Journal of the Endocrine Society, 2024, 8, bvae078

https://doi.org/10.1210/jendso/bvae078
Advance access publication 8 May 2024
Expert Endocrine Consult

Pitfalls in the Diagnostic Evaluation of Pheochromocytomas

Gustavo F. C. Fagundes1 and Madson Q. Almeida1,2
1
Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM/25, Disciplina de Endocrinologia e Metabologia, Departamento
de Medicina Interna, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, 01246-903, São Paulo, SP, Brazil
2
Unidade de Oncologia Endócrina, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo,
01246-903, São Paulo, SP, Brazil
Correspondence: Madson Q. Almeida, MD, PhD, Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM/25, Disciplina de Endocrinologia e

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Metabologia, Departamento de Medicina Interna, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo (FMUSP), 01246-903, São Paulo,
SP, Brazil; or Unidade de Oncologia Endócrina, Instituto do Câncer do Estado de São Paulo (ICESP), FMUSP, Av. Dr. Arnaldo, 455, 4th Floor, Room 4344,
Cerqueira Cesar, 01246-903, São Paulo, SP, Brazil. Email: madson.a@hc.fm.usp.br.

Abstract
Pheochromocytomas and paragangliomas (PPGLs), rare neuroendocrine tumors arising from chromaffin cells, present a significant diagnostic
challenge due to their clinical rarity and polymorphic symptomatology. The clinical cases demonstrate the importance of an integrated
approach that combines clinical assessment, biochemical testing, and imaging to distinguish PPGLs from mimicking conditions, such as
obstructive sleep apnea and interfering medication effects, which can lead to false-positive biochemical results. Although a rare condition,
false-negative metanephrine levels can occur in pheochromocytomas, but imaging findings can give some clues and increase suspicion for a
pheochromocytoma diagnosis. This expert endocrine consult underscores the critical role of evaluating preanalytical conditions and pretest
probability in the biochemical diagnosis of PPGLs. Moreover, a careful differentiation of PPGLs from similar conditions and careful selection
and interpretation of diagnostic tests, with focus on understanding and reducing false positives to enhance diagnostic accuracy and patient
outcomes, is crucial.
Key Words: pheochromocytomas, paragangliomas, diagnosis, pitfalls, false-positive
Abbreviations: 131I-MIBG, metaiodinebenzylguanidine labeled with iodine 131; BMI, body mass index; CPAP, continuous positive airway pressure; CT,
computed tomography; HU, Hounsfield units; LC-MS/MS, liquid chromatography tandem mass spectrometry; MRI, magnetic resonance imaging; PPGL,
pheochromocytomas and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare heterogeneity and are frequently associated with hereditary
neuroendocrine neoplasms arising from chromaffin cells with­ syndromes, with up to 40% of cases linked to genetic disor­
in the adrenal medulla, known as pheochromocytomas, or ders [8, 9]. Surgical excision remains the cornerstone of initial
from paravertebral sympathetic ganglia in thoracic and ab­ treatment, with the potential to achieve complete symptom
dominal regions, as well as from cervical parasympathetic resolution in PPGLs [1].
ganglia or the skull base, referred to as paragangliomas [1]. The diagnostic journey for pheochromocytomas is fraught
Pheochromocytomas account for approximately 80% to with complexities, from nuanced clinical presentations to
85% of all PPGLs, with the remaining 15% to 20% being par­ the intricacies of biochemical and imaging assessments. The
agangliomas [2]. Distinction between these entities is solely rarity of PPGLs juxtaposed with the polymorphic nature of
predicated upon their anatomic location, as they are histo­ their symptoms often leads to misdiagnosis or significant de­
pathologically indistinguishable [3]. Although the term lays in proper identification of the disease, thereby exacerbat­
“pheochromocytoma” has been entrenched in clinical ver­ ing patient morbidity [10]. Moreover, the diagnostic overlap
nacular, the World Health Organization has recently advo­ with more prevalent conditions masks these neoplasms in clin­
cated for the nomenclature “adrenal paraganglioma” in an ical suspicion, culminating in a conundrum for the unwary
effort to standardize terminology [4]. clinician. As we venture further into the subtleties of diagnos­
PPGLs are noted for their clinical rarity, with a prevalence tic criteria, it becomes evident that a comprehensive and
of less than 0.05% in the general population, rising to 0.2% multifaceted approach is essential for an accurate detection.
to 0.6% among patients with hypertension [1]. Despite their This article seeks to dissect these diagnostic intricacies, eluci­
infrequent occurrence, PPGLs carry a substantial burden of date the common pitfalls encountered, and propose methodo­
morbidity and mortality, predominantly due to cardiovascu­ logical enhancements to refine the diagnostic algorithm. By
lar complications and their propensity for metastatic disease amplifying our understanding of these challenges and updat­
[5, 6]. Metastatic lesions are detected in 15% to 20% of ing our diagnostic strategies, we aspire to improve patient out­
PPGL cases, denoted by metastatic dissemination to nonchro­ comes and bridge the gap between initial presentation and
maffin tissues [7]. These tumors exhibit profound clinical definitive treatment.

Received: 28 January 2024. Editorial Decision: 12 April 2024. Corrected and Typeset: 11 May 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
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2 Journal of the Endocrine Society, 2024, Vol. 8, No. 6

Case 1 labeled with iodine 131 (131I-MIBG) scintigraphy was negative.

Cutaneous neurofibromas had already been resected. At physical
A 58-year-old female patient was referred to an endocrinolo­
examination, her weight was 69.6 kg, BMI 29.2 kg/m2, blood
gist due to an incidental finding of a 1.8-cm mass in the right
pressure 120 × 80 mmHg, and heart rate 88 bpm.
adrenal gland during abdominal computed tomography (CT)
performed to investigate abdominal pain. Her medical history
included refractory hypertension diagnosed at the age of 27, Case 3
accompanied by hypertensive retinopathy, type 2 diabetes,
A 5-cm right adrenal mass was incidentally discovered in a
dyslipidemia, grade 2 obesity, and severe obstructive sleep ap­
52-year-old woman with nephrolithiasis. She had a previous
nea (apnea–hypopnea index of 61.6/hour). She has been ir­
diagnosis of hypertension at 25 years of age and a positive famil­
regularly using continuous positive airway pressure (CPAP)
ial history of early hypertension. The patient underwent bilat­
therapy at night. The patient also experienced an acute myo­
eral oophorectomy and hysterectomy without intraoperative
cardial infarction in 2019. Current medications were as fol­
and postoperative complications 10 years previously. She was
lows: carvedilol 50 mg every 12 hours, chlorthalidone 25 mg
taking losartan 50 mg every 12 hours and chlorthalidone
daily, olmesartan 40 mg daily, amlodipine 10 mg daily, spir­
25 mg/day. At physical examination, her weight was 65.6 kg,

