lung cancer [811–814]. Recently, MS-based fingerprinting has revealed the existence of previously unknown diagnostic biomarker information in the low-molecular-weight (LMW) region of the serum proteome [815, 816]. A recent study of Brouwers et al. [817] evaluated the hypothesis that the LMW region of the serum proteome contains information based on which pheochromocytoma patients with metastatic disease can be discriminated from those with benign disease. This bioinformatic tool both correctly classified all metastatic pheochromocytomas and distinguished these from all of the patients with benign pheochromocytomas in a masked validation set. Thus, based on these initial results, proteomic fingerprinting analysis appears to point to the existence of potential diagnostic information which then can

118 Chapter 10

be used as a tool to distinguish between patients with benign and metastatic pheochromocytomas. Nevertheless, the low-molecular fragments need to be identified in order for a new diagnostic tests to be introduced. However, even after identification, it is possible that a diagnostic test would still rely on MS to record the presence of the fragment since the development of a specific antibody that recognizes the diagnostically important fragment and not the parental molecule may prove impossible. Whether measurement of the classifying LMW information performed using direct MS-based protein profiling, a multiplexed immunoassay panel, or a hybrid of each can be used to predict a metastatic pheochromocytoma or the potential to develop metastases in the future in patients with the so-called benign pheochromocytoma is unknown and could not be concluded from that study. Another area of proteomic research is the development of protein arrays that, similar to gene arrays, would allow the study of changes in protein expression or modification in tumor tissues or cell cultures [818]. Two basic approaches are available: (a) forward phase arrays, where antibodies are arrayed and probed with cell lysates and (b) reverse phase arrays, where cell lysates are arrayed and probed with antibodies. Currently, the main limitations are relatively a small numbers of available antibodies. The application of MS linked to proteomics in cancer research to discover new markers and targets is in its infancy and further detailed studies and accurate validation tools including mathematical models are needed. Furthermore, although reproducibility is the key to the use of MS for ion fingerprint analysis, the scientific community has to establish a common platform or standardized operating procedures that are necessary for intra- and inter-laboratory comparison [819]. Finally, further effort needs to be made to integrate proteomics with all the information from the other approaches such as genomics and metabolomics [808]. Nevertheless, proteomics holds tremendous promise for biomarker discovery. If successfully applied, this will help us to uncover new pathogenetic processes in cancer cells and link them to appropriate therapeutic options tailored to the individual patient.

10.3 Future Therapeutic Modalities for Pheochromocytoma Accumulation and retention of [123/131I]-MIBG (metaiodobenzylguanidine) in pheochromocytoma tumor cells depends on expression of catecholamine transporters on the cell surface and in chromaffin granules within which catecholamines are stored [820, 821]. Thus, improved and more toxic substrates for these transporters or strategies designed to increase the expression of transporter systems on tumor cells before [131I]-MIBG therapy offer approaches to improve therapeutic targeting. Such approaches, which to date have been mainly limited to experimental model systems, include norepinephrine transporter gene transfer [822, 823] and increasing expression of the norepinephrine transporter using cisplatin [824] and combinations of interferon-γ, tumor necrosis factor-α, and retinoic acid [825]. Development of other more effective targeted therapies for malignant pheochromocytomas can be expected to take advantage of the wealth of new drugs being developed in

