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.