Endocrine System
Report template: Thyroid scintigraphy and uptake · Parathyroid scintigraphy / PET (MIBI, fluorocholine)
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Solve questions (27) →Contents
- 13.1 Thyroid
- 13.1.1 Thyroid Physiology and Iodine Metabolism
- 13.1.2 Thyroid Scintigraphy (Tc-99m Pertechnetate, I-131, I-123)
- 13.1.3 Thyroid Uptake Test
- 13.1.4 Evaluation of the Thyroid Nodule
- 13.1.5 Hyperthyroidism (Graves, Toxic Nodule, TMNG)
- 13.1.6 Thyroid Cancer and RAI Therapy
- 13.1.7 Whole-Body Iodine Scan (WBS)
- 13.1.8 Stunning and Empirical vs Dosimetric Therapy
- 13.1.9 Thyroid Scintigraphy with Tc-99m MIBI
- 13.2 Parathyroid
- 13.2.1 Parathyroid Physiology
- 13.2.2 Tc-99m MIBI Parathyroid Scintigraphy (Dual-Phase, Subtraction Technique)
- 13.2.3 Correlation with 4D-CT and US
- 13.2.4 The Role of SPECT/CT
- 13.2.5 Localisation of Ectopic Parathyroid Glands
- 13.2.6 Parathyroid PET/CT (F-18 Fluorocholine, C-11 Choline, C-11 Methionine)
- 13.3 Adrenal and Neuroendocrine System
- 13.3.1 Adrenal Cortical Scintigraphy (NP-59)
- 13.3.2 Adrenal Medulla: MIBG Scintigraphy (I-123, I-131)
- 13.3.3 Phaeochromocytoma and Paraganglioma
- 13.3.4 Neuroblastoma (Paediatric MIBG)
- 13.3.5 Somatostatin Receptor Scintigraphy (OctreoScan)
- 13.3.6 Ga-68 DOTATATE PET/CT
- 13.3.7 NET Staging and Treatment Planning
- 13.3.8 Insulinoma Imaging: GLP-1R (Exendin-4) PET/CT
- Key Points for the Board
- Current guidelines on this chapter's topics
Learning objectives and modules5 modules · about 4 h 5 min
Learning objectives
After this chapter you will be able to:
- Explain the steps of iodine metabolism and the drugs that affect them; interpret thyroid scintigraphy and the uptake test.
- Differentiate the causes of thyrotoxicosis from scintigraphy and uptake findings.
- Explain the role of radioiodine scanning and thyroglobulin follow-up in differentiated thyroid cancer, with causes of false-positive and false-negative results.
- Explain dual-phase and subtraction techniques in parathyroid imaging and the role of SPECT/CT and PET tracers.
- Explain patient preparation, drug interactions and the use of MIBG scintigraphy in phaeochromocytoma, paraganglioma and neuroblastoma.
- Explain the indications for and interpretation of somatostatin receptor imaging in neuroendocrine tumours.
Modules
The chapter is divided into study modules without changing the order of the text: read, watch the animations, then answer the questions linked to those headings.
- Module 113.1.1–13.1.4 Thyroid · Thyroid Scintigraphy (Tc-99m Pertechnetate, I-131, I-123) · Thyroid Uptake Test · Evaluation of the Thyroid Nodule55 min · 1 animation · 22 questionsAnswer the questions →
- Module 213.1.5–13.1.7 Hyperthyroidism (Graves, Toxic Nodule, TMNG) · Thyroid Cancer and RAI Therapy · Whole-Body Iodine Scan (WBS)45 min · 21 questionsAnswer the questions →
- Module 313.1.8–13.2 Stunning and Empirical vs Dosimetric Therapy · Thyroid Scintigraphy with Tc-99m MIBI · Parathyroid1 h 5 min · 1 animation · 24 questionsAnswer the questions →
- Module 413.3.1–13.3.6 Adrenal and Neuroendocrine System · Adrenal Medulla: MIBG Scintigraphy (I-123, I-131) · Phaeochromocytoma and Paraganglioma · Neuroblastoma (Paediatric MIBG) · +2 more1 h · 23 questionsAnswer the questions →
- Module 513.3.7–13.3.8 NET Staging and Treatment Planning · Insulinoma Imaging: GLP-1R (Exendin-4) PET/CT · Key Points for the Board20 min · 5 questionsAnswer the questions →
Times are estimates: 130 words per minute, 3 min per animation, 1.5 min per question.
MOST FREQUENTLY ASKED IN THIS CHAPTER
✓
Anti-Tg antibodies cause falsely low values in immunometric (IMA) Tg assays → Tg is always measured together with anti-Tg.
✓
Thyrotoxicosis + low uptake: serum Tg is suppressed in thyrotoxicosis factitia and high in thyroiditis.
✓
Perchlorate discharge test (I-123): >10% fall in uptake after perchlorate → organification defect (Pendred, TPO defect, Hashimoto).
✓
~25% of MTC is hereditary (germline RET) → RET testing in every MTC; MEN2A: MTC + phaeo + HPT, MEN2B: MTC + phaeo + marfanoid habitus + mucosal neuromas (no HPT).
✓
MIBG sensitivity is ~90% in phaeochromocytoma/neuroblastoma, ~50-70% in carcinoid and ~30% in MTC; there is normally no bone/bone marrow uptake → skeletal uptake favours metastasis.
13.1 Thyroid
13.1.1 Thyroid Physiology and Iodine Metabolism1 questions
The main function of the thyroid gland is to synthesise the thyroid hormones (T3 and T4). This process is directly linked to iodine metabolism.
Steps of iodine metabolism:
1. Trapping: Iodide (I⁻) is taken up from the circulation into the thyroid follicular cell by active transport via the sodium-iodide symporter (NIS). NIS is located on the basolateral membrane. This step is stimulated by TSH.
2. Oxidation: Iodide is oxidised by the enzyme thyroid peroxidase (TPO) → reactive iodine is formed.
3. Organification: Oxidised iodine binds to tyrosine residues on thyroglobulin (Tg) → monoiodotyrosine (MIT) and diiodotyrosine (DIT) are formed. This step is also catalysed by TPO.
4. Coupling: MIT + DIT → T3 (triiodothyronine); DIT + DIT → T4 (thyroxine). Catalysed by TPO.
5. Storage: T3 and T4 are stored within the thyroglobulin structure in the colloid.
6. Release: On TSH stimulation, colloid is taken into the cell by endocytosis → lysosomal proteolysis → T3 and T4 are released into the blood.
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The thyroid secretes mainly T4 (T4:T3 ~14-20:1); ~80% of circulating T3 comes from peripheral deiodination. Negative feedback at the pituitary also works mainly through T3, after conversion of T4 to T3 in the pituitary
7. Deiodination: Conversion of T4 → T3 in peripheral tissues (by deiodinase enzymes). T3 is 3-5 times more active than T4.
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70-80% of body iodine (~15-20 mg) is in the thyroid; dietary iodine is almost completely absorbed from the gut and most of it (~90%) is excreted in the urine
BOARD TIP
▸
"Where is NIS located?"
→ On the basolateral membrane of the thyroid follicular cell. NIS is expressed not only in the thyroid but also in the salivary glands, gastric mucosa, lactating breast tissue and choroid plexus → these organs also take up pertechnetate and RAI.
▸
"Which enzyme performs organification?"
→ TPO (thyroid peroxidase). PTU and methimazole inhibit TPO → block organification.
Hypothalamic-Pituitary-Thyroid Axis:
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Hypothalamus → TRH (thyrotropin-releasing hormone) → pituitary
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Pituitary → TSH (thyroid-stimulating hormone) → thyroid
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Thyroid → T3/T4 → suppresses TRH and TSH by negative feedback
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Effects of TSH on the thyroid:
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Increases NIS expression → iodine trapping increases
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Increases TPO activity → organification increases
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Increases thyroglobulin synthesis
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Increases hormone release
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Stimulates thyroid cell growth
Drugs affecting thyroid hormone synthesis:
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Thionamides (PTU, methimazole): TPO inhibition → block organification. PTU also inhibits peripheral T4→T3 conversion.
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Lithium: Blocks iodine release → intrathyroidal iodine accumulation increases → may increase RAI uptake
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Perchlorate (ClO₄⁻): Competes with iodide at NIS → blocks trapping. Perchlorate discharge test: demonstrates an organification defect.
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Wolff-Chaikoff effect: High iodine load → transiently inhibits organification → hormone synthesis falls. An autoregulatory mechanism.
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Jod-Basedow phenomenon: Hyperthyroidism after iodine loading → especially in autonomous thyroid tissue (multinodular goitre, iodine-deficient regions)
The seven steps of iodine metabolism between blood, the thyroid follicular cell and colloid (trapping, oxidation, organification, coupling, storage, endocytosis and release, peripheral conversion) are highlighted in turn; picking a drug stops the flow at the step it inhibits; the last step compares normal and organification defect in the perchlorate discharge test with a thyroid uptake curve.
Continuous stream · no seeking
Perchlorate blocks trapping, thionamides organification and lithium release; if organification is defective, unbound iodide leaves the gland after perchlorate.
Source: book 13.1.1-13.1.2 and the perchlorate discharge test (an animated version of Figure 13.1); pendrin from Bizhanova and Kopp, Endocrinology 2009; endocytosis from OpenStax A&P 2e §17.4. The curve is schematic; the amount discharged is representative.
How to use: a single click on the drawing pauses and resumes; in the second step ↑ ↓ or the buttons below change the drug, in the third step the test result; ← → change steps.
Did this animation help you understand the topic?
Figure 13.1: Steps of iodine metabolism in the thyroid follicular cell and sites of drug action (schematic).
BOARD TIP
▸
"Wolff-Chaikoff effect vs Jod-Basedow phenomenon?"
→ Wolff-Chaikoff: high iodine → inhibition of organification → hypothyroidism (protective mechanism). Jod-Basedow: high iodine → excessive hormone synthesis in autonomous thyroid tissue → hyperthyroidism. They have opposite outcomes!
▸
"What does the perchlorate discharge test show?"
→ An organification defect (such as Pendred syndrome). When perchlorate is given, non-organified iodine leaves the thyroid → uptake falls.
