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.