The Role of ¹²³I in the Management of Differentiated Thyroid Cancer: A Comprehensive Narrative Review

Abstract

Differentiated thyroid carcinoma (DTC) is the most common malignant endocrine tumor, with a generally favorable prognosis. Imaging, including iodine radioactive isotope scintigraphy (IRIS), is crucial for diagnosis and follow-up. While ¹³¹I has long been used for both therapeutic and diagnostic purposes, ¹²³I is reserved for diagnostic imaging due to its shorter half-life and γ emissions. This review highlights the utility of ¹²³I scintigraphy, especially in pre-treatment assessment and dosimetry for DTC. It is particularly valuable before radioiodine (RAI) ablation, providing accurate imaging in patients with iodine-refractory (IR) or biochemically incomplete response (BIR) DTC. When compared to post-therapeutic ¹³¹I scans, ¹²³I scintigraphy appears to have a lower sensitivity for detecting metastatic lesions, particularly in lymph nodes and lungs. However, its diagnostic performance compared to low-dose diagnostic ¹³¹I is more variable, with some studies suggesting superiority due to the absence of stunning. Further research is needed to standardize its use and optimize its role in guiding DTC management.

1. Introduction

Differentiated thyroid carcinoma (DTC) is the most common malignant tumor of the endocrine system [1,2], and it presents a higher incidence in females than in males [3]. DTC is also generally characterized by a low incidence of distant metastases, which are the only features that greatly influence mortality and consequently a favorable prognosis [4,5,6,7]. Imaging examinations are fundamental in the staging and follow-up of the DTC, and they may include ultrasound (US), iodine radioactive isotope scintigraphy (IRIS) [8,9,10], and, in specific cases, ¹⁸F-fluorodesoxyglucose positron emission tomography-computed tomography (¹⁸F-FDG PET-CT) [11,12,13,14].

Since the 1940s, the IRIS represents the most specific and used diagnostic imaging examination in the management of DTC, with ¹³¹I and ¹²³I as the most common isotopes. ¹³¹I has a half-life (T_1/2) of about 8 days and emits low-penetrating β particles (maximum energy 606 kiloelectronvolts (keV), mean energy 190 keV). It is usually administered for DTC treatment [15,16]. However, due to its γ emissions, it can also be used to obtain whole-body scan (WBS) and single-photon emission tomography/computed tomography (SPECT/CT) images after both diagnostic and therapeutic doses [16,17,18]. ¹²³I presents a prevalence of γ emission (primary emission of 159 keV) and a T_1/2 of about 13 h, and it is used only for diagnostic imaging [17,18,19]. Despite being included in the most recent and relevant guidelines for the management of DTC [20], the exact role of ¹²³I scintigraphy—and the clinical contexts in which it may be particularly useful—has yet to be clearly delineated.

A significant concern with using ¹³¹I for diagnostic scanning is the potential ‘stunning’ effect, where the diagnostic dose of ¹³¹I can impair the subsequent uptake of the therapeutic dose, potentially reducing treatment efficacy. Due to its shorter half-life and the absence of high-energy β emissions, ¹²³I is theoretically free from this effect, making it an attractive agent for pre-therapeutic planning. However, its integration into clinical practice is heterogeneous, and its diagnostic performance relative to ¹³¹I, both in diagnostic and therapeutic settings, requires clarification.

The aim of this comprehensive narrative review is to summarize the current evidence regarding the role of ¹²³I scintigraphy in dosimetry and pre-treatment RAI planning and to evaluate its diagnostic performance, particularly in comparison with ¹³¹I scintigraphy using diagnostic and therapeutic doses.

2. Radioiodine and Dosimetry

To quantify the red marrow absorbed dose after ¹³¹I administration, the 2008 European Association of Nuclear Medicine (EANM) procedure guidelines [21] recommend collecting serial blood samples at 2, 6, 24, 96, and 144 h following the administration of a low diagnostic activity (≤15 MBq), using blood activity as a surrogate for red marrow dosimetry and applying a safety threshold of 2 Gy. In addition, whole-body measurements are advised at 2, 6, and 24 h, with at least one further acquisition at approximately 96 h.

Hänscheid et al. [22] subsequently introduced a simplified method for estimating the blood absorbed dose per unit of administered ¹³¹I, relying on a single total-body retention measurement. This approach achieves its greatest accuracy when the measurement is acquired at 24–48 h and appears adequate for routine assessment of individual radiation exposure during radioiodine therapy, although it may carry a risk of underestimating the Maximum Tolerated Activity (MTA).

More recently, Atkins et al. [23] described a bi-exponential model corrected for body surface area (BSA), showing that the 48 h fractional whole-body retention can predict the measured MTA without requiring blood sampling, with an average deviation of only ±1.2%. The authors recommend administering no more than 70% of the calculated MTA, due to the risk of overestimation—particularly in patients prepared with rhTSH: this can occur due to faster RAI biological washout in patients prepared with rhTSH than in patients treated with hormone withdrawal; particularly, it be due to constipation and mild reduction of kidney function, the two main ways of RAI excretion through feces and urine, which are frequent during hypothyroidism.

