Adrenal Medulla Imaging (MIBG) — Phaeochromocytoma and Paraganglioma

1. Snapshot

• What it is: metaiodobenzylguanidine (MIBG) scintigraphy images catecholamine-producing phaeochromocytoma and paraganglioma (PPGL) by localising to the noradrenaline transporter of chromaffin tissue.
• Where it sits now: largely superseded for diagnosis by ⁶⁸Ga-DOTATATE PET/CT (or ¹⁸F-FDOPA in sporadic disease), but it retains a distinct theranostic role.
• The key point: a positive ¹²³I-MIBG scan is the gateway to ¹³¹I-MIBG therapy — always integrate biochemistry, genotype and anatomical imaging.

2. Overview

Phaeochromocytomas (adrenal medullary) and paragangliomas (extra-adrenal, along sympathetic and parasympathetic chains) are catecholamine-associated neuroendocrine tumours arising from chromaffin and paraganglial tissue. Together abbreviated PPGL, they are rare but clinically important: they cause paroxysmal hypertension, are heritable in up to ~40% of cases, and carry a variable but real risk of metastatic disease.

Nuclear medicine contributes functional whole-body localisation — confirming that a lesion is chromaffin in origin, detecting multifocal or metastatic disease that anatomical imaging alone may miss, and selecting patients for radionuclide therapy. Anatomical imaging (contrast CT or MRI) remains first-line for a suspected primary; functional imaging is added for staging, for multifocal/hereditary/metastatic disease, and when biochemistry and cross-sectional imaging disagree.

The historical workhorse — metaiodobenzylguanidine (MIBG) scintigraphy — has been substantially displaced for diagnosis by positron emission tomography (PET) tracers, particularly ⁶⁸Ga-DOTATATE. Its enduring, distinct role is theranostic: a positive ¹²³I- or ¹³¹I-MIBG scan is the gateway to ¹³¹I-MIBG therapy [1,2].

3. Core Concepts & Pathophysiology

MIBG is a guanethidine analogue structurally resembling noradrenaline. It is taken up into chromaffin cells largely via the noradrenaline transporter (NAT / norepinephrine transporter) and stored in neurosecretory granules by the vesicular monoamine transporters. This shared uptake pathway makes radiolabelled MIBG a specific marker of sympathoadrenal tissue.

Somatostatin-receptor (SSTR) imaging exploits a different target: PPGLs, especially those in the pseudohypoxic “cluster 1” pathway, over-express somatostatin receptor subtype 2, which binds ⁶⁸Ga-labelled DOTA-peptides (DOTATATE, DOTATOC). ¹⁸F-fluoro-L-DOPA (FDOPA) is handled by the amino-acid transport and decarboxylation machinery of catecholamine synthesis.

Genotype drives tracer choice. Roughly a third to ~40% of PPGLs carry germline mutations, grouped into: - Cluster 1 (pseudohypoxic): SDHx (succinate dehydrogenase subunits A–D), VHL, FH, EPAS1/HIF2A. These are more often extra-adrenal, multifocal, metastatic (notably SDHB); SDHx-related tumours are best imaged with ⁶⁸Ga-DOTATATE, whereas VHL-, EPAS1- and FH-related PPGLs show very high ¹⁸F-FDOPA sensitivity (EPAS1 and possibly FH tumours concentrate less ⁶⁸Ga-SSA) [1,3,4]. - Cluster 2 (kinase-signalling): RET (multiple endocrine neoplasia type 2, MEN2), NF1, TMEM127, MAX. More often adrenal and benign; ¹⁸F-FDOPA performs particularly well [1,3].

This mechanistic split explains why no single tracer is universally best.

4. Clinical Indications

Established - Localisation of biochemically proven PPGL when CT/MRI is negative, equivocal, or discordant. - Staging of known metastatic or multifocal disease. - Screening for suitability for ¹³¹I-MIBG therapy (a positive MIBG scan is prerequisite). - Surveillance in hereditary syndromes (imaging tracer chosen by genotype).

Selected / conditional - Characterising an adrenal incidentaloma with biochemical evidence of catecholamine excess. - Post-operative restaging when biochemistry re-rises. - Head-and-neck paraganglioma (HNPGL) mapping (functional imaging supplements MRI).

Emerging / investigational - ⁶⁸Ga-DOTATATE selection for peptide-receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTATATE.