13.1.2 Thyroid Scintigraphy (Tc-99m Pertechnetate, I-131, I-123)7 questions
Thyroid scintigraphy provides functional imaging of the thyroid gland. Three different radiopharmaceuticals are used:
Tc-99m Pertechnetate (TcO₄⁻):
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Energy: 140 keV gamma
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T½: 6 hours
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Dose: 37-185 MBq (1-5 mCi) IV
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Imaging: 20-30 minutes after injection
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Mechanism: Trapping via NIS only → not organified → not retained in the cell
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Advantages: Readily available, cheap, low radiation dose, rapid imaging
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Disadvantages: Does not assess organification → risk of discordant nodule; inadequate for retrosternal/ectopic thyroid (low target-to-background ratio)
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Indications: Nodule evaluation (first step), aetiology of hyperthyroidism, congenital hypothyroidism (ectopic thyroid)
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In congenital hypothyroidism, scintigraphy is performed without delaying treatment and while TSH is high. A large gland in its normal position with increased uptake suggests dyshormonogenesis (a perchlorate test is done). If the gland is seen on US but there is no uptake, consider maternal TSH receptor-blocking antibodies, iodine load or a TSHR/NIS defect
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EANM: 74-111 MBq in adults (at least 10 MBq in children). Peak thyroid accumulation occurs at ~20 minutes and uptake is only 2-5% (EANM guideline); the classic normal range is ~0.4-4%. Because the value varies with iodine intake (lower in iodine-rich regions), each centre should establish its own normal range
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Dosimetry: 13 µSv/MBq, i.e. ~1.0 mSv per procedure; if the thyroid is blocked, the colon wall receives the highest organ dose
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Because pertechnetate is not organified, the perchlorate discharge test cannot be performed with pertechnetate
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Breastfeeding is interrupted for 12 hours (milk expressed during this time is discarded); in the newborn the whole body is imaged in a single field of view with a LEHS collimator at 15 minutes
I-123 Sodium Iodide:
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Energy: 159 keV gamma
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T½: 13.2 hours
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Dose: 3.7-14.8 MBq (100-400 µCi) orally
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Imaging: 4-6 hours and/or 24 hours later
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Mechanism: Trapping via NIS + organification → retained in the cell
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Advantages: Assesses organification, low radiation dose (EC decay → no beta), high-quality images, minimal stunning
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Disadvantages: Expensive, cyclotron-produced, limited availability
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Indications: Thyroid nodule, hyperthyroidism, planning before RAI therapy, whole-body iodine scan
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EANM: 7.4-14.8 MBq (at least 3 MBq in children); 150 µSv/MBq, i.e. ~1.2 mSv per procedure. The thyroid receives the highest organ dose (2.7 mGy/MBq)
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With normal TSH the 2-hour uptake is 10-15%; imaging and uptake measurement are usually performed at 2-4 hours (pinhole, 5-15 min)
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Perchlorate discharge test: A fall in I-123 uptake 1 hour after perchlorate indicates an organification defect
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Positivity threshold: A fall of >10% from baseline uptake after perchlorate (>15% in some centres). Causes: Pendred syndrome, TPO defect, Hashimoto thyroiditis, thionamide effect
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Stopping breastfeeding is recommended; in the newborn a 5-minute image is acquired at 1 hour with a LEHS collimator
I-131 Sodium Iodide:
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Energy: 364 keV gamma + β⁻ (Emax = 606 keV)
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T½: 8.02 days
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Diagnostic dose: 0.37-3.7 MBq (10-100 µCi) orally
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Therapeutic dose: 185-7400 MBq (5-200 mCi) orally
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Imaging: 24-48 hours later
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Mechanism: Trapping via NIS + organification
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Advantages: Both diagnosis and therapy (theranostic), long T½ → ideal for 24-hour uptake measurement
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Disadvantages: High radiation dose (beta emission), stunning, poor image quality (high energy → septal penetration of the collimator)
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Indications: Thyroid cancer therapy, hyperthyroidism therapy, whole-body scan (post-therapy)
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Diagnostic whole-body scan (WBS): according to SNMMI/EANM 2022, commonly used activities are 37-74 MBq (1-2 mCi) after thyroid hormone withdrawal and 110-148 MBq (3-4 mCi) with rhTSH; therapeutic activity is usually 1110-3700 MBq
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In benign disease it is used for diagnosis only if Tc-99m pertechnetate or I-123 is unavailable
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Absolute contraindications: Pregnancy and breastfeeding; diagnostic use under 10 years of age other than for thyroid cancer
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The effective dose varies over a very wide range depending on thyroid uptake: from 0.28 mSv/MBq (thyroid blocked) to 14 mSv/MBq (low uptake)
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Rule of thumb for thyroid dose per administered activity: I-131 ~1 rad/µCi, I-123 ~1 rad/100 µCi, Tc-99m pertechnetate ~1 rad/5000 µCi
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Contribution of SPECT/CT: Distinguishing remnant tissue from lymph node in the neck, lung metastasis from rib in the thorax, and bowel/bladder activity from a pelvic bone lesion in the abdomen
Thyroid scintigraphy technique:
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Patient position: Supine, neck slightly extended
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Collimator: Pinhole collimator (highest resolution) or parallel-hole LEHR collimator
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Pinhole collimator: Magnification → superior for detecting small nodules
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Disadvantages: Because magnification depends on the source-to-aperture distance, depth/parallax distortion occurs; gland size and shape cannot be measured accurately; sensitivity is low
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Views: Anterior (standard), oblique (if needed)
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Activity and timing (EANM/SNMMI 2019, adults): Tc-99m pertechnetate 74-111 MBq IV, images at 15-20 minutes; I-123 7.4-14.8 MBq orally, images at 2-6 hours and 24 hours; Tc-99m MIBI 185-370 MBq IV, early at 10-30 minutes and delayed at 60-120 minutes. Immediately before imaging the patient drinks water to clear activity from the mouth and oesophagus; an anterior neck image is acquired for 100-200 thousand counts or 5-10 minutes (whichever comes first), with the collimator as close to the neck as possible
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Because pertechnetate is not organified, it washes out of the thyroid after 30 minutes and is therefore imaged early. Pertechnetate is preferred in a lactating patient because of its shorter half-life, and I-123 in children and when an organification defect is suspected
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Markers: A marker may be placed on the sternal notch, chin or a palpable nodule
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The normal adult thyroid weighs ~15-20 g and each lobe measures ~4-6 × 1.5-2 cm; the gamma camera image does not reliably estimate gland size or weight (US is preferred)
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Isthmus uptake is normally variable (it may be absent or resemble the lobes). The pyramidal lobe is a functioning thyroglossal duct remnant extending upwards from the isthmus, slightly to the left or right of the midline
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If midline activity is suspected to be oesophageal (pertechnetate in swallowed saliva), the patient drinks water and the image is repeated; the activity disappears
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Retrosternal goitre: Pertechnetate is inadequate because of sternal attenuation and blood pool activity; I-123 (high-energy I-131 in large goitres) is preferred, and SPECT/CT helps
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Lingual thyroid: A single functioning mass is seen at the base of the tongue with no uptake in the normal thyroid bed (it is usually the patient's only functioning thyroid tissue). A thyroglossal duct cyst, by contrast, usually contains no functioning tissue and appears cold
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In congenital hypothyroidism, ectopy (the commonest form of dysgenesis, usually lingual) and agenesis are permanent; lifelong LT4 is required. If the gland is in its normal position the condition may be transient; at ~3 years LT4 is stopped and the patient is reassessed
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Pitfalls: a nodule appearing differently on pertechnetate and iodine images (rapid iodine washout from an organification defect, a "trapping-only" nodule) is very rare. Sources of error: contamination of clothing, skin, hair, collimator or table; oesophageal activity; asymmetric salivary gland uptake; breast and thymic uptake; ectopic thyroid tissue; uptake by non-thyroid tumours; inadequate preparation (SNMMI 2020, whole-body iodine scanning)
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Report content (EANM/SNMMI 2019): in addition to the common items (see 27), TSH (and fT4/fT3), thyroid medication and iodine exposure (iodinated contrast, amiodarone), ultrasound findings; imaging time and collimator (pinhole); if uptake was measured, its value, measurement time and the institution's reference range. Findings: position and size of the gland, level and distribution of uptake (homogeneous/heterogeneous), nodules matched to ultrasound and described as hot, warm or cold, whether extranodular tissue is suppressed, pyramidal lobe or ectopic tissue
BOARD TIP
▸
"Which agent shows organification in thyroid scintigraphy?"
→ Iodine (I-123, I-131) → trapping + organification. Pertechnetate → trapping only.
▸
"What is a discordant nodule?"
→ Hot on pertechnetate, cold on iodine → trapping present but no organification → malignancy risk → biopsy required (→ see Chapter 12.3.8).
▸
"Best agent for diagnosis?"
→ I-123 (shows organification, low dose, minimal stunning, good image quality).
13.1.3 Thyroid Uptake Test6 questions
The thyroid uptake test quantitatively measures the iodine-trapping capacity of the thyroid gland.
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Its main uses are to distinguish the cause of thyrotoxicosis (high or low uptake) and to calculate the I-131 activity; because low values overlap with the normal range, it is of no use in diagnosing hypothyroidism
Method:
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Oral I-123 or I-131 is given
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Activity (EANM/SNMMI 2019): as little as 3.7 MBq of I-123 or 0.15 MBq of I-131 is sufficient (adult diagnostic range for I-131 0.15-0.37 MBq); I-123 also allows concurrent imaging. Measurements are made at selected times (e.g. 6 and 24 hours, and 5 days if needed)
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Counts are taken over the thyroid with a probe detector (NaI crystal)
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The probe-to-neck distance (usually 25-30 cm) is kept the same for the patient and the standard in the neck phantom; non-thyroidal background activity in the neck is corrected with a count over the thigh
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Compared with a standard source (capsule of the same activity)
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Measurement times: 4-6 hours and 24 hours
Calculation:
RAIU (%) = (Thyroid counts − Thigh (background) counts) / (Standard counts − Room background counts) × 100
Normal values:
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4-6 hours: 5-15%
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24 hours: 10-30% (most frequently asked)
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With rapid iodine turnover (severe Graves, iodine deficiency) the 4-6-hour uptake may exceed the 24-hour value; a 24-hour measurement alone is therefore misleading and an early measurement should also be made
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EANM/SNMMI 2019: the normal range varies by region according to iodine intake, and each laboratory determines its own range. As a guide, in iodine-sufficient regions a value above 25% in the setting of clinical hyperthyroidism is compatible with hyperfunction. In a small group of patients with rapid iodine turnover the highest value is at 6-12 hours, but almost all of them also keep an elevated 24-hour and 5-day uptake. In elderly hyperthyroid patients (often toxic multinodular goitre) the value may be within the normal range
Causes of high uptake:
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Graves disease (diffusely increased uptake)
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Toxic multinodular goitre (heterogeneously increased uptake)
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Toxic adenoma (focally increased uptake, surrounding tissue suppressed)
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Iodine deficiency
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Elevated TSH (primary hypothyroidism, TSH-secreting adenoma)
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High uptake with hypothyroidism: Dyshormonogenesis (congenital organification defect), early Hashimoto thyroiditis, severe iodine deficiency
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Rebound effect (after stopping antithyroid drugs)
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hCG-mediated thyrotoxicosis: In trophoblastic disease (hydatidiform mole, choriocarcinoma) and hyperemesis gravidarum, hCG stimulates the TSH receptor; uptake is increased
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Lithium use
Causes of low uptake:
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Subacute thyroiditis (De Quervain) → painful, low uptake (<5%)
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Silent (painless) thyroiditis → low uptake
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Postpartum thyroiditis → low uptake
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Exogenous thyroid hormone intake (thyrotoxicosis factitia)
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In thyrotoxicosis factitia serum Tg is suppressed, whereas in thyroiditis it is high; since uptake is low in both, Tg makes the distinction
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Iodine loading (contrast agents, amiodarone, Wolff-Chaikoff)
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After water-soluble iodinated contrast, uptake may remain suppressed for ~4-8 weeks; after amiodarone (stored in fat, very long half-life) and oil-based contrast agents (lipiodol, older myelography agents) this may last months or even years
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Struma ovarii (ectopic thyroid tissue → ovarian teratoma)
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Functioning metastatic thyroid cancer (rare)
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Report content (EANM/SNMMI 2019): in addition to the common items (see 27), radioiodine used (I-123 or I-131) and activity, measurement times (e.g. 4-6 and 24 hours), measurement geometry and background correction; the result is given as a percentage with the time of measurement and the institution's reference range. If performed for therapy planning, the effective half-life or a second measurement is also reported; TSH, thyroid medication and recent iodine exposure are stated for interpretation
Figure 13.2: Radioiodine uptake (RAIU) time curves and normal ranges at 4-6 and 24 hours (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"Hyperthyroidism + low uptake?"
→ Thyroiditis (subacute, silent, postpartum) or exogenous hormone or iodine loading. This combination is asked very often in board exams!
▸
"Hyperthyroidism + high uptake?"
→ Graves, toxic adenoma, toxic MNG.
▸
"Struma ovarii?"
→ Ectopic thyroid tissue in an ovarian teratoma → thyrotoxicosis + low thyroid uptake → pelvic uptake!
13.1.4 Evaluation of the Thyroid Nodule8 questions
Clinical approach:
1. TSH measurement → first step 2. If TSH is low → thyroid scintigraphy (hot/cold nodule) 3. If TSH is normal or high → US + fine-needle aspiration biopsy (FNAB)
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US features suggesting malignancy: Solid and hypoechoic structure, microcalcification, irregular or microlobulated margin, taller-than-wide shape and extrathyroidal extension. The risk is very low in purely cystic and spongiform nodules; hyperechogenicity does not exclude malignancy
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In iodine-deficient regions a substantial proportion of autonomous nodules are euthyroid (TSH is normal); the European (EANM) approach therefore recommends scintigraphy for nodules >1 cm regardless of TSH level
Scintigraphic classification of nodules:
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Hot (hyperfunctioning) nodule: Uptake greater than surrounding parenchyma → autonomous function → very low malignancy risk (1-2%) → FNAB usually not required
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Warm (isofunctioning) nodule: Uptake equal to surrounding parenchyma → low-to-intermediate malignancy risk
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Cold (hypofunctioning) nodule: Less or no uptake compared with surrounding parenchyma → malignancy risk 5-15% → FNAB indicated
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Discordant nodule: Hot on pertechnetate, cold on iodine → malignancy risk → FNAB indicated
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If pertechnetate or iodine uptake is seen in a lateral cervical lymph node on thyroid scintigraphy, it is considered a DTC metastasis until proven otherwise (the concept of 'lateral aberrant thyroid' is no longer used)
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A warm (isofunctioning) nodule is managed like a cold nodule, because overlying normal tissue may mask a cold nodule; oblique views, US ± FNAB are performed. A history of head and neck irradiation increases the risk of malignancy
BOARD TIP
▸
"Cold nodule = cancer?"
→ No! 85-95% of cold nodules are benign (cyst, colloid nodule, adenomatous nodule). However, the malignancy risk is clearly higher than for a hot nodule → FNAB is required.
▸
"Is FNAB required for a hot nodule?"
→ Usually not → very low malignancy risk (1-2%). However, if US shows suspicious features, FNAB may be considered.
Bethesda Classification (FNAB results):
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Bethesda I: Non-diagnostic → repeat FNAB
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Bethesda II: Benign → follow-up
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Bethesda III: Atypia of undetermined significance (AUS) → repeat FNAB or molecular testing
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Bethesda IV: Follicular neoplasm → lobectomy (surgery)
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The cytology of hyperfunctioning nodules often looks like a follicular neoplasm; if a Bethesda III-IV nodule is hot on scintigraphy, the malignancy risk is very low and unnecessary surgery can be avoided
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Bethesda V: Suspicious for malignancy → surgery
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Bethesda VI: Malignant → surgery
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Serum Tg is not used to distinguish malignant from benign nodules (it is also raised in benign goitre and thyroiditis). Routine calcitonin screening for MTC is controversial: some European guidelines recommend it, whereas the ATA makes no recommendation for or against
Figure 13.3: TSH-based approach to the thyroid nodule and scintigraphic nodule classification (schematic).
Did this figure help you understand the topic?
13.1.5 Hyperthyroidism (Graves, Toxic Nodule, TMNG)7 questions
Graves Disease:
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The commonest cause of hyperthyroidism (60-80%)
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Autoimmune → TSH receptor-stimulating antibodies (TRAb/TSI)
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Scintigraphy: Diffuse, homogeneous, increased uptake → symmetric uptake throughout the gland
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Uptake: Markedly high (usually >40-50%)
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A pyramidal lobe may be seen (thyroglossal duct remnant → becomes prominent in Graves)
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Clinical: Thyrotoxicosis + diffuse goitre + extrathyroidal features (Graves ophthalmopathy, pretibial myxoedema, thyroid acropachy)
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RAI therapy: I-131 → definitive treatment (→ see 13.1.6)
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Antithyroid drugs are usually continued for 12-18 months; the relapse rate after stopping is ~50%. Large goitre, young age, high TRAb, smoking and male sex increase the risk of relapse
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Marine-Lenhart syndrome: One or more hypofunctioning (cold) nodules in the setting of Graves disease; a cold area is seen within diffusely increased uptake. The nodule requires separate evaluation; it may be more resistant to RAI
Toxic Multinodular Goitre (TMNG/Plummer disease):
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More common in older patients
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Scintigraphy: Heterogeneous, irregular uptake → multiple hot and cold areas
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Uptake: Normal to high (may not be as high as in Graves)
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Some nodules are autonomous → surrounding tissue partly suppressed
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Non-toxic MNG: Heterogeneous uptake with multiple cold (± hot) areas of varying size; US ± FNAB for a dominant or suspicious cold nodule
Toxic Adenoma (Hot Nodule):
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A single autonomous hyperfunctioning nodule
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Scintigraphy: Focal intense uptake + suppressed surrounding thyroid parenchyma (due to TSH suppression)
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Uptake: Normal to mildly high
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TSH suppression → surrounding tissue not visualised → "single hot nodule" pattern
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Treatment: RAI or surgery
BOARD TIP
▸
"Diffuse homogeneous increased uptake on scintigraphy?"
