Molecular imaging and radioligand therapies in pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors of neural crest origin that exhibit wide clinical and biological heterogeneity. While surgical resection remains the only curative option, many patients have unresectable or metastatic progressive disease with uncontrolled secretion, requiring alternative management strategies. Advances in genetics have revealed germline pathogenic variants in up to 30-40% of cases, refining tumor classification and guiding the use of molecularly targeted imaging. Functional imaging modalities, such as 68Ga or 64Cu-DOTA-SSA (somatostatin analogs), 18F-FDOPA, 18F-FDG and 123I-MIBG, exploit tumor biology, such as somatostatin receptor expression, catecholamine biosynthesis and altered glucose metabolism. These approaches not only improve diagnostic accuracy but also help in prognosis and selection to therapies. Radioligand therapies have emerged as a pivotal option in advanced PPGLs. High-specific-activity 131I-MIBG has demonstrated durable disease control, symptomatic improvement and favorable safety in multicenter studies, leading to US Food and Drug Administration approval for metastatic PPGL, although currently not commercially available. More recently, peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE has shown disease control rates of 80-100% in prospective and retrospective trials, with outcomes enhanced by standardized dosing strategies. Ongoing studies are evaluating PRRT in genetically defined subgroups and exploring synergistic combinations, including radiosensitizing approaches.