Pheochromocytoma and Paraganglioma: Disease Characteristics Report

Executive summary

Pheochromocytomas and paragangliomas (PPGLs) are rare neural-crest-derived neuroendocrine neoplasms. A pheochromocytoma (PCC) arises in adrenal-medullary chromaffin cells; a paraganglioma (PGL) arises in extra-adrenal sympathetic or parasympathetic paraganglia. Approximately 80–85% are adrenal PCCs and 15–20% are extra-adrenal PGLs. Catecholamine excess causes episodic or sustained cardiovascular and metabolic disease, while every PPGL is regarded as having some metastatic potential under current WHO classification. Germline predisposition occurs in roughly 30–40% overall and 70–80% of pediatric cases, making PPGL among the most heritable human tumors. Contemporary practice therefore combines biochemical diagnosis, molecular imaging, universal germline testing, surgery when feasible, lifelong risk-adapted surveillance, and genotype/target-informed systemic therapy. (t.2024pheochromocytomaanupdated pages 1-2, casey2024internationalconsensusstatement pages 1-2, cascon2023geneticbasesof pages 1-2)

A compact quantitative evidence summary is provided below.

Table: This table compiles compact, knowledge-base–ready evidence on pheochromocytoma and paraganglioma across clinical, genetic, diagnostic, and treatment domains. It prioritizes quantitative findings and recent sources, while flagging areas where evidence remains sparse or preprint-only.

1. Disease information

Definition, category, and terminology

Category: rare neuroendocrine neoplasm; neural-crest/chromaffin-cell tumor; hereditary-cancer syndrome when caused by a germline pathogenic variant.

• Pheochromocytoma: adrenal-medullary PPGL.
• Sympathetic PGL: usually thoracic, abdominal, or pelvic; commonly catecholamine-secreting.
• Parasympathetic PGL: usually skull-base/head-and-neck, including carotid-body, vagal, jugulotympanic, and related sites; often nonsecretory.
• Metastatic PPGL: tumor present in a site where normal paraganglial tissue does not occur—commonly lymph node, bone, liver, or lung. Histology alone cannot establish benignity or reliably exclude future metastasis. (casey2020geneticstratificationof pages 4-5)

Synonyms: PPGL; PCC/PGL; phaeochromocytoma/paraganglioma; chromaffinoma; adrenal paraganglioma; extra-adrenal pheochromocytoma (older term); chemodectoma or glomus tumor for selected head-and-neck PGLs.

Identifiers

• MONDO: pheochromocytoma MONDO:0008233; adrenal-gland pheochromocytoma MONDO:0004974; hereditary pheochromocytoma–paraganglioma MONDO:0017366; malignant adrenal-gland pheochromocytoma MONDO:0006288. (OpenTargets Search: pheochromocytoma,paraganglioma)
• OMIM syndromes: PGL1/SDHD 168000; PGL2/SDHAF2 601650; PGL3/SDHC 605373; PGL4/SDHB 115310; PGL5/SDHA 614165; PGL6/SLC25A11 618464; PGL7/DLST 618475; VHL 193300; MEN2 171400; NF1 162200. (cascon2023geneticbasesof pages 4-5, cascon2023geneticbasesof pages 5-6)
• ICD-10-CM: coding is site/behavior dependent, including D35.0 (benign adrenal neoplasm), D44.6/D44.7 (uncertain behavior of carotid body, aortic body, or other paraganglia), C74.1 (malignant adrenal medulla), and C75.4/C75.5 (malignant carotid/aortic body). These behavior-based labels do not fully reflect the WHO concept that all PPGLs have variable metastatic potential.
• MeSH: Pheochromocytoma and Paraganglioma are separate descriptors.

This report synthesizes aggregated disease-level resources, cohorts, trials, and guidelines, not individual EHR records. Variant interpretation for an actual patient still requires the original laboratory report, ACMG/AMP classification, phenotype, family segregation, and—where available—tumor evidence.

2. Etiology, risk, protective, and environmental factors

Causal and susceptibility factors

PPGL is fundamentally a genetic/epigenetic neoplastic disease. Approximately 40% of patients carry an autosomal-dominant germline alteration, about 30% have a recognized somatic driver, and about 30% remain unexplained by currently known genes. More than 20 susceptibility/driver genes are established or strongly implicated. (cascon2023geneticbasesof pages 1-2, cascon2023geneticbasesof pages 2-4)

Major germline causes include SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, NF1, TMEM127, MAX, FH, MDH2, SLC25A11, DLST, EGLN1/2, and less frequently other metabolic-pathway genes. Important somatic/postzygotic events include NF1, VHL, RET, HRAS, FGFR1, EPAS1, H3-3A, CSDE1, and MAML3 rearrangements. Open Targets independently links PCC most strongly to MAX, TMEM127, RET, SDHB, VHL, SDHD, NF1, and SDHA. (OpenTargets Search: pheochromocytoma,paraganglioma, cascon2023geneticbasesof pages 1-2, cascon2023geneticbasesof pages 6-8)

