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\begin{document}

\title{\textsuperscript{68}Ga-DOTATATE PET in Pediatric Paraganglioma /
Pheochromocytoma: A Case-series Highlighting the Role of Functional
Imaging}



\author[1]{Aleksandra Augustynowicz}%
\author[2]{Neha Kwatra}%
\author[2]{Laura Drubach}%
\author[3]{Christopher Weldon}%
\author[4]{Katherine Janeway}%
\author[5]{Steven DuBois}%
\author[5]{Junne Kamihara}%
\author[2]{Stephan Voss}%
\affil[1]{Mt Auburn Hospital}%
\affil[2]{Harvard Medical School}%
\affil[3]{Boston Children’s Hospital and Harvard Medical School}%
\affil[4]{Dana-Farber / Boston Children's Cancer and Blood Disorders Center}%
\affil[5]{Dana-Farber Cancer Institute}%


\vspace{-1em}



  
  \date{June 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors
in childhood. Cancer predisposition syndromes (CPS) are increasingly
recognized as the underlying cause for a number of pediatric
malignancies and up to 40\% of PPGL are currently thought to be
associated with a hereditary predisposition1,2. With the increasingly
widespread availability of functional molecular imaging techniques,
nuclear medicine imaging modalities such as 18F-FDG-PET/CT, 123I-MIBG
SPECT/CT, and 68Ga-DOTATATE PET/CT now play an essential role in the
staging, response assessment and determination of suitability for
targeted radiotherapy in patients with PPGL. Each of these imaging
modalities targets a different cellular characteristic, such as glucose
metabolism (FDG), norepinephrine transporter expression (MIBG), or
somatostatin receptor expression (DOTATATE), and therefore can be
complementary to anatomic imaging and to each other. Given the recent
FDA approval3 and increasing use of 68Ga-DOTATATE for imaging in
children4, the purpose of this article is to use a case-based approach
to highlight both the advantages and limitations of DOTATATE imaging as
it compares to current radiologic imaging techniques in the staging and
response assessment of pediatric PPGL, and to offer a decision algorithm
for the use of functional imaging that can be applied to PPGL, as well
as other neuroendocrine malignancies.%
\end{abstract}%



\sloppy


\textsuperscript{68}Ga-DOTATATE PET in Pediatric Paraganglioma /
Pheochromocytoma: A Case-series Highlighting the Role of Functional
Imaging

Aleksandra Augustynowicz\textsuperscript{1}, Neha
Kwatra\textsuperscript{2}, Laura Drubach\textsuperscript{2}, Christopher
B. Weldon\textsuperscript{3,4,5}, Katherine A.
Janeway\textsuperscript{4}, Steven G. DuBois\textsuperscript{4}, Junne
Kamihara\textsuperscript{4}, and Stephan D. Voss\textsuperscript{2,4}

Author Affiliations:

\textsuperscript{1}Department of Radiology, Mount Auburn Hospital

\textsuperscript{2}Department of Radiology, Boston Children's Hospital

\textsuperscript{3}Department of Surgery, Boston Children's Hospital

\textsuperscript{4}Dana-Farber/Boston Children's Cancer and Blood
Disorders Center

\textsuperscript{5}Department of Anesthesiology, Critical Care \& Pain
Medicine. Boston Children's Hospital

Keywords: Paraganglioma,
Pheochromocytoma,\textsuperscript{68}Ga-DOTATATE PET/CT

Title character count: 108

Number of references: 36

Number of figures: 4

Abstract word count: 198

Word count Text: 2919

Corresponding Author:

Stephan D. Voss, MD, PhD Department of Radiology, Boston Children's
Hospital Boston Children's Hospital, 300 Longwood Avenue Boston, MA
02115\emph{email: stephan.voss@childrens.harvard.edu}

Conflicts of Interest/funding:

SGD has received consulting fees from Bayer and travel expenses from
Loxo, Roche, and Salarius. The other authors declare no conflicts of
interest.

\emph{Abbreviations:} Cancer predisposition syndromes -- CPS;
Pheochromocytoma Paraganglioma -- PPGL; Inflammatory myofibroblastic
tumor -- IMT; Whole body MRI - wbMRI

Running Title: \textsuperscript{68}Ga-DOTATATE PET in Pediatric
Paragangloma Pheochromocytoma

ABSTRACT

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors
in childhood. Cancer predisposition syndromes (CPS) are increasingly
recognized as the underlying cause for a number of pediatric
malignancies and up to 40\% of PPGL are currently thought to be
associated with a hereditary predisposition\textsuperscript{1,2}. With
the increasingly widespread availability of functional molecular imaging
techniques, nuclear medicine imaging modalities such
as\textsuperscript{18}F-FDG-PET/CT,\textsuperscript{123}I-MIBG SPECT/CT,
and\textsuperscript{68}Ga-DOTATATE PET/CT now play an essential role in
the staging, response assessment and determination of suitability for
targeted radiotherapy in patients with PPGL. Each of these imaging
modalities targets a different cellular characteristic, such as glucose
metabolism (FDG), norepinephrine transporter expression (MIBG), or
somatostatin receptor expression (DOTATATE), and therefore can be
complementary to anatomic imaging and to each other. Given the recent
FDA approval\textsuperscript{3} and increasing use
of\textsuperscript{68}Ga-DOTATATE for imaging in
children\textsuperscript{4}, the purpose of this article is to use a
case-based approach to highlight both the advantages and limitations of
DOTATATE imaging as it compares to current radiologic imaging techniques
in the staging and response assessment of pediatric PPGL, and to offer a
decision algorithm for the use of functional imaging that can be applied
to PPGL, as well as other neuroendocrine malignancies.