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onolactone 50 mg daily, clonidine 0.2 mg every 8 hours, hy­
BMI 25.6 kg/m2, blood pressure 150 × 90 mmHg, and heart
dralazine 50 mg every 6 hours, acetylsalicylic acid 100 mg
rate 96 bpm.
daily, atorvastatin 80 mg daily, and metformin XR 1000 mg
Abdominal CT revealed a right adrenal nodule measuring
daily. At physical examination, weight was 92 kg, body mass
5.2 × 4.0 cm with 34 HU in the precontrast phase with arterial
index (BMI) 37 kg/m2, blood pressure 150 × 90 mmHg, heart
phase peak enhancement of 122 HU and an absolute washout
rate 64 bpm. No other signs of Cushing syndrome were noted.
of 75% (Fig. 1C). Hormone evaluation showed normal plas­
Abdominal CT revealed an undetermined right adrenal nodule
ma normetanephrine and metanephrine levels for age refer­
measuring 1.8 × 1.2 cm with 18 Hounsfield units (HU) in the
ence interval measured by LC-MS/MS. Cortisol after the
precontrast phase with arterial phase peak enhancement of
1-mg dexamethasone overnight test was 1.7 μg/dL (Table 1).
117 HU and an absolute washout of 65% (Fig. 1A). A slight
Hormone work-up was negative and laparoscopic resection
nodular thickening up to 1.4 × 0.8 cm (−4 HU) in the left ad­
of the right adrenal mass was indicated.
renal gland was suggestive of an adenoma (Fig. 1B).
Hormone evaluation showed a slight elevation in plasma
normetanephrine (1.3 nmol/L) at recumbent position for Clinical Presentation and Diagnosis
30 minutes before sampling and measured by liquid chro­
The diagnosis of PPGL is typically suggested by 1 of 3 scenarios:
matography tandem mass spectrometry (LC-MS/MS).
(1) clinical suspicion, incidental adrenal lesions, or screening
Cortisol after a 1-mg dexamethasone overnight test was
after the identification of an allelic variant pathogenic/likely
2.3 μg/dL (Table 1). Due to the refractory hypertension,
pathogenic in a susceptibility gene for PPGL [6]. Diagnosis
stopping interfering antihypertensive medications to rule
via incidental lesions and genetic screening of asymptomatic
out primary aldosteronism was not possible. A clonidine
carriers have increased in recent years, possibly representing
suppression test was indicated to investigate pheochromo­
up to half to two-thirds of patients diagnosed with PPGLs [12].
cytoma because this patient had an undetermined adrenal
Among symptomatic patients, hypertension is the most strik­
nodule (18 HU), high arterial phase peak enhancement
ing presentation, occurring in paroxysms or as a sustained con­
(117 HU), and plasma normetanephrine between 1.5 and
dition [7]. The classic presentation consists of adrenergic
2× the upper limit of normal range in 2 different measure­
paroxysms due to sudden tumoral catecholamine release,
ments. Pheochromocytoma is excluded if there is a greater
with the triad being composed of headache, sweating, and
than 40% drop and normetanephrine is less than 80% of
tachycardia. Adrenergic paroxysms can occur spontaneously
the upper limit of normal level for age after 180 minutes
or be provoked by medications (ephedrine, amphetamines, me­
of clonidine with a sensitivity of 94% and a specificity of
toclopramide, opioids, antidepressants, and anesthetics), phys­
97% [11]. The clonidine suppression test yielded a 25% re­
ical exertion, increased abdominal pressure, stress, or certain
duction in plasma normetanephrine levels, indicating the
foods [13]. They are present in approximately 50% of cases,
biochemical diagnosis of pheochromocytoma (Table 2).
while the remainder of patients exhibit sustained hypertension
or, less frequently (10-15% of cases), normal blood pressure [7,
12, 14]. Other less common signs and symptoms in PPGL pa­
Case 2 tients include weight loss, headache, constipation, tremors, pal­
A 47-year-old woman with type 1 neurofibromatosis was re­ lor, blood pressure lability, and flushing [12]. None of the signs
ferred to the endocrinologist to investigate pheochromocytoma. or symptoms, alone or grouped, are sufficiently sensitive or spe­
She had no adrenergic symptoms and ambulatory blood pressure cific to allow firm diagnosis simply on clinical grounds.
monitoring showed normal blood pressure. Biochemical and im­ The extensive clinical diversity of PPGLs is elucidated by the
aging investigation for pheochromocytoma was previously re­ quantity, frequency, and type of catecholamine released by the
quested by her cardiologist. Plasma norepinephrine levels were tumor [15]. The catecholamines encompass dopamine, nor­
814.6 pg/mL (<460 pg/mL), epinephrine 19.7 pg/mL (<90 pg/ epinephrine, and epinephrine (Fig. 2). All are derived from
mL), and dopamine <15 pg/mL. Plasma normetanephrines tyrosine and are metabolized into 3-methoxytyramine, norme­
were elevated (1.2 nmol/L; 97.5th percentile for age tanephrine, and metanephrine, respectively. Approximately
0.689 nmol/L) and metanephrines were 0.3 nmol/L (97.5th per­ 50% of all pheochromocytomas synthesize and release a blend
centile for age 0.324 nmol/L) measured by LC-MS/MS (Table 2). of epinephrine and norepinephrine, whereas the majority of
She was using only zolpidem 10 mg/day for insomnia. Adrenals the remaining tumors, particularly sympathetic paraganglio­
were normal at abdominal CT. Metaiodinebenzylguanidine mas, predominantly secrete norepinephrine [16]. This
Journal of the Endocrine Society, 2024, Vol. 8, No. 6 3

Figure 1. (A, B) Case 1. (A) Abdominal CT revealing an undetermined right adrenal nodule measuring 1.8 × 1.2 cm (white arrow) with 18 Hounsfield unit
(HU) in the precontrast phase with arterial phase peak enhancement of 117 HU and an absolute washout of 65%. (B) Slight nodular thickening up to 1.4 ×
0.8 cm (−4 HU) in the left adrenal gland (white arrow), suggestive of adenoma. (C) Case 3. Abdominal CT revealing a right adrenal nodule measuring 5.2 ×
4.0 cm (white arrow) with 34 HU in the precontrast phase with arterial phase peak enhancement of 122 HU and an absolute washout of 75%.

