2025 欧洲临床指南：儿童和青少年肾上腺和肾上腺外副神经节瘤的治疗

Abstract

Background: Adrenal (formerly termed pheochromocytomas) and extra-adrenal paragangliomas (PGLs) in children and adolescents are rare neuroendocrine tumors characterized by unique biological behavior, a strong hereditary component, and significant risk of recurrence and metastatic progression. Their management requires specialized, multidisciplinary care.

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Objective: This guidance provides harmonized, evidence-graded recommendations for the diagnosis, treatment, and follow-up of pediatric PGL, developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) as part of the European Standard Clinical Practice (ESCP) initiative.

Methods: Recommendations were formulated through structured consensus by a multidisciplinary panel of experts in pediatric oncology, endocrinology, surgery, nuclear medicine, genetics, and pathology, based on literature review, existing international guidelines, and integration of external adviser feedback. Levels of evidence and grades of recommendation follow a simplified GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system.

Recommendations: Diagnosis should be based on plasma-free metanephrine and normetanephrine as first-line test, complemented by appropriate anatomical and functional imaging guided by biochemical phenotype and genotype. Germline genetic testing is recommended. Tumor resection remains the mainstay of curative treatment, with cortical-sparing adrenalectomy advised in bilateral hereditary cases (except SDHB). Management of metastatic disease should be individualized, incorporating radionuclide therapy, systemic treatments, focal therapies, and palliative care as appropriate. Lifelong surveillance is essential, tailored to genotype and disease characteristics.

Conclusion: This European clinical guidance offers practical recommendations to support multidisciplinary management of pediatric PGL within European healthcare systems, complementing existing international consensus statements and supporting harmonization of care.

Keywords: pediatric PGL, pheochromocytoma, paraganglioma, rare tumors, EXPeRT, clinical guidance

Significance

Children and adolescents with intra- and extra-adrenal paragangliomas (PGLs) differ biologically and clinically from adults and require age-adapted care. This European Standard Clinical Practice (ESCP) guidance, developed by the EXPeRT network, translates current evidence and expert consensus into pragmatic, graded recommendations for diagnosis, peri-operative management, surgery, imaging and genetic testing pathways, and long-term surveillance tailored to genotype and initial presentation. It clarifies when to use functional imaging, how to sequence focal and systemic therapies in unsectable/metastatic disease, and how to structure follow-up and transition to adult care. By harmonizing practice across European centers, this guidance aims to reduce diagnostic delay, improve peri-operative safety, and standardize longitudinal care for children and adolescents with PGL.

Introduction

Pheochromocytomas and paragangliomas (PGLs) are rare neu- roendocrine tumors arising from chromaffin cells of the adrenal medulla or from extra-adrenal paraganglia.$^{1,2}$ In the 2022 World Health Organization (WHO) classification, pheochro- mocytoma is designated as (intra-) adrenal PGL, within the uni- fied PGL family.$^{3}$ PGLs are further divided by autonomic lineage into sympathetic PGLs including adrenal PGLs and extra-adrenal sympathetic chain tumor, typically catechol- amine producing, and parasympathetic PGLs (predominantly head-and-neck; usually non-secretory). While more common in adults, their manifestation in children and adolescents presents unique biological and clinical challenges.$^{4,5}$ Pediatric PGLs differ from adult-onset disease in genetic predisposition, anatomical distribution, clinical presentation, and long-term behavior—necesitating age-adapted strategies for diagnosis, treatment, and follow-up. A hallmark of pediatric PGL is its strong hereditary basis. Up to 80% of pediatric patients harbor germline pathogenic variants (PV), in contrast to approximately 40% in adults.$^{6-12}$ These most commonly involve genes of the pseudohypoxia pathway—particularly Von Hippel Lindau (VHL) and SDHx (SDHB, SDHD, SDHC, SDHA, and SDHAF2)— but may also include multiple endocrine neoplasia (RET), Neurofibromatosis type 1 (NFI), MAX, and TMEM127.$^{8,9}$ The clinical phenotype typically reflects the underlying genotype: VHL PV often cause bilateral adrenal PGLs; SDHB and SDHD predispose to extra-adrenal PGLs, with SDHB associated with high metastatic risk; RET PVs (as in RET type 2; MEN2) lead to bilateral adrenal PGLs with as- sociated other endocrine neoplasms; and NF1-associated tu- mors occur in the context of neurocutaneous features. MAX and TMEM127 PVs are rare but recognized.

The estimated annual incidence is 0.5-2 cases per million children, with a median age at diagnosis between 11 and 15

years.$^{4-6,13-15}$ Although hypertension—often paroxysmal—is the most common presenting feature, additional or isolated symptoms of catecholamine excess such as palpitations, headaches, diaphoresis, pallor, or anxiety are frequent. In some cases, hypertensive crises may lead to seizures or hypertensive encephalopathy. Notably, even biochemically functional tumors may not present with hypertension, requiring a high index of suspicion.$^{5,15-18}$

Most pediatric PGLs are located in the abdomen: 70%-80% in the adrenal glands, 15%-20% as extra-adrenal PGLs near the aorta or organ of Zuckerkandl, and fewer in the pelvis or head and neck (HNPGLs).$^{6,8,9,19}$ Multifocal and bilateral disease is particularly common in hereditary cases. Among children with bilateral adrenal PGLs, genetic syndromes—especially VHL and RET PVs—are frequently identified, and long-term risks of metachronous disease must be considered.$^{20}$

The differential diagnosis depends on tumor location and age. For adrenal masses, key differential diagnoses include neuroblastoma (particularly in younger children), ganglioneuroma, adrenocortical tumors, and less common lesions such as teratomas, desmoid tumors, or adrenal cysts.

Given the rarity and complexity of pediatric PGL, affected patients should be managed in specialized centers with access to multidisciplinary teams (MDTs). While the recent international consensus statement offers broadly applicable recommendations for pediatric PGL diagnosis and management, it was designed for global generalizability and does not account for region-specific healthcare, regulatory, or pediatric oncology frameworks.$^{21}$ In contrast, this European Standard Clinical Practice (ESCP) guidance—developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT)—is explicitly designed for implementation across European pediatric oncology centers. It emphasizes actionable pathways tailored to European systems, integration

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into rare-tumor registries, biobanking and molecular networks, and harmonized workflows in European clinical practice. In doing so, it complements the consensus document by translating its principles into regionally appropriate, evidence-graded strategies for European children and adolescents with PGL.

Methods

This clinical guidance was developed through a structured consensus process led by EXPeRT, within the framework of the ESCP initiative and the PARTNER project, co-funded by the European Union Health Program. The guidance reflects multidisciplinary input from pediatric oncologists, endocrinologists, pediatric surgeons, radiologists, nuclear medicine physicians, geneticists, pathologists, and palliative care experts from multiple European countries.

The guidance was generated through a stepwise methodology:

1. A systematic review of the literature on pediatric and adult PGL, including existing international guidelines, consensus statements, and relevant clinical studies.

2. Drafting of initial recommendations by a core writing group based on available evidence and expert clinical practice.

3. Iterative review cycles within the EXPeRT network and with selected external reviewers to refine recommendations and address feedback.

4. Alignment of guidance with existing European pediatric oncology standards, rare tumor registry initiatives, and molecular biobanking efforts.

Recommendations were graded using a modified Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, as outlined in Table S1.

Grades of recommendation (A-C) were assigned based on both the level of evidence and the degree of clinical agreement. All recommendations included in this document represent consensus decisions by the full writing group, with endorsement from all contributors and advisers involved in the review process.

Recommendations

Initial clinical evaluation

PGLs in children and adolescents require a high index of clinical suspicion due to their rarity and often subtle or intermittent manifestations. A structured and multidisciplinary diagnostic approach is essential to facilitate early recognition, initiate timely investigations, and avoid critical complications.

Clinical presentation

Hypertension—either sustained or paroxysmal—is the most common presenting feature, occurring in approximately 70%-90% of pediatric cases. However, its absence does not exclude the diagnosis. Even biochemically functional tumors may fail to produce overt hypertension, and small or biochemically non-functional tumors may initially evade detection. Clinical vigilance is therefore required, especially in children with suggestive symptoms.