Risk is increased by a pathogenic germline variant, family history, young age, multifocal/bilateral disease, previous PPGL, and syndromic findings such as medullary thyroid carcinoma, VHL lesions, neurofibromas/café-au-lait macules, renal-cell carcinoma, GIST, pituitary tumor, polycythemia, or uterine/cutaneous leiomyomas. SDHB alteration, extra-adrenal location, larger primary tumor, and a norepinephrine/dopamine biochemical phenotype correlate with metastatic risk. (giacche2024pheochromocytoma–paragangliomasyndromea pages 5-6, t.2024pheochromocytomaanupdated pages 7-8)

Environment and gene–environment interaction

No infectious agent, toxin, occupational exposure, diet, smoking pattern, alcohol exposure, or other modifiable environmental factor is established as a primary PPGL cause. Likewise, no replicated protective lifestyle factor or protective human allele supports primary-prevention advice beyond general cardiovascular health. Hypoxia is mechanistically relevant because cluster-1 tumors constitutively activate a hypoxia-response program, but ordinary environmental hypoxia has not been shown to cause PPGL. Pregnancy can reveal or aggravate a previously occult secretory tumor; LHCGR expression in some tumors offers a plausible hormonal mechanism. (cascon2023geneticbasesof pages 2-4, t.2024pheochromocytomaanupdated pages 3-6)

Accordingly, validated gene–environment interactions remain an evidence gap. This is absence of convincing evidence, not proof that environmental modifiers never operate.

3. Phenotypes

These frequencies are heterogeneous across referral populations and genotypes and should not be interpreted as universal penetrance estimates. Cluster-1 tumors tend to be noradrenergic/dopaminergic and may produce sustained hypertension; cluster-2 adrenal tumors more often produce epinephrine and paroxysmal attacks. Nonsecretory head-and-neck PGLs can remain clinically silent until a mass or cranial-nerve deficit develops. (giacche2024pheochromocytoma–paragangliomasyndromea pages 5-6, t.2024pheochromocytomaanupdated pages 6-7, t.2024pheochromocytomaanupdated pages 3-6)

Quality of life: attacks restrict activity, sleep, driving, employment, and social participation; chronic uncertainty, hereditary risk, repeated imaging, cranial-nerve morbidity, pain, fatigue, and treatment toxicities further impair well-being. Robust genotype-stratified EQ-5D/SF-36 estimates remain limited in the retrieved literature.

4. Genetic and molecular information

Molecular classes and causal chain

1. Cluster 1A—TCA-cycle/SDH pseudohypoxia: biallelic loss of SDHx, FH, MDH2, DLST, or related metabolism genes → succinate/fumarate accumulation → inhibition of α-ketoglutarate-dependent dioxygenases → HIF stabilization plus DNA/histone hypermethylation (CIMP) → angiogenesis, altered differentiation, invasion, and predominantly noradrenergic/dopaminergic secretion. SDHB tumors are particularly enriched for metastatic behavior. Suggested GO terms: tricarboxylic-acid cycle (GO:0006099), mitochondrial electron transport (GO:0006121), response to hypoxia (GO:0001666), DNA methylation (GO:0006306), angiogenesis (GO:0001525). (cascon2023geneticbasesof pages 2-4, cascon2023geneticbasesof pages 4-5, t.2024pheochromocytomaanupdated pages 3-6)
2. Cluster 1B—VHL/EPAS1 pseudohypoxia: impaired VHL-mediated HIF degradation or activating EPAS1/HIF-2α alteration → constitutive hypoxia transcription → vascular/metabolic tumor program. EPAS1 alterations can be postzygotic mosaic and associated with polycythemia and somatostatinoma. (cascon2023geneticbasesof pages 6-8, t.2024pheochromocytomaanupdated pages 3-6)
3. Cluster 2—kinase signaling: RET gain of function or loss of NF1, TMEM127, MAX and related regulators → RAS–MAPK, PI3K–AKT–mTOR, receptor-tyrosine-kinase, MYC/MAX, and translational activation → proliferation and an adrenal/adrenergic phenotype. Suggested GO: MAPK cascade (GO:0000165), PI3K signaling (GO:0014065), TOR signaling (GO:0031929), cell proliferation (GO:0008283). (cascon2023geneticbasesof pages 2-4, cascon2023geneticbasesof pages 5-6)
4. Cluster 3—WNT altered: somatic MAML3–UBTF fusions or CSDE1 alterations → WNT/β-catenin and developmental transcriptional dysregulation → proliferation, angiogenesis, and invasion. MAML3 rearrangements represented 5–7% in one synthesis; 37.5% of fusion-positive tumors developed metastases in the cited series. (cascon2023geneticbasesof pages 1-2, cascon2023geneticbasesof pages 6-8)

Variant interpretation

Pathogenic alterations include missense, nonsense, frameshift, splice, copy-number, deletion, loss-of-heterozygosity, fusion, promoter/epigenetic, and postzygotic mosaic events. Tumor-suppressor genes generally operate through loss of function and a somatic second hit; RET and EPAS1 commonly act through gain of function. Population frequency alone is insufficient, especially for low-penetrance SDHA variants. VUS must not direct predictive testing or irreversible management. Tumor LOH, metabolomics, and IHC—loss of SDHB/SDHA/MAX or positive 2-succinocysteine in FH-deficient disease—can supply functional evidence. (cascon2023geneticbasesof pages 6-8, cascon2023geneticbasesof pages 4-5)

