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Review Article
Sandi-Jo Galati, MD*; Meena Said, MD*; Rebekah Gospin, MD; Nikolina Babic, PhD;Karen Brown, MS; Eliza B. Geer, MD; Lale Kostakoglu, MD, MPH; Lawrence R. Krakoff, MD;Andrew B. Leibowitz, MD; Lakshmi Mehta, MD, FACMG; Simone Muller, BS, PharmD, BCPS;
Randall P. Owen, MD, MS, FACS; David S. Pertsemlidis, MD, FACS; Eric Wilck, MD;Guang-Qian Xiao, MD; Alice C. Levine, MD; William B. Inabnet III, MD, FACS
Submitted for publication January 24, 2014Accepted for publication May 25, 2014From The Mount Sinai Adrenal Center, Icahn School of Medicine at Mount Sinai, New York, New York. *Co-first authorsAddress correspondence to Dr. Sandi-Jo Galati, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place #1055, New York, NY 10029. Email: [email protected] as a Rapid Electronic Article in Press at http://www.endocrinepractice.org on October 8, 2014. DOI: 10.4158/EP14036.RATo purchase reprints of this article, please visit: www.aace.com/reprints.Copyright © 2015 AACE.
ABSTRACT
Objective: Pheochromocytomas are complex tumors that require a comprehensive and systematic management plan orchestrated by a multidisciplinary team. Methods: To achieve these ends, The Mount Sinai Adrenal Center hosted an interdisciplinary retreat where experts in adrenal disorders assembled with the aim of developing a clinical pathway for the management of pheochromocytomas. Results: The result was a consensus for the diagnosis, perioperative management, and postoperative management of pheochromocytomas, with specific recommendations from our team of adrenal experts, as well as a review of the current literature. Conclusion: Our clinical pathway can be applied by other institutions directly or may serve as a guide for institution-specific management. (Endocr Pract. 2015;21: 368-382)
Abbreviations:CCB = calcium-channel blocker; CT = computed tomography; MEN = multiple endocrine neoplasia; MIBG = 123I-metaiodobenzylguanidine; MRI = mag-netic resonance imaging; NF1 = neurofibromatosis type 1; PET = positron emission tomography; SPECT = single-photon emission computed tomography; VHL = von Hippel-Lindau
INTRODUCTION
Pheochromocytoma is a catecholamine-secreting tumor of the adrenal medulla that has an incidence of 2 to 8 cases per million annually (1,2). Given the rarity of pheo-chromocytomas, as well as the challenges of treatment, interdisciplinary management with a well-defined clinical pathway is essential.
METHODS
The Mount Sinai Adrenal Center convened an inter-disciplinary pheochromocytoma clinical pathway retreat that brought specialists together with expertise in adrenal disorders in order to delineate the optimal clinical pathway for the management of pheochromocytomas. The follow-ing disciplines participated in this 1-day retreat: anesthesia, cardiology, endocrinology, endocrine surgery, genetics, pathology, pharmacology, nuclear medicine, and radiol-ogy. The agenda was organized into 3 broad categories: diagnosis, perioperative management, and postoperative management and surveillance.
RESULTS
Diagnosis
Biochemical Testing Pheochromocytomas arise from the chromaffin cells of the adrenal medulla, whereas paragangliomas (extra-adrenal pheochromocytomas) arise from sympathetic gan-glia. Norepinephrine is the predominant catecholamine synthesized by the sympathetic ganglia. Epinephrine is synthesized in the adrenal medulla by N-methylation of norepinephrine, catalyzed by the enzyme phenylethanol-amine N-methyltransferase, which is restricted to the chro-maffin cells of the medulla and induced by cortisol from the cortex (Fig. 1). Catecholamines continually leak from secretory granules and are inactivated by the enzyme cat-echol-O-methyltransferase into free normetanephrine and
369
metanephrine (3). Free normetanephrine and metaneph-rine circulate in the plasma in low concentrations and have short half-lives, undergoing further sulfate conjugation by sulfotransferase isoenzyme (3,4) (Fig. 1). In contrast to the free metabolites, sulfated metanephrines are present in 20- to 40-fold higher concentrations, have a longer half-life, and are eliminated by urinary excretion (4). Catecholamine production by pheochromocytomas is variable and depends on the activity of the enzymes required for catecholamine synthesis (Fig. 1). This vari-ability in synthesis governs the clinical presentation of pheochromocytomas, which ranges from asymptomatic to mild, continuous symptoms to episodic pronounced symp-toms or crises (5,6). Up to 20% of pheochromocytomas are biochemically “silent,” with normal concentrations of plasma and urine catecholamines (6). However, these silent tumors metabolize catecholamines into metaneph-rines in increased concentrations in the plasma and urine and may only demonstrate elevated catecholamine concen-trations in the setting of a pheochromocytoma crisis (7). This provides a rationale for the measurement of catechol-amine metabolites as more sensitive and specific markers of excess over direct catecholamine measurement (8,9).