Typical features of catecholamine excess may include:

1. Episodic headaches

2. Palpitations or tachycardia

3. Excessive sweating (diaphoresis)

4. Pallor or flushing

5. Tremor

6. Anxiety or behavioral disturbance

7. Nausea or vomiting, particularly after exertion

8. Unexplained weight loss or failure to thrive

9. Hypertensive emergencies, including hypertensive encephalopathy, seizures, or transient visual disturbances (eg, bilateral scotoma)

These symptoms may occur singly or in combination and are often intermittent, contributing to delayed or missed diagnosis.$^{4,9,19,22-24}$

Family history and syndromic features

A thorough family history should assess for:

1. Known PGL, medullary thyroid carcinoma, or other (neuro-)endocrine tumors in first- or second-degree relatives

2. Early-onset or unexplained hypertension in family members

3. Manifestations consistent with hereditary syndromes, such as VHL disease, MEN2, or NF1.

Clinical recognition of syndromic stigmata (eg, retinal hemangioblastomas, mucosal neuromas, café-au-lait spots, or axillary freckling) may provide critical diagnostic clues and should prompt early referral for genetic counseling. [Level IV; Grade A]

Physical examination

Physical examination should be comprehensive and tailored to the suspected diagnosis. Important components include:

1. Repeated blood pressure measurements, including both supine and upright readings, to detect orthostatic changes

2. Cardiac auscultation for arrhythmias or murmurs

3. Abdominal and neck palpation to assess for masses

4. Detailed neurological assessment, especially in cases where PGL (eg, head and neck, spinal, or thoracic) is suspected

5. Fundoscopy to evaluate for hypertensive retinopathy

6. Ambulatory blood pressure monitoring in patients with suspected paroxysmal hypertension. [Level IV; Grade A]

Biochemical diagnosis

Biochemical confirmation of catecholamine excess is a cornerstone in diagnosing pediatric PGL. It guides the need for imaging, genetic testing, and preoperative management. Because PGL symptoms such as hypertension, palpitations, and headache are nonspecific, biochemical screening serves to identify high-risk cases and avoid unnecessary investigations in low-probability scenarios (Table 1).

Recommended tests

Plasma-free metanephrine are the recommended first-line investigations for suspected PGL in children. These metabolites reflect continuous catecholamine metabolism and offer superior sensitivity compared to direct

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Table 1. Recommended biochemical testing in pediatric PGL.

|Test|Indication|Notes| |---|---|---| |Plasma-free metanephrine and normetanephrine|First-line test for suspected PGL, especially in high-risk/genetic cases|Highest sensitivity; preferred in surveillance and early detection; most evidence from adult cohorts| |Urinary free metanephrine and normetanephrine|Alternative in younger children or when blood sampling is difficult|Requires age-adjusted reference ranges; lower sensitivity vs plasma| |Plasma 3-methoxytyramine|Noradrenergic tumors, known SDHx PV, metastatic disease surveillance|Marker of dopaminergic activity; associated with higher metastatic potential|

catecholamine measurement. This is especially relevant in children under surveillance for hereditary predisposition. However, the evidence base derives predominantly from adult cohorts $\frac{21,25-32}{3}$ [Level IV; Grade A]

Urinary free or fractionated normanephrine and meta-nephrine—particularly spot urine collections—are acceptable alternatives in younger children, where blood sampling may be challenging or distressing. Spot collections can be per-formed using urine collection bags in infants and toddlers, making this approach more feasible than 24-hour collections in this age group.$^{29}$ [Level IV; Grade B] Regardless of the matrix, age-adjusted reference intervals must be applied due to developmental variation in catecholamine metabolism and ex-cretion (Table S2).$^{21,32-35}$

Adjunct biomarkers

Plasma 3-Methoxytyramine (3-MT): Recommended in patients with noradrenergic biochemical profiles, known SDHx mutations, or suspected metastatic disease.$^{36}$ Elevated 3-MT indicates dopaminergic activity, which is often linked to higher metastatic potential (eg, SDHB mutations, some head and neck PGLs), and may raise suspicion for metastatic spread warranting further evaluation.$^{37,38}$ [Level IV; Grade B]

Serum Chromagranin A (CgA): May be considered in selected cases—particularly for suspected non-functional tumors—but has limited diagnostic utility in pediatric PGL. Pediatric-specific data are lacking. In mixed-age or adult cohorts, CgA demonstrates variable performance, with sensitivity ranging from 79%-84% and specificity from 77%-91%, depending on tumor secretory profile, renal function, and use of proton pump inhibitors. CgA may be useful when elevated at baseline prior to surgery, allowing for postoperative monitoring in individual cases.$^{39,40}$ [Level V; Grade C]

Biochemical phenotypes and interpretation

Categorization of tumors by biochemical phenotype supports targeted imaging and management:

1. Adrenergic phenotype: Elevated plasma free metanephrine above the reference limit, contributing > 5% of the combined excess of metanephrine and normetanephrine. Associated with adrenal tumors, RET PVs, or NF1 PVs.

2. Noradrenergic phenotype: Predominant elevation of normethanephrine, with metanephrine within range or accounting for <5% of the total excess. Typical in extra-adrenal PGLs and pseudohypoxic cluster variants (eg, VHL, SDHx).

3. Dopaminergic phenotype: Elevated 3-MT alone or in combination with normetanphrine. In SDHB-associated tumors, this pattern correlates with an increased risk of metastatic disease. In HNPGL, isolated

3-MT elevation does not in itself imply metastatic potential.

These biochemical phenotypes may provide clues to tumor site, heritable background, or metastatic potential, but are not definitive and must always be interpreted in conjunction with imaging and genetic testing. [Level IV; Grade B]

Pre-analytical considerations

Several modifiable factors influence the accuracy of biochemical testing:

1. Dietary intake: For 3-MT measurement, patients should avoid catecholamine-precursor foods (eg, bananas, chocolate, caffeine) for at least 12 hours or overnight.$^{21,36,41}$ [Level V; Grade B]

2. Medication interference: Tricyclic antidepressants, nasal decongestants, and beta-blockers may alter test results. Where feasible, interfering medications should be paused, particularly in cases of borderline elevation.

3. Sampling conditions: Supine blood sampling after at least 20 minutes of rest reduces stress-related fluctuations.$^{21,25,42-45}$

These factors are especially relevant when results are bor-derline—defined as less than a twofold increase above the upper reference limit. In such cases, repeat testing is warranted after modifying confounding factors. Persistent uncertainty should prompt MDT review.$^{21,36,46}$ [Level IV; Grade B]

Imaging

Imaging is a cornerstone in the diagnosis and management of pediatric PGL, essential for confirming tumor presence, delin-eating anatomical extent, detecting multifocal or metastatic disease, and guiding surgical planning. In children, imaging protocols must prioritize diagnostic accuracy while minimizing cumulative radiation exposure due to their long-term risk of radiation-induced malignancy.

Anatomical imaging is mandatory. Functional imaging is recommended when multifocal or metastatic disease is suspected, or when genetic/biochemical features indicate higher metastatic risk (eg, extra-adrenal tumors, SDHB PV). Where feasible, these modalities should be coordinated to avoid during, reduce anesthetic requirements, and streamline staling. [Level V; Grade B]

Anatomical imaging

Magnetic resonance imaging (MRI) is the preferred modality for initial anatomical assessment. It provides excellent soft tissue contrast and avoids ionizing radiation, making it suitable for repeated use during surveillance.$^{47-49}$ MRI of the abdomen

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and pelvis should be considered the minimum initial imaging in all patients, as these sites represent the most common tumor locations.$^{21,50}$ [Level IV; Grade A]

When germline results are pending or unavailable prior to surgery, consider a one-time extended baseline staging (adding thoracic and neck/skull-base MRI) to exclude multifocal or synchronous disease, given the high prevalence of heritable PGL in children and the potential delay in genetic results. This is especially pertinent when biochemistry is noradrenergic/dopaminergic, tumor is extra-adrenal, symptoms suggest thoracic or cervical mass effect, or there is clinical/family suspicion of SDHx. [Level IV; Grade A]

Computed tomography (CT) is reserved for specific indications—such as MRI contraindications (eg, incompatible implants, severe claustrophobia), or inconclusive MRI findings. In particular, contrast-enhanced CT is recommended for evaluating mediastinal PGLs or for detailed preoperative planning in extra-adrenal abdominal and pelvic tumors, where visualization of surrounding vascular and soft tissue structures is essential. Bone involvement and vascular invasion may also be better appreciated on CT. When used, low-dose pediatric CT protocols should be applied$^{21}$,$^{47}$⁻$^{49}$,$^{51}$ [Level IV; Grade B]

Functional imaging

Functional imaging complements MRI/CT and identifies biologically active tumor tissue, supports whole-body staging, and informs theranostic eligibility. It should be considered particularly in suspected multifocal/metastatic disease, extra-adrenal tumors, high-risk genotypes (SDHx), or when results of biochemistry/anatomical studies are inconclusive. Selection should be guided primarily by genetic background, tumor site, and local availability. (Table 2)$^{21,27}$ [Level IV; Grade B] SDHx-related PGL and HNPGLs: [68Ga]Ga-DOTATATE PET/CT is preferred owing to higher sensitivity, particularly

in metastatic sympathetic and head- and neck-disease.$^{52-56}$ [Level IV; Grade B]

Non-SDHx adrenal PGL (including sporadic and VHL, RET, MAX, TMEM127): [18F]F-DOPA PET/CT is generally most sensitive for adrenal PGL and small-volume disease.$^{21}$,$^{56}$,$^{57}$ [Level IV; Grade B]

Metastatic non-SDHx adrenal PGL: [18F]F-DOPA PET/CT and [68Ga]Ga-DOTA-SSA PET/CT show similar sensitivity; selection can be individualized based on availability and the clinical question (staging vs. theranostics).$^{56}$ [Level IV; Grade B]