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variation in catecholamine production is contingent on the ex­ catecholamines or their metabolites. The initial investigation
pression of phenylethanolamine-N-methyltransferase, the en­ for suspected PPGLs should be conducted through measure­
zyme responsible for the conversion of norepinephrine to ment of free plasma metanephrines or fractionated 24-hour
epinephrine. A subset of tumors, exhibiting minimal or no ex­ urinary metanephrines determined by LC-MS/MS [1, 13].
pression of dopamine-β-hydroxylase (the enzyme that catalyzes Free plasma metanephrines or fractionated urinary meta­
the transformation of dopamine to norepinephrine) may secrete nephrines have superior diagnostic accuracy than fractionated
mixtures of dopamine and norepinephrine or, in certain cases of catecholamines (epinephrine, norepinephrine, and dopamine)
paragangliomas, solely dopamine. In the clinical context, pa­ and vanillylmandelic acid (VMA) in urine, due to the continu­
tients with tumors secreting adrenaline typically exhibit episodic ous intratumoral metabolization of catecholamines [21].
manifestations, though intervals of normotension and asymp­ Historically, urinary VMA measurements were the predomin­
tomatic phases are not uncommon [7]. In contrast, those with ant diagnostic tool for PPGLs. However, urinary VMA appli­
tumors primarily secreting noradrenaline frequently present cation has significantly declined with the advent of newer and
with a clinical picture resembling essential hypertension, often more precise diagnostic methods [15]. In a comprehensive
exhibiting a more subclinical presentation. The chronic eleva­ study involving 214 patients with PPGLs, the diagnostic sensi­
tion of noradrenaline can lead to adrenoceptor desensitization, tivity of urinary vanillylmandelic acid was 77% for patients
further attenuating clinical symptoms and potentially normaliz­ with sporadic PPGLs, which markedly decreased to 46% in
ing blood pressure [16]. those with hereditary forms of the disease [22].
Tumors exclusively secreting dopamine are relatively rare and The initial identification of the diagnostic utility of plasma
reflect an absence of dopamine β-hydroxylase activity. free metanephrines in detecting PPGLs was reported in 1995
Dopamine levels in these cases can be quantified through plasma [15, 23]. This revelation has since been corroborated by a
assessments or by analyzing its metabolite 3-methoxytyramine multitude of studies, which have consistently demonstrated
in plasma or urine [17]. Elevated levels of 3-methoxytyramine the superior diagnostic performance of LC with electrochem­
may indicate malignancy. Elevated plasma dopamine may in­ ical detection or LC-MS/MS in measuring plasma free or urin­
duce vasodilation and inhibit the release of noradrenaline, con­ ary metanephrines [23, 24]. These studies have reported
sequently moderating the hemodynamic effects associated with sensitivities ranging from 95% to 100% and specificities be­
elevated noradrenaline levels [7]. Most paragangliomas that tween 89% and 100% [15, 23]. In contemporary clinical
do not produce catecholamines (noncatecholamine-producing practice, LC-MS/MS has become the predominant method­
paragangliomas) originate from the parasympathetic nervous ology adopted by most laboratories for these measurements
system, typically situated in the head or neck [16]. The absence [1]. Despite the known limitations in accuracy, some labora­
of catecholamine secretion in these PPGLs may be attributed to tories continue to utilize commercially available immunoassay
their conversion into inactive metabolites or a deficiency in syn­ methods for the quantification of plasma free metanephrines.
thesis, frequently due to abnormalities in tyrosine hydroxylase The sensitivity of free plasma metanephrines and normeta­
function. However, the existing literature on this subject remains nephrines is higher than that of their urinary counterparts
limited and requires further exploration and documentation. (98% vs 93%), but both possess similar specificities (94%)
A regular follow-up of genetically affected relatives will per­ [25]. In patients with adrenal incidentaloma or carriers of sus­
mit a diagnosis of PPGLs at an early stage when the tumor is ceptibility gene mutations, free plasma metanephrines demon­
still small, and the clinical picture is mild or even silent. In aut­ strate greater accuracy and sensitivity than urinary
opsy studies, the mean prevalence of adrenal masses was metanephrines [26]. In contrast, measurement of urinary frac­
found to be approximately 6% [18]. This observation appears tionated catecholamines (epinephrine, norepinephrine, and
to be corroborated by the approximately 5% prevalence of dopamine) is less sensitive, but clearly elevated values (>2 times
adrenal masses detected through CT [6, 15, 19, 20]. the upper limit of the normal range) indicate the diagnosis of
PPGLs [6]. The preferential production of normetanephrine
over norepinephrine in chromaffin cells, as opposed to sympa­
Biochemical Diagnosis thetic nerves, plays a pivotal role in enhancing the diagnostic val­
The first step for a symptomatic patient suspected for PPGL or ue of this metabolite compared with its precursor amine in the
incidentally adrenal lesion is the proof of excessive release of detection of PPGLs. However, it is crucial to acknowledge
4 Journal of the Endocrine Society, 2024, Vol. 8, No. 6

Table 1. Hormone work-up of the 3 clinical cases

Cases 1 2 3
a
Metanephrine (nmol/L) 0.3 (<0.375) 0.3 (<0.324) <0.2 (<0.375)
a
Normetanephrine (nmol/L) 1.3 (<0.747) 1.2 (<0.6889) 0.6 (<0.747)
Renin (4.4-46 μIU/mL) 36.8 15.4
Aldosterone (ng/dL) 9.9 6.8
ACTH (pg/mL) 15.7 28
Cortisol (μg/dL) 7.0 11.2
Cortisol after overnight 1 mg dexamethasone (μg/dL) 2.3 1.7
DHEA sulfate (ng/mL) 1152 (189-2050) 872 (189-2050)

Abbreviations: ACTH, adrenocorticotropin; DHEA, dehydroepiandrosterone.

a
97.5th percentile for age.

