Pheochromocytoma and paraganglioma (PPGL)
Pheochromocytomas and paragangliomas are tumours of adrenaline-producing tissue that cause dangerous blood pressure surges. Surgery after careful blood-pressure blockade cures most, genetic testing finds an inherited cause in nearly half, and for the minority that spread there are now radioactive drugs that home to the tumour and, since 2025, the first oral targeted pill, belzutifan.
Overview
PPGL are catecholamine-secreting tumours of the adrenal medulla (pheochromocytoma) or extra-adrenal sympathetic and parasympathetic paraganglia. They have the highest heritability of any human tumour: about 40 percent carry germline mutations in one of more than 15 genes, grouped into cluster 1 (pseudohypoxia: SDHA/B/C/D, VHL, FH, EPAS1) and cluster 2 (kinase signalling: RET, NF1, TMEM127, MAX). SDHB carriers have the highest metastatic risk. Diagnosis rests on plasma free or urinary fractionated metanephrines, then anatomical imaging and functional imaging with 68Ga-DOTATATE PET (most sensitive for SDHx and metastatic disease) or 18F-FDOPA. Endocrine Society guidance recommends germline testing for every patient.
Surgery after 7 to 14 days of alpha-adrenergic blockade is curative for localised disease, with cortical-sparing adrenalectomy in hereditary bilateral cases. Metastatic disease is treated to control catecholamine excess and tumour burden: 177Lu-DOTATATE for SSTR-positive tumours (NCCN-listed; prospective trials ongoing), high-specific-activity 131I-MIBG (iobenguane I-131, Azedra; FDA 2018, though the manufacturer later announced its commercial discontinuation), cyclophosphamide-vincristine-dacarbazine or temozolomide chemotherapy (particularly SDHB-mutant), and sunitinib, which improved progression-free survival versus placebo in the randomised FIRSTMAPPP trial (Lancet 2024). Belzutifan, the HIF-2alpha inhibitor first approved for VHL-associated tumours, received FDA approval on 14 May 2025 for locally advanced, unresectable or metastatic PPGL in patients aged 12 and older on the basis of the LITESPARK-015 cohort (objective response rate 26 percent), the first oral therapy approved for the disease and a direct hit on the pseudohypoxia biology of cluster 1 tumours.
Open problems are predicting metastasis (no histological criterion is reliable), lifelong surveillance of gene carriers, and sequencing radioligand, HIF-2alpha and kinase therapy.
State of the art
- Belzutifan is the first drug to target the pseudohypoxia biology (HIF-2alpha) shared by SDHx- and VHL-driven tumours, and the first oral therapy approved for PPGL (2025).
- Theranostics matured here early: 123I-MIBG and 68Ga-DOTATATE imaging select patients for 131I-MIBG or 177Lu-DOTATATE treatment of the same target.
- FIRSTMAPPP was the first randomised phase 2 in metastatic PPGL, showing that trials are possible in a disease this rare and that sunitinib delays progression.
- Universal germline testing has turned PPGL into a model for hereditary cancer surveillance, with SDHB carriers identified before tumours form.
Anatomy and lymph node drainage
- Renal cortex (RCC)
- Renal pelvis and ureter (upper tract urothelial)
- Bladder lining (non-muscle-invasive)
- Bladder muscle wall (muscle-invasive)
- Adrenal cortex
- Adrenal medulla and sympathetic chain (neuroblastoma)
- Developing kidney (Wilms tumour)
- Nodes: renal hilar
- Nodes: para-aortic and paracaval
- Nodes: obturator and iliac (bladder)
Renal cell carcinoma comes from the kidney's filtering cortex, urothelial cancer from the lining of the collecting system and bladder, and the adrenal on top hosts cortical and medullary (neuroblastoma) tumours.
- Renal cortex (RCC)Hereditary PPGL (SDHx, VHL, RET/MEN2, NF1, MAX, TMEM127)
- Renal pelvis and ureter (upper tract urothelial)
- Bladder lining (non-muscle-invasive)
- Bladder muscle wall (muscle-invasive)
- Adrenal cortexAdrenal pheochromocytoma
- Adrenal medulla and sympathetic chain (neuroblastoma)Adrenal pheochromocytoma · Sympathetic paraganglioma (abdominal, thoracic) · Head and neck (parasympathetic) paraganglioma, usually non-secreting · Hereditary PPGL (SDHx, VHL, RET/MEN2, NF1, MAX, TMEM127) · Metastatic PPGL
- Developing kidney (Wilms tumour)
- renal hilar
- para-aortic and paracaval
- obturator and iliac (bladder)
Same organ: Renal cell carcinoma, Neuroblastoma (paediatric), High-risk neuroblastoma, Hereditary pheochromocytoma and paraganglioma (SDHx, VHL, RET, NF1, MAX and TMEM127), Metastatic pheochromocytoma and paraganglioma
About 2 to 8 cases per million people per year; roughly one in ten pheochromocytomas and a higher share of paragangliomas are metastatic, and about 40 percent of all cases are hereditary.
- Fluorodopa F-18Approved
- MIBG imaging and 131I-MIBG therapyEstablished
- Somatostatin receptor PET (68Ga/64Cu-DOTATATE)Standard of care
Nothing recorded yet.
Nothing recorded yet.
Also on Nuclide: Roadmaps.
Alpha-blockade (phenoxybenzamine or doxazosin) for 7 to 14 days, volume expansion, then laparoscopic or open adrenalectomy; cortical-sparing surgery in hereditary bilateral disease.