→ Graves.
▸
"Heterogeneous, irregular uptake?"
→ Toxic MNG.
▸
"Single hot nodule + suppressed surroundings?"
→ Toxic adenoma.
▸
"Low/absent uptake + thyrotoxicosis?"
→ Thyroiditis (subacute, silent, postpartum) or exogenous hormone.
Subacute (De Quervain) Thyroiditis:
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After a viral infection → painful, tender thyroid
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Scintigraphy: Very low or absent uptake (<2%)
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Thyrotoxic phase (release of stored hormone) → hypothyroid phase → recovery
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ESR raised, thyroid antibodies usually negative
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Treatment: NSAIDs; short-course steroids in severe cases
Silent (Painless) Thyroiditis:
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Autoimmune → painless, low uptake
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Postpartum thyroiditis: 2-6 months after delivery → a variant of silent thyroiditis
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Scintigraphy: Low uptake (as in subacute thyroiditis)
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Anti-TPO antibodies usually positive
•
Hashimoto (chronic lymphocytic) thyroiditis: Anti-TPO (antimicrosomal) and anti-Tg are raised, with lymphocytic infiltration. The scintigraphic appearance is variable (heterogeneous/patchy; uptake may be normal, increased or decreased) and may mimic a cold nodule
•
Primary thyroid lymphoma (mostly DLBCL or MALT type) almost always arises on a background of Hashimoto thyroiditis and presents as a rapidly enlarging goitre. It is FDG-avid (Ga-67 was used in the past); diffuse involvement may be confused with thyroiditis
•
Because Hashimoto thyroiditis may involve an organification defect, early (2-4-hour) RAIU may be high with a relatively low 24-hour value; the perchlorate discharge test may be positive
Figure 13.4: Main uptake patterns on Tc-99m pertechnetate thyroid scintigraphy (schematic).
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13.1.6 Thyroid Cancer and RAI Therapy12 questions
Types of thyroid cancer and RAI response:
•
Papillary thyroid cancer (PTC): Most common (80-85%) → RAI-avid (NIS expressed)
•
DTC is ~3 times more common in women; PTC is often multifocal. In iodine-deficient regions the proportion of FTC (and anaplastic cancer) is higher; after iodine prophylaxis the proportion of PTC rises and that of FTC falls
•
Follicular thyroid cancer (FTC): 10-15% → RAI-avid (NIS expressed)
•
In children the risk that a thyroid nodule is malignant is higher than in adults (~20-25%). In paediatric DTC lymph node (40-90%) and lung metastases (20-30%) are common, yet survival is still excellent; the strongest prognostic factor is age (AJCC 8: age threshold 55 years)
•
Molecular alterations: In PTC, BRAF V600E (most common; associated with reduced RAI uptake and refractoriness) and RET/PTC fusion; in FTC, RAS mutations and PAX8-PPARγ
•
Spread: PTC spreads mainly via lymphatics (cervical lymph nodes), FTC mainly haematogenously (lung, bone)
•
Distant metastases of DTC: Most commonly lung (micronodular/miliary in the young and in PTC) and bone (FTC); brain and liver are rare. The prognosis is good in small RAI-avid lung metastases; in bone metastases cure is rare and the prognosis is worse
•
Radiation exposure (Chernobyl, head and neck radiotherapy) increases mostly the risk of papillary cancer
•
Oncocytic (Hürthle) carcinoma: a separate entity (WHO 2022) → variable RAI response (usually low)
•
Medullary thyroid cancer (MTC): Arises from C cells (parafollicular) → not RAI-avid (no NIS expression) → follow-up with calcitonin and CEA
•
Treatment of MTC: Total thyroidectomy and central neck dissection; RAI and TSH suppression are of no benefit. Distant metastases occur in the liver (often small/miliary; contrast-enhanced MRI is more sensitive), lung and bone; brain metastases are rare
–
MEN2A: MTC + phaeochromocytoma + hyperparathyroidism. MEN2B: MTC + phaeochromocytoma + marfanoid habitus + mucosal neuromas + gastrointestinal ganglioneuromatosis (no hyperparathyroidism). Both have a RET mutation
–
~25% of MTCs are hereditary (autosomal dominant, germline RET, chromosome 10). Germline RET testing is recommended for every MTC patient; if positive, first-degree relatives are screened. The timing of prophylactic thyroidectomy is set by the risk level of the RET codon
•
Anaplastic thyroid cancer: Dedifferentiated → not RAI-avid → very poor prognosis
•
Anaplastic carcinoma is always stage IV at diagnosis (AJCC 8: IVA confined to the thyroid, IVB extrathyroidal extension/N1, IVC distant metastasis); FDG PET/CT is preferred for staging
BOARD TIP
▸
"Which thyroid cancers take up RAI?"
→ Differentiated thyroid cancers (papillary and follicular) → NIS expressed.
▸
"Does medullary thyroid cancer take up RAI?"
→ No → it arises from C cells, no NIS expression. Tumour marker in MTC = calcitonin (and CEA).
▸
"RAI in anaplastic cancer?"
→ No → dedifferentiated, loss of NIS.
RAI (I-131) Therapy – Indications:
•
Remnant ablation: Destruction of remaining thyroid tissue after thyroidectomy → makes interpretation of Tg and WBS easier during follow-up
•
Adjuvant therapy: In patients at risk of microscopic residual disease
•
Treatment of metastatic disease: Local/regional recurrence, distant metastases (lung, bone)
RAI treatment activities:
•
Low risk: routine remnant ablation is not recommended; if given in a selected patient, 1.1-1.85 GBq (30-50 mCi) (ATA 2025)
•
Low-intermediate and intermediate-high risk: adjuvant RAI may be considered; activity is generally 1.1-3.7 GBq (30-100 mCi)
•
High risk: adjuvant RAI is recommended routinely; 3.7-5.55 GBq (100-150 mCi). For distant metastases at diagnosis, 3.7-7.4 GBq (100-200 mCi) or dosimetry. Empiric activities above 5.5 GBq (150 mCi) are avoided in patients over 70 and in renal failure; if such an activity is needed, its safety is confirmed by dosimetry
•
Cumulative dose limit: There is no strict upper limit, but >600 mCi → increased risk of bone marrow suppression and secondary malignancy
Preparation before RAI therapy:
1. Raising TSH (target >30 mIU/L):
–
Thyroid hormone withdrawal: Levothyroxine is stopped 3-4 weeks before (or switched to T3 → T3 stopped 2 weeks before)
–
Recombinant human TSH (rhTSH/Thyrogen®): 0.9 mg IM × 2 days → TSH rises without stopping thyroid hormone → hypothyroid symptoms are avoided; according to ATA 2025 it is preferred over hormone withdrawal for ablation and adjuvant therapy
2. Low-iodine diet: 1-2 weeks → reduces the endogenous iodine pool → increases RAI uptake (iodine <50 µg/day; non-iodised salt is not restricted, because of the risk of hyponatraemia during hormone withdrawal) 3. Withdrawal of iodine-containing drugs: Amiodarone (3-6 months), IV contrast (6-8 weeks), antithyroid drugs (methimazole 2-5 days; PTU longer)
4. Pregnancy test: Mandatory in women of childbearing age (RAI is absolutely contraindicated in pregnancy).
5. Stopping breastfeeding: Because breast tissue expresses NIS, RAI may accumulate there; breastfeeding and pumping should be stopped at least 3 months before RAI (ATA 2025); in a recently lactating woman, an I-123 scan may be performed before treatment to detect breast uptake. Pregnancy is avoided for at least 6 months after treatment.
Figure 13.5: Timeline of preparation steps before RAI (I-131) therapy (schematic).
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BOARD TIP
▸
"Why should TSH be raised before RAI therapy?"
→ TSH increases NIS expression → RAI uptake by thyroid cells increases → treatment efficacy increases.
▸
"Advantage of rhTSH?"
→ TSH rises without hypothyroid symptoms → patient comfort, less loss of working time.
▸
"Why a low-iodine diet?"
→ The endogenous iodine pool falls → less competition with RAI → uptake increases.
Management after RAI therapy:
•
Isolation: According to radiation safety rules (→ see Chapter 10.8)
•
Hydration: Plenty of fluids → renal clearance is accelerated → bladder dose is reduced
•
Laxative: Speeds bowel transit → colon dose is reduced
•
Sour sweets/lemon: Increase salivary flow → reduce the risk of sialadenitis (timing is controversial → some centres start 24 hours later)
•
Starting levothyroxine: TSH suppression therapy → reduces the risk of recurrence in differentiated thyroid cancer
–
Levothyroxine and a normal diet are usually resumed 1-3 days after RAI
–
Excellent or indeterminate response: TSH within the reference range
–
Biochemically or structurally incomplete response: TSH below the reference range (the optimal target is uncertain; comorbidities such as atrial fibrillation and osteoporosis are taken into account)
–
Long-term TSH suppression is not suggested for low- and intermediate-risk patients without evidence of disease; the target is re-evaluated over time (ATA 2025)
Follow-up:
•
Thyroglobulin (Tg): Tumour marker → after total thyroidectomy + RAI, Tg should be undetectable
–
The half-life of Tg is ~1-3 days; after thyroidectomy it reaches its nadir at ~3-4 weeks. Postoperative Tg is therefore not interpreted before this time
–
Rising Tg → suspicion of recurrent/residual disease
–
Anti-Tg antibodies → may interfere with Tg measurement → Tg is unreliable in their presence
–
Tg is now measured by immunometric assay (IMA); anti-Tg antibodies cause falsely low Tg in IMA. Tg is therefore always measured together with anti-Tg, and the antibody trend is also followed as a surrogate marker
–
In RIA, by contrast, anti-Tg usually causes falsely high Tg; the LC-MS/MS method is largely unaffected by antibody interference, but its sensitivity is low. ATA 2025: anti-Tg is measured quantitatively with every Tg measurement; in anti-Tg-positive patients, imaging is the mainstay of monitoring
•
Neck US: every 6-12 months
•
Stimulated Tg: Tg measurement after rhTSH or hormone withdrawal → more sensitive
•
Whole-body iodine scan (WBS): When needed (→ see 13.1.7)
•
Response to therapy (ATA 2025; after total thyroidectomy and RAI):
–
Excellent: non-stimulated Tg <0.2 ng/mL or stimulated Tg <1 ng/mL and negative imaging
–
Indeterminate: non-specific findings on imaging, or non-stimulated Tg 0.2-1, stimulated Tg 1-10, or stable/declining anti-Tg
–
Biochemically incomplete: non-stimulated Tg >1 or stimulated Tg >10 or rising anti-Tg, with negative imaging
–
Structurally incomplete: local or distant disease shown on imaging or by biopsy
–
After total thyroidectomy without RAI the thresholds use non-stimulated Tg: excellent <2.5, indeterminate 2.5-5, biochemically incomplete >5. The first response assessment is made within 3 months of surgery and guides the decision on RAI and its activity
–
Patients at low and low-intermediate risk with an excellent response do not need routine diagnostic WBS during follow-up; WBS is not used for surveillance after lobectomy or total thyroidectomy without RAI
13.1.7 Whole-Body Iodine Scan (WBS)2 questions
Indications:
•
After RAI therapy (post-therapy scan → generally days 2-10; ATA 2025 recommends it after every treatment)
•
Suspected recurrence during follow-up (raised stimulated Tg)
•
Planning before RAI therapy: a diagnostic I-123 or low-activity I-131 scan may be considered to guide treatment planning (ATA 2025); a large remnant with uptake above 15% or unexpected metastases may change management. The concept of stunning is controversial
Diagnostic WBS:
•
I-123 (2-5 mCi) or low-dose I-131 (1-3 mCi)
–
•
I-123 is preferred → minimal stunning
•
Imaging: I-123 → 24 hours; I-131 → 48-72 hours
Post-therapy WBS:
•
Performed after high-dose I-131 therapy, generally between days 2 and 10; no additional radiopharmaceutical is needed
•
More sensitive than diagnostic WBS → more lesions can be detected because of the high dose
•
Additional metastatic foci may be detected → staging may change
Sites of physiological uptake (causes of false positives):
•
Salivary glands (NIS expression)
•
Nasal mucosa
•
Stomach (NIS expression)
•
Bladder (renal excretion)
•
Liver (T4 metabolism)
•
Breast (increased NIS during lactation)
•
Colon (hepatobiliary excretion)
•
Thyroid bed (residual thyroid tissue)
Causes of false positives (non-pathological):
•
Contamination (saliva, sweat, urine)
•
Ectopic thyroid tissue (thyroglossal cyst)
•
Struma ovarii
•
Ectopic gastric mucosa (Meckel diverticulum)
•
Bronchiectasis / pleural effusion (non-specific)
•
Thymus: RAI uptake in the anterior mediastinum, especially in young patients (and after rhTSH or high doses), may be benign and should not be mistaken for metastasis; on FDG, thymic hyperplasia in the young is a similar pitfall
•
Sebaceous cyst
•
Report content (SNMMI/EANM 2022): in addition to the common items (see 27), method of TSH stimulation (withdrawal or rhTSH) and the stimulated TSH value, stimulated thyroglobulin with anti-Tg antibodies, adherence to the low-iodine diet and recent iodine load (iodinated contrast, amiodarone), diagnostic activity and imaging time, whether SPECT/CT was performed. Findings: thyroid bed remnant, cervical and mediastinal nodal uptake and distant uptake are reported separately; physiological or false positive uptake (salivary glands, stomach, breast, thymus, contamination) is distinguished; in a negative scan it is stated that causes of false negatives were reviewed
BOARD TIP
▸
"Post-therapy WBS vs diagnostic WBS?"
