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SECONDARY HYPERTENSION: NERVOUS SYSTEM MECHANISMS (M WYSS, SECTION EDITOR)
Pheochromocytomas and Hypertension
Joseph M. Pappachan
1
&Nyo Nyo Tun
2
&Ganesan Arunagirinathan
2
&Ravinder Sodi
3
&Fahmy W. F. Hanna
4
#Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Purpose of Review Pheochromocytomas and paragangliomas (PPGLs) are uncommon catecholamine-producing neuroendocrine
neoplasms that usually present with secondary hypertension. This review is to update the current knowledge about these
neoplasms, the pathophysiology, genetic aspects and diagnostic and therapeutic algorithms based on scientific literature mostly
within the past 3 years.
Recent Findings Eighty to eighty-five percent of PPGLs arise from the adrenal medulla (pheochromocytomas; PCCs) and the
remainder from the autonomic neural ganglia (paragangliomas; PGLs). Catecholamine excess causes chronic or paroxysmal
hypertension associated with sweating, headaches and palpitations, the presenting features of PPGLs, and increases the
cardiovascular morbidity and mortality. Genetic testing should be considered in all cases as mutations are reported in 35–
40% of cases; 10–15% of PCCs and 20–50% of PGLs can be malignant. Measurements of plasma-free metanephrines or
24-h urine-fractionated metanephrines help biochemical diagnosis with high sensitivity and specificity. Initial anatomical
localization after biochemical confirmation is usually with computed tomography (CT) or magnetic resonance imaging
(MRI).
123
Iodine metaiodobenzylguanidine (
123
I-MIBG) scintigraphy, positron emission tomography (PET) or single-
photon emission computed tomography (SPECT) is often performed for functional imaging and prognostication prior to
curative or palliative surgery. Clinical and biochemical follow-up is recommended at least annually after complete tumour
excision. Children, pregnant women and older people have higher morbidity and mortality risk. De-bulking surgery, che-
motherapy, radiotherapy, radionuclide agents and ablation procedures are useful in the palliation of incurable disease.
Summary PPGLs are unique neuroendocrine tumours that form an important cause for endocrine hypertension. The diagnostic
and therapeutic algorithms are updated in this comprehensive article.
Keywords Pheochromocytomas (PCCs) .Paragangliomas (PGLs) .Hypertension .Plasma free metanephrines .Urine
fractionated metanephrines
Introduction
Pheochromocytomas (PCCs) are catecholamine-producing
chromaffin cell tumours that commonly arise from the
adrenal medulla and less often from the autonomic neural
ganglia [1••,2•]. Embryologically, both the adrenal me-
dulla and autonomic ganglia share a common origin as
chromaffin tissues arising from the neural crest cells,
and therefore, PCCs are categorized as neuroendocrine
tumours. Tumours arising from the autonomic ganglia
are also known as paragangliomas (PGLs). Together,
PCCs and PGLs are termed as PPGLs. Although a major-
ity of PCCs secrete catecholamines such as epinephrine,
norepinephrine and dopamine, a small proportion of tu-
mours are biochemically silent [1••,3].
This article is part of the Topical Collection on Secondary Hypertension:
Nervous System Mechanisms
*Joseph M. Pappachan
drpappachan@yahoo.co.in
1
Department of Endocrinology and Metabolism, University Hospitals
of Morecambe Bay NHS Foundation Trust, Lancaster LA1 4RP, UK
2
Metabolic Unit, Western General Hospital, Edinburgh, UK
3
Department of Biochemistry and Blood Sciences, University
Hospitals of Morecambe Bay NHS Foundation Trust, Lancaster LA1
4RP, UK
4
Department of Endocrinology and Metabolism, The Royal Stoke
University Hospital and North Staffordshire University,
Stoke-on-Trent ST4 6QG, UK
Current Hypertension Reports (2018) 20:3
https://doi.org/10.1007/s11906-018-0804-z
Endocrine hypertension is the second most common
cause for secondary hypertension after chronic kidney
disease, although PPGLs form only a minor proportion
of endocrine causes [4•,5]. It is has been shown that
PPGLs account for only 0.1–0.6% of hypertension cases
in the community [2•,4•,5]. Most of the clinical se-
quelae and complications of PPGLs are related to hy-
pertension and this article updates the pathophysiologi-
cal mechanisms, clinical features, diagnostic evaluation
and management aspects of PPGLs and hypertension.
Pathophysiology of PPGLs and Hypertension
Induced by PPGLs
PPGLs originate from cells of the embryonic neural crest de-
rived from the ectoderm. The neural crest develops into the
sympathetic ganglia (the adrenal medulla and organ of
Zuckerkandl) and parasympathetic ganglia (carotid body).
Majority of the tumours originate from the adrenal gland
(PCCs), while approximately 15–20% occur at extra-adrenal
sites (PGLs) [1••].
The enzyme phenylethanolamine-N-methyl transferase
(PNMT) is responsible for the conversion of norepinephrine to
epinephrine within the adrenal glands. PNMT is unique to the
adrenal gland, brain and organ of Zuckerkandl. Consequently,
the adrenal medulla secretes the catecholamines predominantly
as epinephrine (about 80%) and the remainder as norepinephrine
and dopamine [6].
Functional PPGLs produce and metabolise catecholamines
to their O-methylated metabolites within the tumour.
Dopamine is metabolised to methoxytyramine, norepineph-
rine to normetanephrine and epinephrine to metanephrine.
Measurements of these metabolites in plasma and urine pro-
vide useful tools for the biochemical diagnosis.
As these tumours are rare, suitable animal models are
sought to define the pathophysiological consequences and
to develop new therapeutic strategies for aggressive forms
of PPGLs. A recent illustration is the MENX rat model,
which develops PCC with complete penetrance. MENX
rats develop tumours producing increase in urinary O-
methylated metabolites—normetanephrine, metanephrine
and methoxytyramine—while lack of parallel increases in
urinary epinephrines and dopamine provides specific in-
dicators of tumour production [7].
Even though majority of the cases of PPGLs are benign, 10
to 15% of PCCs and 20 to 50% of PGLs can be malignant [2].
Although the pathogenic pathways for development of PPGLs
have not been fully elucidated, transcriptomic studies have re-
vealed two dominant molecular pathways leading to tumori-
genesis viz., the hypoxic (cluster-1 genes) pathway involving
succinate dehydrogenase (SDH) genes and Von Hippel-Lindau
(VHL) genes, and the mammalian target of rapamycin (mTOR;
cluster-2 genes) pathway involving RET and neurofibromin 1
(NF1) genes [8–10]. There is a 15–20% chance of recurrence of
PPGLs at 10 years with a 20% malignancy rate [10,11].
Understanding the genetic and molecular pathways of tumori-
genesis would therefore help clinicians for follow-up of patients
anddevelopingtargetedtherapies.
Catecholamine overproduction is the main contributing
factor for hypertension and many of the other metabolic
effects of PPGLs. Epinephrine, norepinephrine and dopa-
mine are the usual catecholamines secreted by these tu-
mours. While normal adrenal glands produce predominant-
ly epinephrine, a majority of PPGLs predominantly secrete
norepinephrine with only about 15% secreting only epi-
nephrine [12••]. Predominantly, dopamine-secreting tu-
mours are rare and may suggest malignant PPGL as the
enzyme dopamine decarboxylase is absent in these cases,
and run more aggressive course [13•]. Surge of catechol-
amines may be continuous or intermittent from the PPGLs
resulting in variations of the clinical picture with some
cases presenting with sustained hypertension, while others
exhibiting paroxysmal hypertension [12••].
The effects of various catecholamines vary in different types
of arterial beds that results in the pathognomonic symptoms and
signs of PPGLs in some cases. Norepinephrine-mediated α-
receptor stimulation results in vasoconstriction, volume con-
traction and elevation of blood pressure, while β
2
-receptor
stimulation (predominantly from epinephrine) results in skeletal
muscle vasodilatation and consequent postural hypotension [2•,
12••,14••]. Depending on the type of catecholamines produced,
PPGLs may be grouped into noradrenergic phenotype—pre-
dominantly norepinephrine-secreting with sustained hyperten-
sion, and the adrenergic phenotype—mainly epinephrine-
secreting with paroxysmal symptoms [12••]. Hypertension
may be uncommon in cases with purely dopamine-producing
tumours.