Plasma Versus Urinary Metanephrines The principle screening tests for diagnosis of pheo-chromocytoma are plasma free and urine fractionated metanephrines. The term “fractionated” historically has been used to distinguish the more recent methods that quantify both metanephrine and normetanephrine from the older chromatographic methods that measured only total metanephrines. Today, both plasma and urine screens report metanephrine and normetanephrine levels. Major reference laboratories use liquid chromatography-tandem mass spectrometry for measurement of catecholamine metabolites in plasma and urine. This is the most sensitive and specific methodology available and is free from ana-lytical drug interferences. Measurement of plasma free metanephrines is the recommended initial approach in screening for pheochro-mocytoma (10). This test is 96 to 100% sensitive and 89 to 98% specific for disease detection (4,11,12), depending upon the analytical method and patient population studied (11). Plasma metanephrines are elevated 4-fold over the upper limit of normal in 80% of patients with pheochromo-cytoma and are diagnostic of the disease (13). Clearance of plasma free metanephrines is independent of renal func-tion and is unaffected in patients with renal disease (9). Measurement of urine 24-hour fractionated metaneph-rines confirms mild to moderate elevations of plasma free metanephrine levels and is less sensitive (86 to 97%) and slightly less specific (86 to 95%) (11) (Fig. 2). Pre-analytical factors may affect measurement of both plasma and urine metanephrines. False elevations in plasma normetanephrine levels can be seen in patients over
age 60 years (14), whereas metanephrine levels are less affected (4). Plasma free normetanephrines and metaneph-rines are 30% and 12% higher, respectively, in the seated versus supine position (15). Diets rich in catecholamine-containing foods result in appreciable increases in urinary normetanephrines, but plasma normetanephrines are unaf-fected (15) (Table 1). False positives may also occur with use of certain medications, the most common of which are tricyclic antidepressants and phenoxybenzamine (13), due to elevation in blood catecholamine concentrations (Table 1). In equivocal cases, the clonidine suppression test can be used to distinguish true- from false-positive norepineph-rine elevations. Clonidine activates α-2 adrenergic recep-tors, inhibiting norepinephrine discharge. Persistent nor-epinephrine or normetanephrine elevations following the administration of clonidine suggests the presence of pheo-chromocytoma (16), whereas normalization of values (17) or a 50% decrease in concentration (18,19) has been used to define nonpathologic sympathetic activation. Eisenhofer et al (13) compared the diagnostic accuracy of norepineph-rine or normetanephrine concentrations following cloni-dine administration, reporting a specificity of 98 to 100% when postclonidine values remained above the upper limit of normal. However, the sensitivity of normetanephrine (96%) significantly exceeded norepinephrine (67%), con-firming 40% more cases (13).
Mount Sinai Recommendations Our approach is to measure plasma free metanephrines as the initial biochemical test given the ease of collection and high sensitivity, such that a negative value excludes pheochromocytoma. Values 3- to 4-times above the upper limit of normal are considered diagnostic of pheochro-mocytoma. Significant metanephrine elevations imply epinephrine excess, which localizes tumors to the adrenal medulla, whereas lone normetanephrine elevations suggest extra-adrenal disease. Mild elevations (false positives), particularly in plasma free normetanephrines, are common and require subsequent evaluation with 24-hour urine fractionated metanephrines. Patients are asked to avoid consumption of nonessential medications 1 week prior to testing. Chronic, essential medications such as tricyclic antidepressants, phenoxybenzamine, levodopa, α-methyldopa, and labet-alol should not be stopped abruptly and may require moni-tored titration to an alternative agent prior to biochemical testing.
Imaging Imaging plays a critical role in distinguishing pheo-chromocytomas from adrenal cortical tumors. Commonly used imaging modalities include computed tomography (CT), magnetic resonance imaging (MRI), and functional nuclear-medicine images.
370
Cortex
Medulla
CH2—CH—C—O-‐
NH3
O
+
HO
CH2—CH—C—O-‐
NH3
O
+
HO OH
CH2—CH2—NH2
HO OH
CH—CH2—NH2
HO OH
OH
CH—CH2—NH—CH3
HO OH
OH
Tyrosine
DOPA
Dopamine
Norepinephrine
Epinephrine
Tyrosine Hydroxylase
DOPA Decarboxylase
Dopamine b-‐hydroxylase
Phenylethanolamine N-‐transferase
Cor�sol
Epinephrine
a)
Norepinephrine
b)
Catechol-‐O-‐methyltransferase
Metanephrine Normetanephrine cytoplasm
Sulfotransferase Isoenzyme
Metanephrine Sulfate
Normetanephrine Sulfate
plasma
Renal Excre�on
Fig. 1. Catecholamine synthesis and metabolism. (A) The catecholamine synthetic cascade begins in the adrenal medulla with tyrosine, which is converted to dopa in a rate-limiting reaction by tyrosine hydroxylase. Dopa is subsequently decarboxylated to dopamine, which is hydroxylated to norepinephrine. Epinephrine is synthesized from norepinephrine by the enzyme phenylethanolamine N-methyltransferase, which is restricted to the chromaffi n cells of the adrenal medulla and induced by cortisol from the adrenal cortex. (B) Norepinephrine and epinephrine continuously leak from their storage granules into the cell cytoplasm, where catechol-O-methyltransferase metabolizes norepinephrine and epinephrine into normetanephrine and metanephrine, respectively. Free normetanephrine and metanephrine circulate in the plasma and undergo further sulfate conjugation by sulfotransferase isoenzyme and are eliminated by urinary excretion.
On unenhanced CT scans, the attenuation of pheo-chromocytomas ranges from low density to that of soft tissue. Almost all have attenuation values greater than 10 Hounsfi eld units (HU) (20). On contrast-enhanced CT, pheochromocytomas demonstrate enhancement with delayed washout (21). This feature helps to distinguish pheochromocytomas from lipid-rich adenomas, which are characterized by low density on unenhanced CT scans (<10 HU) and early washout (21). Necrosis, cystic changes, and internal calcifi cations can also be seen in pheochro-mocytomas (21). The sensitivity of CT scans for detecting pheochromocytomas ranges from 90 to 100%, whereas the specifi city ranges from 70 to 80% (22). Pheochromocytoma sizes range from 1.2 to 15 cm, with a mean of 5.5 cm (Fig. 3) (20,23).
The typical appearance of a pheochromocytoma on MRI is hyperintense on T2-weighted images. However, internal hemorrhage and cystic components contribute to the heterogeneity of these lesions, and thus, 35% may not exhibit this hyperintense pattern on T2 imaging (24). On T1-weighted images, pheochromocytomas are often isoin-tense to muscle and hypointense to liver (20). The sensi-tivity and specifi city of MRI for detecting pheochromocy-toma is similar to that of CT (22). CT and MRI are very sensitive in detecting adre-nal pheochromocytomas but exhibit lower sensitivities for extra-adrenal and metastatic disease (25). Functional imaging using various radiotracers allows for whole-body images and detection of lesions outside the primary tumor site. The main modality of functional imaging used is the
371
Figure 2: Biochemical testing algorithm for diagnosing catecholamine excess.
