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 tumors18. These conditions are driven by germline pathogenic
variants in a number of different genes, including the genes encoding
succinate dehydrogenase subunits (SDHx genes), and others such asSDHAF2 , FH , MAX , NF1 , RET ,TMEM127 , MEN2 , and VHL . Other tumor predisposition
syndromes exist, such as the case presented here in which anEPAS1 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 SDH genes , these include gastrointestinal stromal tumors,
renal cell carcinoma, and others19. Patients withEPAS1 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 abnormalities18,19. Patients with pathogenic
variants in the von Hippel Lindau (VHL ) tumor suppressor gene are
predisposed not only to paragangliomas, but also to central nervous
system hemangioblastoma, clear cell renal cell carcinoma and
others15. 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 18F-FDG PET/CT,68Ga-DOTATATE PET/CT, and 123I-MIBG
scintigraphy, and each exam is best suited for evaluation of certain
types of disease. 18F-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.123I-MIBG scintigraphy is very specific in its
targeting of tumors expressing the norepinephrine transport receptor,
however, in patients with PPGL, 68Ga-DOTATATE PET has
been shown to be more sensitive in disease
detection20-22. 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. 68Ga-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 17,23,24, while decreased123I-MIBG uptake may be related to an underlying
genetic mutation, usually associated with SDHB 23. In
one study, up to 50% of patients with metastatic PPGL, especially those
with pathogenic variants in SDHB , reportedly lacked
norepinephrine transporter expression and derived no benefit from131I-MIBG therapy25, emphasizing the
importance of establishing tumor MIBG avidity when considering131I-MIBG therapy. It is also important to note that
non-MIBG-avid PPGL are more aggressive than their123I-MIBG avid counterparts, and are associated with
increased malignancy rates and increased rates of metastasis17,23-28.
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,131I-MIBG is the only targeted radiotherapy option
currently approved for treating metastatic pediatric neuroendocrine
tumors. 177Lu-DOTATATE (Lutathera, theranostic partner
to 68Ga-DOTATATE) is not yet approved for pediatric
use despite success in treating metastatic neuroendocrine tumors in
adults29. Current recommendations for PPGL are68Ga-DOTATATE PET/CT for staging and follow-up, with123I-MIBG reserved for evaluating patients prior to
potential 131I-MIBG therapy30.
68Ga-DOTATATE PET/CT and 18F-FDG
PET/CT have similar rates of detection for paragangliomas and
pheochromocytomas with reported sensitivities of
~72-100% and ~66-78%, respectively,
although 68Ga-DOTATATE has greater specificity and
comparatively better contrast between lesions and background
tissues17,22. 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
avidity22,28,31. Several authors have noted that18F-FDG SUV values were higher in PGLs harboring
mutations in SDHx and VHL when compared to the PGL associated with NF-1
and MEN-2A28,32,33, 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
HIF1A2,34, emphasizing the importance of considering a
patient’s genetic background when choosing a particular radiotracer and
interpreting the functional imaging results.
Historically, 18F-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 18F-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 uptake17, 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 phenotypes2,35, which could include the degree to which
hypermetabolic brown adipose tissue responds to catecholamine excess and
accumulates FDG.
More recently, studies have shown superiority of68Ga-DOTATATE PET over 18F-FDG PET
in detecting SDHB -related metastatic
paragangliomas/pheochromocytomas 17,23,24,28. In fact,
Janssen et al. showed that 68Ga-DOTATATE PET was more
effective in detecting SHDB -related paragangliomas than18F-FDG, 18F-fluorodopamine
(18F-FDA), 18F-
fluorodihydroxyphenylalanine (18F-FDOPA), and anatomic
imaging with either CT or MRI23. Advantages to68Ga-DOTATATE PET imaging also include a relatively
short uptake time of 60 minutes, which is similar to18F-FDG PET but shorter than123I-MIBG (18-24 hour delay between injection and
imaging). 68Ga-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 68Ga-DOTATATE PET is also less than both123I-MIBG and 18F-FDG, which remains
an important consideration in a pediatric population often with cancer
predisposition syndromes and protracted disease courses necessitating
multiple serial evaluations32,36.
For these reasons, our imaging algorithm (Figure 4) includes68Ga-DOTATATE PET as the initial functional imaging
technique of choice for evaluation of most subtypes of pheochromocytoma
and paraganglioma, with 18F-FDG PET and123I-MIBG SPECT/CT reserved for characterizing
DOTATATE-negative lesions and for evaluating patients for possible131I-MIBG therapy. If 68Ga-DOTATATE
PET is not readily available, 18F-FDG PET is the
functional imaging study of choice.