Differentiated Thyroid Cancer: Radioiodine Imaging and Therapy

1. Overview

Differentiated thyroid cancer (DTC) — papillary and follicular carcinoma and their variants — arises from follicular epithelial cells that retain the sodium/iodide symporter (NIS) and, to varying degrees, the ability to trap iodide and synthesise thyroglobulin (Tg). This retained physiology is the basis of a unique theranostic pairing: the same molecule, radioiodine, both images residual/metastatic disease (¹³¹I or ¹²³I whole-body scan) and treats it (therapeutic ¹³¹I). [1,2]

Most DTC has an excellent prognosis; the clinical challenge is to concentrate aggressive treatment on the minority who benefit while sparing low-risk patients unnecessary radiation. Nuclear medicine contributes across the pathway: post-operative staging, remnant ablation and adjuvant/therapeutic ¹³¹I, molecular follow-up (Tg plus imaging), and — when tumours dedifferentiate and lose iodine avidity — ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) to localise radioiodine-refractory (RAIR) disease. [2,3]

Management has shifted markedly toward de-escalation: lower activities, selective use of radioiodine, recombinant thyrotropin (rhTSH) preparation, and risk-adapted, response-adapted decision-making anchored in the 2025 American Thyroid Association (ATA) guideline (which supersedes ATA 2015) and the 2022 Society of Nuclear Medicine and Molecular Imaging (SNMMI) / European Association of Nuclear Medicine (EANM) procedure guideline. [2,10,11]

2. Core Concepts and Pathophysiology

• NIS-mediated trapping. Follicular and DTC cells actively import iodide via NIS on the basolateral membrane. Thyroid-stimulating hormone (TSH) upregulates NIS, so raising TSH increases iodide uptake into tumour — the rationale for TSH stimulation before ¹³¹I. [1,2]
• ¹³¹I therapy mechanism. ¹³¹I decays with a physical half-life of ~8.02 days, emitting beta particles (mean tissue path ~0.4 mm, maximum ~2 mm) that deliver the therapeutic cytocidal dose, plus a 364 keV gamma photon used for imaging. [2]
• Iodine pool competition. A large stable-iodine pool (dietary iodine, iodinated contrast) dilutes radioiodine and reduces tumour uptake — hence the low-iodine diet and avoidance of recent contrast. [2]
• Dedifferentiation (“flip-flop”). As DTC dedifferentiates, NIS expression falls (loss of iodine avidity) while glucose metabolism (GLUT glucose-transporter expression) rises. Such lesions become ¹³¹I-negative but ¹⁸F-FDG-avid — the biological basis of the flip-flop phenomenon and of FDG PET in RAIR disease. [1]
• Thyroglobulin as tumour marker. After total thyroidectomy and ablation, Tg should be undetectable; a detectable or rising Tg signals residual/recurrent disease. Anti-Tg antibodies (TgAb) interfere with the assay and must always be measured alongside. [1,2]

3. Clinical Indications

Established - Post-thyroidectomy ¹³¹I: routinely recommended for ATA high-risk DTC and for distant metastases; considered (individualised) for low-intermediate and intermediate-high risk (adjuvant treatment or treatment of known disease) (ATA 2025). [10] - Post-therapy whole-body scan (PT-WBS) after every therapeutic ¹³¹I administration for staging. [2] - Diagnostic whole-body scan (DxWBS) to assess remnant/metastatic burden and guide activity selection when the surgical/pathological picture is incomplete. [2] - ¹⁸F-FDG PET/computed tomography (CT) for Tg-positive, ¹³¹I scan-negative disease and known/suspected RAIR disease. [1,3]

Selected / conditional - Remnant ablation in low-risk DTC — not routinely recommended (ATA 2025, strong recommendation). [10] - rhTSH preparation is now preferred over withdrawal for remnant ablation and adjuvant therapy (ATA 2025). [5,10] - FDG PET for staging/prognostication in poorly differentiated, oncocytic or high-Tg disease. [1,10]