[18F]F-FDG PET/CT is not first-line for initial localization; consider in aggressive, dedifferentiated, or rapidly progressive disease (eg, some SDHB-associated tumors) to assess glucose-tytic activity.$^{52-55,58,59}$ [Level IV; Grade B]

[123]IJ-MIBG scintigraphy is no longer preferred for diagnostic localization given lower sensitivity versus PET tracers. Its main role is therasonic selection where [131I]I MIBG therapy is contemplated.$^{52,59,61}$ [Level IV; Grade B]

Functional imaging complements anatomical studies for whole-body staging and theranostic eligibility. When genetic testing is pending, inconclusive, or negative—and especially with a noradrenergic phenotype—whole body imaging may be considered to exclude multifocal or metastatic disease. Begin with the most likely genotype-/site-appropriate tracer based on tumor location and family history, and confirm once results are available. [Level IV; Grade B]

Genetic testing

Given the high rate of heritability in pediatric PGL, genetic testing plays a central role in diagnosis, management, family counseling, and long-term surveillance. Unlike adult-onset PGL, where sporadic forms are more common, approximately

Table 2. Functional imaging in pediatric PGL—genotype-/site-first selection.

|Genetic background/clinical context|Preferred functional imaging|Acceptable alternatives/when to use|Primary purpose(s)/notes| |---|---|---|---| |SDHx-related PGL|[$^{68}$Ga]Ga-DOTA-SSA PET/CT|[$^{18}$F]F-FDG PET/CT (aggressive/rapidly progressive disease); [$^{18}$F]F-DOPA PET/CT (if DOTA-SSA unavailable|Highest sensitivity for SDHx, incl. metastatic & head/neck sites; FDG not first-line but helpful for aggressive biology| |Head & neck PGL (parasympathetic, often non-secretory; many SDHx)|[$^{68}$Ga]Ga-DOTA-SSA PET/CT|—|DOTA-SSA outperforms other tracers for HNPGL localization and staging| |Non-SDHx adrenal PGL (incl. VHL, RET/MEN2, MAX, TMEM127; sporadic)|[$^{18}$F]F-DOPA PET/CT|[$^{84}$Ga]Ga-DOTA-SSA PET/CT (similar sensitivity in metastatic non-SDHx adrenal PGL); [$^{123}$I]I-MIBG scintigraphy (if considering MIBG therapy)|FDOPA generally most sensitive for adrenal PGL and small-volume disease; choose DOTA-SSA or FDOPA pragmatically where similar| |Metastatic non-SDHx adrenal PGL|[$^{18}$F]F-FDG PET/CT or [$^{68}$Ga]Ga-DOTA-SSA PET/CT|Selection based on availability and clinical question (staging vs theranositics)|Adult evidence suggests similar sensitivity; tailor to downstream therapy (eg, PRT eligibility).| |Unknown/negative germline PV, noradrenergic phenotype, extra-adrenal location suspected|[$^{68}$Ga]Ga-DOTA-SSA PET/CT|[$^{18}$F]F-DOPA PET/CT (if adrenal primary more likely)|While genetics pending, use genotype-/site-based likelihood; escalate to whole-body staging when risk higher| |Aggressive, poorly differentiated, rapidly progressive disease (any genotype)|[$^{18}$F]F-FDG PET/CT|Add DOTA-SSA or FDOPA as per genotype/site to complete staging|FDG reflects glycolytic activity; not first-line for localization but useful in high-grade/aggressive behavior| |Theranostic selection for MIBG therapy|[$^{123}$I]I-MIBG scintigraphy therapy|—|Diagnostic role mainly to confirm avidity for [$^{131}$I]I-MIBG therapy; lower sensitivity than PET for localization.|

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80% of pediatric cases harbor germline PVs. Consequently, pediatric PGL should be considered hereditary until proven otherwise.$^{6,9,10}$

Rationale and timing

Universal germline genetic testing is recommended for all children and adolescents with PGL, irrespective of tumor site, biochemical profile, or family history. [Level IV; Grade A] Early identification of a causative PV:

1. Supports risk stratification by predicting the likelihood of multifocality, bilateral involvement, or metastatic potential, thus guiding surgical planning and follow-up intensity.$^{62}$

2. Enables syndrome-specific surveillance, such as screening for associated neoplasms in patients with VHL, RET, or other syndromes

3. Facilitates cascade testing in family members, allowing for early detection and preventive care in asymptomatic carriers.

4. Informs long-term care, including transition into adult services and reproductive counseling.

Genetic testing should ideally be initiated as early as possible—preferably preoperatively if the result might influence surgical decisions (eg, cortical-sparing adrenalectomy). If this is not feasible, testing should be expedited postoperatively, assuming a hereditary basis until results are available. [Level IV; Grade B]

Genes to be included

Comprehensive panels should encompass genes from both major molecular clusters:

1. Pseudohypoxic cluster: VHL, SDHA, SDHB, SDHC, SDHD, EPAS1, FH (note: germline EPAS1 variants are rare; most variants are in this gene are somatic or mosaic)

2. Kinase signaling cluster: RET, TMEM127, MAX.

While NF1 is strongly associated with PGL, its diagnosis is generally based on clinical criteria (eg, revised NIH diagnostic features), and it is typically not included in standard germline panels. Somatic variants (eg, in CSDE1, MAML3) may be informative for tumor profiling but do not affect heritability. Panels should be periodically revised to incorporate novel gene associations. [Level IV; Grade A]

Tumor and somatic testing

In the absence of germline PVs, somatic tumor sequencing may yield additional insights, particularly in patients with multi-focal disease or atypical histopathology. Somatic profiling can also help identify candidates for clinical trials or future molecularly guided therapies.$^{21,63}$ [Level V; Grade B]

Counseling and family implications

Pre- and post-test genetic counseling are essential for informed decision-making. Families should be supported throughout the testing process, including the psychosocial implications of positive findings. [Level IV; Grade A]

When germline PV is confirmed, cascade testing and risk-adapted surveillance should be offered to first-degree relatives.

In cases where variants of uncertain significance (VUS) are detected, interpretation requires expert input. Routine cascade screening for VUS is not recommended. Psychological support should be available to families navigating the uncertainty or emotional burden associated with genetic findings.

Preoperative management

Preoperative preparation is critical in pediatric PGL to mitigate perioperative cardiovascular risks, particularly hypertensive crises and arrhythmias triggered by tumor manipulation, and optimize surgical outcomes. Management focuses on cateholamine blockade, intravascular volume restoration, and coordinated surgical planning. Early multidisciplinary involvement is essential to optimize outcomes.

Medical preparation

Alpha-adrenergic blockade is the cornerstone of preoperative management and should be initiated at least 7-14 days prior to surgery.$^{21,25,64}$

Phenoxybenzamine, a non-selective, long-acting alpha-blocker, is widely used for its sustained antihypertensive effect, though it may cause nasal congestion, fatigue, or reflex tachycardia. However, it is not available in all countries.

Selective alpha-1 lockers (eg, doxazosin) offer a shorter half-life and potentially fewer side effects, and may be preferred in some centers.

The dosing goal is to achieve mild orthostatic hypotension, typically a fall in systolic blood pressure of up to ~20 mmHg or a diastolic of ~10 mmHg on standing, while maintaining tolerable supine pressures. Interpretation should reference age-, sex-, and height-specific pediatric blood pressure percences (eg, European Society of Hypertension 2016 guidelines, German KIGGS study/percentile curves).$^{65}$⁻$^{67}$ [Level IV; Grade A]

Beta-blockers may be introduced only after alpha blockade has been established to control tachycardia or arrhythmias. Initiation before alpha blockade is contraindicated due to the risk of hypertensive crises from unopposed alpha stimula- tion.$^{21}$,$^{25}$,$^{68}$⁻$^{70}$ [Level IV; Grade A]

Calcium channel blockers (eg, nicardipine) or methyltyro-sine (if available) may be used in selected cases with refractory hypertension, although pediatric-specific evidence is limited.$^{25,64}$ [Level V; Grade B]

Volume expansion is vital to reverse chronic vasoconstric- tion and restore plasma volume. Liberal salt intake and in- creased oral fluids are recommended, with intravenous hydration considered before and on the day of surgery.$^{21}$ [Level IV; Grade A]

Constipation prevention should be implemented proactive-ly as alpha-blockade may impair gut motility. High-fiber diet, adequate hydration, stool softeners, and osmotic laxatives may be used to minimize discomfort and avoid perioperative complications. [Level IV; Grade B]

Cardiovascular assessment

Chronic catecholamine exposure can result in myocardial dysfunction, necessitating preoperative cardiac evaluation in at-risk patients:

Echocardiography is advised for those with sustained hypertension, dual catecholaminergic profiles, or signs of cardiac impairment. It helps assess left ventricular hypertrophy,

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systolic and diastolic dysfunction, or catecholamine-induced cardiomyopathy. [Level IV; Grade B]

ECG and/or Holter monitoring are recommended in the presence of arrhythmias, persistent tachycardia, or high arrhythmic risk, to detect conduction abnormalities and guide intraoperative planning. [Level V; Grade B]

