Residency · Residency · Nuclear Medicine

Adrenal Imaging: MIBG and NP-59

Introduction

Nuclear medicine offers functional imaging of the adrenal glands through agents targeting the adrenal medulla (MIBG) and the adrenal cortex (NP-59). I-123/I-131 MIBG is the primary agent for evaluating catecholamine-producing tumors such as pheochromocytoma and paraganglioma. I-131 NP-59 (6-beta-iodomethyl-19-norcholesterol) evaluates adrenocortical function in hyperaldosteronism, Cushing syndrome, and incidentalomas. These studies provide functional characterization that complements anatomic imaging.

MIBG Scintigraphy

Mechanism of Action

Metaiodobenzylguanidine (MIBG) is a guanethidine analog structurally similar to norepinephrine. It enters chromaffin cells through the type 1 uptake mechanism (the norepinephrine transporter, NET) and is subsequently stored in neurosecretory granules via the vesicular monoamine transporter (VMAT). MIBG concentrates in tumors of neural crest origin that retain the capacity for catecholamine synthesis and storage.

Radiopharmaceutical Options

I-123 MIBG is preferred for diagnostic imaging. Its 159 keV gamma photon is ideal for gamma camera detection, yielding superior image quality that permits SPECT/CT acquisition while delivering a lower radiation dose. I-131 MIBG, with its 364 keV gamma and beta emissions, produces poorer diagnostic images and a higher radiation dose but is used therapeutically for neuroblastoma and malignant pheochromocytoma, and diagnostically when I-123 is unavailable.

Clinical Indications

MIBG scintigraphy is indicated for localization of adrenal and extra-adrenal pheochromocytoma, detection of multifocal or metastatic paraganglioma, staging and response assessment of neuroblastoma, and, in a limited role, evaluation of medullary thyroid carcinoma and carcinoid tumors.

Protocol

Thyroid blockade with potassium iodide or Lugol solution begins 24-48 hours before injection and continues for 2-3 days afterward to prevent thyroid accumulation of free iodide. The administered activity for I-123 MIBG is 370 MBq (10 mCi), and for I-131 MIBG is 37-74 MBq (1-2 mCi). Imaging occurs at 24 hours post-injection, with optional 4-hour early images when using I-123. Whole-body planar and SPECT/CT of the abdomen are obtained. Medications that interfere with norepinephrine uptake or storage -- including tricyclic antidepressants, labetalol, reserpine, calcium channel blockers, and sympathomimetics -- must be withheld for at least 48-72 hours.

Normal Biodistribution

Normal uptake appears in the heart, liver, spleen, salivary glands, urinary bladder, and bowel. Normal adrenal medullary uptake is typically faint or absent. Non-specific lung uptake may be seen.

Interpretation and Pitfalls

I-123 MIBG achieves a sensitivity of 85-95% and specificity of 95-100% for pheochromocytoma. False negatives occur with dedifferentiated tumors, SDH-mutated paragangliomas (especially SDHB mutations), and medication interference. False positives are rare but may include adrenal hyperplasia or normal adrenal variant uptake. Importantly, SDH-mutated paragangliomas, particularly those with SDHB mutations, are frequently MIBG-negative and require Ga-68 DOTATATE PET/CT for detection.

NP-59 Adrenocortical Scintigraphy

Mechanism

I-131 NP-59 is a cholesterol analog taken up by the adrenal cortex via LDL receptor-mediated endocytosis. It is incorporated into the cholesterol ester pool without further metabolism, so uptake directly reflects adrenocortical function and ACTH stimulation.

Clinical Indications

NP-59 scintigraphy is used to differentiate adenoma from bilateral hyperplasia in primary hyperaldosteronism, to lateralize cortisol-producing adenomas in ACTH-independent Cushing syndrome, to characterize adrenal incidentalomas as functioning or non-functioning, and to detect adrenal remnant tissue after bilateral adrenalectomy.

Protocol

The administered activity is 37 MBq (1 mCi) of I-131 NP-59 intravenously. For hyperaldosteronism evaluation, dexamethasone suppression (1 mg twice daily) begins 7 days before injection to suppress the normal cortex and enhance visualization of an autonomously functioning adenoma. For Cushing syndrome evaluation, no dexamethasone is given. Imaging occurs at days 3, 5, and 7 post-injection with posterior views of the abdomen.