Episodic catecholamine surge by the PPGLs results in the
classic triad of headache, sweating and palpitations known as
“an attack”that may be pathognomonic. Although spontane-
ous attacks may occur in some cases, there can be multiple
triggers for this presentation that include anaesthesia, tumour
manipulation, positional change, exercise and different medi-
cations such as anti-depressants, β-blockers, opioid analge-
sics, metoclopramide, sympathomimetics and radio-contrast
agents [1••,2•,12••]. Repeated episodes of such hormone
surge may also result in a form of catecholaminergic cardio-
myopathy (Takotsubo cardiomyopathy). This could be
through direct damage of the myocytes due to excess intracel-
lular catecholamines and/or indirect ischaemic injury due to
brief microvascular dysfunction [14••]. Patients’first presen-
tation could be with heart failure [14••]. Pregnant women may
first present with pre-eclampsia or eclampsia secondary to
excess catecholamine release resulting from the pressure of
enlarging gravid uterus on the tumour.
3 Page 2 of 13 Curr Hypertens Rep (2018) 20:3
Genetic of PPGLs
PPGLs can occur sporadically or as a consequence of an
inherited germline mutation (approximately 35–40%
cases) as shown in Table 1[15••]. More genetic variants
are being recently associated with PPGLs. Of the hereditary
syndromes, VHL and SDH are two genes involved in reg-
ulating the hypoxia pathway. This association has led to the
discovery of other pathway-related genes that have been
associated with PPGL development—ELGN1 and EPAS1
[16]. MITF (microphthalmia-associated transcription
factor) is a germline variant that has recently been associ-
ated with an increased risk of PPGLs in a French popula-
tion [17]. A novel mutation in exon 7 of RET gene was
recently identified in a patient with bilateral PCCs and
medullary thyroid cancer and emphasised the importance
of sequencing the entire coding region of RET in patients
with MEN2 when no mutation is identified in the common-
ly affected exons [18].
Genetic screening in all patients with PPGLs requires
some consideration including appropriate patient counsel-
ling. The exact value of screening germline mutations in all
patients and their family members still remains unclear al-
though prevalence of germline mutations is quite high even
in apparently sporadic tumours without significant family
history. A positive screening can help direct clinical inves-
tigations, provide prognostic information and identify
screening requirement for other family members.
However, positive mutations do not always imply complete
clinical manifestations and may lead to unnecessary clini-
cal, biochemical and imaging work-up that can lead to un-
warranted anxiety for the patient. An important factor to
consider in screening is age. In one retrospective study,
80% of paediatric patients (n= 44/55) with PCCs and
PGLs had a germline mutation [19].
Bilateral PCCs, predominantly observed in germline muta-
tions leading to syndromic diseases relating to MEN2, VHL or
NF1, can lead to major functional morbidity and mortality even
after surgical management. Bilateral adrenalectomy in such pa-
tients results in lifelong steroid dependence and potentially ex-
cessive steroid replacement. Cortical sparing adrenal surgery is
a consideration, but requires expertise in tertiary centres with
close follow-up for recurrence [20]. For these reasons, genetic
screening would be advocated in patients presenting with bilat-
eral PCCs.
PPGLs have also been associated with epigenetic alter-
ations but the details remain incompletely characterised to
establish their diagnostic and therapeutic relevance [21].
Further studies are necessary to clarify the role of epigenetics
in the investigation and management of PPGLs.
Table 1 An update on genetic aspects of pheochromocytomas and paragangliomas (PPGLs)
Gene Chromosome Protein Molecular function
VHL 3p25–26 pVHL19
pVHL30
Ubiquitin ligase activity
RET 10q11.2 Tyrosine-kinase receptor Tyrosine-kinase receptor
NF1 17q11.2 Neurofibromin GTPase
SDHA 5p15.33 Succinate dehydrogenase complex,
subunit A, flavoprotein variant
Succinate dehydrogenase subunit of mitochondrial respiratory chain
SDHB 1p36.13 Catalytic iron-sulfur protein Succinate dehydrogenase subunit of mitochondrial respiratory chain
SDHC 1q23.3 Succinate dehydrogenase complex
subunit C
Succinate dehydrogenase subunits of mitochondrial respiratory chain
SDHD 11q23 CybS (membrane-spanning subunit) Succinate dehydrogenase subunits of mitochondrial respiratory chain
SDHAF2 11q12.2 Succinate dehydrogenase complex
assembly factor 2
Cofactor for succinate dehydrogenase complex
TMEM127 2q11.2 Transmembrane protein Controls a signaling pathway that leads to cell growth and survival
MAX 14q23.3 Transcription factor Forms homodimers and heterodimers with other basic helix-loop-helix
leucine zipper (bHLHZ) family members and compete with
common DNA target sites for transcriptional regulation
FH 1q43 Fumarase Catalyzes reversible hydration/dehydration of fumarate to malate
MDH2 7q11.23 Malate dehydrogenase, mitochondrial Catalyzes the oxidation of malate to oxaloacetate, utilizing
NAD/NADH cofactor system in the citric acid cycle
HRAS 11p15.5 Small G protein GTPase regulating cell division in response to growth factor stimulation
EGLN1/PHD2 1q42.2 Subunit of a heterodimeric transcription
factor hypoxia-inducible factor 1
Transcriptional regulator of cellular and developmental response to hypoxia
EPAS1 2p21 Transcription factor Transcription factor involved in the induction of genes regulated by
oxygen, which is induced as oxygen levels fall (hypoxia)
Curr Hypertens Rep (2018) 20:3 Page 3 of 13 3
Clinical Characteristics
No single clinical finding has value in diagnosing or excluding
PPGLs. However, a combination of signs and symptoms can
potentially aid in the clinical diagnosis. The classical triad of
symptoms—headache, palpitations and sweating in a patient
with hypertension—is the primary example. Unexplained or-
thostatic hypotension in a patient with a background of parox-
ysmal or refractory hypertension may be an important diagnos-
tic clue, although such a clinical presentation is rather unusual
[22••]. Table 2provides the likelihood ratios and sensitivity of
signs and symptoms associated with PCCs [12••].
In the literature, cases have been reported whereby PCCs
presented with Takotsubo-pattern cardiomyopathy but in
younger patients and with lower female preponderance.
Cardiac symptoms as well as specific PCC symptoms were
observed in these patients. The most common presenting
symptoms were chest and abdominal pain, dyspnoea, head-
ache and hypertension [22••,23,24,25•].
Diagnostic Evaluation
Biochemical Tests Initial testing for suspected cases of PPGLs
should include measurements of plasma-free metanephrines
and/or urinary fractionated metanephrines as outlined in the
2014 Endocrine Society Clinical Practice Guidelines [1••].
The guidelines provide clear evidence of the diagnostic accu-
racy of measuring plasma-free metanephrines from several
independent studies. Measurement of urinary fractionated
metanephrines was the only other test for which diagnostic
sensitivity reached up to that of plasma metanephrines (97
vs 99%). However, the reported diagnostic specificity of uri-
nary fractionated metanephrines was lower than that of
plasma-free metanephrines [1••,2•,29••]. The gold standard
analytical method with the highest sensitivity and specificity
is liquid chromatography-tandem mass spectrometry (LC-
MS/MS), though it is much more expensive.
Recent systematic reviews and meta-analyses also show
high sensitivities and specificities of plasma metanephrines
irrespective of the assay methods and position of the patient
(sitting or lying down) during sampling [26,27•]. A slight
increase in the diagnostic sensitivity was recently reported
by the addition of plasma 3-methoxytyramine (the dopamine
metabolite) in the testing panel along with free metanephrines
(97.2 vs 98.6%) while the specificity was reduced slightly by
such an addition (95.9 vs 95.1%) in a large multicentre study
[28]. Predominantly dopamine-producing tumours are not
missed by this approach which is important for the detection
of malignant tumours. The 2016 European Endocrine Society
guidelines endorse the addition of 3-methoxytyramine in the
screening panel for diagnosis and follow-up of patients with
PPGLs [29••,30••]. However, patients need to be fasting over-
night to avoid interference from dietary items that can increase
plasma dopamine metabolites [31]. Addition of plasma
chromogranin A (CgA) to the screening panel was reported
to increase the sensitivity without significant loss of specific-
ity especially in patients with some genetic forms of PPGLs
Table 2 Pooled estimation of likelihood ratios (LR) and sensitivity of signs and symptoms of pheochromocytomas and paragangliomas (PPGLs).