→ Post-therapy WBS is more sensitive → more lesions are detected with high-dose I-131. Lesions not seen on diagnostic WBS may be seen on post-therapy WBS → additional lesions are found in 10-26% of patients and staging may change.
▸
"What does liver uptake on WBS mean?"
→ (1) Hepatic metabolism of iodinated Tg/hormones produced by functioning thyroid tissue (remnant or metastasis) or (2) liver metastasis (focal). Diffuse uptake is not specific for metastasis.
Figure 13.6: Sites of physiological uptake and non-pathological causes of false positives on radioiodine whole-body scanning (schematic).
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13.1.8 Stunning and Empirical vs Dosimetric Therapy6 questions
Stunning:
Stunning is the reduction of NIS expression caused by sublethal damage to thyroid cells from diagnostic I-131, which lowers uptake of the subsequent therapeutic dose.
Mechanism:
•
Diagnostic I-131 → DNA damage in the thyroid cell (sublethal) → the cell survives but NIS expression falls → uptake of the therapeutic dose falls → treatment efficacy falls
•
The clinical significance of stunning is controversial: reduced uptake after a diagnostic dose has been shown, but it has not been conclusively proven that this significantly affects ablation success or outcomes
Strategies to prevent stunning:
•
Use of I-123: I-123 is preferred for diagnostic WBS → no beta emission → minimal/no stunning
•
Low-dose I-131: ≤3 mCi (111 MBq) → low risk of stunning
•
Short interval: Giving the therapy within 72 hours of the diagnostic dose → therapy is given before stunning develops
•
Avoiding diagnostic WBS: Some centres give the therapeutic dose directly without a diagnostic WBS → evaluation by post-therapy WBS
BOARD TIP
▸
"What is stunning?"
→ A diagnostic I-131 dose given before therapy → reduces NIS expression → treatment efficacy falls.
▸
"How is it prevented?"
→ (1) Use I-123, (2) low-dose I-131 (≤3 mCi), (3) ≤72 hours between the diagnostic dose and therapy, (4) direct therapy without a diagnostic WBS.
▸
"What is the star artefact?"
→ Very intense uptake in the thyroid bed on post-therapy WBS after high-dose I-131 → septal penetration → star-shaped artefact.
Empirical vs Dosimetric Treatment Approach:
Empirical (Fixed-Dose) Approach:
•
A fixed dose is given according to clinical and pathological risk factors
•
The most widely used method
•
Advantages: Simple, practical, broad clinical experience
•
Disadvantages: Does not take individual differences into account; under-/overdosing in some patients
•
Typical doses:
–
Remnant ablation and adjuvant therapy (ATA 2025): 1.1-1.85 GBq (30-50 mCi) at low risk (selected patients), 1.1-3.7 GBq (30-100 mCi) at intermediate risk, 3.7-5.55 GBq (100-150 mCi) at high risk
–
Residual cervical disease: up to 5.55 GBq (150 mCi) as adjuvant therapy for suspected microscopic residual disease; for isolated cervical lymph node metastases, additional RAI is considered after local therapy or if local therapy is not feasible
–
Distant metastasis: empiric 3.7-7.4 GBq (100-200 mCi) (3.7-5.55 GBq for pulmonary metastases in patients over 70) or a dosimetry-based activity (ATA 2025)
Dosimetric Approach:
•
The maximum tolerated dose is calculated for the individual patient
•
Bone marrow dosimetry: Blood and whole-body retention measurements → the aim is to deliver no more than 200 cGy to the bone marrow
•
Lesion dosimetry: Planned to deliver an adequate dose (>8000 cGy) to the target lesion
•
Lung dosimetry: In diffuse lung metastases, lung retention at 48 hours should be <80 mCi → risk of radiation pneumonitis/fibrosis
•
According to the Benua-Leeper safe dose criteria, whole-body retained activity at 48 hours should also be <4.4 GBq (120 mCi)
•
Advantages: Individualised, safe maximum dose
•
Disadvantages: Complex, time-consuming, not feasible in every centre
Lesion Dosimetry with I-124 PET/CT:
•
A positron-emitting iodine radionuclide (T½ 4.18 days); because it is taken up via NIS like iodide, it is used both for diagnosis and for dosimetry
•
Uses: Persistent or recurrent DTC, deciding on a second RAI therapy, patient-specific dosimetry before I-131
•
Diagnostic activity: 20-74 MBq orally (up to 185 MBq if needed). Preparation: TSH ≥30 mIU/L and a 4-week low-iodine diet
•
Most accurate dosimetry: Imaging at 5 time points: 4, 24, 48, 72 and 96 hours
•
Target absorbed doses: ~300 Gy for thyroid remnant, 80-100 Gy for DTC metastases
•
Contraindicated in pregnancy and breastfeeding; inadequate TSH stimulation and iodine load are relative contraindications
BOARD TIP
▸
"Bone marrow dose limit in the dosimetric approach?"
→ 200 cGy (2 Gy).
▸
"Lung retention limit?"
→ <80 mCi at 48 hours (in diffuse lung metastases).
▸
"Empirical vs dosimetric – which is more common?"
→ Empirical → practical, with broad experience. The dosimetric approach is preferred especially in elderly patients, those with renal failure or those requiring high doses.
13.1.9 Thyroid Scintigraphy with Tc-99m MIBI2 questions
Principle:
•
A lipophilic cation retained according to the mitochondrial membrane potential; its uptake is independent of TSH and NIS and is seen only in viable cells
•
Used as an alternative when NIS agents (iodine, pertechnetate) are not taken up, e.g. with iodine load from iodinated contrast or amiodarone
Distinguishing the types of amiodarone-induced thyrotoxicosis (AIT):
•
AIT-1: Excess hormone synthesis due to iodine excess (usually in pre-existing thyroid disease); MIBI uptake is normal or increased
•
AIT-2: Destructive thyroiditis due to a direct cytotoxic effect of the drug; MIBI uptake is reduced or absent
•
AIT-3 (mixed type): Defined by quantitative comparison of early and delayed images
•
Colour Doppler US is also used to distinguish AIT: vascularity is normal or increased in AIT-1 and reduced or absent in AIT-2. Graves and Hashimoto are diffusely hypoechoic on US; vascularity is markedly increased in Graves
Indeterminate thyroid nodule:
•
Patient selection: Nodules >1 cm that are hypofunctioning on scintigraphy, EU-TIRADS 4-5 on US and Bethesda III/IV on cytology
•
Visual assessment: Hypointense nodule benign; isointense nodule malignancy possible; hyperintense nodule malignancy likely
•
Washout index (WOind): Early (10 min) and delayed (60 min) images are compared; slow washout by the −19% threshold supports malignancy and increases specificity
•
A nodule without MIBI uptake has a high negative predictive value; this finding helps exclude malignancy
•
Oncocytic (Hürthle) adenoma: Washout is slow because it is rich in mitochondria; in follicular adenoma washout is fast
Technique:
•
370 MBq (at least 80 MBq in children), ~3.3 mSv; no preparation required
•
The basic images are early and delayed planar images; SPECT/CT is used in selected cases (e.g. to establish whether a mediastinal mass is of thyroid origin)
–
EANM/SNMMI 2019: 185-370 MBq in adults; early images at 10-30 minutes and delayed images at 60-120 minutes
BOARD TIP
▸
"Which scintigraphy for thyrotoxicosis in a patient on amiodarone?" Because of the iodine load, pertechnetate and iodine uptake are low and non-discriminating; Tc-99m MIBI is used: uptake is normal/increased in AIT-1 and reduced/absent in AIT-2.
▸
"If an indeterminate (Bethesda III/IV) nodule does not take up MIBI?" The negative predictive value is high; the finding supports benignity.
13.2 Parathyroid
13.2.1 Parathyroid Physiology1 questions
Parathyroid glands:
•
Normally 4 (2 superior, 2 inferior)
•
Superior glands: Arise from the 4th pharyngeal (branchial) pouch → more constant location (posterior to the upper pole of the thyroid)
•
Inferior glands: Arise from the 3rd pharyngeal (branchial) pouch → more variable location (migrate with the thymus → higher risk of ectopic position)
•
Weight: ~30-50 mg each
•
Contain oxyphil cells and chief cells
•
Chief cells: Synthesise PTH (MIBI uptake lower than in oxyphil cells)
•
Oxyphil cells: Rich in mitochondria → high MIBI uptake
Effects of parathyroid hormone (PTH):
•
Bone: Osteoclast activation → bone resorption → release of Ca²⁺ and PO₄³⁻
•
Kidney: Reduces phosphate reabsorption in the proximal tubule (phosphaturia), increases Ca²⁺ reabsorption in the distal tubule, activates 1-alpha-hydroxylase → synthesis of active vitamin D (1,25(OH)₂D₃) increases
•
Intestine: Indirect effect → Ca²⁺ absorption increases via vitamin D
•
Net effect: Serum Ca²⁺ ↑, serum PO₄³⁻ ↓
Primary Hyperparathyroidism (PHPT):
•
80-85% single adenoma (most common)
•
10-15% hyperplasia (4 glands)
•
1-2% carcinoma
•
2-5% double adenoma
•
Clinical: Hypercalcaemia → "stones, bones, groans, moans, psychiatric overtones"
–
Kidney stones, bone pain/osteoporosis, abdominal pain/constipation, muscle weakness, depression/confusion
•
Laboratory: Ca²⁺ ↑, PTH ↑ (or inappropriately normal), PO₄³⁻ ↓
BOARD TIP
▸
"Commonest cause of PHPT?"
→ Single adenoma (80-85%).
▸
"Why are the inferior parathyroid glands more often ectopic?"
→ They arise from the 3rd pharyngeal pouch → migrate with the thymus → higher risk of mediastinal ectopy.
▸
"Superior glands?"
→ 4th pharyngeal pouch → more constant location.
▸
"Why are oxyphil cells important?"
→ Rich in mitochondria → high MIBI uptake → the basis of parathyroid scintigraphy.
13.2.2 Tc-99m MIBI Parathyroid Scintigraphy (Dual-Phase, Subtraction Technique)9 questions
Parathyroid scintigraphy is used for preoperative localisation of the adenoma in primary hyperparathyroidism.
Tc-99m MIBI (Sestamibi) – Mechanism of Retention:
•
MIBI is a lipophilic cationic complex → retained according to the mitochondrial membrane potential
•
Taken up by both thyroid and parathyroid cells
•
Parathyroid adenomas have a high mitochondrial density (especially oxyphil cells) → more intense and prolonged uptake
•
Slower washout than from thyroid tissue → the parathyroid adenoma becomes conspicuous on delayed images
Dual-Phase Technique:
•
Early phase: 10-15 minutes after injection → both thyroid and parathyroid uptake are seen
•
Delayed phase: 90-150 min (1.5-2.5 hours) after injection → washout from the thyroid, while retention continues in the parathyroid adenoma
•
Interpretation: Thyroid + parathyroid uptake in the early phase → only parathyroid uptake remains in the delayed phase → the "differential washout" principle
•
Sensitivity: 80-90% for a single adenoma, 50-60% for hyperplasia (lower)
Subtraction Technique:
•
Two different radiopharmaceuticals are used:
•
Tc-99m MIBI: Both thyroid and parathyroid uptake
•
Tc-99m pertechnetate or I-123: Thyroid uptake only
•
Digital subtraction: The thyroid image is subtracted from the MIBI image → remaining activity = parathyroid adenoma
•
Advantage: Higher sensitivity than the dual-phase technique (especially in adenomas with rapid washout)
•
Disadvantage: Two injections are needed; patient motion → misregistration artefact
Neck MIBI images are shown early and as time passes; thyroid washout and adenoma retention are traced on a remaining-activity curve, with rapid-washout and MIBI-avid nodule scenarios. The second step subtracts a scaled pertechnetate image from the MIBI image and shows the result of correct, under- and over-scaling.
Continuous stream · no seeking
Key idea: dual phase relies on differential washout between thyroid and adenoma, subtraction on a second agent taken up by the thyroid only; each has its own false results.
Source: book (13.3: early 10-15 min, late 90-150 min — EANM 2021, differential washout; rapid washout → false negative; MIBI-avid thyroid nodule → false positive; MIBI − pertechnetate/I-123 subtraction, misregistration). Images and washout rates are representative (left at 180 min: thyroid ~30%, adenoma ~85%); each image is scaled to its own maximum.
How to use: ↑ ↓ or the buttons below change the scenario in the first step and the subtraction scale in the second; in the first step a single click on the drawing pauses and resumes; ← → change steps.
Did this animation help you understand the topic?
Figure 13.7: Dual-phase (differential washout) and subtraction techniques in Tc-99m MIBI parathyroid scintigraphy (schematic).
