Cell and Tissue Research

https://doi.org/10.1007/s00441-018-2791-4

REVIEW

Molecular imaging and theranostic approaches

in pheochromocytoma and paraganglioma
David Taïeb 1 & Karel Pacak 2

Received: 12 July 2017 / Accepted: 6 January 2018

# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Pheochromocytomas and their extra-adrenal counterpart paragangliomas (PGLs; together called PPGLs), belong to the family of
neural crest-derived tumors. Given the overexpression of a wide variety of specific targets in PPGLs, it seems that these tumors
are optimally suited to be imaged by specific radiopharmaceuticals. Thus, theranostics approaches with somatostatin agonists and
antagonists are rapidly evolving in the setting of these tumors and may be considered as the next step in the therapeutic arsenal of
metastatic PPGLs.

Keywords Positron emission tomography . Gallium-68 . DOTA-analogues . 6-(18F)fluoro-L-3,4-dihydroxyphenylalanine .

Somatostatin . Paragangliomas . Neuroendocrine

Epidemiology catecholamine excess (McNeil et al. 2000; Platts et al. 1995;

Sutton et al. 1981).
Pheochromocytoma (PHEOs) and paragangliomas (PGLs; to-
gether called PPGLs) belong to the same family of neuroen-
docrine neoplasms. PPGLs are rare tumors with an annual
Tumor origin and genetic background
incidence of about 1–8 patients per million (Stenstrom and
Svardsudd 1986). Based on the World Health Organization
Chromaffin cells and sympathetic neurons derive from a com-
classification published in 2004 and 2017, the term PHEO
mon sympathoadrenal (SA) progenitor cell. SA progenitor
should be reserved solely for adrenal PGLs. PHEOs account
cells aggregate at the dorsal aorta, where they acquire a cate-
for about 4% of adrenal incidentalomas with a higher preva-
cholaminergic neural fate. Subsquently, the cells migrate ven-
lence in an autopsy series (Mantero et al. 2000). Around 5% of
trally and invade the fetal adrenal cortex to form the adrenal
solitary PHEOs are hereditary, but the presence of multiple
medulla. PHEOs are neuroendocrine tumors that arise from
PHEOs or combination of a PHEO and PGL are related to a
the chromaffin cells of the adrenal medulla. PHEOs can be
germline mutation in more of 70% of cases, caused by at least
sporadic or can occur as components of hereditary syndromes.
12–15 well-characterized genes. It is also estimated that about
Some important correlations between the gene(s) involved
30–50% of these tumors are initially unrecognized, resulting
and tumor location have been found as described below:
in serious consequences to the patient, including death from
1: for unilateral PHEOs: succinate dehydrogenase complex
subunit B or D (SDHB or SDHD), VHL, and RET.
2: bilateral PHEOs: SDHB, RET, VHL, NF1, MYC associ-
* David Taïeb
david.taieb@ap-hm.fr ated factor X (MAX), and TMEM127.
3: PHEO with sympathetic PGL: SDHB, SDHD, SDHC,
1
VHL, RET, MAX, and HIF2A.
Department of Nuclear Medicine, La Timone University Hospital,
CERIMED, Aix-Marseille University, 264, rue Saint-Pierre,
4: PHEO with head and neck PGL (HNPGL): SDHD,
13385 Marseille, France SDHB, SDHC, TMEM127, and VHL.
2
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver
National Institute of Child Health and Human Development, Major predictors for hereditary PPGLs are: a family history
National Institutes of Health, Bethesda, MD, USA of PGL (especially those related to SDHD mutations); a
 Cell Tissue Res

previous personal history of PPGL; and multifocality or a
characteristic syndromic presentation (Jafri et al. 2013;
Neumann et al. 2009). Currently, a well-characterized
syndromic presentation includes the existence of other tumor
types associated with the presence of a PGL (e.g., renal cell
carcinoma, gastrointestinal stromal tumor, pituitary adenoma
can also be related to SDHx mutations) (Papathomas et al.
2014; Pasini et al. 2008) (Table 1).
Clinical presentation and diagnosis
PHEOs can be diagnosed clinically by the presence of symp-
toms of catecholamine oversecretion or cardiovascular attack
(stroke, cardiomyopathy, arrhythmia) that could appear spon-
taneously or caused by various drugs. They can also be re-
vealed by screening patients who harbor mutations in one of
the PHEO/PGL susceptibility genes. Hereditary PPGLs occur
most often during young adult to mid-adult life.
A thorough family and personal history is important and
should include questions regarding endocrine (medullary thy-
roid carcinoma, PPGLs, primary hyperparathyroidism) and
non-endocrine (renal, pancreatic, pituitary, gastrointestinal
stromal tumors) malignancies or unexplained sudden
Bcardiovascular system-related^ death in family members,
especially of younger age (potentially secondary to an undi-
agnosed PHEO or PGL).
Symptoms and signs of catecholamine oversecretion
should be considered (e.g., sustained or paroxysmal elevations
in blood pressure, headache, episodic profuse sweating, pal-
pitations, pallor, and apprehension, or anxiety).
Physical examination should focus on detecting features
particularly suggestive of hereditary PHEOs: thyroid nodule,
as well as presence of neck lymphadenopathy or any pheno-
typic feature of MEN2, NF1, or VHL syndromic presenta-
tions. There are a few true single pathognomonic findings that
will allow for definitive diagnosis of MEN2 by clinical in-
spection, including the presence of nostalgia paraesthetica
(posterior pigmented pruritic patch and nostalgia) in
MEN2A with codon 634 mutation or marfanoid body habitus
(excessively long arms and legs) and thickened protruding lips
due to multiple mucosal neuromas (also present on the distal
portion of the tongue and gingiva) in MEN2B. NF1 is char-
acterized by the presence of multiple neurofibromas, café-au-
lait spot, and Lisch nodules of the iris. VHL patients may also
have ocular lesions, consisting of retinal capillary
hemangioblastomas.
The diagnosis of PHEOs relies on the presence of elevated
plasma or urinary metanephrines. PHEOs present in three
well-defined biochemical phenotypes: noradrenergic, adrener-
gic, and dopaminergic. Norepinephrine-secreting tumors are