Interpretation Patterns

In primary hyperaldosteronism with dexamethasone suppression, unilateral uptake indicates an aldosterone-producing adenoma (Conn syndrome), bilateral uptake indicates bilateral hyperplasia (idiopathic hyperaldosteronism), and non-visualization suggests a non-functioning mass or insufficient suppression. In Cushing syndrome without dexamethasone, unilateral uptake with contralateral suppression indicates a cortisol-producing adenoma, bilateral uptake reflects ACTH-dependent bilateral hyperplasia, and bilateral non-visualization suggests adrenal carcinoma, which disrupts normal cholesterol metabolism.

Limitations

The prolonged imaging protocol (5-7 days), limited availability of NP-59, and the development of adrenal vein sampling for aldosteronism lateralization have relegated NP-59 scintigraphy to rare clinical use. CT and MRI now provide anatomic characterization of most incidentalomas.

Ga-68 DOTATATE for Adrenal Medullary Tumors

Ga-68 DOTATATE PET/CT is increasingly used as the first-line imaging agent for paragangliomas, particularly those with SDH mutations. It demonstrates superior sensitivity to MIBG for extra-adrenal and metastatic paragangliomas, exploiting SSTR expression in pheochromocytoma and paraganglioma. It also identifies concurrent neuroendocrine tumors in patients with syndromic conditions such as MEN, VHL, and SDHx mutations.

F-18 FDG PET/CT

FDG PET is useful for malignant pheochromocytoma and paraganglioma, particularly SDHB-mutated metastatic disease, where it achieves high sensitivity. It complements MIBG and DOTATATE in discordant cases. Adrenal incidentalomas with high FDG uptake raise concern for malignancy and warrant further evaluation.

Clinical Pearls

I-123 MIBG is the preferred diagnostic agent for pheochromocytoma and paraganglioma, but SDH-mutated paragangliomas (especially SDHB) may be MIBG-negative, necessitating Ga-68 DOTATATE PET/CT as an alternative. Medications affecting catecholamine uptake and storage -- particularly tricyclic antidepressants, labetalol, and reserpine -- must be withheld before MIBG imaging to avoid false-negative results. NP-59 adrenocortical scintigraphy with dexamethasone suppression can lateralize aldosterone-producing adenomas, though adrenal vein sampling has largely supplanted this technique in clinical practice. Bilateral non-visualization on NP-59 in the setting of Cushing syndrome suggests adrenal carcinoma, which disrupts normal cholesterol metabolism pathways.

References

1. Lenders JWM, et al. "Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline." J Clin Endocrinol Metab. 2014;99(6):1915-1942.
2. Taïeb D, et al. "European Association of Nuclear Medicine Practice Guideline for MIBG Scintigraphy." Eur J Nucl Med Mol Imaging. 2020;47(6):1372-1414.
3. Gross MD, et al. "Adrenal Scintigraphy with NP-59." Semin Nucl Med. 2006;36(3):209-218.
4. Chang CA, et al. "Ga-68 DOTATATE PET/CT for Pheochromocytoma and Paraganglioma: A Systematic Review and Meta-Analysis." J Nucl Med. 2019;60(7):929-935.

For the intern

When you're called at 3am about a patient with suspected pheochromocytoma, your immediate concern is hemodynamic stability—not imaging. Secure the diagnosis biochemically with plasma or urine metanephrines first. MIBG and other functional imaging studies are scheduled electively after biochemical confirmation. If a patient is about to receive I-123 MIBG tomorrow, verify thyroid blockade has started (potassium iodide or Lugol solution) and check that interfering medications were stopped 48-72 hours ago—labetalol, tricyclics, calcium channel blockers, and sympathomimetics all cause false negatives. NP-59 studies are rare and never urgent; they require multi-day protocols that get scheduled through your attending.

Common pitfalls

• Forgetting medication interference: Labetalol is commonly used for blood pressure control in pheochromocytoma but blocks MIBG uptake. Switch to alternative agents (phenoxybenzamine, doxazosin) at least 72 hours before imaging. Tricyclic antidepressants and cocaine also interfere.

• Missing SDHB mutations: These paragangliomas are frequently MIBG-negative (50-70% sensitivity) because of altered catecholamine handling. Order Ga-68 DOTATATE PET/computed tomography (CT) instead, especially for extra-adrenal or metastatic disease.

• Inadequate dexamethasone suppression for NP-59: When evaluating hyperaldosteronism, dexamethasone must suppress normal cortex for 7 days before injection. Without suppression, bilateral uptake occurs even with unilateral adenoma.

• Skipping thyroid blockade: Free iodide from radiotracer degradation concentrates in thyroid, causing unnecessary radiation exposure and potential hypothyroidism. Start blockade 24-48 hours before injection.

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