Penetrance and genotype–phenotype examples

• SDHD: autosomal dominant with parent-of-origin effect, usually disease after paternal transmission; reported penetrance 86% by age 50; predominantly head-and-neck PGL.
• SDHB: autosomal dominant, incomplete age-dependent penetrance—approximately 30% by age 80 in one synthesis; often a solitary thoracoabdominal PGL without family history; substantial metastatic concern.
• SDHA: low penetrance, approximately 10% by age 70; many probands appear sporadic.
• VHL: approximately 20% develop PPGL; 43–45% multifocal/bilateral, <5% metastatic, median diagnosis around 29 years.
• RET/MEN2: approximately 50% lifetime PCC risk; 50–80% bilateral; metastatic disease uncommon.
• NF1: clinically recognized PPGL in approximately 0.1–5.7%, higher in autopsy series; usually unilateral adrenal tumors.
• MAX: preferential paternal transmission has been reported. A 2024 aggregation of 109 carriers found 101 PCC cases, 59 bilateral tumors, 18.8% metastasis, and mean diagnosis age 32.8 years. (cascon2023geneticbasesof pages 4-5, cascon2023geneticbasesof pages 5-6)

No repeat expansion is implicated. Routine karyotyping and FISH are not first-line tests; chromosomal microarray may detect large deletions but is less efficient than a sequencing panel that includes deletion/duplication analysis. Mitochondrial nuclear genes are central, but mitochondrial-DNA testing is not routine.

Recent single-cell and multi-omics research

A 2024 single-cell preprint analyzed 133,894 cells from 16 tissues in five PCC patients and proposed metabolism-type tumors marked by NDUFA4L2/COX4I2 and kinase-type tumors marked by RET/PNMT, with distinct FGF, annexin, inflammatory, HLA-I, and T-cell microenvironments. This is hypothesis-generating because of the very small patient sample and preprint status. A separate 2024 preprint integrating seven assays in 94 SDHB-deficient tumors from 79 patients associated TERT/ATRX alterations with metastasis and identified MGMT overexpression and mismatch-repair deficiency as possible alkylator-resistance mechanisms. (OpenTargets Search: pheochromocytoma,paraganglioma)

A concise quote from the 2023 genetics review captures the field: “there are currently more than 20 driver genes implicated in either the hereditary or the sporadic nature of the disease.” It further reports that genetic diagnosis is achieved in approximately 75–80%. Published April 2023; DOI. (cascon2023geneticbasesof pages 1-2)

5. Environmental information

There is no established infectious etiology and no evidence supporting vaccination, antimicrobial prophylaxis, toxin avoidance, or a specific diet as PPGL prevention. Exercise, caffeine, nicotine, sympathomimetics, stress, anesthesia, tumor manipulation, and selected drugs can trigger symptoms or interfere with biochemical testing, but are not proven tumor initiators. Pregnancy is a clinically important physiologic context because catecholamine excess threatens both mother and fetus; early recognition and alpha blockade improve outcomes. (t.2024pheochromocytomaanupdated pages 6-7, t.2024pheochromocytomaanupdated pages 3-6)

6. Pathophysiology

The clinical causal chain is:

driver alteration/second hit → chromaffin or paraganglial-cell transformation → cluster-specific metabolic or kinase program → tumor growth ± catecholamine synthesis → α-adrenergic vasoconstriction, β-adrenergic chronotropy/inotropy, volume contraction, insulin suppression and lipolysis → hypertension, headache, sweating, palpitations, arrhythmia, cardiomyopathy, hyperglycemia and crisis. Chronic or extreme catecholamine exposure can produce myocarditis/cardiomyopathy, stroke, pulmonary edema, intestinal ischemia/ileus, and acute kidney injury. (t.2024pheochromocytomaanupdated pages 6-7, t.2024pheochromocytomaanupdated pages 3-6)

Relevant cells include adrenal chromaffin cells (CL:0000166), sympathetic neurons (CL:0000095), sustentacular cells, endothelial cells (CL:0000115), fibroblasts (CL:0000057), macrophages (CL:0000235), and lymphocytes. Relevant compartments are mitochondrion (GO:0005739), mitochondrial respiratory-chain complex II (GO:0005749), nucleus (GO:0005634), and cytosol (GO:0005829). Immune-checkpoint therapy has shown limited activity to date; low CD8 infiltration and genotype-dependent antigen-presentation programs may contribute, but the immune landscape remains investigational.