\textbf{INTRODUCTION}

Hereditary cancer predisposition syndromes (CPS) have contributed to our
growing understanding of pheochromocytoma and paraganglioma (PPGL)
biology and clinical behavior. At least 12 different genetic syndromes
are known to have a predisposition to developing PPGL and PPGL are
associated with at least 15 well-characterized driver genes as well as
additional disease-modifying genes \textsuperscript{2}, underscoring the
heterogeneous nature of these tumors. Paragangliomas~(PGL) arise from
neuroendocrine cells (paraganglia) that extend from the skull base to
the pelvis and have variable functional hormone secretion depending on
their location and genetic makeup, while pheochromocytoma (PCC) are
catecholamine-secreting tumors arising from chromaffin cells of the
adrenal medulla. These predominantly well-differentiated tumors can be
evaluated anatomically by CT and MRI and with functional imaging
techniques such as \textsuperscript{123}I-MIBG scintigraphy, in which
the norepinephrine analog MIBG is taken up by cells expressing the
norepinephrine transport receptor, and \textsuperscript{18}F-FDG PET/CT,
in which the glucose analogue \textsuperscript{18}F-FDG is transported
into and trapped in metabolically active cells. Well-differentiated
neuroendocrine tumors such as PPGL also express somatostatin receptors
and \textsuperscript{111}In-pentetreotide scintigraphy, using a
conjugate of octreotide that binds to somatostatin receptors, has
historically been the functional imaging method of choice for staging
neuroendocrine tumors (NETs). With the recent FDA approval
of\textsuperscript{68}Ga-DOTATATE for localization of somatostatin
receptor positive neuroendocrine tumors in adult and pediatric
patients\textsuperscript{3}, \textsuperscript{111}In-pentetreotide
scintigraphy has largely been replaced by\textsuperscript{68}Ga-DOTATATE
PET/CT based on improved diagnostic accuracy, shorter imaging protocol,
and lower radiation dose\textsuperscript{5-8}.

Although most PPGL are not malignant, distinguishing benign from
malignant disease is important since operative treatment can be curative
for PPGL that are amenable to resection and have not metastasized.
Because there are no histopathologic techniques currently available to
distinguish primary benign from malignant PPGL\textsuperscript{9}, both
functional and anatomic imaging approaches have been advocated for the
detection of metastatic disease. Moreover, these tumors frequently arise
in the setting of specific cancer predisposition syndromes with multiple
synchronous primary tumors of identical or separate histologies, and
functional imaging may help in discriminating between distinct tumor
types. In patients with PPGL, the functional imaging techniques most
commonly used are \textsuperscript{68}Ga-DOTATATE
PET/CT,\textsuperscript{18}F-FDG PET/CT, and \textsuperscript{123}I-MIBG
scintigraphy, each of which have advantages and limitations. For
example, while \textsuperscript{68}Ga-DOTATATE PET/CT is reported to
have higher sensitivity for detection of well-differentiated, less
aggressive NETs, there is evidence to suggest
that~\textsuperscript{18}F-FDG PET/CT may be preferable for more
aggressive, less well-differentiated tumors \textsuperscript{10}, with
other reports suggesting an association between
higher~\textsuperscript{18}F-FDG uptake and worse outcome, even in
patients with well-differentiated or low-grade
tumors\textsuperscript{11}. \textsuperscript{123}I-MIBG scintigraphy has
greater specificity for disease characterization than CT and MRI, but
much lower sensitivity than somatostatin-receptor directed PET imaging
techniques. Despite its lower sensitivity, \textsuperscript{123}I-MIBG
may still be used to establish MIBG avidity in individuals with
metastatic disease in whom treatment with \textsuperscript{131}I-MIBG is
a consideration \textsuperscript{12,13}. This latter point is critical
in pediatrics since \textsuperscript{131}I-MIBG has US regulatory
approval for therapeutic use in children while somatostatin-targeted
therapies such as \textsuperscript{177}Lu-DOTATATE (Lutathera?) are not
yet approved in children.

Other pediatric neuroendocrine tumors, including medullary thyroid
carcinoma, carcinoid, gastrinoma, insulinoma, VIPoma, glucagonoma also
demonstrate increased expression of somatostatin receptors. The approach
outlined here, focusing on PPGL as a model for the use
of\textsuperscript{68}Ga-DOTATATE to target these receptors, can be
applied more generally to patients with other known neuroendocrine tumor
types for staging, response-assessment, identifying the primary tumor
site(s) in patients with known metastatic disease, and for off-treatment
surveillance. This article will highlight both the advantages and
limitations of \textsuperscript{68}Ga-DOTATATE imaging as it compares to
other functional and anatomic imaging techniques. With emphasis on the
complementary information, as shown in three specific index cases, we
propose a diagnostic algorithm to aid in selecting the appropriate
functional imaging technique in patients with PPGL.

\textbf{Methods}

For this retrospective case series review, the requirement for patient
informed consent was waived by the Boston Children's Hospital
Institutional Review Board.

