Editing Adrenal: Pheochromocytoma (section)

== Diagnosis and Evaluation ==

=== History and Physical Exam ===

* '''<span style="color:#ff0000">History'''
** '''<span style="color:#ff0000">Signs and Symptoms'''
*** '''<span style="color:#ff0000">Classic triad (3):'''
***# '''<span style="color:#ff0000">Headache'''
***# '''<span style="color:#ff0000">Episodic sudden perspiration'''
***# '''<span style="color:#ff0000">Tachycardia'''
*** '''<span style="color:#ff0000">Other symptoms (12):[https://pubmed.ncbi.nlm.nih.gov/10096149/ §]'''
***#'''<span style="color:#ff0000">Anxiety'''
***#'''<span style="color:#ff0000">Sweating'''
***#'''<span style="color:#ff0000">Palpitations'''
***#'''<span style="color:#ff0000">Abdominal pain'''
***#'''<span style="color:#ff0000">Chest pain'''
***#'''<span style="color:#ff0000">Pallor'''
***#'''<span style="color:#ff0000">Nausea'''
***#'''<span style="color:#ff0000">Dyspnea'''
***#'''<span style="color:#ff0000">Tremor'''
***#'''<span style="color:#ff0000">Weight loss'''
***#'''<span style="color:#ff0000">Flushing'''
***#'''<span style="color:#ff0000">Visual disturbance'''
***'''Can have heterogenous clinical behavior due to the variability in the amount and ratio of the different catecholamines (norepinephrine, epinephrine, dopamine)''' '''secreted:'''
**** '''Norepinephrine-predominant tumours''' (e.g., patients with von Hippel- Lindau [VHL] syndrome) '''have hypertension and sweating because of norepinephrine's vasoconstricting action through the α adrenoreceptor'''
**** '''Epinephrine-predominant tumours (rare, usually limited to adrenals or the organ of Zuckerkandl)''' '''have syncope or hypotensive episodes because of epinephrine’s vasodilatory action through the β2 receptor'''
**** Agonist potency order:
***** '''α1: epinephrine ≥ norepinephrine''' >> isoprenaline
***** '''α2: epinephrine ≥ norepinephrine''' >> isoprenaline
***** β1: isoprenaline > epinephrine = norepinephrine
***** '''β2:''' isoprenaline > '''epinephrine >> norepinephrine'''
***** β3: isoprenaline = norepinephrine > epinephrine
*** Episodic hypertensive episodes may be triggered by events such as induction of anesthesia, labor and delivery, instrumentation and biopsy of the tumor, strenuous physical activity and consumption of tyramine rich foods, such as red wine, chocolate and cheeses.
*** Another serious clinical presentation may result from catecholamine induced cardiomyopathy when patients present with congestive heart failure and cardiac arrhythmias.

=== Labs ===

* '''Metanephrine/catecholamine Testing'''
** '''The enzyme phenylethanolamine-N-methyltransferase (PNMT), catalyzes the conversion of norepinephrine to epinephrine, is relatively unique to the adrenal medulla (the brain and organ of Zuckerkandl also express this enzyme).'''
*** '''Localization of PNMT to the adrenal medulla explains why the gland is the primary source of systemic epinephrine, despite the presence of similar chromaffin cells elsewhere in the sympathetic nervous system'''
** '''Catecholamines''' (dopamine, norepinephrine, and epinephrine) '''are produced by pheochromocytomas in varying amounts; release of these compounds into the bloodstream is often paroxysmal'''
** '''Metanephrines are the methylated metabolites of catecholamines'''
*** '''O-methylation of catecholamines is catalyzed by the COMT enzyme'''
**** '''O-methylation of norepinephrine produces normetanephrine, whereas epinephrine’s methylation results in formation of metanephrine.'''
**** '''Together, normetanephrine and metanephrine are known as metanephrines.'''
** '''The conversion of catecholamines to metanephrines within pheochromocytomas is an uninterepted process. As such, measurement of plasma concentration of metanephrines is much more sensitive for detecting pheochromocytomas than the measurement of rises in plasma catecholamines, which may be paroxysmal.'''
*** In the past, measurement of both urinary and serum catecholamine levels was the mainstay for evaluation of pheochromocytoma. However, these tests had moderated sensitivity and specificity and have been largely replaced by measurements of levels of metanephrines.
*** Measurement of urinary catecholamines, nevertheless, is still recommended in conjunction with urinary fractionated (see below) metanephrine testing
** '''<span style="color:#ff0000">Measurement of plasma fractionated metanephrines and 24-hour urinary fractionated metanephrines and catecholamines are the mainstay biochemical tests to diagnose pheochromocytoma.</span>''' 
***'''Plasma fractionated metanephrines is used primary in those with high index of suspicion with 24-hour urinary fractionated metanephrines for those with low index.'''
*** '''2011 CUA Incidental Adrenal Mass guidelines recommend screening with a 24-hour urinary fractionated metanephrines and/or catecholamines.'''
*** '''2014''' [most recent as of October 2019] '''Endocrine Society Pheochromocytoma Guidelines recommend plasma free metanephrines or 24-hour urinary fractionated metanephrines'''
*** 2019 AUA Update on Pheochromocytoma recommended initial screening with plasma free metanephrines. Urinary fractionated metanephrines are an alternative, with slightly lower diagnosis sensitivity.
*** The term fractionated is used when the laboratory report details not only the amount of each compound type (e.g., metanephrines), but also the relative concentrations of each compound (e.g., normetanephrine and metanephrine).
*** The blood sample should be drawn after placing an intravenous cannula, dimming the room lights and having the patient lay supine for 30 minutes after minimizing any pain or anxiety.
**** Prior to the blood draw, patients should be counseled on avoiding caffeine for a minimum of 24 hours
**** '''Acetaminophen can produce a false-positive''' result owing to cross reactivity in the [serum?] assay and '''should be stopped for at least 5 days before testing.'''
**** '''Tricyclic antidepressants and phenoxybenzamine should also be stopped, because these have been shown to be responsible for false-positive results.'''
**** '''Usual antihypertensive therapy can be continued.'''
***** '''Although β-blockade can potentially result in a false-positive test result, the current recommendation is to stop the medication only on repeat testing'''
* '''Vanillylmandelic Acid (VMA) Testing'''
** '''VMA is the primary end metabolite of catecholamines'''
** '''The sympathetic nervous system lacks the ability to produce epinephrine''' (lacks PNMT enzyme) '''and therefore contributes to the serum level of only normetanephrine''' (from norepinephrine) '''but not metanephrine (from epinephrine).''' Indeed, '''> 90% of metanephrine (an epinephrine metabolite) and some 20% or more of normetanephrine (a norepinephrine metabolite) in the bloodstream are derived from the adrenal medulla''' (PNMT is present in the brain and organ of Zuckerkandl). Therefore the relative rise of VMA levels, the combined total end metabolite of norepienphrine and epinephrine, in the presence of a pheochromocytoma is much less dramatic than the rise seen in the levels of metanephrines (from epinephrine), and therefore, '''the sensitivity of urine VMA levels is low'''. However, '''the specificity of VMA is high,''' especially in nonfamilial cases.
* '''Oral clonidine testing'''
** '''Used to distinguish suspected pheochromocytoma vs. essential hypertension in patients with minimally elevated plasma catecholamines.'''
*** Patients with suspected pheochromocytoma usually present with elevated plasma catecholamines. However, they can rarely present with normal or mildly elevated plasma catecholamines.
*** The oral clonidine test can help distinguish whether the signs and symptoms and minimally elevated plasma catecholamines are related to pheochromocytoma vs. essential hypertension, oral clonidine test.
*** '''Patients with essential hypertension will experience a significant drop in norepinephrine due to suppression of production by the sympathetic nervous system, while those with pheochromocytoma will not.'''