Table 1 Summary of common clinical and biochemical presentations of PPGLs with detectable mutations

First manifestation Context at presentation PHEO at Additional extra-adrenal Biochemical Malignancy

(in index cases) presentation PGL phenotype risk

MEN2 MTC Adult Uni- or Exceptional EPI Very low

Possible phenotypic features of bilateral
MEN2
Frequent family history of
MTC/PHEO
NF1 Neurofibromas Adult Often Exceptional EPI Very low
Phenotypic feature of NF1 unilateral
Possible family history of NF1
TMEM127 PHEO Adult Uni- or No EPI Low
Possible family history of PHEO bilateral
MAX PHEO Young adult Bilateral Possible EPI and NE Moderate
Frequent family history of PHEO
VHL PHEO/PGL Young adult Uni- or Moderate (retroperitoneum) NE Low
Frequent family history of bilateral
PHEO/PGL
SDHB PHEO/PGL Adult Often Frequent (retroperitoneum) NE and/or High
Possible family history of unilateral DA
PHEO/PGL
SDHD PHEO/PGL Adult Uni- or Frequent (head and neck) NE and/or Moderate
Frequent family history of HNPGL bilateral DA
SDHC PHEO/PGL Adult Rare Frequent (mediastinum) NE Low
Possible family history of PPGL
HIF2A Congenital Adolescent-young adult Very rare Almost constant NE Moderate
polycythemia females (retroperitoneum)
Absence of family history of PGL
Cell Tissue Res
characteristic for extra-adrenal PGLs, either sporadic, or those
with hereditary background, mainly including mutations in
succinate dehydrogenase subunits (SDHx), VHL, and fuma-
rate dehydrogenase (FH). Epinephrine production in these
tumors reflects the presence of the enzyme phenylethanol-N-
methyltransferase, which is uniquely found in the adrenal me-
dulla. They can be sporadic or hereditary, including mutations
in ret. oncogene (RET), neurofibromatosis type 1 (NF1), and
transmembrane protein 127 (TMEM127) genes. A dopaminer-
gic phenotype is characterized by significant elevation of ei-
ther dopamine or its metabolite methoxytyramine (MTY), or
both. Usually, dopamine or MTY elevation is associated with
an increase in norepinephrine or normetanephrine, which is
commonly seen in patients with SDHx mutations (Table 1).
CT and MRI
On non-contrast computed tomography (CT), PHEOs can
demonstrate a variety of appearances. Two-thirds of PHEOs
are solid adrenal tumors, while the remainder are complex or
have undergone cystic or necrotic changes (Park et al. 2007).
Typically, the CT attenuation of a PHEO is similar to soft
tissue attenuation and, thus, greater than 10 HU, with most
PHEOs having a HU of 20–30 or higher. PHEOs can present
with a high attenuation due to the presence of hemorrhage or
calcifications. In contrast, necrotic tissue presents with a low
attenuation. Typically, a PHEO demonstrates avid enhance-
ment (often greater than 30 HU) (Blake et al. 2004). In addi-
tion, enhancement can be heterogenous, or there may be no
enhancement due to cystic, necrotic, or degenerated regions
within the lesion (Park et al. 2006). On magnetic resonance
imaging (MRI), the classic imaging appearance of a PHEO is
Blight-bulb^ bright on T2-weighted imaging. In reality, 30 %
of PHEOs demonstrate moderate or low T2-weighted signal
intensity (Blake et al. 2004; Mayo-Smith et al. 2001). PHEOs
typically demonstrate avid contrast enhancement following
the administration of intravenous gadolinium-based contrast
material (Mitchell 1992; Varghese et al. 1997).
Molecular imaging
The role of molecular imaging are multiple:
1. Diagnosis of PHEO when metanephrine levels are
bordeline in the presence of indeterminate adrenal mass
on conventional imaging;
2. Assessement of locoregional extension;
3. Identification of tumor multiplicity, especially in the set-
ting of hereditary forms;
4. Exclusion of metastases, especially in presence of large
PHEOs, and in patients with certain genotypes (SDHB,
SDHA, SDHD, MAX). Malignancy is defined only by
the presence of metastatic lesions at sites where chromaf-
fin cells are normally absent (i.e. bone, liver, lymph
nodes).
5. Assessment of potential future aggressive behavior of a
PHEO
6. Detection of therapeutic molecular targets
Beyond its localization value, molecular imaging has
emerged at the forefront of personalized medicine.
Molecular imaging provides unique opportunities for in-
creased characterization of tumors at the molecular lev-
el—mirroring ex vivo histological classification, but on
a whole-body, in vivo, scale. A number of excellent ra-
diopharmaceuticals have been introduced that target dif-
ferent functional and molecular pathways involved in the
pathogenesis and clinical behavior of these tumors (e.g.,
tumor metabolism, specific transporter/receptor expres-
sion), which provides unique in vivo biomarkers.
Molecular imaging enables identification of three
metabolic-imaging phenotypes: catecholamine metabo-
lism, somatostatin receptors, and glucose uptake-imaging
phenotypes (Table 2).
Catecholamine metabolism-imaging
phenotype
Radiolabeled metaiodobenzylguanidine
Several excellent studies have demonstrated the superiority of
the Metaiodobenzylguanidine (123I/131I–MIBG) compared to
the Octreoscan for the diagnosis of PHEOs. The recently in-
troduced hybrid SPECT/CT cameras have increased diagnos-
tic confidence in image interpretation and enhanced sensitiv-
ity. However, practical constraints such as long imaging times
remain important limitations. To circumvent these limitations
and drawbacks, the use of 124I–MIBG could provide higher
resolution images with potential additional benefits of pro-
spective dosimetry for radionuclide therapy (Hartung-
Knemeyer et al. 2012). Very recently, a first-in-human study
with 18F–MFBG (an analog of MIBG) for PET imaging was
conducted and also showed promising results (Pandit-Taskar
et al. 2017).
18
F–fluorodihydroxyphenylalanine
18
F–fluorodihydroxyphenylalanine (18F–fluorodopa, 18F–
FDOPA) is taken up through neutral amino acid transporters
(mainly LAT1/LAT2), decarboxylated into 18F–fluorodopamine
by aromatic L-amino acid decarboxylase, and concentrated in
intracellular vesicles. 18F–FDOPA PET/CT was found to
be a highly sensitive (>90%) and specific (95–100%)
 Cell Tissue Res