Diagnostic CT and MRI examinations were performed using standard
techniques; MRI was performed at 3T.

PET/CT exams were performed using a Siemens Biograph mCT Flow PET/CT
scanner equipped with 64 slice CT. Low dose attenuation correction CT
images utilized CARE kV dose reduction and CARE Dose 4D tube current
modulation. PET images were acquired in 3D mode with dead time
correction, decay correction, scatter correction, and time of flight and
reconstructed with standard iterative reconstruction parameters at 3 mm
increments.

\textsuperscript{18}F-FDG: 5.55 MBq/kg (0.15 mCi/kg, 10 mCi maximum) was
administered 60 min prior to imaging.

\textsuperscript{68}Ga-DOTATATE: 2.74 MBq/kg (0.074 mCi/kg; 5.4 mCi
maximum) was administered 60 min prior to imaging.

\textsuperscript{123}I-MIBG scintigraphy was performed using a Siemens
Intevo SPECT/CT equipped with medium energy collimators and 16 slice CT.
Low dose attenuation correction SPECT/CT images were acquired at 80-100
kVp using CARE Dose 4D tube current modulation. SPECT images were
acquired in continuous non-circular mode with 2x360\selectlanguage{ngerman}° camera head
rotations at 15sec per stop equivalent and reconstructed with FLASH 3D
iterative reconstruction per manufacturer recommendations. Static planar
images were acquired in anterior/posterior and lateral projections.

\textsuperscript{123}I-MIBG: 5.18 MBq/kg (0.14 mCi/kg, 10 mCi maximum)
was administered 24hrs prior to imaging.

\textbf{CASE SERIES}

\textbf{Case 1: Metastatic paraganglioma without an identified
pathogenic germline variant.}

A 12-year-old male presented with weight loss of 4.5 pounds over 18
months, loss of appetite, intermittent vomiting, constipation, and
fatigue. CT of the chest, abdomen and pelvis showed a heterogeneous left
paraspinous/retroperitoneal mass with multiple pulmonary nodules that
were suspicious for metastases; both adrenals were normal. A right
ileo-ileal intussusception was also present and initial differential
considerations included inflammatory myofibroblastic tumor (IMT),
sarcoma, lymphoma, and neuroblastoma. Biopsy yielded a broad
differential, with low-grade spindle-cell sarcoma and extra-intestinal
GIST variant among the considerations.
Staging\textsuperscript{18}F-FDG-PET/CT (Fig. 1A-D) showed low-level
uptake in the abdominal mass and the pulmonary nodules, but no other
sites of FDG-avid disease were detected. Upon surgical resection, the
mass appeared to be paraspinous in orgin, extending into the
retroperitoneum. Pathology was consistent with paraganglioma, with cells
positive for chromogranin, synaptophysin, INSM1, CH56, GATA3, and S100,
with evidence of multifocal vascular invasion and positive resection
margins. Germline pathogenic variants in genes typically associated with
hereditary paraganglioma were not identified.
\textsuperscript{68}Ga-DOTATATE PET was performed to evaluate for
metastatic disease and revealed widespread somatostatin
receptor-expressing disease throughout the axial and appendicular
skeleton, lungs, and right hepatic lobe (Fig 1E). The hepatic lesions
were seen by MRI, but were not initially evident by CT. Based on the
extensive burden of systemic disease,\textsuperscript{131}I-MIBG therapy
was a consideration. Staging\textsuperscript{123}I-MIBG scintigraphy
(Fig. 1F) demonstrated a similar distribution of disease compared to
the\textsuperscript{68}Ga-DOTATATE PET, with numerous axial and
appendicular lesions, although there were far fewer MIBG-avid lesions
(no MIBG uptake seen in the ribs, humeri, left scapula, and tibiae) in
comparison with the \textsuperscript{68}Ga-DOTATATE PET/CT. Known liver
lesions detected by DOTATATE PET were also not well visualized on
the\textsuperscript{123}I-MIBG study, due to background physiologic
hepatic MIBG uptake. These studies were all performed within 21 days of
each other, and \textsuperscript{68}Ga-DOTATATE PET showed both
increased sensitivity and specificity for detecting disease.

\textbf{Case 2: Cancer predisposition with germline pathogenic variant
in \emph{SDHC} and co-existing GIST and paraganglioma.}

A 17-year-old male with known germline pathogenic variant in
\emph{SDHC}and metastatic GIST with lesions in the liver, peritoneum,
and lungs was being treated with the tyrosine kinase inhibitor
regorafenib. Biochemical monitoring showed progressive elevation in
chromogranin A over a 12-month period, from 46 ng/mL to 505
ng/dL.\textsuperscript{68}Ga-DOTATATE PET revealed an intensely avid
lesion in the porta hepatis (Fig. 2), histologically confirmed to
represent paraganglioma. This DOTATATE-avid paraganglioma was also FDG
avid, but there were multiple FDG-avid metastatic GIST lesions
remarkably negative by \textsuperscript{68}Ga-DOTATATE PET, indicating
two functionally distinct tumor types co-existing in the same patient.
The co-existence of two tumor types in the same patient would be unusual
in most circumstances, but not in patients with underlying CPS.
Complicating the discovery of a new paraganglioma was the heterogeneous
pattern of\textsuperscript{18}F-FDG uptake in the GIST lesions,
resulting both from prior RF ablations and ongoing treatment with
tyrosine kinase inhibitors, which are known to alter the pattern of
FDG-uptake in GIST lesions \textsuperscript{14,15}.