=== Imaging ===

* '''18F-FDG PET''' (fluorine-18 fluorodeoxyglucose positron emission tomography)
** '''Gold standard imaging modality for definitive staging in patients with pheochromocytoma.'''
** Superior test characteristics to CT, MRI, and metaiodobenzylguanidine (MIBG) scintigraphy.
** Better accuracy than 123I-MIBG in nearly all patients, especially for identification of metastatic disease.[[File:Pheochromocytoma Scan.jpg|alt=Pheochromocytoma MIBG|thumb|Pheochromocytoma (dark circular shadow near body center) localized by MIBG scintigraphy. See corresponding CT below. Source: [[commons:File:Pheochromocytoma_Scan.jpg|Wikipedia]]]]
* '''MIBG'''
** Utilizes a small-molecule analog of norepinephrine
** High specificity but low sensitivity for diagnostic disease identification.
** '''Useful modality when a suspected pheochromocytoma cannot be localized or when metastatic disease is suspected.'''
*** '''In the most common and urologically most relevant clinical scenario, a solitary adrenal mass on cross sectional imaging in the setting of a biochemical evaluation indicative of pheochromocytoma, MIBG or 18F-FDG PET may be safely be omitted''' '''because these functional studies only serve to confirm what is already known and do not alter management.''' '''However, MIBG or 18F-FDG PET imaging for large (>5 cm) tumors is likely prudent to assess for metastatic disease before surgery and thereby counsel the patient appropriately'''

* '''MRI'''
** Distinct low signal intensity on T1-weighted imaging
** '''High signal intensity on T2-weighted imaging.'''
* '''CT'''
** '''On unenhanced CT, pheochromocytomas are typically > 10 HU''' (mean ≈35 HU) given their rich vascularity and low lipid content. This can help differentiate them from lipid-rich adenomas
*** '''If the lesion is not an adenoma, an adrenal mass protocol CT with IV contrast allows for evaluation of tumor washout.'''
**** '''Benign adrenal lesions wash out >50% on delayed imaging while pheochromocytoma, adrenocortical carcinoma and metastatic tumors do not.'''
*** [[File:Phaeochromozytoma CT coronal.jpg|thumb|CT scan with enhancement demonstrating suspicous left adrenal mass. See corresponding MIBG scan above. Source: [[commons:File:Phaeochromozytoma_CT.jpg|Wikipedia]]]]'''Pheochromocytomas usually measure greater than 10 HU on unenhanced CT and >100 HU on contrast imaging,''' and are often well circumscribed in appearance with or without necrotic or cystic elements. Nevertheless, any evaluation of an adenoma should still include testing for plasma free metanephrines to rule out pheochromocytoma.

* CT scan with enhancement demonstrating suspicious left adrenal mass.  See corresponding MIBG scan above.  Source: Wikipedia

=== Other ===

* Genetic counselling
** Investigation for familial syndromes is warranted in a patient younger than 50 years with a significant family history of an extraadrenal pheochromocytoma (hereditary paraganglioma syndrome), or bilateral or multifocal tumors.
*** If a mutation is identified, screening should also be offered to asymptomatic at risk family members.