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that approximately 75% of normetanephrine originates from Table 2. Clonidine suppression test indicated to investigate
the sympathoneural release of norepinephrine, a factor which pheochromocytoma in case 1 with undetermined adrenal nodule
(18 HU), high arterial phase peak enhancement (117 HU), and
is essential for understanding the etiology of false-positive re­ plasma normetanephrine between 1.5 and 2 × the upper limit of
sults in plasma or urinary normetanephrine [15]. normal range
Nonfunctional PPGLs are characterized by their lack of cat­
echolamine synthesis and secretion. These tumors predomin­ Clonidine suppression test (0.3 mg) Baseline 180 minutes
antly occur within the head and neck region and, less a
frequently, within the upper or anterior mediastinum [27]. Plasma metanephrine (<0.375 nmol/L) 0.3 0.3
These tumors tend to be diagnosed at larger sizes, frequently Plasma normetanephrine (<0.747 nmol/L)a 1.2 0.9b
as a result of mass effects or incidental findings during imaging a
procedures [16]. The absence of catecholamine secretion and 97.5th percentile for age (50-59 years old).
b
Pheochromocytoma is excluded if there is a greater than 40% drop and
metabolism in these neoplasms is typically due to a deficiency normetanephrine is less than 80% of the upper limit of normal level for age.
in catecholamine synthesis, likely stemming from the lack of
tyrosine hydroxylase activity rather than an impairment in
the storage or exocytosis of these neurotransmitters. Given CT or magnetic resonance imaging (MRI) of the entire abdomen
that the aggregate levels of plasma free metanephrines correl­ [1, 13]. Ultrasound is generally not recommended owing to its
ate with tumor size, it may be feasible to discern nonfunctional limited sensitivity in detecting PPGLs [6, 19]. Predominantly,
tumors from those that are merely biochemically negative [7]. extra-adrenal catecholamine-secreting tumors are situated in
Nonfunctional tumors are thus delineated by the absence of the retroperitoneum, as opposed to the pelvis or thorax.
biochemical evidence of catecholamine excess and by a mean Pheochromocytomas can present with a range of radiological
tumor diameter exceeding 2 cm [16]. Consequently, the desig­ characteristics including homogeneity or heterogeneity, solid or
nation “nonfunctional”, assigned to patients with PPGLs who cystic composition, or the presence of necrosis and calcification
exhibit negative biochemical test results for plasma free meta­ [30]. Owing to their broad spectrum of radiological features,
nephrines, was demonstrated in 2% (5 out of 236 cases) of PPGLs lesions may be erroneously identified as adrenal cortical
PPGLs [25]. carcinoma, cystic infectious lesions, or metastatic lesions, and,
A small minority of head and neck paragangliomas, ap­ albeit less frequently, adrenal lipid-poor adenomas and retroperi­
proximately 3% to 4%, are known to produce norepineph­ toneal lymphomas. Consequently, the measurement of meta­
rine. However, a significant portion, up to one-third, may nephrines plays a crucial role in the presumptive diagnosis of
synthesize dopamine. Inclusion of measurements of free me­ pheochromocytomas [26].
thoxytyramine in the plasma panel is useful for detecting Performing contrast-enhanced CT is usually the first meth­
dopamine-producing tumors, whereas measurements of urin­ od to locate the PPGLs. The nonionic contrast media is consid­
ary dopamine or methoxytyramine are less useful since the an­ ered safe in patients who have not undergone adrenergic
alytes in urine are largely derived from sources independent of receptor blockade [31, 32]. In a comprehensive multicenter
the circulating amines [15, 28]. The plasma concentrations of retrospective analysis focused on assessing the radiologic
methoxytyramine have been observed to be markedly higher characteristics of pheochromocytomas via CT imaging, only
in patients who have not observed fasting than in those who 0.5% of the cases, precisely 2 cases, exhibited unenhanced at­
have maintained an overnight fast [29]. Therefore, to ensure tenuation at exactly 10 HU [32]. From these observations, the
the reliability of methoxytyramine measurements, it is recom­ authors recommended that it is not necessary to perform
mended that patients adhere to a strict overnight fasting regi­ biochemical testing for pheochromocytomas in adrenal
men, which should be sustained until the time of blood incidentalomas with unenhanced attenuation ≤10 HU.
collection in the following morning. Nonetheless, they caution that reliance solely on contrast
washout metrics for the exclusion of pheochromocytomas is
not sufficiently reliable. In a meta-analysis, Woo and col­
Anatomical Diagnosis leagues corroborate the aforementioned caution regarding
When biochemical testing yields suggestive results, it is advisable the diagnostic efficacy of washout metrics [33]. A significant
to proceed with cross-sectional imaging using contrast-enhanced proportion (35%) of pheochromocytomas met the criteria
Journal of the Endocrine Society, 2024, Vol. 8, No. 6 5

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Figure 2. Pathway of catecholamine biosynthesis and metabolism of the most relevant metabolites for biochemical diagnosis of pheochromocytomas
and paragangliomas.

131
for adrenal adenoma when using adrenal washout CT [33]. I-MIBG is greater for pheochromocytoma (88%) than for
Although pheochromocytomas show a high peak enhance­ paraganglioma (67%) [30]. Notably, MIBG sensitivity is
ment in early arterial phase, a cut-off of 100 HU had only a markedly reduced in patients with SDHx gene mutations
moderate sensitivity (63.6%) and a high specificity (100%) [39, 40]. With the advent of newer radiopharmaceuticals,
to differentiate pheochromocytoma from other lipid-poor ad­ the once central role of radiolabeled MIBG in pheochromocy­
renal lesions [34]. toma/paraganglioma imaging has shifted towards a screening
MRI is the preferred imaging modality for patients with tool for 131I-MIBG therapy [41].
68
metastatic disease, head and neck paragangliomas, iodine Ga-DOTA-SSA studies have shown excellent lesion-
contrast allergy, or those requiring reduced radiation expos­ based sensitivity in detecting PPGLs, often more than 92%
ure, such as children, pregnant women, and individuals with [30]. A metanalysis comparing the sensitivity of 18F-FDG
germline genetic defects [13]. The utility of high signal inten­ and 68Ga-DOTA-SSA found that the sensitivity of
68
sity on T2-weighted MRI images in localizing pheochromocy­ Ga-DOTA-SSA (95%) was superior to that of 18F-FDG
tomas, although less common than previously believed, can (85%) [30]. An additional metanalysis demonstrated that
still be valuable [7, 11]. Head and neck paragangliomas typic­ the sensitivity of 68Ga-DOTA-SSA (93%) was superior to
18
ally shows slowly enlarging masses, often manifesting as F-FDOPA (80%), 18F-FDG (74%), and 123I/131I-MIBG
carotid-body tumors and vagal tumors, or as conductive hear­ (38%) [42]. Overall, 68Ga-DOTATATE should be considered
ing loss and pulsatile tinnitus in cases of jugulotympanic para­ the tracer of choice for evaluating metastatic pheochromocy­
gangliomas [6, 35]. The tumor’s low-signal voids, typical of toma, metastatic paraganglioma, SDHx mutant carriers, and
paragangliomas, present a “salt-and-pepper” pattern on head and neck paragangliomas [7, 43]. An exception is pheo­
MRI spin echo imaging sequences [36]. chromocytoma or paraganglioma associated with polycy­
Nuclear imaging serves as a valuable adjunct to morphological themia, MAX mutations, or apparently sporadic
imaging in the diagnosis and staging of diseases [20]. It has the pheochromocytoma, for which 18F-FDOPA may be preferable
added advantage in accurately predicting tumor response to even­ [20, 41]. Genetics of PPGLs translates into 3 main clusters
tual treatment with radiolabeled nuclear analogs in patients with with distinct tumor locations, biochemical features, tumor re­
avidity for the tracer. Radiopharmaceuticals, distinct from ceptor characteristics, and risk of metastatic disease.
contrast agents, offer specificity to the PPGL lesions, thus facilitat­ Nowadays, the choice of radionuclides to diagnostic work-up
ing the detection of diminutive lesions in scenarios of multifocal and treatment is based on the germline genotype [44].
or metastatic disease [37]. These agents yield critical molecular in­
sights, exemplified by compounds like 131I- MIBG, 18F-FDOPA,
and somatostatin receptor positron emission tomography, Pretest Probability
though it is notable that 18F-FDG lacks this specificity [38]. The pursuit of PPGLs is frequent, yet their actual detection re­
MIBG functions as a functional analog of norepinephrine, mains a rarity. This leads to a scenario where the pretest
being incorporated into secretory granules for storage and prevalence of PPGLs is notably low, and the incidence of false-
subsequent exocytosis [19]. Recent research, including a positive results in biochemical assessments is correspondingly
broader spectrum of paraganglioma cases, indicates a general­ high [10, 45]. Contrasting with singular, subjective indica­
ly lower sensitivity of MIBG in detecting these tumors, par­ tions, the presence of 3 or more symptoms indicative of cat­
ticularly in hereditary undifferentiated pheochromocytoma echolamine excess (including hyperhidrosis, palpitations,
or paraganglioma [37]. Typically, the sensitivity of pallor, tremor, or nausea), in conjunction with a BMI below
6 Journal of the Endocrine Society, 2024, Vol. 8, No. 6

