Key Words:
Pheochromocytoma
Pheochromocytoma arises from adrenal medulla,
which actually comprises about 10 % of adrenal gland.
Sympathochromaffin system is the major
neuroendocrine system in the body, it contains 2
components. Symapthetic neurons and chromaffin
cells in adrenal medulla.
The sympathochromaffin system and the parasympathetic nervous
system comprise the autonomic nervous system.
Catecholamine synthesis, storage and inactivation
Cathechol nucleus is esenatially an dihydroxy phenyl
ring. The catecholamines - dopamine (DA), norepinephrine (NE)
and ephinephrine (E) are synthesized from tyrosine which is
actively taken to neurons. Tyrosine is made from
phenylalanine, an essential aminoacid.
Catecholamines are found in the adrenal medulla and in
sympathetically innervated organs. Catecholamines are stored
in electron-dense granules that also contain ATP,
neuropeptides (e.g., adrenomedullin, corticotropin [ACTH],
vasoactive intestinal polypeptide), calcium, magnesium, and
chromogranins. Uptake into the storage vesicles is facilitated
by active transport by vesicular monoamine transporters
(VMAT).
The catecholamines are degraded by two principal enzyme
systems, catechol-O-menthyl transferase (COMT) and monamine
oxidase (MAO). COMT converts NE and E to their O-methyl
metabolites, normetanephrine and metanephrine respectively;
after further metabolism these serve as substrates for MAO
leading to formation of 3-methoxy 4-hydroxymandelic acid,
better known as vanillylmandelic acid (VMA), the major end
product of catecholamine metabolism (R)
Catecholamines act through plasma membrane receptors of two
broad types, alpha and beta adrenergic receptors
(adrenoceptors). Each type includes multiple subtypes (α1, α2,
β1, β2, β3, D1); NE and E are mixed agonists. They interact
with both alpha and beta adrenergic receptors, although NE has
a relatively low affinity for β2 adrenergic receptors
including those that mediate vasodilation in skeletal muscles.
This probably explains the differences in the hemodynamic
responses to E (increased systolic, but not diastolic, blood
pressure and increased heart rate) and NE (increased systolic
and diastolic blood pressure with reflex restraint of the
increase in heart rate).
Clinical presentation
Catecholamine secreting tumors have incidence in male
and females in same range and usually occur in middle aged
people. In children it is rare, and if it occurs, tends to be
multifocal and as a part of genetic syndromes. Classical
symptoms are paroxysms which includes sudden onset of
headache, sweating, diaphoresis, anxiety and palpitations. It
is also associated with labile or sustained hypertension.
Typical Spells may be either spontaneous or precipitated by
postural change, anxiety, medications (e.g., β-adrenergic
antagonists, metoclopramide, anesthetic agents), exercise, or
maneuvers that increase intra-abdominal pressure (e.g., change
in position, lifting, defecation, exercise, colonoscopy,
pregnancy, trauma). Although the types of spells are highly
variable but spells tend to be stereotypical for each
patient. Frequency of spells are variable.
Signs and Symptoms Associated with Catecholamine-Secreting
Tumors [1]
Spell-Related Signs and Symptoms
Anxiety and fear of impending death
Diaphoresis
Dyspnea
Epigastric and chest pain
Headache
Hypertension
Nausea and vomiting
Pallor
Palpitation (forceful heartbeat)
Tremor
Chronic Signs and Symptoms
Anxiety and fear of impending death
Cold hands and feet
Congestive heart failure - dilated or hypertrophic
cardiomyopathy
Constipation
Diaphoresis
Dyspnea
Ectopic hormone secretion-dependent symptoms (e.g.,
CRH/ACTH, GHRH, PTHrP, VIP)
Epigastric and chest pain
Fatigue
Fever
General increase in sweating
Grade II to IV hypertensive retinopathy
Headache
Hyperglycemia
Hypertension
Nausea and vomiting
Orthostatic hypotension
Painless hematuria (associated with urinary bladder
paraganglioma)
Pallor
Palpitation (forceful heartbeat)
Tremor
Weight loss
Diagnosis
The diagnosis of pheochromocytoma is based upon clinical
suspicion and biochemical confirmation and anatomical
localization. Rarely does it happen during investigation for
adrenal incidentaloma.
