Renaissance of ¹⁸F-FDG Positron Emission Tomography in the Imaging of Pheochromocytoma/Paraganglioma

The synthesis of 2-[18F]-fluoro-2-deoxy-D-glucose (¹⁸F-FDG) was a major scientific discovery after years of work to develop chemically synthesized fluorosugars. FDG was first synthesized in the Czech Republic by Pacák and Černý in 1968 (1). Ten years later, FDG was prepared in a positron-emitting form with the isotope ¹⁸F by Ido et al (2) at the Brookhaven National Laboratory (Upton, NY) and used for positron emission tomography (PET) imaging. Clinical PET imaging was introduced as a diagnostic methodology in the mid-1970s and was soon considered irreplaceable, especially in the imaging of oncology patients.

Most cancer cells have a voracious appetite for glucose; thus, they readily take up ¹⁸F-FDG and can be easily visualized via PET. This feature is related to several mechanisms in cancer cells, including a shift in cellular metabolism from respiration to glycolysis, despite the presence of adequate oxygen (aerobic glycolysis). This phenomenon is known as the Warburg effect and is well known to be present in some pheochromocytoma (PHEO)/paraganglioma (PGL). Nevertheless, the use of PET, particularly ¹⁸F-FDG PET, for localizing PHEO/PGL was delayed until 1999, when the first large study was published (3). The initial study included PHEO/PGL regardless of their genetic status, leading to somewhat disappointing results. At the same time, the scientific effort focused on developing radiopharmaceuticals that would be very specific for localizing PHEO/PGL. This priority was not surprising because PHEO/PGL are considered nearly ideal for localization by functional imaging. This is based on the fact that PHEO/PGL cells harbor several important transporters; the most specific ones are the cell membrane norepinephrine transporter (NET), which mediates cellular reuptake of norepinephrine/dopamine, and the cytosolic vesicular monoamine transporters, which sequester cytoplasmic dopamine into synaptic vesicles. Indeed, the radiopharmaceutical ¹²³I/¹³¹I-metaiodobenzylguanidine (¹²³/¹³¹I-MIBG), which targets the NET and vesicular monoamine transporters, was initially introduced in 1981 with excellent results in PHEO/PGL (4). Moreover, ¹³¹I-MIBG became the best radiotherapeutic option for metastatic PHEO/PGL, which is still valid today. Well-designed studies have since shown that ¹²³/¹³¹I-MIBG scintigraphy is suboptimal, especially when used to detect metastatic PHEO/PGL (especially those related to mutations in mitochondrial succinate dehydrogenase subunit B [SDHB]) (5). These and other results accelerated the implementation of ¹⁸F-FDG and novel PHEO/PGL-specific radiopharmaceuticals in PET imaging evaluations of these tumors.

In the early 2000s, [18F]-fluorodihydroxyphenylalanine (¹⁸F-FDOPA), which was initially developed to investigate dopaminergic neurotransmission entering cells via L-type amino acid transporter system 1, was used to localize PHEO/PGL (6). ¹⁸F-FDOPA now shows the best results in the detection of head and neck paragangliomas (HNPGL) and is often used when ¹²³I-MIBG is not available (7). Two other radiopharmaceuticals that target NET, ¹¹C-hydroxyephedrine and [18F]-fluorodopamine (¹⁸F-FDA), were also used to detect benign and metastatic PHEO/PGL with greater sensitivity than ¹²³/¹³¹I-MIBG scintigraphy. The very short half-life of ¹¹C, complicated synthesis of ¹⁸F-FDA, and comparable sensitivity to ¹⁸F-FDG PET have limited their use. Furthermore, ¹⁸F-FDOPA and ¹⁸F-FDA were found to be suboptimal for evaluating a subset of PHEO/PGL that were first termed “apparently sporadic.” It was Baysal et al (8) who discovered that mutations in the SDHD subunit play an important role in the pathogenesis of these tumors. Of all the known genetic mutations, mutations in SDHD are currently the leading cause of hereditary HNPGLs (>50%), followed by SDHB (20–35%) and SDHC (15%) mutations. SDHB-linked PHEO/PGL syndrome is characterized by a high rate of retroperitoneal PGL, and it is associated with a higher risk of aggressive behavior, development of metastatic disease, and ultimately death. ¹⁸F-FDA, ¹⁸F-FDOPA, and ¹²³I-MIBG were found to be suboptimal in the localization of these particular tumors. In contrast, initial large studies from the National Institutes of Health and later from other medical centers demonstrated that ¹⁸F-FDG PET is the most sensitive functional imaging tool for detecting and following SDHB-related PHEO/PGL (9). These studies partially attributed this finding to the Warburg effect, a very prominent feature of these tumors.

As our knowledge of the genetics of these tumors has increased, ¹⁸F-FDG has been used in a different manner in these tumors (5, 10). Now we know that genotype alone is not sufficient to drive a PET radiopharmaceutical-specific imaging phenotype because different tumors in the same patient exhibit different imaging patterns. This may be in agreement with recent microarray gene expression data showing different profiles between SDHD-HNPGLs and SDHD-thoracoabdominal PGLs. An excellent example is SDHx-related sympathetic PHEO/PGL that often exhibits a “flip-flop phenomenon”: ¹⁸F-FDOPA and ¹⁸F-FDA-negative/¹⁸F-FDG-positive pattern of imaging (9). Additional new results with ¹⁸F-fluoro-L-thymidine PET have also suggested that a high FDG uptake in these tumors is not well correlated with their proliferation index, which is usually very low (Pacak, K, unpublished observations). Thus, it is hypothesized that a high ¹⁸F-FDG uptake in these tumors may be explained by SDH dysfunction that leads to stabilization of hypoxia-inducible factor α proteins, thereby resulting in the up-regulation of angiogenesis, glucose transporters, and hexokinase activity.

In conclusion, we predict that the continuing renaissance of ¹⁸F-FDG in the evaluation of these tumors will be further supported by assessing the role of quantification studies of ¹⁸F-FDG uptake in the specific behavioral characteristics of existing and newly discovered hereditary PHEO/PGL. Additionally, ¹⁸F-FDG PET/magnetic resonance imaging using an integrated system with simultaneous acquisition of both techniques holds a new promise for providing information in the assessment of these tumors at a molecular level and in surgically affected areas or HNPGL. Furthermore, determining the metabolized and unmetabolized ¹⁸F-FDG fractions in these tumors will help optimize the use of treatment agents for metastatic PHEO/PGL. Finally, evaluating how to treat and follow-up metastatic PHEO/PGL with a mismatch between ¹⁸F-FDG PET and anatomical studies will be needed. Due to the worldwide availability of ¹⁸F-FDG PET imaging, this imaging modality will continue to provide unique and essential information for localizing and characterizing PHEO/PGL that are biochemically proven. Nevertheless, different functional imaging studies using specific radiopharmaceuticals like ¹²³I-MIBG, ¹⁸F-FDA, or ¹⁸F-FDOPA PET may be initially performed in patients with PHEO. However,¹⁸F-FDG PET is preferred in patients with extra-adrenal sympathetic PGLs, tumor multifocality, and/or SDHx-related PHEO/PGL in whom this imaging method currently has the highest sensitivity when compared to other functional imaging modalities.