Overview

Pheochromocytomas arise from adrenal chromaffin cells, paragangliomas from extra-adrenal autonomic ganglia. 10-15% malignant. Hereditary in 30-40% (SDHx, VHL, RET, NF1). Clinical presentation: catecholamine excess with hypertension, headache, palpitations, sweating. Pre-operative alpha-blockade essential. Surgical resection curative for localized disease. I-131 MIBG and peptide receptor radionuclide therapy for metastatic disease.

Clinical Management: Treatment individualized based on stage, histology, molecular profile, and patient factors. Multidisciplinary tumor board review recommended. Refer to NCCN guidelines and FDA package inserts for complete dosing and administration.

Epidemiology & Impact

PPGLs are rare neuroendocrine tumors from chromaffin cells (pheochromocytomas from adrenal medulla, paragangliomas from extra-adrenal ganglia). Incidence is 2-8 per million. Approximately 30-40% are hereditary (the most heritable tumor type), associated with over 20 susceptibility genes. About 10-15% are malignant. Classic presentation includes episodic hypertension, headache, sweating, and palpitations.

Molecular Biology & Biomarkers

Germline mutations in 30-40% of patients across SDHx subunits, VHL, RET, NF1, TMEM127, MAX, and others. SDHB mutations confer highest malignancy risk (30-70%). Molecular clustering divides into pseudohypoxic, kinase signaling, and Wnt-altered subtypes. All patients should receive genetic testing.

Pheochromocytomas and paragangliomas (PPGLs) have the highest heritability of any solid tumor, with approximately 40% of cases carrying germline mutations in susceptibility genes. Three main molecular clusters exist: pseudohypoxia cluster 1 (SDHx, VHL, FH, EPAS1 mutations β€” characterized by HIF pathway activation and aggressive behavior), kinase signaling cluster 2 (RET, NF1, TMEM127, MAX, HRAS mutations β€” activating RAS/MAPK and mTOR pathways), and Wnt-altered cluster 3 (CSDE1, MAML3 fusions β€” associated with cortical admixture). SDHB mutations carry the highest malignancy risk (30-70% metastatic rate) and require lifelong surveillance. Succinate accumulation in SDH-deficient tumors causes a hypermethylator phenotype, and immunohistochemistry for SDHB protein loss is a powerful screening tool for genetic counseling referral.

Evolving Treatment Landscape

Surgery with perioperative alpha-blockade is primary. Metastatic disease options include I-131-MIBG (Azedra), CVD chemotherapy, temozolomide (especially SDHB-mutated), and Lu-177-DOTATATE for somatostatin receptor-positive tumors. The rarity of metastatic PPGLs limits clinical trial development.

Surgical resection is the definitive treatment for localized PPGLs, requiring careful preoperative alpha-blockade (phenoxybenzamine or doxazosin) to prevent hypertensive crisis. Laparoscopic adrenalectomy is standard for pheochromocytomas <6 cm. For malignant/metastatic disease, therapeutic options are limited: high-specific-activity I-131 MIBG (Azedra) is FDA-approved for MIBG-avid metastatic PPGL. CVD chemotherapy (cyclophosphamide, vincristine, dacarbazine) achieves partial responses in 30-40% of cases. Temozolomide shows particular activity in SDHB-mutant tumors due to MGMT promoter methylation. Belzutifan (Welireg), a HIF-2Ξ± inhibitor, is approved for VHL-associated tumors including pheochromocytomas. Lu-177 DOTATATE (Lutathera) is used for somatostatin receptor-positive tumors. Clinical trials are evaluating combination checkpoint inhibitors and targeted therapies.

Approved Pheochromocytoma & Paraganglioma Therapies

Azedra
iobenguane I 131
FDA Approved 2018 Advanced
Approved Indications (US/FDA)
Treatment of adult and pediatric patients 12 years and older with iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.
Dosing Schedule
500 mCi (18.5 GBq) IV for Dose 1, followed by 500 mCi IV for Dose 2 approximately 90 days later
Drug Class
Radiopharmaceutical
Manufacturer
Progenics/Lantheus
Approval Year
2018
Pivotal Trial
NCT00874614 β†—
Key Publication
Pryma et al. JCO 2019 β†—
FDA Approved 2025 Advanced
Approved Indications (US/FDA)
Treatment of adult patients with advanced pheochromocytoma or paraganglioma requiring systemic anticancer therapy. FDA approved May 2025 based on LITESPARK-015.
Dosing Schedule
120 mg orally once daily
Drug Class
HIF-2Ξ± Inhibitor
Manufacturer
Merck
Approval Year
2025
Pivotal Trial
NCT04924075 β†—
Key Publication
LITESPARK-015 (awaiting publication)