Unlikely to help - Screening asymptomatic patients with normal biochemistry. - As a substitute for anatomical imaging in surgical planning of a single resectable primary.

5. Radiopharmaceuticals

Preferred use (guideline- and evidence-supported first-line by scenario) [1,3,5,6]: - Metastatic / SDHx (esp. SDHB): ⁶⁸Ga-DOTATATE (lesion-based detection 98.6% in SDHB-related metastatic PPGL vs 85.8% for ¹⁸F-FDG and 61.4% for ¹⁸F-FDOPA [5]; ¹²³I-MIBG is positive in fewer than half of SDHx-related PPGLs [1]). - Head-and-neck paraganglioma: ⁶⁸Ga-DOTATATE (30/30 HNPGLs detected [6]); ¹⁸F-FDOPA second line; MIBG poor (~18–50% [1]). - Sporadic, non-metastatic adrenal: ¹⁸F-FDOPA (sensitivity close to 100%); ¹²³I-MIBG is adequate for large sporadic phaeochromocytomas but less sensitive; ⁶⁸Ga-DOTATATE may miss phaeochromocytomas [1,6]. - Selection for ¹³¹I-MIBG therapy: ¹²³I-MIBG (mandatory).

Radiopharmaceutical notation is used consistently throughout: ¹²³I, ¹³¹I, ¹⁸F-FDG, ¹⁸F-FDOPA, ⁶⁸Ga-DOTATATE, ¹⁷⁷Lu-DOTATATE.

6. Patient Selection & Preparation (MIBG focus)

History & investigations: confirm biochemistry (plasma free or 24-h urinary fractionated metanephrines), genotype where known, prior imaging, and current medications [9]. Renal function and full blood count are relevant before therapy.

Thyroid blockade (essential): free radioiodide is released and concentrates in the thyroid. Block with potassium iodide / Lugol’s solution (or potassium perchlorate) before injection: for ¹²³I-MIBG, potassium iodide 130 mg ~1 h (30 min–2 h) beforehand; for diagnostic ¹³¹I-MIBG, from 24 h before and daily for at least 5 days after [1]; for ¹³¹I-MIBG therapy (Azedra label), from at least 24 h before to 10 days after each dose [7]. Protocols are institution-dependent — follow local guidance [2].

Medication modification: many drugs inhibit NAT-mediated uptake and cause false negatives. Where clinically safe, withhold for an appropriate interval (drug-dependent: most interfering drugs 1–3 days, labetalol ~10 days, antipsychotics ~3–4 weeks [1]): - Tricyclic antidepressants, labetalol and combined α/β-blockers, sympathomimetics (including decongestants), cocaine. - Some calcium-channel blockers, reserpine, and certain antipsychotics. Do not stop essential cardiovascular medication without the managing physician’s agreement — consult local pharmacy/formulary lists.

Fasting/glucose: not required for MIBG. For ¹⁸F-FDG PET, standard fasting and glucose control apply.

Pregnancy/breastfeeding: MIBG imaging is generally avoided in pregnancy; ¹³¹I-MIBG therapy is contraindicated. Breastfeeding should be interrupted (¹²³I) or discontinued (¹³¹I) per local radiation-safety rules.

Consent & safety: explain radiation exposure and, for therapy, isolation and myelosuppression risks. ¹³¹I-MIBG therapy requires inpatient radioprotection.

7. Imaging / Treatment Protocol

Diagnostic ¹²³I-MIBG scintigraphy (typical, protocol-dependent) [2]: 1. Thyroid blockade before injection (~1 h beforehand suffices for ¹²³I-MIBG [1]). 2. Administered activity: ≈370 MBq (10 mCi) for a 70-kg adult [1]; paediatric activity is weight-scaled — 5.2 MBq/kg (minimum 37 MBq; maximum 370 MBq in North America, 400 MBq in Europe) [1], consistent with the 2024 North American consensus, or per the European Association of Nuclear Medicine (EANM) dosage card. Slow IV injection; monitor blood pressure. 3. Uptake interval: imaging at ~24 h; ¹²³I often also permits earlier ~4 h images. 4. Planar whole-body anterior/posterior + spot views; low-energy high-resolution or medium-energy collimator (the latter reduces septal penetration from high-energy ¹²³I photons), 20% window at the 159 keV photopeak [1]. 5. SPECT/CT over the region of interest markedly improves lesion localisation and specificity — strongly recommended when available. 6. ¹³¹I-MIBG diagnostic imaging (largely superseded): lower activity (~40–80 MBq), imaging at 24–72 h.