\textbf{Case 3: Cancer predisposition associated with polycythemia and
multiple functional paragangliomas (Pacak-Zhuang syndrome).}

A 16-year-old female with somatic mosaicism for an activating mutation
in the \emph{EPAS1} (\emph{HIF2A} ) gene leading to polycythemia and
paraganglioma (Pacak-Zhuang syndrome) was found to have a right
suprarenal mass and 3 additional retroperitoneal masses. These were
resected and identified as paragangliomas\textsuperscript{16}.
Surveillance whole-body MRI (wbMRI) obtained almost 2 years later
identified a 1.5 cm left suprarenal mass. Plasma normetanephrine levels
were slowly rising, and re-staging \textsuperscript{18}F-FDG PET
demonstrated an FDG-avid suprarenal mass, as well as additional small
FDG-avid retroperitoneal nodules concerning for paragangliomas which had
not been identified on the earlier MRI exams (Fig.
3A-D).\textsuperscript{18}F-FDG PET/CT obtained 6 months later for
continued clinical progression (worsening hypertension along with
progressive elevations in normetanephrine and chromogranin A levels) was
limited secondary to a marked increase in hypermetabolic brown fat
activity that presumably resulted from the elevated serum catecholamines
(Fig. 3E), a phenomenon that has been described in adult PGL patients
with elevated catecholamines\textsuperscript{17}. This degree of intense
brown fat uptake, in addition to obscuring primary tumor sites along the
sympathetic chain, has a ``sink effect'', with the marked increase in
FDG uptake in brown fat FDG uptake limiting availability of tracer for
detecting disease elsewhere. Tracers targeting somatostatin receptors
are unaffected by elevated catecholamines and a
subsequent\textsuperscript{68}Ga-DOTATATE PET, performed 2 weeks after
the patient started systemic targeted therapy\textsuperscript{16},
clearly demonstrated the left suprarenal lesion and the para-aortic
paraganglioma (Fig. 3F-K), with no other sites of disease seen.

\textbf{DISCUSSION}

Nuclear medicine studies have become essential when evaluating pediatric
neuroendocrine tumors. They provide relatively specific anatomic
localization of both primary and metastatic lesions, insight into tumor
function, and inform treatment decisions. These examinations are
particularly useful in cancer predisposition syndromes where
neuroendocrine tumors, such as PPGL are component
tumors\textsuperscript{18}. These conditions are driven by germline
pathogenic variants in a number of different genes, including the genes
encoding succinate dehydrogenase subunits (\emph{SDHx} genes), and
others such as\emph{SDHAF2} , \emph{FH} , \emph{MAX} , \emph{NF1} ,
\emph{RET} ,\emph{TMEM127} , \emph{MEN2} , and \emph{VHL} . Other tumor
predisposition syndromes exist, such as the case presented here in which
an\emph{EPAS1} activating mutation resulted in development of multiple
paragangliomas. Depending on the underlying genotype patients may also
be predisposed to other tumors. For individuals with pathogenic variants
in the \emph{SDH genes} , these include gastrointestinal stromal tumors,
renal cell carcinoma, and others\textsuperscript{19}. Patients
with\emph{EPAS1} mutations (encoding for the transcriptional regulator
HIF2-alpha) are not only at risk for pheochromocytoma and paraganglioma,
but can also develop somatostatinomas, vascular malformations, and
ocular abnormalities\textsuperscript{18,19}. Patients with pathogenic
variants in the von Hippel Lindau (\emph{VHL} ) tumor suppressor gene
are predisposed not only to paragangliomas, but also to central nervous
system hemangioblastoma, clear cell renal cell carcinoma and
others\textsuperscript{15}. In these settings, it is especially
important to detect new lesions early and to be able to differentiate
between possible tumor types in a patient at risk for synchronous or
metachronous co-existing malignancies.

Functional imaging options to evaluate pheochromocytoma and
paraganglioma include \textsuperscript{18}F-FDG
PET/CT,\textsuperscript{68}Ga-DOTATATE PET/CT, and
\textsuperscript{123}I-MIBG scintigraphy, and each exam is best suited
for evaluation of certain types of disease. \textsuperscript{18}F-FDG
PET/CT is very sensitive and well suited to detecting small,
hypermetabolic lesions, especially when structural imaging findings are
subtle and/or non-specific.\textsuperscript{123}I-MIBG scintigraphy is
very specific in its targeting of tumors expressing the norepinephrine
transport receptor, however, in patients with PPGL,
\textsuperscript{68}Ga-DOTATATE PET has been shown to be more sensitive
in disease detection\textsuperscript{20-22}. This is partially
attributable to inherently better spatial resolution of PET/CT compared
to SPECT/CT, which was shown here in Figure 1, and potentially to
differences in norepinephrine transporter expression as compared to
somatostatin receptor expression. \textsuperscript{68}Ga-DOTATATE binds
to somatostatin receptor type 2 which has a high level of expression in
well-differentiated paragangliomas and pheochromocytomas and most
SDHB-deficient tumors \textsuperscript{17,23,24}, while
decreased\textsuperscript{123}I-MIBG uptake may be related to an
underlying genetic mutation, usually associated with SDHB
\textsuperscript{23}. In one study, up to 50\% of patients with
metastatic PPGL, especially those with pathogenic variants in
\emph{SDHB} , reportedly lacked norepinephrine transporter expression
and derived no benefit from\textsuperscript{131}I-MIBG
therapy\textsuperscript{25}, emphasizing the importance of establishing
tumor MIBG avidity when considering\textsuperscript{131}I-MIBG therapy.
It is also important to note that non-MIBG-avid PPGL are more aggressive
than their\textsuperscript{123}I-MIBG avid counterparts, and are
associated with increased malignancy rates and increased rates of
metastasis\textsuperscript{17,23-28}.