INDICATIONS FOR TESTING:
• Hypertension • Tachycardia • Adrenal abnormality • Diaphoresis • Family history of MEN2 • von Hippel-Landau syndrome, • Familial paraganglioma syndrome • Neurofibromatosis type 1
ORDER Metanephrines, Plasma (free)
ORDER Metanephrines, fractionated by HPLC-MS/MS, Urine
Pheochromocytoma likely. Proceed with imaging studies
Rule out Pheochromocytoma
Not elevated
Mildly elevated or Intermediate
Not elevated
Elevated
High clinical suspicion for pheochromocytoma exists
Mildly elevated or
Intermediate
Repeat testing in 6-12 months
Yes
No No further testing
required
No
Yes High clinical suspicion for
pheochromocytoma
>4x upper limit of normal
Fig. 2. Biochemical testing algorithm for diagnosing catecholamine excess. HPLC-MS/MS = high-performance liquid chromatography-tandem mass spectrometry; MEN = multiple endocrine neoplasia.
372
Table 1Factors That May Affect Biochemical Testing for Pheochromocytoma, Causing False-Positive or False-Negative Results
Factor Examples
Effect on plasma free metanephrines
NMN MN 3MT
Effect on urine fractionated
metanephrines
NMN MN 3MT
Diet (4,15)d Fruits, nuts, potatoes, tomatoes, beans, fermented foods, processed meat, coffee (caffeic acid) (4), cereals (4)a
↔ ↔ ↑ ↔ ↔ ↑↑
Medications (4,13)
Tricyclic antidepressants
Serotonin norepinephrine reuptake inhibitors (81)
Monoamine oxidase inhibitors
Pheonoxybenzamine
Selective α-adrenergic blockers (doxazosin, terazosin, prazosin)
β-Adrenergic receptor blockers (atenolol, metoprolol, propranolol, labetalolb)
Calcium-channel blockers
Levodopa
Sympathomimetics (pseudoephedrine, nicotine, amphetamines)
Acetaminophena
Buspironec
Abrupt discontinuation of clonidine or BZD (11)
↑
↑
↑ ↑
↑
↔
↔ ↑
↔
↑ ↑ ↔ ↔
↑
↔
↑
↑
↑ ↑
↑
↔
↑ ↑
↔
↑ ↑ ↑ ↑
↑
Physiologic influences
ExercisePosition (sitting vs. supine for 20 minutes before blood draw) (15,82)Cigarette smoking (83)d
↑ ↑
↑ ↑
Comorbidities or other characteristics
CHF (14)Untreated OSA (11)Renal dysfunction (4,84)e
HTN (4)Alcohol excess (11)Age >60 (4,14)Gender (female) (4)
↑ ↑↑ ↑↔ ↔ ↑ ↑ ↓
↑
↓
Abbreviations: 3MT = 3-methoxytyramine; BZD = benzodiazepine; CHF = congestive heart failure; HTN = hypertension; MN = metanephrine; NMN = normetanephrine; OSA = obstructive sleep apnea.a Interferes directly with the assay and analysis of plasma free normetanephrines.b Interferes directly with the assay and analysis of urinary catecholamines and metanephrines, variable increases in plasma epinephrine.c Interferes directly with the assay and analysis of urinary metanephrines.d Increases epinephrine and norepinephrine levels.e Diet most dramatically effects plasma and urine deconjugated normetanephrines and 3MT. Plasma and urine deconjugated metanephrines is unchanged. Therefore, it is recommended that patients fast beginning at midnight to avoid interference with biochemical testing (15). Renal dysfunction results in increases in plasma and urine deconjugated normetanephrines and metanephrines as well as vanillylmandelic acid levels (84).
373
123I-metaiodobenzylguanidine (MIBG) scan. MIBG is a guanethidine analog that is taken up by cells in the sym-pathomedullary system (26). Functional imaging can be done by labeling MIBG with either 131I or 123I. However, 123I is preferred because of its lower radiation dose, lack of beta emission, and shorter half-life (27). Its sensitivity ranges from 77 to 90%, with a specificity of 95 to 100% (20). Tracer activity in which the uptake is greater than that of the liver and marked asymmetry of the adrenal glands is suspicious for pheochromocytoma (28). MIBG is particu-larly useful in assisting when MRI/CT results are equivo-cal. MIBG allows for whole body evaluation and can detect extra-adrenal tumors, metastatic disease, and recurrence. Single-photon emission computed tomography (SPECT) is the standard application for cross-sectional evaluation but has limited spatial resolution for small lesions (29,30). The combination of functional and ana-tomic imaging in the form of 123I MIBG SPECT/CT and interpretation of SPECT data with MRI have recently emerged as useful imaging methods for pheochromocyto-mas (28). 123I MIBG SPECT/CT has a sensitivity of 87.5% and a specificity of 93.8% (28). However, investigations combining the use of SPECT and MRI are ongoing and have not reached a routine clinical platform yet (Fig. 4) (28). Positron emission tomography (PET) imaging with fluorodeoxyglucose (FDG) has limited sensitivity in benign pheochromocytomas, but malignant lesions are
readily detected (29,31). More specific imaging is pos-sible with the catecholamine precursor 6-[18F]fluoro-L-dihydroxyphenylalanine (18F-DOPA) or the catechol-amine 18F-fluorodopamine. Small studies have confirmed the feasibility of 18F-DOPA as a tracer for staging pheo-chromocytomas (29,32-35). Detection is also possible with a somatostatin receptor ligand using the PET radio-tracer 68Ga-dotatate. Preliminary studies have shown that 68Ga-dotatate PET/CT is useful as a first-line agent for those at high risk for paragangliomas and metastatic dis-ease (36). However, most studies involving research radiotrac-ers included only those with a high clinical suspicion of pheochromocytoma or paraganglioma, and sensitivities and specificities for an unbiased population have yet to be elucidated.