EANM Protocol Details:
•
Activity: MIBI 400-900 MBq (at least 80 MBq in children); in the dual-tracer protocol, pertechnetate 74-150 MBq or I-123 7.4-14.8 MBq is added
•
Imaging: Early (10-15 min) and delayed (1.5-2.5 hours) anterior neck and upper thorax images; SPECT/CT is added for ectopic and <1 cm lesions
•
Effective dose: ~7 µSv/MBq; for 400-900 MBq ~2.8-6.3 mSv. In the dual-tracer protocol the dose of pertechnetate (at most ~2.4 mSv) or I-123 is added. The gallbladder and kidneys receive the highest organ doses
•
The pooled detection rate of MIBI SPECT/CT is ~88% at both patient and lesion level
•
Tc-99m tetrofosmin: An alternative lipophilic cation with similar pharmacokinetics but different washout; Tl-201 was used for this purpose in the 1980s
•
EMA indication: Preoperative localisation in primary HPT and in tertiary HPT due to chronic kidney disease; sensitivity is low in secondary and tertiary HPT
•
Preparation: In the subtraction protocol, thyrostatics and L-T4 are stopped ~1 week before and iodinated contrast is avoided for ≥6 weeks. No preparation is needed for dual-phase MIBI (calcium channel blockers may affect uptake)
•
Breastfeeding: Need not be stopped; with a 24-hour interruption the infant's dose is almost zero (if I-123 NaI is used the current recommendation is ~3 days; the former recommendation was ≥3 weeks, see 10.7.3)
•
Causes of false positives: MIBI-avid thyroid nodules (the most important pitfall), lymph nodes, brown fat, thymus, salivary gland tissue and muscle
•
Causes of false negatives: Small (low-weight) or oxyphil-poor (chief cell-predominant) adenoma, rapid washout due to P-gp/MDR expression, multiglandular hyperplasia and calcium channel blockers
–
EANM 2021: sensitivity drops markedly in multiglandular disease (61% vs 97% for single-gland disease with the dual-tracer method; 26.7% vs 92.6% with MIBI in another series). In multinodular goitre MIBI may be falsely negative; ultrasound is mandatory, and the dual-tracer method and fluorocholine PET/CT are useful. Patients taking calcium channel blockers have about a threefold higher likelihood of a negative scan (OR 2.88)
–
Incidental findings are reported: MIBI uptake in the pituitary region or lungs, abnormal bone uptake of MIBI (27.8% of patients in one series). Brown tumours appear lytic or cystic on CT; they are mostly negative with MIBI and positive with choline analogues
–
Fluorocholine PET/CT pitfalls: a focus within the thyroid is mostly a benign or malignant thyroid nodule (especially oncocytic adenoma) but may be an intrathyroidal parathyroid; small thyroid remnants after thyroidectomy may give false positives. Reactive lymph nodes (especially mediastinal and axillary) are often avid. False negatives may occur with moderate hypercalcaemia and non-elevated PTH, in multiglandular disease (secondary HPT, MEN) and with too restricted a field of view (especially recurrence after parathyroidectomy). Images are acquired 1 hour after injection, if possible preceded by imaging at 5 minutes (some lesions show uptake only in the early phase)
•
Report content (EANM 2021): in addition to the common items (see 27), serum calcium, PTH and vitamin D, previous neck surgery and thyroid disease, ultrasound or other imaging; protocol (dual-phase, dual-tracer or PET), imaging times and SPECT/CT. Findings: site of each focus (relation to the thyroid, or anatomical relations if ectopic), size and uptake behaviour; likelihood of multiglandular disease; thyroid nodules or lymph nodes that may cause false positives
BOARD TIP
▸
"Causes of false negatives with the dual-phase technique?"
→ (1) Adenoma with rapid washout (disappears in the delayed phase), (2) small adenoma, (3) multiglandular disease (hyperplasia), (4) coexisting thyroid nodule (an MIBI-avid thyroid nodule masks the adenoma).
▸
"When is the subtraction technique superior?"
→ In adenomas with rapid washout and in the presence of coexisting thyroid disease.
▸
"MIBI-avid thyroid nodules?"
→ Thyroid adenoma, Hürthle cell neoplasm, thyroid cancer → false positives.
13.2.3 Correlation with 4D-CT and US
Ultrasonography (US):
•
First-line imaging (in many centres)
•
Advantages: No radiation, cheap, readily available, FNAB guidance
•
Disadvantages: Operator-dependent, cannot show ectopic (mediastinal) glands, limited in obese/short-necked patients
•
Typical findings: Hypoechoic, oval, solid lesion → posterior to the thyroid
•
Sensitivity: 70-80% (single adenoma)
•
FNA with PTH measurement in the aspirate (PTH washout): Increases specificity in sonographically accessible lesions; recommended only in highly selected cases (atypical ultrasound appearance, uninformative scintigraphy, an intrathyroidal gland mistaken for a thyroid nodule)
•
Reported sensitivity is 70-100% and specificity 75-100%, more reliable than cytology alone; the method is not standardised and there is no agreed cut-off (some authors take any value above serum PTH as positive, others an aspirate-to-serum ratio of ≥2)
•
Drawbacks: Fibrosis of the gland and surrounding tissue (makes surgery harder and can mimic malignancy on histopathology), rarely haematoma, abscess, parathyromatosis. Not recommended when parathyroid carcinoma is suspected (cytology cannot separate benign from malignant; risk of seeding)
How Ultrasound Works
•
Diagnostic ultrasound uses sound waves of 1-20 MHz (human hearing is 20 Hz-20 kHz). Wavelength is inversely proportional to frequency (λ = v/f)
•
Piezoelectric transducer: Crystals in the probe (usually lead zirconate titanate, PZT) vibrate when stimulated electrically and produce sound; the returning echo is converted back into an electrical signal by the same crystals
•
Choice of frequency: The lower the frequency, the greater the penetration and the poorer the detail; superficial structures are examined at high frequency
•
Probe types: A linear probe gives a wide field of view and superficial focus (soft tissue and superficial structures); a curvilinear probe is used for deep, wide fields and a phased-array probe for narrow windows such as between ribs
•
Gain does not change the emitted pulse; it amplifies the returning echo
•
Imaging assumptions and artefacts: The scanner assumes that sound travels in a straight line, returns along the same line and moves at 1540 m/s in tissue. Acoustic shadow → an echo-free area behind air or stones. Comet tail → a bright streak from reverberation between two closely spaced reflectors. Mirror image → a second copy of a structure behind a smooth, strong reflector
•
Bioeffects: Thermal and non-thermal (mechanical) mechanisms; scanners display a thermal index and a mechanical index for them
How Doppler Ultrasound Works
•
Grey-scale (B-mode) imaging uses the amplitude of the returning echo; Doppler uses its frequency. If the moving reflector (a red blood cell) is approaching the probe, the returning frequency rises; if it is moving away, it falls
•
Doppler shift: fd = 2 · ft · (v/c) · cos θ (ft: transmitted frequency, v: flow velocity, c: speed of sound in tissue, θ: angle between flow and beam). Because the velocity calculation depends on cos θ, the angle is kept as low as possible; less than 60° is acceptable for diagnostic purposes
•
Colour Doppler: Overlays the direction and mean velocity of flow on the B-mode image; by convention flow towards the probe is red and flow away from it is blue. It gives mainly qualitative information
•
Power Doppler: Shows the strength of the signal rather than the frequency shift; it gives no direction or velocity information, is less affected by angle and is more sensitive to slow flow
•
Spectral Doppler: Pulsed-wave (PW) Doppler plots the velocities in a chosen sample volume against time; continuous-wave (CW) Doppler measures all velocities along the beam and is used for high velocities
•
Aliasing: Occurs when the measured velocity exceeds half the pulse repetition frequency (Nyquist limit = PRF/2). The spectral trace wraps around to the other end of the scale; on colour Doppler the colour reverses abruptly with no black band in between. It is reduced by increasing the PRF (scale) and does not occur with CW Doppler
Figure 13.7a: Choice of frequency in ultrasound and three common artefacts: acoustic shadow, comet tail, mirror image (schematic, not to scale).
4D-CT (Four-Dimensional CT):
•
Non-contrast + arterial + venous phases → perfusion dynamics are assessed
•
"4th dimension" = time (contrast passage)
•
Parathyroid adenoma: Low density on the non-contrast phase → rapid and intense enhancement in the arterial phase → rapid washout in the venous phase
•
Advantages: High spatial resolution, can show ectopic glands, anatomical detail
•
Disadvantages: High radiation dose; requires iodinated contrast (caution if RAI therapy is planned)
•
Sensitivity: 85-93% (single adenoma)
Multimodal approach:
•
US + Tc-99m MIBI SPECT/CT → the most common combination
•
Concordant result (same location on both) → sufficient for minimally invasive parathyroidectomy (MIP)
•
Discordant result → 4D-CT or additional imaging
13.2.4 The Role of SPECT/CT
Advantages of SPECT/CT:
•
Higher sensitivity and specificity than planar imaging
•
Anatomical localisation → makes operative planning easier for the surgeon
•
Superior for detecting ectopic parathyroid glands (mediastinal, retro-oesophageal, carotid sheath)
•
Multiplanar reconstruction → 3D assessment
•
Helps distinguish coexisting thyroid disease
Indications:
•
Equivocal or negative planar MIBI scintigraphy
•
Patients planned for reoperation (altered anatomy)
•
Suspected ectopic parathyroid
•
Patients planned for minimally invasive surgery (precise localisation needed)
BOARD TIP
▸
"When should SPECT/CT be added to parathyroid scintigraphy?"
→ Always (many guidelines recommend routine SPECT/CT) → clearly superior to planar imaging.
▸
"Greatest advantage of SPECT/CT?"
→ Anatomical localisation → road map for the surgeon + detection of ectopic glands.
13.2.5 Localisation of Ectopic Parathyroid Glands2 questions
Ectopic parathyroid gland locations:
•
Undescended: Inferior glands → at the level of the carotid bifurcation/angle of the mandible
•
Retro-oesophageal/para-oesophageal
•
Within the carotid sheath
•
Intrathyroidal: Embedded within the thyroid parenchyma
•
Upper mediastinal
•
Aortopulmonary window
•
Intrathymic (the commonest ectopic location): Inferior glands migrate with the thymus → in the anterior mediastinum
Imaging strategy:
•
If standard neck imaging is negative → SPECT/CT including the chest or 4D-CT (should cover the neck + upper mediastinum)
•
In reoperation patients: Combination of MIBI SPECT/CT + 4D-CT + US
•
In rare cases: Selective venous sampling (PTH gradient) or C-11 methionine PET/CT can be used; F-18 fluorocholine PET/CT is now preferred (→ see 13.2.6)
Figure 13.8: Embryological migration, normal positions and ectopic locations of the parathyroid glands (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"Commonest ectopic parathyroid location?"
→ Within the thymus (intrathymic) → inferior glands arise from the 3rd pharyngeal pouch → migrate with the thymus.
▸
"Imaging for suspected ectopic parathyroid?"
→ MIBI SPECT/CT (neck + chest) → 4D-CT → selective venous sampling if needed.
13.2.6 Parathyroid PET/CT (F-18 Fluorocholine, C-11 Choline, C-11 Methionine)4 questions
Uptake mechanism:
•
F-18 fluorocholine / C-11 choline: Increased phospholipid-dependent choline kinase activity accompanying excess PTH secretion, and the mitochondrial richness of the cells (chief/oxyphil)
•
C-11 methionine: Taken up via the LAT1/LAT2 neutral amino acid transporters (PTH synthesis is increased)
Indications:
•
Where available, it is the first-line nuclear medicine method in HPT planned for surgery: similar radiation dose, higher resolution and shorter acquisition
•
Priority indications (suspected multiglandular disease): MEN, renal HPT, persistent or recurrent HPT after parathyroidectomy, and normocalcaemic HPT
•
Used as a second-line method when MIBI and US are negative or discordant
Performance:
•
F-18 fluorocholine: Pooled patient-level sensitivity 94%, PPV 97%; cure rate 93% with PET-guided surgery
•
More sensitive than US, MIBI SPECT/CT and 4D-CT alone; combining PET with contrast-enhanced 4D-CT adds little in routine primary HPT
•
MEN1: Lesion-level sensitivity 84-87%, specificity 95-99%; Ga-68 DOTATOC has low sensitivity and NPV for the parathyroids
•
C-11 methionine: Pooled sensitivity ~77%; lower than choline agents
•
Criterion of surgical success in renal HPT: A fall in PTH of >50% (normalisation is not required)
•
Suspected parathyroid carcinoma: If PTH is 3-10 times the upper limit of normal, Ca >3 mmol/L and the lesion >3 cm, choline and FDG PET are performed together; liver metastases may be missed because of physiological liver activity
Protocol:
•
F-18 fluorocholine: 100-300 MBq (1.5-3.2 MBq/kg); imaging at 5 and 60 minutes or at 20 minutes (and at 60-90 minutes if needed), because some glands are seen only on early images
•
C-11 choline 370 MBq; C-11 methionine 370-1100 MBq (single image at 10-20 minutes)
•
Effective dose: F-18 fluorocholine 20 µSv/MBq (2.0-6.0 mSv; critical organ kidney), C-11 choline ~0.9-2.9 mSv (200-650 MBq), C-11 methionine ~2.0-6.0 mSv (370-1100 MBq)
•
Preparation: ≥4 hours fasting, good hydration and avoidance of physical activity; breastfeeding interrupted for 12 hours
Pitfalls:
•
Physiological uptake: Salivary glands and liver; to a lesser extent thyroid and bone marrow. In children: thymus, growth plates and brown fat (can be reduced by waiting in a warm room)
•
Causes of false positives: Thyroid adenoma or carcinoma (most common: a choline-avid nodule within the thyroid), thymoma, reactive lymph node, breast, lung and cervical cancers
•
Bone foci: Brown tumour (osteitis fibrosa cystica); a focus in the jaw suggests hyperparathyroidism-jaw tumour (HPT-JT) syndrome
•
The 3 commonest sites of ectopic parathyroid glands: Thymus, para/retro-oesophageal region and thyroid
BOARD TIP
▸
"Best imaging when multiglandular disease is suspected (MEN1, renal HPT) or before reoperation?" F-18 fluorocholine PET/CT.