Reproduced with permission from Soltani et al. [12••]
Sign/symptom Positive LR (95% CI) Negative LR (95% CI) Pooled sensitivity
(random effects) (%)
95% CI
Headache 1.607 (1.124–2.297) 0.240 (0.094–0.613) 60.4 53.2–67.4
Palpitation 1.88 (1.161–3.073) 0.518 (0.333–0.806) 59.3 51.9–66.6
Diaphoresis 2.184 (1.411–3.382) 0.451 (0.310–0.657) 52.4 0.457–59.1
Classic triad 6.312 (0.217–183.217) 0.139 (0.059–0.331) 58 28.6–84.7
Hypertension 0.762 (0.562–1.033) 1.682 (1.093–2.589) 80.7 74.7–85
Pallor 4.667 0.718 31.6 17.3–47.9
Chest pain N/A N/A 17.3 11.4–24.2
Abdominal pain N/A N/A 16.5 11.9–216
Dyspnoea N/A N/A 23.4 16.2–31.5
Anxiety 1.127 (0.500–2.541) 0.933 (0.635–1.369) 28.6 22.9–34.7
Tremor 0.560 1.096 20.2 14.5–26.6
Flushing 0.283 (0.058–1.391) 1.466 (0.754–2.850) 15 9.3–21.7
Dizziness 0.431 1.493 17.7 13.5–22.3
Paresthesia 1.867 0.933 13.6 10–17.8
Diarrhoea 0.311 1.188 4 0.8–9.4
Orthostatic hypotension 1.885 0.792 N/A N/A
3 Page 4 of 13 Curr Hypertens Rep (2018) 20:3
(SDHB gene mutation) [32,33]. The 2016 European guide-
lines recommend the addition of CgA for patients tested neg-
ative for plasma and/ or urinary metanephrines and 3-
methoxytyramine for diagnosis and biochemical follow-up
of PPGLs after resection. The guidelines also recommend that
genetic testing should be considered in all patients with
PPGLs to rule out genetic mutations in these patients [30••].
The extent and nature of elevation of metanephrines in the
laboratory analyte also helps the biochemical diagnosis of a
major proportion of PPGLs as mild elevation can occur in a
significant number of cases (false positives) because of patient
position (sitting rather than supine results in peripheral sympa-
thetic activation) and chemicals in the plasma such as caffeine
and various medications including acetaminophen that cause
false positive results [1••,2•]. For example, raised levels of both
normetanephrines and metanephrines are rather unusual in pa-
tients without adrenal PCCs. Such cases should be evaluated
further to exclude the tumour. Similarly, an elevated level of
either normetanephrine or metanephrines greater than or equal
to threefold the upper limit of normal laboratory values should
be treated as highly suspicious of a PPGL in a clinically
suspected case and warrant further evaluation by imaging stud-
ies for localization [1••,2•,29••]. Details about these interfering
medications can be found in the 2014 Endocrine Society guide-
line [1••]. Cases with marginal elevation of these catecholamine
metabolites need further evaluation by repeating the test in su-
pine position (≥30 min) and after discontinuation of the inter-
fering medications (if feasible). Cases with isolated elevation of
plasma normetanephrines less than threefold the upper limit of
normal range could be further evaluated with a clonidine sup-
pression test to exclude a false positive result [1••,2•,6,34•].
Lack of < 40% suppression of the elevated baseline
normetanephrine levels has a reported sensitivity of 97% and
specificity of 100% in diagnosis of PPGLs [34•]. However,
repeated biochemical testing usually avoids the necessity for
clonidine suppression test in clinical practice.
Other biochemical markers such as plasma and urinary
catecholamines and urine vanillylmandelic acid (VMA) are
less often used currently because of suboptimal sensitivities
and specificities. Catecholamine secretion by PPGLs can be
episodic and inadequate (especially in asymptomatic tu-
mours), and therefore, measurement of plasma and urinary
catecholamines may not have adequate diagnostic sensitivity
as a screening tool. For example, plasma catecholamines only
had a reported sensitivity of 72% and specificity of 90% [35•].
Similarly, in another recent study, the reported sensitivity,
specificity, positive predictive value (PPV) and negative pre-
dictive value (NPV) of 24-h urinary VMA testing were 68.4,
96.9, 72.2 and 96.3% respectively [36].
Diagnostic Imaging Imaging studies should be performed only
after biochemical confirmation. Computed tomography (CT)
and magnetic resonance imaging (MRI) are the major imaging
modalities used for the localization of PPGLs. While PCCs
show similar imaging phenotypes as malignancies, they are
significantly different from adenomas. The presence of intra-
cellular lipid with an unenhanced attenuation (UA) values ≤10
Hounsfield units (HU) showed the highest specificity (97%) for
excluding PCCs as a single phenotype in CT imaging [36]. A
tumour size ≤3cmandUA≤10 HU without suspicious mor-
phology in the CT scan excluded PCCs and malignancy with
100% specificity in this study. However, in lesions larger than
4 cm or in patients with a known malignancy, intracellular lipid
should be interpreted more cautiously. Both adrenal cortical
carcinoma and metastases (from lipid-containing primary tu-
mours, such as renal cell carcinoma or hepatocellular cell car-
cinoma) must also be considered in the differential diagnosis as
these lesions can mimic adenoma on the basis of quantitative
imaging thresholds alone [36,37]. PCCs are hyper-enhancing
with specific contrast washout characteristics in the multiphase
CT, although there may be overlap of these features with adre-
nal adenomas in approximately one-third of cases [38••,39•].
Detection of intracytoplasmic lipid in the images virtually ex-
cludes PPGL as a diagnostic possibility [37].
In the MRI scans, 2/3rd of PCCs show increased signal
intensity on T2-weighted images, referred to as being “light-
bulb bright”, although this pattern is also exhibited by large
adrenal adenomas because of cystic changes [38••,40]. Use of
quantitative T2-weighted signal intensity (SI) ratio was recent-
ly reported to effectively differentiate between PPGLs and
adrenal adenomas [37,41•]. In these studies, normalization
of T2 SI of the adrenal lesion to an internal reference to muscle
tissue was used in the MRI protocol. An adrenal-to-muscle SI
threshold ratio of ≥3.95 showed a sensitivity of 81% and
specificity of 88% specificity for diagnosing PPGLs (after
exclusion of adrenal cysts that possess unique MRI appear-
ance) [41•]. MRI has better sensitivity compared to CT for
PGLs, residual, recurrent or metastatic tumours although CT
is better for lung metastasis [1••].
While functional imaging is an alternative approach, there
is little evidence to suggest the general use of this additional
modality as diagnostic tool. A recent systematic review
showed functional imaging minimally added to the localiza-
tion studies of 24/1445 primary cases (1.4%) and 28/805 met-
astatic cases (3.5%) [42•]. However, functional imaging helps
treatment planning and follow-up of cases, and therefore, it is
often performed by most endocrinologists prior to surgery.
Iodine-131-tagged metaiodobenzylguanidine (
131
I-MIBG),
the radiopharmaceutical initially used for functional imaging,
was subsequently replaced by
123
I-MIBG given its lower bi-
ological half-life, lower radiation risk and better sensitivity
and specificity. The reported sensitivities were 85–88% for
PCCs and 56–75% for PGLs, while specificities were 70–
100% and 84–100% respectively with
123
I-MIBG scans [1••].
Newer imaging modalities using radiopharmaceuticals
yielded better diagnostic sensitivities and specificities and also
Curr Hypertens Rep (2018) 20:3 Page 5 of 13 3
helped planning tumour ablation with these agents in patients
with malignant disease.
18
Flourodeoxyglucose positron emis-
sion tomography (
18
F-FDG PET) scans showed better sensi-
tivity compared to
123
I-MIBG scans although the specificity
was less [43••,44]. In a meta-analysis involving 11 studies
and 275 patients, the pooled sensitivity and specificity of
18
F-
dihydroxyphenylalanine (
18
F-FDOPA) PET/CT in detecting
PPGLs were 79 and 95% respectively [45]. This imaging mo-
dality is better than
123
I-MIBG in patients with MEN-2 as the
dye is not taken up by the normal adrenal gland [43••]. Newer
somatostatin analogues such as [1,4,7,10-
tetraazacyclododecane-N,N′,N″,N″-tetraacetic acid, D-Phe1,
Tyr3]-octreotide (DOTATOC) and other peptides (DOTA-
NOC and DOTATATE) have shown better affinity to somato-
statin receptors and can be used for functional imaging with
better sensitivities.
68
Ga-DOTATOC and
68
Ga-DOTATATE
PET/CT have been found to be superior to
123
I-MIBG
SPECT in some patients with aggressive PGLs probably be-
cause of a certain level of functional differentiation [44,46].
Other promising diagnostic approaches are currently un-
der evaluation. Catecholamine in vivo detection by proton
magnetic resonance spectroscopy (1H-MRS) may provide
an important role in the differential diagnosis of adrenal
tumours to confirm or exclude the presence of PCCS and
allow assessment for therapeutic responses of the tumors by
monitoring catecholamine response in these tumours [47].