Future Trends and Perspectives 119

response to advances in the elucidation of pathways responsible for other cancers. Use of microarray and proteomics technologies for understanding the pathways contributing to benign and malignant pheochromocytoma should be useful for guiding the choice of the most appropriate of these agents for future therapeutic trials. Already there are suggestions of possible targets in malignant pheochromocytoma for new classes of anticancer drugs being developed in response to improved understanding of genes and pathways/ markers involved in other malignancies (e.g. vascular endothelial growth factor, N-cadherin, HIF-2α) [264, 265, 468, 803, 826]. Over-expression of heat shock protein 90 in malignant pheochromocytomas [83], in particular, indicates one promising therapeutic target for a new class of anticancer drugs being developed to inhibit this protein [827]. Heat shock protein 90 is now understood to function as a molecular chaperone that maintains the folding and conformation of proteins crucial in regulating the balance between degradation and synthesis of cell signaling proteins, including many involved in multiple oncogenic pathways. Such proteins include the human telomerase reverse transcriptase, which also shows increased expression in malignant pheochromocytoma [83, 828]. Should heat shock protein 90 be proven to be involved in the transition from a benign to a malignant pheochromocytoma phenotype, then new inhibitors of the protein, such as 17-allylamino, 17-demethoxygeldamycin [829], may be of value as treatments for the malignancy. Findings from several groups that malignant pheochromocytomas are characterized by increased expression of factors associated with angiogenesis suggest other pathways that may respond to new anti-angiogenic drugs currently in development or approved by the Food and Drug Administration for specific types of cancer. For example, recently it has been demonstrated that the anti-angiogenic agent linomide significantly inhibits the growth of VHL-related pheochromocytoma explants in nude mice reflecting decreased tumor vascularity and vascular endothelial growth factor mRNA levels [830]. Another anti-angiogenic drug halofuginone has been introduced and showed a significant tumor growth inhibition in nude mice implanted with pheochromocytoma obtained from a VHL patient [831]. Therefore, it has been proposed that targeting vascular endothelial growth factor may constitute an effective anti-tumoral therapy in VHL patients. However, even with the advent of new therapeutic targets and drugs it remains likely that a combination of therapies will be required for effective treatment. Given the heterogeneous nature of pheochromocytomas, it is also likely that for best therapeutic results, treatments may have to be tailored according to differences in underlying pathways. Developing such approaches will benefit from the opportunities available from the new genomic and proteomic methodologies and other developments associated with new drug discovery technologies, such as highthroughput screening of drug candidates.

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Index Acetaminophen 87 Acute peripheral ischemia 18–19 Addisonian crisis 113 Adrenal chromaffin cells 41, 42, 45, 47, 48, 50, 51, 52, 55, 61, 62 Adrenal incidentalomas 8, 14–15, 81 Adrenal medullary hormonal system 60–62 Adrenal pheochromocytomas 2, 21, 37, 38, 44, 91, 94, 102, 109, 113 Adrenergic receptors 20, 99 and catecholamines 41 classification 65 and functions 64–69 mediated response 66–68 Adrenergic sweating 71 Adrenoceptor blockers 16, 110–112 Albuterol 64 Alcohol dehydrogenase (ADH) 51, 52 Aldehyde/aldose reductase 48 Aldehyde dehydrogenase (AD) 48, 51 Aldomet, See Alpha-methyl-L-dopa Alezais, H. 3 Alpha-adrenergic blockers 17, 24, 26, 27, 89, 110, 112, 113 Alpha-methyl-L-dopa 60 Alpha-methyl-L-tyrosine 60 Alprenolol 64 Amphetamine 14, 46 Anatomical imaging 34 computed tomography 94–96 magnetic resonance imaging 96–97 Anti-angiogenic drugs 119 Apomorphine 69 Apoptosis hypothesis 37–38 Armstrong, M.D. 3 Aromatic-L-amino acid decarboxylase 42, 43, 60 Arrhythmias 17 Atenolol 16, 26, 64 Autoreceptor 46 Axelrod, J. 3 Benign pheochromocytoma 5, 20–21, 104, 113, 115, 117, 118 Beta-blockers 17, 24, 26, 110, 113 Biochemical diagnosis 1, 15, 26–28, 33, 72

algorithm 90 catecholamine excess 72–74 diet and drugs, interferences 85–88 follow-up testing 81–84 initial testing 78–81, 89 interpretative considerations 91 measurement methods 74–76 pharmacologic tests 88–91 plasma and urine specimens, collection and storage 84–85 reference intervals 76–78 Bromocriptine 69 Buspirone 87 Caffeic acid 85 Calcium channel blockers 15, 87, 100, 111, 112 Carbidopa 60, 87 Cardiac emergencies 17 arrhythmias 17 catecholamine-induced cardiomyopathy 17–18 myocardial infarction 18 myocardial ischemia 18 Cardura, See Doxazosin Carney’s triad 39 Castleman’s disease 11 Catapres, See Clonidine Catechol-O-methyltransferase (COMT) 48, 51, 54–55, 84 Catecholamine-induced cardiomyopathy 17–18 Catecholamine-producing tumors 1 “Catecholamine storm” 24 Catecholamines 41 actions 69–71 adrenergic receptors 64–69 biosynthetic pathway 41–43 elimination 58–60, 78 excess 12, 14, 18, 25 biochemical tests 72–74 signs 24 symptoms 37 kinetics 58–60 measurement 73, 79 metabolism in hepatomesenteric organs 51–54