25 kg/m2 and a heart rate exceeding 85 beats per minute, [49]. In previous reports where blood sampling was con­
markedly increases (by 7.5 times) the likelihood of an under­ ducted with subjects in a seated posture, a reduced diagnostic
lying PPGL [12]. specificity (approximately 76% to 85%) was observed, not­
In addition to identifying these neoplasms in individuals pre­ withstanding the preservation of a notably high diagnostic
senting with overt signs and symptoms of catecholamine ex­ sensitivity (ranging from 93% to 97%) was observed [15].
cess, there is a growing trend of detecting these tumors The incidence of false-positive results for plasma methoxytyr­
incidentally [1, 6]. This often occurs during anatomical im­ amine is notably higher in nonfasting patients than in those
aging procedures conducted for reasons unrelated to the pri­ who observe an overnight fast. Dopamine, which significantly
mary clinical suspicion of PPGL. Parallel to these influences measured levels of itself and its metabolites, is
developments, the acknowledgment of hereditary factors in abundantly present in bananas, and is also found in various
the etiology of PPGLs has led to their increased identification other fruits, vegetables, and assorted foods [15, 50].
within surveillance programs [37]. These programs specifically In the diagnostic investigation of PPGLs, it is crucial to me­
target individuals harboring germline pathogenic variants of ticulously assess the patient’s medication history, as various
genes associated with tumor susceptibility, intensifying the fo­ drugs can significantly influence biochemical test results, lead­
cus on preemptive testing. Within this cohort, a notable pro­ ing to potential misdiagnoses. Drug interactions contribute to

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portion, approximately 20% to 50%, may present as approximately 20% of all false-positive biochemical test re­
normotensive and/or entirely asymptomatic [15]. Yet, it is sults for PPGLs [47]. Tricyclic antidepressants, known for
not uncommon for the manifestations of catecholamine excess blocking norepinephrine reuptake, have been consistently
to be overlooked in others within this group. These tumors, linked to elevated false-positive rates for plasma and urinary
when detected via surveillance protocols, are typically smaller normetanephrine [15, 50]. Phenoxybenzamine, identified as
and may secrete relatively modest quantities of catechol­ a nonselective alpha-adrenoceptor antagonist, similarly inhib­
amines. Consequently, this can result in minimal or even non­ its norepinephrine uptake. Notably, these 2 drug types were
elevated levels of the relevant biomarkers within established responsible for 41% to 45% of the increased levels of norepin­
reference intervals. Nonetheless, it is imperative to note that ephrine and normetanephrine observed in patients who did
the pretest prevalence of PPGL in such patients is higher than not have a PPGL, as previously documented [51].
in those evaluated primarily based on clinical signs and False-positive results remain a problem in patients taking
symptoms. serotonin–norepinephrine (dual) reuptake inhibitors. Plasma
While only 4% of patients who presented with suggestive concentrations of normetanephrine in patients taking sero­
signs and symptoms were finally diagnosed with PPGL, detec­ tonin–norepinephrine reuptake inhibitors were 35% higher
tion rates were 42% in patients with a history of a previously according to Schürfeld et al [51]. Similar to other interfering
resected PPGL, 40% in case of genetic predisposition, and medications, dual reuptake inhibitors, such as venlafaxine
28% in adrenal incidentalomas [11]. Therefore, the pretest and duloxetine, cause false-positive results with mild eleva­
risk of harboring an actual PPGL can be summarized as tions in metanephrine levels. Previous case reports have dem­
high in patients with a prior history of PPGL, carriers of onstrated that venlafaxine can result in significantly false
pathogenic variants in susceptibility genes, and those with ad­ elevated normetanephrine levels, exceeding 4 times the upper
renal incidentalomas [15]. Conversely, patients presenting reference limit [52, 53]. In contrast, selective serotonin re­
solely with adrenergic clinical manifestations, particularly uptake inhibitors did not increase plasma concentrations of
those with a lower point score, are deemed to have a low pre­ catecholamine metabolites [51].
test risk [7]. This risk stratification may aid in the appraisal of Unlike phenoxybenzamine, selective α1-adrenoceptor block­
biochemical or imaging examinations that present with con­ ers, including doxazosin, terazosin, and prazosin, do not ele­
flicting results. vate false-positive rates for plasma norepinephrine and
normetanephrine [15]. However, these medications are associ­
ated with a 4-fold increase in false-positive rates for urinary
False-Positive Situations norepinephrine, while having no significant impact on urinary
In clinical settings, the occurrence of false-positive results in metanephrine levels [48]. Other antihypertensive drugs, such
biochemical testing for PPGLs is relatively common [46]. as calcium channel blockers, diuretics, and β-adrenoceptor
When considering unselected patient populations, the inci­ blockers, are not associated with false-positive results, and
dence of false-positive results for plasma free or urinary frac­ their withdrawal before testing is not necessary.
tionated metanephrines can be around 20% to 25% [29, 47]. Atypical antipsychotics, including quetiapine, clozapine,
While concurrent elevations in both metanephrines and nor­ and risperidone, represent other group of psychiatric medica­
metanephrines are uncommon, isolated increases in normeta­ tions known to cause false-positive results for norepinephrine
nephrines, reaching levels up to 2 to 3 times the upper and normetanephrine [15]. These agents act as antagonists on
reference limit, are more frequently observed [48]. dopaminergic, adrenergic, and serotonergic receptors. The
Preanalytical considerations, such as the method of blood precise mechanism by which this drug class leads to increased
collection (immediate needle stick vs an indwelling catheter), norepinephrine secretion remains unclear, but antagonism at
abstaining from smoking, physical activity, and avoiding α2-adrenergic and D2 dopaminergic receptors might contrib­
interfering medications, along with establishing intravenous ute. Zolpidem is a GABAA receptor agonist of the imidazopyr­
access 30 minutes before the blood draw, are critical factors idine class, primarily used for short-term treatment of sleeping
to ensure accurate results [1, 15, 49] (Fig. 3). Strictly con­ problems. In our practice, zolpidem was associated with false-
trolled preanalytical conditions, including supine positioning positive normetanephrine levels, but the mechanism to ex­
and age-adjusted plasma measurements, demonstrates that plain this effect is not known.
less than 8% of patients require additional testing, thereby re­ Finally, recreational drugs such as cocaine, which inhibits
ducing the necessity for most confirmatory tests for PPGLs norepinephrine reuptake, amphetamines, attention-deficit
Journal of the Endocrine Society, 2024, Vol. 8, No. 6 7