A new gene-expression diagnostic test called Pheo-type has
recently been developed for the classification of PPGL tu-
mours based on the underlying genetic driver of the disease
[15••].
A diagnosticalgorithm for investigating suspected PPGL is
shown in Fig. 1.
Management
Surgical Excision This is the mainstay of management for
PPGLs. Recent evidence suggests that surgical excision of
the tumours is associated with regression of vascular and myo-
cardial abnormalities. A recent study compared carotid
intima-media thickness (IMT) and left ventricular (LV) mass
index in patients with PPGLs before tumour removal and
5 years later, revealing significant regression of both after
tumour removal [48].
A thorough preoperative blood pressure management is
mandatory to prevent perioperative cardiovascular complica-
tions. A 10–14-day-long preoperative preparation is often nec-
essary with increased oral fluid and salt intake to replenish the
plasma volume [1••,2•,49•]. Initial management includes an
α-blocker, and phenoxybenzamine is commonly used because
of its non-selective, irreversible action at the level of the re-
ceptor and its long duration of action. After achieving ade-
quate α-blockade, a β-blocker can be started to counteract
the tachycardia and postural hypotension associated with α-
blockers. Blood pressure < 130/80 mmHg while sitting and
systolic pressure > 90 are the therapeutic targets [1••].
Patients who cannot tolerate phenoxybenzamine are treated
with a selective α-blocker such as doxazosin [1••,2•,50].
Calcium channel blockers or other antihypertensive agents
could be added to control blood pressure. Despite meticulous
Fig. 1 A diagnostic algorithm for
pheochromocytomas and
paragangliomas (PPGLs). CT
computed tomography, MRI
magnetic resonance imaging,
PET positron emission
tomography, SPECT single-
photon emission computed
tomography,
123
I-MIBG
123
iodine
metaiodobenzyl guanidine. The
2016 European guidelines also
recommend plasma or urine 3-
methoxytyramine measurement
in the initial biochemical
screening. If metanephrines and
3-methoxytyramine are negative,
plasma chromogranin A is
recommended for screening in
cases with a clinical probability
3 Page 6 of 13 Curr Hypertens Rep (2018) 20:3
preoperative management, perioperative haemodynamic in-
stability can occur and is often challenging. Predictors of
higher risk for instability include larger tumour size and great-
er urinary/plasma metanephrine levels [51]. Comparison of
the beneficial effects of selective versus non-selective α-
blockers for perioperative management of hypertension
showed mixed results in different studies that makes definitive
recommendation about the choice of drug difficult in the ab-
sence of large clinical trials with head to head comparison
[52–54].
A list of useful drugs for perioperative management of
hypertension in patients with PPGLs, the dosage ranges and
common side effects are shown in Table 3.
Laparoscopic surgery is the standard operative approach for
tumour resection because of lower mean operative time, shorter
length of stay, decreased need for intensive support, less blood
loss and reduced pain management requirements compared to
open surgery. Although complication rates remained the same
between the two methods and tumour size did not appear to
affect these outcomes [50], recent evidence favours minimally
invasive approach over open surgery with retroperitoneoscopic
approach having the lowest operating time and length of stay
for adrenalectomies [55•]. Potential risk factors for postopera-
tive complications include history of coronary artery disease,
female gender and intraoperative haemodynamic instability
[56•]. Open surgery may be generally preferable for resection
of large tumours (> 6 cm), invasive PCCs and PGLs. Partial
adrenalectomy/adrenocortical sparing surgery may be preferred
in bilateral disease and small tumours [1••].
Thorough intraoperative hemodynamic monitoring is es-
sential with support from an anaesthetist with experience in
PPGL surgeries. Intravenous antihypertensive therapy with
phentolamine is usually preferred for control of the hyperten-
sive crisis, with β-blockade and other agents to treat cardiac
arrhythmias. Postoperative hypotension is usually dealt with
by intravenous fluid therapy and rarely requires vasopressor
support. Postoperative hypoglycemia is managed with intra-
venous glucose administration [1••,2•].
Palliative Surgery Resection of malignant PPGLs decreases
the tumour burden and therefore reduces the disease severity
along with symptoms because of reduction of hormonal out-
put from the tumours. Male gender, older age at primary tumor
diagnosis, dopamine hypersecretion, synchronous metastases,
larger tumour size and lack of primary tumour resection were
found to be the risk factors associated with an aggressive
course and excess mortality in a recent large series reported
from the Mayo Clinic, USA [13•]. Cases with malignant
PGLs had poorer outcomes compared to malignant PCCs in
this series. Open surgery is ideal option for patients with ma-
lignant PPGLs as local exploration can be performed simulta-
neously with lymph node clearance and resection of metasta-
sis whenever feasible.
Palliative Chemotherapy With malignant PCCs/PGLs, a re-
cent meta-analysis had shown treatment with combination of
cyclophosphamide, vincristine and dacarbazine (CVD) che-
motherapy provided partial response in 37% (95% CI 25–
51%) of 50 patients from four studies [57]. Partial response
(based on catecholamine response) had been observed in 40%
(95% CI 25–57%) of the 35 patients assessed. Complete re-
sponse based on tumour volume could only be achieved in 4%
of patients with toxicity, leading to discontinuation of therapy
on several occasions. Nevertheless, the study provides valu-
able information to patients regarding efficacy of treatment
with chemotherapy which should be balanced with that pro-
vided by active surveillance only. Hesco et al. published a
study in which the natural history of patients with malignant
PCCs/PGLs remained stable at 1 year without any interven-
tion [58].
There is only limited data with newer chemotherapeutic
agents such as everolimus [59], sunitinib and sorafenib [60],
selective hypoxia-inducible factor-2 antagonist PT2399 [61]
and temozolomide [62] for management of patients with PPGLs.
Radionuclide Therapy Selective uptake of various radiophar-
maceuticals is made use in this approach for palliative treatment
in cases that are not amenable to surgery or conventional che-
motherapy.
131
I-MIBG is the conventional agent in this group
with proven benefit in multiple studies [63–65]. Partial re-
sponse to treatment without major adverse outcomes was ob-
served in these studies favouring this treatment option for in-
curable disease. Newer radiopharmaceutical agents with so-
matostatin receptor affinity such as 177Lu-DOTATATE have
been successfully used in the treatment of malignant disease
with better-efficacy and lower-toxicity profiles compared to
131
I-MIBG therapy in patients with advanced PPGLs [66,67].
External Beam Radiotherapy Although PPGLs are less radio-
sensitive tumours, external beam radiotherapy (EBRT) is a
treatment option for cases with compressive symptoms and
bone metastasis causing pain. Good treatment response that
has been reported in patients with local disease has been re-
ported with EBRT [68]. When combined with
131
I-MIBG
therapy, EBRT was found to be very effective in reducing
tumour burden in malignant PPGLs. The main side effect
was related to irradiation of surrounding tissues.
Ablation Procedures for Malignant PPGLs Various ablation
procedures to palliate cases with advanced disease such as
radiofrequency ablation, chemoembolization and alcohol ab-
lation are options in selected cases [69]. Trans-arterial
chemoembolization (TACE) procedure effectively treated pa-
tients in some cases with primary as well as metastatic disease
[70]. However, case selection for such procedures depends
highly on the expertise of the interventional radiologists and
the centre with these facilities.
Curr Hypertens Rep (2018) 20:3 Page 7 of 13 3
Follow-up of Patients with PPGLs
All patients with PPGLs should have a lifelong follow-up
even after complete excision because of the uncertainties
about the chances of recurrence and malignant potential of
the tumours. Furthermore, given the expanding knowledge
of underlying mutations and the expanding gene panels tested,
patients with negative genetic screen currently may prove to
have germ line mutation in the future.
Follow-up needs regular clinical and biochemical monitor-
ing periodically, and the same applies to that of established
complications such as hypertension and cardiovascular damage
from the disease. Dose adjustments of antihypertensive agents
and hypoglycemic agents (if patients had secondary diabetes/
worsening diabetes from PPGLs) are necessary in many cases
after successful tumour resection. Patients who underwent bi-
lateral adrenalectomy may need lifelong steroid replacement if
a cortex preserving approach could not be undertaken.
Plasma or urine metanephrines remain elevated in the im-
mediate postoperative period, and therefore, measurements
should be performed only after 10–14 days to ensure complete
tumour resection [2•,30••,71]. Normalization of
metanephrines and 3-MT indicates complete excision of the
tumour. Thereafter, annual biochemical follow-up is indicated
unless patient develops clinical signs and symptoms of recur-
rence. Annual screening of plasma CgA is recommended for
operated cases of PPGLs who initially had only CgA-positive
with negative metanephrines and 3-methoxytyramine results,
for possible local or metastatic recurrences or new tumours
[30••].