167

168 Index Catecholamines (Contd.) metabolism (Contd.) and release by pheochromocytoma 54–58 in paroxysmal attack 10, 18, 20, 55–56 pharmacology 60 physiology adrenal medullary hormonal system 60–62 peripheral dopamine systems 62–64 rate-limiting step 41 in pheochromocytoma 43–45 regulation 43 release 14, 16, 17, 21, 26, 55–57, 79, 83, 91 by sympathoadrenal system 45–46 sources 41–43 storage by sympathoadrenal system 45–46 synthesis 41–43, 111 cDNA microarray study 115 Chemotherapy 23–24 Childhood pheochromocytoma 24–26 differential diagnosis 25 measurements 25–26, 27 signs and symptoms 25 treatment 26 Chromaffin cells 7, 46 Chromaffin reaction 3, 7 mixture 7 trabecular 7 “zellballen” 7 Chromatographic methods 75 Chromogranins 7, 45–46, 62, 72 Cisplatin 24, 118 Clinical presentation 8 in children 24–26 differential diagnosis 12–14, 25, 59 endocrine emergency 15–20 factitious pheochromocytoma 14, 29 incidentally discovered adrenal mass 14–15 malignant pheochromocytoma 20–24 in pregnancy 26–28 pseudopheochromocytoma 14, 28–29 signs and symptoms 8–12 Clonidine 14, 64, 88–89 Clonidine suppression test 14, 33, 88–89 Cocaine 14, 100 Computed tomography (CT) 34, 94–96 advantages 95 disadvantages 96 CT densitometry 94

Current imaging algorithm 108 Cyclophosphamide 23, 24 Dacarbazine 23 Demser 60, 110, 111 See also Alpha-methyl-L-tyrosine; Metyrosine Diabetes mellitus 11 Dibenzyline 87, 111, 112 See also Phenoxybenzamine Diet and drugs, interferences 85–88 [111In]-Diethylenetriamine pentaacetic acid (DTPA) 105 Differential diagnosis 12–14, 25, 59 conditions 13 drug-induced states 14 hyperadrenergic hypertension 13–14 Dihydrocaffeic acid 85 3,4-Dihydroxyphenylaceticacid (DOPAC) 51, 52 [18F]-Dihydroxyphenylalanine ([18F]-DOPA) 21, 34, 97, 102–103, 108 3,4-Dihydroxyphenylglycol (DHPG) 48, 51, 52, 54, 59, 60 Diltiazem 16 Dobutamine 64 Domperidone 69 L-Dopa 42–43, 60, 62–63, 80 Dopamine 9, 34, 38, 42, 43, 46, 48, 51, 62–64, 80, 85, 101 Dopamine β-hydroxylase 42, 43 Dopamine transporter 47 [86Y]-Dotatoc 23 Doxazosin 15, 110 Doxorubicin 24 Electron microscopy 7 Emergency situations 12 acute peripheral ischemia 18–19 cardiac emergencies 17–18 gastrointestinal emergencies 19 hypertensive crisis 15–16 hypotension and shock 16 multisystem failure 16 nephrological emergencies 19–20 neurological emergencies 20 pulmonary emergencies 19 Endocytosis 46 Epinephrine 3, 43, 61, 70 metabolism 53 Esmolol 16, 17 Ethylenediamine 74 Ethylenediamine terraacetic acid (EDTA) 85 Exocytosis 46 External beam radiation 24