Mount Sinai Recommendations We recommend MRI or CT with contrast as the initial localization study. In the event that the diagnosis and/or imaging is equivocal, 123I MIBG scan can be considered. If the 123I MIBG scan is negative and a clinical suspicion still exists, then an FDG-PET scan should be performed.
Pre-operative Management Prevention of intra-operative hypertensive crisis is the principal goal of pre-operative management. Close intra-operative monitoring by an anesthesiologist familiar with
Fig. 3. Appearance of pheochromocytoma on different phases of a computed tomogra-phy scan with intravenous contrast.
374
the management of pheochromocytoma may abrogate the need for pre-operative medical treatment (37); however, most institutions have established a pre-operative treat-ment plan addressing both blood pressure control and vol-ume expansion to minimize surgical risk (38,39). α-Adrenergic blocking agents lower blood pressure by antagonizing catecholamine-stimulated vasoconstric-tion. They are the agents of choice in controlling pre-operative blood pressure, although there are no published data on the dose, agent selection, duration of therapy, or therapeutic goals (40). Phenoxybenzamine is a nonselec-tive, irreversible α-antagonist that is the preferred ini-tial agent due to its long duration of action and irrevers-ibility. Its tolerability is limited by its side effects (39). Alternative agents include the selective α1-adrenergic antagonists, which are used in patients that cannot toler-ate phenoxybenzamine and in those who require long-term medical treatment (41). β-Adrenergic blockade is indicated for management of tachycardia or arrhythmias induced by catecholamine excess after an α-antagonist has been introduced. β1-Selective drugs are preferred, as nonselec-tive β-blockers may antagonize β2-vasodilator action (42) (Table 2). Calcium-channel blockers (CCBs) can be used in conjunction with α- and β-adrenergic blockers or used alone as the primary agent for blood pressure control (41).
β-Adrenergic-stimulated renin secretion is present in a subset of patients with pheochromocytoma, so agents tar-geting the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers may improve blood pressure control in these patients (43). The less noxious side effect profiles of these agents make them useful alternatives for patients who can-not tolerate the α-blockading agents (Table 2). Catecholamine-synthesis inhibitors can be added in patients with catecholamine burdens that are unresponsive to adrenergic and calcium-channel blockade. α-Methyl-l-tyrosine (metyrosine) inhibits tyrosine hydroxylase (5,40), the rate-limiting step of the catecholamine biosynthetic cascade (Fig. 1), reducing catecholamine stores after 3 days of use (44). Because there is incomplete depletion of catecholamine stores, α-adrenergic blockade must be used in conjunction (5). The side effects of metyrosine can be disabling, including extrapyramidal symptoms, depres-sion, galactorrhea, and sedation, particularly with long-term use, and may require discontinuation (5). Therefore, its use should be reserved for widespread disease with intractable symptoms despite α-adrenergic blockade (45). Chronic vasoconstriction from catecholamine excess results in a volume-depleted state. A rational approach to minimizing pre-operative hypovolemia is institution of a liberalized salt diet in addition to oral fluid loading for
Fig. 4. Transaxial images of a large left adrenal mass in a 28-year-old man: computed tomography (CT) image (A); 123I-metaiodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT)/CT image (B); T2 turbo spin echo magnetic resonance (MR) image (C); and 123I-MIBG SPECT/MR image using a T1 fast field echo sequence (D). Both high signal intensity on T2-weighted magnetic resonance imaging and high tracer uptake are consistent with pheochromocytoma. This lesion contains areas of cystic necrosis.
375
Tabl
e 2
Pre-
oper
ativ
e, In
tra-
oper
ativ
e, a
nd P
osto
pera
tive
Phar
mac
olog
ic M
anag
emen
t of P
heoc
hrom
ocyt
oma
Cla
ssD
rug
and
dosin
gC
linic
al u
se
Pre-
oper
ativ
em
anag
emen
t
α-A
dren
ergi
c bl
ocka
de
Cal
cium
-cha
nnel
blo
ckad
e
Cat
echo
lam
ine
synt
hesis
inhi
bitio
n
Oth
ers
Non
sele
ctiv
e α
-blo
ckad
e: p
heno
xybe
nzam
ine
10-2
0 m
g 2-
3 tim
es/d
ay (1
00
mg
max
dai
ly)
Sele
ctiv
e α
-blo
ckad
e: d
oxaz
osin
1 m
g da
ily, t
eraz
osin
1 m
g 2
times
/day
, pr
azos
in 1
mg
3 tim
es/d
ay (a
ll 20
mg
max
dai
ly)
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
-----
-
Nife
dipi
ne S
R 3
0-12
0 m
g da
ilyN
icar
dipi
ne 3
0 m
g 2
times
/day
(120
mg
max
dai
ly)
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
-----
-
Met
yros
ine
250
mg
3-4
times
/day
(4 g
max
dai
ly)
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
-----
-β-
bloc
kade
, ang
iote
nsin
-con
vert
ing
enzy
me
inhi
bito
rs,
angi
oten
sin r
ecep
tor b
lock
ers
• Ph
enox
yben
zam
ine
is th
e pr
efer
red
agen
t as i
t pro
vide
s lon
g-ac
ting
nons
elec
tive
α-b
lock
ade
• Si
de e
ffect
s: e
xtre
me
fatig
ue, n
asal
con
gest
ion,
and
orth
osta
sis
• Si
de e
ffect
s are
less
pro
noun
ced
in se
lect
ive
α-b
lock
ade
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
• B
lock
s nor
epin
ephr
ine-
med
iate
d ca
lciu
m tr
ansp
ort i
nto
the
vasc
ular
sm
ooth
mus
cle
• C
an b
e us
ed a
s an
adju
nctiv
e ag
ent t
o α
- and
β-b
lock
ade
or in
pat
ient
s who
ca
nnot
tole
rate
α-b
lock
ing
agen
ts--
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
-----
-•
Not
rout
inel
y us
ed p
re-o
pera
tivel
y un
less
for s
hort
cour
se d
ue to
seve
re
sym
ptom
s•
Mai
n sh
ort-t
erm
side
effe
ct is
som
nole
nce
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
• β-
Blo
ckad
e ca
n be
inst
itute
d af
ter α
-blo
ckad
e fo
r tac
hyca
rdia
• β1
-sel
ectiv
e bl
ocka
de is
pre
ferr
ed (m
etop
rolo
l, bi
sopr
olol
and
ate
nolo
l)
Intr
a-op
erat
ive
man
agem
ent
Adr
ener
gic
bloc
kade
Cal
cium
-cha
nnel
blo
ckad
e
Vaso
dila
tors
Ane
sthe
tic a
gent
s/ ne
urom
uscu
lar
bloc
kade
Ana
lges
ia
Phen
tola
min
e 1-
5 m
g in
trave
nous
bol
uses
or i
nfus
ion
Esm
olol
0.5
mg/
kg o
ver 1
min
then
0.0
5 m
g/kg
/min
infu
sion
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
-----
Nic
ardi
pine
5 m
g/h
infu
sion
titra
tabl
e to
15
mg/
hC
levi
dipi
ne 1
-2 m
g/h
infu
sion
titra
tabl
e to
32
mg/
h--
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
---N
itrop
russ
ide
2 m
g/kg
/min
, not
to e
xcee
d 80
0 m
g/h
Mag
nesiu
m su
lfate
bol
us 4
0 m
g/kg
, inf
usio
n 1-
2 g/
h--
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
---Pr
opof
ol 4
0 m
g ev
ery
10 s,
not
to e
xcee
d 24
0 m
g
Etom
idat
e 0.