Although association between tumour size and the risk for
recurrence after complete resection is not strong, 5% of cases
recur within 5 years of follow-up, with PGLs and familial
disease being the main independent risk factors for relapse
in a recent meta-regression analysis of published data [72].
The 2016 European guidelines suggest follow-up of all pa-
tients successfully operated for at least 10 years, young pa-
tients and those with genetic abnormalities, large tumours and
PGLs to be followed up lifelong [30••]. The guidelines also
recommend imaging studies every 1–2 years in biochemically
Table 3 Drugs used in the management of hypertension in patients with pheochromocytomas and paragangliomas (PPGLs), the dosages and the
commonly seen side effects
Drug Usual dosage range Common side effects
Phenoxybenzamine (non-selective α-blocker) Oral: 20–120 mg/day in divided doses.
Intravenous: 1 mg/kg/day (maximum)
Orthostatic hypotension, nasal congestion, tachycardia,
nausea, abdominal pain and retrograde ejaculation
Phentolamine (non-selective α-blocker) Bolus doses of 2.5–5mgintravenously
as required
Orthostatic hypotension, tachycardia and priapism
Doxazosin (α
1
-adrenergic blocker) 1–16 mg/day in divided doses 1–3
times/day
Orthostatic hypotension, dizziness, oedema, tachycardia
and priapism
Prazosin (α
1
-adrenergic blocker) 2–15 mg/day in 2–3 divided doses Orthostatic hypotension, dizziness, fainting, oedema
and tachycardia
Ter azo si n ( α
1
-adrenergic blocker) 1–5 mg/day (maximum dose 20 mg/day) Orthostatic hypotension, dizziness, fainting, oedema
and tachycardia
Propranolol (non-selective β-blocker) 40–240 mg/day in 2–3 divided doses Bradycardia, asthma exacerbation, fatigue, dizziness
disturbed sleep and worsening of heart failure
Metoprolol (cardio-selective β-blocker) 50–400 mg/day in 2 divided doses Bradycardia, asthma exacerbation, fatigue, dizziness
and confusion
Bisoprolol (cardio-selective β-blocker) 2.5–10 mg/day Bradycardia, asthma exacerbation, fatigue and
dizziness
Nicardipine (calcium channel blocker) Oral: 30–60 mg twice daily
Intravenous: 15 mg/h (maximum)
Head ache, oedema, tachycardia, nausea, chest
tightness and sweats
Amlodipine (calcium channel blocker) 2.5–10 mg daily Head ache, oedema, tachycardia, breathlessness and
chest tightness
Nifedipine (calcium channel blocker) 30–120 mg once daily
(sustained-release orally)
Head ache, oedema, tachycardia, breathlessness and
weight gain
Verapamil (calcium channel blocker) 120–240 mg once daily
(sustained-release orally)
Constipation, head ache, oedema, bradycardia and
heartburns
Metyrosine (tyrosine hydroxylase
inhibitor)
1000–4000 mg orally in 3–4
divided doses
Severe tiredness, crystalluria and extrapyramidal
side effects
Nitroglycerine infusion 5–100 μg/min (for hypertensive
crisis)
Head ache, orthostasis, tachycardia, breathlessness
and heartburns
Sodium nitropruside infusion 10–200 μg/min (for hypertensive
crisis)
Hypotension and cyanide toxicity
3 Page 8 of 13 Curr Hypertens Rep (2018) 20:3
inactive cases after surgery to screen local recurrence or new
tumours.
Figure 2shows a management and follow-up algorithm for
patients with PPGLs.
Special Population Subgroups with PPGLs
Children PPGLs occur much less commonly in the paediatric
population compared to adults with only 10% of the disease
reported from children [73]. Analysis of a recent large
multicentre data from Germany and the USA showed the fol-
lowing characteristics of paediatric vs adult cases with
PPGLs: hereditary—80.4 vs 52.6%, extra-adrenal—66.3 vs
35.1%, multifocal—32.6 vs 13.5%, metastatic—49.5 vs
29.1%, recurrent—29.5 vs 14.2%, tumours due to cluster 1
mutations—76.1 vs 39.3% and noradrenergic tumours
(characterised by relative lack of high plasma
metanephrines)—93.2 vs 57.3% respectively [74]. These
finding imply that children with PPGLs run a more aggressive
course of the disease with higher malignant potential that
mandates closer follow-up and monitoring. Genetic testing is
essential in the paediatric cases, and lifelong follow-up is nec-
essary. Management of tumours can be as in the adult patients
with PPGLs.
Pregnant Women Situations can arise when patients with
PPGLs present with clinical features for the first time during
pregnancy. The pressure from the enlarging uterus in the latter
half of pregnancy, movement of the fetus, uterine contractions
and abdominal palpation increase the catecholamine output
from the tumour that may even precipitate a Takotsubo-
pattern cardiomyopathy during late pregnancy [14••,22••].
Severe cases are associated with serious fetal and maternal
adverse outcomes. Although the reported incidence of
PPGLs during pregnancy was only 0.007% (from a large se-
ries), the maternal and fetal mortality can be as high as 40–
50% in untreated cases that come down to 5% of maternal and
15% fetal mortality if appropriate and timely treatment is in-
stituted [75,76]. Although most clinical features are similar to
those in nonpregnant cases, unexplained orthostatic hypoten-
sion in a pregnant female with hypertension and peripartum
cardiomyopathy should raise the clinician suspicion of a
PPGL [22••,76].
Clinical manifestations during pregnancy includes pre-
eclampsia, eclampsia, cardiac arrhythmias, acute coronary
syndromes, pulmonary oedema, stroke, aortic dissection,
pheochromocytoma crisis and cardiomyopathy [2•,22••].
Placental abruption, fetal hypoxia, growth retardation and in-
trauterine death are the severe consequences of extreme vaso-
constriction of the uteroplacental circulation that results from
recurrent catecholamine surge from PPGLs. Biochemical di-
agnosis is usually by plasma/urine metanephrine assay with
caution in interpreting the results when patients are on meth-
yldopa or labetalol for treatment of hypertension [76].
Anatomical localisation of the tumours is ideally by non-
contrast MRI as CT and functional imaging modalities are
contraindicated during pregnancy. Genetic testing is
Fig. 2 Management algorithm for
pheochromocytomas and
paragangliomas (PPGLs). PGLs
paragangliomas. The 2016
European guidelines also
recommend plasma or urine 3-
methoxytyramine measurement
biochemical follow-up. If
metanephrines and 3-
methoxytyramine were initially
negative and plasma
chromogranin A (CgA) was
positive, biochemical follow-up
should be with CgA monitoring
Curr Hypertens Rep (2018) 20:3 Page 9 of 13 3
recommended in all cases as the prevalence of mutations can
be ≥30% [76,77].
Management of hypertension should be to optimise end-
organ complications while maintaining uteroplacental circula-
tion, and therefore, blood pressure targets are not as strict as in
the usual cases. Doxazosin is preferred over
phenoxybenzamine for α-blockade as the reported incidence
of neonatal respiratory depression and hypotension is less
[76]. β-Blockers can be subsequently added to counteract
tachycardia after sufficient α-blockade is achieved.
Sufficient repletion of plasma volume should be attained
along with adequate blood pressure control for optimal mater-
nal and fetal outcomes. Usual antihypertensive agents such as
methyldopa and labetalol are ideally avoided in these cases
[76]. Several drugs used in pregnancy including some of the
anaesthetic agents can precipitate pheochomocytoma crisis
during pregnancy, and therefore, obstetricians, surgeons, en-
docrinologists and anaesthetists should adopt a multidisciplin-
ary approach. Trans-peritoneal laparoscopic adrenalectomy
should ideally be performed in the second trimester after
24 weeks of gestation if the diagnosis of PPGL is made before
this period [2•,22••,76] Medical management is feasible in
the third trimester to plan surgery in the postpartum period or a
simultaneous adrenalectomy during caesarean section.
Older Individuals PPGLs may be associated with higher mor-
bidity and mortality in the elderly population because of the
higher prevalence of cardiovascular disorders. The diagnostic
approach and perioperative management are not different in
this group. However, surgical complications and mortality risk
are higher among the elderly [2•]. Higher proportion of ma-
lignant tumours with greater numbers of open adrenalec-
tomies was reported among older people. A recent series from
Brazil showed that older patients had six times higher chance
of receiving postoperative vasopressor support, longer periods
of intensive care after surgery, higher postoperative complica-
tions and mortality [78].