Emerging / investigational - Redifferentiation (e.g. MAPK [mitogen-activated protein kinase]-pathway inhibitors) to restore iodine avidity before repeat ¹³¹I in selected progressive RAIR disease with a targetable mutation (ATA 2025 conditional; not recommended as adjuvant in unselected high-risk patients). [10] - Lesional and blood-based dosimetry-guided ¹³¹I. [2]

Unlikely to help - Routine ¹³¹I in low-risk intrathyroidal microcarcinoma. [1] - ¹³¹I in proven RAIR disease. [1,8,10] - FDG PET when Tg is very low and antibody-negative (low yield). [1]

4. Radiopharmaceuticals

¹³¹I is preferred for therapy (beta emission) and remains widely used for DxWBS. ¹²³I gives superior diagnostic image quality and avoids the theoretical concern of stunning (reduced uptake of the therapy dose after a diagnostic ¹³¹I dose); however, some data show ¹²³I may miss small foci detected by ¹³¹I. ¹⁸F-FDG is the alternative when disease is no longer iodine-avid. [2,3]

5. Patient Selection and Preparation

History and workup: surgical/pathology report (completeness of resection, histology, extrathyroidal extension, nodal status, margins, vascular invasion), staging imaging, TSH, Tg, TgAb, and pregnancy status. Establish ATA risk category (ATA 2025 four-tier system). [10]

TSH stimulation (to raise TSH to ≥30 mIU/L): [2] - Thyroid hormone withdrawal (THW): stop levothyroxine ~3–4 weeks (a liothyronine [T3] bridge for the first 2 weeks then 2 weeks off T3 shortens the hypothyroid interval). - rhTSH (recombinant human TSH, thyrotropin alfa): 0.9 mg intramuscularly on two consecutive days; ¹³¹I given ~24 h after the second injection. Avoids hypothyroid morbidity; preferred (ATA 2025) for remnant ablation and adjuvant therapy, and for patients of any risk who cannot tolerate hypothyroidism or cannot mount adequate TSH. For known distant metastases ATA 2025 accepts either withdrawal or rhTSH (conditional recommendation), while the SNMMI/EANM guideline favours withdrawal with dosimetry-guided therapy where feasible. [2,10]

Low-iodine diet (LID): ~1–2 weeks, targeting <50 µg iodine/day; avoid iodinated contrast and iodine-based antiseptics for at least 4–6 weeks and amiodarone (3–6 months, confirm clearance with urinary iodine). Compliance can be checked with urinary iodine. [2]

Pregnancy/breastfeeding: ¹³¹I is absolutely contraindicated in pregnancy; exclude with testing. Breastfeeding must be stopped and ¹³¹I postponed until at least 3 months after cessation of breastfeeding or milk expression (breast involution; ¹²³I can confirm absent breast uptake); breastfeeding is not resumed for that infant. Advise deferring conception for at least 6 months in women (ATA 2025; 6–12 months in ATA 2015); 6–12 months is also commonly advised for men. [2,3,10]

Other considerations: renal impairment prolongs ¹³¹I retention and raises whole-body/marrow dose — reduce activity or use dosimetry; diffuse pulmonary metastases risk radiation pneumonitis/fibrosis; document consent and radiation-safety instructions. [2]