7. Anatomical structures affected

Primary sites are adrenal medulla (UBERON:0001235), sympathetic chain/paraganglia, organ of Zuckerkandl, retroperitoneum, mediastinum, urinary bladder, pelvis, carotid body, vagal body, jugulotympanic region, and skull base. Sympathetic tumors are generally secretory; parasympathetic head-and-neck tumors are often nonsecretory. Hereditary disease is more often bilateral or multifocal. (t.2024pheochromocytomaanupdated pages 1-2, cascon2023geneticbasesof pages 2-4)

Secondary injury involves cardiovascular, cerebrovascular, renal, pulmonary, gastrointestinal, endocrine/metabolic, and peripheral/cranial nervous systems. Metastatic targets are especially lymph node, bone, liver, and lung. In an aggregation of 107 SDHA-associated cases, tumors were head-and-neck in 46% and abdominal in 43%; among metastatic cases, bone and lymph nodes were involved in 82% and 71%, respectively. (t.2024pheochromocytomaanupdated pages 1-2)

8. Temporal development

Most sporadic diagnoses occur at age 30–50, with similar sex distribution. Pediatric PPGL represents approximately 10–20% of all PPGL, has annual incidence around 0.5–2 per million children, and presents at median age 11–15. Childhood disease is hereditary in 70–80%. (t.2024pheochromocytomaanupdated pages 1-2, casey2024internationalconsensusstatement pages 1-2)

The course ranges from an incidental stable mass to episodic catecholamine attacks, acute crisis, slowly progressive multifocal disease, or aggressive metastasis. Recurrence/metastasis can emerge decades after apparently complete resection; therefore “five-year cure” is unsafe for high-risk genotypes. Approximately half of treatment-naïve metastatic pediatric patients may remain stable at one year, illustrating that immediate systemic treatment is not obligatory for every asymptomatic patient. (casey2024internationalconsensusstatement pages 11-13)

9. Inheritance and population epidemiology

PPGL is rare; precise incidence varies with case ascertainment and incidental imaging. It accounts for roughly 0.1% of hypertension in the 2024 synthesis. About 35–45% harbor a germline pathogenic variant, including 10–12% of apparently sporadic presentations. The usual pattern is autosomal dominant with incomplete, age-dependent, gene-specific penetrance; SDHD, SDHAF2, and sometimes MAX show parent-of-origin effects. De novo and postzygotic mosaic disease occur, notably in VHL, EPAS1, H3-3A, and NF1. (t.2024pheochromocytomaanupdated pages 1-2, giacche2024pheochromocytoma–paragangliomasyndromea pages 5-6, cascon2023geneticbasesof pages 6-8)

No consistent overall sex bias is established. Founder variants exist in particular populations, but population-specific carrier frequency cannot be safely inferred from unselected gnomAD frequency because penetrance differs sharply by gene and variant. Consanguinity is not a major general risk factor for these predominantly dominant syndromes.

10. Diagnostics

Biochemistry

First-line testing is plasma free metanephrines or 24-hour urinary fractionated metanephrines, preferably measured by LC–MS/MS. Plasma sampling should occur after at least 20–30 minutes supine rest. A 2024 synthesis reported plasma sensitivity 96% and specificity 85%, and urinary sensitivity 87.5% and specificity 99.7%, although performance varies by assay and referral setting. Plasma 3-methoxytyramine improves detection of dopamine-producing and SDHx-related disease. Exercise, acute illness, stress, posture, tricyclics, MAO inhibitors, sympathomimetics, selected antipsychotics, and analytical interference can cause false positives. Borderline normetanephrine elevation may be evaluated with clonidine suppression after correcting confounders. (casey2020geneticstratificationof pages 4-5, t.2024pheochromocytomaanupdated pages 6-7, t.2024pheochromocytomaanupdated pages 3-6)

Localization and staging

After biochemical confirmation, contrast CT of abdomen/pelvis is a usual first localization study; MRI is preferred in children, pregnancy, head-and-neck disease, and repeated hereditary surveillance. One review reported CT sensitivity of 88% and 90–95% localization accuracy for tumors >1.3 cm. (t.2024pheochromocytomaanupdated pages 6-7)

Functional imaging should be selected by genotype and therapeutic question:

• ^68Ga-DOTATATE/DOTA-SSA PET/CT: favored for SDHx, multifocal, metastatic, and head-and-neck disease; pooled detection approximately 93%.
• ^18F-FDOPA PET/CT: strong performance in VHL and cluster-2 adrenal disease; detection about 80% in one synthesis.
• ^18F-FDG PET/CT: useful for aggressive, dedifferentiated, and SDHB-associated disease; reported detection about 74%.
• ^123I-MIBG: principally to establish eligibility for ^131I-MIBG therapy; sensitivity 50–75% overall and <50% in SDHB-associated disease. (giacche2024pheochromocytoma–paragangliomasyndromea pages 10-12, t.2024pheochromocytomaanupdated pages 7-8, t.2024pheochromocytomaanupdated pages 8-9)

Pathology and genetics

Histology typically shows nests/trabeculae (“zellballen”) of granular neuroendocrine cells with sustentacular cells. Useful markers include chromogranin A, synaptophysin, INSM1, GATA3, tyrosine hydroxylase, and sustentacular S100/SOX10. Cytokeratin is usually absent or focal. SDHB loss screens for SDH deficiency; combined SDHA loss points toward SDHA. FH/2SC and MAX staining can guide genotype. PASS and GAPP provide risk stratification but cannot prove benignity or reliably predict an individual outcome. (casey2020geneticstratificationof pages 4-5, t.2024pheochromocytomaanupdated pages 7-8, t.2024pheochromocytomaanupdated pages 3-6)