Conclusions
PPGLs are associated with higher risk of morbidity and mor-
tality. The endocrine societies recommend biochemical
screening with plasma or urine metanephrines (and 3-
methoxytyramine) in all patients with suspected disease be-
fore proceeding to imaging studies for anatomical localiza-
tion. Genetic screening should be considered in all cases be-
cause of high prevalence of mutations in PPGLs that increases
the risk of recurrence and malignancy (and necessitate family
screening). CT scan and MRI are useful for initial localization
followed by functional imaging with radiopharmaceutical
agents for confirmation and planning appropriate therapy.
Adequate control of hypertension with α-blockers and then
β-blockers is mandatory before pursuing surgical excision,
preferably by laparoscopic adrenalectomy. Regular periodic
biochemical and/or imaging follow-up is necessary after exci-
sion of the tumours on a long-term basis (lifelong in familial
and malignant disease). Palliative chemotherapy, radionuclide
agents and/or ablation procedures will need to be considered
for patients with nonresectable tumours and advanced malig-
nant disease unfit for surgery. A multidisciplinary team ap-
proach involving endocrinologists, biochemists, radiologists,
anaesthetists, surgeons and oncologists is necessary in the
management of this complex disease entity.
Compliance with Ethical Standards
Conflict of Interest The authors declare no conflicts of interest relevant
to this manuscript.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
•Of importance
•• Of major importance
1.•• Lenders JW, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe
SK, Murad MH, et al. Pheochromocytoma and paraganglioma: an
endocrine society clinical practice guideline. J Clin Endocrinol
Metab. 2014; 99:1915-42. Current clinical practice guidelines
(2014) by the American Endocrine Society that give readers
clear idea how to approach cases with PPGLs. Readers are
strongly recommended to read this free paper in the journal
for thorough understanding of the clinical problem.
2.•Pappachan JM, Raskauskiene D, Sriraman R, Edavalath M, Hanna
FW. Diagnosis and management of pheochromocytoma: a practical
guide to clinicians. Curr Hypertens Rep. 2014;16:442. A2014re-
view in Current Hypertension Reports discussing the practical
aspects of diagnostic and therapeutic approaches to PPGLs.
3. Andreoni C, Krebs RK, Bruna PC, Goldman SM, Kater CE, Alves
MT, et al. Cystic phaeochromocytoma is a distinctive subgroup
with special clinical, imaging and histological features that might
mislead the diagnosis. BJU Int. 2008;101(3):345–50. https://doi.
org/10.1111/j.1464-410X.2007.07370.x.
4.•Pappachan JM, Buch HN. Endocrine hypertension: a practical ap-
proach. Adv Exp Med Biol. 2017;956:215–37. A book chapter on
approach to the practical aspects of endocrine hypertension.
The chapter gives brief discussion on PPGLs also.
5. Wang L, Li N, Yao X, Chang G, Zhang D, Heizhati M, et al.
Detection of secondary causes and coexisting diseases in hyperten-
sive patients: OSA and PA are the common causes associated with
hypertension. Biomed Res Int. 2017;2017:8295010.
6. Verberne AJ, Korim WS, Sabetghadam A, Llewellyn-Smith IJ.
Adrenaline: insights into its metabolic roles in hypoglycaemia and
diabetes. Br J Pharmacol. 2016;173:1425–37.
3 Page 10 of 13 Curr Hypertens Rep (2018) 20:3
7. Wiedemann T, Peitzsch M, Qin N, Neff F, Ehrhart-Bornstein M,
Eisenhofer G, et al. Morphology, biochemistry, and pathophysiolo-
gy of MENX-related pheochromocytoma recapitulate the clinical
features. Endocrinology. 2016;157(8):3157–66. https://doi.org/10.
1210/en.2016-1108.
8. Dahia PL. Pheochromocytoma and paraganglioma pathogenesis:
learning from genetic heterogeneity. Nat Rev Cancer. 2014;14(2):
108–19. https://doi.org/10.1038/nrc3648.
9. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and
phaeochromocytoma: from genetics to personalized medicine. Nat
Rev Endocrinol. 2015;11(2):101–11. https://doi.org/10.1038/
nrendo.2014.188.
10. Angelousi A, Dimitriadis GK, Zografos G, Nölting S, Kaltsas G,
Grossman A. Molecular targeted therapies in adrenal, pituitary and
parathyroid malignancies. Endocr Relat Cancer. 2017;24:R239–59.
11. Ayala-Ramirez M, Feng L, Johnson MM, Ejaz S, Habra MA, Rich
T, et al. Clinical risk factors for malignancy and overall survival in
patients with pheochromocytomas and sympathetic
paragangliomas: primary tumor size and primary tumor location
as prognostic indicators. J Clin EndocrinolMetab. 2011;96(3):
717–25. https://doi.org/10.1210/jc.2010-1946.
12.•• Soltani A, Pourian M, Davani BM. Does this patient have pheo-
chromocytoma? A systematic review of clinical signs and symp-
toms. J Diabetes Metab Disord. 2016;15:6. A very useful system-
atic review detailing the clinical features of PPGLs. Readers are
strongly recommended to use this paper for better understand-
ing of the symptomatology and pathophysiology of PPGLs.
13.•Hamidi O, Young WF Jr, Iñiguez-Ariza NM, et al. Malignant pheo-
chromocytoma and paraganglioma: 272 patients over 55 years. J
Clin Endocrinol Metab. 2017;102:3296–305. Ausefulpaperto
get better understanding about the characteristics of malignant
PPGLs and their epidemiology.
14.•• Ross JJ, Desai AS, Chutkow WA, Economy KE, Dec GW Jr.
Interactive medical case. A crisis in late pregnancy. N Engl J
Med. 2009;361:e45. An interactive medical case with a lot of
multi-media learning material that gives readers excellent un-
derstanding of the pathophysiology and clinical features of
PPGLs.
15.•• Flynn A, Dwight T, Harris J, et al. Pheo-type: a diagnostic gene-
expression assay for the classification of pheochromocytoma and
paraganglioma. J Clin Endocrinol Metab. 2016;101:1034–43. A
paper that discusses the latest genetic aspects of PPGLs.
16. Amorim-Pires D, Peixoto J, Lima J. Hypoxia pathway mutations in
pheochromocytomas and paragangliomas. Cytogenet Genome Res.
2016;150(3-4):227–41. https://doi.org/10.1159/000457479.
17. Castro-Vega LJ, Kiando SR, Burnichon N, Buffet A, Amar L,
Simian C, et al. The MITF, p. E318K variant, as a risk factor for
pheochromocytoma and paraganglioma. J Clin Endocrinol Metab.
2016;101(12):4764–8. https://doi.org/10.1210/jc.2016-2103.
18. Latteyer S, Klein-Hitpass L, Khandanpour C, Zwanziger D,
Poeppel TD, Schmid KW, et al. A 6-base pair in frame germline
deletion in exon 7 of RET leads to increased RET phosphorylation,
ERK activation, and MEN2A. J Clin Endocrinol Metab.
2016;101(3):1016–22. https://doi.org/10.1210/jc.2015-2948.
19. Babic B, Patel D, Aufforth R, Assadipour Y, Sadowski SM,
Quezado M, et al. Pediatric patients with pheochromocytoma and
paraganglioma should have routine preoperative genetic testing for
common susceptibility genes in addition to imaging to detect extra-
adrenal andmetastatic tumors. Surgery. 2017;161(1):220–7. https://
doi.org/10.1016/j.surg.2016.05.059.
20. Castinetti F, Taieb D, Henry JF, Walz M, Guerin C, Brue T, et al.
Management of endocrine disease: outcome of adrenal sparing sur-
gery in heritable pheochromocytoma. Eur J Endocrinol.
2016;174(1):R9–R18. https://doi.org/10.1530/EJE-15-0549.
21. Björklund P, Backman S. Epigenetics of pheochromocytoma and
paraganglioma. Mol Cell Endocrinol. 2017; https://doi.org/10.
1016/j.mce.2017.06.016.
22.•• Desai AS, Chutkow WA, Edelman E, Economy KE, Dec GW Jr.
Clinical problem-solving. A crisis in latepregnancy. N Engl J Med.
2009;361:2271–7. An excellent write-up based on a case study
that gives details of pathophysiology of catecholaminergic car-
diomyopathy in PPGLs. The article also provides basic insights
into the clinical aspects and management of PPGLs.
23. Chiang Y-L, Chen P-C, Lee C-C, Chua S-K. Adrenal pheochromo-
cytoma presenting with Takotsubo-pattern cardiomyopathy and
acute heart failure: a case report and literature review. Medicine
(Baltimore). 2016;95(36):e4846. https://doi.org/10.1097/MD.
