Imaging and Targeted Radiation Therapy for Pheochromocytoma and Paraganglioma: A Patient’s Guide

Table of Contents

• Key Points
• What Are Pheochromocytomas and Paragangliomas (PPGLs)?
• Genetics: The Cluster Framework That Guides Imaging
• Cellular Targets: Why These Tumors Light Up on Scans
• Where Diagnosis Begins: Blood and Urine Testing
• Choosing the Right Imaging Test
• SSTR PET: A First-Line Scan and Gateway to PRRT
• 18F-FDOPA PET: Best for Certain Gene Types
• 18F-FDG PET: A Window Into Aggressive Tumor Biology
• 123I-MIBG Imaging: The Theranostic Bridge to Therapy
• Radioligand Therapies: How Targeted Radiation Works
• 131I-MIBG Therapy: FDA-Approved Option
• PRRT With 177Lu-DOTATATE: High Disease Control Rates
• Investigational Alpha-PRRT (225Ac-DOTATATE)
• What This Means for Patients
• Limitations of the Current Evidence
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• PPGLs are rare neuroendocrine tumors; up to 30–40% are linked to germline pathogenic variants, so genetic testing should guide imaging and family screening.
• SSTR PET is recommended first-line for SDHx (cluster 1A) tumors, with sensitivity reaching 94–100% across prospective and retrospective trials.
• 18F-FDOPA is preferred for VHL/EPAS1 and many adrenal or cluster 2 tumors, but currently has no matched therapeutic radionuclide partner in PPGLs.
• HSA 131I-MIBG is FDA-approved for metastatic PPGL but not commercially available; in its pivotal phase II trial, disease control exceeded 90%.
• In a prospective NIH phase II trial of 36 evaluable patients, 177Lu-DOTATATE PRRT gave 6-month progression-free survival of 86% and median PFS of 20 months.

What Are Pheochromocytomas and Paragangliomas (PPGLs)?

Pheochromocytoma (PHEO) and paraganglioma (PGL), together called PPGLs, are rare neuroendocrine tumors (NETs). They arise from neural crest cells, the same cells that form parts of the nervous system during development. PHEOs start in the adrenal medulla, the inner core of the adrenal glands. PGLs start in paraganglia, clusters of nerve-related cells outside the adrenal glands.

These tumors are highly vascular, meaning they grow a dense network of blood vessels. Tumors of the sympathetic nervous system, located in the abdomen and some posterior thoracic (chest) areas, can secrete catecholamines. Catecholamines are hormones such as epinephrine (adrenaline), norepinephrine, and dopamine that drive the body’s “fight or flight” response. By contrast, the parasympathetic tumors of the head, neck, and mediastinum (the space between the lungs) usually do not produce hormones. Only about 4% of these secrete catecholamines.

The current World Health Organization (WHO) classification avoids the words “benign” and “malignant.” Every PPGL has metastatic potential, meaning it can spread. Metastasis is the defining criterion of malignancy in these tumors. In practice, metastatic disease occurs in roughly 10% of PHEOs and in 20–40% of PGLs.

PPGLs are among the most strongly inherited of all tumors. Up to 30–40% of cases are linked to germline pathogenic variants, which are gene changes present from birth that increase disease risk. Genetic research has identified more than 20 key contributing genes. These include SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2), VHL, RET, MEN1, NF1, FGFR1, TMEM127, MAX, FH, EPAS1/HIF2A, SUCGL2, SLC25A11, DLST, IDH2, and MDH2.

Genetics: The Cluster Framework That Guides Imaging

Molecular profiling now directly guides imaging through a practical framework built around genetic clusters. The gene a patient carries strongly predicts which scan will see the tumor best. This genotype-first approach improves lesion detection and matches diagnostic imaging to its therapeutic counterpart.