6. Protocol (Chronological)

1. Preparation: LID; TSH stimulation as above; confirm TSH ≥30 mIU/L; measure stimulated Tg/TgAb; exclude pregnancy. [2]
2. Optional DxWBS: ¹²³I or low-activity ¹³¹I, typically 37–74 MBq (1–2 mCi) after withdrawal and 110–148 MBq (3–4 mCi) after rhTSH; image at ~24 h (¹²³I) or 24–72 h (¹³¹I). The higher activity after rhTSH compensates for stable iodine from continued levothyroxine. [2]
3. Therapeutic ¹³¹I: administered orally (capsule/liquid). Typical activities (ATA 2025) — remnant ablation 1.1–1.85 GBq (30–50 mCi); adjuvant therapy 1.1–3.7 GBq (30–100 mCi), 3.7–5.55 GBq (100–150 mCi) in high risk; known structural disease ≥3.7 GBq (≥100 mCi), typically up to 7.4 GBq (200 mCi) for distant metastases; dosimetry-guided above 7.4 GBq (200 mCi), and empiric activities >5.5 GBq (150 mCi) should be avoided in patients >70 years or with renal impairment. [2,5,6,7,10]
4. Radiation safety: hydration, frequent voiding, isolation/distancing per local regulations. [2]
5. PT-WBS ± single-photon emission CT (SPECT)/CT: planar whole-body imaging ~2–10 days post-therapy (commonly ~3–7 days); SPECT/CT of neck/thorax whenever feasible improves localisation, staging and management. [2]
6. Post-procedure: resume/adjust levothyroxine (ATA 2025: TSH within the reference range for excellent/indeterminate response, below it for biochemical/structural incomplete response); schedule response assessment. [10]

7. Normal Findings

• Physiological ¹³¹I/¹²³I biodistribution: salivary/lacrimal glands, nasal mucosa, stomach, bowel (secreted iodide), bladder and kidneys (excretion), liver (on PT-WBS, from metabolised radioiodinated Tg), and often diffuse blood-pool/breast activity. A small thyroid-bed remnant is expected after “total” thyroidectomy. [2]
• ¹⁸F-FDG normal uptake: brain, myocardium (variable), liver, bowel, renal collecting system/bladder, and lymphoid/muscle activity. [3]
• Temporal expectation: after successful ablation, subsequent DxWBS shows no abnormal neck uptake and Tg becomes undetectable. [1]

8. Interpretation

Recommended sequence: correlate with surgery/pathology and Tg/TgAb → identify physiological uptake → assess thyroid bed → survey neck/mediastinum, lungs, skeleton → use SPECT/CT to anatomically localise and distinguish physiological from pathological foci. [2]

Key abnormal patterns: focal neck-bed uptake (remnant vs residual tumour), cervical/mediastinal nodal foci, diffuse or micronodular lung uptake (miliary metastases, often radiographically occult), and focal skeletal uptake (bone metastases). [2]

ATA 2015 risk stratification (recurrence risk): [1] Superseded: ATA 2025 uses a four-tier, histotype-specific system (papillary; follicular/invasive encapsulated follicular variant; oncocytic) that also integrates postoperative Tg/TgAb and imaging within ~3 months of surgery — low (<10% structural recurrence), low-intermediate (10–15%), intermediate-high (16–30%) and high (>30%). The 2015 features below are retained for orientation; consult ATA 2025 for the defining features of each tier. [10]

ATA 2015 response-to-therapy (dynamic risk restratification): [1]

These categories drive TSH targets, imaging intensity and further therapy. [1] ATA 2025 applies the response criteria from ~3 months after surgery and adds criteria for total thyroidectomy without RAI (excellent: non-stimulated Tg <2.5 ng/mL with negative imaging and no TgAb; indeterminate: 2.5–5 ng/mL; biochemical incomplete: >5 ng/mL or rising TgAb) and for lobectomy (imaging-based, no Tg threshold). A sustained excellent response for 10–15 years in low-risk patients is termed complete remission. The RAI-treated thresholds tabulated above are those of ATA 2015. [10,11]

9. Differential Diagnosis (radioiodine WBS)

10. Pitfalls and Artefacts

False positive: salivary/GI physiological activity, oesophageal retention, cutaneous contamination (saliva, urine, sweat), inflammation, and non-thyroidal NIS-expressing tissue. Recognise via symmetry, clearance on repeat/delayed imaging, and SPECT/CT. [2]