Index Extra-adrenal pheochromocytoma 24, 39, 91, 93, 96, 102, 106

1–2,

Factitious pheochromocytoma 14, 29 Familial pheochromocytoma 2, 8, 24, 31, 33, 38, 114 genetic abnormalities 31 Fenoldopam 15 [18F]-Fluorodeoxyglucose PET 34, 97, 108 [18F]-Fluorodopamine PET 36, 97, 101–105 Fluorometric methods 74, 75, 85–86 Follow-up biochemical testing 81–84 Fränkel, F. 3 Functional imaging 34, 94, 96, 97 current imaging algorithm 108 MIBG scintigraphy 99–100 positron emission tomography 100–105 radioligands in 98, 106–107 somatostatin receptor scintigraphy 105–108 Future trends and perspectives 114 genomics 114–115 proteomics 115–118 therapeutic modalities 118–119 Gadolinium 96 Gas chromatography–mass spectrometry 75 Gastrointestinal emergencies 19 Genetics 30 MEN syndromes 30–33 diagnostic approaches 33–34 NF type 1 36–37 SDH gene related 37–38 sporadic, genetic problems in 38–40 VHL syndrome 34–36 Genomics 114–115 microarray technology 115 QRT-PCR technique 115 Glial cell line-derived neurotrophic factor (GDNF) 30 Glucagon 10, 33, 36, 70, 89 Glucocorticoid receptor-mediated mechanism 44 “Great mimic”, See Pheochromocytoma Guanabenz 64 Halofuginone 119 Haloperidol 69 Headache 10 Heat shock protein 90 119 Heparin 85 Hepatomesenteric organs, catecholamine metabolism in 51–54

169

High-performance liquid chromatography (HPLC) 74–75, 85, 86 Histamine 10 Historical comments 3 Holton, P. 3 Holtz, P. 3 Homovanillic acid (HVA) 49, 51, 58, 59, 63 Hypernoradrenergic essential hypertension, See Pseudopheochromocytoma Hypertensive crisis 15–16, 17, 19, 26, 27, 60, 95, 111 in pregnancy 26–27 Hypertensive episode 10–11, 79, 89, 110 Hypocalcemia 16 Hypocortisolism 113 Hypoglycemia 61, 113 Hypotension 8, 25, 91, 110, 112, 113 causes 9–10 and shock 16 Hytrin, See Terazosin Immunohistochemical markers 5–7 Incidentally discovered adrenal mass 14–15 111 Indium 23 Initial biochemical testing 78–81, 89 plasma-free metanephrines 81 urinary fractionated metanephrines 81 Interleukin-6 (IL-6) 11 Intra-adrenal pheochromocytoma 2, 5, 105 Ion fingerprint analysis 118 Isoetharine 64 Kelly, H.M. 3 Knudson’s two-hit model Kohn, A. 3

35

Labetalol 86, 110, 111 LaBrosse, E.H. 3 Laparoscopic technique 27, 109 Lergotrile 69 Levodopa 87 Lidocaine 17 Linomide 119 Liquid chromatography–tandem mass spectrometry 75 Localization 21, 26, 93 anatomical imaging 34 computed tomography 94–96 magnetic resonance imaging 96–97 functional imaging 34, 94, 96, 97 current imaging algorithm 108

170 Index Localization (Contd.) functional imaging (Contd.) MIBG scintigraphy 99–100 positron emission tomography 100–105 radioligands in 98, 106–107 somatostatin receptor scintigraphy 105–108 Lund, A. 3 Lysergic acid diethylamide 14 Magnesium sulfate 28 Magnetic resonance imaging (MRI) 26, 34, 93, 94, 96–97, 103, 108 advantages 98 Malignant pheochromocytoma 5, 20–24, 97, 104–105, 118–119 clinical manifestations 20 features 21 frequency 20 localization 21, 26, 93 management first-line systemic treatment 21 pharmacologic presurgical treatment 21 metastatic sites 20, 39 scales 5 telomerase activity 5 treatment 21, 23–24 Malingering 29 “Manic-depressive behavior” 8 Mass spectrometry (MS) 75, 117, 118 Maternal imprinting 38 Matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) 117 Mayo, C.H. 3 MDR-1 gene activity 24 Measurement methods 74–76 Medical therapy 110–112 MEN syndromes, See Multiple endocrine neoplasia syndromes Mesenteric organs 51–52, 53, 63, 83 “Metabolic volcano” 10 Metabolism, of catecholamines 48 extraneuronal pathway 48, 50, 60 in hepatomesenteric organs 51–54 neuronal pathways 48, 50 and release by pheochromocytoma 54–58 Metaiodobenzylguanidine, See MIBGs Metanephrine 29, 49, 52, 54, 72, 76, 81, 83, 91, 94 Metanephrine sulfate 50, 52, 59 Metaproterenol 64 Metastatic pheochromocytoma 23, 44, 93, 94, 102, 105, 106, 117–118

