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 today
- 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.
Where it starts and where it drains
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: Bladder & urothelial cancer, Renal cell carcinoma, Wilms tumour (nephroblastoma), Neuroblastoma (paediatric), Adrenocortical carcinoma, Urethral cancer, Penile cancer
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.
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- DNA methylation profilingEstablished
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- High-risk pancreatic surveillance (CAPS / PRECEDE)Established
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
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
Target prevalence in this cancer
- 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.
Open problems, and what is being done about each
No reliable predictor of metastasis at diagnosis: molecular classifiers and SDHB status are being validated.
and how the field plans to fix it →What is being done about thisAdvanced and metastatic diseaseAvailable now- Radioligand therapy (beta emitters)Approved
- TemozolomideStandard of care
- Bone-modifying agents (bisphosphonates, denosumab)Standard of care
- DordaviproneApproved
- HIPEC / PIPAC (intraperitoneal chemotherapy)Established
- Laser interstitial thermal therapy (LITT)Established
In trials- ACTIONRecruiting
- CAR-T for glioma (IL13Rα2, GD2, EGFRvIII, multi-target)Phase 1
- CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)Active
- DESTINY-Breast12Positive
- DYNAMICPositive
- EF-14Positive
Ideas and roadmaps- A billion-dollar prize for the first durable cure of a lethal metastatic cancer
- A blood test for the pre-metastatic niche
- A global rapid tissue donation network for metastatic disease
- A national rapid research autopsy network for end-stage cancer
- A regulatory endpoint for drugs that block spread, not tumours
- A ring-fenced metastasis programme with metastasis-specific endpoints
Background: Blood-brain barrier (BBB), Circulating tumour DNA (ctDNA), EGFRvIII, Epithelial–mesenchymal transition & drug efflux, H3 K27M (diffuse midline glioma). Also on OnCo: Atlas: what treats advanced disease · Mechanics: invasion and metastasis.
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
topRecruiting now (live from ClinicalTrials.gov)
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Expert centres
topCentres linked to this cancer in OnCo
- A.C. Camargo Cancer CenterSão Paulo, BRvia Germline (hereditary) testing, Hereditary cancer syndromes
- Hospital de Clínicas de Porto AlegrePorto Alegre, BRvia Germline (hereditary) testing, Hereditary cancer syndromes
- Catalan Institute of Oncology (ICO)L'Hospitalet de Llobregat, ESvia Germline (hereditary) testing
- Children's Hospital of PhiladelphiaPhiladelphia, PA, USvia Germline (hereditary) testing
- via Lutetium-177 dotatate
- Edinburgh Cancer Centre / CRUK Scotland CentreEdinburgh, GBvia Germline (hereditary) testing
- Erasmus MC Cancer InstituteRotterdam, NLvia Lutetium-177 dotatate
- European Association of Nuclear MedicineVienna, ATvia Lutetium-177 dotatate
- via Germline (hereditary) testing
- via Germline (hereditary) testing
- Groote Schuur Hospital / University of Cape TownCape Town, ZAvia Germline (hereditary) testing
- Hadassah Medical CenterJerusalem, ILvia Germline (hereditary) testing
- via Germline (hereditary) testing
- via Belzutifan
- via Lutetium-177 dotatate
- Hospital Universitari i Politècnic La FeValencia, ESvia Germline (hereditary) testing
- via Germline (hereditary) testing
- via Germline (hereditary) testing
- via Lutetium-177 dotatate
- via Germline (hereditary) testing
- via Lutetium-177 dotatate
- via Germline (hereditary) testing
- King Hussein Cancer CenterAmman, JOvia Germline (hereditary) testing
- Korle Bu Teaching HospitalAccra, GHvia Germline (hereditary) testing
- Lagos University Teaching HospitalLagos, NGvia Germline (hereditary) testing
- MovemberMelbourne, AUvia Germline (hereditary) testing
- Peking Union Medical College HospitalBeijing, CNvia Germline (hereditary) testing
- via Lutetium-177 dotatate
- QIMR Berghofer Medical Research InstituteBrisbane, AUvia Germline (hereditary) testing
- Ramathibodi Hospital, Mahidol UniversityBangkok, THvia Germline (hereditary) testing
- Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicago, IL, USNCI comprehensivevia Temozolomide
- Shaare Zedek Medical CenterJerusalem, ILvia Germline (hereditary) testing
- Shizuoka Cancer CenterNagaizumi, Shizuoka, JPvia Germline (hereditary) testing
- via Germline (hereditary) testing
- Society of Nuclear Medicine and Molecular ImagingReston, VA, USvia Lutetium-177 dotatate
- The Hospital for Sick Children (SickKids)Toronto, ON, CAvia Germline (hereditary) testing
- Tohoku University HospitalSendai, JPvia Germline (hereditary) testing
- via Lutetium-177 dotatate
- University of Malaya Medical CentreKuala Lumpur, MYvia Germline (hereditary) testing
- via Lutetium-177 dotatate
- via Lutetium-177 dotatate
Questions to ask
topQuestions to ask your oncologist about Pheochromocytoma and paraganglioma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example Plasma free or urinary fractionated metanephrines, Germline panel testing, SDHB immunohistochemistry, 68Ga-DOTATATE PET, 123I-MIBG scintigraphy), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Adrenal pheochromocytoma, Sympathetic paraganglioma, Head and neckparaganglioma, usually non-secreting.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Localised, secreting
- For my situation (localised, secreting), which of the standard options do you recommend and why?Why: Guideline options include: Alpha-blockade (phenoxybenzamine or doxazosin) for 7 to 14 days, volume expansion, then laparoscopic or open adrenalectomy; cortical-sparing surgery in hereditary bilateral disease.
All patients
- For my situation (all patients), which of the standard options do you recommend and why?Why: Guideline options include: Germline genetic testing and, for carriers, lifelong biochemical and imaging surveillance; cascade testing of relatives.
Metastatic or unresectable
- For my situation (metastatic or unresectable), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Belzutifan, Lutetium-177 dotatate, 131I-MIBG (iobenguane I-131) therapy or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Belzutifan, Lutetium-177 dotatate, Peptide receptor radionuclide therapy (PRRT), Sunitinib?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “No reliable predictor of metastasis at diagnosis: molecular classifiers and SDHB status are being validated”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Withdrawal of 131I-MIBG from the market left a gap that 177Lu-DOTATATE and alpha-emitters are filling”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
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topQuery for this cancer: (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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