False negative: small-volume or dedifferentiated (non-avid) disease; competition from a large stable-iodine pool (poor LID, recent contrast); inadequate TSH; and lesions below scanner resolution. Confirm TSH ≥30 mIU/L and iodine status. [2]

Physiological variants: liver activity on PT-WBS (metabolised radioiodinated hormone — a sign of functioning tissue somewhere, not a liver metastasis), diffuse breast uptake, thymic uptake in the young. [2]

Technical: ¹³¹I “stunning” from a diagnostic ¹³¹I dose (mitigated by ¹²³I or low activity/short interval); star artefact and poor resolution from ¹³¹I high-energy photons; TgAb causing falsely low Tg (false reassurance) — always report TgAb. [2]

11. Reporting Guidance

Checklist: indication and ATA risk; preparation (THW vs rhTSH), TSH, LID compliance; stimulated Tg and TgAb; administered activity and route; scan type/timing; SPECT/CT performed; thyroid-bed uptake; loco-regional and distant foci with anatomical localisation; physiological uptake; comparison with prior; impression and management implication.

Conclusion approach: state ablation adequacy, presence/absence and site of residual/metastatic disease, correlation with Tg, and a recommendation (follow-up interval, further therapy, or FDG PET if Tg-positive and scan-negative).

Sample conclusion: “Post-therapy ¹³¹I whole-body scan with SPECT/CT shows focal uptake confined to the thyroid bed consistent with remnant, without loco-regional or distant metastatic uptake. Findings correlate with a low stimulated thyroglobulin. Recommend risk-adapted TSH suppression and interval clinical, biochemical and sonographic follow-up.”

12. Clinical Management Impact

¹³¹I imaging and Tg together determine whether disease is present, iodine-avid, and where it is — directly setting activity selection, decisions on repeat ¹³¹I versus systemic therapy, TSH-suppression targets, and surveillance intensity. DxWBS/SPECT-CT findings alter management (staging or prescribed activity) in a substantial minority of cases. A diagnosis of RAIR disease shifts patients toward FDG PET-guided assessment, tumour biomarker testing and systemic therapy (multikinase inhibitors such as lenvatinib or sorafenib, or biomarker-directed agents) rather than further ¹³¹I. [2,3,4,10]

13. Comparison with Alternatives

• Neck ultrasound: first-line, radiation-free for loco-regional recurrence and node assessment; complements Tg; operator-dependent, limited beyond the neck. [1]
• Contrast CT/MRI: anatomical mapping of bulky, mediastinal, pulmonary or skeletal disease; iodinated CT contrast delays subsequent ¹³¹I. [1]
• Serum Tg/TgAb: sensitive, inexpensive marker of disease burden; TgAb interference limits it in ~20–25% of patients. [1]
• ¹⁸F-FDG PET/CT: superior for RAIR/dedifferentiated and Tg-positive scan-negative disease; prognostic (FDG avidity predicts worse outcome and RAI resistance). [3]
• Biopsy: definitive for indeterminate structural findings. [1]

14. Special Situations

• Paediatric: DTC is often more advanced but prognosis remains good; activities are weight/body-surface-area (BSA)-adjusted, ideally dosimetry-informed to limit cumulative dose.
• Pregnancy/breastfeeding: ¹³¹I contraindicated; defer therapy and conception as above. [2]
• Renal impairment/dialysis: delayed clearance raises whole-body dose — reduce activity, use dosimetry, coordinate dialysis timing. [2]
• Diffuse pulmonary metastases: cap activity/retention to limit pulmonary radiation; consider dosimetry. [2]
• Prior therapy / cumulative activity: monitor cumulative ¹³¹I and marrow/salivary toxicity; declining benefit and rising cumulative dose favour reassessment for RAIR status. [1,3]

