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TitleTietz Fundamentals of Clinical Chemistry
TagsFundamentals Of Chemistry
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Page 485

Catec :holamines and Serotonin 467

in other clinical conditions, pheochromocytom~ must be con-
sidered in many patients with and without hypertension.
Patients with a high risk for pheochromocytoma, in whom
testing may be carried out independently of the presence of
signs and symptoms, include those with a family or previous
history of the tumor, or the incidental finding of an adrenal
mass during routine abdominal imaging procedures. See Box
26-1 for summary of the key points of pheochromocytomas.

Most pheochromocytomas are sporadic, but up to about a
quarter have a hereditaty basis.'' Hereditq forms of the tumor
occur because of mutations of five disease-causing genes iden-
tified to date. Pheo~hromoc~tomas in multiple endocrine neo-
plasia type 2 result from mutations of the ret proto-oncogene.
These mutations also result in a predisposition to medullary
thyroid cancer and several other tumors or hyperplastic condi-
tions. In von Hippel-Lindau syndrome (VHL), family-specific
mutations of the VHL tumor suppressor gene determine the
varied clinical presentation of tumors, including retinal angio-
mas, central nervous system hemangioblastornas, pheochromo-
cytomas, and tumors in the kidneys, pancreas, and testis.
Familial paragangliomas and pheochromocytomas also occur
secondary to mutations of genes for succinate dehydrogenase
subunits B and D (SDHB and SDHD). Pheochromocytomas
also occur in about 1% of patients with neurofibromatosis

OX 26-1 1 Phsochromocytoma Key Points

type 1. Periodic testing for pheochromocytomas in patients
with the first three of the above four familial syndromes is
now recommended as part of a routine screening and surveil-
lance plan.

Although mosrly benign, about 10% to 1% of pheochro-
mocytomas are malignant. The risk of malignant pheochromo-
cytomas is higher in patients with extraadrenal tumors,
particularly in patients with SDHB mutations. Diagnosis of
malignant pheochromocytoma is not possible based on histo-
pathological features, hut instead requires evidence of meta-
static lesions (e.g., in liver, lungs, lymphatic nodes, and bones).
All patients with a previous history of the tumor are at risk for
recurrent or malignant disease and should undergo periodic
screening for the tumor.

Even if benign, pheochromocytomas and catecholamine-
producing paragangliomas are treacherous tumors that will
almost invariably cause devastating cardiovascular complica-
tions and death if not recognized and properly treated.8 Thus,
once such a tumor is suspected, it is imperative that appropri-
ate biochemical tests are employed for accurate diagnosis. Bio-
chemical diagnosis of pheochromocytoma has traditionally
relied on measurements of urinary catecholamines, metaneph-
rines, and VMA.12 Most patients with hypertension and symp-
toms caused by active pheochromocytomas have large increases
in these analytes, making the tumor relatively easy to diagnose.
Problems occur in those patients in whom hypertension is
paroxysmal and where there may be negligible catecholamine
secretion between episodes. False-negative test results are more
commonly encountered in patients with "silent pheochromo-
cytomas" in whom testing is carried out, not because of signs
or symptoms, but because of an adrenal tumor discovered inci-
dentally (an incidentaioma) or as part of a routine surveillance
plan for recurrent or hereditary pheochromocytomas.

Because missing a pheochromocytoma can have deadly con-
sequences, one of the most important considerations in choice
of initial test is a high level of reliability that the test will
provide a positive result in that rare patient with the tumor.
This conversely also provides confidence that a negative
result reliably excludes the tumor, thus avoiding the need for
multiple or repeat biochemical testing or even costly and
unnecessary imaging studies to rule out the tumor. Therefore
suitably sensitive biochemical tests remain the first choice in
the initial work-up of a patient suspected of harboring a

With the above considerations in mind, a panel of experts
meeting at the First International Symposium on Pheochro-
mocytoma in October 2005 recommended that initial bio-
chemical testing for pheochromocytoma should include
measurements of urinary excretion or plasma concentrations
of fractionated metanephrines (n~rmetane~hrine and meta-
nephtine).l0The basis for the high diagnostic efficacy of plasma
free and urinary fractionated inetanephrines is explained by
the presence within adrenal medullary and pheochromocy-
toma tumor cells of catechol-0-methyltransferase, the enzyme
that metabolizes catecholamines to metanephrines. This
contrasts with sympathetic nerves, which contain M A 0 but
not catechol-0-methyltransferase. Since catecholamines are
metabolized mainly within the cells where they are synthe-
sized, the presence of a pheochromocytoma leads to a dispro-
portionate increase in production of 0-methylated rather than
deaminated metabolites. More importantly the metanephrines
are produced continuously as a result of ongoing leakage of