Despite the inherently lower sensitivity of MIBG scintigraphy, along
with physiologic uptake of MIBG in liver and adrenal glands potentially
obscuring detection of small adrenal lesions and hepatic
metastases,\textsuperscript{131}I-MIBG is the only targeted radiotherapy
option currently approved for treating metastatic pediatric
neuroendocrine tumors. \textsuperscript{177}Lu-DOTATATE (Lutathera,
theranostic partner to \textsuperscript{68}Ga-DOTATATE) is not yet
approved for pediatric use despite success in treating metastatic
neuroendocrine tumors in adults\textsuperscript{29}. Current
recommendations for PPGL are\textsuperscript{68}Ga-DOTATATE PET/CT for
staging and follow-up, with\textsuperscript{123}I-MIBG reserved for
evaluating patients prior to potential \textsuperscript{131}I-MIBG
therapy\textsuperscript{30}.

\textsuperscript{68}Ga-DOTATATE PET/CT and \textsuperscript{18}F-FDG
PET/CT have similar rates of detection for paragangliomas and
pheochromocytomas with reported sensitivities of
\textasciitilde{}72-100\% and \textasciitilde{}66-78\%, respectively,
although \textsuperscript{68}Ga-DOTATATE has greater specificity and
comparatively better contrast between lesions and background
tissues\textsuperscript{17,22}. However, as presented here, these two
imaging techniques may be complementary to one another, particularly
among patients with CPS in whom histologically and functionally distinct
tumors are present (Case 2). As shown in Case 2, the identification of a
new neuroendocrine tumor that was separate and distinct from known
metastatic GIST disease was essential and led to surgical resection.
This treatment course may not have been considered for a new GIST lesion
in a patient with known metastatic disease, emphasizing how distinct
tumor phenotypes, based on differences in tumor glucose metabolism and
expression of somatostatin receptors, could be exploited by functional
imaging and ultimately impact treatment.

PPGL also differ from other neuroendocrine tumors in that
well-differentiated tumors are not necessarily hypometabolic, and in
fact, even benign tumors may show marked FDG
avidity\textsuperscript{22,28,31}. Several authors have noted
that\textsuperscript{18}F-FDG SUV values were higher in PGLs harboring
mutations in SDHx and VHL when compared to the PGL associated with NF-1
and MEN-2A\textsuperscript{28,32,33}, and have speculated that this may
be the result of a genetically driven Warburg effect (aerobic
glycolysis) in which SDHx or VHL inactivation results in a pseudohypoxic
state, leading to increased glucose utilization (and FDG uptake) in this
subset of PPGL. The pathways leading to enhanced glucose utilization
(and FDG uptake) in PPGL are like to involve other mediators, such as
HIF1A\textsuperscript{2,34}, emphasizing the importance of considering a
patient's genetic background when choosing a particular radiotracer and
interpreting the functional imaging results.

Historically, \textsuperscript{18}F-FDG PET had been the imaging
modality of choice for evaluation of pheochromocytomas and
paragangliomas in adults, with multiple studies supporting this imaging
method's effectiveness over other imaging techniques. As shown in Case 3
(Figure 3), the increased sensitivity of \textsuperscript{18}F-FDG PET
allowed identification of sub-cm FDG-avid lesions that were not evident
by MRI. However, this same case highlighted the limitations of FDG PET
imaging for patients in whom elevated levels of catecholamine secretion
from metabolically active paragangliomas may lead to non-specific FDG
uptake at sites of hypermetabolic brown fat activity, decreasing both
the sensitivity for detecting other sites of disease and the specificity
for characterizing known sites of tumor. Interestingly, not all patients
with elevated catecholamine levels show increased brown fat
uptake\textsuperscript{17}, suggesting that PPGL tumor heterogeneity may
be the result of an evolving molecular taxonomy tumor with PPGL disease
clusters defined by unique
molecular/imaging/clinical/biochemical/imaging
phenotypes\textsuperscript{2,35}, which could include the degree to
which hypermetabolic brown adipose tissue responds to catecholamine
excess and accumulates FDG.