3-Methoxy-4-hydroxyphenylglycol (MHPG) 51, 52, 54, 59 Methyldopa 10, 26, 64, 87 Metoclopramide 10, 111 Metoprolol 16, 64, 111 Metyrosine 60, 110, 111, 112 See also Alpha-methyl-L-tyrosine; Demser MIB-1 5 [123I]-MIBG 99, 100, 101, 108 [131I]-MIBG 21–24, 99, 100, 118 [123/131I]-MIBG 99, 106, 118 MIBG scintigraphy 26, 36, 93, 99–100 Minipress, See Prazosin Moller, K. 3 Monoamine oxidase 10, 14, 45, 48, 54, 88 Monoamine oxidase inhibitors 10, 14, 60, 87, 88 MS-based fingerprinting 117 Multiple endocrine neoplasia (MEN) syndromes 30, 44, 109, 115 diagnostic approaches 33–34 sensitivity of biochemical tests 34 MEN-1 32, 33 MEN-2 30–33, 34, 109, 117 signs and symptoms 32 MEN-2A 32, 38, 115 MEN-2B 32–33, 38 RET mutation 30–31, 32 Multisystem failure 16 Munchausen’s syndrome 29 Myocardial infarction 15, 16, 17, 18, 111 Myocardial ischemia 18 Nadolol 64 Naloxone 111 Nephrological emergencies 19–20 Neurogenic pulmonary edema 19 Neurological emergencies 20 Neuronal monoamine transporter 47 Neuronal release, of catecholamines 46 Neurofibromatosis type 1 (NF-1) 30, 32, 36–37 NF-1 gene 36–37 Nicardipine 15–16 Nifedipine 111 Nitroprusside 15 Norepinephrine 43, 44, 47, 48, 61 metabolism 53 Norepinephrine transporter 47, 101, 102, 106, 118 Normetanephrine 3, 48, 52, 75, 89, 90, 91

Index Normetanephrine sulfate 50, 52, 53 Normodyne, See Labetalol; Trandate O-methylated metabolites 3, 51–52, 54, 59, 60, 81 Octreoscan 97, 105–108 See also Somatostatin receptor scintigraphy Octreotide 23, 105 Opiates 10 Orthostatic hypotension 8–9, 22, 112 Oxygen-sensing hypothesis 37 Pallor 8, 9, 10, 11, 18, 25 Palpitations 9–10, 20, 22, 28, 43–44 Paragangliomas (PG) 2, 7, 38, 40, 43 extra-adrenal pheochromocytomas 1–2, 24, 39, 91, 93, 96, 102, 106 parasympathetic-associated tissues 1 Paroxysm 10, 16 Paroxysmal attack 10, 18, 20, 55–56 Paroxysmal hypertension 2, 8, 14, 28 Pathology 4 of benign pheochromocytoma 5 of intra-adrenal pheochromocytoma 2, 5, 105 of malignant pheochromocytoma 5, 20–24 of sporadic pheochromocytoma 2, 4–5, 32 Peripheral dopamine systems 62–64 dietary constituents 63–34 Peyron, A. 3 Pharmacological tests 88–91 clonidine suppression test 14, 33, 88–89 provocation test 89 Phencyclidine (PCP) 14 Phenolsulfotransferase type 1A3 50, 51 Phenothiazine 10 Phenoxybenzamine 15, 26, 87, 110, 112 Phentolamine 15, 27, 89, 111 Phenylalanine hydroxylase 41 Phenylephrine 64 Phenylethanolamine N-methyl transferase (PNMT) 43, 44 Pheochromocytoma adrenal 2, 102, 103, 113 autopsy studies 1, 3, 36 biochemical diagnosis 72 in children 24–26 clinical presentation 8 differential diagnosis 12–14 electron microscopy 7 familial 2, 8, 24, 31, 33, 38, 114 future trends and perspectives 114 genetics 30