Table 2 Comparison of different PET radiopharmaceuticals for the localization and staging of PPGLs

PET Cellular uptake Cellular retention Specificity Sensitivity Sensitivity

Radiopharamecuticals (%) sporadic SDHx
18
F–FDA Norepinephrine transporter Neurosecretory vesicles 100 78 52
(NET) (via VMATs)
18
F–FDOPA Neutral amino acid Decarboxylation (AADC) >95% 75 61
transporter system L and Neurosecretory
(LATs) vesicles (via VMATs)
68
Ga-SSA Somatostatin receptors Internalization (agonists) 90% 98 99
18
F–FDG Glucose transporters Decarboxylation 80% 49 86
(GLUTs) (hexokinase)
into 18F–FDG-6P

imaging modality for PHEO detection (Fiebrich et al. 2009;
Fonte et al. 2012; Hoegerle et al. 2002; Ilias et al. 2008; Kaji
et al. 2007; Timmers et al. 2009a, b). A special advantage of
18
F–FDOPA over other specific radiopharmaceuticals is the
lack of uptake by the healthy adrenal tissue. This would enable
a better detection of multiple PHEOs that may coexist in the
same gland and are highly suggestive of MEN2 or MAX-re-
lated PHEOs (Figs. 1, 2). Tumor uptake is significantly corre-
lated with levels of metanephrines (D.T., unpublished person-
al observations). 18F–FDOPA PET/CT is also very sensitive in
the diagnosis of extra-adrenal PHEOs that are often present in
the setting of SDHx (Timmers et al. 2009a).
18
F–fluorodopamine and 11C–HED
18
F–Fluorodopamine (18F–FDA) and 11C–hydroxyephedrine
11
( C–HED) are the most specific tracers for chromaffin tu-
mors, but are only available in very few centers worldwide.
Their use should be restricted to primary PHEOs or sympa-
thetic PGLs. Their role in the detection of metastatic PHEOs is
most likely suboptimal.
Somatostatin receptors- imaging phenotype
More recently, PET/CT imaging with 68Ga-labeled so-
matostatin analogues ( 68 Ga-DOTA-SSAs) has rapidly
evolved, since it does not require a cyclotron to make
the radiotracer. All 68 Ga-DOTA-SSAs (DOTATOC,
DOTATATE and DOTANOC) effectively target somato-
statin receptor subtype 2 (SST2) (IC50: 2.5 nM; 0.2 nM;
and 1.9 nM, respectively), which is the most over-
expressed subtype in PGLs.
Moreover, a special advantage of labeled SSAs is that,
unlike 18F–FDOPA, they can be used in the radioactive
treatment of these tumors (as theranostic agents). The use
of 68Ga-DOTA-SSA in the context of primary PHEOs has
been less studied, but has shown excellent results in lo-
calizing these tumors when they are metastatic or extra-
adrenal (Hofman et al. 2015; Kroiss et al. 2015; Naji and
Al-Nahhas 2012; Naji et al. 2011; Sharma et al. 2013,
2015). Head-to-head comparison between 68Ga-DOTA-
SSA and 18F–FDOPA PET has been performed in only
four studies: one retrospective study from Innsbruck
Medical University (68Ga-DOTATOC in 20 patients with