15. Complications and Adverse Effects

• Early/transient: nausea, transient neck pain or swelling (radiation thyroiditis), taste alteration, and mild, self-limiting bone-marrow suppression. [2]
• Salivary/lacrimal: sialadenitis, xerostomia and, less commonly, nasolacrimal duct obstruction; risk rises with cumulative activity. Hydration and sialagogues may reduce salivary dose, though optimal timing is debated. [2]
• Gonadal: transient reduction in sperm counts (men) and temporary menstrual irregularity or slightly earlier menopause (women), chiefly at higher cumulative activities; ¹³¹I has not been shown to impair long-term female fertility, and men receiving >14.8 GBq (400 mCi) cumulatively should be counselled on infertility risk. [2,10]
• Bone marrow: usually mild and reversible; cumulative activity and renal impairment increase risk, with a small, activity-related excess of second primary malignancy (including leukaemia); no safe threshold has been defined, but the absolute risk is low and extra screening is not advised. [2,10]
• Pulmonary: radiation pneumonitis/fibrosis with diffuse iodine-avid pulmonary metastases — limit administered activity/retention and consider dosimetry. [2]
• These recognised risks underpin the shift toward risk-adapted, lowest-effective-activity strategies and cumulative-dose monitoring. [1,2]

16. Recent Advances (label investigational where noted)

• Redifferentiation therapy (investigational): short-course MEK/BRAF or other MAPK-pathway inhibitors to restore NIS and re-enable ¹³¹I in selected progressive RAIR patients with targetable mutations (ATA 2025 conditional recommendation; trials encouraged). [10]
• Multikinase and selective inhibitors: after tumour biomarker testing, lenvatinib (preferred) or sorafenib first line and cabozantinib second line for progressive RAIR DTC; RET-, NTRK-, ALK- or BRAF V600E-directed therapy when an actionable alteration is present (ATA 2025). [4,10]
• Quantitative SPECT/CT and lesion dosimetry: increasingly used to personalise activity. [2]
• AI/radiomics (investigational): automated Tg-trend and image analysis for risk prediction.

17. High-Yield Numbers

Activities vary by guideline, risk category, age, dosimetry availability and institution.

18. Reporting Pearls

1. Always report TgAb status — it governs how much to trust Tg. [1]
2. Liver uptake on PT-WBS indicates functioning tissue somewhere, not a liver metastasis. [2]
3. Use SPECT/CT to separate physiological neck/mediastinal activity from true metastases. [2]
4. Contamination mimics disease — repeat/clean and reimage if a focus is odd. [2]
5. Distinguish remnant from residual tumour by location, intensity and Tg trend. [2]
6. State whether ¹³¹I preparation used withdrawal or rhTSH and the achieved TSH. [2]
7. In a Tg-positive, ¹³¹I-negative patient, recommend ¹⁸F-FDG PET/CT. [3]
8. Recent iodinated contrast can cause a false-negative scan — check history. [2]

19. Common Examination Traps

1. Low-risk microcarcinoma does not routinely require ¹³¹I. [1]
2. rhTSH is now preferred for ablation/adjuvant therapy; for distant metastases ATA 2025 accepts either rhTSH or withdrawal (SNMMI/EANM favours withdrawal plus dosimetry where feasible). [2,10]
3. Stunning is a concern with diagnostic ¹³¹I, not ¹²³I. [2]
4. TgAb causes falsely low Tg — a dangerous false negative. [1]
5. “Flip-flop”: dedifferentiated lesions are ¹³¹I-negative but FDG-positive. [3]
6. FDG avidity is a poor prognostic marker and predicts RAI resistance. [3]
7. RAIR status, not a fixed dose ceiling alone, ends ¹³¹I therapy. [1,3]
8. LID targets <50 µg/day; the goal is depleting the stable-iodine pool, not zero iodine. [2]
9. Basal Tg <1 ng/mL does not exclude distant metastases. [2]
10. ¹³¹I emits both a therapeutic beta and an imageable 364 keV gamma — one isotope, both roles. [2]