0000000000004846.
24. Shams Y. Clinical features and outcome of pheochromocytoma-
induced Takotsubo syndrome: analysis of 80 published cases. Am
J Cardiol. 2016;117:1836–44.
25.•Batisse-Lignier M, Pereira B, Motreff P, et al. Acute and chronic
pheochromocytoma-induced cardiomyopathies: different progno-
ses?: a systematic analytical review. Medicine (Baltimore).
2015;94:e2198. An important paper that details cardiomyopa-
thy related to PPGLs.
26. Därr R, Kuhn M, Bode C, Bornstein SR, Pacak K, Lenders JWM,
et al. Accuracy of recommended sampling and assay methods for
the determination of plasma-free and urinary fractionated
metanephrines in the diagnosis of pheochromocytoma and
paraganglioma: a systematic review. Endocrine. 2017;56(3):495–
503. https://doi.org/10.1007/s12020-017-1300-y.
27.•Chen Y, Xiao H, Zhou X, Huang X, Li Y, Xiao H, et al. Accuracy of
plasma free metanephrines in the diagnosis of pheochromocytoma
and paraganglioma: a systematic review and meta-analysis. Endocr
Pract. 2017;23:1169–77. A systematic review that looks at the
diagnostic test accuracy of biochemical aspects of PPGL
diagnosis.
28. Rao D, Peitzsch M, Prejbisz A, Hanus K, Fassnacht M, Beuschlein
F, et al. Plasma methoxytyramine: clinical utility with
metanephrines for diagnosis of pheochromocytoma and
paraganglioma. Eur J Endocrinol. 2017;177(2):103–13. https://
doi.org/10.1530/EJE-17-0077.
29.•• van Berkel A, Lenders JW, Timmers HJ. Diagnosis of endocrine
disease: biochemical diagnosis of phaeochromocytoma and
paraganglioma. Eur J Endocrinol. 2014;170:R109–19. A very use-
ful paper examining the practical aspects of biochemical diag-
nosis of PPGLs. The article also provide readers insights into
the testing algorithm when tests are just borderline positive.
30.•• Plouin PF, Amar L, Dekkers OM, et al. European Society of
Endocrinology Clinical Practice Guideline for long-term follow-
up of patients operated on for a phaeochromocytoma or a
paraganglioma. Eur J Endocrinol. 2016;174:G1–G10. The paper
with most recent European Society guidelines on PPGL care
and follow-up. Readers are strongly recommended to review
this paper to get better understanding about the practical as-
pects of care of patients with PPGLs.
31. de Jong WH, Eisenhofer G, Post WJ, Muskiet FA, de Vries EG,
Kema IP. Dietary influences on plasma and urinary metanephrines:
implications for diagnosis of catecholamine-producing tumors. J
Clin EndocrinolMetab. 2009;94:2841–9.
32. Zuber S, Wesley R, Prodanov T, Eisenhofer G, Pacak K,
Kantorovich V. Clinical utility of chromogranin A in SDHx-
related paragangliomas. Eur J Clin Invest. 2014;44:365–71.
33. Bílek R, Zelinka T, Vlček P, Dušková J, et al. Radioimmunoassay
of chromogranin A and free metanephrines in diagnosis of pheo-
chromocytoma. Physiol Res. 2017;66(Supplementum 3):S397–
408.
34.•Eisenhofer G, Goldstein DS, Walther MM, Friberg P, Lenders JW,
Keiser HR, et al. Biochemical diagnosis of pheochromocytoma:
Curr Hypertens Rep (2018) 20:3 Page 11 of 13 3
how to distinguish true- from false-positive test results. J Clin
Endocrinol Metab. 2003;88:2656–66. A study that gives practical
tips to predictive values and interpretation of biochemical tests
in PPGLs.
35.•Grouzmann E, Drouard-Troalen L, Baudin E, Plouin PF, Muller B,
Grand D, et al. Diagnostic accuracy of free and total metanephrines
in plasma and fractionated metanephrines in urine of patients with
pheochromocytoma. Eur J Endocrinol. 2010;162:951–60. Another
study that gives practical tips to predictive values and interpre-
tation of biochemical tests in PPGLs.
36. Jun JH, Ahn HJ, Lee SM, Kim JA, Park BK, Kim JS, et al. Is
preoperative biochemical testing for pheochromocytoma necessary
for all adrenal incidentalomas? Medicine (Baltimore). 2015;94(45):
e1948. https://doi.org/10.1097/MD.0000000000001948.
37. Schieda N, Alrashed A, Flood TA, Samji K, Shabana W, McInnes
MD. Comparison of quantitative MRI and CT washout analysis for
differentiation of adrenal pheochromocytoma from adrenal adeno-
ma. Am J Roentgenol. 2016;206(6):1141–8. https://doi.org/10.
2214/AJR.15.15318.
38.•• Schieda N, Siegelman ES. Update on CT and MRI of adrenal nod-
ules. AJR Am J Roentgenol. 2017;208:1206–17. A very useful
review on the radiological aspects on adrenal imaging and di-
agnosing PPGLs. The review gives physicians and radiologists
excellent understanding about the appropriate imaging and al-
so how to confidently avoid unnecessary imaging follow-up for
cases with adrenal nodules.
39.•Patel J, Davenport MS, Cohan RH, Caoili EM. Can established CT
attenuation and washout criteria for adrenal adenoma accurately
exclude pheochromocytoma? AJRAm J Roentgenol. 2013;201:
122–7. Another review that gives practical imaging diagnostic
tips for PPGL diagnosis.
40. Newhouse JH, Heffess CS, Wagner BJ, Imray TJ, Adair CF,
Davidson AJ. Large degenerated adrenal adenomas: radiologic-
pathologic correlation. Radiology. 1999;210(2):385–91. https://
doi.org/10.1148/radiology.210.2.r99fe12385.
41.•Borhani AA, Hosseinzadeh K. Quantitative versus qualitative
methods in evaluation of T2 signal intensity to improve accuracy
in diagnosis of pheochromocytoma. AJR Am J Roentgenol.
2015;205:302–10. A paper that gives readers idea about MRI
features of PPGLs.
42.•Brito JP, Asi N, Gionfriddo MR, et al. The incremental benefit of
functional imaging in pheochromocytoma/paraganglioma: a sys-
tematic review. Endocrine. 2015;50:176–86. An article that helps
readers the need for functional imaging and the utility of that
for planning management.
43.•• Taïeb D, Timmers HJ, Hindié E, et al. EANM 2012 guidelines for
radionuclide imaging of phaeochromocytoma and paraganglioma.
Eur J Nucl Med Mol Imaging. 2012;39:1977–95. The most recent
European guidelines on functional imaging of PPGLs. Readers
are strongly recommended to review this article for better un-
derstanding about functional imaging in PPGLs.
44. Rufini V, Treglia G, Castaldi P, Perotti G, Giordano A. Comparison
of metaiodobenzylguanidine scintigraphy with positron emission
tomography in the diagnostic work-up of pheochromocytoma and
paraganglioma: a systematic review. Q J Nucl Med Mol Imaging.
2013;57(2):122–33.
45. Treglia G, Cocciolillo F, de Waure C, di Nardo F, Gualano MR,
Castaldi P, et al. Diagnostic performance of 18F-
dihydroxyphenylalanine positron emission tomography in patients
with paraganglioma: a meta-analysis. Eur J Nucl Med Mol
Imaging. 2012;39(7):1144–53. https://doi.org/10.1007/s00259-
012-2087-y.
46. Naji M, AL-Nahhas A.
68
Ga-labelled peptides in the management
of neuroectodermal tumours. Eur J Nucl Med Mol Imaging.
2012;39(Suppl 1):S61–7.
47. Imperiale A, Battini S, Averous G, Mutter D, Goichot B, Bachellier
P, et al. In vivo detection of catecholamines by magnetic resonance
spectroscopy: a potential specific biomarker for the diagnosis of
pheochromocytoma. Surgery. 2016;159(4):1231–3. https://doi.org/
10.1016/j.surg.2015.03.012.
48. Majtan B, Zelinka T, Rosa J, et al. Long-term effect of adrenalec-
tomy on cardiovascular remodeling in patients with pheochromo-
cytoma. J Clin Endocrinol Metab. 2016;102:1208–17.
49.•Romero M, Kapur G, Baracco R, Valentini RP, Mattoo TK, Jain A.
Treatment of hypertension in children with catecholamine-secreting
tumors: a systematic approach. J Clin Hypertens (Greenwich).
2015;17:720–5. A paper that gives some practical aspects of
an approach to paediatric endocrine hypertension.