More recently, studies have shown superiority
of\textsuperscript{68}Ga-DOTATATE PET over \textsuperscript{18}F-FDG PET
in detecting \emph{SDHB} -related metastatic
paragangliomas/pheochromocytomas \textsuperscript{17,23,24,28}. In fact,
Janssen et al. showed that \textsuperscript{68}Ga-DOTATATE PET was more
effective in detecting \emph{SHDB} -related paragangliomas
than\textsuperscript{18}F-FDG, \textsuperscript{18}F-fluorodopamine
(\textsuperscript{18}F-FDA), \textsuperscript{18}F-
fluorodihydroxyphenylalanine (\textsuperscript{18}F-FDOPA), and anatomic
imaging with either CT or MRI\textsuperscript{23}. Advantages
to\textsuperscript{68}Ga-DOTATATE PET imaging also include a relatively
short uptake time of 60 minutes, which is similar
to\textsuperscript{18}F-FDG PET but shorter
than\textsuperscript{123}I-MIBG (18-24 hour delay between injection and
imaging). \textsuperscript{68}Ga-DOTATATE PET/CT requires 20-45 minutes
of imaging, which is similar to FDG PET/CT but dramatically shorter than
typical MIBG imaging protocols which include both static planar and
SPECT imaging. In addition to the shorter exam times which allow younger
patients to be imaged without sedation, the effective radiation dose
from \textsuperscript{68}Ga-DOTATATE PET is also less than
both\textsuperscript{123}I-MIBG and \textsuperscript{18}F-FDG, which
remains an important consideration in a pediatric population often with
cancer predisposition syndromes and protracted disease courses
necessitating multiple serial evaluations\textsuperscript{32,36}.

For these reasons, our imaging algorithm (Figure 4)
includes\textsuperscript{68}Ga-DOTATATE PET as the initial functional
imaging technique of choice for evaluation of most subtypes of
pheochromocytoma and paraganglioma, with \textsuperscript{18}F-FDG PET
and\textsuperscript{123}I-MIBG SPECT/CT reserved for characterizing
DOTATATE-negative lesions and for evaluating patients for
possible\textsuperscript{131}I-MIBG therapy. If
\textsuperscript{68}Ga-DOTATATE PET is not readily available,
\textsuperscript{18}F-FDG PET is the functional imaging study of choice.

\textbf{CONCLUSION}

We present here three unique clinical cases, each of which highlights
both advantages and limitations to the use
of\textsuperscript{68}Ga-DOTATATE PET, \textsuperscript{18}F-FDG PET,
and\textsuperscript{123}I-MIBG SPECT/CT in the evaluation of patients
with PPGL. In these patients, who frequently have complex clinical
manifestations of their disease, no single imaging technique can be
forwarded as the single ``best test''. Rather, as the cases shown here
emphasize, different clinical considerations necessitate a customized
choice of functional imaging techniques. The proposed algorithm may
serve as a guideline for physicians when determining which of the
available imaging selections is best suited to an individual patient's
care.

REFERENCES

1. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and
paraganglioma: an endocrine society clinical practice guideline. \emph{J
Clin Endocrinol Metab.} 2014;99(6):1915-1942.

2. Crona J, Taieb D, Pacak K. New Perspectives on Pheochromocytoma and
Paraganglioma: Toward a Molecular Classification. \emph{Endocr
Rev.}2017;38(6):489-515.

3. NETSPOT (kit for the preparation of gallium Ga 68 dotatate
injection), for intravenous use Initial U.S. Approval: 2016. United
States Food and Drug Administration. Online Document. Published June,
2016. Accessed July 24, 2021. .
https://www.accessdata.fda.gov/drugsatfda\_docs/label/2016/208547s000lbl.pdf

4. McElroy KM, Binkovitz LA, Trout AT, et al. Pediatric applications of
Dotatate: early diagnostic and therapeutic experience. \emph{Pediatr
Radiol.} 2020;50(7):882-897.

5. Haug AR, Cindea-Drimus R, Auernhammer CJ, et al. Neuroendocrine tumor
recurrence: diagnosis with 68Ga-DOTATATE PET/CT.
\emph{Radiology.}2014;270(2):517-525.

6. Hofman MS, Kong G, Neels OC, Eu P, Hong E, Hicks RJ. High management
impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and
other somatostatin expressing tumours. \emph{J Med Imaging Radiat
Oncol.} 2012;56(1):40-47.

7. Srirajaskanthan R, Kayani I, Quigley AM, Soh J, Caplin ME, Bomanji J.
The role of 68Ga-DOTATATE PET in patients with neuroendocrine tumors and
negative or equivocal findings on 111In-DTPA-octreotide
scintigraphy.\emph{J Nucl Med.} 2010;51(6):875-882.

8. Win Z, Al-Nahhas A, Towey D, et al. 68Ga-DOTATATE PET in
neuroectodermal tumours: first experience. \emph{Nucl Med
Commun.}2007;28(5):359-363.

9. Else T, Greenberg S, Fishbein L. Hereditary
Paraganglioma-Pheochromocytoma Syndromes. In: Adam MP, Ardinger HH,
Pagon RA, et al., eds. \emph{GeneReviews((R)).} Seattle (WA)1993.

10. Panagiotidis E, Alshammari A, Michopoulou S, et al. Comparison of
the Impact of 68Ga-DOTATATE and 18F-FDG PET/CT on Clinical Management in
Patients with Neuroendocrine Tumors. \emph{J Nucl Med.}2017;58(1):91-96.

11. Garin E, Le Jeune F, Devillers A, et al. Predictive value of 18F-FDG
PET and somatostatin receptor scintigraphy in patients with metastatic
endocrine tumors. \emph{J Nucl Med.} 2009;50(6):858-864.

12. Gonias S, Goldsby R, Matthay KK, et al. Phase II study of high-dose
{[}131I{]}metaiodobenzylguanidine therapy for patients with metastatic
pheochromocytoma and paraganglioma. \emph{J Clin
Oncol.}2009;27(25):4162-4168.

