Thyroid Scintigraphy and Sestamibi Parathyroid Scan: Principles, Indications, and Limitations

Overview

• Nuclear medicine imaging of the thyroid and parathyroid glands provides functional information complementing the anatomical data of ultrasound, CT, and MRI.
• Thyroid scintigraphy assesses gland physiology and nodule function; sestamibi parathyroid imaging localises hyperfunctioning parathyroid tissue prior to minimally invasive surgery.
• Both studies exploit differential uptake and washout kinetics of specific radiopharmaceuticals.

Thyroid Scintigraphy

Radiopharmaceuticals

• Tc-99m pertechnetate is the most widely used diagnostic agent.
• Dose ≈ 3-5 mCi IV; imaging at 20-30 min post-injection.
• Physiological uptake: thyroid, salivary glands, oral cavity.
• Because it is not organified, it does not reflect iodine incorporation into thyroid hormone, an important limitation when dyshormonogenesis is suspected.
• I-123 is preferred when organification must be assessed (e.g. suspected dyshormonogenesis), for true radioiodine uptake (RAIU) measurement, or when a pre-therapy scan is required before I-131 ablation.
• Lower radiation dose and superior imaging characteristics compared with I-131.
• Imaging at 4-6 h (early uptake) or 24 h (standard RAIU).
• I-131 for diagnostics is largely reserved for post-thyroidectomy whole-body surveillance of differentiated thyroid carcinoma (DTC).
• High radiation dose and the theoretical "stunning" effect on residual thyroid tissue have led many centres to prefer I-123 for pre-therapy scintigraphy.
• I-131 is the primary treatment for Graves disease, toxic adenoma, toxic multinodular goitre, thyroid remnant ablation, and treatment of thyroid cancer metastases.

Indications for Thyroid Scintigraphy

Note: Routine scintigraphy for nodule characterisation is not recommended by current guidelines (ATA 2015). US is the primary anatomical modality; scintigraphy is specifically indicated to evaluate functional status. Nodules < 1 cm are typically below the spatial resolution of scintigraphy and cannot be diagnostically assessed.

Normal Scan Appearance

• Butterfly-shaped structure in the anterior lower neck with homogeneous distribution throughout both lobes and isthmus.
• Pyramidal lobe may be visible.
• Salivary gland and oral cavity uptake is expected.
• Normal 24-hour RAIU ≈ 10-30% (varies with dietary iodine intake; lower in iodine-replete populations).

Pathological Patterns

• Graves disease: Diffuse homogeneous enlargement with markedly elevated RAIU; intense homogeneous uptake.
• Elevated hCG (hydatidiform mole, choriocarcinoma) can mimic Graves by direct TSH receptor stimulation, clinical context and serum hCG are discriminating.

Toxic adenoma: Single focus of markedly elevated uptake; surrounding normal parenchyma suppressed due to TSH suppression.

Destructive thyroiditis (subacute/de Quervain's, post-partum, amiodarone-induced): Globally absent or markedly reduced uptake despite biochemical thyrotoxicosis, a critical discriminating feature from Graves disease.

Cold nodules: Cannot distinguish benign from malignant; require US and FNA for further characterisation.

Thyroid Cancer Follow-Up

Post-thyroidectomy whole-body I-131/I-123 scanning:

