Pheochromocytoma: Diagnosis, Localization, and Treatment

178 Pages·2007·1.576 MB·English

by  Karel Pacak, Jacques W. M. Lenders, Graeme Eisenhofer(auth.)

Pheochromocytoma
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
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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
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Contents
1 Introduction 1
2 Historical comments 3
3 Pathology 4
4 Clinical presentation of pheochromocytoma 8
4.1 Signs and Symptoms 8
4.2 Differential Diagnosis 12
4.3 Special Presentations 14
4.3.1 Diagnosis of Pheochromocytoma in Patients with an
Incidentally Discovered Adrenal Mass 14
4.3.2 Pheochromocytoma as an Endocrine Emergency 15
4.3.2.1 Hypertensive Crisis 15
4.3.2.2 Hypotension and Shock 16
4.3.2.3 Multisystem Failure 16
4.3.2.4 Cardiac Emergencies 17
4.3.2.5 Acute Peripheral Ischemia 18
4.3.2.6 Pulmonary Emergencies 19
4.3.2.7 Gastrointestinal Emergencies 19
4.3.2.8 Nephrological Emergencies 19
4.3.2.9 Neurological Emergencies 20
4.3.3 Malignant Pheochromocytoma 20
4.3.4 Pheochromocytoma in Children 24
4.3.5 Pheochromocytoma in Pregnancy 26
4.3.6 Pseudopheochromocytoma 28
4.3.7 Factitious Pheochromocytoma 29
5 Current trends in genetics of pheochromocytoma 30
5.1 MEN Syndromes 30
5.1.1 Diagnostic Approaches 33
5.2 VHL Syndrome 34
5.3 NF Type 1 36
5.4 Succinate Dehydrogenase Gene Related Pheochromocytoma 37
5.5 Genetic Problems in Sporadic and Other
Pheochromocytomas 38
6 Catecholamines and adrenergic receptors 41
6.1 Synthesis and Sources of Catecholamines 41
6.2 Synthesis of Catecholamines in Pheochromocytoma 43
6.3 Storage and Release of Catecholamines by the
Sympathoadrenal System 45
vi Contents
6.4 U ptake and Metabolism of Catecholamines Produced by the
Sympathoadrenal System 46
6.5 Catecholamine Metabolism in Hepatomesenteric
Organs 51
6.6 Catecholamines Metabolism and Release by
Pheochromocytoma 54
6.7 Kinetics and Elimination of Catecholamines and Their
Metabolites 58
6.8 Pharmacology of Catecholamine Systems:
Implications for Pheochromocytoma 60
6.9 Physiology of Catecholamine Systems 60
6.9.1 Adrenal Medullary Hormone System 60
6.9.2 Peripheral Dopamine Systems 62
6.10 Adrenergic Receptors and Their Functions 64
6.11 Actions of the Catecholamines 69
7 Current trends in biochemical diagnosis of pheochromocytoma 72
7.1 Biochemical Tests of Catecholamine Excess 72
7.2 Measurement Methods 74
7.3 Reference Intervals 76
7.4 Initial Biochemical Testing 78
7.5 Follow-up Biochemical Testing 81
7.6 Collection and Storage of Plasma and Urine
Specimens 84
7.7 Interferences from Diet and Drugs 85
7.8 Pharmacologic Tests 88
7.9 Additional Interpretative Considerations 91
7.10 Summary 91
8 Current trends in localization of pheochromocytoma 93
8.1 Anatomical Imaging of Pheochromocytoma 94
8.1.1 Computed Tomography 94
8.1.2 Magnetic Resonance Imaging 96
8.2 Functional Imaging of Pheochromocytoma 97
8.2.1 MIBG Scintigraphy 99
8.2.2 Positron Emission Tomography 100
8.2.3 Somatostatin Receptor Scintigraphy
(Octreoscan) 105
8.2.4 Current Imaging Algorithm 108
9 Treatment of pheochromocytoma 109
9.1 Medical Therapy and Preparation for Surgery 110
9.2 Postoperative Management 112
10 Future trends and perspectives 114
10.1 Genomics in Pheochromocytoma Research 114
10.2 Proteomics in Pheochromocytoma Research 115
10.3 Future Therapeutic Modalities for Pheochromocytoma 118
References 120
Index 167
To our children Tomáš, Ruud, Koen, Anne, and Suzanne
The glory of medicine is that it is constantly moving forward, that there is
always more to learn.
Dr. William J. Mayo, 1928
CHAPTER 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 diag-
nosis [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 pheochromocyto-
mas 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 pathophysiol-
ogy and genetics of pheochromocytoma (the role of succinate dehydroge-
nase 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 paragangli-
omas. The 2004 WHO classification of endocrine tumors defines pheochro-
mocytoma 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 tis-
sues (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 multi-
focal and bilateral [1, 4, 7, 15, 40]. Although metastases may be rare for adre-
nal (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 pheochromocy-
toma 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 hyper-
tension [1, 15, 47–49]. However, this probably accounts for only 50% of per-
sons harboring the tumor, when it is considered that about half the patients
with pheochromocytoma have only paroxysmal hypertension or are normo-
tensive. Also, despite the low incidence of pheochromocytoma among patients
with sustained hypertension, it must also be considered that the current preva-
lence of sustained hypertension in the adult population of Western countries
is up to 30% [50–52]. Thus, the prevalence of pheochromocytoma can be esti-
mated 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].
CHAPTER 2
Historical comments
Alfred Kohn, Professor of Histology at the Charles University in Prague, intro-
duced 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 noradreno-
chrome, 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. Extra-
adrenal 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 success-
ful 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 nor-
epinephrine 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 pheo-
chromocytoma [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