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Figure 3. Flowchart pointing out some important scenarios and conditions to be evaluated during the investigation of suspicious PPGLs.

hyperactivity disorder treatments with methylphenidate, and at least one month [1]. The consumption of beverages contain­
antiobesity drugs such as phentermine, all known to stimulate ing caffeine within the last 24 hours should be avoided, particu­
catecholamine release, may contribute to false-positive results. larly in situations where tests have shown previously mild
L-DOPA, frequently prescribed for Parkinson disease, can also elevations [15, 54].
lead to false elevations of 3-methoxytyramine and metanephr­ In chronic kidney disease, the biochemical evaluation for
ines. Similarly, sympathomimetics including ephedrine and PPGLs is rendered complex due to a confluence of factors, in­
pseudoephedrine enhance catecholamine production along cluding sympathoadrenal activation, the accrual of interfer­
with their metabolites [50]. Additionally, withdrawal from sed­ ents in the bloodstream, and altered circulatory and renal
atives such as benzodiazepines, opioids, clonidine, and alcohol clearance dynamics [15]. The utility of urinary metanephrines
can elevate sympathetic activity, further leading to false-positive measurements is compromised in chronic kidney disease due
results. The medications that interfere with the diagnosis of to the effect of renal impairment on catecholamine and meta­
PPGLs and their respective implicated mechanisms are summar­ nephrine excretion, although this impact is less pronounced in
ized in Table 3. Prior to the sampling of metanephrines, it is rec­ cases of mild to moderate renal dysfunction [55]. Plasma free
ommended for patients to discontinue all medications that could metanephrines, predominantly cleared via extraneuronal
potentially influence urinary or plasma metanephrines levels for mechanisms similarly to catecholamines and with minimal
8 Journal of the Endocrine Society, 2024, Vol. 8, No. 6

Table 3. Medications that interfere with the biochemical diagnosis of pheochromocytomas and paragangliomas and their respective implicated
mechanisms

Medication class Examples Impact on catecholamines

Tricyclic antidepressants Amitriptyline, nortriptyline Inhibit reuptake of norepinephrine and serotonin, potentially increasing
catecholamine levels
Nonselective α-adrenoceptor Phenoxybenzamine Inhibits norepinephrine uptake
antagonist
Serotonin–norepinephrine Venlafaxine, desvenlafaxine, duloxetine Inhibit reuptake of serotonin and norepinephrine, potentially raising
reuptake inhibitors catecholamine levels
Atypical antipsychotics Quetiapine, clozapine, and risperidone Adrenergic activity of some antipsychotics may affect catecholamine levels
Monoamine oxidase inhibitors Phenelzine, tranylcypromine Inhibit monoamine oxidase, an enzyme involved in catecholamine
breakdown, potentially increasing catecholamine levels
Sympathomimetics Pseudoephedrine, albuterol, phentermine, Directly stimulate adrenergic receptors or increase catecholamine release,

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caffeine, and nicotine raising catecholamine levels
Anti-Parkinson Levodopa Precursor to dopamine, can increase catecholamine synthesis
Amphetamines Methylphenidate, dextroamphetamine Increase release and inhibit reuptake of catecholamines
Opioids Oxycodone, hydrocodone, codeine, May indirectly influence catecholamine levels through central nervous
morphine system mechanisms
Agonist of GABAA receptors Zolpidem unknown
Cocaine and derivatives Inhibit reuptake of catecholamines, increasing their levels
Alcohol or sedative withdrawal Withdrawal can lead to increased sympathetic activity and catecholamine
release
Clonidine withdrawal Rebound increase in catecholamines after discontinuation
β-Blockers (nonselective) Atenolol, propranolol Inhibit catecholamine breakdown and metabolism, potentially leading to
increased levels

renal involvement, emerge as a more reliable indicator in pa­ Given the widespread occurrence of obesity and obstructive
tients with severe renal impairment or end-stage renal disease sleep apnea, distinguishing between the latter condition and
[15, 19]. In the setting of hemodialysis, re-evaluating plasma PPGLs has become a prevalent and challenging scenario.
metanephrines levels postdialysis and from dialysis shunt sam­ Interestingly, CPAP therapy improved the dysregulation of
ples is recommended [15]. The 97.5th percentile for normeta­ the autonomic nervous system [61] and normalized elevated
nephrine and metanephrine levels has been established in urinary normetanephrine levels [62]. Recently, King et al
patients with stage III and stage IV/hemodialysis chronic kid­ [63] demonstrated that plasma normetanephrines are less like­
ney disease [56]. ly to yield false-positive results for the diagnosis of PPGL than
In the acute clinical setting, accurately diagnosing a PPGL 24-hour urinary normetanephrines in patients with obstruct­
as the underlying cause of a catecholamine-induced hyperten­ ive sleep apnea.
sive crisis presents significant challenges [57]. This condition Additional factors including BMI, gender, time of
is often compounded by various comorbidities and acute sample collection during the day, and menstrual cycle phase
stressors such as panic disorders, hypoglycemia, ischemic seem to have a negligible impact on the biochemical diagnosis
heart disease, or circumstances surrounding emergency de­ of PPGLs [50].
partment admission, which can interfere with biochemical
evaluations and potentially lead to misdiagnosis. Severe acute
and chronic illnesses are itself frequently accompanied by Differential Diagnosis
sympathoadrenal activation as a part of the body’s homeo­ In the clinical diagnostic landscape, the identification of pheo­
static response [50]. These acute states can cause mild to sig­ chromocytoma stands as a complex endeavor, demanding
nificant increases in plasma and urinary metanephrines, careful differentiation from principal alternative diagnoses.
especially normetanephrine [15]. Consequently, biochemical This spectrum includes conditions that mimic adrenergic re­
testing for catecholamine excess in these scenarios is less likely sponses, such as hypoglycemia, climacteric hot flashes, other
to produce interpretable results [58]. secretory gastrointestinal neuroendocrine neoplasms, and
Obstructive sleep apnea is a very prevalent and underdiag­ psychiatric and cardiovascular disorders, each potentially pre­
nosed disease associated with a high cardiovascular morbi­ senting with symptoms similar to those observed in PPGL
mortality [59]. The pathophysiological mechanisms of the presentation [64]. The differential diagnoses for PPGLs are
development of arterial hypertension in patients with ob­ comprehensively compiled and enumerated in Table 4.
structive sleep apnea include a disorder of the autonomic ner­ Anxiety crises and panic disorders are conditions that should
vous system with excessive sympathetic activation due to frequently be considered in the assessment of patients present­
intermittent hypoxia during the night [60]. Obstructive sleep ing with symptoms of adrenergic paroxysms. Nevertheless, in
apnea leads to increased nocturnal catecholamine release instances of long-standing panic disorder that is resistant to
and a higher rate of false-positive test for norepinephrine medication, it is crucial to rule out the diagnosis of pheochro­
and normetanephrine. mocytoma [13, 65]. This intricate diagnostic scenario
Journal of the Endocrine Society, 2024, Vol. 8, No. 6 9