• Assesses completeness of surgical resection (thyroid bed remnant)
• Stages disease (nodal or distant metastases)
• Guides and assesses response to radioiodine ablation
• TSH stimulation (TSH > 30 mIU/L) is required before diagnostic or therapeutic radioiodine, achieved by thyroid hormone withdrawal or recombinant human TSH (rhTSH).
• Physiological activity is expected in salivary glands, stomach, bowel, bladder, and breast tissue.
• Nasal secretions may contain radioiodine (contamination artefact).
• Focal uptake in lungs, skeleton, or neck remote from the thyroid bed is pathological.
• SPECT/CT significantly improves anatomical localisation and alters management in 11-58% of cases.
• Non-iodine-avid tumours (medullary carcinoma, anaplastic carcinoma, Hürthle cell carcinoma) or elevated thyroglobulin with negative radioiodine whole-body scan → F-18 FDG PET/CT is the investigation of choice (sensitivity and specificity each ~60-89%).
• This reflects the inverse relationship between iodine avidity and glucose metabolism ("flip-flop" phenomenon).
• Tl-201, Tc-99m sestamibi, and Tc-99m tetrofosmin have shown some utility in non-iodine-avid thyroid cancer but have been largely replaced by FDG PET/CT.
• FDG thyroid incidentaloma: Focal FDG-avid thyroid lesion carries significant malignancy risk → prompt US ± biopsy.
• Diffuse FDG uptake is typically inflammatory.

Iodinated contrast media must be avoided if papillary carcinoma is suspected as it precludes radioiodine treatment for approximately 2 months due to competitive iodide loading.

Limitations of Thyroid Scintigraphy

Sestamibi Parathyroid Scan

Principles and Radiopharmaceutical

Tc-99m sestamibi (2-methoxyisobutylisonitrile; MIBI) is a lipophilic cationic molecule that crosses the cell membrane by passive diffusion and concentrates within mitochondria in proportion to regional blood flow and cellular metabolic activity. Parathyroid adenomas exhibit:

• High cellularity and vascularity
• Abundant oxyphil cells rich in mitochondria
• These properties drive high initial uptake and slow washout from adenoma tissue, whereas normal thyroid tissue washes out rapidly.
• Normal parathyroid glands are not visualised on scintigraphy.

Standard injected activity: 15-20 mCi Tc-99m sestamibi IV.

• Physiological distribution: parotid glands, submandibular salivary glands, thyroid, myocardium, liver, bone marrow (mild diffuse), thymus (mild uptake in young individuals), brown fat.
• Normal parathyroid glands: no uptake.

Other available tracers: thallium-201 (Tl-201; now largely superseded, unfavourable dosimetry, poor image quality), Tc-99m tetrofosmin (similar mechanism; used in some centres), C-11 methionine PET, F-18 FDG PET.

Parathyroid Anatomy Relevant to Scintigraphy

• 80% of individuals have four parathyroid glands; 20% have three, five, or six
• Superior glands derive from the fourth branchial pouch (with thyroid), rarely ectopic
• Inferior glands derive from the third branchial pouch (with thymus), more commonly ectopic, most often in the anterosuperior mediastinum or around the thymus
• Normal glands measure approximately $5 \times 3 \times 1\text{ mm}$, weigh 10-80 mg, not visible on any imaging modality
• Parathyroid adenomas: characteristically oval, 8-15 mm greatest diameter, homogeneous internal architecture
• Parathyroid carcinoma: usually ≥ 2 cm, heterogeneous, may show cystic degeneration and invasion of adjacent muscle/vessels; histological distinction from large adenoma is usually required

Indications

Context: PHPT is most commonly caused by a solitary parathyroid adenoma (~85-90%). Parathyroid hyperplasia accounts for ~10%. Parathyroid carcinoma is rare (<1% of PHPT). Secondary hyperparathyroidism (renal failure, GI malabsorption) and tertiary hyperparathyroidism (autonomous function after chronic secondary HPT) involve multiglandular disease where scintigraphy is less reliable.

Imaging Techniques

Dual-Phase (Washout) Scintigraphy

• Most widely used technique.
• No patient preparation is usually required.
• Active vitamin D supplementation should be withheld for 1 week.

• Planar images of neck and upper thorax (anterior view) using low-energy, high-resolution, parallel-hole collimator (matrix ≥ 128 × 128).
• Pinhole collimator has higher sensitivity and is preferred where available.
• SPECT or SPECT/CT is recommended in addition to planar imaging.

$$\text{Parathyroid adenoma} \Rightarrow \text{focal uptake on early \textbf{and} delayed images}$$

$$\text{Normal thyroid} \Rightarrow \text{uptake on early image, washout on delayed image}$$

SPECT should be performed immediately after early planar images to avoid false-negative results from rapid washout cases.