13. Pryma DA, Chin BB, Noto RB, et al. Efficacy and Safety of
High-Specific-Activity (131)I-MIBG Therapy in Patients with Advanced
Pheochromocytoma or Paraganglioma. \emph{J Nucl Med.}2019;60(5):623-630.

14. Hong X, Choi H, Loyer EM, Benjamin RS, Trent JC, Charnsangavej C.
Gastrointestinal stromal tumor: role of CT in diagnosis and in response
evaluation and surveillance after treatment with
imatinib.\emph{Radiographics.} 2006;26(2):481-495.

15. Levy AD, Quiles AM, Miettinen M, Sobin LH. Gastrointestinal
schwannomas: CT features with clinicopathologic correlation. \emph{AJR
Am J Roentgenol.} 2005;184(3):797-802.

16. Kamihara J, Hamilton KV, Pollard JA, et al. Use of belzutifan, a
potent HIF2a inhibitor, in a pediatric patient with Pacak-Zhuang
syndrome. \emph{NEJM.} 2021;in press.

17. Chang CA, Pattison DA, Tothill RW, et al. (68)Ga-DOTATATE and
(18)F-FDG PET/CT in Paraganglioma and Pheochromocytoma: utility,
patterns and heterogeneity. \emph{Cancer Imaging.} 2016;16(1):22.

18. Erlic Z, Rybicki L, Peczkowska M, et al. Clinical predictors and
algorithm for the genetic diagnosis of pheochromocytoma
patients.\emph{Clin Cancer Res.} 2009;15(20):6378-6385.

19. Bardella C, Pollard PJ, Tomlinson I. SDH mutations in
cancer.\emph{Biochim Biophys Acta.} 2011;1807(11):1432-1443.

20. Kroiss A, Shulkin BL, Uprimny C, et al. (68)Ga-DOTATOC PET/CT
provides accurate tumour extent in patients with extraadrenal
paraganglioma compared to (123)I-MIBG SPECT/CT. \emph{Eur J Nucl Med Mol
Imaging.} 2015;42(1):33-41.

21. Maurice JB, Troke R, Win Z, et al. A comparison of the performance
of (6)(8)Ga-DOTATATE PET/CT and (1)(2)(3)I-MIBG SPECT in the diagnosis
and follow-up of phaeochromocytoma and paraganglioma. \emph{Eur J Nucl
Med Mol Imaging.} 2012;39(8):1266-1270.

22. Mojtahedi A, Thamake S, Tworowska I, Ranganathan D, Delpassand ES.
The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of
neuroendocrine tumors compared to current FDA approved imaging
modalities: a review of literature. \emph{Am J Nucl Med Mol
Imaging.}2014;4(5):426-434.

23. Janssen I, Blanchet EM, Adams K, et al. Superiority of
{[}68Ga{]}-DOTATATE PET/CT to Other Functional Imaging Modalities in the
Localization of SDHB-Associated Metastatic Pheochromocytoma and
Paraganglioma. \emph{Clin Cancer Res.} 2015;21(17):3888-3895.

24. Janssen I, Chen CC, Millo CM, et al. PET/CT comparing
(68)Ga-DOTATATE and other radiopharmaceuticals and in comparison with
CT/MRI for the localization of sporadic metastatic pheochromocytoma and
paraganglioma. \emph{Eur J Nucl Med Mol Imaging.} 2016;43(10):1784-1791.

25. Fonte JS, Robles JF, Chen CC, et al. False-negative (1)(2)(3)I-MIBG
SPECT is most commonly found in SDHB-related pheochromocytoma or
paraganglioma with high frequency to develop metastatic
disease.\emph{Endocr Relat Cancer.} 2012;19(1):83-93.

26. Milardovic R, Corssmit EP, Stokkel M. Value of 123I-MIBG
Scintigraphy in Paraganglioma.
\emph{Neuroendocrinology.}2010;91(1):94-100.

27. Swensen SJ, Brown ML, Sheps SG, et al. Use of 131I-MIBG scintigraphy
in the evaluation of suspected pheochromocytoma. \emph{Mayo Clin
Proc.}1985;60(5):299-304.

28. Taieb D, Neumann H, Rubello D, Al-Nahhas A, Guillet B, Hindie E.
Modern nuclear imaging for paragangliomas: beyond SPECT. \emph{J Nucl
Med.} 2012;53(2):264-274.

29. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of
(177)Lu-Dotatate for Midgut Neuroendocrine Tumors. \emph{N Engl J
Med.}2017;376(2):125-135.

30. Ambrosini V, Kunikowska J, Baudin E, et al. Consensus on molecular
imaging and theranostics in neuroendocrine neoplasms. \emph{Eur J
Cancer.} 2021;146:56-73.

31. Subramaniam RM, Bradshaw ML, Lewis K, Pinho D, Shah C, Walker RC.
ACR Practice Parameter for the Performance of Gallium-68 DOTATATE PET/CT
for Neuroendocrine Tumors. \emph{Clin Nucl Med.} 2018;43(12):899-908.

32. Swami M. Hypoxia: The HIF2alpha puzzle. \emph{Nat Rev
Cancer.}2010;10(9):603.

33. Tarade D, Robinson CM, Lee JE, Ohh M. HIF-2alpha-pVHL complex
reveals broad genotype-phenotype correlations in HIF-2alpha-driven
disease. \emph{Nat Commun.} 2018;9(1):3359.

