Radiopharmaceuticals in paraganglioma imaging: too many members on board?

Excerpt

Since the development of radioiodinated metaiodobenzylguanidine (MIBG) over 30 years ago, nuclear imaging has had a central role in managing patients with paraganglioma (PGL), aiding in the diagnosis and staging of this rare but, for many patients, devastating disease [1]. This role is complemented by anatomical imaging, including computed tomography (CT) and magnetic resonance imaging (MRI). The major advantage of nuclear imaging is in providing high visual contrast between tumor and healthy tissue, which enables the detection of tumors that could potentially be missed by conventional imaging. Beyond its localization value, this imaging modality provides unique opportunities for better characterizing these tumors at molecular levels (e.g., catecholamine synthesis, specific receptor and transporter expression), mirroring ex vivo histological classification but on a whole-body, in vivo, scale. This opportunity has more recently been augmented by a number of excellent radiopharmaceuticals, which target different functional and molecular pathways that often reflect the diverse genetic landscape of PGL. Based on these characteristics, nuclear imaging provides a means of linking imaging phenotype to genotype and can be considered a member of the multi-omics approach. For example, an intense 2-fluoro-2-deoxy-D-glucose (¹⁸F-fluorodeoxyglucose, ¹⁸F-FDG) uptake by a PGL is mostly associated with mutations involving one of the genes encoding the succinate dehydrogenase (SDH) complex. Conversely, a low uptake can often rule out a classic SDH deficiency linked to SDH mutations [2]. In addition to genetic mutation, epigenetic mechanisms (histones and methylation modifications) and the tissue of origin may also impact the imaging phenotype. For example, whereas PGLs associated with the sympathetic nervous system often exhibit high ¹⁸F-FDG uptake, parasympathetic PGLs (typically arising in the head and neck region) may have very low uptake values. The ¹⁸F-FDG uptake pattern SDHx-PGLs reflects metabolic reprogramming, a hypermethylator phenotype, and abnormal mitochondrial respiratory function [3] and it is predominantly linked with high succinate and low fumarate metabolomic pattern [4]. Such tumors are classified as exhibiting “pseudohypoxia.” There are further differences based on the site of origin. For example, parasympathetic-associated PGLs almost always have an intense uptake of 6-fluoro-3,4-dihydroxyphenylalanine (¹⁸F-fluorodopa, ¹⁸F-FDOPA) or somatostatin analogs (SSA) labeled with ⁶⁸Ga (e.g., ⁶⁸Ga DOTA analogs), regardless of their genetic background [5]. …