Dual-Tracer Subtraction Scintigraphy

• A thyroid-specific tracer is used to image the thyroid, then digitally subtracted from the sestamibi image.
• Residual focal activity after subtraction = hyperfunctioning parathyroid tissue.

Some centres administer potassium perchlorate 400 mg orally immediately before pertechnetate acquisition to accelerate pertechnetate washout from the thyroid, reducing thyroid counts in the sestamibi image and improving parathyroid conspicuity.

• Digital subtraction should use progressive incremental subtraction with real-time display: residual activity in the thyroid after subtraction should not fall below surrounding neck tissue (prevents oversubtraction and missing multiple adenomas).
• Patient motion between sequential acquisitions may require image realignment.

Subtraction preferred over dual-phase in:

• Known nodular goitre
• Recurrent/persistent PHPT
• Suspected multiple hyperfunctioning parathyroid glands

SPECT and SPECT/CT

• SPECT provides higher target-to-background ratio than planar imaging; improves detectability, particularly for ectopic and deeply situated glands.
• SPECT/CT fuses functional data with anatomical CT, enabling precise localisation relative to adjacent structures and identification of ectopic/mediastinal glands.
• Adding arterial-phase CT to SPECT/CT further improves detection in challenging cases (recurrent HPT, obesity, multinodular goitre).

Parathyroid hyperplasia cannot be differentiated from multiple adenomas by imaging alone; both may appear as multiple foci of retained uptake and the individual glands have the same imaging appearance.

Sensitivity Data

Sensitivity is adversely affected by multiglandular disease (hyperplasia, double adenomas), small gland size, and coexisting thyroid pathology.

Radionuclide-Guided Surgery

Surgery is performed 2-3 hours after tracer injection. Intraoperative thresholds with a handheld gamma probe:

$$\text{In vivo parathyroid-to-thyroid ratio} > 1.5 \Rightarrow \text{pathological parathyroid location}$$

$$\text{Parathyroid-to-background ratio} > 2.5 \Rightarrow \text{pathological parathyroid location}$$

• Well-collimated probe is essential because surrounding background thyroid activity can be significantly higher than in other radio-guided surgery contexts.
• Ex vivo counting of excised specimen confirms complete removal.
• Benefits: reduced operative time, shorter hospital stay, on-table verification.

Limitations

Differential Diagnosis: Focal Sestamibi Uptake in Neck/Mediastinum

Key Pitfalls

• Rapid washout misread as normal: Large or predominant chief-cell adenomas may show early washout → false-negative dual-phase study. Perform SPECT immediately after early planar images; consider subtraction technique.
• Thyroid nodule mimicking parathyroid adenoma: A nonfunctioning thyroid nodule may persist as focal activity on subtraction. Combined US is essential; guidelines recommend combined US and scintigraphy interpretation in the same session.
• Oversubtraction: Removes genuine parathyroid activity, particularly relevant with multiple adenomas. Use progressive incremental subtraction so residual thyroid activity does not fall below surrounding neck tissue.
• Failing to image the mediastinum: Ectopic inferior parathyroid glands will be missed if only neck images are acquired. All protocols must include neck and upper thorax.
• Iodinated contrast before thyroid scintigraphy: Delays thyroid scanning by approximately 2 months; critical before planning I-131 ablation.
• Interfering medications: Thyroid hormone, anti-thyroid drugs, excess dietary iodine, amiodarone, and active vitamin D supplementation all affect scan quality.
• Negative scan does not exclude PHPT: Scintigraphy localises disease, not diagnoses it. Biochemically confirmed PHPT with negative imaging still warrants surgical consideration; bilateral neck exploration remains the definitive approach in equivocal cases.
• Multiglandular disease: Parathyroid hyperplasia is indistinguishable from multiple adenomas by imaging; combined US and scintigraphy is standard, supplemented by 4D-CT for recurrent/ectopic disease.

Summary Comparison