20. One-Minute Review

• DTC retains NIS → radioiodine is both imaging agent and therapy (theranostics). [2]
• TSH (≥30 mIU/L) upregulates NIS; achieve via withdrawal or rhTSH. [2]
• LID (<50 µg/day) depletes competing stable iodine. [2]
• ATA 2025 risk (low/low-intermediate/intermediate-high/high) guides whether and how much ¹³¹I. [10]
• Low-risk: ablation not routine (1.1–1.85 GBq if given); adjuvant 1.1–3.7 GBq; structural/metastatic ≥3.7 GBq or dosimetry. [2,10]
• Always do PT-WBS with SPECT/CT after therapy. [2]
• Tg + TgAb are the biochemical backbone of follow-up. [1]
• Response-to-therapy categories drive dynamic restratification. [1]
• Flip-flop → RAIR disease → ¹⁸F-FDG PET/CT + multikinase inhibitors. [3,4]
• ¹³¹I contraindicated in pregnancy; stop breastfeeding. [2]

21. Clinical Bottom Line

Radioiodine exploits retained NIS to image and treat DTC in a single theranostic system, with activity and preparation individualised by ATA risk and response-to-therapy status rather than a one-size protocol. Thyroglobulin (with TgAb) and post-therapy SPECT/CT anchor follow-up, and de-escalation is now standard for low-risk disease. When tumours dedifferentiate and become radioiodine-refractory, ¹⁸F-FDG PET/CT localises disease and multikinase inhibitors replace further ¹³¹I.

22. Key References

1. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1–133. doi:10.1089/thy.2015.0020.
2. Avram AM, Giovanella L, Greenspan B, et al. SNMMI Procedure Standard/EANM Practice Guideline for Nuclear Medicine Evaluation and Therapy of Differentiated Thyroid Cancer: Abbreviated Version. J Nucl Med. 2022;63(6):15N–35N.
3. Silberstein EB, Alavi A, Balon HR, et al. The SNMMI Practice Guideline for Therapy of Thyroid Disease with ¹³¹I 3.0. J Nucl Med. 2012;53(10):1633–1651. doi:10.2967/jnumed.112.105148.
4. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus Placebo in Radioiodine-Refractory Thyroid Cancer (SELECT). N Engl J Med. 2015;372(7):621–630. doi:10.1056/NEJMoa1406470.
5. Mallick U, Harmer C, Yap B, et al. Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer (HiLo). N Engl J Med. 2012;366(18):1674–1685. doi:10.1056/NEJMoa1109589.
6. Schlumberger M, Catargi B, Borget I, et al. Strategies of Radioiodine Ablation in Patients with Low-Risk Thyroid Cancer (ESTIMABL1). N Engl J Med. 2012;366(18):1663–1673. doi:10.1056/NEJMoa1108586.
7. Tuttle RM, Ahuja S, Avram AM, et al. Controversies, Consensus, and Collaboration in the Use of ¹³¹I Therapy in Differentiated Thyroid Cancer: A Joint Statement from the ATA, EANM, SNMMI, and ETA (Martinique Principles). Thyroid. 2019;29(4):461–470. doi:10.1089/thy.2018.0597.
8. Schlumberger M, Brose M, Elisei R, et al. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol. 2014;2(5):356–358. doi:10.1016/S2213-8587(13)70215-8.
9. Perros P, Boelaert K, Colley S, et al. Guidelines for the management of thyroid cancer (British Thyroid Association). Clin Endocrinol (Oxf). 2014;81(Suppl 1):1–122. doi:10.1111/cen.12515.
10. Ringel MD, Sosa JA, Baloch Z, et al. 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer. Thyroid. 2025;35(8):841–985. doi:10.1177/10507256251363120.
11. Praw SS, Gigliotti BJ, Tessnow A, et al. Executive Summary of the 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer. Thyroid. 2025;35(11):1214–1220. doi:10.1177/10507256251390877.