2-0.
6 m
g/kg
ove
r 30-
60 s
Thio
pent
al 3
-4 m
g/kg
Sevo
flura
ne 0
.5-3
% w
ith o
r with
out n
itrou
s oxi
deIs
oflur
ane
1-2%
with
nitr
ous o
xide
, add
0.5
-1%
with
oxy
gen
Des
flura
ne 2
.5-8
.5%
with
or w
ithou
t nitr
ous o
xide
Atr
acur
ium
0.4
-0.5
mg/
kg b
olus
, 0.0
8-0.
1 m
g/kg
20-
45 m
in a
fter b
olus
, rep
eat
mai
nten
ance
dos
e ev
ery
15-2
5 m
in O
R 0
.005
-0.0
1 m
g/kg
/min
infu
sion
for
mai
nten
ance
R
ocur
oniu
m b
olus
0.4
5-0.
6 m
g/kg
, 0.1
-0.2
mg/
kg e
very
20-
30 m
in fo
r m
aint
enan
ce O
R 0
.01-
0.01
2 m
g/kg
/min
infu
sion
for m
aint
enan
ce
Vecu
roni
um b
olus
0.0
8-0.
1 m
g/kg
, 0.0
1-0.
015
mg/
kg e
very
20-
45 m
in fo
r m
aint
enan
ce O
R
for c
ontin
uous
infu
sion
: int
ubat
ing
dose
of 0
.000
8-0.
001
mg/
kg fo
llow
ed 2
0-40
m
in la
ter w
ith 0
.000
8-0.
0012
mg/
kg/m
in in
fusi
on fo
r mai
nten
ance
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
---
Fent
anyl
1-3
mg/
kg/h
• Ph
ento
lam
ine
is a
non
sele
ctiv
e α
-blo
ckin
g ag
ent
• Es
mol
ol is
a β
-blo
cker
that
shou
ld b
e us
ed fo
r tac
hyar
rhyt
hmia
s--
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
-----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
• Th
iocy
anat
e le
vels
mus
t be
mea
sure
d w
ith n
itrop
russ
ide
use
• M
agne
sium
sulfa
te is
safe
in p
regn
ancy
and
chi
ldre
n--
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
-----
-
• D
esflu
rane
cau
ses s
ympa
thet
ic a
ctiv
atio
n
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
-*
O
ther
age
nts c
an b
e us
ed, f
enta
nyl i
s our
inst
itutio
nal p
refe
renc
e
Post
oper
ativ
em
anag
emen
t
Adr
ener
gic
bloc
kade
Cat
echo
lam
ine
synt
hesis
inhi
bitio
n
Phen
oxyb
enza
min
e 10
-20
mg
2-3
times
/day
, dox
azos
in 1
mg
daily
, ter
azos
in 1
m
g 2
times
/day
, pra
zosin
1 m
g 3
times
/day
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
Met
yros
ine
250
mg
3-4
times
/day
• α
-Blo
cker
s sho
uld
be re
sum
ed p
osto
pera
tivel
y fo
r res
idua
l or m
etas
tatic
di
seas
e--
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
---
• Po
stop
erat
ive
use
of m
etyr
osin
e is
indi
cate
d fo
r res
idua
l or m
etas
tatic
di
seas
e•
Side
effe
cts w
ith lo
ng-te
rm u
se in
clud
e di
arrh
ea, a
nxie
ty, n
ight
mar
es,
crys
tallu
ria, g
alac
torr
hea,
ext
rapy
rimid
al sy
mpt
oms i
n ad
ditio
n to
seda
tion
376
volume expansion once blood pressure control has been achieved, although limited data exist for this practice (39). There are no data to support inpatient admission for intra-venous fluid prior to surgery, although in patients with hemodynamic volatility or cardiomyopathy, this may be considered. Hyperglycemia due to catecholamine excess is a common metabolic derangement seen in patients with pheochromocytomas (46). The etiology is multifacto-rial, including increased gluconeogenesis and glycoge-nolysis by stimulation of hepatic β-adrenergic receptors (47), decreased insulin secretion by stimulation of pan-creatic α-adrenergic receptors (48), and decreased skel-etal muscle glucose uptake (49). All patients should be assessed pre-operatively for the presence of abnormal glucose metabolism with a fasting blood glucose mea-surement, an oral glucose tolerance test, or a hemoglobin A1c measurement.