Fig. 1 Right sporadic PHEO. a 18F–FDG PET/CT, b 68Ga-DOTATATE features which contrast with the moderately avidity for 18F–FDG
PET/CT, c 18 F–FDOPA PET/CT. Scale bar 5 cm. High 68 Ga- (arrows). See the high 68 Ga-DOTATATE uptake by the normal
DOTATATE and 18 F–FDOPA tumor uptake with heterogeneous contralateral adrenal gland
Cell Tissue Res

Fig. 2 Multifocal MAX-related

PHEOs. a, c, e, g Contrast-
enhanced CT, b, d, f, h 18F–
FDOPA PET/CT. Bilateral PHEO
with multiple lesions within the
same glands. Scale bar 5 cm

unknown genetic background) (Kroiss et al. 2013), two
prospective studies from the NIH (68Ga-DOTATATE in
17 and 20 patients) (Hofman and Hicks 2015; Janssen
et al. 2015a, b), and one prospective study from La
Timone University Hospital (68Ga-DOTATATE in 30 pa-
tients) (Archier et al. 2015). In these studies, 68Ga-DOTA-
SSA PET/CT detected more than 18F–FDOPA PET/CT,
regardless of the genotype and even 18F–FDG PET/CT
in SDHx, metastatic, and head and neck PPGLs
(Figure 3).
It should be noted that SST-based imaging may be
s o m e w h a t l e s s s p e c i f i c t h a n 1 8 F – F D O PA , 1 8 F –
fluorodopamine, and 11C–HED in the evaluation of these
tumors and could be falsely positive in metastatic lymph
nodes due to various cancers, meningiomas, inflammatory
processes, and some rare conditions such as fibrous dys-
plasia (Archier et al. 2015; Hofman and Hicks 2015). In
clinical practice, most experienced readers of SSA-based
imaging are well aware of these pitfalls (often significant-
ly less avid than typical sites of disease and other
 Cell Tissue Res

Fig. 3 Metastatic SDHB-related PPGL. Previous history of surgery for
PHEOs and extradrenal PGLs. The anterior maximum intensity
projection images of 68Ga-DOTATATE (a), 18F–FDG (b), 18F–FDA (c),
and 18F–FDOPA (d) demonstrates 68Ga-DOTATATE and 18F–FDG
identifies similar number of lesions and perform superior than 18F–FDA
and 18F–FDOPA. The right adrenal recurrent pheochromocytoma
(marked by green arrows) is missed on 18F–FDOPA but identified by
other radiotracers. All the scans identify liver lesion in dome of right lobe
(red arrows), intensity is low in 18F–FDA, whereas the liver lesion
located in inferior right lobe of liver (black arrows) is missed on 18F–
FDA. The localization of skeletal metastases is similar on 68Ga-
DOTATATE, 18F–FDG, and 18F–FDA whereas it is suboptimal on 18F–
FDOPA

distinguishing features explained in the above reference)
and unlikely to make these mistakes.
Glucose metabolism-imaging phenotype
Although this imaging modality is not specific, data has clearly
shown that 18F–FDG PET has a superior sensitivity over CT/
MRI or 123/131I–MIBG in the localization of SDHx-related
PPGLs, especially those with metastatic disease (Timmers et al.
2012). Although previously a first-line imaging modality in this
group of patients, it has recently been surpassed by 68Ga-DOTA-
SSA PET/CT. Recent studies suggest that the accumulation of
succinate due to the TCA defect plays a major role in glucose
uptake by PHEO cells, not only via stabilization of hypoxia-
inducibal factors (HIFs) proteins (pseudohypoxia) but also by
endothelial cells via hormone-like action (Garrigue et al. 2017).
In non-SDHx PHEOs, the uptake is usually low to moderate.
Current proposed algorithm for molecular imaging
in the diagnosis and staging of PHEO
Based on the currently available imaging techniques, we pro-
pose the following approach to investigate a patient with a
PHEO (Table 3):