Cluster 1 (pseudohypoxia) tumors behave as if starved of oxygen. They divide into two subgroups:

• Cluster 1A: Defects in the succinate dehydrogenase (SDH) complex, involving the SDHA, SDHB, SDHC, SDHD, or SDHAF2 genes, and other Krebs cycle or mitochondrial genes such as FH, MDH2, SUCGL2, DLST, and SLC25A11.
• Cluster 1B: Defects in VHL and EPAS1/HIF2A genes.

Cluster 1 tumors are often extra-adrenal (outside the adrenal gland). SDHx-related disease is strongly positive for somatostatin receptors (SSTRs) and shows intense uptake on 18F-FDG-PET scans.

Cluster 2 (kinase signaling) involves genes such as RET, NF1, MAX, and TMEM127, and occasionally HRAS. These typically appear as PHEOs, including both inherited and sporadic (non-inherited) cases.

Imaging choices should be tailored to genotype and tumor location:

• SSTR-related PET/CT with 68Ga or 64Cu DOTA-peptide tracers is a high-yield first platform, especially for SDHx tumors, parasympathetic head-and-neck PGLs, and metastatic PPGLs, including sporadic cases.
• 18F-FDOPA is preferred for VHL/EPAS1 tumors and many adrenal/cluster 2 tumors.
• 18F-FDG complements the other scans by assessing aggressive tumor biology.
• 123I-MIBG is prioritized when 131I-MIBG therapy is being considered.

Cellular Targets: Why These Tumors Light Up on Scans

The expression of peptide hormone receptors, particularly somatostatin receptors (SSTRs), is well characterized in neuroendocrine tumors, including PPGLs. These G-protein-coupled receptors sit on the cell surface. They can inhibit hormone secretion and induce cell cycle arrest through activation of enzymes called phosphotyrosine phosphatases (PTPs).

SSTR subtypes 1 through 5 have been identified in pheochromocytomas, both with and without metastatic disease. Surface expression varies across tumor models. Among the subtypes, SSTR2 is the most consistently expressed in PPGLs. Notably, Elston and colleagues found strong expression of SSTR2A and SSTR3 in SDHB-mutated PPGLs. That finding established these receptors as key diagnostic and therapeutic targets.

Catecholamine biosynthesis and transport also create imaging targets. 123I/131I-MIBG localizes tumors through the norepinephrine transporter, with storage in vesicles via a protein called VMAT. By contrast, 18F-FDOPA (a fluorine-18 labeled analog of L-DOPA) enters cells through L-type amino acid transporters (LAT1/2) and is converted by aromatic L-amino-acid decarboxylase (AADC). It does not use the norepinephrine transporter. The two tracers are therefore complementary.

PPGLs are metabolically active tumors, especially in SDHx-related and metastatic forms. This activity is exploited with radiolabeled glucose analogs such as 18F-FDG, which tumor cells take up preferentially.

Where Diagnosis Begins: Blood and Urine Testing

The diagnostic pathway starts with biochemical confirmation for catecholamine-secreting lesions. This step immediately anticipates the imaging choices that will later inform radioligand therapy (RLT), treatment that delivers radioactive molecules directly to tumor cells.

Biochemical screening is best performed with plasma free metanephrines, the breakdown products of catecholamines. Blood should be drawn after at least 20 minutes of supine rest (lying flat). A 24-hour urinary fractionated metanephrine test is an alternative. Pre-analytical rigor matters. Posture, stress, acute illness, and common medications can alter results. These medications include tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, decongestants, and stimulants.

For borderline elevations, doctors may use a clonidine suppression test when clinical suspicion remains high. Clonidine normally suppresses catecholamine release; in PPGL patients, levels stay elevated. Catecholamines themselves are less sensitive and are reserved for specific contexts, such as dopamine-predominant tumors.

Choosing the Right Imaging Test

Anatomical imaging with contrast-enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) establishes disease burden, shows surgical relationships, and identifies sites that demand urgent control. Functional imaging should be added early for whole-body staging when metastatic risk is appreciable.