All patients should be offered pre-test counseling and a germline multigene NGS panel with deletion/duplication detection. A practical panel includes SDHA/B/C/D, SDHAF2, VHL, RET, NF1, TMEM127, MAX, FH, MDH2, SLC25A11, DLST and other validated laboratory genes. If germline testing is negative, paired tumor-normal sequencing can identify somatic drivers and mosaicism. Combined analysis detects a driver in approximately 75–80%. VUS must not trigger cascade testing. (cascon2023geneticbasesof pages 1-2, casey2020geneticstratificationof pages 4-5, cascon2023geneticbasesof pages 6-8)

Differential diagnosis

Differentials include essential hypertension, panic disorder, hyperthyroidism, hypoglycemia, carcinoid syndrome, mast-cell activation, obstructive sleep apnea, medication/drug withdrawal, baroreflex failure, pseudopheochromocytoma, neuroblastoma, adrenal cortical adenoma/carcinoma, renal-cell carcinoma, schwannoma, and other neuroendocrine tumors. Biochemical metanephrine patterns, imaging location, and pathology resolve most cases.

11. Outcome and prognosis

Localized completely resected disease often has excellent long-term survival, but recurrence remains possible. Metastasis occurs in a minority—approximately 10–30% across heterogeneous series—and is more likely with SDHB/FH biology, extra-adrenal primary, larger tumor, dopamine/3-methoxytyramine production, high burden, and TERT/ATRX/MAML3 alterations. No single histologic or molecular marker is sufficiently accurate; expert reviews favor composite clinical, biochemical, imaging, pathological, and genomic assessment. (t.2024pheochromocytomaanupdated pages 1-2, giacche2024pheochromocytoma–paragangliomasyndromea pages 5-6, casey2020geneticstratificationof pages 4-5)

Morbidity reflects catecholamine-mediated cardiovascular injury, treatment toxicity, cranial-nerve deficits after head-and-neck intervention, metastatic pain/fracture, renal dysfunction, and lifelong surveillance burden. The precise median survival of metastatic disease is highly variable and should not be represented by one pooled number. In the pivotal high-specific-activity ^131I-MIBG cohort, median overall survival was 36.7 months, but that selected treatment population is not equivalent to all metastatic PPGL. (t.2024pheochromocytomaanupdated pages 7-8)

12. Treatment

Localized disease

Surgical excision is the only established curative treatment. Minimally invasive adrenalectomy is generally used for localized PCC under approximately 5–6 cm; open resection is favored for invasion, large/fragile tumors, selected SDHB-related PGLs, or when en-bloc resection and nodal dissection are required. Cortical-sparing adrenalectomy can preserve steroid function in selected bilateral hereditary PCC. Head-and-neck management may use observation, surgery, or radiotherapy according to growth, symptoms, cranial-nerve risk, age, and genotype. (t.2024pheochromocytomaanupdated pages 7-8)

Secretory tumors require preoperative alpha blockade first—phenoxybenzamine or a selective α1 antagonist such as doxazosin—plus salt/fluid repletion. A beta blocker may be added only after adequate alpha blockade for tachycardia; unopposed beta blockade can precipitate crisis. One guideline-based regimen starts phenoxybenzamine 10 mg twice daily, titrating up to 1 mg/kg/day, with beta blockade added 3–4 days later. Suggested NCIt concepts include adrenalectomy, tumor resection, phenoxybenzamine, doxazosin, and beta-adrenergic blockade. (t.2024pheochromocytomaanupdated pages 7-8)

Metastatic/unresectable disease

• Observation/local control: appropriate for asymptomatic, low-volume, stable disease. Surgery, ablation, embolization, external-beam or stereotactic radiotherapy, and cementoplasty can address oligometastases, pain, impending fracture, compression, or hormone burden.
• High-specific-activity ^131I-MIBG: FDA-approved in 2018 for MIBG-avid advanced PPGL. In 68 treated patients, 25% had durable antihypertensive-medication reduction, 92% had partial response or stable disease within 12 months, and median OS was 36.7 months; nausea, fatigue, and myelosuppression were common. (t.2024pheochromocytomaanupdated pages 7-8)
• ^177Lu-DOTATATE PRRT: used for strongly somatostatin-receptor-positive disease; current PPGL evidence is largely retrospective, with prospective phase II evaluation ongoing. (taieb2023clinicalconsensusguideline pages 19-21, t.2024pheochromocytomaanupdated pages 8-9)
• CVD chemotherapy: cyclophosphamide–vincristine–dacarbazine for rapidly progressive/high-burden disease; aggregated response approximately 37%, with complete responses uncommon.
• Temozolomide: oral alkylator, particularly rational in SDHB-deficient/MGMT-silenced disease; acquired MGMT expression or mismatch-repair defects may cause resistance. (t.2024pheochromocytomaanupdated pages 8-9)
• Sunitinib: FIRSTMAPP demonstrated 12-month progression-free survival in 36% versus 19% with placebo; grade 3–4 toxicities included asthenia and hypertension.
• Cabozantinib: Natalie phase II trial objective response 25% (4/16 evaluable patients).
• Axitinib: phase II partial response approximately 36% in the cited synthesis.
• Immunotherapy: not standard; response evidence remains limited. (t.2024pheochromocytomaanupdated pages 8-9)

Pharmacogenomic treatment selection currently reflects tumor biology more than host drug-metabolism genotype: MIBG/SLC6A2 avidity, SSTR expression, SDHB/MGMT status, VEGF-driven pseudohypoxia, and VHL/HIF-2α biology.