▸
"Mechanism of choline uptake?" Increased choline kinase activity.
▸
"Criterion of surgical success in renal HPT?" A fall in PTH of more than 50%.
13.3 Adrenal and Neuroendocrine System
13.3.1 Adrenal Cortical Scintigraphy (NP-59)5 questions
I-131 6β-Iodomethyl-19-Norcholesterol (NP-59):
•
Cholesterol analogue → taken up in the adrenal cortex via LDL receptors
•
ACTH-dependent uptake → combined with a dexamethasone suppression test
•
Dexamethasone suppression is used in primary aldosteronism and adrenal hyperandrogenism; in ACTH-independent Cushing syndrome the study is done without suppression, because cortisol excess has already suppressed ACTH
•
Energy: I-131 (364 keV gamma + beta)
•
Imaging: 5-7 days later (slow uptake; EANM: days 5 and 8)
•
Activity: 37 MBq (1 mCi) IV (US practice); EANM recommends 20 MBq
•
Other adrenocortical agents: Se-75 selenomethylnorcholesterol (the European alternative to NP-59); PET with C-11 metomidate, an 11β-hydroxylase inhibitor, shows that a lesion is of adrenocortical origin and identifies aldosterone-producing adenoma
Indications:
•
Primary hyperaldosteronism (Conn syndrome) → adenoma vs hyperplasia
•
Cushing syndrome → localisation of an adrenal source
•
Adrenal incidentaloma → functional assessment
•
NP-59 in incidentaloma: Increased uptake on the side of the mass (concordant) suggests a benign cortical adenoma; absent or reduced uptake (discordant) favours carcinoma, metastasis or a lesion not of cortical origin
•
Adrenal remnant (after adrenalectomy)
•
EANM: Effective dose 1.8 mSv/MBq, i.e. ~36 mSv per procedure; this is one reason it is rarely used today
•
Because the thyroid dose can reach 29 mGy/MBq, thyroid blockade is mandatory (iodide 100-150 mg/day or perchlorate 200-400 mg/day; started 1 day before injection and continued for 5-10 days)
•
Dexamethasone suppression: 4 mg per day; started 1 week before injection and continued until the study is complete
•
Drugs: Oral contraceptives, diuretics, propranolol, ketoconazole, cholestyramine and corticosteroids are stopped ≥48 hours before; spironolactone, which increases uptake, is stopped ≥6 weeks before
•
Imaging: On days 5 and 8 in the standard study; under dexamethasone, daily from day 2; the posterior image is centred at the level of T12. SPECT/CT improves accuracy
•
Gallbladder activity may be confused with the adrenal; a fatty meal resolves this. Pregnancy is an absolute contraindication, and breastfeeding is stopped
Interpretation (under dexamethasone suppression):
•
Unilateral early uptake (<day 5): Autonomous adenoma (aldosteronoma or cortisol-producing adenoma)
•
Bilateral symmetric uptake: Normal or bilateral hyperplasia
•
Bilateral asymmetric uptake: Bilateral hyperplasia (asymmetric)
•
No uptake on either side: Under dexamethasone this is a normal finding (the normal cortex is suppressed). In a study without suppression, absence of uptake on both sides suggests adrenal carcinoma (the dedifferentiated carcinoma does not take up NP-59, and the contralateral gland does not either because ACTH is suppressed)
•
Normal finding under dexamethasone: No uptake on either side, or symmetric faint uptake after day 5. Bilateral uptake before day 5 suggests bilateral hyperplasia
•
Causes of absent bilateral uptake in a non-suppressed study: Adrenal carcinoma, hypercholesterolaemia/hyperlipidaemia, hormone therapy and poor labelling
Figure 13.9: Patterns of I-131 NP-59 adrenal cortical scintigraphy under dexamethasone suppression, posterior views (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"Why is dexamethasone given in NP-59 scintigraphy?"
→ It suppresses ACTH → suppresses normal adrenal tissue → tissue with autonomous function (adenoma) becomes conspicuous.
▸
"Does adrenal carcinoma take up NP-59?"
→ Usually not → dedifferentiated → impaired cholesterol metabolism.
▸
"Disadvantage of NP-59?"
→ Very long imaging time (5-7 days), use of I-131 (high dose), limited availability → its use has declined (CT/MRI and adrenal venous sampling are preferred).
13.3.2 Adrenal Medulla: MIBG Scintigraphy (I-123, I-131)3 questions
MIBG (Metaiodobenzylguanidine):
•
Structural analogue of norepinephrine (NE) → a guanethidine + benzylguanidine derivative
•
Taken up into adrenergic neurons and chromaffin cells by the uptake-1 (NET = norepinephrine transporter) mechanism
•
Stored in neurosecretory granules (via VMAT)
•
Not metabolised → remains in the cell for a long time
I-123 MIBG:
•
Energy: 159 keV gamma
•
T½: 13.2 hours
•
Dose: 370 MBq (10 mCi) IV (adult)
•
Imaging: 24 hours (± 4-hour early image)
•
Advantages: Better image quality, SPECT possible, lower radiation dose
•
The preferred agent (for diagnosis)
I-131 MIBG:
•
Energy: 364 keV gamma + β⁻
•
T½: 8.02 days
•
Diagnostic dose: 18.5-37 MBq (0.5-1 mCi) IV
•
Therapeutic dose: 3.7-18.5 GBq (100-500 mCi) IV
•
Imaging: 24-48 hours
•
Advantages: Both diagnosis and therapy (theranostic)
•
Disadvantages: Poor image quality, high radiation dose
Activity and dosimetry (EANM):
•
I-123 MIBG 185-370 MBq (at least 37 MBq in children); I-131 MIBG 40-80 MBq (at least 35 MBq); post-therapy scan 3700-7400 MBq
•
Effective dose: I-123 MIBG 13 µSv/MBq (2.4-4.8 mSv), I-131 MIBG 140 µSv/MBq (5.6-11.2 mSv); the liver receives the highest organ dose
•
Breastfeeding: Stopped after I-131 MIBG; interrupted for 24 hours after I-123 MIBG
•
Activity is reduced in renal failure; MIBG cannot be removed by dialysis
Patient preparation:
•
Thyroid blockade: Lugol's solution or SSKI or potassium iodide → prevents thyroid uptake of free iodine from MIBG → started 1 day before injection; continued for 2-3 days with I-123 MIBG and 5-10 days with I-131 MIBG
•
Drug withdrawal (drugs affecting MIBG uptake):
–
Antipsychotics: ~3-4 weeks, depot ~1 month (longest)
–
Cocaine, amphetamine: 1 week
–
Labetalol: 10 days; tricyclic antidepressants: 1-3 days
–
Reserpine, guanethidine: 2 weeks
–
Calcium channel blockers: 48 hours
–
Sympathomimetics (ephedrine, pseudoephedrine): 48 hours
Figure 13.10: Mechanism of MIBG uptake (uptake-1 and granule storage via VMAT) and sites of action of drugs that reduce uptake (schematic).
Did this figure help you understand the topic?
Physiological MIBG uptake:
•
Adrenal medulla (bilateral, symmetric)
•
Salivary glands
•
Liver (most intense physiological uptake)
•
Heart (adrenergic innervation)
•
Bladder (renal excretion)
•
Nasal mucosa
•
Colon (variable)
•
Pitfalls: Contamination, hypertrophy of the contralateral adrenal medulla after unilateral adrenalectomy, and hydronephrosis
•
Other tumours that may take up MIBG: Carcinoid, MTC, Merkel cell tumour, small cell lung cancer, melanoma, retinoblastoma and neurofibromatosis
–
MIBG sensitivity is ~90% in phaeochromocytoma and neuroblastoma, intermediate in carcinoid (~50-70%) and lowest in MTC (~30%)
•
There is normally no uptake in bone and bone marrow, so skeletal uptake suggests metastasis. The normal adrenal medulla may be seen faintly with I-123 MIBG but is usually not seen with I-131 MIBG
BOARD TIP
▸
"By what mechanism is MIBG taken up?"
→ Uptake-1 (NET) → the norepinephrine transporter.
▸
"Why should tricyclic antidepressants be stopped?"
→ They block uptake-1 → MIBG uptake falls → false negatives.
▸
"Longest withdrawal time?"
→ Antipsychotics (~3-4 weeks; depot ~1 month).
▸
"Why is thyroid blockade needed?"
→ Free radioactive iodine released from MIBG accumulates in the thyroid → unnecessary thyroid dose.
13.3.3 Phaeochromocytoma and Paraganglioma2 questions
Phaeochromocytoma:
•
Arises from chromaffin cells of the adrenal medulla
•
Secretes catecholamines → paroxysmal hypertension, headache, sweating, palpitations
•
10% rule (classic, revised with current data):
–
10% bilateral
–
10% extra-adrenal (paraganglioma)
–
10% malignant
–
10% in children
–
10% familial/hereditary
•
Current data: The hereditary proportion may reach 30-40% (SDH mutations, VHL, MEN2, NF1)
Paraganglioma:
•
Arises from extra-adrenal chromaffin tissue
•
Sympathetic paraganglioma: Retroperitoneum, pelvis, thorax → usually functioning (secretes catecholamines)
•
Parasympathetic paraganglioma: Head and neck (carotid body, glomus jugulare, glomus vagale) → usually non-functioning
Role of MIBG scintigraphy:
•
Diagnosis and localisation of phaeochromocytoma/paraganglioma
•
Functional imaging is performed after the biochemical diagnosis (raised plasma free or urinary fractionated metanephrines) is confirmed; if biochemistry is normal, MIBG scanning is not indicated
•
Screening for metastatic disease
•
Patient selection for I-131 MIBG therapy
•
Sensitivity: Phaeochromocytoma 85-95%, paraganglioma 60-75% (lower)
•
Specificity: >95%
Alternative imaging:
•
Ga-68 DOTATATE PET/CT: More sensitive than MIBG in paraganglioma (especially SDH-mutant tumours and head and neck paragangliomas)
•
F-18 FDG PET/CT: In malignant/aggressive tumours and MIBG-negative cases
•
F-18 FDOPA PET/CT: High sensitivity but limited availability
•
EANM: F-18 FDOPA in phaeochromocytoma; Ga-68 SSTR PET stands out in metastatic, head and neck and SDHx-related paraganglioma
•
Advantages of MIBG over newer agents: Close link to catecholamine production, and selection of patients suitable for I-131 MIBG therapy (image-guided therapy)
•
F-18 FDOPA: An L-DOPA analogue transported by LAT1/LAT2; 4 MBq/kg (50-400 MBq), 4 hours fasting, 25 µSv/MBq
–
Other indications: Congenital hyperinsulinism (sensitivity 89%, specificity 98% for focal vs diffuse), recurrent MTC, midgut NET and glioma
•
Report content (EANM/SNMMI 2019): in addition to the common items (see 27), personal and family history, known genetic mutation, metanephrine/methoxytyramine and other laboratory results, previous surgery, chemotherapy and radiotherapy; drugs withheld during preparation, tracer, activity, acquisition protocol and CT parameters in hybrid imaging. Findings are reported separately for head and neck, chest, abdomen and pelvis, and bone/bone marrow; every non-physiological focus, including atypical sites, is described; comparison with prior imaging is made. The conclusion interprets the findings in terms of compatibility with a particular diagnosis and lists limitations; further studies or follow-up are recommended where needed; in metastatic disease the feasibility of radionuclide therapy is stated; genetic testing may be suggested if a hereditary syndrome, family history or multiplicity is suspected
BOARD TIP
▸
"Most sensitive imaging in phaeochromocytoma?"
→ F-18 FDOPA PET (EANM/SNMMI 2019); I-123 MIBG is less sensitive. In paraganglioma, however, Ga-68 DOTATATE PET/CT is more sensitive (especially SDH-mutant and head and neck paragangliomas).
▸
"What to do in MIBG-negative phaeochromocytoma/paraganglioma?"
→ FDG PET/CT or Ga-68 DOTATATE PET/CT.
▸
"Phaeochromocytoma in MEN2?"
→ High risk of bilateral adrenal phaeochromocytoma → bilateral MIBG uptake.
13.3.4 Neuroblastoma (Paediatric MIBG)1 questions
Neuroblastoma:
•
The commonest extracranial solid tumour of childhood
•
Of neural crest origin → arises from the sympathetic nervous system and adrenal medulla
•
Median age at diagnosis: 17-18 months
•
Commonest locations: Adrenal (35%) > retroperitoneum > posterior mediastinum > pelvis > neck
•
Tumour markers: Urinary VMA and HVA (vanillylmandelic acid, homovanillic acid), serum NSE, LDH, ferritin
I-123 MIBG scintigraphy in neuroblastoma:
•
The gold-standard functional imaging for primary tumour localisation and staging
•
Sensitivity: 88-93%, specificity: >95%
•
MIBG scanning is mandatory in the INRG (International Neuroblastoma Risk Group) staging system
•
Curie score: Semi-quantitative scoring system → 9 skeletal regions + soft tissue → each region scored 0-3 → the total score correlates with treatment response and prognosis
•
MIBG-avid neuroblastoma → candidate for I-131 MIBG therapy (→ see Chapter 26.3)
MIBG-negative neuroblastoma (8-10%):
•
Evaluation with FDG PET/CT
•
F-18 FDOPA PET/CT (investigational)
•
Report content (EANM 2018; SIOPEN): in addition to the common items (see 27), MIBG status at diagnosis or previously (FDG is preferred in MIBG-negative tumours), stage of treatment; imaging time and coverage of whole-body planar imaging and SPECT/CT. Findings: the primary tumour and soft-tissue disease are reported separately from skeletal and marrow involvement; skeletal involvement is given as a semi-quantitative score (SIOPEN: 12 skeletal segments, each 0-6, total 0-72; or the Curie score) and compared with the previous score at follow-up; physiological uptake and pitfalls (adrenal, brown fat, salivary glands) are distinguished
BOARD TIP
▸
"MIBG sensitivity in neuroblastoma?"