Table 3 First-line choice

radiopharmaceuticals according Location Related other tumor conditions First-choice
to mutational status radiopharmaceutical
18
MEN2 Adrenal MTC, parathyroid adenomas or hyperplasia F–FDOPA
18
NF1 Adrenal Neurofibromas, peripheral nerve sheath tumors F–FDOPA
and gliomas
18
TMEM127 Adrenal RCCs F–FDOPA
18
MAX Adrenal None reported F–FDOPA
18
VHL PHEO/PGL RCCs and CNS emangioblastomas F–FDOPA
Pancreatic and testicular tumors
68
SDHB PHEO/PGL GISTs, and RCCs Ga-DOTATATE
Pituitary adenomas
68
SDHD PHEO/PGL GISTs, RCCs and pituitary adenomas Ga-DOTATATE
68
SDHC PHEO/PGL GISTs Ga-DOTATATE
18
HIF2A PHEO/PGL Somatostatinomas F–FDOPA
Cell Tissue Res
i. For diagnosis, the specificity provided by functional im-
aging techniques using 18F–FDOPA PET/CT or 68Ga-
DOTA-SSA is superior to anatomical imaging.
ii. For detecting additional tumor sites (multifocality, metas-
tases), functional imaging techniques are superior to ana-
tomical imaging. Based on the most recent studies, both
SDHx and non-SDHx PPGLs, especially metastatic ones,
are better visualized by 68Ga-DOTA-SSA than 18F–
FDOPA PET/CT or even 18F–FDG PET/CT in SDHx-
tumors.
iii. For patients with a high risk of developping tumors lim-
ited to the adrenal glands with potential multifocality
(i.e., RET, MAX), 18F–FDOPA PET/CT should be used
as the first-line approach due to the low tracer uptake by
extranodular adrenal tissue.
Theranostic approaches
Therapeutic nuclear medicine (Bradionuclide therapy,^
Btargeted internal,^ or Bmolecular^ radiotherapy) is defined
as a radiation therapy that uses local, loco-regional, or system-
ic administration of radionuclides to achieve a transfer of ra-
diation energy to a pathological target tissue, and, by this
means, exert a destructive effect on culprit tissue. Most often,
tissue-specific radionuclide delivery is performed via a
targeting biomolecule, which exploits the targeting of radia-
tion through transporters, receptors, or antigens on tumor
cells. A complex set of factors determine the success (or fail-
ure) of this approach, such as affinity of the carrier molecule,
radionuclide–carrier complex binding stability, pharmacoki-
netics, biodistribution, or radiosensitivity of the tumor cells.
Theranostics encapsulates the integration of diagnostics
and therapeutics in individualized disease management. In
the context of nuclear medicine, it refers to the use of molec-
ular targeting vectors, (e.g., peptides) labeled with either diag-
nostic radionuclides (e.g., positron or gamma emitters) or with
therapeutic radionuclides. The prime example of theranostics
in nuclear medicine is the use of 123I–MIBG imaging, while
MIBG labeled with iodine-131 (131I–MIBG) is used for mo-
lecular radiotherapy. Intense uptake of 123I–MIBG by differ-
ent tumor sites indicates a high expression of norepinephrine
transporter on tumor cells that can, therefore, be targeted with
131
I–MIBG. 123I–MIBG is still recommended for determining
if a patient is eligible for molecular radiotherapy with 131I–
MIBG. In metastatic PPGLs, 131I–MIBG provides symptom-
atic relief in approximately 75% of cases, and a partial radio-
logical response in about 30%, with relatively limited side
effects. Administration of higher activities is associated with
increased response rates but also increased toxicity (Gonias
et al. 2009). As the transport of MIBG by the norepinephrine
transporter is a saturable event, the specific activity of the
preparation may have important effects on both the efficacy
and safety of the theranostic agent. Using a solid labeling
approach (Ultratrace ® ), noncarrier-added radiolabelled
MIBG has been efficiently produced. Ultratrace ®
(Iobenguane 131I) is currently being evaluated at a high fixed
dosage activity. The next step will be to evaluate if an individ-
ual patient dosimetry leads to a better outcome. PRRT using
177
Lu-DOTA-Octreotate is another example of a theranostic
approach. Eligibility to PRRT is based on 68Ga-DOTA-
Octreotate or Octreoscan uptake by tumors. 177Lu-DOTA-
Octreotate has shown excellent results in the treatment of pro-
gressive metastatic midgut neuroendocrine tumors in the
Netter-1 study (Strosberg et al. 2017). 177 Lu-DOTA-
Octreotate will be rapidly implemented into the therapeutic
arsenal for PPGLs (Zovato et al. 2012), especially for inoper-
able and metastatic tumors (Kong et al. 2017). Recent reports
have shown excellent results with SST antagonists. According
to these observations, it is possible that SST antagonists may
be considered as the next step for peptide-based internal ra-
diotherapy in metastatic PPGL patients.
Acknowledgements This research was supported, in part, by the
Intramural Research Program of the NIH, Eunice Kennedy Shriver
NICHD.
References
Archier A, Varoquaux A, Garrigue P, Montava M, Guerin C, Gabriel S,
Beschmout E, Morange I, Fakhry N, Castinetti F, Sebag F, Barlier A,
Loundou A, Guillet B, Pacak K, Taieb D (2015) Prospective com-
parison of Ga-DOTATATE and F-FDOPA PET/CT in patients with
various pheochromocytomas and paragangliomas with emphasis on
sporadic cases. Eur J Nucl Med Molec Imaging 43:1248–1257
Blake MA, Kalra MK, Maher MM, Sahani DV, Sweeney AT, Mueller
PR, Hahn PF, Boland GW (2004) Pheochromocytoma: an imaging
chameleon. Radiographics 24(Suppl 1):S87–S99
Fiebrich HB, Brouwers AH, Kerstens MN, Pijl ME, Kema IP, de Jong JR,
Jager PL, Elsinga PH, Dierckx RA, van der Wal JE, Sluiter WJ, de Vries
EG, Links TP (2009) 6-[F-18]Fluoro-L-dihydroxyphenylalanine posi-
tron emission tomography is superior to conventional imaging with
(123)I-metaiodobenzylguanidine scintigraphy, computer tomography,
and magnetic resonance imaging in localizing tumors causing catechol-
amine excess. J Clin Endocrinol Metab 94:3922–3930
Fonte JS, Robles JF, Chen CC, Reynolds J, Whatley M, Ling A, Mercado-
Asis LB, Adams KT, Martucci V, Fojo T, Pacak K (2012) False-
negative 123I-MIBG SPECT is most commonly found in SDHB-
related pheochromocytoma or paraganglioma with high frequency to
develop metastatic disease. Endocr Relat Cancer 19:83–93
Garrigue P, Bodin-Hullin A, Balasse L, Fernandez S, Essamet W, Dignat-
George F, Pacak K, Guillet B, Taieb D (2017) The evolving role of
succinate in tumor metabolism: an 18F–FDG-based study. J Nucl
Med 58:1749–1755
Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J,
Damon L, Linker C, Sznewajs A, Shiboski S, Fitzgerald P (2009)
Phase II study of high-dose [131I]metaiodobenzylguanidine therapy
for patients with metastatic pheochromocytoma and paraganglioma.
J Clin Oncol 27:4162–4168