Mount Sinai Recommendations The initial agent of choice in pre-operative blood pres-sure management is phenoxybenzamine due to its non-selective, irreversible action at the level of the receptor and long duration of action. Patients who cannot tolerate phenoxybenzamine should be transitioned to a selective α-blocker if tolerated or a CCB. Pre-operative α-blockade should be instituted a minimum of 7 days prior to surgery, unless the patient is normotensive. In cases of silent pheo-chromocytomas in which there is no α-blockade, consulta-tion with anesthesia prior to surgery is especially essential. Once the blood pressure is controlled, all patients are encouraged to increase salt and water intake for pre-oper-ative volume expansion. We do not suggest admission the day prior to surgery for intravenous fluid loading unless severe hemodynamic fluctuations or cardiomyopathy is present. All patients should undergo hemoglobin A1c and fast-ing glucose measurements at the time of diagnosis, given the increased incidence of hyperglycemia.
Perioperative Management
Operative Approach Adrenalectomy is the mainstay of management for pheochromocytomas. Laparoscopic surgery is the standard operative approach for the resection of pheochromocyto-mas. This can be done via a transabdominal or retroperito-neal route, depending on the size of the tumor. The superi-ority of the laparoscopic approach over the open approach has been established by numerous studies (50,51). When compared with open adrenalectomies, the laparoscopic method has lower mean operative time, shorter hospital stay, decreased need for intensive care, less blood loss, and lower pain medication requirement. The complication rates
are equivalent between the two methods. Tumor size does not affect outcome (50). Tumors larger than 9 cm can be removed safely with this method (50). The laparoscopic retroperitoneal approach has been shown to be a safe alternative to the laparoscopic transabdominal method for smaller adrenal tumors (52). An open approach is warranted when malignancy is suspected. Imaging characteristics raising suspicion for malignancy include large size, necrosis, hemorrhage, retained contrast on CT studies, and evidence of invasion into surrounding structures (53,54).
Mount Sinai Recommendations We recommend laparoscopic adrenalectomy in patients with pheochromocytomas, which can be per-formed safely with either the transabdominal laparoscopic approach or the retroperitoneal laparoscopic method. In the event that malignancy is suspected, open adrenalectomy is recommended.
Anesthesia The intra-operative management of patients with pheochromocytoma is complex and challenging. Life-threatening fluctuations in blood pressure and cardiovascu-lar collapse can occur. Several measures are recommended in order to mitigate the chance of cardiovascular complica-tions. Euvolemia should be maintained by administering a balanced salt solution (e.g., lactated Ringers, Plasmalyte A) at a 10 to 30 mL/kg/hour rate based upon blood loss and hemodynamic assessment. Induction agents that have been safely used include propofol, etomidate, and thiopental (37,38,55). Etomidate may provide more cardiovascular stability, but myoc-lonus, increased postoperative nausea/vomiting, and decreased steroid-genesis need to be considered. Agents that cause catecholamine release, such as ketamine and ephedrine (37,56,57), must be avoided, as the response is unpredictable. Muscle relaxants that are used with success include atracurium, rocuronium, and vecuronium (55,58,59). Pancuronium is not recommended given its vagolytic effect and prolonged duration of action (58,60). Maintenance of anesthesia with any volatile agent is safe (57,58,61,62), and even though desflurane causes sympathetic activation, it too has been used in these cases (58,63). Mount Sinai Recommendations We recommend the use of propofol as an induction agent and sevoflurane or desflurane as maintenance drugs. We recommend maintaining euvolemia by administering a balanced salt solution. Vecuronium and rocuronium should be used for muscle relaxation, whereas fentanyl should be the mainstay of analgesia.
377
Intra-operative Managementof Hypertension
Routine use of an arterial line is recommended for intra-operative blood pressure monitoring and should be placed before the induction of anesthesia. A central line is part of routine care for many teams but may be used more selectively. Intra-operative hypertension can be managed with a variety of agents. In a review of the current data, the most commonly used agents were nitrates (67%) and β-adrenergic blockers (47%). α-Adrenergic blockers were used in 33% of cases. In the control of intra-operative hypertension, 1 to 3 different agents are often used (64). Sodium nitroprusside is used as a first-line agent in treating intra-operative hypertension. Its onset of action is immediate and recovery occurs within 1 to 2 minutes. Toxic metabolites are a concern when it is administered in high doses or for greater than 4 to 72 hours (58). Nitroglycerin is also used to control intra-operative hypertension. Its onset of action and duration are rapid. Phentolamine is an α-adrenergic blocker that is used commonly for intra-operative control of hypertension. Its action is immediate, lasting 15 to 30 minutes, and it can be used as a continuous infusion (65). Esmolol is a β-adrenergic blocker used for blood pres-sure and heart rate control intra-operatively. It is particu-larly helpful when patients exhibit tachycardia. Its onset of action is 60 seconds and lasts 10 to 20 minutes (58). Magnesium sulfate is also used for intra-operative hypertension management. It is safe and effective to use in children and pregnant patients (66). Clevidipine butyrate is a novel short-acting CCB. Its onset is approximately 2 to 4 minutes and lasts approxi-mately 5 to 15 minutes. Its quick onset and rapidly titrat-able qualities make it a desirable agent for intra-operative hypertension (66). Another benefit is its cost. Clevidipine costs approximately $130.00 per case. In contrast, phentol-amine costs approximately $9,000.00 per case. Nicardipine is a second-generation CCB commonly used for intra-operative hypertension. Its half-life is 3 to 7 minutes and it decreases blood pressure in a dose-depen-dent fashion, with a response time of 1 to 3 minutes (67).
Mount Sinai Recommendations We recommend the use of clevidipine, phentolamine, and esmolol as first-line agents for intra-operative control of hypertension. Clevidipine is preferred, as it is more cost effective. Second-line agents include nicardipine and sodium nitroprusside.