Trials and recent development

Retrieved ClinicalTrials.gov examples include NCT03206060, phase II ^177Lu-DOTATATE, recruiting, target n=130; NCT04394858, temozolomide±olaparib, active/not recruiting, n=46; NCT05636540, ^18F-fluorThanatrace PARP-1 PET, recruiting, n=30; NCT03946527, lanreotide, active/not recruiting, n=10; and NCT06429397, anlotinib plus benmelstobart, phase II, not yet recruiting, n=22. Trial status changes over time and should be rechecked before clinical use.

13. Prevention

There is no vaccine or proven population-level primary prevention. The effective prevention strategy is secondary and tertiary prevention:

1. universal germline testing of affected patients;
2. cascade testing of relatives only for pathogenic/likely pathogenic actionable variants;
3. lifelong gene-specific biochemical and MRI surveillance;
4. recognition and treatment before pregnancy or elective surgery;
5. perioperative alpha blockade to prevent crisis;
6. prompt management of hypertension, arrhythmia, cardiomyopathy, diabetes, and skeletal metastases. (casey2024internationalconsensusstatement pages 11-13, taieb2023clinicalconsensusguideline pages 19-21, t.2024pheochromocytomaanupdated pages 7-8)

For SDHD carriers, expert consensus recommends annual plasma metanephrines and whole-body MRI every 2–3 years; other genes use age- and risk-adapted intervals. Reproductive counseling may include prenatal or preimplantation genetic testing after a familial pathogenic variant is established. Population newborn screening is not indicated.

14. Other species and natural disease

Naturally occurring PCC/PGL occurs in companion and laboratory animals, especially dogs, cattle, and rats, but the retrieved evidence did not support reliable breed-specific incidence or VBO mappings. These tumors are not infectious or zoonotic and have no cross-species transmission. Orthologues of SDHx, VHL, RET, NF1, TMEM127, MAX, FH, and EPAS1 are broadly conserved, making comparative pathology biologically relevant. Veterinary PCC commonly resembles human chromaffin neuroendocrine morphology and catecholamine biology, but species-specific natural history limits direct therapeutic extrapolation.

Suggested taxonomy identifiers are Homo sapiens NCBI:9606, Mus musculus NCBI:10090, Rattus norvegicus NCBI:10116, Canis lupus familiaris NCBI:9615, and Bos taurus NCBI:9913.

15. Model organisms and experimental systems

Common models include rat PC12 pheochromocytoma cells, mouse MPC cells and metastatic derivatives, human PPGL primary cultures, patient-derived xenografts, organoids/spheroids, SDHB/SDHD knockdown systems, and genetically engineered mice affecting Nf1, Ret, Vhl, Sdh genes, Hif2a/Epas1, or Myc pathways. Three-dimensional cultures better model gradients, extracellular matrix, and drug penetration than conventional monolayers. (OpenTargets Search: pheochromocytoma,paraganglioma)

Major limitations are difficulty maintaining differentiated human chromaffin cells, incomplete spontaneous metastasis, species-specific catecholamine biology, and failure of many single-gene mouse models to reproduce the complete human syndrome. Current best practice uses complementary systems: human tumor multi-omics for discovery; isogenic cell models for mechanism; 3-D cultures for microenvironment/drug screening; and xenograft or engineered-animal models for pharmacology and dissemination.

Evidence appraisal and authoritative interpretation

The 2024 WHO-oriented molecular review emphasizes that all PPGLs are neoplasms with variable metastatic potential and that “no single biomarker alone can reliably predict metastatic risk.” Published October 2024; DOI. (t.2024pheochromocytomaanupdated pages 1-2)

The 2024 pediatric consensus—developed by 43 international experts—places germline testing, multidisciplinary care, genotype-adapted imaging, and lifelong surveillance at the center of management. Published September 2024; DOI. (casey2024internationalconsensusstatement pages 1-2, casey2024internationalconsensusstatement pages 11-13)

The clearest 2023–2024 advances are: broader universal paired germline/tumor sequencing; genotype-specific PET selection; prospective evidence for antiangiogenic TKIs; expansion of SSTR-directed theranostics; HIF-2α and DNA-repair-directed trials; and single-cell/multi-omics identification of microenvironment and resistance states. However, most treatment studies remain small because PPGL is rare, and several advanced-omics results are still preprints. (cascon2023geneticbasesof pages 1-2, t.2024pheochromocytomaanupdated pages 8-9)

Principal sources: Cascón et al., Journal of Molecular Endocrinology, April 2023, DOI 10.1530/JME-22-0167; Taïeb et al., Lancet Diabetes & Endocrinology, May 2023, DOI 10.1016/S2213-8587(23)00038-4; Casey et al., Nature Reviews Endocrinology, September 2024, DOI 10.1038/s41574-024-01024-5; Giacché et al., October 2024, DOI 10.3390/biomedicines12102385; Saavedra et al., Frontiers in Endocrinology, December 13, 2024, DOI 10.3389/fendo.2024.1433582.