Routine testing for pheochromocytoma in patients with
hypertension is both cost-inefficient and unwise - false
positive tests would outweigh true positives by a large
margin.
Measurement of Fractionated Metanephrines and
Catecholamines in Urine and Blood
The diagnosis of catecholamine secreting tumor is
established by the presence of increased concentrations of
fractionated catecholamines and fractionated metanephrines in
urine or plasma. Measurement of fractionated metanephrines and
catecholamines in a 24-hour urine collection has high
sensitivity, 98%; and specificity, 98%. [2,3]
If Measurement of plasma fractionated
metanephrines has a sensitivity of 96% to 100%, [3,4]
the specificity is poor at 85% to 89%, [3,4,5]. Plasma
fractionated metanephrines are useful if used to
diagnose pheochromocytoma in high risk patients and in
children in whom 24 hour urine collection is difficult.24-hour
urinary VMA excretion has poor diagnostic sensitivity and
specificity compared with fractionated 24-hour urinary
metanephrines. Other tests like estimation of chromogranin and
neuropeptide Y lack specificity. Confirmatory tests like
clonidine stimulation tests are rarely used.
Localization
Localization studies should not be initiated until biochemical
studies have confirmed the diagnosis of a
catecholamine-secreting tumor. About 90% of Pheochromocytomas
are in the adrenal medullae and 99% are in the abdomen. Most
of the remainder are in the mediastinum. Pheochromocytomas are
usually localized by computed tomography or magnetic resonance
imaging. Although CT is still the primary adrenal imaging
modality, MRI has advantages in certain clinical
situations.[6]
Imaging characteristics of pheochromocytoma in CT scan
are usually large tumors(>3 cms), with smooth
margins, and with non homogenous texture and with cystic
areas.In MRI it appears hyperintense. Areas of
necrosis and calcification are common with
pheochromoctoma.
Chemical shift MRI is a form of lipid-sensitive imaging, which
helps to differentiate cortical adenoma and
pheochromocytoma in difficult situations. If the results
of abdominal imaging are negative, scintigraphic
localization with 123I-MIBG is indicated. This
radiopharmaceutical agent accumulates preferentially in
catecholamine-producing tumors; however, this procedure is not
as sensitive (sensitivity, 80%; specificity, 99%). [6,7,8]
Normally MIBG is not required in a otherwise diagnosed
pheochromocytoma but especially useful in if the adrenal
pheochromocytoma is more than 10 cm in diameter or if a
paraganglioma is identified on CT or MRI.
Treatment
The treatment of choice for pheochromocytoma is complete
surgical resection. Surgical survival rates are 98% to 100%
and are highly dependent on the skill of the endocrinologist,
endocrine surgeon, and anesthesiologist team. [9,10]
Tumor excision usually cures hypertension.
Preoperative preparation of patient is very important as
far smooth perioperative course and post operative blood
pressure control. Commonest approach is combined and
sequential blockade of Alpha & beta adrenergic receptors.
Target blood pressure is less than 120/80 mm Hg (seated), with
systolic blood pressure greater than 90 mm Hg (standing).
Along with Alpha adrenergic blockade, patients are
advised high salt (≥5000 mg/day) for
intravascular volume expansion. After adequate α- adrenergic
blockade has been achieved, β-adrenergic blockade is
initiated, typically 2 to 3 days preoperatively, primarly for
control heart rate
Rate of adrenergic blockade and degree of volume
expansion depends upon the patient characteristics. Patients
with catecholamine induced vascular changes may require longer
period off adrenergic blockade before surgery. Similarly large
volume expansion is contraindicated in patients with
congestive heart failure or renal insufficiency.
Alpha Blockade is achieved primarily with Phenoxybenazamine,
It is an irreversible, long-acting, nonspecific α-adrenergic
blocking agent. The initial dosage is 10 mg once or twice
daily, and the dose is increased by 10 to 20 mg in divided
doses every 2 to 3 days as needed to control blood pressure
and spells. Selective α1-adrenergic blocking agents (e.g.,
prazosin, terazosin, doxazosin) are preferable to
phenoxybenzamine in many patients and there is a growing trend
of using prazosin for preoperative preparation. Patients
to be cautioned regarding orthostatic hypotension and nasal
congestion.