Postoperative Managementand Surveillance
Immediate Postoperative Period Close inpatient observation is required for 24 hours after surgery because withdrawal of catecholamine excess
may result in significant hemodynamic changes (37,68). Postoperative hypotension results from a number of dif-ferent factors, including the loss of peripheral vasocon-striction after tumor removal and the prolonged effects of irreversible α-adrenergic blockade. This may result in catecholamine-resistant hypotension in which vasopressin is required for hemodynamic support (37,69). Postoperative hypoglycemia may also occur as a result of transient catecholamine deficiency and hyper-insulinemia. Hypoglycemia is worsened by prolonged α-adrenergic blockade. Thus, close monitoring of blood glucose is needed in the postoperative period (37,70-72).
Mount Sinai Recommendations We recommend close hemodynamic monitoring of all patients in the 24 hours following surgery. This can be done in the typical floor-bed setting. Monitoring includes close attention to vitals, urine output, and fluid status. The use of a monitored step-down unit is not routinely neces-sary. However, if there is pre-operative or intra-operative concern about hemodynamic instability, then a step-down unit would be appropriate. We recommend blood glucose monitoring with fingerstick or serum glucose every 4 to 6 hours for 24 hours postoperatively.
Biochemical Monitoring andResidual Hypertension
Plasma free or urinary deconjugated metanephrines should be tested 2 to 6 weeks postoperatively to assess for complete tumor resection (10,38). Normalization of biochemical parameters does not unequivocally indicate cure due to the potential presence of residual microscopic disease. Therefore, biochemical screening should be per-formed annually (10). Hypertension typically resolves within days of sur-gery; however, residual hypertension may persist up to 2 months postoperatively. In the setting of normalization of plasma or urinary metanephrines after tumor resection, residual hypertension present after 2 months is typically essential hypertension and should be managed following the seventh report of the Joint National Committee (JNC 7) hypertension guidelines (73). Persistent metanephrine elevations may signal resid-ual tumor, multifocal disease, or metastatic disease and determine the need for additional imaging. Hypertension and symptoms of catecholamine excess in patients with residual or metastatic disease should be managed as they were pre-operatively, primarily with α-adrenergic block-ade; however, the selective α-blocking agents (prazosin, doxazosin, or terazosin) may be employed in these cases to minimize the side effects of expected long-term use. In patients with refractory disease, metyrosine can be used to manage the catecholamine burden (5,40). Because of its side effects, particularly with long-term use, mety-rosine should be reserved for patients with widespread
378
disease and intractable symptoms despite α-adrenergic blockade (45).
Mount Sinai Recommendations Biochemical testing with plasma free metanephrines is performed during the initial outpatient follow-up visit 2 to 6 weeks postoperatively and annually thereafter. In patients in whom biochemical remission has been demon-strated, persistent hypertension is managed according to JNC-7 guidelines for essential hypertension.
Genetic Testing Historically, approximately 10% of pheochromocyto-mas and paragangliomas were estimated to be due to one of the known hereditary syndromes conferring susceptibility to the tumors: neurofibromatosis type 1(NF1 gene), multi-ple endocrine neoplasia (MEN) 2 (RET gene), von Hippel-Lindau (VHL) disease (VHL gene), and, rarely, MEN 1 (MEN1 gene) (74). In recent years, multiple studies have shown that this figure is higher, particularly with the discovery of addi-tional susceptibility genes. These include germline muta-tions in the genes encoding components of the succinate dehydrogenase complex (i.e., SDHB, SDHC, SDHD, SDHA, and SDHAF2), as well as mutations in TMEM127, MAX, KIF1Bβ, EGLN1/PHD2, and HIF2A (75). Germline mutations in RET, VHL, SDHD, and SDHB were identified in one-fourth of patients with nonsyn-dromic sporadic disease (76). In a subsequent retrospective study of 139 patients, 41% had mutations in one of five genes (SDHB, SDHD, VHL, RET, NF1) (77). In patients with at least one paraganglioma outside the adrenal gland, 53% had an identified mutation (77). Most familial cases of pheochromocytoma or paraganglioma and 10 to 20% of sporadic cases will have a germline mutation in one of the 10 known genes (78). Several clinical algorithms have been suggested to guide genetic testing, focusing on limiting the cost of test-ing by identifying the genes most likely to be involved in each clinical scenario based on the characteristics of the tumor (Table 3). A next-generation sequencing (NGS) strategy allow-ing simultaneous analysis of nine of the susceptibility genes (all but NF1) has been recently validated (79). This approach is likely to be more cost effective. An inevita-ble result of this technology is the detection of sequence variants of unknown significance, which require complex interpretation before any conclusions can be made regard-ing their pathogenicity. As experience grows with sequenc-ing these genes, information will be refined and fewer vari-ants of unknown significance will be reported. Risk factors for the presence of an underlying genetic syndrome or susceptibility include extra-adrenal pheochro-mocytoma, head or neck paraganglioma, age younger than 45 years, bilateral or multicentric disease, and malignant
tumors (80). Family history of pheochromocytoma or paraganglioma or clinical presentation consistent with one of the known hereditary syndromes should also prompt genetic counseling and testing (74).
Mount Sinai Recommendations Our practice is to refer all patients with pheochromo-cytoma or paraganglioma for genetic counseling and test-ing who have:
(1) syndromic features suggestive of NF1, VHL, or MEN2. Hallmark features include personal or family history of multiple café-au-lait spots, neurofibromas, renal cell carcinoma, heman-gioblastomas, medullary thyroid cancer, or hyperparathyroidism;
(2) a family history of pheochromocytomas or para gangliomas or sudden unexplained death of a family member at a young age;
(3) presence of extra-adrenal or multifocal tumors;(4) age of diagnosis prior to 50 years;(5) malignant tumors.
Because the estimate for germline mutations in spo-radic pheochromocytomas or paragangliomas approaches 10 to 20%, screening of all patients with pheochromocyto-mas or paragangliomas should be strongly considered. In the future, the availability of NGS panels will enable more widespread and comprehensive testing at lower cost.
DISCUSSION
This review presents our institutional approach in treating patients with pheochromocytomas and paragan-gliomas. Given the complexity of the disease and potential for serious adverse outcomes, a collaborative approach is required for the systematic management of pheochromocy-tomas and paragangliomas. This is achieved by following an evidence-based outline of specific therapeutic goals and measures for each time period (pre-operative diagnosis, perioperative management, and postoperative manage-ment and surveillance). In order to implement this strategy, a multidisciplinary team involving experts who are experi-enced in the evaluation and treatment of pheochromocyto-mas is required.