Functional imaging is particularly valuable in these situations:

• Extra-adrenal (outside the adrenal) tumors
• Multifocal disease (tumors in multiple sites)
• Hereditary (inherited) cases
• High-risk features such as SDHB/SDHA-associated disease
• Large primary tumors, defined as larger than 5 cm
• A noradrenergic biochemical phenotype (tumors that produce norepinephrine rather than epinephrine)
• High proliferation indices, including Ki-67 and mitotic count
• Suspected metastatic spread

Functional imaging is also especially useful in parasympathetic head-and-neck paragangliomas, where multiplicity is common and biochemical screening can be negative.

However, functional imaging is not mandatory in every case. A clearly localized adrenal pheochromocytoma with concordant biochemistry and typical cross-sectional imaging may not need it, especially in lower-risk settings such as many VHL- or RET/MEN2-associated adrenal tumors. Exceptions include extra-adrenal lesions and large tumors, where whole-body staging should be added.

In asymptomatic SDHx mutation carriers, screening and follow-up remain primarily MRI- and biochemistry-based. PET/CT is considered mainly at adult initial screening rather than as routine surveillance. Once functional imaging is indicated, tracer selection should be individualized according to tumor biology and the intended radioligand therapy.

SSTR PET: A First-Line Scan and Gateway to PRRT

Somatostatin receptor imaging was pioneered with 111In-pentetreotide, known commercially as Octreoscan®, following the seminal work of Krenning and colleagues. Octreoscan is a gamma-camera/SPECT radiotracer with affinity for SSTR2 receptors, but it has intrinsically lower sensitivity and spatial resolution. That technical limitation, plus the higher sensitivity and more practical workflow of PET, led most centers to replace it with 68Ga- or 64Cu-labeled PET tracers (DOTA-TATE, DOTA-TOC, or DOTA-NOC). These PET tracers provide superior staging accuracy when combined with CT.

SSTR2-dependent imaging has shown greater diagnostic performance in SDHB/SDHx-associated PPGL (cluster 1A). Across various prospective and retrospective trials, sensitivity reaches 94–100%. Study populations included metastatic PPGLs in pediatric patients, head-and-neck and spine tumors, sporadic tumors, and SDHA-, SDHD-, and SDHB-mutated tumors.

The figures in the original paper illustrate this clearly. In one case, a 23-year-old man with a germline pathogenic variant in the SDHB gene had widespread metastatic bone disease. His whole-body PET/CT images showed 68Ga-DOTATATE detecting far more lesions than 18F-FDOPA or 18F-FDG. In fact, 18F-FDOPA was negative in this patient. In another case, a 24-year-old man with no germline variants in any pheochromocytoma-susceptibility gene had recurrence in the right nephrectomy bed (the area where a kidney was removed) plus metastatic lesions in the lungs, liver, and bones. Again, 68Ga-DOTATATE outperformed both 18F-FDOPA and 18F-FDG; 18F-FDG was negative in this patient.

Not all pseudohypoxic tumors behave alike. In a limited small series, tumors driven by pseudohypoxia genes outside the SDH complex, such as EPAS1, HIF2A, and PHD, tend to concentrate less 68Ga-DOTATATE. In those cases, lesion detection sensitivity drops to 50%.

Because of its high sensitivity in SDHx disease, [68Ga/64Cu]Ga/Cu-DOTA-peptide scanning is recommended as the first-line imaging modality in cluster 1A (SDHx)-mutated PPGL. It also directly maps whether a patient is a candidate for SSTR-targeted PRRT.

18F-FDOPA PET: Best for Certain Gene Types

18F-FDOPA was first developed for PET imaging of the dopaminergic system and later adopted for neuroendocrine tumors, including PPGLs. Tumor uptake is mediated by L-type amino acid transporters (LAT1/LAT2). Inside the cell, aromatic L-amino-acid decarboxylase (AADC) converts FDOPA to 18F-fluorodopamine, which is then sequestered in secretory vesicles via VMAT. This pathway explains the high tumor-to-background contrast seen in many neuroendocrine tumors.