References

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3. (cascon2023geneticbasesof pages 1-2): Alberto Cascón, Bruna Calsina, María Monteagudo, Sara Mellid, Alberto Díaz-Talavera, Maria Currás-Freixes, and Mercedes Robledo. Genetic bases of pheochromocytoma and paraganglioma. Journal of Molecular Endocrinology, Apr 2023. URL: https://doi.org/10.1530/jme-22-0167, doi:10.1530/jme-22-0167. This article has 92 citations and is from a peer-reviewed journal.

4. (t.2024pheochromocytomaanupdated pages 3-6): J. S. Saavedra T., Humberto Alejandro Nati-Castillo, L. A. Valderrama Cometa, Wilfredo A. Rivera-Martínez, Josué Asprilla, C. M. Castaño-Giraldo, Leonardo Sánchez S., Mishell Heredia-Espín, Marlon Arias-Intriago, and Juan S. Izquierdo-Condoy. Pheochromocytoma: an updated scoping review from clinical presentation to management and treatment. Frontiers in Endocrinology, Dec 2024. URL: https://doi.org/10.3389/fendo.2024.1433582, doi:10.3389/fendo.2024.1433582. This article has 47 citations.

5. (t.2024pheochromocytomaanupdated pages 6-7): J. S. Saavedra T., Humberto Alejandro Nati-Castillo, L. A. Valderrama Cometa, Wilfredo A. Rivera-Martínez, Josué Asprilla, C. M. Castaño-Giraldo, Leonardo Sánchez S., Mishell Heredia-Espín, Marlon Arias-Intriago, and Juan S. Izquierdo-Condoy. Pheochromocytoma: an updated scoping review from clinical presentation to management and treatment. Frontiers in Endocrinology, Dec 2024. URL: https://doi.org/10.3389/fendo.2024.1433582, doi:10.3389/fendo.2024.1433582. This article has 47 citations.

6. (casey2020geneticstratificationof pages 4-5): Ruth Casey, Hartmut PH Neumann, and Eamonn R Maher. Genetic stratification of inherited and sporadic phaeochromocytoma and paraganglioma: implications for precision medicine. Human molecular genetics, Oct 2020. URL: https://doi.org/10.1093/hmg/ddaa201, doi:10.1093/hmg/ddaa201. This article has 38 citations and is from a domain leading peer-reviewed journal.

7. (t.2024pheochromocytomaanupdated pages 7-8): J. S. Saavedra T., Humberto Alejandro Nati-Castillo, L. A. Valderrama Cometa, Wilfredo A. Rivera-Martínez, Josué Asprilla, C. M. Castaño-Giraldo, Leonardo Sánchez S., Mishell Heredia-Espín, Marlon Arias-Intriago, and Juan S. Izquierdo-Condoy. Pheochromocytoma: an updated scoping review from clinical presentation to management and treatment. Frontiers in Endocrinology, Dec 2024. URL: https://doi.org/10.3389/fendo.2024.1433582, doi:10.3389/fendo.2024.1433582. This article has 47 citations.

8. (giacche2024pheochromocytoma–paragangliomasyndromea pages 10-12): Mara Giacché, Maria Chiara Tacchetti, Claudia Agabiti-Rosei, Francesco Torlone, Francesco Bandera, Claudia Izzi, and Enrico Agabiti-Rosei. Pheochromocytoma–paraganglioma syndrome: a multiform disease with different genotype and phenotype features. Oct 2024. URL: https://doi.org/10.3390/biomedicines12102385, doi:10.3390/biomedicines12102385. This article has 10 citations.

9. (cascon2023geneticbasesof pages 6-8): Alberto Cascón, Bruna Calsina, María Monteagudo, Sara Mellid, Alberto Díaz-Talavera, Maria Currás-Freixes, and Mercedes Robledo. Genetic bases of pheochromocytoma and paraganglioma. Journal of Molecular Endocrinology, Apr 2023. URL: https://doi.org/10.1530/jme-22-0167, doi:10.1530/jme-22-0167. This article has 92 citations and is from a peer-reviewed journal.

10. (cascon2023geneticbasesof pages 4-5): Alberto Cascón, Bruna Calsina, María Monteagudo, Sara Mellid, Alberto Díaz-Talavera, Maria Currás-Freixes, and Mercedes Robledo. Genetic bases of pheochromocytoma and paraganglioma. Journal of Molecular Endocrinology, Apr 2023. URL: https://doi.org/10.1530/jme-22-0167, doi:10.1530/jme-22-0167. This article has 92 citations and is from a peer-reviewed journal.