¹³¹I-MIBG therapy — two accepted approaches: - Fixed/empirical high activity: typically in the order of 3.7–11.1 GBq (100–300 mCi) per cycle (institution-dependent). - High-specific-activity iobenguane I-131 (Azedra, FDA-approved 2018; production discontinued by the manufacturer in early 2024) [7,8,11]: patients ≥12 years, MIBG-scan positive. A dosimetric dose (185–222 MBq / 5–6 mCi if >50 kg; 3.7 MBq/kg / 0.1 mCi/kg if ≤50 kg) precedes two therapeutic doses ≥90 days apart — 18,500 MBq (500 mCi) if >62.5 kg, or 296 MBq/kg (8 mCi/kg) if ≤62.5 kg, with reductions for myelosuppression or organ-dose limits.

Post-therapy: thyroid blockade continued, hydration, radiation-precaution instructions, blood-count monitoring; post-therapy scan documents biodistribution.

8. Normal Findings

Physiological MIBG uptake: salivary glands, myocardium, liver, spleen, bowel, and urinary bladder; variable normal adrenal uptake (usually faint and symmetrical, more visible on ¹²³I and on delayed images). Nasopharynx, lungs and skeletal muscle show low activity. Free iodide (inadequate blockade) causes thyroid, gastric and salivary uptake. Normal adrenal uptake is mild (no greater than liver), symmetrical and without adrenal enlargement on CT; asymmetry or intensity greater than liver raises suspicion [1].

9. Interpretation

Recommended sequence: correlate with biochemistry and CT/MRI → assess physiological biodistribution and blockade adequacy → identify focal uptake exceeding expected physiology → localise with SPECT/CT → grade intensity and count lesions.

Abnormal pattern: focal uptake greater than adjacent background/liver, not matching normal biodistribution, concordant with an anatomical lesion. Bilateral adrenal uptake suggests hereditary/multifocal disease; extra-adrenal or skeletal foci suggest paraganglioma or metastasis.

For therapy planning, note MIBG-avidity of all known lesions — non-avid lesions on CT/MRI predict incomplete response to ¹³¹I-MIBG and may favour ⁶⁸Ga-DOTATATE-directed PRRT instead.

There is no single universal quantitative cut-off; interpretation is predominantly qualitative, supported by SPECT/CT and, for PET tracers, the standardised uptake value (SUV). On ⁶⁸Ga-DOTATATE, uptake exceeding normal liver (a Krenning-type visual scale, extrapolated from neuroendocrine practice) generally indicates PRRT-relevant SSTR expression.

10. Differential Diagnosis

11. Pitfalls & Artefacts

False positives: free-iodide thyroid/salivary/gastric uptake; bowel and urinary-tract activity mimicking abdominal/pelvic lesions; adrenal hyperplasia; focal degenerative skeletal uptake.

False negatives: interfering medications (labetalol, tricyclics, sympathomimetics); very small (<7 mm) lesions or dedifferentiated SDHB metastases; necrotic/haemorrhagic tumour; inadequate delayed imaging. Non-avidity does not exclude PPGL — cross-check with PET.

Physiological variants: asymmetric normal adrenal uptake; prominent myocardial or hepatic activity obscuring adjacent lesions.

Technical: wrong collimator (septal penetration with ¹³¹I), photopeak/energy-window error, patient motion, attenuation on planar images — mitigated by SPECT/CT.

12. Reporting Guidance

Structured checklist - Clinical indication, biochemistry, genotype, relevant medications and blockade status. - Radiopharmaceutical, administered activity, imaging times, planar ± SPECT/CT. - Biodistribution normal/abnormal; adequacy of thyroid blockade. - Site, number, and intensity of abnormal foci (relative to liver); anatomical correlate on SPECT/CT. - MIBG-avidity of all known lesions (critical for therapy decisions). - Comparison with prior imaging; limitations. - Conclusion linking findings to management.

Sample conclusion (not patient-specific): “Intense MIBG-avid uptake corresponding to the known left adrenal mass, without additional avid foci elsewhere, consistent with a solitary catecholamine-secreting phaeochromocytoma. Uptake intensity supports suitability for ¹³¹I-MIBG therapy should it be required.”