In clinical practice, 18F-FDOPA-PET/CT performs especially well in these settings:

• Pheochromocytomas (adrenal tumors)
• Head-and-neck paragangliomas
• Cluster 1B genotypes (such as VHL, EPAS1/HIF2A)
• Cluster 2 kinase-pathway tumors (such as RET, NF1, MAX, TMEM127)
• FH- and IDH2-related PPGLs, where it is superior to SSTR imaging

Sensitivity is lower in metastatic disease, especially SDHx-related (particularly SDHB/SDHA) tumors. In those cases, SSTR PET and/or 18F-FDG often outperform 18F-FDOPA. Some centers use carbidopa premedication to raise tumor-to-background contrast, but it is not required routinely in PPGL imaging. Its use should be individualized.

One important distinction: unlike SSTR imaging and MIBG imaging, 18F-FDOPA currently lacks an established therapeutic radionuclide partner in PPGLs. A highly 18F-FDOPA-avid phenotype does not automatically translate into a corresponding theranostic pathway. Theranostics means using one molecule to image a tumor and a radioactive version to treat it.

The review notes one potential future option. 131I-iodophenylalanine (131I-IPA) also targets LAT1. It has so far been evaluated only in patients with recurrent glioblastoma (a type of brain tumor) in the open-label, multicenter IPAX-1 trial (NCT03849105). Preliminary data are encouraging and provide a rationale for investigating it in other LAT1-expressing tumors, including PPGLs. This matters for genetic mutations such as HIF2A, VHL, RET, and MAX, where 18F-FDOPA is diagnostically superior to SSTR imaging.

The figures also reveal lesion-level heterogeneity. In one apparent sporadic metastatic PPGL case, some lesions took up only SSTR tracer, while others took up both 18F-FDOPA and SSTR tracer. This pattern may reflect variable preservation of two biologic programs across metastatic sites: somatostatin receptor expression and catecholamine precursor uptake/decarboxylation/storage. Dual-avid lesions may represent a more differentiated chromaffin cell phenotype. SSTR-positive but 18F-FDOPA-negative lesions may retain receptor expression despite partial loss of catecholamine-handling machinery.

The absence of 18F-FDG avidity in that case suggests heterogeneity within an overall well-differentiated, non-glycolytic disease, rather than global dedifferentiation (loss of mature cell features). However, differences in lesion size and tracer sensitivity, particularly for bone metastases, must also be considered. This interpretation remains hypothesis-generating.

18F-FDG PET: A Window Into Aggressive Tumor Biology

The biologic meaning of 18F-FDG uptake in PPGL depends on the underlying genotype. In SDHx-related and other pseudohypoxia-driven tumors, 18F-FDG avidity is high. Across metastatic PPGL cohorts, 18F-FDG sensitivity is high, making it valuable for staging and for detecting dedifferentiated disease.

18F-FDG also complements SSTR PET by revealing intrapatient heterogeneity. Lesions with high 18F-FDG but low SSTR uptake may respond less well to radioligand therapy. This tracer mismatch is especially important when theranostic planning is being considered.

Marked 18F-FDG avidity in PPGLs largely reflects intrinsic metabolic reprogramming, such as:

• Impaired oxidative phosphorylation (the cell’s energy-producing process)
• Pseudohypoxic/hypoxia-inducible factor (HIF) signaling, which makes cells act oxygen-starved
• Increased glucose phosphorylation mediated by hexokinase enzymes

These metabolic changes, rather than the proliferative rate itself, drive the bright FDG signal. Intense 18F-FDG avidity with absent or poor SSTR expression in metastatic PPGLs, whether SDHx-related or apparently sporadic, may indicate de-differentiated or biologically aggressive disease.

In non-pseudohypoxic (cluster 2) disease, however, the role of 18F-FDG is less well defined. Limited genotype-specific data, such as small MAX series, do not yet support treating 18F-FDG uptake as a generalized biomarker of aggressive behavior in these tumors. In bulky lesions, intratumoral heterogeneity, including viable tumor, hypoxic zones, and central necrosis (dead tissue in the tumor core), may further complicate the biologic interpretation of 18F-FDG distribution.