Surgical management

Surgical resection is the mainstay of curative treatment for localized pediatric PGL. (Figure 1) Surgery should be performed in specialized centers with expertise in pediatric endocrine oncologic and minimally invasive techniques (laparoscopic and/or robotic). Preoperative planning must occur within an MDT, including pediatric surgeons, endocrinologists, oncologists, anesthetists, radiologists, and nuclear medicine specialists. The surgical strategy should be individualized based on tumor characteristics, genetic background, and anatomical considerations. [Level III; Grade A]

Surgical principles

The primary goal is complete resection with clear margins while minimizing morbidity and preserving adrenal and surrounding organ function. Preoperative imaging and biochemical findings inform the surgical approach, particularly in the context of hereditary disease, multifocality, or suspected malignancy. [Level III; Grade A]

Cortical-sparing adrenalectomy

Cortical-sparing adrenalectomy should be considered in synchronous bilateral adrenal PGLs, particularly in hereditary syndromes such as VHL or MEN2, to preserve adrenal cortical function and avoid lifelong adrenal insufficiency.$^{21,71,72}$ [Level IV–V; Grade B]

In unilateral adrenal PGL with a known or suspected hereditary background (eg, VHL, RET), this approach may also be appropriate owing to the high risk of metachronous contratateral tumors, enabling preservation of future adrenal reserve. [Level IV-V; Grade B]

Cortical-sparing adrenalectomy is not indicated in patients with SDHB PVs, due to increased risk of local recurrence and malignant transformation. [Level IV-V; Grade B]

Where germline results are pending, the default is total adrenalectomy unless clinical features strongly support a low-malignancy hereditary context (eg, classic VHL/RET phenotype with small bilateral adrenal PGLs and adrenergic biochemistry). Cortical-sparing surgery should be avoided while awaiting results if features suggest SDHB/SDHx (eg, noradre-nergic/dopaminergic profile with elevated 3-MT, extra-adrenal or metastatic disease, large/heterogeneous mass). Decisions should be finalized in an MDT prioritizing onco-logic safety. [Level V; Grade B]

Adrenal tumor approach

Minimally invasive adrenalectomy (laparoscopic or robotic) is the preferred technique for localized tumors without evidence of invasion, provided it is performed in centers with expertise in pediatric endocrine and oncologic surgery. It offers faster recovery and reduced postoperative morbidity.$^{73-75}$ [Level IV; Grade A]

Open adrenalectomy is indicated when there is suspicion of local invasion, when tumors are anatomical complex, or when tumor size makes minimally invasive approaches technically challenging. [Level III; Grade B] Note: Tumor size is an important consideration: while many centers apply a threshold of 5-6 cm to favor open resection, others report safe minimally invasive approaches for larger tumors in experienced hands.

![graph TD\n A1[Intra-/ extra-adrenal Paraganglioma(PGL) Multidisciplinary discussion] --> A2[(Multi-) Focal?]\n A2 -->|Yes| A3[Resectable at all sites?]\n A2 -->|No| A4[Metastatic PGL]\n A3 -->|Yes| A5[First-line Surgery]\n A3 -->|No| A6[Unresectable PGL]\n A4 --> A6\n A5 --> A8[R0/R1 resection?]\n A6 --> A7[Threatening symptoms and/or progressive disease?]\n A7 -->|Yes| A10[Discuss focal therapies#]\n A7 -->|No| A11[Watch & Wait*]\n A8 -->|Yes| A9[Surveillance]\n A8 -->|No| A12[R2 resection and threatening symptoms?]\n A12 -->|Yes| A13[Re-resection]\n A12 -->|No| A14[Watch & Wait*]\n](1/parseimages/figured54dfb8cae12447d9fb5ee1605704fcf_0_15.png) Figure 1. Flowchart of recommended diagnostic and therapeutic approach for localized or resectable pediatric adrenal and extra-adrenal PGL. This diagram outlines key decision points including assessment of focality, resectability, surgical management, and the role of surveillance, re-resection, or focal therapies following initial surgery.

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Whenever feasible, children should be referred to expert centers to optimize outcomes. [Level IV; Grade B]

Extra-adrenal PGLs

These tumors are often located near critical neurovascular structures (eg, para-aortic, pelvic, mediastinal). Open resection remains standard in complex or high-risk locations. [Level IV; Grade B]

Minimally invasive approaches (laparoscopic or thoracoscopic, standard and/or robotic-assisted) may be considered in selected cases, but should be performed only in high-volume centers with established expertise in both pediatric oncologic and minimally invasive surgery. [Level IV; Grade C]

Detailed preoperative imaging and intraoperative neuromonitoring may aid in safe dissection and reduce complications. [Level IV; Grade B]

Anesthetic considerations

Anesthetic planning is essential and should be coordinated with the surgical team well in advance.

Invasive arterial blood pressure monitoring and large-bore intravenous access are mandatory.

Anesthesia teams should be experienced in managing catecholamine-secreting tumors, with access to vasoactive medications and antiarrhythmic agents intraoperatively. [Level III; Grade A]

Biopsy

Preoperative biopsy is generally contraindicated due to the risk of catecholamine surge and tumor seeding. [Level IV; Grade A]

If histological confirmation is required for unresectable disease or atypical tumors, biopsy should proceed only after

MDT consensus, be performed via a retroperitoneal approach in experienced centers, and—when biochemistry is positive—only under prior α-adrenergic blockade with appropriate per-procedural monitoring and vasoactive medications immediately available. [Level V; Grade B]

Management of metastatic and unresectable disease

Metastatic and unresectable pediatric PGL requires individualized, multidisciplinary care aimed at balancing disease control, symptom palliation, and preservation of quality of life over what is often a prolonged disease course (Figure 2).$^{21}$,$^{76}$,$^{77}$ Metastatic disease is present in approximately 10%-20% of pediatric patients at diagnosis, with higher frequencies—up to 30%-50%—reported in cohorts enriched for hereditary conditions, particularly SDHB PVs.$^{6}$,$^{15}$,$^{47}$ Clinical behavior ranges from indolent to rapidly progressive disease, necessitating risk-adapted strategies informed by tumor burden, symptom profile, and molecular background.

General principles

In asymptomatic patients with low-volume, indolent disease active surveillance (“watchful waiting”) may be appropriate, with regular biochemical and imaging follow-up. [Level V; Grade B]

Intervention is indicated for symptomatic or progressive disease, high tumor burden, or functional tumors with uncontrolled catecholamine secretion. In SDHB-associated PGL, MDTs should more proactively evaluate cytoreductive strategies (eg, debulking surgery or focal therapies), given the higher malignant potential and young age at onset. Decisions should be guided by MDTs with expertise in nuclear medicine, systemic therapies, surgery, and supportive care. [Level IV; Grade A]

![graph TD\n A1[Metastatic PGL] --> A2[Primary resectable?]\n A1 --> A7[Distant sites treatable?]\n A2 -->|Yes| A3[Primary Surgery]\n A2 -->|No| A4[Threatening symptoms and/or progressive disease?]\n A3 --> A5[Primary complete resection?Complete control of distant sites?]\n A4 -->|Yes| A11[Possibility of partial therapy of various tumor sites?]\n A4 -->|No| A12[Watch & Wait*]\n A5 -->|Yes （R0/RI）| A6[Watch & Wait*]\n A5 -->|No| A4\n A7 -->|Yes| A8[Focal therapies #]\n A7 -->|No| A9[Threatening symptoms and/or progressive disease?]\n A8 --> A5\n A9 -->|Yes| A11\n A9 -->|No| A12\n A11 -->|Yes| A10[Debulking resection（s）Focal therapies #]\n A11 -->|No| A13[Systemic therapy]\n A13 --> A14[Tumor symptoms controlled?]\n A14 -->|Yes| A12\n A14 -->|No| A13\n](1/parseimages/figure6e5c2176ca97412b80c5ece0b64fb0d3_0_20.png) Figure 2. Flowchart of recommended management of metastatic or unresectable pediatric adrenal and extra-adrenal PGL. The diagram illustrates treatment pathways for metastatic disease, including decision points for surgery, focal therapies, debulking, systemic therapies (PRRT, MIBG therapy, targeted therapy, chemotherapy), and indications for surveillance (watch and wait). Abbreviations: PRRT = somatostatin receptor-directed peptide receptor radionuclide therapy; MIBG = metaiodobenzylguanidine.

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Systemic radionuclide therapies

[131]IJ-MIBG therapy is recommended for MIBG-avid meta-static PGL requiring tumor control or symptomatic relief. Treatment should be delivered in experienced centers with appropriate radiation safety protocols.$^{78-80}$ [Level IV; Grade B]

Note: The high-specific-activity [131]I-I-MIBG formulation (iobenguane, Azedra®), which showed improved tumor targeting, is no longer commercially available. Conventional [131]I-I-MIBG remains in clinical use.