→ 88-93%.
▸
"Proportion of MIBG-negative neuroblastoma?"
→ 8-10% → evaluate with FDG PET/CT.
▸
"What is the Curie score?"
→ Semi-quantitative assessment of MIBG uptake → 9 skeletal regions + soft tissue → indicator of treatment response and prognosis.
▸
"Commonest location of neuroblastoma?"
→ Adrenal (35%).
13.3.5 Somatostatin Receptor Scintigraphy (OctreoScan)2 questions
In-111 Pentetreotide (OctreoScan):
•
Somatostatin analogue (octreotide derivative) → binds to somatostatin receptors (SSTR)
•
Affinity mainly for SSTR2 and partly SSTR5
•
Energy: In-111 → 171 keV and 245 keV gamma
•
T½: 67.3 hours (In-111)
•
Dose: 222 MBq (6 mCi) IV
•
Imaging: 4 hours (early) and 24 hours (standard), and 48 hours if needed
•
Planar + SPECT/CT
Indications:
•
Neuroendocrine tumours (NET) → staging, detection of recurrence
•
Carcinoid syndrome (flushing, diarrhoea, bronchospasm) is seen mostly in midgut NETs with liver metastases; the biochemical diagnosis is made with 24-hour urinary 5-HIAA, and the general NET marker is chromogranin A
•
Carcinoid tumours
•
Gastrinoma, insulinoma (low SSTR2 → low sensitivity), VIPoma, glucagonoma
•
Phaeochromocytoma/paraganglioma
•
Medullary thyroid cancer
•
Merkel cell carcinoma
•
Small cell lung cancer (variable SSTR expression)
•
Meningioma, lymphoma (limited)
Physiological uptake:
•
Spleen (most intense → high SSTR2 expression)
•
Kidneys (renal excretion)
•
Liver
•
Thyroid
•
Pituitary
•
Bladder
•
Bowel (variable)
Limitations of OctreoScan:
•
Low spatial resolution (SPECT → ~10-12 mm)
•
Inadequate for detecting small lesions (<1 cm)
•
Low sensitivity in insulinoma (50-60%) → low SSTR2 expression
•
Long imaging time (24-48 hours)
•
High radiation dose of In-111
•
Largely replaced by Ga-68 DOTATATE PET/CT
•
Tc-99m HYNIC-TOC (Tektrotyd®): Today usually the first choice among gamma-emitting SSTR agents; 370-740 MBq, imaging at 1-2 and 4 hours, 5 µSv/MBq (1.8-3.7 mSv)
•
In-111 pentetreotide (EANM): 110-220 MBq; 54 µSv/MBq, i.e. ~12 mSv per procedure. Imaging at 4 and 24 hours with at least one SPECT/CT; if abdominal activity is equivocal, imaging is extended to 48 hours
•
Preparation (SNM 2.0, 2011; EANM technologist's guide 2023): when safe, and in consultation with the referring clinician, somatostatin analogue therapy is interrupted: at least 1 day for short-acting agents and 4-6 weeks for long-acting agents. The patient is well hydrated before and for at least 1 day after injection. When the abdomen is of interest a mild oral laxative is given the evening before and the evening after injection; laxatives are not used in active diarrhoea or in insulinoma
–
When insulinoma is suspected an intravenous line is kept and a glucose infusion is available; the tracer is not injected through a total parenteral nutrition line. The date of the last analogue dose and any history of cholecystectomy or splenectomy are recorded. For Tc-99m HYNIC-TOC, preparation is as for Ga-68 SSTR PET, with a liquid diet and a laxative also recommended
•
Causes of false positives: Inflammation, sarcoidosis, rheumatoid arthritis, Graves orbitopathy, after thoracic radiotherapy and recent surgery (activated immune cells express SSTR)
•
Current uses: Centres without PET, PRRT dosimetry and radioguided surgery
•
Report content (SNM 2.0, 2011): in addition to the common items (see 27), tumour type and hormonal activity, neuroendocrine tumour markers, recent radiotherapy or chemotherapy, octreotide therapy and the time since it was stopped, laxatives if given; imaging times (4, 24 and if needed 48 hours), areas imaged and the timing and coverage of SPECT/CT. As a limitation the referrer is reminded that some tumours lack the appropriate receptor subtypes and may not be seen; false positive causes (see above) are considered in the differential
Figure 13.11: Physiological biodistribution on I-123 MIBG and somatostatin receptor imaging (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"Where is the most intense physiological uptake on OctreoScan?"
→ Spleen (high SSTR2 expression).
▸
"Why is OctreoScan sensitivity low in insulinoma?"
→ Insulinomas usually have low SSTR2 expression → weak OctreoScan uptake.
▸
"What replaced OctreoScan?"
→ Ga-68 DOTATATE PET/CT → much higher sensitivity and resolution.
13.3.6 Ga-68 DOTATATE PET/CT10 questions
Ga-68 DOTATATE (NETSPOT®):
•
Somatostatin analogue (DOTA-Tyr3-octreotate) → high affinity for SSTR2
•
Ga-68: Positron emitter, T½ = 68 minutes
•
Production: Ge-68/Ga-68 generator (→ see Chapter 11.3) or cyclotron
•
Dose: 74-185 MBq (2-5 mCi) IV bolus. SNMMI/EANM 2023: Ga-68 DOTATATE 2 MBq/kg (maximum 200 MBq); Ga-68 DOTATOC 148 MBq (FDA 111-185, EMA 100-200 MBq; in children 1.59 MBq/kg, 11-111 MBq); Cu-64 DOTATATE 148 MBq
•
Imaging: 60 minutes after injection; per the prescribing information the range is 40-90 min for Ga-68 DOTATATE, 55-90 min for Ga-68 DOTATOC and 45-90 min for Cu-64 DOTATATE (with Cu-64, lesion detection at 1 and 3 hours is comparable; SNMMI/EANM 2023). Acquired from the vertex to mid-thigh
•
Imaging with PET/CT
•
Preparation (SNMMI/EANM 2023): short-acting somatostatin analogues are stopped 12 hours before the scan; the scan is scheduled just before the next dose of the long-acting analogue (EANM: 3-4 weeks after a long-acting dose). A prospective study with lanreotide found little effect on organ and tumour uptake when it was given immediately before the scan; in patients on stable doses a long interval may matter less than previously thought (unclear for octreotide LAR). Patients drink plenty of water and void frequently during the first hours. In pregnancy the scan is performed only if there is a clear clinical benefit; a breastfeeding mother interrupts for 24 hours. It is safe in children
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Approved SSTR PET agents: Ga-68 DOTATOC (EMA 2016, FDA 2019), Ga-68 DOTATATE (FDA 2016), Cu-64 DOTATATE (FDA 2020) and Ga-68 DOTANOC (European Pharmacopoeia 2024)
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Receptor affinity: DOTATATE binds SSTR2 (very low affinity for SSTR3/5); DOTANOC binds SSTR2, SSTR3 and SSTR5; DOTATOC binds SSTR2 and SSTR5 (SSTR5 affinity lower than NOC)
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They are considered clinically equivalent; however, SUV values measured with different agents cannot be compared directly
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EANM: Sensitivity 93%, specificity 96% (AUC 0.98); imaging between 40 and 90 minutes
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Ga-68 DOTATATE: 23 µSv/MBq (2.3-4.6 mSv); the spleen receives the highest organ dose. SNMMI/EANM 2023 (75 kg adult): 3.2 mSv for 150 MBq Ga-68 DOTATATE, 3.1 mSv for 148 MBq Ga-68 DOTATOC and 4.7 mSv for 148 MBq Cu-64 DOTATATE (dose per unit activity 20-25% higher with Cu-64)
Advantages over OctreoScan:
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Much higher sensitivity (92-97% vs 52-64% OctreoScan)
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Higher spatial resolution (PET → ~4-5 mm vs SPECT → ~10-12 mm)
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Shorter imaging time (1 hour vs 24-48 hours)
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Lower radiation dose
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Better target-to-background ratio
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Quantitative analysis (SUV measurement)
Indications:
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NET staging and restaging (gold-standard functional imaging)
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Primary tumour localisation (NET of unknown primary)
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Assessment of treatment response
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Patient selection for PRRT (Lu-177 DOTATATE) → SSTR2 expression must be confirmed before therapy
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Phaeochromocytoma/paraganglioma (superior to MIBG, especially SDH-mutant)
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Medullary thyroid cancer (limited data)
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Response assessment after PRRT: Performed 3-12 months after the last cycle
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SNMMI/EANM 2023: an increase or decrease in lesion uptake should not by itself be taken as a sign of response or progression, as it is with other tracers. Non-functioning tumours are more often SSTR-negative than functioning NETs; small lesions and lesions near organs with high physiological uptake may be false negative. Visual grading: mild = blood pool, moderate = liver, intense = clearly above liver
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Pitfalls: Physiological uptake in the pancreatic head (uncinate process), accessory spleen (splenule), pituitary, urinary tract and inflammation. SNMMI/EANM 2023: SSTR2 is also expressed by osteoblasts (degenerative change, fracture, fibrous dysplasia) and by leucocytes/macrophages (post-radiation change, reactive lymph nodes, sarcoidosis, tuberculosis). Uncinate uptake is present in many patients and stable over time; in doubtful cases MRI or multiphase CT and follow-up. For an intrapancreatic splenule or splenosis after splenectomy, heat-damaged red cell or sulphur colloid SPECT/CT confirms splenic tissue
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If a lesion shows heterogeneous uptake, adding FDG PET/CT should be considered
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Krenning score / assessment of SSTR expression:
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Tumour uptake is compared with the liver (with spleen/kidney for grade 4)
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For PRRT, tumour uptake is expected to be at least at liver level (Krenning score ≥2)
Krenning Score (developed for OctreoScan, also adapted to DOTATATE):
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Grade 0: No uptake
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Grade 1: Very low uptake (less than liver)
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Grade 2: Uptake equal to or slightly greater than liver
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Grade 3: Uptake greater than liver
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Grade 4: Uptake equal to or greater than spleen (most intense)
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PRRT indication: Usually Grade ≥2 (tumour uptake ≥ liver)
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Report content (SNMMI/EANM 2023): in addition to the common items (see 27), site and grade of the primary tumour (Ki-67), somatostatin analogue therapy (agent, duration, date of last dose); uptake interval, whether CT was contrast-enhanced and image quality issues (motion, halo artefact from high urinary activity). Findings: site and size of lesions, qualitative grade of uptake (mild at blood pool level, moderate at liver level, intense clearly above liver) and the modified Krenning score of the most avid lesion (for the definition see 13.3.6); comparison with FDG if available (SSTR-negative, FDG-positive lesions); findings that may cause false positives (osteoblastic activity, uncinate process, inflammation). An increase or decrease in uptake alone is not taken as response or progression
Figure 13.12: Krenning score: grading of SSTR uptake relative to liver and spleen (schematic).
Did this figure help you understand the topic?
BOARD TIP
▸
"Gold-standard functional imaging for NET staging?"
→ Ga-68 DOTATATE PET/CT.
▸
"Why is Ga-68 DOTATATE performed before PRRT?"
→ To confirm SSTR2 expression → to select patients who will respond to therapy (theranostic pair: Ga-68 DOTATATE diagnosis → Lu-177 DOTATATE therapy).
▸
"What does a Krenning score ≥2 mean?"
→ Tumour uptake equal to or greater than liver → PRRT candidate.
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"Ga-68 DOTATATE vs FDG PET?"
→ Well-differentiated (low-grade) NET → DOTATATE positive, FDG negative. Poorly differentiated (high-grade) NET → DOTATATE negative, FDG positive → "flip-flop phenomenon".
13.3.7 NET Staging and Treatment Planning3 questions
Neuroendocrine Tumours (NET) – General Features:
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Arise from neuroendocrine cells → can occur anywhere in the body
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Commonest locations: GI tract (55-70%) > lung (25-30%) > pancreas (5-10%)
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GI NET: Small bowel (ileum most common), appendix, rectum, colon, stomach
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Functioning (hormone-secreting) vs non-functioning
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MEN1 (Wermer syndrome): Combination of parathyroid hyperplasia or adenoma, pancreatic NET (gastrinoma, insulinoma) and pituitary adenoma
WHO Grading System (GEP-NET):
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Grade 1 (low): Ki-67 <3%, mitoses <2/2 mm² → well differentiated
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Grade 2 (intermediate): Ki-67 3-20%, mitoses 2-20/2 mm² → well differentiated
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Grade 3 (high): Ki-67 >20%, mitoses >20/2 mm² → well or poorly differentiated
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NEC (Neuroendocrine Carcinoma): Ki-67 usually >55%, poorly differentiated → small cell or large cell type
Imaging strategy – by grade:
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Grade 1-2 (well differentiated): Ga-68 DOTATATE PET/CT → high SSTR2 expression → high sensitivity
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Grade 3 NET: SSTR + FDG assessed together; NEC (poorly differentiated): FDG high, SSTR2 low → low DOTATATE uptake
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Grade 2-3 (intermediate group): Both modalities may be considered → "flip-flop phenomenon"
Flip-Flop Phenomenon:
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Well-differentiated NET → DOTATATE positive, FDG negative
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Poorly differentiated NET/NEC → DOTATATE negative, FDG positive
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In heterogeneous tumours both patterns may coexist → provides prognostic information
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FDG-positive lesions → more aggressive biology, poor prognosis
Figure 13.13: SSTR and FDG uptake by NET grade: the flip-flop phenomenon (schematic).