11. (cascon2023geneticbasesof pages 2-4): Alberto Cascón, Bruna Calsina, María Monteagudo, Sara Mellid, Alberto Díaz-Talavera, Maria Currás-Freixes, and Mercedes Robledo. Genetic bases of pheochromocytoma and paraganglioma. Journal of Molecular Endocrinology, Apr 2023. URL: https://doi.org/10.1530/jme-22-0167, doi:10.1530/jme-22-0167. This article has 92 citations and is from a peer-reviewed journal.

12. (cascon2023geneticbasesof pages 5-6): Alberto Cascón, Bruna Calsina, María Monteagudo, Sara Mellid, Alberto Díaz-Talavera, Maria Currás-Freixes, and Mercedes Robledo. Genetic bases of pheochromocytoma and paraganglioma. Journal of Molecular Endocrinology, Apr 2023. URL: https://doi.org/10.1530/jme-22-0167, doi:10.1530/jme-22-0167. This article has 92 citations and is from a peer-reviewed journal.

13. (OpenTargets Search: pheochromocytoma,paraganglioma): Open Targets Query (pheochromocytoma,paraganglioma, 32 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

14. (giacche2024pheochromocytoma–paragangliomasyndromea pages 5-6): Mara Giacché, Maria Chiara Tacchetti, Claudia Agabiti-Rosei, Francesco Torlone, Francesco Bandera, Claudia Izzi, and Enrico Agabiti-Rosei. Pheochromocytoma–paraganglioma syndrome: a multiform disease with different genotype and phenotype features. Oct 2024. URL: https://doi.org/10.3390/biomedicines12102385, doi:10.3390/biomedicines12102385. This article has 10 citations.

15. (t.2024pheochromocytomaanupdated pages 8-9): J. S. Saavedra T., Humberto Alejandro Nati-Castillo, L. A. Valderrama Cometa, Wilfredo A. Rivera-Martínez, Josué Asprilla, C. M. Castaño-Giraldo, Leonardo Sánchez S., Mishell Heredia-Espín, Marlon Arias-Intriago, and Juan S. Izquierdo-Condoy. Pheochromocytoma: an updated scoping review from clinical presentation to management and treatment. Frontiers in Endocrinology, Dec 2024. URL: https://doi.org/10.3389/fendo.2024.1433582, doi:10.3389/fendo.2024.1433582. This article has 47 citations.

16. (taieb2023clinicalconsensusguideline pages 19-21): David Taïeb, George B Wanna, Maleeha Ahmad, Charlotte Lussey-Lepoutre, Nancy D Perrier, Svenja Nölting, Laurence Amar, Henri J L M Timmers, Zachary G Schwam, Anthony L Estrera, Michael Lim, Erqi Liu Pollom, Lucas Vitzthum, Isabelle Bourdeau, Ruth T Casey, Frédéric Castinetti, Roderick Clifton-Bligh, Eleonora P M Corssmit, Ronald R de Krijger, Jaydira Del Rivero, Graeme Eisenhofer, Hans K Ghayee, Anne-Paule Gimenez-Roqueplo, Ashley Grossman, Alessio Imperiale, Jeroen C Jansen, Abhishek Jha, Michiel N Kerstens, Henricus P M Kunst, James K Liu, Eamonn R Maher, Daniele Marchioni, Leilani B Mercado-Asis, Ozgur Mete, Mitsuhide Naruse, Naris Nilubol, Neeta Pandit-Taskar, Frédéric Sebag, Akiyo Tanabe, Jiri Widimsky, Leah Meuter, Jacques W M Lenders, and Karel Pacak. Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline sdhd pathogenic variants. May 2023. URL: https://doi.org/10.1016/s2213-8587(23)00038-4, doi:10.1016/s2213-8587(23)00038-4. This article has 113 citations and is from a highest quality peer-reviewed journal.

17. (casey2024internationalconsensusstatement pages 11-13): Ruth T Casey, Emile Hendriks, Cheri Deal, Steven G Waguespack, Verena Wiegering, Antje Redlich, Scott Akker, Rathi Prasad, Martin Fassnacht, Roderick Clifton-Bligh, Laurence Amar, Stefan Bornstein, Letizia Canu, Evangelia Charmandari, Alexandra Chrisoulidou, Maria Currás Freixes, Ronald De Krijger, Luisa De Sanctis, Antonio Fojo, Amol J Ghia, Angela Huebner, Vasilis Kosmoliaptsis, Michaela Kuhlen, Marco Raffaelli, Charlotte Lussey-Lepoutre, Stephen D Marks, Naris Nilubol, Mirko Parasiliti-Caprino, Henri HJLM Timmers, Anna Lena Zietlow, Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Ashley B Grossman, David Taïeb, Eamonn R Maher, Jacques WM Lenders, Graeme Eisenhofer, Camilo Jimenez, Karel Pacak, and Christina Pamporaki. International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents. JournalArticle, Sep 2024. URL: https://doi.org/10.17863/cam.111911, doi:10.17863/cam.111911. This article has 69 citations.

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