50. Galati S-J, Said M, Gospin R, et al. The mount Sinai clinical path-
way for the management of pheochromocytoma. Endocr Pract.
2014;21:368–82.
51. Namekawa T, Utsumi T, Kawamura K, Kamiya N, Imamoto T,
Takiguchi T, et al. Clinical predictors of prolonged postresection
hypotension after laparoscopic adrenalectomy for pheochromocy-
toma. Surgery. 2016;159(3):763–70. https://doi.org/10.1016/j.surg.
2015.09.016.
52. van der Zee PA, de Boer A. Pheochromocytoma: a review on pre-
operative treatment with phenoxybenzamine or doxazosin. Neth J
Med. 2014;72(4):190–201.
53. Li J, Yang CH. Improvement of preoperative management in pa-
tients with adrenal pheochromocytoma. Int J Clin Exp Med.
2014;7(12):5541–6.
54.•Randle RW, Balentine CJ, Pitt SC, Schneider DF, Sippel RS.
Selective versus non-selective α-blockade prior to laparoscopic
adrenalectomy for pheochromocytoma. Ann Surg Oncol.
2017;24:244–50. A study detailing the benefits and demerits of
the choices of α-blockers in the preoperative management of
PPGLs.
55.•Heger P, Probst P, Hüttner FJ, et al. Evaluation of open and mini-
mally invasive adrenalectomy: a systematic review and network
meta-analysis. World J Surg. 2017;41:2746–57. Astudythathelps
in deciding the operative management of PPGLs.
56.•Brunaud L, Nguyen-Thi P-L, Mirallie E, et al. Predictive factors for
postoperative morbidity after laparoscopic adrenalectomy for pheo-
chromocytoma: a multicenter retrospective analysis in 225 patients.
Surg Endosc. 2016;30:1051–9. Another study helping us to de-
cide the right operative approach to patients with PPGLs.
57. Niemeijer N, Alblas G, Hulsteijn L, Dekkers O, Corssmit E.
Chemotherapy with cyclophosphamide, vincristine and
dacarbazine for malignant paraganglioma and pheochromocytoma:
systematic review and meta-analysis. Clin Endocrinol(Oxf).
2014;81:642–51.
58. Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-
Salinas C, etal. One-year progression-free survival oftherapy-naive
patients with malignant pheochromocytoma and paraganglioma. J
Clin Endocrinol Metab. 2013;98(10):4006–12. https://doi.org/10.
1210/jc.2013-1907.
59. DY O, Kim TW, Park S, et al. Phase 2 study of everolimus mono-
therapy in patients with nonfunctioning neuroendocrine tumors or
pheochromocytomas-paragangliomas. Cancer. 2012;118:6162–70.
60. Denorme M, Yon L, Roux C, Gonzalez BJ, Baudin E, Anouar Y,
et al. Both sunitinib and sorafenib are effective treatments for pheo-
chromocytoma in a xenograft model. Cancer Lett. 2014;352(2):
236–44. https://doi.org/10.1016/j.canlet.2014.07.005.
61. Chen W, Hill H, Christie A, et al. Targeting renal cell carcinoma
with a HIF-2 antagonist.Nature 2016;539112–7.
62. Hadoux J, Favier J, Scoazec JY, Leboulleux S, al Ghuzlan A,
Caramella C, et al. SDHB mutations are associated with response
to temozolomide in patients with metastatic pheochromocytoma or
paraganglioma. Int J Cancer. 2014;135(11):2711–20. https://doi.
org/10.1002/ijc.28913.
3 Page 12 of 13 Curr Hypertens Rep (2018) 20:3
63. Carrasquillo JA, Pandit-Taskar N, Chen CC. I-131
metaiodobenzylguanidine therapy of pheochromocytoma and
paraganglioma. Semin Nucl Med. 2016;46:203–14.
64.•Rutherford MA, Rankin AJ, Yates TM, Mark PB, Perry CG, Reed
NS, et al. Management of metastatic phaeochromocytoma and
paraganglioma: use of iodine-131-meta-iodobenzylguanidine ther-
apy in a tertiary referral centre. QJM. 2015;108:361–8. A useful
paper for readers to consider the benefit of radiopharmaceuti-
cals in malignant PPGLs.
65. Yoshinaga K, Oriuchi N, Wakabayashi H, Tomiyama Y, Jinguji M,
Higuchi T, et al. Effects and safety of
131
I-metaiodobenzylguanidine
(MIBG) radiotherapy in malignant neuroendocrine tumors: results
from a multicenter observational registry. Endocr J. 2014;61(12):
1171–80. https://doi.org/10.1507/endocrj.EJ14-0211.
66. Nastos K, Cheung VTF, Toumpanakis C, Navalkissoor S, Quigley
AM, Caplin M, et al. Peptide receptor radionuclide treatment and
(131)I-MIBG in the management of patients with metastatic/
progressive phaeochromocytomas and paragangliomas. J Surg
Oncol. 2017;115:425–34.
67.•Ballal S, Yadav MP, Damle NA, Sahoo RK, Bal C. Concomitant
177Lu-DOTATATE and capecitabine therapy in patients with ad-
vanced neuroendocrine tumors: a long-term-outcome, toxicity, sur-
vival, and quality-of-life study. Clin Nucl Med. 2017;42:e457–66.
A paper that gives details of modern radionuclide therapy in
PPGLs.
68. Fishbein L, Bonner L, Torigian DA, Nathanson KL, Cohen DL,
Pryma D, et al. External beam radiation therapy (EBRT) for patients
with malignant pheochromocytoma and non-head and -neck
paraganglioma: combination with 131IMIBG. Horm Metab Res.
2012;44(5):405–10. https://doi.org/10.1055/s-0032-1308992.
69. McBride JF, Atwell TD, Charboneau WJ, Young WF Jr, Wass TC,
Callstrom MR. Minimally invasive treatment of metastatic pheo-
chromocytoma and paraganglioma: efficacy and safety of
radiofrequencyablation and cryoablation therapy. J Vasc Interv
Radiol. 2011;22:1263–70.
70. Kumar P, Bryant T, Breen D, Stedman B, Hacking N. Transarterial
embolization and doxorubicin eluting beads-transarterial
chemoembolization (DEB-TACE) of malignant extra-adrenal pheo-
chromocytoma. Cardiovasc Intervent Radiol. 2011;34:1325–9.
71.•• Tsirlin A, Oo Y, Sharma R, Kansara A, Gliwa A, Banerji MA.
Pheochromocytoma: a review. Maturitas. 2014;77:229–38. Avery
useful review article that gives detailed literature on PPGLs.
Readers are recommended to read this excellent paper.
72.•• Amar L, Lussey-Lepoutre C, Lenders JW, Djadi-Prat J, Plouin PF,
Steichen O. MANAGEMENT OF ENDOCRINE DISEASE: recur-
rence or new tumors after complete resection of pheochromocytomas
and paragangliomas: a systematic review and meta-analysis. Eur J
Endocrinol. 2016;175:R135–45. A recent article to help readers to
understand the management aspects of recurrent PPGLs.
73. Barontini M, Levin G, Sanso G. Characteristics of pheochromocy-
toma in a 4- to 20-year-old population. Ann N Y Acad Sci.
2006;1073(1):30–7. https://doi.org/10.1196/annals.1353.003.
74.•• Pamporaki C, Hamplova B, Peitzsch M, et al. Characteristics of pedi-
atric vs adult pheochromocytomas and paragangliomas. J Clin
Endocrinol Metab. 2017;102:1122–32. An excellent review to up-
date readers about age-specific clinical characteristics of PPGLs.
75. Sarathi V, Lila AR, Bandgar TR, Menon PS, Shah NS.
Pheochromocytoma and pregnancy: a rare but dangerous combi-
nation. Endocr Pract. 2010;16:300–9.
76.•• van der Weerd K, van Noord C, Loeve M, et al.
ENDOCRINOLOGY IN PREGNANCY: pheochromocytoma in
pregnancy: case series and review of literature. Eur J Endocrinol.
2017;177:R49–58. An excellent review to update readers about
the practical aspects of care of patients with PPGLs during
pregnancy.
77. Biggar MA, Lennard TW. Systematic review of
phaeochromocytoma in pregnancy. Br J Surg. 2013;100(2):182–
90. https://doi.org/10.1002/bjs.8976.
78.•Srougi V, Chambo JL, Tanno FY, et al. Presentation and surgery
outcomes in elderly with pheocromocytoma: a comparative analy-
sis with Young patients. Int Braz J Urol. 2016;42:671–7. A useful
paper to understand the difference in surgical outcomes in pa-
tients of different ages, old vs. young, with PPGLs.
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