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Treatment planning:
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Surgery: Curative in localised disease
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Somatostatin analogues (SSA): Octreotide LAR, lanreotide → control functional symptoms + antiproliferative effect (PROMID, CLARINET trials)
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PRRT (Lu-177 DOTATATE): SSTR2-positive, advanced, inoperable NET → NETTER-1 trial → PFS benefit (→ see Chapter 26.4)
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Dose: 7.4 GBq × 4 cycles (8 weeks apart)
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Renal protection: Amino acid infusion (lysine + arginine)
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Patient selection: Adequate uptake on Ga-68 DOTATATE PET/CT (Krenning ≥2)
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Everolimus: mTOR inhibitor → advanced NET (RADIANT trials)
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Sunitinib: Tyrosine kinase inhibitor → pancreatic NET
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Chemotherapy: Poorly differentiated NEC → cisplatin/etoposide
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I-131 MIBG therapy: In MIBG-avid tumours (phaeochromocytoma, paraganglioma, neuroblastoma)
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Liver-directed therapies: For hepatic metastases → embolisation, chemoembolisation, Y-90 radioembolisation
BOARD TIP
▸
"NET with Ki-67 15% → grade?"
→ Grade 2 (Ki-67 3-20%).
▸
"Which imaging for a grade 2 NET?"
→ Ga-68 DOTATATE PET/CT (well differentiated → high SSTR2).
▸
"Indication for PRRT?"
→ Advanced, inoperable, SSTR2-positive NET (Krenning ≥2 on Ga-68 DOTATATE).
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"What did the NETTER-1 trial show?"
→ Lu-177 DOTATATE → PFS benefit in midgut NET (compared with octreotide LAR).
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"Treatment of carcinoid syndrome?"
→ SSA (octreotide LAR) → symptom control + antiproliferative.
13.3.8 Insulinoma Imaging: GLP-1R (Exendin-4) PET/CT2 questions
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Exendin-4: A peptide that binds selectively to the GLP-1 receptor (GLP-1R) on pancreatic β cells
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Benign insulinomas express GLP-1R strongly but SSTR2 weakly; false negatives are therefore common on SSTR imaging, whereas the accuracy of exendin PET/CT is 94.4%
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Main indication: Preoperative localisation of benign insulinoma; its importance in congenital hyperinsulinism is also growing
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Ga-68 exendin-4: ~80 MBq, given as a slow IV injection; blood glucose is monitored at regular intervals because of the risk of hypoglycaemia. For 100 MBq the effective dose is ~0.71 mSv; the kidneys receive the highest organ dose
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Physiological uptake: Salivary glands, pancreas, kidneys and bladder
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Causes of false positives: Nesidioblastosis and Brunner glands; false negatives: <1 cm lesions
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Preparation and protocol: because food stimulates endogenous intestinal GLP-1 secretion, which may compete for the receptor, the patient fasts for a few hours (3-4 hours in studies). Exendin lowers blood glucose, so a glucose infusion (usually 10%) is started before or immediately after injection and glucose is monitored; the tracer is injected slowly over 1-3 minutes. Nausea and vomiting may occur; keeping the injected peptide amount low reduces them. Imaging is performed over the abdomen at 30-90 minutes (usually 60 minutes); if the first scan is negative or the pancreatic tail overlaps the left kidney, a delayed scan is acquired at 2-3 hours (retention lasts longer in the tumour than in the kidney)
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Interpretation: focal uptake outside the physiological distribution is pathological; an insulinoma is clearly more intense than the diffuse physiological pancreatic uptake. Further causes of false negatives: malignant insulinoma that has lost GLP-1R expression (these often express SSTR2, so SSTR PET is preferred), extrapancreatic (ectopic) insulinoma and other causes of hyperinsulinism (nesidioblastosis gives diffuse uptake)
BOARD TIP
▸
"Best nuclear medicine method for localising a benign insulinoma?" GLP-1R PET/CT (Ga-68 exendin-4).
▸
"Why are OctreoScan/DOTATATE inadequate in insulinoma?" SSTR2 expression is low in benign insulinomas.
Key Points for the Board
THYROID
1. NIS location: Basolateral membrane. NIS is expressed not only in the thyroid but also in the salivary glands, gastric mucosa, lactating breast and choroid plexus.
2. Pertechnetate vs iodine: Pertechnetate → trapping only (no organification). Iodine (I-123, I-131) → trapping + organification. Discordant nodule: hot on pertechnetate, cold on iodine → FNAB required.
3. Normal thyroid uptake values: 24 hours → 10-30%. 4. Hyperthyroidism + low uptake: Thyroiditis (subacute, silent, postpartum), exogenous hormone, iodine loading, struma ovarii.
5. Hyperthyroidism + high uptake: Graves (diffuse homogeneous), toxic MNG (heterogeneous), toxic adenoma (focal + suppressed surroundings).
6. Cold nodule: Malignancy risk 5-15% → FNAB indicated. 85-95% of cold nodules are benign. 7. Wolff-Chaikoff: High iodine → inhibition of organification → hypothyroidism (protective). Jod-Basedow: high iodine → hyperthyroidism in autonomous tissue (pathological).
8. Before RAI therapy: TSH target >30 mIU/L (hormone withdrawal or rhTSH), low-iodine diet for 1-2 weeks, mandatory pregnancy test, iodine-containing drugs stopped.
9. Stunning: Diagnostic I-131 → NIS expression falls → treatment efficacy falls. Prevention: use I-123, low-dose I-131 (≤3 mCi), give therapy within ≤72 hours.
10. Differentiated thyroid cancer: Papillary (80-85%) and follicular (10-15%) → RAI-avid. Medullary → not RAI-avid (C cell, no NIS). Anaplastic → not RAI-avid (dedifferentiated).
11. Post-therapy WBS: More sensitive than diagnostic WBS → additional lesions in 10-26% of patients. 12. Dosimetric therapy limits: Bone marrow ≤200 cGy, lung retention <80 mCi at 48 hours. 13. Thyroglobulin (Tg): Tumour marker after total thyroidectomy + RAI. Anti-Tg antibodies interfere with Tg measurement.
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Anti-Tg antibodies cause falsely low values in immunometric (IMA) Tg assays → Tg is always measured together with anti-Tg.
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Thyrotoxicosis + low uptake: serum Tg is suppressed in thyrotoxicosis factitia and high in thyroiditis.
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Perchlorate discharge test (I-123): >10% fall in uptake after perchlorate → organification defect (Pendred, TPO defect, Hashimoto).
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~25% of MTC is hereditary (germline RET) → RET testing in every MTC; MEN2A: MTC + phaeo + HPT, MEN2B: MTC + phaeo + marfanoid habitus + mucosal neuromas (no HPT).
PARATHYROID
14. Causes of PHPT: Single adenoma 80-85%, hyperplasia 10-15%, carcinoma 1-2%, double adenoma 2-5%. 15. Mechanism of MIBI retention: Lipophilic cationic complex → mitochondrial membrane potential. Oxyphil cells → rich in mitochondria → intense MIBI uptake.
16. Dual-phase principle: Slow washout in parathyroid adenoma → retention in the delayed phase. False negative: adenoma with rapid washout.
17. Subtraction technique: MIBI − pertechnetate (or I-123) = parathyroid. Superior to dual-phase in adenomas with rapid washout.
18. Ectopic parathyroid: Most commonly intrathymic. Inferior glands → 3rd pharyngeal pouch → migrate with the thymus. Superior glands → 4th pharyngeal pouch → more constant.
19. SPECT/CT: Superior to planar imaging → anatomical localisation + detection of ectopic glands. Many guidelines recommend routine SPECT/CT.
ADRENAL AND NEUROENDOCRINE
20. NP-59: Cholesterol analogue → adrenal cortex. Unilateral early uptake under dexamethasone → autonomous adenoma; absent bilateral uptake under dexamethasone is normal. No bilateral uptake in a non-suppressed study → suggests carcinoma (dedifferentiated). Its use has declined.
21. MIBG: Norepinephrine analogue → taken up by uptake-1 (NET). Thyroid blockade mandatory. Longest withdrawal: antipsychotics (~3-4 weeks; depot ~1 month). Physiological uptake: liver (most intense), heart, salivary glands, adrenal, bladder.
22. Phaeochromocytoma: 10% rule (currently: hereditary proportion up to 30-40%). MIBG sensitivity 85-95%. In paraganglioma Ga-68 DOTATATE > MIBG.
23. Neuroblastoma: The commonest extracranial solid tumour of childhood. MIBG sensitivity 88-93%. Curie score: semi-quantitative MIBG assessment. 8-10% MIBG-negative → FDG PET/CT.
24. OctreoScan: Binds SSTR2. Most intense physiological uptake: spleen. Low sensitivity in insulinoma. Replaced by Ga-68 DOTATATE.
25. Ga-68 DOTATATE PET/CT: Gold standard for NET staging. Sensitivity 92-97%. PRRT patient selection (Krenning ≥2). Theranostic pair: Ga-68 diagnosis → Lu-177 therapy.
26. Flip-flop phenomenon: Well-differentiated NET → DOTATATE (+), FDG (−). Poorly differentiated NET/NEC → DOTATATE (−), FDG (+).
27. NET grading: Grade 1: Ki-67 <3%. Grade 2: Ki-67 3-20%. Grade 3: Ki-67 >20%. 28. PRRT (Lu-177 DOTATATE): 7.4 GBq × 4 cycles, 8 weeks apart. Renal protection: amino acid infusion. NETTER-1 trial: PFS benefit in midgut NET.
29. Krenning score: Grade 0-4. For PRRT ≥Grade 2 (tumour ≥ liver). Grade 4 = equal to/greater than spleen.
30. Carcinoid syndrome: SSA (octreotide LAR) → symptom control + antiproliferative (PROMID, CLARINET trials).
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MIBG sensitivity is ~90% in phaeochromocytoma/neuroblastoma, ~50-70% in carcinoid and ~ 30% in MTC; there is normally no bone/bone marrow uptake → skeletal uptake favours metastasis.
ADDITIONAL NOTES FROM EANM GUIDELINES
31. Pertechnetate: 74-111 MBq, peak uptake at ~20 min (2-5%), ~1 mSv; perchlorate test not possible. I-123: 7.4-14.8 MBq, normal 2-hour uptake 10-15%, ~1.2 mSv.
32. I-131 diagnostic WBS: 37-74 MBq after hormone withdrawal, 110-148 MBq with rhTSH (SNMMI/EANM 2022); not used diagnostically under 10 years of age except for thyroid cancer. SPECT/CT: remnant vs lymph node, lung vs rib, bowel vs pelvic bone.
33. I-124 PET/CT: 20-74 MBq orally; dosimetry at 4-24-48-72-96 hours; target dose ~300 Gy for remnant, 80-100 Gy for metastases.
34. Thyroid MIBI: Independent of TSH/NIS, requires viable cells. AIT-1 normal/increased, AIT-2 reduced/absent, AIT-3 mixed. Indeterminate nodule (>1 cm, EU-TIRADS 4-5, Bethesda III/IV): MIBI-negative → high NPV; WOind threshold −19%.
35. Parathyroid MIBI: 400-900 MBq; early 10-15 min, delayed 1.5-2.5 hours; MIBI SPECT/CT detection rate ~88%; main pitfall an MIBI-avid thyroid nodule.
36. Parathyroid PET: F-18 fluorocholine (choline kinase) → sensitivity 94%, PPV 97%, cure 93%; first choice in MEN, renal HPT, persistent/recurrent and normocalcaemic HPT. C-11 methionine (LAT1/2) less sensitive. Success in renal HPT = >50% fall in PTH.
37. NP-59 (EANM): 20 MBq, ~36 mSv/procedure; thyroid blockade mandatory; dexamethasone 4 mg/day from 1 week before; spironolactone stopped ≥6 weeks before; imaging on days 5 and 8.
38. MIBG (EANM): I-123 185-370 MBq (13 µSv/MBq), I-131 40-80 MBq (140 µSv/MBq); critical organ liver. Thyroid blockade for 2-3 days with I-123 and 5-10 days with I-131.
39. SSTR imaging: Tc-99m HYNIC-TOC (Tektrotyd®) first choice among gamma agents; In-111 pentetreotide ~12 mSv. DOTANOC has the broadest affinity (SSTR2/3/5); SUV values of different SSTR PET agents cannot be compared; critical organ for Ga-68 DOTATATE is the spleen.
40. Benign insulinoma: High GLP-1R, low SSTR2 → Ga-68 exendin-4 PET/CT (accuracy 94.4%); false positives nesidioblastosis, Brunner glands.
Current guidelines on this chapter's topics
The latest guidelines and consensus documents on the procedures covered in this chapter (official EANM index and primary sources, November 2026). Comparison of the text with these versions is in progress; consult the guideline itself for details.
- 20252025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer (opens in a new tab)
- 2023SNMMI Procedure Standard/EANM Practice Guideline for SSTR Receptor PET: Imaging Neuroendocrine Tumors (opens in a new tab)
- 2022Joint SNMMI/EANM practice guideline for Nuclear Medicine Evaluation and Therapy of Differentiated Thyroid Cancer: Abbreviated Version (opens in a new tab)
- 2021The EANM practice guidelines for parathyroid imaging (opens in a new tab)
- 2019The EANM practice guideline/SNMMI procedure standard for RAIU and thyroid scintigraphy (opens in a new tab)
- 2019The EANM practice guideline for PET/CT imaging in medullary thyroid carcinoma (opens in a new tab)
- 2019EANM Practice Guideline/SNMMI Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma (opens in a new tab)
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