Hartung-Knemeyer V, Rosenbaum-Krumme S, Buchbender C, Poppel T,
Brandau W, Jentzen W, Antoch G, Forsting M, Bockisch A, Kuhl H
(2012) Malignant pheochromocytoma imaging with [124I]mIBG
PET/MR. J Clin Endocrinol Metab 97:3833–3834
Hoegerle S, Nitzsche E, Altehoefer C, Ghanem N, Manz T, Brink I,
Reincke M, Moser E, Neumann HP (2002) Pheochromocytomas:
detection with 18F DOPA whole body PET–initial results.
Radiology 222:507–512
Hofman MS, Hicks RJ (2015) Moving beyond BLumpology^: PET/CT
imaging of Pheochromocytoma and Paraganglioma. Clin Canc Res
21:3815–3817
Hofman MS, Lau WF, Hicks RJ (2015) Somatostatin receptor imaging
with 68Ga DOTATATE PET/CT: clinical utility, normal patterns,
pearls, and pitfalls in interpretation. Radiographics 35:500–516
Ilias I, Chen CC, Carrasquillo JA, Whatley M, Ling A, Lazurova I,
Adams KT, Perera S, Pacak K (2008) Comparison of 6-18F-
fluorodopamine PET with 123I-metaiodobenzylguanidine and
111in-pentetreotide scintigraphy in localization of nonmetastatic
and metastatic pheochromocytoma. J Nucl Med 49:1613–1619
Jafri M, Whitworth J, Rattenberry E, Vialard L, Kilby G, Kumar AV, Izatt
L, Lalloo F, Brennan P, Cook J, Morrison PJ, Canham N, Armstrong
R, Brewer C, Tomkins S, Donaldson A, Barwell J, Cole TR,
Atkinson AB, Aylwin S, Ball SG, Srirangalingam U, Chew SL,
Evans DG, Hodgson SV, Irving R, Woodward E, Macdonald F,
Maher ER (2013) Evaluation of SDHB, SDHD and VHL gene sus-
ceptibility testing in the assessment of individuals with non-
syndromic phaeochromocytoma, paraganglioma and head and neck
paraganglioma. Clin Endocrinol 78:898–906
Janssen I, Blanchet EM, Adams K, Chen CC, Millo CM, Herscovitch P,
Taieb D, Kebebew E, Lehnert H, Fojo AT, Pacak K (2015a)
Superiority of [68Ga]-DOTATATE PET/CT to other functional im-
aging modalities in the localization of SDHB-associated metastatic
Pheochromocytoma and Paraganglioma. Clin Canc Res 21:3888–
3895
Janssen I, Chen CC, Taieb D, Patronas NJ, Millo CM, Adams KT,
Nambuba J, Herscovitch P, Sadowski SM, Fojo AT, Buchmann I,
Kebebew E, Pacak K (2015b) 68Ga-DOTATATE PET/CT in the lo-
calization of head and neck paragangliomas compared to other func-
tional imaging modalities and CT/MRI. J Nucl Med 57:186–191
Kaji P, Carrasquillo JA, Linehan WM, Chen CC, Eisenhofer G, Pinto PA,
Lai EW, Pacak K (2007) The role of 6-[18F]fluorodopamine posi-
tron emission tomography in the localization of adrenal pheochro-
mocytoma associated with von Hippel-Lindau syndrome. Eur J
Endocrinol 156:483–487
Kong G, Grozinsky-Glasberg S, Hofman MS, Callahan J, Meirovitz A,
Maimon O, Pattison DA, Gross DJ, Hicks RJ (2017) Efficacy of
peptide receptor radionuclide therapy for functional metastatic
Paraganglioma and Pheochromocytoma. J Clin Endocrinol Metab
102:3278–3287
Kroiss A, Putzer D, Frech A, Decristoforo C, Uprimny C, Gasser RW,
Shulkin BL, Url C, Widmann G, Prommegger R, Sprinzl GM,
Fraedrich G, Virgolini IJ (2013) A retrospective comparison be-
tween (68)Ga-DOTA-TOC PET/CT and (18)F-DOPA PET/CT in
patients with extra-adrenal paraganglioma. Eur J Nucl Med Molec
Imaging 40:1800–1808
Kroiss A, Shulkin BL, Uprimny C, Frech A, Gasser RW, Url C, Gautsch
K, Madleitner R, Nilica B, Sprinzl GM, Gastl G, Fraedrich G,
Virgolini IJ (2015) (68)Ga-DOTATOC PET/CT provides accurate