Page 486

468 T IV Analytes

catecholamines from chromaffin granule stores into the cell
cytoplasm; in contrast, the catecholamines may be released

The high diagnostic sensitivity of measurements of plasma
or urinary fractionated normetanephrine and metanephrine
makes these tests the most suitable choice for the initial work-
up of a patient with a suspected pheochromocytoma. Negative
results by these tests virtually exclude a pheochr~moc~toma.
Exceptions include small ( 4 cm) tumors encountered during
routine screening or tumors that do not synthesize norepineph-
rine and epinephrine. Tumors that produce exclusively dopa-
mine may be missed by measurements of normetanephrine and
metanephrine and the parent amines. Such tumors, however,
may be detected by measurements of plasma or urinary
methoxytyramine, the Omethylated metabolite of dopamine.
Measurements of plasma dopamine can also be useful, whereas
urinary doparnine is largely derived from renal extraction and
decarb~x~lation of L-dopa and therefore provides a relatively
insensitive and nonspecific test for detection of a dopamine-
producing tumor (see Figure 26-6).

increases in plasma or urinary fractionated metanephrines
are usually high enough to conclusively establish the presence
of most cases of pheochr~moc~tomas. However, if the patient
has a tumor producing a small amount of catecholamines, false-
positive results remain difficult to distinguish from true-
positive resultsandadditional biochemical testingisnece~sary.'~
Before further biochemical testing is initiated, consideration
should be given to eliminating possible causes of false-positive
results. These may occur because of inappropriate sampling
conditions (e.g., bloodsampling without apreceding 20-minute
period of supine rest) or because of medications.

When biochemical testing continues to yield equivocal
results, the clonidine suppression test may be useful for further
confirming or excluding a pheochromocytoma. As originally
introduced, this test was designed to distinguish patients with
increases in plasma catecholamines caused by pheochrornocy-
tomas from those with increases caused by sympathetic activa-
tion. By activating alpha,-adrenoceptors in the brain and on
sympathetic nerve endings, clonidine suppresses norepineph-
rine release by sympathetic nerves. Decreases in elevated
plasma norepinephrine after clonidine therefore suggest sym-
pathetic activation, whereas lack of decrease suggests a pheo-
chromocytoma. The test has subsequently also been shown to
be useful for distinguishing increases in plasma normetaneph-
rine due to a pheochromocytoma from those due to sympa-
thetic activation.'

Neuroblastomas are neoplasms that derive from primordial
neural crest cells of the sympathetic nervous system.15 Neuro-
blastomas are almost exclusively a pediatric cancer, accounting
for approximately 7% of cancer in childhood and the most
common malignancy in the first year of life. The incidence of
neuroblastomas is approximately 10 cases per million children.
Although familial cases have been reported, the vast majority
of neuroblastomas develop sporadically. The majority of neuro-
blastomas are intraabdominal, arising in the adrenal gland or
the upper abdomen. Less frequent locations include the chest,
neck, or pelvis regions. About 60% are extraadrenal. Metasta-
ses in disseminated neuroblastomas may involve bone marrow,
bone, lymph nodes, liver, and less frequently the skin, testis,
and intracranial structures.

The biological behavior of a neuroblastoma ranges from
regression and maturation to an aggressive course with an
unfavorable outco~ne.'~ Neuroblastomas are most notable for a
subset of cases with complete regression or maturation to gan-
glioneuroma, a benign neoplasm. Most clinically diagnosed
tumors, however, are aggressive and have an unfavorable
outcome. The clinical stage of the disease (localized versus
disseminated) is an important prognostic factor. Patients with
early more localized stages of disease, or infants less than age
1 with a localized primary tumor and dissemination limited to
skin, liver, and/or bone marrow, are considered to have a better
prognosis than other stages. Unfortunately the overall inci-
dence of metastatic neuroblastorna at the time of diagnosis is
approximately 60%, and the need for earlier detection of chil-
dren with the progressive disseminating tumors remains a diag-
nostic challenge. See Box 26-2 for a summary of the key points
of neuroblastomas.

Hypertension and signs and symptoms of catecholamine
excess are uncommon in aneuroblastoma, a result of inefficient
storage of catecholamines leading to intracellular metabolism
and release as mainly inactive metabolites. Patients commonly
present with a tumor mass and clinical signs from compression
effects on neighboring structures or hematological abnormali-
ties from bone marrow involvement.

Laboratory evidence of a functional catecholamine-
producing tumor is important in the clinical evaluation when
a neuroblastorna is suspected. The catecholamine and metabo-
lite secretion patterns, however, may differ markedly among
patients with the tumor. Neuroblastoma cells have the capac-
ity to synthesize dopamine and norepinephrine, depending
upon their degree of metabolic maturity, but, like postgangli-

BOX 26-2 1 Neuroblastoma Key Points

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