Peptide receptor radionuclide therapy (PRRT) using radioactive STTR ligands such as [177Lu]Lu-DOTATATE may be considered in DOTATATE-avid tumors unsuitable for MIBG therapy.$^{81}$ Given the limited pediatric data, PRRT should ideally be delivered in clinical trials or following detailed MDT review.$^{82-86}$ [Level V; Grade B]

Chemotherapy

Cyclophosphamide, vincristine, dacarbazine (CVD) chemotherapy is reserved for aggressive or rapidly progressing disease due to its toxicity profile.$^{87}$⁻$^{90}$ [Level IV; Grade C]

Temozolomide is generally well tolerated and has demonstrated activity in adult and limited pediatric series.$^{91,92}$ [Level IV; Grade B]

Targeted therapies

Tyrosine kinase inhibitors (eg, sunitinib) may be considered in refractory progressive disease, though monitoring for toxicity (eg, hypertension, fatigue) is essential.$^{93}$,$^{94}$ [Level V; Grade B]

HIF2α inhibitors (eg, belzutifan) have been considered investigational in PGL, with little pediatric data. However, as of May 14, 2025, the U.S. Food and Drug Administration has approved belzutifan for adult and pediatric patients aged 12 years and older with locally advanced, unresectable, or metastatic PGL.$^{95,96}$ Despite this approval, experience in children, long-term outcomes, optimal dosing, and integration with other therapies remain limited. [Level V; Grade C]

Local and focal therapies

Surgical debulking may be appropriate in oligometastatic cases to relieve symptoms or reduce catecholamine output. [Level V; Grade B]

Radiotherapy (conventional or stereotactic) may be used for unresectable or symptomatic lesions such as bone metastases. Highly conformal techniques are preferred to reduce long-term toxicity.$^{21,70}$ [Level V; Grade B]

Surveillance and palliative care

Ongoing surveillance with periodic imaging, biochemical monitoring, and clinical assessment is essential for patients managed conservatively. [Level V; Grade B]

Early integration of palliative care supports symptom control and enhances quality of life. It should be part of the MDT for patients with advanced or symptomatic disease. [Level V; Grade A]

Follow-up and surveillance

Given the lifelong risk of recurrence, development of new primary tumors, and metastatic progression—particularly in those with hereditary PGL—long-term follow-up is essential. Surveillance strategies should be risk-adapted, reflecting

|Measure|First 5 years post-treatment|Beyond 5 years| |---|---|---| |Biochemistry (metanephrine ± 3-methoxytyramine)|Every 6-12 months|Every 1-2 years, tailored to risk| |MRI|Baseline at 6-12 months post-op, then every 1-3 years|Every 1-3 years, tailored to risk| |Functional imaging|As indicated by abnormal biochemistry or symptoms|As indicated|

tumor biology, genetic background, and prior treatments (Table 3).$^{8}$,$^{21}$,$^{97}$

Biochemical surveillance

Regular monitoring of plasma-free or urinary metanephrine and normetanephrine is recommended to detect biochemical recurrence. [Level IV; Grade A]

Plasma 3-MT should be added in patients with noradrener- gic or dopaminergic tumors, SDHx PVs, or prior metastatic disease, where it may serve as an early marker of recurrence or progression.$^{21}$ [Level IV; Grade A]

Suggested intervals:

1. Every 6-12 months during the first 5 years post-resection. Interist intervals (6 months) are advised for high-risk patients (eg, SDHB PV carriers).

2. Every 1-2 years thereafter, based on risk factors, prior recurrence, and stability of biochemical parameters. [Level IV; Grade B]

Imaging surveillance

MRI is the modality of choice due to its lack of ionizing radiation. Surveillance protocols should be tailored to the patient's genotype and initial tumor presentation. Standard follow-up includes abdominal and pelvic MRI. Cervical and thoracic imaging is warranted in those with SDHx PVs or prior extra-adrenal disease, or when the primary tumor arose in these regions. In SDHx-related disease, skull base and neck MRI at 3-5 year intervals is specifically recommended, in addition to abdominal and and pelvic imaging. [Level IV; Grade A]

Suggested intervals:

1. Baseline MRI at 6-12 months postoperatively.

2. Repeat MRI every 1-3 years, tailored to genotype, tumor characteristics, and biochemical results. Annual imaging may be warranted in high-risk scenarios. [Level IV; Grade B]

Functional imaging (eg, [68Ga]Ga-DOTATATE PET/CT, MIBG scintigraphy) should be reserved for cases with biochemical relapse or inconclusive anatomical imaging.$^{21}$ [Level IV; Grade B]

Syndrome-specific surveillance

Patients with hereditary PGL require tumor screening according to the associated syndrome:

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1. VHL syndrome: CNS hemangioblastomas, pancreatic neuroendocrine neoplasms, renal cell carcinoma

2. RET: Medullary thyroid carcinoma, parathyroid disease

3. NF1: Optic pathway gliomas, other neurocutaneous manifestations

Coordination with syndrome-specific specialists is essential for comprehensive care.$^{21}$ [Level IV; Grade A]

Documentation and education

Surveillance plans should be clearly documented, including genetic findings, surgical history and biochemical/imaging schedules. Families should receive education on recurrence signs, associated tumor risks, and the importance of adherence to long-term follow-up. Patient engagement is critical to ensure continuity of care. [Level V; Grade A]

Transition to adult care

Given the lifelong risk of recurrence and the need for continued surveillance in pediatric PGL, a structured and well-coordinated transition to adult care is essential. Poorly managed transitions may lead to gaps in monitoring, loss to follow-up, and delayed recognition of recurrence or associated tumors.$^{21}$

Transition planning should begin in adolescence, with a gradual process that includes education, empowerment, and shared consultations between pediatric and adult care teams to ensure familiarity and continuity.

A comprehensive transition summary should be provided to the adult team and include:

1. Genetic findings and implications for cascade testing and reproductive counseling

2. Details of prior surgical and medical management

3. Individualized surveillance schedules with justification

4. Recommendations for syndrome-specific tumor screening and risk-based monitoring of late effects. [Level V; Grade A]

Psychosocial support should be incorporated to address the emotional and practical challenges of transitioning care, particularly for adolescents with chronic health needs or complex genetic syndromes. [Level V; Grade B]

Conclusion

Pediatric PGLs represent rare, complex neuroendocrine tumors that require highly specialized, multidisciplinary management and lifelong surveillance. Their distinct biological characteristics—including a high prevalence of hereditary pre-disposition, early onset, and increased risk of multifocality and metastatic progression—necessitate pediatric-specific approaches that differ substantially from practice in adult patients.

This guidance, developed under the ESCP initiative by the EXPeRT group, offers practical, evidence-graded recommendations to support standardized, high-quality care for children and adolescents with PGL across Europe. It underscores the importance of MDT decision-making, the integration of genotype-driven diagnostic and surgical strategies, and individualized long-term follow-up tailored to risk profiles.

While these recommendations reflect current best practices, several aspects of pediatric PGL remain under-researched. Ongoing collaboration across European and international networks is essential to strengthen the evidence base, address remaining uncertainties, and improve outcomes for affected children, adolescents, and families.

Acknowledgments

The authors gratefully acknowledge the continuous collaboration of the wider EXPeRT community. Special thanks to all participating institutions, clinicians, and patient families whose engagement with rare tumour research contributes to improved care. Several authors of this publication are members of the European Reference Network on Paediatric Cancer (ERN PaedCan).

Supplementary material

Supplementary material is available at European Journal of Endocrinology online.

Funding

The authors received funding for this work. The French FRACTURE group is supported by „SFCE—Enfants Cancers et Santé“. The German MET-Registry is supported by the German Childhood Cancer Foundation. The Italian TREP Registry has been partially supported by Fondazione Giovanni Celeghin, ONLUS. The open access publication of this article was supported by the publication fund of the University of Augsburg.

Authors' contributions

Michaela Kuhlen (Conceptualization [equal], Data curation [lead], Formal analysis [lead], Funding acquisition [equal], Methodology [equal], Project administration [lead], Resources [lead], Visualization [equal], Writing—original draft [lead]), Caloger Virgone (Formal analysis [supporting], Writing—review & editing [equal]), Charlotte Rigaud (Formal analysis [supporting], Writing—review & editing [equal]), Sabine Irtan (Formal analysis [supporting], Writing—review & editing [equal]), Ruth Casey (Formal analysis [supporting], Writing—review & editing [equal]), Christina Pamporaki (Formal analysis [supporting], Writing—review & editing [equal]), Marina Kunstreich (Writing—review & editing [equal]), Ricardo Lopez-Almaraz (Writing—review & editing [equal]), Tal Ben-Ami (Writing—review & editing [equal]), Ewa Bien (Writing—review & editing [equal]), Malgorzata A. Krawczyk (Writing—review & editing [equal]), Andrea Ferrari (Writing—review & editing [equal]), Gianni Bisogno (Writing—review & editing [equal]), Yves Reguerre (Writing—review & editing [equal]), Michael Abele (Formal analysis [supporting], Writing—review & editing [equal]), Dominik T. Schneider (Writing—review & editing [equal]), Jörg Fuchs (Formal analysis [supporting], Writing—review & editing [equal]), Ines B. Brecht (Writing—review & editing [equal]), Beate Timmermann (Formal analysis [supporting], Writing—review & editing [equal]), Ronald R. de Kiriger (Formal analysis [supporting], Writing—review & editing [equal"), Constantin Lapa (Formal analysis [supporting], Writing—original draft [supporting], Writing—review & editing [equal]), Constantin Lapa (Formal analysis [supporting], Writing—original draft [supporting], Writing—review & editing

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editing [equal]), Antje Redlich (Formal analysis [supporting], Writing—review & editing [equal]), and Daniel Orbach (Formal analysis [equal], Writing—original draft [equal], Writing—review & editing [equal])

All authors contributed to the development of these clinical practice recommendations. The manuscript was conceptualized and coordinated by Michaela Kuhlen and Daniel Orbach. Literature review, drafting of individual sections (Beate Timmermann, Constantin Lapa, and Ronald R. de Krijger), and iterative review were performed by coauthors within a multidisciplinary working group. All authors contributed to the final manuscript, approved its content, and agreed to its submission for publication.