Beta adrenergic blockade: Usually done with
relatively small doses of short acting betablockers and once
tolerates well, change to longacting agents. Titration of dose
is done to maintain heart rate less than 80 /minute.
Other Agents: Many patients will require
other agents to control the blood pressure apart
from Alpha and beta adrenergic antagonists.
Major agents used are Calcium channel blockers. Metyrosine
(tyrosine hydroxylase inhibitor) is rarely used especially
in clinical settings like other drugs are
ineffective and in patients whom tumor manipulation is
expected.
Follow up
Approximately 1 to 2 weeks after surgery, fractionated
catecholamines and metanephrines should be measured by
collection of a 24-hour urine specimen and if normal, the
resection of the pheochromocytoma should be considered
complete. Further Follow up is yearly measurement of
Fractionated cathecholamines and metanephrines. If levels are
high recurrence is suspected and anatomical
diagnosis has to be made.
Genetic sydromes
Genetic syndromes associated with
pheochromocytomas are MEN1, MEN 2 A, MEN 2 B,
neurofibromatosis type 1, von Hippel Lindau syndrome and
familial pheochromocytoma.
Genetic testing
Genetic testing to be carried out in patients with
family history of pheochromocytoma; paraganglioma; and any
sign that suggests a genetic cause, such as retinal angiomas,
axillary freckling, cafe au lait spots, cerebellar tumor, MTC,
or hyperparathyroidism. In addition, all first-degree
relatives of a patient with pheochromocytoma or paraganglioma
should have biochemical testing.
Paraganglionomas
Cathecholamine secreting tumors originating from
sympathetic ganglia are known as paragnagliomas. Clinically
and biochemically they are similar to
pheochromocytomas. These tumors are suspected after confirming
high catecholamine levels and adrenals are found normal in
imaging . Major genetic syndrome associated with
paragangliomas is SDH mutations (succinate
dehydrogenase) This is subdivided to SDH B,
SDH C & SDH D types .
References
1. Young WF Jr. Pheochromocytoma, 1926-1993. Trends Endocrinol
Metab. 1993;4:122-127.
2. Kudva YC, Sawka AM, Young WF Jr. Clinical review 164: the
laboratory diagnosis of adrenal pheochromocytoma-the Mayo
Clinic experience. J Clin Endocrinol Metab. 2003;88:4533-4539.
3. Sawka AM, Jaeschke R, Singh RJ, et al. A comparison of
biochemical tests for pheochromocytoma: measurement of
fractionated plasma metanephrines compared with the
combination of 24-hour urinary metanephrines and
catecholamines. J Clin Endocrinol Metab. 2003;88:553-558.
4. Lenders JW, Pacak K, Walther MM, et al. Biochemical
diagnosis of pheochromocytoma: which test is best? JAMA.
2002;287:1427-1434.
5. Sawka AM, Prebtani AP, Thabane L, et al. A systematic
review of the literature examining the diagnostic efficacy of
measurement of fractionate plasma free metanephrines in the
biochemical diagnosis of pheochromocytoma. BMC Endocr Disord.
2004;4:2.
6 Brink I, Hoegerle S, Klisch J, et al. Imaging of
pheochromocytoma and paraganglioma. Fam Cancer. 2005;4:61-68
7. Havekes B, King K, Lai EW, et al. New imaging approaches to
phaeo-chromocytomas and paragangliomas. Clin Endocrinol (Oxf).
2010;72:137-145.
8. Jalil ND, Pattou FN, Combemale F, et al. Effectiveness and
limits of preoperative imaging studies for the localisation of
pheochromocytomas and paragangliomas: a review of 282 cases.
French Association of Surgery (AFC) and The French Association
of Endocrine Surgeons (AFCE). Eur J Surg. 1998;164:23-28.
9. Kinney MA, Warner ME, vanHeerden JA, et al. Perianesthetic
risks and outcomes of pheochromocytoma and paraganglioma
resection. Anesth Analg. 2000;91:1118-1123.
10. Plouin PF, Duclos JM, Soppelsa F, et al. Factors
associated with periop-erative morbidity and mortality in
patients with pheochromocytoma: analysis of 165 operations at
a single center. J Clin Endocrinol Metab. 2001;86:1480-1486.