13. Clinical Management Impact

Functional imaging changes management by (a) confirming chromaffin origin, (b) revealing multifocal/metastatic disease that alters staging and surgical planning, (c) triaging hereditary surveillance, and (d) selecting radionuclide therapy — MIBG-avidity gates ¹³¹I-MIBG therapy, while SSTR-avidity gates ¹⁷⁷Lu-DOTATATE PRRT. Genotype (especially SDHB) escalates surveillance intensity and metastatic vigilance.

14. Comparison with Alternatives

• CT/MRI: superior spatial resolution and first-line for primaries; cannot confirm function or reliably stage whole-body disease.
• Biochemistry (metanephrines): most sensitive diagnostic test but non-localising [9].
• ⁶⁸Ga-DOTATATE PET/CT: highest overall sensitivity, best for SDHx, metastatic and head-and-neck disease; preferred first functional study in most modern algorithms [1,3,5].
• ¹⁸F-FDOPA PET/CT: excellent for sporadic/cluster 2 and HNPGL.
• ¹⁸F-FDG PET/CT: useful in SDHB/dedifferentiated metastatic disease [10].
• ¹²³I/¹³¹I-MIBG: now chiefly a theranostic selection tool rather than a primary diagnostic modality [1].

15. Special Situations

• Paediatric: weight-based activity (EANM dosage card); MIBG also central to neuroblastoma.
• Pregnancy/breastfeeding: imaging deferred where possible; ¹³¹I-MIBG therapy contraindicated in pregnancy.
• Renal impairment: relevant to ¹³¹I clearance and therapy dosimetry.
• Marrow reserve: assess before ¹³¹I-MIBG therapy (myelosuppression risk).
• Post-therapy: post-treatment scans confirm targeting; biochemistry tracks response.
• Incidental findings: SSTR-avid or MIBG-avid foci require correlation before attribution.

16. Recent Advances

• ⁶⁸Ga-DOTATATE established as preferred functional tracer for most PPGL scenarios (HNPGL, SDHx, extra-adrenal and metastatic disease) in the joint EANM/Society of Nuclear Medicine and Molecular Imaging (SNMMI) framework, with ¹⁸F-FDOPA preferred for apparently sporadic phaeochromocytoma [1].
• Theranostics: ¹⁷⁷Lu-DOTATATE PRRT for SSTR-positive metastatic PPGL (evidence emerging/investigational for this indication).
• High-specific-activity ¹³¹I-MIBG (iobenguane I-131) with prospective dosimetry [7,8] — no longer manufactured since early 2024 [11].
• Quantitative PET (SUV, tumour dosimetry) and AI-assisted lesion detection — investigational.

17. High-Yield Numbers

Values vary by guideline, age, equipment and institution.

18. Reporting Pearls

1. Always state thyroid-blockade adequacy and interfering-drug status.
2. Grade lesion intensity relative to liver — it informs therapy eligibility.
3. Explicitly note MIBG-avidity of all known lesions, not just the primary.
4. Use SPECT/CT before calling an abdominal/pelvic focus abnormal.
5. Bilateral adrenal uptake → think hereditary/multifocal disease.
6. A negative MIBG scan does not exclude PPGL — recommend ⁶⁸Ga-DOTATATE PET.
7. Distinguish free-iodide physiological uptake from true tumour.
8. Tie the conclusion to the specific management question (localise vs stage vs treat).

19. Common Examination Traps

1. ⁶⁸Ga-DOTATATE, not MIBG, is preferred for SDHx/metastatic and head-and-neck PPGL [1,3].
2. MIBG’s principal modern value is selecting ¹³¹I-MIBG therapy, not diagnosis.
3. Labetalol and tricyclics cause false-negative MIBG scans.
4. Thyroid blockade is mandatory — omission causes artefactual thyroid/gastric uptake.
5. SDHx (cluster 1) favours SSTR/FDG; cluster 2 and VHL/EPAS1 favour FDOPA.
6. ¹²³I gives better images and dosimetry than ¹³¹I for imaging.
7. Metanephrines (not catecholamines) are the preferred biochemical test.
8. SDHB predicts higher metastatic risk and often MIBG-negative lesions.
9. Fasting/glucose control matters for FDG, not MIBG.
10. Azedra requires a positive iobenguane scan and age ≥12 years [7].