Conflict of interest: The authors have no conflicts of interest to declare.

Compliance with ethical standards

Ethics approval and consent to participate: Not applicable. This article is a clinical guideline/consensus statement that synthesizes published literature and expert opinion; no new human subjects, interventions, or access to identifiable patient data were involved, and institutional review board/independent ethics committee approval was therefore not required.

Compliance with the Declaration of Helsinki: This work does not report research involving human participants. Recommendations were developed in accordance with accepted standards for guideline methodology and good clinical practice.

References

1. Furlan A, Adameyko I. Schwann cell precursor: a neural crest cell in disguise? Dev Biol. 2018;444(Suppl 1):S25-S35. https://doi.org/10.1016/j.ydbio.2018.02.008

2. Kameneva P, Artemov AV, Kastriti ME, et al. Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin. Nat Genet. 2021;53(5):694-706. https://doi.org/10.1038/s41588-021-00818-x

3. Mete O, Asa SL, Gill AJ, Kimura N, de Krijger RR, Tischler A. Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas. Endocr Pathol. 2022;33(1):90-114. https://doi.org/10.1007/s12022-022-09704-6

4. Ciftio AO, Tanyel FC, Senocak ME, Buyukpamku N. Pheochromocytoma in children. J Pediatr Surg. 2001;36(3): 447-452. https://doi.org/10.1053/jpuu.2001.21612

5. Hume DM. Pheochromocytoma in the adult and in the child. Am J Surg. 1969;99(4):458-496, https://doi.org/10.1016/0002-961(60):90410-6

6. Pamporaki C, Hamplova B, Peitzsch M, et al. Characteristics of pediatric vs adult pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2017;102(4):1122-1132. https://doi.org/10.1210/jc.2016-3829

7. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in non-drom the paphecromocytoma. N Engl J Med. 2002; 346(19):1459-1466. https://doi.org/10.1056/NEJMoa020152

8. de Tersant M, Genere L, Freycon C, et al. Pheochromocytoma and paraganglioma in children and adolescents: experience of the French society of pediatric oncology (SFCE). J Endocr Soc. 2020;4(5):bvaa039, https://doi.org/10.1210/jendsoo/bvaa039

9 Redlich A, Pamporaki C, Lessel L, Fruhwald MC, Vorserb P, Kuhlen M. Pseudohypoxic pheochromocytomas and paragangliomas dominate in children. Pediatr Blood Cancer. 2021;68(7): e28981. https://doi.org/10.1002/pbc.28981

10. Fishbein L, Lesh�iner I, Walter V, et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31(2):181-193. https://doi.org/10.1016/j.ccell.2017.01.001

11. Gieldon L, William D, Hackmann K, et al. Optimizing genetic workup in pheochromocytoma and paraganglioma by integrating diagnostic and research approaches. Cancers (Basel). 2019;11(6): 809. https://doi.org/10.3390/cancers11060809

12. Monteagudo M, Calsina B, Salazar-Hidalgo ME, et al. MAML3-fusions modulate vascular and immune tumour micro-environment and confer high metastatic risk in pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2024;38(6):101931. https://doi.org/10.1016/j.beem.2024.101931

13. Bausch B, Wellner U, Bausch D, et al. Long-term prognosis of patients with pediatric pheochromocytoma. Endocr Relat Cancer. 2014;21(1):17-25. https://doi.org/10.1530/ERC-13-0415

14. Wyszynska T, Cichocka E, Wieteska-Klimczak A, Jobs K, Januszewicz P. A single pediatric center experience with 1025 children with hypertension. Acta Paediatr. 1992;81(3):244-246. https://doi.org/10.1111/j.1651-2227.1992.tb12213.x

15. Barontini M, Levin G, Sanso G. Characteristics of pheochromocytoma in a 4- to 20-year-old population. Ann N Y Acad Sci. 2006;1073(1):30-37. https://doi.org/10.1196/annals.1353.003

16. Chandar J, Zilleruelo G. Hypertensive crisis in children. Pediatr Nephrol. 2012;27(5):741-751. https://doi.org/10.1007/s00467-011-1964-0

17. Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366(9486):665-675. https://doi.org/10.1016/S0140-6736(05)67139-5

18. Reddy VS, O'Neill JA, Jr., Holcomb GW, 3rd, et al. Twenty-five-year surgical experience with pheochromocytoma in children. Am Surg. 2000;66(12):1085-1091; discussion 92. https://doi.org/10.1177/000313480006601201

19. Virgone C, Andreetta M, Avanzini S, et al. Pheochromocytomas and paragangliomas in children: data from the Italian Cooperative Study (TREP). Pediatr Blood Cancer. 2020;67(8): e28332. https://doi.org/10.1002/pbc.28332

20. Kittah NE, Gruber LM, Bancos I, et al. Bilateral pheochromocytoma: clinical characteristics, treatment and longitudinal follow-up. Clin Endocrinol (Oxf). 2020;93(3):288-295. https://doi.org/10.1111/cen.14222

21. Casey RT, Hendriks E, Deal C, et al. International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents. Nat Rev Endocrinol. 2024;20(12):729-748. https://doi.org/10.1038/s41574-024-01024-5

22. Perel Y, Schlumberger M, Marguerite G, et al. Pheochromocytoma and paraganglioma in children: a report of 24 cases of the French Society of Pediatric Oncology. Pediatr Hematol Oncol. 1997; 14(5):413-422. https://doi.org/10.3109/08880019709028771

23. King KS, Darmani NA, Hughes MS, Adams KT, Pacak K. Exercise-induced nausea and vomiting: another sign and symptom of heochromocytoma and paraganglioma. Endocrine. 2010; 37(3):403-407. https://doi.org/10.1007/s12020-010-9319-3

24. Geroula A, Deutschbein T, Langton K, et al. Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion. Eur J Endocrinol. 2019;181(4):409-420. https://doi.org/10.1530/EJE-19-0159

25. Lenders JW, Dub QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942. https://doi.org/10.1210/jc.2014-1499

26. Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR. Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med. 1999;340(24): 1872-1879. https://doi.org/10.1056/NEJM199906173402404