tumour extent in patients with extraadrenal paraganglioma com-
pared to (123)I-MIBG SPECT/CT. Eur J Nucl Med Mol Imaging
42:33–41
Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Ali A,
Giovagnetti M, Opocher G, Angeli A (2000) A survey on adrenal
incidentaloma in Italy. Study Group on Adrenal Tumors Italian
Society of Endocrinology. J Clin Endocrinol Metab 85:637–644
Cell Tissue Res
Mayo-Smith WW, Boland GW, Noto RB, Lee MJ (2001) State-of-the-art
adrenal imaging. Radiographics 21:995–1012
McNeil AR, Blok BH, Koelmeyer TD, Burke MP, Hilton JM (2000)
Phaeochromocytomas discovered during coronial autopsies in
Sydney, Melbourne and Auckland. Aust NZ J Med 30:648–652
Mitchell DG (1992) Chemical shift magnetic resonance imaging: applications
in the abdomen and pelvis. Top Magn Reson Imaging 4:46–63
Naji M, Al-Nahhas A (2012) (68)Ga-labelled peptides in the management
of neuroectodermal tumours. Eur J Nucl Med Molec Imaging
39(Suppl 1):61-67
Naji M, Zhao C, Welsh SJ, Meades R, Win Z, Ferrarese A, Tan T, Rubello
D, Al-Nahhas A (2011) 68Ga-DOTA-TATE PET vs. 123I-MIBG in
identifying malignant neural crest tumours. Mol Imaging Biol 13:
769–775
Neumann HP, Erlic Z, Boedeker CC, Rybicki LA, Robledo M, Hermsen
M, Schiavi F, Falcioni M, Kwok P, Bauters C, Lampe K, Fischer M,
Edelman E, Benn DE, Robinson BG, Wiegand S, Rasp G, Stuck
BA, Hoffmann MM, Sullivan M, Sevilla MA, Weiss MM,
Peczkowska M, Kubaszek A, Pigny P, Ward RL, Learoyd D,
Croxson M, Zabolotny D, Yaremchuk S, Draf W, Muresan M,
Lorenz RR, Knipping S, Strohm M, Dyckhoff G, Matthias C,
Reisch N, Preuss SF, Esser D, Walter MA, Kaftan H, Stover T,
Fottner C, Gorgulla H, Malekpour M, Zarandy MM, Schipper J,
Brase C, Glien A, Kuhnemund M, Koscielny S, Schwerdtfeger P,
Valimaki M, Szyfter W, Finckh U, Zerres K, Cascon A, Opocher G,
Ridder GJ, Januszewicz A, Suarez C, Eng C (2009) Clinical predic-
tors for germline mutations in head and neck paraganglioma pa-
tients: cost reduction strategy in genetic diagnostic process as fall-
out. Cancer Res 69:3650–3656
Pandit-Taskar N, Zanzonico PB, Staton KD, Carrasquillo JA, Reidy-
Lagunes D, Lyashchenko SK, Burnazi E, Zhang H, Lewis JS,
Blasberg R, Larson SM, Weber WA, Modak S (2017)
Biodistribution and dosimetry of (18)F-meta Fluorobenzyl guani-
dine (MFBG): a first-in-human PET-CT imaging study of patients
with neuroendocrine malignancies. J Nucl Med 117.193169
Papathomas TG, Gaal J, Corssmit EP, Oudijk L, Korpershoek E, Heimdal
K, Bayley JP, Morreau H, van Dooren M, Papaspyrou K, Schreiner
T, Hansen T, Andresen PA, Restuccia DF, van Kessel I, van
Leenders GJ, Kros JM, Looijenga LH, Hofland LJ, Mann W, van
Nederveen FH, Mete O, Asa SL, de Krijger RR, Dinjens WN (2014)
Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in
patients with succinate dehydrogenase-related PCC-PGL syn-
dromes: a clinicopathological and molecular analysis. Eur J
Endocrinol 170:1–12
Park BK, Kim B, Ko K, Jeong SY, Kwon GY (2006) Adrenal masses
falsely diagnosed as adenomas on unenhanced and delayed contrast-
enhanced computed tomography: pathological correlation. Eur
Radiol 16:642–647
Park BK, Kim CK, Kwon GY, Kim JH (2007) Re-evaluation of pheo-
chromocytomas on delayed contrast-enhanced CT: washout en-
hancement and other imaging features. Eur Radiol 17:2804–2809