123I-MIBG Imaging: The Theranostic Bridge to Therapy

Metaiodobenzylguanidine (MIBG) is a norepinephrine analog. It is taken up via the norepinephrine transporter (NET, also called uptake-1) and stored in catecholamine vesicles through VMAT. 123I-MIBG SPECT/CT is a contemporary diagnostic technique that offers better image quality and lower radiation exposure than older 131I diagnostic imaging.

Other norepinephrine transporter-targeted PET radiopharmaceuticals exist, including 124I-MIBG, 18F-metafluorobenzylguanidine (18F-MFBG), and 18F-fluorodopamine (18F-FDA). These are available in select centers, but accessibility remains limited. Diagnostic performance is 38% per a meta-analysis by Han and colleagues. It is highest in adrenal PHEOs but falls in PGLs, particularly head-and-neck and SDHB-related metastatic disease.

Consequently, the principal role of MIBG imaging today is theranostic. Its job is to confirm MIBG avidity, meaning the tumor visibly takes up the tracer, when a doctor is considering treatment with 131I-MIBG.

Radioligand Therapies: How Targeted Radiation Works

Radioligand therapies (RLT) have emerged as a pivotal option in advanced PPGLs. The concept is simple in principle: a targeting molecule carries a radioactive atom to the tumor cell. The radiation then damages the tumor from within, while sparing most healthy tissue.

The review details three main approaches:

• High-specific-activity (HSA) 131I-MIBG, which is FDA-approved for metastatic PPGL
• Low/intermediate specific-activity (LSA) 131I-MIBG, used off-label
• Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE, also used off-label in PPGL
• Investigational alpha-particle therapy with 225Ac-DOTATATE

Each requires a diagnostic scan first. MIBG therapy requires demonstrated MIBG avidity on 123I-MIBG SPECT/CT. PRRT requires SSTR-PET-positive disease, meaning lesion uptake is at least as bright as the liver.

131I-MIBG Therapy: FDA-Approved Option

High-specific-activity (HSA) 131I-MIBG, also called iobenguane, is the only FDA-approved radioligand therapy for metastatic PPGL. Approval was based on a pivotal phase II trial and supported by a multicenter study and an observational registry. However, the drug is currently not commercially available.

The typical regimen uses dosimetry, meaning radiation measurements guide the dose. Patients receive 2 therapeutic doses at least 90 days apart. The dose is 500 mCi if the patient weighs more than 62.5 kg (about 138 pounds), or 8 mCi/kg if the patient weighs 62.5 kg or less. The maximum per dose is 500 mCi. (mCi stands for millicurie, a unit of radioactivity.)

Outcomes in the pivotal phase II study were as follows:

• Objective response rate (ORR), meaning measurable tumor shrinkage, was about 22–23%
• Disease control rate (DCR) exceeded 90%
• About 25–32% of patients achieved a 50% or greater reduction in antihypertensive (blood pressure) medication use that lasted at least 6 months
• Durable blood pressure and biochemical responses were observed

In the observational registry, the combined rate of partial response and stable disease was 84.6%. Treatment requires special precautions. Patients must hold uptake-interfering drugs when safe, including labetalol, tricyclic antidepressants, reserpine, and amiodarone. Thyroid blockade is needed to protect the thyroid gland from radioactive iodine.

Key side effects include myelosuppression (reduced bone marrow production of blood cells), nausea, and fatigue. Rare therapy-related myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), both bone marrow diseases, have been reported. Because patients emit radiation, treatment requires inpatient radiation safety precautions. Thyroid stimulating hormone (TSH) should be monitored annually after treatment.

Low/intermediate specific-activity (LSA) 131I-MIBG is used off-label in PPGL. The typical low/intermediate dose regimen is 74 MBq/kg (2 mCi/kg), often repeated, with a total activity below 9.25 GBq. (MBq and GBq are gigabecquerel and megabecquerel, units of radioactivity.) An alternative “very low dose” schedule is 5.5 GBq every 6 months for 3 cycles.

