Metastatic pheochromocytoma and paraganglioma

No pathological feature reliably separates benign from malignant pheochromocytoma and paraganglioma; malignancy is defined by metastases at sites where chromaffin tissue does not normally occur, above all bone, lymph nodes, liver and lung. Metastatic disease occurs in about a tenth of adrenal tumours and a much larger share of extra-adrenal sympathetic paragangliomas, and SDHB mutation, large size, extra-adrenal site and a noradrenergic or dopaminergic profile are the main risk factors. The course is heterogeneous: some patients live for decades with stable bone metastases, others progress within months, so the first decision is whether to treat at all. Catecholamine excess is controlled throughout with alpha-blockade (phenoxybenzamine or doxazosin) and beta-blockade added second, with metyrosine for refractory cases, and any procedure, including biopsy and embolisation, is done under blockade to avoid a hypertensive crisis. Somatostatin receptor PET (68Ga-DOTATATE) and 123I-MIBG scintigraphy stage the disease and, by showing uptake, select patients for the corresponding radionuclide therapy.

Treatment is sequenced by pace. Indolent disease is watched or treated locally with surgery, radiotherapy, ablation or embolisation of dominant lesions. For progressive disease, radionuclide therapy is the first systemic step: high-specific-activity 131I-MIBG (iobenguane, Azedra) was approved in 2018 after a phase 2 trial in which a quarter of patients halved their antihypertensive medication and about a fifth had tumour responses, though the manufacturer withdrew it from the market in 2024, and lutetium-177 dotatate, approved for gastroenteropancreatic neuroendocrine tumours, is used for somatostatin-receptor-positive disease on the strength of retrospective series and phase 2 trials. Sunitinib is the one systemic drug with randomised evidence: FIRSTMAPPP (Lancet 2024), an academic phase 2 trial that took twelve years to enrol 78 patients, showed 12-month progression-free survival of 36 percent against 19 percent on placebo. Cyclophosphamide, vincristine and dacarbazine (CVD) chemotherapy, in use since 1988, and temozolomide, which is active particularly in SDHB-mutant tumours, are the cytotoxic options, and cabozantinib showed activity in the phase 2 NATALIE trial. Belzutifan, the HIF-2 alpha inhibitor, was approved in the United States in May 2025 for adults and children over 12 with locally advanced, unresectable or metastatic disease after a response rate of 26 percent in the LITESPARK-015 cohort, the first approval for the disease in seven years and the first to exploit the pseudohypoxia biology of cluster 1 tumours; the imipridone ONC206 and radioligand combinations are in trials. Bone metastases, the commonest site, are treated with denosumab or bisphosphonates and palliative radiotherapy.