171

historical comments 3 localization 21, 26, 93 occurrence 1 pathology 4–7 in pregnancy 26–28 pseudopheochromocytoma 14, 28–29 SDH gene related 37–38 signs and symptoms 8–12 size 7 sporadic 2, 4–5, 32, 34, 38, 114 treatment 109 WHO definition 1 Pheochromocytoma of the adrenal gland scaled score (PASS) 5, 6 Pheochromocytoma tumor cells 29, 54, 55, 79, 83, 84, 100, 118 Pick, L. 3 Plasma and urine specimens, collection and storage 84–85 Plasma-free metanephrines 15, 33, 79–80, 81, 89, 112 Plasma-free normetanephrine 87, 90 Plasma membrane monoamine transporters 47–48 Positron emission tomography (PET) 1, 34, 100–105 advantages 105 Postoperative management 112–113 of hypertension 112–113 of hypotension 112, 113 Prazosin 64, 110 Prednisone 24 Pregnancy-related pheochromocytoma 26–28 biochemical diagnosis 26 hypertensive crisis 26–27 treatment 26 Propranolol 16, 64, 87, 89, 111 Proteomics 115 fingerprinting analysis 117 mass spectrometry 117 protein arrays 118 two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) 117 Provocation test 89 Pseudopheochromocytoma 14, 28–29 clinical characteristic 28 treatment 29 “Pseudoshock” 16 Pulmonary emergencies 19 Quantitative real-time polymerase chain reaction (QRT-PCR) 115 Radioenzymatic assay 74, 75 Radioligands 98, 106–107

172 Index Receiver operating characteristic curves 80 Reference intervals 76–78 Regitine, See Phentolamine Renal toxicity 22, 23 Reserpine 45, 100 RET mutation 32, 33, 38, 40 Roux 3 Rule of six “H”s 12 Sample classification 38 SDH genes 1, 25, 30, 37–38 Signs and symptoms 8–12 hypotension 8–10 paroxysomal hypertension 2, 8, 14, 28 patient evaluation 11–12 Sinemet, See Carbidopa Sipple’s syndrome, See Multiple endocrine neoplasia syndromes Size of pheochromocytoma 7 Sodium nitroprusside 27, 111 Somatostatin 23, 105 Somatostatin receptor scintigraphy (SRS) 34, 97, 105–108 Spectrophotometric assays 75 Sporadic pheochromocytoma 2, 4–5, 32, 34, 114–115 genetic problems 38–40 histopathology 4 Succinate dehydrogenase genes, See SDH genes Sulfotransferase isoenzyme (SULT1A3) 51, 52, 54, 63, 72–73 Surface enhanced laser desorption ionization time-of-flight (SELDI-TOF) 117 Surgical preparation 110–112 Sustained hypertension 2, 8, 24 Sympathetic-associated chromaffin tissue, See Extra-adrenal pheochromocytoma Sympathoadrenal system 45 catecholamines metabolism 48–51 release 46 storage 45–46

uptake 46–48 Sympathomimetics

100

Terazosin 110 Terbutaline 64 3UCH-S-adenosylmethionine 75 Timolol 64 Trandate, See Labetalol; Normodyne Treatments 109 medical therapy 110–112 postoperative management 112–113 surgical preparation 110–112 Tricyclic antidepressants 10, 87, 88, 100, 111 Tryptophan hydroxylase 41 Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) 117 Tyramine 10, 14, 46 Tyrosine hydroxylase 41, 43, 60, 62, 63, 110 Urinary fractionated metanephrines 15, 33, 75, 76, 79–80, 81, 83, 89 Vanillylmandelic acid (VMA) 3, 51, 52, 59, 83 Verapamil 16 Verner–Morrison syndrome 11 Vesicular monoamine transporters (VMAT) 36, 45, 48, 99 VHL mutation 34–36, 38 Vincristine 23, 24 von Euler, U.S. 3 von Hippel–Lindau (VHL) syndrome 30, 34–36, 44, 115 types 35–36 von Recklinghausen syndrome, See Neurofibromatosis type 1 (NF-1) Wermer’s syndrome 33 Western blot 44, 54 Yohimbine 64 Yttrium 23

90

“Zellballen”

7