34. Hayashi Y, Yokota A, Harada H, Huang G.
Hypoxia/pseudohypoxia-mediated activation of hypoxia-inducible
factor-1alpha in cancer. \emph{Cancer Sci.} 2019;110(5):1510-1517.

35. Fishbein L, Leshchiner I, Walter V, et al. Comprehensive Molecular
Characterization of Pheochromocytoma and Paraganglioma. \emph{Cancer
Cell.} 2017;31(2):181-193.

36. Walker RC, Smith GT, Liu E, Moore B, Clanton J, Stabin M. Measured
human dosimetry of 68Ga-DOTATATE. \emph{J Nucl Med.} 2013;54(6):855-860.

FIGURE LEGENDS

\textbf{Figure 1} : \textbf{Metastatic paraganglioma.} Fused axial PET
and CT images from \textsuperscript{18}F-FDG PET/CT at diagnosis (A)
demonstrate a large heterogeneous retroperitoneal mass (circle) with
central photopenia and hypoattenuation suggestive of necrosis (*).
Multiple lung nodules were seen by CT (B, white arrow), the largest of
which were FDG avid (C, black arrow), consistent with metastatic
disease. Coronal MIP image shows no FDG avid disease elsewhere (D).
Coronal MIP image from \textsuperscript{68}Ga-DOTATATE PET/CT (E) shows
widespread skeletal metastatic disease (red arrows), none of which was
present on the \textsuperscript{18}F-FDG PET/CT (D). Coronal static
planar image from \textsuperscript{123}I-MIBG scan (F) revealed
MIBG-avid metastatic disease in the calvarium, axial, and appendicular
skeleton, although the image quality is inferior to the DOTATATE PET/CT
and the overall disease burden is underestimated
by\textsuperscript{123}I-MIBG. Although some lesions not seen by planar
imaging were discernable by SPECT/CT, many lesions seen
by\textsuperscript{68}Ga-DOTATATE PET, for example in the liver, ribs,
humeral shafts, femoral shafts, and tibiae (arrows) were not evident
by\textsuperscript{123}I-MIBG scintigraphy.

\textbf{Figure 2:} \textbf{Cancer predisposition with SDHC germline
mutation and co-existing GIST and
paraganglioma.}\textsuperscript{18}F-FDG PET MIP images (A) demonstrates
diffuse metastatic disease from the patient's known gastrointestinal
stromal tumor. Axial contrast-enhanced CT and \textsuperscript{18}F-FDG
PET images (B, C) highlight numerous hepatic masses with varying degrees
of\textsuperscript{18}F-FDG avidity (red arrows), complicating the
detection of new lesions with a different histology. Axial non-contrast
CT and \textsuperscript{68}Ga-DOTATATE PET images (E, F) reveal an
intensely avid mass in the porta hepatis (circle), consistent with
paraganglioma. The adjacent lesions that had been FDG-avid on the
earlier \textsuperscript{18}F-FDG PET/CT (white arrow) showed no
DOTATATE uptake, indicating co-existing GIST and paraganglioma in the
same patient. The paraganglioma was resected surgically; the patient
continues on medical therapy for his metastatic GIST.

The low attenuation region near the periphery that has neither FDG nor
DOTATATE uptake (*) represents a site of prior RF ablation.

\textbf{Figure 3: Cancer predisposition associated with polycythemia and
multiple functional paragangliomas (Pacak-Zhuang
syndrome).}\textsuperscript{18}F-FDG PET/CT was obtained for restaging
after surveillance wbMRI revealed new sites of disease.
Coronal\textsuperscript{18}F-FDG PET MIP image (A) and axial fused
PET/CT images (D) from \textsuperscript{18}F-FDG PET/CT, demonstrate
increased\textsuperscript{18}F-FDG uptake in the left suprarenal mass
(B, arrow) seen by MRI. Multiple additional foci of FDG uptake, for
example in an aortocaval lesion (A, D: circle), were also concerning for
paraganglioma, and even in retrospect were difficult to convincingly see
by MRI (C).

\textsuperscript{18}F-FDG PET/CT obtained six months later when serum
catecholamine and chromogranin A levels were continuing to rise, was
markedly limited for evaluation of metastatic lesions, secondary to
intensely FDG-avid hypermetabolic brown adipose tissue uptake, best
illustrated on the coronal MIP image (E) from the FDG PET/CT.

Given the patient's hyper-catecholamine secreting state resulting from
her underlying \emph{HIF2A} activating mutation, she was started on
molecularly targeted therapy. \textsuperscript{68}Ga-DOTATATE PET/CT,
obtained just 17 days after drug initiation (F), showed no background
brown fat uptake and demonstrated the suprarenal lesion (arrow) and
aorto-caval lesion (circle), with the suprarenal lesion having already
decreased slightly in size in response to targeted therapy. She
continues on treatment and has been monitored by surveillance MRI
and\textsuperscript{68}Ga-DOTATATE PET/CT.

\textbf{Figure 4:} \textbf{Proposed algorithm
for\textsuperscript{68}Ga-DOTATATE imaging children with known PPGL or
PPGL predisposition syndrome.}\selectlanguage{english}
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