accentuates the necessity for a thorough and meticulous evalu­ overactivity may arise independent of catecholamine-
ative process to accurately diagnose PPGLs [13]. secreting tumors [67, 68]. In the elucidation of pseudo­
Pseudopheochromocytoma is an atypical medical pheochromocytoma pathophysiology, Sharabi et al pro­
condition that mirrors the clinical presentation of a vided evidence of an atypical catecholaminergic profile in
true pheochromocytoma without the presence of a these patients [66]. Their findings indicated that, compared
catecholamine-secreting tumor. Patients with pseudopheo­ with healthy controls, individuals with pseudopheochro­
chromocytoma exhibit episodic hypertension, headaches, mocytoma did not exhibit elevated norepinephrine levels
palpitations, and diaphoresis, the classic symptoms associ­ but did demonstrate significantly increased baseline plasma
ated with pheochromocytoma, yet biochemical testing does concentrations of epinephrine and metanephrines [66, 68].
not demonstrate elevated catecholamine levels as expected This dysregulation may be intrinsically linked to psycho­
in true pheochromocytoma [66]. The precise pathophysio­ logical stressors, with some studies suggesting a higher
logical mechanisms underlying this condition remain elu­ prevalence of underlying psychiatric conditions such as
sive and are believed to be multifactorial. There is a anxiety or panic disorders among these patients [66].
consensus that the aberrant regulation of the autonomic The management of pseudopheochromocytoma is inherent­
nervous system plays a central role, wherein sympathetic ly challenging due to its symptomatic mimicry of pheochromo­

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cytoma and the lack of a definitive biochemical marker. The
primary approach involves a thorough exclusion of a
Table 4. Comprehensive differential diagnosis for pheochromocytomas
catecholamine-secreting tumor via comprehensive biochemical
and paragangliomas (PPGLs) screening. Upon exclusion of pheochromocytoma, the focus
shifts to the management of the episodic hypertension and as­
Differential Diagnosis Description sociated symptoms [69]. Pharmacological interventions may
include the use of antihypertensive agents, particularly those
Pseudopheochromocytoma Hypertension and symptoms mimicking targeting the sympathetic nervous system, such as α-blockers
PPGL without actual tumor presence or β-blockers [68, 69]. These medications can mitigate the
Panic disorder/anxiety Episodes of intense fear and discomfort hypertensive episodes and control the adrenergic symptoms.
potentially mimicking catecholamine In contrast, conventional antihypertensive medications such
excess symptoms
as angiotensin-converting enzyme inhibitors, angiotensin re­
Hypoglycemia Low blood sugar levels causing ceptor blockers, and diuretics often prove ineffective [68].
symptoms that can overlap with
PPGL
Additionally, a multidisciplinary approach involving psycho­
logical support and psychiatric care is important.
Obstructive sleep apnea Disorder characterized by pauses in
breathing or periods of shallow
breathing during sleep, leading to
arterial hypertension and sympathetic
False-Negative Situations
activation With rare exceptions, contemporary assays for plasma and
Menopausal hot flashes Sudden feelings of warmth, which are urinary metanephrines exhibit exceptionally high sensitivity
usually most intense over the face, in diagnosing patients suspected of harboring PPGLs
neck, and chest (Fig. 3). In a prospective study involving patients with and
Drug withdrawal syndromes Symptoms arising from the cessation or without PPGLs, it was observed that the immunoassay meth­
reduction in the intake of addictive od yielded a significant number of false-negative results, fail­
substances ing to detect PPGLs in up to 25% of the cases [23]. In
Carcinoid syndrome A set of symptoms associated with assessing the sensitivity of plasma free metanephrine measure­
carcinoid tumors, especially flushing ments, currently considered the most sensitive diagnostic test,
and diarrhea
a recent prospective study reported a false-negative rate of
Cardiovascular emergencies Including ischemic heart disease, heart 2.1% [25]. However, among the patients with false-negative
failure, postural orthostatic
results, none of the 5 individuals with false-negative outcomes
tachycardia syndrome, syncope, acute
ischemic stroke for plasma free metanephrines and only 1 out of the 16 with
false-negative results for urinary metabolites were evaluated
Acute baroreflex failure A rare condition presenting as severe
labile hypertension and orthostatic on the basis of adrenergic signs and symptoms [15].
hypotension Small tumors or incipient recurrences might generate min­
Autonomic epilepsy Seizures originating from the autonomic imal levels of epinephrine and norepinephrine, leading to their
nervous system, presenting with nondetection. There is a positive correlation between the com­
various autonomic symptoms bined levels of plasma free metanephrines and tumor size,
Early dumping syndrome A group of symptoms, typically which can aid in distinguishing nonfunctional tumors from
gastrointestinal, that occur after those that are merely biochemically inactive [21]. The lack
eating, most commonly following of a biochemical signal was likely due to the small size of
gastric surgery the tumors, rather than an absence of catecholamine produc­
Acrodynia (mercury poisoning) A symptom complex primarily affecting tion. Hence, carriers of a predisposition gene mutation for
young children, involving pain and PPGL may present with a negative biochemical work-up
pink discoloration of the hands and
[50]. Tumors identified during initial screening often exhibit
feet
a biochemical phenotype classified as indeterminate due to
Factitious catecholamine Administration of catecholamines
their small or microscopic tumor burden (less than 2 cm) or
administration leading to symptoms mimicking
PPGL as nonfunctional in the context of larger tumors (greater
than 2 cm). This distinction is based on the understanding
10 Journal of the Endocrine Society, 2024, Vol. 8, No. 6