CONCLUSION
Our clinical pathway can be applied directly or used by others as a platform from which they can develop their institutional methods for the treatment and management of this neuroendocrine disease.
DISCLOSURE
The authors have no multiplicity of interest to disclose.
379
Tabl
e 3
Path
ophy
siolo
gy a
nd F
eatu
res o
f Kno
wn
Synd
rom
es a
nd S
usce
ptib
ilitie
s A
ssoc
iate
d W
ith P
heoc
hrom
ocyt
oma
and
Para
gang
liom
as (7
4,75
)
Gen
e/pa
thop
hysio
logy
Clin
ical
feat
ures
Syndromes
Mul
tiple
end
ocri
ne n
eopl
asia
(MEN
) 2a
and
2b:
activ
atin
g m
utat
ion
of th
e RE
T pr
oto-
onco
gene
• Ep
inep
hrin
e an
d no
repi
neph
rine
secr
etio
n, 5
0% b
ilate
ral,
typi
cally
ben
ign,
typi
cally
intra
-adr
enal
• M
EN 2
A: m
edul
lary
thyr
oid
canc
er, h
yper
para
thyr
oidi
sm
• M
EN 2
B: m
edul
lary
thyr
oid
canc
er, m
ucos
al g
angl
ione
urom
as, m
arfa
noid
feat
ures
von
Hip
pel-L
inda
u (V
HL)
dise
ase:
VH
L ge
ne
prom
otes
deg
rada
tion
of th
e hy
poxi
a-in
duci
ble
fact
or
(HIF
) 1α
• N
orep
inep
hrin
e se
cret
ion,
bila
tera
l, ty
pica
lly b
enig
n, ty
pica
lly in
tra-a
dren
al
• C
ereb
ella
r and
spin
al h
eman
giob
last
omas
, ret
inal
hem
angi
omas
, pan
crea
tic n
euro
endo
crin
e tu
mor
s, ep
idid
ymal
cy
sts,
rena
l cel
l car
cino
mas
Neu
rofib
rom
atos
is (N
F) ty
pe 1
: los
s-of
-fun
ctio
n m
utat
ion
of N
F1, a
tum
or su
ppre
ssor
• Ep
inep
hrin
e se
cret
ion,
uni
late
ral,
intra
-adr
enal
, ben
ign
• C
afé-
au-la
it sp
ots,
neur
ofibr
omas
, iris
ham
arto
mas
, ski
nfol
d fr
eckl
ing,
opt
ic n
erve
glio
mas
, phe
noid
bon
e dy
spla
sia
MEN
1: M
EN1
tum
or su
ppre
ssor
gen
e•
Rar
e ph
eoch
rom
ocyt
omas
• A
ssoc
iate
d w
ith p
ituita
ry tu
mor
s, hy
perp
arat
hyro
idis
m, a
nd p
ancr
eatic
tum
ors
Susceptibilities
Succ
inat
e de
hydr
ogen
ase
(SD
H) c
ompl
ex: o
xidi
zes
succ
inat
e in
to fu
mar
ate,
m
utat
ions
resu
lt in
su
ccin
ate
accu
mul
atio
n w
ith
stab
iliza
tion
of H
IF-1
α
SDH
B•
Nor
epin
ephr
ine
and
dopa
min
e, e
xtra
-adr
enal
, hig
h ra
te o
f mal
igna
ncy
• A
ssoc
iatio
ns: r
enal
cel
l car
cino
ma,
bre
ast c
ance
r, ga
stro
inte
stin
al st
rom
al tu
mor
s, pa
pilla
ry th
yroi
d ca
ncer
SDH
C•
Nor
epin
ephr
ine
and
dopa
min
e, e
xtra
-adr
enal
esp
ecia
lly h
ead
and
neck
, ben
ign
SDH
D•
Nor
epin
ephr
ine
and
dopa
min
e, e
xtra
-adr
enal
esp
ecia
lly h
ead
and
neck
, mul
tifoc
al, t
ypic
ally
ben
ign
SDH
A•
Typi
cally
ext
ra-a
dren
al, a
lso
asso
ciat
ed w
ith L
eigh
synd
rom
e (n
euro
dege
nera
tive
diso
rder
)SD
HAF
2•
Typi
cally
ext
ra-a
dren
al e
spec
ially
hea
d an
d ne
ck, m
ultif
ocal
Tran
smem
bran
e (T
MEM
) pro
tein
127
: TM
EM12
7 is
a tu
mor
supp
ress
or in
the
rapa
myc
in p
athw
ay•
Epin
ephr
ine
and
nore
pine
phrin
e se
cret
ion,
intra
-adr
enal
, ben
ign
MY
C-a
ssoc
iate
d fa
ctor
X: M
AX re
gula
tes c
ellu
lar
prol
ifera
tion
and
apop
tosi
s•
Epin
ephr
ine
and
nore
pine
phrin
e se
cret
ion,
intra
-adr
enal
, ofte
n bi
late
ral,
mal
igna
nt c
ases
repo
rted
Kin
esin
fam
ily m
embe
r 1B:
KIF
1B in
duce
s ap
opto
sis
• Si
ngle
pat
ient
with
phe
ochr
omoc
ytom
a, a
ssoc
iate
d w
ith n
euro
blas
tom
as
EGLN
1/PH
D2
enco
des P
HD
2 en
zym
e w
hich
is
invo
lved
in H
IF-1
α d
egra
datio
n•
Extra
-adr
enal
tum
ors a
nd e
ryth
rocy
tosi
s
Hyp
oxia
-indu
cibl
e fa
ctor
1α
HIF
2A g
ene
• A
ssoc
iate
d w
ith p
olyc
ythe
mia
• A
lso
repo
rted
in so
mat
ic m
utat
ions
380
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