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 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 123I-MIBG scintigraphy, in which
the norepinephrine analog MIBG is taken up by cells expressing the
norepinephrine transport receptor, and 18F-FDG PET/CT,
in which the glucose analogue 18F-FDG is transported
into and trapped in metabolically active cells. Well-differentiated
neuroendocrine tumors such as PPGL also express somatostatin receptors
and 111In-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 of68Ga-DOTATATE for localization of somatostatin
receptor positive neuroendocrine tumors in adult and pediatric
patients3, 111In-pentetreotide
scintigraphy has largely been replaced by68Ga-DOTATATE PET/CT based on improved diagnostic
accuracy, shorter imaging protocol, and lower radiation
dose5-8.
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 PPGL9, 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 68Ga-DOTATATE PET/CT,18F-FDG PET/CT, and 123I-MIBG
scintigraphy, each of which have advantages and limitations. For
example, while 68Ga-DOTATATE PET/CT is reported to
have higher sensitivity for detection of well-differentiated, less
aggressive NETs, there is evidence to suggest
that 18F-FDG PET/CT may be preferable for more
aggressive, less well-differentiated tumors 10, with
other reports suggesting an association between
higher 18F-FDG uptake and worse outcome, even in
patients with well-differentiated or low-grade
tumors11. 123I-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, 123I-MIBG
may still be used to establish MIBG avidity in individuals with
metastatic disease in whom treatment with 131I-MIBG is
a consideration 12,13. This latter point is critical
in pediatrics since 131I-MIBG has US regulatory
approval for therapeutic use in children while somatostatin-targeted
therapies such as 177Lu-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 of68Ga-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 68Ga-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.