Results from two meta-analyses, mostly based on retrospective and heterogeneous protocols, plus a Japanese phase II study, show:

• Objective response rate of 30%, with complete responses (CR, meaning no detectable tumor) in 3–4%
• Disease control rate of 82–87%
• Symptomatic improvement reported in up to 76% of patients in pooled data
• Hormonal response in 45% of patients in one study (Loh) and 72% in another (van Hulsteijn)

Side effects include myelosuppression (rarely full pancytopenia, a drop in all blood cell types), nausea, vomiting, and diarrhea. Pressor crisis (dangerous blood pressure spikes) and symptom exacerbation can occur, so alpha-blockade and close blood pressure monitoring are essential. Other possible effects include hepatic (liver) dysfunction, orthostatic hypotension (blood pressure drop on standing), and rare dry mouth or parotitis (salivary gland inflammation) and hypothyroidism (underactive thyroid). Blood counts (CBC) and TSH require follow-up.

PRRT With 177Lu-DOTATATE: High Disease Control Rates

Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE targets somatostatin receptors on tumor cells. It is currently used off-label for PPGL. The common regimen is 7.4 GBq given every 8 weeks for 4 cycles. Amino acid solutions are given alongside treatment to protect the kidneys (nephroprotection).

Evidence comes from multiple retrospective studies, two 2023 meta-analyses, and a prospective NIH phase II trial. Overall results show:

• Disease control rates of approximately 80–90%
• Median progression-free survival (PFS, time before the disease worsens) of approximately 17–39 months

The prospective NIH phase II trial included 36 evaluable patients and reported:

• 6-month progression-free survival of 86%
• Median progression-free survival of 20 months
• Partial responses (measurable shrinkage) deepened over time, growing from 14% at end of treatment to 28% on follow-up
• Strikingly, sporadic (non-inherited) tumors responded better than SDHx-related tumors, with median PFS of 24.3 months versus 12.9 months

These outcomes are enhanced by standardized dosing strategies. Toxicity is generally manageable. The most common side effects are transient cytopenias (temporary drops in blood counts) and nausea. An important caution applies to functional (hormone-secreting) tumors: catecholamine-release events occurred in about 17–18% of patients during or after treatment. For this reason, doctors should optimize alpha-blockade before PRRT and consider intensified monitoring for patients with high secretion or bulky disease.

Investigational Alpha-PRRT (225Ac-DOTATATE)

Alpha-particle PRRT with 225Ac-DOTATATE is an investigational approach. Instead of beta radiation, it delivers alpha particles, which are more powerful over a shorter distance. Dosing varies by center and protocol.

Small series suggest responses are possible in refractory paraganglioma, but the data are early. Endocrine toxicities (effects on hormone-producing glands) have been reported. Long-term safety data are still maturing. This approach is typically considered after or instead of 177Lu-DOTATATE, within clinical trials or early-report series. It represents a promising frontier for patients whose tumors stop responding to other treatments.

What This Means for Patients

This review carries several practical messages for patients facing a PPGL diagnosis.

First, genetic testing shapes imaging. Knowing whether a tumor is SDHx-related, VHL-related, or driven by a kinase pathway gene changes which scan will find disease most reliably. Patients with SDHx mutations generally benefit most from SSTR PET scans, which detect 94–100% of lesions. Patients with VHL, EPAS1, or cluster 2 tumors often do better with 18F-FDOPA.

Second, imaging is a bridge to therapy. The scan that finds the tumor also determines which targeted radiation treatment can be offered. SSTR-positive disease can be treated with 177Lu-DOTATATE. MIBG-avid disease can be treated with 131I-MIBG. A purely 18F-FDOPA-positive tumor currently has no matched therapy, though research on 131I-IPA is underway.