20. One-Minute Review

• MIBG localises via the noradrenaline transporter; specific for chromaffin tissue.
• Confirm biochemistry (metanephrines) before functional imaging.
• ⁶⁸Ga-DOTATATE PET/CT is the highest-sensitivity, generally preferred functional tracer for PPGL [1,3].
• Choose tracer by genotype/cluster: SDHx → DOTATATE; sporadic/cluster 2 → FDOPA; SDHB metastatic → DOTATATE ± FDG.
• ¹²³I-MIBG’s key remaining role is theranostic selection for ¹³¹I-MIBG therapy.
• Thyroid blockade and drug review are essential; labetalol/tricyclics cause false negatives.
• SPECT/CT improves localisation and specificity.
• High-specific-activity ¹³¹I-MIBG (Azedra): two doses of 500 mCi ≥90 days apart, dosimetry-guided [7,8]; production discontinued in early 2024 [11].
• A negative MIBG does not exclude PPGL — escalate to PET.
• Grade lesion avidity vs liver; document avidity of all lesions for therapy decisions.
• Up to ~40% of PPGL are hereditary — imaging supports genetic surveillance.

21. Clinical Bottom Line

For most PPGL diagnostic questions, ⁶⁸Ga-DOTATATE PET/CT (or ¹⁸F-FDOPA in sporadic/cluster 2 disease) now outperforms MIBG scintigraphy. Radiolabelled MIBG’s enduring, distinct value is theranostic — a positive ¹²³I-MIBG scan selects patients for ¹³¹I-MIBG therapy. Always integrate biochemistry, genotype and anatomical imaging, because tracer choice and management hinge on the underlying molecular cluster.

22. Key References

1. Taïeb D, Hicks RJ, Hindié E, et al. European Association of Nuclear Medicine and Society of Nuclear Medicine and Molecular Imaging practice guideline/procedure standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2019;46(10):2112–2137. doi:10.1007/s00259-019-04398-1
2. Bombardieri E, Giammarile F, Aktolun C, et al. ¹³¹I/¹²³I-metaiodobenzylguanidine (mIBG) scintigraphy: procedure guidelines for tumour imaging. Eur J Nucl Med Mol Imaging. 2010;37:2436–2446. doi:10.1007/s00259-010-1545-7
3. Carrasquillo JA, Chen CC, Jha A, et al. Imaging of pheochromocytoma and paraganglioma. J Nucl Med. 2021;62(8):1033–1042. doi:10.2967/jnumed.120.259689
4. 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. doi:10.1097/MPA.0000000000001792
5. Janssen I, Blanchet EM, Adams K, et al. Superiority of [⁶⁸Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma. Clin Cancer Res. 2015;21(17):3888–3895. doi:10.1158/1078-0432.CCR-14-2751
6. Archier A, Varoquaux A, Garrigue P, et al. Prospective comparison of ⁶⁸Ga-DOTATATE and ¹⁸F-FDOPA PET/CT in patients with various pheochromocytomas and paragangliomas with emphasis on sporadic cases. Eur J Nucl Med Mol Imaging. 2016;43(7):1248–1257. doi:10.1007/s00259-015-3268-2
7. US Food and Drug Administration. AZEDRA (iobenguane I 131) injection — prescribing information. FDA, 2018 (label rev. 5/2021). https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/209607Orig1s002lbl.pdf
8. Pryma DA, Chin BB, Noto RB, et al. Efficacy and safety of high-specific-activity ¹³¹I-MIBG therapy in patients with advanced pheochromocytoma or paraganglioma. J Nucl Med. 2019;60(5):623–630. doi:10.2967/jnumed.118.217463
9. Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915–1942. doi:10.1210/jc.2014-1498
10. Chang CA, Pattison DA, Tothill RW, et al. ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT in paraganglioma and pheochromocytoma: utility, patterns and heterogeneity. Cancer Imaging. 2016;16:22. doi:10.1186/s40644-016-0084-2
11. Society of Nuclear Medicine and Molecular Imaging. Lantheus to discontinue production of Azedra. SNMMI News, 18 August 2023. https://snmmi.org/Web/Web/News/Articles/Lantheus-to-Discontinue-Production-of-Azedra.aspx