G124

European Journal of Endocrinology, 2025, Vol. 193, No. 6

27. Eisenhofer G, Lenders JW, Timmers H, et al. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011;57(3):411-420. https://doi.org/10.1373/clinchem.2010.153320 28. Eisenhofer G, Peitzsch M, Bechmann N, Huebner A. Biochemical diagnosis of catecholamine-producing tumors of childhood: neuroblastoma, pheochromocytoma and paraganglioma. Front Endocrinol (Lausanne). 2022;13:901760. https://doi.org/10.3389/fendo.2022.901760 29. Eisenhofer G, Prejbisz A, Peitzsch M, et al. Biochemical diagnosis of chromaffin cell tumors in patients at high and low risk of disease: plasma versus urinary free or deconjugated O-methylated catecholamine metabolites. Clin Chem. 2018;64(11):1646-1656. https://doi.org/10.1373/clinchem.2018.291369 30. Sarathi V, Pandit R, Patil VK, Lia AR, Bandgar TR, Shah NS. Performance of plasma fractionated free metanephrines by enzyme immunoassay in the diagnosis of phochemocytoma and paraganglioma in children. Endocr Pract. 2012;18(5):694-699. https://doi.org/10.4158/EP12050.OR 31. Weise M, Merke DP, Pacak K, Walther MM, Eisenhofer G. Utility of plasma free metanephrines for detecting childhood pheochromocytoma. J Clin Endocrinol Metab. 2002;87(5):1955-1960. https://doi.org/10.1210/jcem.87.5.8444 32. Peitzsch M, Kaden D, Pamporaki C, et al. Overnight/first-morning urine free metanephries and methoxytyramine for diagnosis of pheochromocytoma and paraganglioma: is this an option? Eur J Endocrinol. 2020;182(5):499-509. https://doi.org/10.1530/EJE-19-1016 33. Zuo M, Zhen Q, Zhang X, et al. High specificity of spot urinary free metanephries in diagnosis and prognosis of pheochromocytomas and paragangliomas by HPLC with electrochemical detection. Clin Chim Acta. 2018;478:82-89. https://doi.org/10.1016/j.cca.2017.12.026 34. Peitzsch M, Mangelis A, Eisenhofer G, Huebner A. Age-specific pediatric reference intervals for plasma free normetanephrine, metanephrine, 3-methoxytyramine and 3-O-methyldopa: particular importance for early infancy. Clin Chim Acta. 2019;494: 100-105. https://doi.org/10.1016/j.cca.2019.03.1620 35. Pussard E, Neveux M, Guigueno N. Reference intervals for urinary catecholamines and metabolites from birth to adulthood. Clin Biochem. 2009;42(6):536-539. https://doi.org/10.1016/j.clinbiochem.2008.10.022 36. Eisenhofer G, Pamporaki C, Lenders JWM. Biochemical assessment of pheochromocytoma and paraganglioma. Endocr Rev. 2023;44(5):862-909. https://doi.org/10.1210/endrev/bnad011 37. Gao X, Eladari D, Levi F, et al. Deletion of hensin/DMBT1 blocks conversion of beta-to alpha-intercalated cells and induces distal re nal tubular acidosis. Proc Natl Acad Sci U S A. 2010;107(50): 21872-21877. https://doi.org/10.1073/pnas.1010364107 38. Patin F, Criniere L, Francia T, et al. Low specificity of urinary 3-methoxytyramine in screening of dopamine-secreting pheochromocytomas and paragangliomas. Clin Biochem. 2016;49(15): 1205-1208. https://doi.org/10.1016/j.clinbiochem.2016.05.008 39. Bilek R, Vlck V, Safarik L, et al. Chromagranin A in the laboratory diagnosis of pheochromocytoma and paraganglioma. Cancers (Basel). 2019;11(4):586. https://doi.org/10.3390/cancers11040586 40. Xing Y, Shi H, Guo Q, Wang C, Li C, Hao C. Chromagranin A as a diagnostic marker of pheochromocytoma and paraganglioma: a systematic review and meta-analysis. Int J Urol. 2024;31(6): 637-645. https://doi.org/10.1111/iju.15423 41. de Jong WH, Eisenhofer G, Post WJ, Muskiet FA, de Vries EG, Kema IP. Dietary influences on plasma and urinary metanephries: implications for diagnosis of catecholamine-producing tumors. J Clin Endocrinol Metab. 2009;94(8):2841-2849. https://doi.org/10.1210/jc.2009-0303 42. Robertson D, Johnson GA, Robertson RM, Nies AS, Shand DG, Oates JA. Comparative assessment of stimuli that release neuronal

and adrenomedullary catecholamines in man. Circulation. 1979;59(4):67-643. https://doi.org/10.1161/01.CIR.59.4.637 43. Deutschbein T, Unger N, Hauffa BP, Schaaf K, Mann K, Petersenn S. Monitoring medical treatment in adolescents and young adults with congenital adrenal hyperplasia: utility of salivary 17alpha-hydroxyprogesterone day profiles. Exp Clin Endocrinol Diabetes. 2011;119((0331):131-138. https://doi.org/10.1055/s-0030-1255104 44. Darr R, Pamporaki C, Peitzsch M, et al. Biochemical diagnosis of phaeochromocytoma using plasma-free normetanephrine, meta-nephrine and methoxytyramine: importance of supine sampling under fasting conditions. Clin Endocrinol (Oxf). 2014;80(4): 478-486. https://doi.org/10.1111/cen.12327 45. Boyd J, Leung AA, Sadrzadeh HS, et al. A high rate of modestly ele-vated plasma normetanephrine in a population referred for sus-pected PPLG when measured in a seated position. Eur J Endocrinol. 2019;181(3):301-309. https://doi.org/10.1530/EJE-19-0176 46. Eisenhofer G, Goldstein DS, Walther MM, et al. Biochemical diag-nosis of pheochromocytoma: how to distinguish true- from false-positive test results. J Clin Endocrinol Metab. 2003;88(6): 2656-2666. https://doi.org/10.1210/jc.2002-030005 47. Pham TH, Moir C, Thompson GB, et al. Pheochromocytoma and paraganglioma in children: a review of medical and surgical man-agement at a tertiary care center. Pediatrics. 2006;118(3): 1109-1117, https://doi.org/10.1542/peds.2005-2299 48. Hanafy AK, Mujtaba B, Roman-Colon AM, et al. Imaging features of adrenal gland masses in the pediatric population. Abdom Radiol (NY). 2020;45(4):964-981. https://doi.org/10.1007/s00261-019-02213-x 49. Melo-Leite AF, Elias PC, Teixeira SR, et al. Adrenocortical neo-plasms in adulthood and childhood: distinct presentation. Review of the clinical, pathological and imaging characteristics. J Pediatr Endocrinol Metab. 2017;30(3):253-276. https://doi.org/10.1515/jpem-2016-0080 50. Ilias I, Pacak K. Current approaches and recommended algorithm for the diagnostic localization of pheochromocytoma. J Clin Endocrinol Metab. 2004;89(2):479-491. https://doi.org/10.1210/jc.2003-031091 51. Goldstein RE, O'Neil JA, Jr., Holcomb GW, 3rd, et al. Clinical ex-perence over 48 years with pheochromocytoma. Ann Surg. 1999;229(6):755-764; discussion 64-6. https://doi.org/10.1097/0000658-199906000-00001 52. Taieb D, Hicks RJ, Hindie E, et al. European association of nuclear medicine practice guideline/society of nuclear medicine and molecu-lar imaging procedure standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2019;46(10):2112-2137. https://doi.org/10.1007/s00259-019-04398-1 53. Jha A, Patel M, Carrasquillo JA, et al. Sporadic primary pheochro-mocytoma: a prospective intraindividual comparison of six imaging tests (CT, MRI, and PET/CT using (68)Ga-DOTATATE, FDG, (18)F-FDOPA, and (18)F-FDA). AJR Am J Roentgenol. 2022;218(2):342-350. https://doi.org/10.2214/AJR.21.26071 54. Janssen I, Blanchet EM, Adams K, et al. Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modal-ities in the localization of SDHB-associated metastatic pheochro-mocytoma and paraganglioma. Clin Cancer Res. 2015;21(17): 3888-3895. https://doi.org/10.1158/1078-0432.CCR-14-2751 55. Janssen I, Chen CC, Taieb D, et al. 68Ga-DOTATATE PET/CT in the localization of head and neck paragangliomas compared with other functional imaging modalities and CT/MRI. J Nucl Med. 2016;57(2):186-191. https://doi.org/10.2967/jnumed.115.161018 56. Ebbehoj A, 1versen P, Kramer S, et al. Positron emission tomog-raphy imaging of pheochromocytoma and paraganglioma. -18-FDOPA vs somatostatin analogues. J Clin Endocrinol Metab. 2025;110(2):303-316. https://doi.org/10.1210/clinem/dgae 764

Kuhlen et al.

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57. Fiebrich HB, Brouwers AH, Kerstens MN, et al. 6-[F-18]fluoro-L-dihydroxyphenylalanine positron emission tomography is superior to conventional imaging with (123)I-metaiodobenzylguanidine scintigraphy, computer tomography, and magnetic resonance imaging in localizing tumors causing catecholamine excess. J Clin Endocrinol Metab. 2009;94(10): 3922-3930. https://doi.org/10.1210/jc.2009-1054 58. Jaiswal SK, Sarathi V, Malhotra G, et al. The utility of (68(Ga-DOTATATE PETCT in localizing primary/metastatic pheochromocytoma and paraganglioma in children and adolescents—a single-center experience. J Pediatr Endocrinol Metab. 2021;34(1):109-119. https://doi.org/10.1515/jpem-2020-0354 59. Timmers H, Taieb D, Pacak K, Lenders JVM. Imaging of pheochromocytomas and paraganglioma. Endor Rev. 2024;45(3): 414-434. https://doi.org/10.1210/endrev/bnae001 60. Timmers HJ, Kozupa A, Chen CC, et al. Superiority of fluorodeoxygucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma. J Clin Oncol. 2007;25(16): 2262-2269. https://doi.org/10.1200/CO.2006.09.6297 61. Sung C, Lee HS, Lee DY, et al. A prospective comparative study of 18F-FDOPA PET/CT versus 1231-MIBG scintigraphy with SPECT/CT for the diagnosis of pheochromocytoma and paraganglioma. J Clin Nducel Med. 2024;49(1):27-36. https://doi.org/10.1097/RLU.00000000004963 62. Jongmans MC, Loeffen JL, Waanders E, et al. Recognition of genetic predisposition in pediatric cancer patients: an easy-to-use selection tool. Eur J Med Genet. 2016;59(3):116-125. https://doi.org/10.1016/j.ejmg.2016.01.008 63. Crona J, Verdugo AD, Granberg D, et al. Next-generation sequencing in the clinical genetic screening of patients with pheochromocytoma and paraganglioma. Endor Connect. 2013;2(2):104-111. https://doi.org/10.1530/EC-13-0009 64. Seamon ML, Yamaguchi I. Hypertension in pheochromocytoma and paraganglioma: evaluation and management in pediatric patients. Carr Hypertens Rep. 2021;23(3):32. https://doi.org/10.1007/s11906-021-01150-9 65. Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140(3):e20171904. https://doi.org/10.1542/peds.2017-1904 66. Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016; 34(10):1887-1920. https://doi.org/10.1097/HJH.00000000000000001039 67. Neuhauser HK, Thamm M, Ellert U, Hense HW, Rosario AS. Blood pressure percentiles by age and height from nonoverweight children and adolescents in Germany. Pediatrics. 2011;127(4):e978-e988. https://doi.org/10.1542/peds.2010-1290 68. Lenders JWM, Kerstens MN, Amar I, et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J Hypertens. 2020;38(8):1443-1456. https://doi.org/10.1097/HJH.000000000000002438 69. Yip L, Duh QY, Wachtel H, et al. American association of endocrine surgeons guidelines for adrenalectomy: executive summary. JAMA Surg. 2022;157(10):870-877. https://doi.org/10.1001/jamasurg.2022.3544 70. Fishbein L, Del Rivero J, Else T, et al. The north American neuroendocrine tumor society consensus guidelines for surveillance and management of metastatic and/or unresectable pheochromocytoma and paraganglioma. Pancreas. 2021;50(4):469-493. https://doi.org/10.1097/MPA.000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000000