that a tumor size greater than 2 cm is consider sufficient to Case 2

yield elevated metanephrine levels [16, 21, 45]. Plasma metanephrines were repeated to make sure the patient
It has been observed that paragangliomas producing dopa­ was recumbent for 30 minutes before sampling, and plasma
mine can be overlooked if only epinephrine, norepinephrine, normetanephrine levels remained elevated (1.3 nmol/L;
and their metabolites are measured, or if the tumor rapidly me­ 97.5th percentile for age = 0.6889 nmol/L). Then, we decided
tabolizes dopamine to methoxytyramine due to a highly active to change zolpidem by clonazepam 0.25 mg for 2 weeks and
catechol-O-methyltransferase isoenzyme [15]. Consequently, repeat biochemical investigation for PPGL. After zolpidem
methoxytyramine is considered a more effective marker for suspension, plasma normetanephrine normalized (0.5 nmol/
detecting dopamine-producing tumors [19, 70, 71]. L; 97.5th percentile for age = 0.6889 nmol/L) and pheochro­
Hypertension is not typically associated with dopamine- mocytoma was excluded. Although zolpidem (a GABAA re­
producing paragangliomas. Indeed, these tumors may present ceptor agonist) is not listed as an interfering medication, we
with hypotension and other atypical symptoms [7, 37, 50]. have described here a false-positive biochemical screening
caused by zolpidem.

The Clonidine Suppression Test

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The clonidine (central α2-adrenoceptor agonist) suppression Case 3
test leverages clonidine’s capacity to inhibit noradrenaline re­ The patient underwent laparoscopic right adrenalectomy.
lease from normal adrenal glands, a response not observed in She presented hypertensive crisis during the intraoperative
patients with PPGL tumors. This test is particularly valuable period managed with intravenous sodium nitroprusside.
in distinguishing true PPGLs from other conditions that ele­ Histopathological analysis revealed a pheochromocytoma
vate catecholamines, like essential hypertension, stress, or cer­ (PASS score = 3, Ki 67% 2%, chromogranin positive, synapto­
tain drugs, especially in patients with borderline elevated physin positive). We present here an adrenal incidentaloma with
noradrenaline or normetanephrine levels. It should be empha­ a false-negative biochemical investigation for pheochromocyto­
sized that this test is not indicated when only adrenaline and/ ma. Although the patient had a previous surgery without intra­
or metanephrine are elevated [48]. Recently, an improved cut­ operative complications and negative biochemical investigation,
off for plasma normetanephrine at 180 minutes after cloni­ she had an adrenal tumor with >30 HU, a high arterial phase
dine (instead of a suppression <40%) was established at peak enhancement (122 HU), and an absolute washout of
80% of the age-related upper limit of normal, resulting in a 75%, which can happen in pheochromocytomas due to their hy­
sensitivity of 94% and a specificity of 97% [11]. pervascularization. False-negative results of plasma normeta­
A critical point to be considered before performing the clo­ nephrine and metanephrine measurements might be caused by
nidine test is the concomitant use of norepinephrine reuptake low metabolization of catecholamines within tumor because
blockers, which will interfere with clonidine action, not result­ of the deficiency in catechol-O-methyltransferase expression.
ing in the reduction of plasma norepinephrine or normeta­
nephrine [15, 19]. Therefore, clinicians should not perform
the clonidine suppression test in patients taking norepinephrine
uptake blockers or other interfering medications [15, 51].
Conclusions
Similarly, the accuracy of the clonidine suppression test can This expert endocrine consult critically examined the diagnos­
also be compromised if the underlying clinical conditions ele­ tic intricacies of PPGLs, emphasizing the pivotal role of com­
vating catecholamines were not removed or treated. prehensive evaluation in accurately identifying these tumors.
Our clinical cases underscored the necessity of a meticulous
approach that integrates clinical assessment, biochemical test­
Back to the Cases ing, and imaging. The potential for false-positive results, espe­
cially in the context of adrenergic symptoms, elevated
Case 1
catecholamines, or incidental adrenal tumors, indicated the
Alpha-blockade with doxazosin 4 mg was started and importance of a cautious and comprehensive approach to cor­
the patient underwent right adrenalectomy after 4 weeks. rectly diagnosis PPGLs.
Doxazosin was stopped 12 hours before adrenalectomy and Notably, the diagnostic journey is complicated by the var­
hemodynamic instability did not occur in the intraoperative ied clinical manifestations of PPGLs, from classic adrenergic
period. Pathological examination revealed a Weiss score 0 ad­ paroxysms to atypical presentations in dopamine-secreting
enoma with positive immunohistochemistry for CYP11B2 (al­ or nonfunctional tumors. A careful consideration of patient’s
dosterone synthase). After adjustments in CPAP therapy medication history, comorbid conditions, and lifestyle factors
(reduction of pressure and ramp settings), a significant im­ that can influence biochemical test outcomes is crucial.
provement in the obstructive sleep apnea occurred and plasma Additionally, it draws attention to the importance of selecting
normetanephrine normalized (0.7 nmol/L; 97.5th percentile appropriate diagnostic tests and interpreting their results
for age = 0.747 nmol/L). It is noteworthy that the clonidine within the broader clinical context.
test was conducted during the period of undertreated ob­
structive sleep apnea, reinforcing that this test is more reliable
when interfering conditions are removed. Therefore, this pa­
tient had primary aldosteronism diagnosis and a false-positive Financial Support
biochemical test for pheochromocytoma caused by a severe This work was supported by Sao Paulo Research Foundation
obstructive sleep apnea. After surgery, aldosterone decreased (FAPESP) grant 2019/15873-6 (to M.Q.A.). M.Q.A was also
to <3 ng/dL and blood pressure became well-controlled with supported by National Council for Scientific and
only amlodipine and carvedilol. Technological Development (CNPq) 304091/2021-9.
Journal of the Endocrine Society, 2024, Vol. 8, No. 6 11

Disclosures for pheochromocytoma and paraganglioma: which is the best diag­

nostic strategy. Clin Endocrinol (Oxf) 2022;96(2):132-138.
M.Q.A. is an associate editor of the Journal of the Endocrine 18. Kloos RT, Gross MD, Francis IR, Korobkin M, Shapiro B.
Society. G.F.C.F. has nothing to declare. Incidentally discovered adrenal masses. Endocr Rev 1995;16(4):
460-484.
19. Sbardella E, Grossman AB. Pheochromocytoma: an approach to
Data Availability diagnosis. Best Pract Res Clin Endocrinol Metab 2020;34(2):
101346.
Data sharing is not applicable to this article as no data sets
20. Taïeb D, Hicks RJ, Hindié E, et al. European association of nuclear
were generated or analyzed during the current study. medicine practice guideline/society of nuclear medicine and mo­
lecular imaging procedure standard 2019 for radionuclide imaging
of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol
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