Third, treatment responses are real but variable. 177Lu-DOTATATE controls disease in 80–100% of patients in prospective and retrospective trials. 131I-MIBG achieves disease control above 90% in its pivotal trial, with durable blood pressure improvement in about a quarter to a third of patients. However, SDHx-related tumors showed shorter progression-free survival (12.9 months) than sporadic tumors (24.3 months) in the NIH PRRT trial, so expectations should be individualized.

Fourth, hormone control is patient safety. Both therapies can trigger catecholamine-release events. Alpha-blockade and close blood pressure monitoring are essential before, during, and after treatment.

Limitations of the Current Evidence

This article is a review, not a single new clinical trial, and the authors note several evidence gaps.

Much of the data on radioligand therapies comes from retrospective studies and heterogeneous protocols. Two meta-analyses of LSA 131I-MIBG were mostly retrospective. Dosing for 225Ac-DOTATATE varies by center, and only pilot studies or early reports exist. Long-term safety, especially for alpha-PRRT, is still maturing.

Interpretations of tracer heterogeneity remain hypothesis-generating. The suggestion that dual-avid lesions represent a more differentiated phenotype, for example, is complicated by differences in lesion size and tracer sensitivity for bone metastases. In addition, 18F-FDG’s role as a biomarker of aggressive behavior is not established in non-pseudohypoxic disease, where genotype-specific data are limited to small series such as MAX cohorts.

Finally, several promising agents face practical barriers. HSA 131I-MIBG is FDA-approved but currently not commercially available. New tracers like 18F-MFBG and 124I-MIBG exist only in select centers. 131I-IPA has been studied only in glioblastoma so far, not yet in PPGL patients.

Recommendations for Patients

Based on this review, patients and caregivers can take the following steps:

1. Ask about genetic testing. Because 30–40% of PPGLs are inherited and more than 20 genes are involved, germline testing should guide your imaging plan and family screening.
2. Confirm the biochemical diagnosis first. Plasma free metanephrines drawn after 20 minutes of supine rest, or a 24-hour urine test, is the gold standard. Tell your doctor about all medications, since common drugs such as tricyclic antidepressants, decongestants, and stimulants can skew results.
3. Match the scan to your genotype. If you have SDHx disease, ask whether SSTR PET (68Ga- or 64Cu-DOTATATE) is available. If you have VHL/EPAS1 or a cluster 2 tumor, 18F-FDOPA may be the better first choice.
4. Expect a theranostic workup. Treatment planning requires a companion scan: 123I-MIBG before 131I-MIBG therapy, and SSTR-PET before PRRT. Lesions with high 18F-FDG but low SSTR uptake may respond less well to radioligand therapy.
5. Prepare for blood pressure management. Alpha-blockade and careful blood pressure monitoring are required before 131I-MIBG and PRRT, because catecholamine-release events occur in up to 17–18% of functional PPGL patients receiving PRRT.
6. Plan for long-term follow-up. Blood counts need monitoring for bone marrow effects. After 131I-MIBG, thyroid function (TSH) should be checked annually.
7. Consider expert centers and trials. Because these tumors are rare and treatments are evolving, care at a specialized neuroendocrine tumor center with access to clinical trials, including alpha-PRRT studies, may offer the best outcomes.

Frequently Asked Questions

What are pheochromocytomas and paragangliomas?

Pheochromocytomas (PHEOs) and paragangliomas (PGLs), together called PPGLs, are rare neuroendocrine tumors. PHEOs start in the adrenal medulla, the inner core of the adrenal glands. PGLs start in paraganglia, clusters of nerve-related cells outside the adrenal glands. These tumors are highly vascular, meaning they grow a dense network of blood vessels. Some PPGLs secrete catecholamines, hormones such as adrenaline that drive the body's fight-or-flight response.

How common is inherited PPGL?

PPGLs are among the most strongly inherited of all tumors. Up to 30–40% of cases are linked to germline pathogenic variants, which are gene changes present from birth that increase disease risk. Genetic research has identified more than 20 key contributing genes, including SDHx, VHL, RET, MEN1, NF1, and others. Because inheritance is common, germline testing should guide your imaging plan and family screening.