2(8):e198898. https://doi.org/10.1001/jamanetworkopen.2019.8898 72. Jochmanova I, Abcede AMT, Guerrero RJS, et al. Clinical characteristics and outcomes of SDHB-related pheochromocytoma and paraganglioma in children and adolescents. J Cancer Res Clin Oncol. 2020;146(4):1051-1063. https://doi.org/10.1007/s00432-020-03138-5 73. Walz MK, Iova LD, Deimel J, et al. Minimally invasive surgery (MIS) in children and adolescents with pheochromocytomas and retroperitoneal paragangliomas: experiences in 42 patients. World J Surg. 2018;42(4):1024-1030. https://doi.org/10.1007/s00268-018-4488-y 74. Heloury Y, Muthucumaru M, Panabokke G, Cheng W, Kimber C, Leclair MD. Minimally invasive adrenalectomy in children. J Pediatr Surg. 2012;47(2):415-421. https://doi.org/10.1016/j.ipedsurg.2011.08.003 75. Chen Y, Scholten A, Chomsky-Higgins K, et al. Risk factors associated with perioperative complications and prolonged length of stay after laparoscopic adrenalectomy. JAMA Surg. 2018;153(11):1036-1041. https://doi.org/10.1001/jamasurg.2018.2648 76. Hescot S, Lebolleux S, Amar L, et al. One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98(10):4006-4012. https://doi.org/10.1210/jc.2013-1907 77. Pamporaki C, Prodanov T, Meuter L, et al. Determinants of disease-specific survival in patients with and without metastatic pheochromocytoma and paraganglioma. Eur J Cancer. 2022;169:32-41. https://doi.org/10.1016/j.ejca.2022.03.032 78. Thorpe MP, Kane, Zhu J, Morse MA, Wong T, Borges-Neto S. Long-term outcomes of 125 patients with metastatic pheochromocytoma or paraganglioma treated with 131-I MIBG. J Clin Endocrinol Metab. 2020;105(3):e494-e501. https://doi.org/10.12101/cm.dinz/047.1001/nedz/074 79. Wakabayashi H, Inaki A, Yoshimura K, et al. A phase I clinical trial for [(131)I]meta-iodobenzylguanidine therapy in patients with re-fractory pheochromocytoma and paraganglioma. Sci Rep. 2019;9(1):7625. https://doi.org/10.1038/s41598-019-43880-6 80. van Hulsteijn LT, Niemeijer ND, Dekkers OM, Corssmit EP. (131)I-MIBG therapy for malignant paraganglioma and phaeo-chromocytoma: systematic review and meta-analysis. Clin Endocrinol (Oxf). 2014;80(4):487-501. https://doi.org/10.1111/cen.12341 81. Gaze MN, Handkiewicz-Junak D, Hladun R, et al. Safety and dos-imetry of [(177)Lu-DOTA-TATE in adolescent patients with somatostatin receptor-positive gastroenteropancreatic neuroendo-crine tumours, or pheochromocytomas and paragangliomas: Primary analysis of the Phase II NETTER-P study. Eur J Nucl Med Mol Imaging. 2025;52(11):4001-4015. https://doi.org/10.1007/s00259-025-07246-7 82. Ziegler CG, Brown JW, Schally AV, et al. Expression of neurope-tide hormone receptors in human adrenal tumors and cell lines: antiproliferative effects of peptide analogues. Proc Natl Acad Sci U S A. 2009;106(37):15879-15884. https://doi.org/10.1073/pnas.0907843106 83. Van Essen M, Krenning EP, Jong DM, Valkema R, Kwekkeboom DJ. Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor posi-tive tumours. Acta Oncol. 2007;46(6):723-734. https://doi.org/10.1080/02841860701441848 84. Foster JH, Sher A, Seghers V, et al. Peptide receptor radionuclide therapy for treatment of metastatic neuroendocrine tumors in chil drenan. Pediatr Blood Cancer. 2021;68(7):e29056. https://doi.org/10.1002/pbc.29056 85. Kuo MJM, Nazari MA, Jha A, Pacak K. Pediatric metastatic pheochromocytoma and paraganglioma: clinical presentation and diag-nosis, genetics, and therapeutic approaches. Front Endocrinol (Lausanne). 2022;13:936178. https://doi.org/10.3389/fendo.2022.936178

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86. Huibregtse KE, Vo KT, DuBois SG, et al. Incidence and risk factors for secondary malignancy in patients with neuroblastoma after treatment with (131)I-metaiodobenzylguanidine. Eur J Cancer. 2016;66:144-152. https://doi.org/10.1016/j.ejca.2016.07.017 87. Huang H, Abraham J, Hung E, et al. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22-year follow-up of 18 patients. Cancer. 2008;113(8):2020-2028. https://doi.org/10.1002/cncr.23812 88. Jawed I, Velarde M, Darr R, et al. Continued tumor reduction of metastatic pheochromocytoma/paraganglioma harboring succinate dehydrogenase subunit B mutations with cyclical chemotherapy. Cell Mol Neurobiol. 2018;38(5):1099-1106. https://doi.org/10.1007/s10571-018-0579-4 89. Asai S, Katabami T, Tsuiki M, Tanaka Y, Naruse M. Controlling tumor progression with cyclophosphamide, vincristine, and dacarbazine treatment improves survival in patients with metastatic and unresectable malignant pheochromocytomas/paragangliomas. Horm Cancer. 2017;8(2):108-118. https://doi.org/10.1007/s126-720-017-0284-7 90. Ayala-Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra-adrenal paragangliomas: insights from the largest single-institutional experience. Cancer. 2012;118(11): 2804-2812. https://doi.org/10.1002/cncr.26577 91. Urquhart C, Fleming B, Harper I, et al. The use of temozolomide in paediatric metastatic phaeochromocytoma/paraganglioma: a case

report and literature review. Front Endocrinol (Lausanne). 2022;13:1066208. https://doi.org/10.3389/fendo.2022.1066208 92. Perez K, Jacene H, Hornick JL, et al. SDHx mutations and temozo-lomide in malignant pheochromocytoma and paraganglioma. Endocr Relat Cancer. 2022;29(9):533-544. https://doi.org/10.1530/ERC-21-0392 93. O'Kane GM, Ezzat S, Joshua AM, et al. A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial. Br J Cancer. 2019;120(12):1113-1119. https://doi.org/10.1038/s41416-019-0474-x 94. Zhou Y, Cui Y, Zhang D, Tong A. Efficacy and safety of tyrosine kinase inhibitors in patients with metastatic pheochromocytomas/ paragangliomas. J Clin Endocrinol Metab. 2023;108(3):755-766. https://doi.org/10.1210/clinem/dgac657 95. Kamihara J, Hamilton KV, Pollard JA, et al. Belzutifan, a potent HIF2alpha inhibitor, in the pacak-zhuang syndrome. N Engl J Med. 2021;385(22):2059-2065. https://doi.org/10.1056/NEJMoa 2110051 96. Toledo RA, Jimenez C, Armaiz-Pena G, Arenillas C, Capdevila J, Dahia PLM. Hypoxia-inducible factor 2 alpha (HIF2alpha) inhibi-tors: targeting genetically driven tumor hypoxia. Endocr Rev. 2023;44(2):312-322. https://doi.org/10.1210/endrev/bnac025 97. King KS, Prodanov T, Kantorovich V, et al. Metastatic pheochro-mocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol. 2011;29(31):4137-4142. https://doi.org/10.1200/ J Clin Oncol. 2011;29(31):4137-4142. https://doi.org/10.1200/ JCO.2011.34.6353