Germline genetic testing and, for carriers, lifelong biochemical and imaging surveillance; cascade testing of relatives.
Belzutifan (FDA May 2025, LITESPARK-015); 177Lu-DOTATATE for SSTR-positive disease; 131I-MIBG where available; sunitinib (FIRSTMAPPP); CVD or temozolomide chemotherapy for rapidly progressive or SDHB-mutant disease; alpha-blockade throughout.
Subtypes & biomarkers
top- Adrenal pheochromocytoma
- Sympathetic paraganglioma (abdominal, thoracic)
- Head and neck (parasympathetic) paraganglioma, usually non-secreting
- Hereditary PPGL (SDHx, VHL, RET/MEN2, NF1, MAX, TMEM127)
- Metastatic PPGL
- Plasma free or urinary fractionated metanephrines
- Germline panel testing (SDHA/B/C/D, SDHAF2, VHL, RET, NF1, MAX, TMEM127, FH, EPAS1)
- SDHB immunohistochemistry (loss indicates SDHx)
- 68Ga-DOTATATE PET (SSTR2 expression; selects for PRRT)
- 123I-MIBG scintigraphy (selects for 131I-MIBG)
- Tumour size, extra-adrenal location and SDHB status as metastatic risk factors
How often this target appears
- 1886Fränkel describes bilateral adrenal tumours in an 18-year-old
Later shown by genetic analysis to be a case of MEN2.
- 1926First successful resection (Roux in Lausanne, Mayo in Rochester)
- 2000SDHD mutations in hereditary paraganglioma
Baysal and colleagues, Science: metabolic enzyme genes as tumour suppressors.
- 2014Endocrine Society guideline recommends germline testing for all
- 2018High-specific-activity 131I-MIBG (Azedra) approved
FDA, July 2018, for unresectable MIBG-positive PPGL; later discontinued commercially.
- 2024FIRSTMAPPP: sunitinib delays progression
Baudin and colleagues, Lancet: first randomised trial in metastatic PPGL.
- 2025Belzutifan approved for PPGL
FDA, 14 May 2025, LITESPARK-015 cohort A1; first oral therapy for the disease.
Dated changes read from the records linked to this indication: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 11 changes by month →- 2026-09-10This recordPheochromocytoma and paraganglioma (PPGL)Facts on this page last checked
When this page itself was last checked or edited.
- 2025MilestonePheochromocytoma and paraganglioma (PPGL)Belzutifan approved for PPGL
FDA, 14 May 2025, LITESPARK-015 cohort A1; first oral therapy for the disease.
- 2024MilestoneSunitinibFIRSTMAPPP: sunitinib delays progression
Baudin and colleagues, Lancet: first randomised trial in metastatic PPGL.
- 2018Milestone131I-MIBG (iobenguane I-131) therapyHigh-specific-activity 131I-MIBG (Azedra) approved
FDA, July 2018, for unresectable MIBG-positive PPGL; later discontinued commercially.
- 2014GuidelinePheochromocytoma and paraganglioma (PPGL)Guideline Endocrine Society 2014: All patients
Germline genetic testing and, for carriers, lifelong biochemical and imaging surveillance; cascade testing of relatives.
- 2014GuidelinePheochromocytoma and paraganglioma (PPGL)Guideline Endocrine Society clinical practice guideline 2014; NCCN Neuroendocrine and Adrenal Tumors: Localised, secreting
Alpha-blockade (phenoxybenzamine or doxazosin) for 7 to 14 days, volume expansion, then laparoscopic or open adrenalectomy; cortical-sparing surgery in hereditary bilateral disease.
What is in development for Pheochromocytoma and paraganglioma (PPGL), drawn from the whole corpus: 2 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Trials under way · 2
- Study to Evaluate Safety and Dosimetry of Lutathera in Adolescent Patients With GEP-NETs and PPGLs · phase 2 · Advanced Accelerator Applications
- Targeted Alpha-Particle Therapy for Advanced Somatostatin Receptor Type 2 (SSTR2) Positive Tumors · phase 1/2 · Perspective Therapeutics
Open problems and what is being done
No reliable predictor of metastasis at diagnosis: molecular classifiers and SDHB status are being validated.
What is being done about thisAdvanced and metastatic diseaseAvailable nowIn trialsNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Also on Nuclide: Indications.
Withdrawal of 131I-MIBG from the market left a gap that 177Lu-DOTATATE and alpha-emitters are filling.
Sequencing belzutifan, radioligand therapy and kinase inhibitors: no comparative data.
Lifelong surveillance burden for gene carriers, with children of SDHB carriers screened from early childhood.
Trials
topTrials recruiting now
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Landmark trials
Direct links plus the targets, companies, and technologies of this cancer's products.
isotopes
5technologies
7targets
2drugs
7companies
5pathways
1trials
2Latest papers
topQuery for this indication: (TITLE:"Pheochromocytoma and paraganglioma" OR ABSTRACT:"Pheochromocytoma and paraganglioma" OR TITLE:"PPGL" OR ABSTRACT:"PPGL" OR TITLE:"Pheochromocytoma" OR ABSTRACT:"Pheochromocytoma" OR TITLE:"Paraganglioma" OR ABSTRACT:"Paraganglioma" OR TITLE:"Phaeochromocytoma" OR ABSTRACT:"Phaeochromocytoma") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Pheochromocytoma and paraganglioma (PPGL), not a curated reading list.
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