Which imaging scan is right for my PPGL?

Imaging choices should be tailored to genotype and tumor location. SSTR-related PET/CT with 68Ga or 64Cu DOTA-peptide tracers is a high-yield first platform, especially for SDHx tumors, parasympathetic head-and-neck PGLs, and metastatic PPGLs. 18F-FDOPA is preferred for VHL/EPAS1 tumors and many adrenal or cluster 2 tumors. 18F-FDG complements other scans by assessing aggressive tumor biology. 123I-MIBG is prioritized when 131I-MIBG therapy is being considered.

What is 131I-MIBG therapy and who can receive it?

High-specific-activity 131I-MIBG, also called iobenguane, is the only FDA-approved radioligand therapy for metastatic PPGL. However, the drug is currently not commercially available. Treatment requires demonstrated MIBG avidity on 123I-MIBG SPECT/CT. The typical regimen uses dosimetry to guide the dose, with two therapeutic doses at least 90 days apart. In the pivotal phase II study, objective response rate was about 22–23% and disease control rate exceeded 90%.

What is PRRT with 177Lu-DOTATATE and what results were seen?

Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE targets somatostatin receptors on tumor cells. It is currently used off-label for PPGL. The common regimen is 7.4 GBq given every 8 weeks for 4 cycles, with amino acid solutions to protect the kidneys. In a prospective NIH phase II trial of 36 evaluable patients, 6-month progression-free survival was 86% and median progression-free survival was 20 months.

What side effects and safety precautions should I expect?

Both 131I-MIBG and PRRT can cause myelosuppression (reduced bone marrow blood cell production), nausea, and fatigue. Rare therapy-related myelodysplastic syndrome and acute myeloid leukemia have been reported with 131I-MIBG. Catecholamine-release events occurred in about 17–18% of patients during or after PRRT. Alpha-blockade and close blood pressure monitoring are essential before, during, and after treatment. Thyroid blockade is needed with 131I-MIBG, and TSH should be monitored annually.

What follow-up and monitoring will I need after treatment?

Blood counts need monitoring for bone marrow effects after radioligand therapy. After 131I-MIBG, thyroid function (TSH) should be checked annually. Because these tumors are rare and treatments are evolving, care at a specialized neuroendocrine tumor center with access to clinical trials, including alpha-PRRT studies, may offer the most appropriate outcomes. Ask your doctor about genetic testing to guide imaging and family screening.

When should a patient with pheochromocytoma or paraganglioma seek a second opinion?

A second opinion is worth considering when the imaging plan does not match the tumor's genotype. SSTR PET detects 94–100% of lesions in SDHx disease, while 18F-FDOPA is preferred for VHL, EPAS1, and cluster 2 tumors. Because treatment depends on a companion scan, a patient should also seek review when 131I-MIBG or PRRT is proposed without documented MIBG avidity or SSTR-PET-positive disease, or when high 18F-FDG but low SSTR uptake raises questions about likely response. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Molecular imaging and radioligand therapies in pheochromocytomas and paragangliomas.

Authors: Hernandez-Felix JH, Golagha M, Jha A, Varghese D, Grozinsky-Glasberg S, Riechelmann R, Fazio N, Pavel M, Lin FI, Taïeb D, Pacak K, Del Rivero J.

Journal: Endocrine-Related Cancer (2026) 33 e260036. Published by Bioscientifica Ltd. Available online 14 July 2026; version of record published 28 July 2026.

DOI: https://doi.org/10.1530/ERC-26-0036

Funding and affiliations: The authors are affiliated with the National Cancer Institute (NCI) and Eunice Kennedy Shriver National Institute of Child Health and Human Development at the US National Institutes of Health, along with institutions in Mexico, Israel, Brazil, Italy, Germany, France, and the Czech Republic.

Note: This patient-friendly article is based on peer-reviewed research. It is provided for educational purposes and does not replace individualized medical advice from your healthcare team.