Pasini B, McWhinney SR, Bei T, Matyakhina L, Stergiopoulos S,
Muchow M, Boikos SA, Ferrando B, Pacak K, Assie G, Baudin
E, Chompret A, Ellison JW, Briere JJ, Rustin P, Gimenez-
Roqueplo AP, Eng C, Carney JA, Stratakis CA (2008) Clinical
and molecular genetics of patients with the Carney-Stratakis syn-
drome and germline mutations of the genes coding for the succinate
dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum
Genet 16:79–88
Platts JK, Drew PJ, Harvey JN (1995) Death from phaeochromocytoma:
lessons from a post-mortem survey. J R Coll Physicians Lond 29:
299–306
Sharma P, Mukherjee A, Karunanithi S, Naswa N, Kumar R, Ammini
AC, Bal C (2015) Accuracy of 68Ga DOTANOC PET/CT imaging
in patients with multiple endocrine Neoplasia syndromes. Clin Nucl
Med 40:e351–e356
Cell Tissue Res
Sharma P, Thakar A, Suman Kc S, Dhull VS, Singh H, Naswa N, Reddy
RM, Karunanithi S, Kumar R, Malhotra A, Bal C (2013) 68Ga-
DOTANOC PET/CT for baseline evaluation of patients with head
and neck Paraganglioma. J Nucl Med 54:841–847
Stenstrom G, Svardsudd K (1986) Pheochromocytoma in Sweden 1958-
1981. An analysis of the National Cancer Registry Data. Acta Med
Scand 220:225–232
Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra
E, Kunz PL, Kulke MH, Jacene H, Bushnell D, O’Dorisio TM,
Baum RP, Kulkarni HR, Caplin M, Lebtahi R, Hobday T,
Delpassand E, Van Cutsem E, Benson A, Srirajaskanthan R, Pavel
M, Mora J, Berlin J, Grande E, Reed N, Seregni E, Oberg K, Lopera
Sierra M, Santoro P, Thevenet T, Erion JL, Ruszniewski P,
Kwekkeboom D, Krenning E, Investigators N-T (2017) Phase 3 trial
of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J
Med 376:125–135
Sutton MG, Sheps SG, Lie JT (1981) Prevalence of clinically unsuspect-
ed pheochromocytoma. Review of a 50-year autopsy series. Mayo
Clin Proc 56:354–360
Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Eisenhofer
G, King KS, Rao JU, Wesley RA, Adams KT, Pacak K (2012)
Staging and functional characterization of pheochromocytoma and
paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron
emission tomography. J Natl Cancer Inst 104:700–708
Timmers HJ, Chen CC, Carrasquillo JA, Whatley M, Ling A, Havekes B,
Eisenhofer G, Martiniova L, Adams KT, Pacak K (2009a)
Comparison of 18F-Fluoro-L-DOPA, 18F-Fluoro-Deoxyglucose,
and 18F-Fluorodopamine PET and 123I-MIBG Scintigraphy in the
localization of Pheochromocytoma and Paraganglioma. J Clin
Endocrinol Metab 94:4757–4767
Timmers HJ, Eisenhofer G, Carrasquillo JA, Chen CC, Whatley M, Ling
A, Adams KT, Pacak K (2009b) Use of 6-[18F]-fluorodopamine
positron emission tomography (PET) as first-line investigation for
the diagnosis and localization of non-metastatic and metastatic
phaeochromocytoma (PHEO). Clin Endocrinol 71:11–17
Varghese JC, Hahn PF, Papanicolaou N, Mayo-Smith WW, Gaa JA, Lee
MJ (1997) MR differentiation of phaeochromocytoma from other
adrenal lesions based on qualitative analysis of T2 relaxation times.
Clin Radiol 52:603–606
Zovato S, Kumanova A, Dematte S, Sansovini M, Bodei L, Di Sarra D,
Casagranda E, Severi S, Ambrosetti A, Schiavi F, Opocher G,
Paganelli G (2012) Peptide receptor radionuclide therapy (PRRT)
with 177Lu-DOTATATE in individuals with neck or mediastinal
paraganglioma (PGL). Horm Metab Res 44:411–414