Despite the increasing use of ¹²³I scintigraphy, often combined with multiple SPECT/CT acquisitions, to determine the optimal therapeutic activity of ¹³¹I, the timing and methodology of ¹²³I-based dosimetry remain non-standardized [24,25,26].

In preclinical work, Kim et al. [24] investigated the optimal timing for determining tissue-absorbed dose in DTC xenograft mouse models. They identified two key imaging time-points, at the estimated Tmax of 2.91 h and at 26 h following ¹²³I administration.

Following the recommendations of Atkins et al., Durski et al. [25] tested a protocol involving two scintigraphic acquisitions at 24 and 48 h after ¹²³I administration to estimate the ¹³¹I MTA in a patient with metastatic DTC; subsequently, 70% of the calculated MTA was administered.

Brown SR et al. [26] conducted a clinical trial investigating the potential role of selumetinib in promoting redifferentiation in DTC. The protocol incorporated ¹²³I scintigraphy both for patient selection and for pre-treatment dosimetry in ¹³¹I therapy. Although the precise imaging schedule was not reported, the authors indicated that three to four acquisitions were performed, consisting of a standard scan followed by two or three additional time-point measurements.

Finally, the 2025 American Thyroid Association (ATA) guidelines for DTC management [20] also do not provide a standardized protocol for ¹²³I-based dosimetry.

In summary, while ¹³¹I-based dosimetry is relatively well established, ¹²³I dosimetry represents a promising and more patient-friendly alternative that eliminates the need for multiple blood samples. Emerging protocols—often based on two imaging time-points (e.g., 24 and 48 h)—appear feasible for estimating the MTA for ¹³¹I therapy, particularly in metastatic disease. However, the lack of a standardized ¹²³I dosimetry procedure in the 2025 ATA guidelines highlights the need for larger, prospective studies to validate and harmonize these methods before they can be broadly implemented in clinical practice.

3. ¹²³I WBS in Pre- RAI Treatment: Comparison with ¹³¹I Diagnostic Dose Scintigraphies

As reported in the recent 2025 ATA guidelines [20], the use of WBS prior to RAI therapy appeared to be a possible procedure to guide the treatment, preferably the use of WBS with ¹²³I rather than WBS with ¹³¹I. Possible changes determined by WBS include the following:

(1)

Detection of very large thyroid remnants, which require additional surgery prior to ablation;

(2)

Absence of a remnant with negative thyroglobulin (Tg), particularly in patients at low risk of recurrence who do not require RAI therapy or who may require a low dose of RAI in other cases;

(3)

Detection of RAI-avid metastases, offering the opportunity for high-dose treatment. Instead, the strongest arguments against this practice are provided by the 2008 EANM guidelines, which suggest not performing diagnostic WBS in the presence of a clear indication for RAI therapy, and the 2022 ETA guidelines, which state that diagnostic WBS should not be used routinely [27,28]. In addition, multiple studies analyzed its usefulness and concluded that, in several cases, ¹²³I WBS findings modified the therapeutic approach [29,30,31]. In some cases, this involved making a conservative decision in the absence of ¹²³I uptake; in others, it implies increasing the ¹³¹I dose administered in the presence of suspected metastases. ¹²³I appeared to be favored over ¹³¹I due to its pure gamma emission, shorter half-life, and lower probability of stunning effect. In this context, it is interesting to evaluate the experience of using ¹²³I WBS compared to ¹³¹I diagnostic WBS, considering the studies published in the literature.

Sarkar SD et al. [32] retrospectively reviewed 12 cases of patients who underwent thyroidectomy for DTC and compared the results of ¹²³I whole-body scintigraphy (WBS), performed 24–96 h after administering 2–5 mCi (74–185 MBq) of ¹²³I, with those of ¹³¹I WBS, performed at the same time points using a diagnostic dose of 111–185 MBq. They found that both ¹²³I and ¹³¹I WBS correctly identified residual thyroid tissue in nine patients, but only ¹³¹I WBS detected metastatic lesions in five scans from four patients. No lesion was more clearly visualized with ¹²³I than with ¹³¹I, leading the authors to conclude that ¹²³I WBS is less sensitive than ¹³¹I WBS for imaging DTC metastases. The study’s limitations included the small sample size and the lack of single-photon emission computed tomography (SPECT/CT) imaging.

Mandel SJ et al. [33] prospectively evaluated 14 patients with DTC who underwent total thyroidectomy and were subsequently staged using ¹²³I and ¹³¹I diagnostic scintigraphy. For the ¹²³I WBS, images were acquired five hours after the administration of 48–56 MBq of ¹²³I, and for the ¹³¹I scintigraphy, images were acquired 48 h after the administration of 111 MBq of ¹³¹I. They found that ¹²³I scintigraphy detected three more foci of increased uptake than ¹³¹I WBS (35 versus 32 foci). The study’s limitations include the small sample size and the absence of SPECT/CT image acquisition.

Siddiqi A et al. [34] prospectively evaluated 12 patients with DTC previously treated with thyroidectomy and RAI and with negative ¹³¹I diagnostic scan and raised Tg levels. They performed a ¹²³I scan on all the patients before RAI therapy, revealing positive findings in 10 out of 12 patients. A fundamental limitation was the selection bias, considering only patients with a negative ¹³¹I scan.

The comparison between ¹²³I and diagnostic-dose ¹³¹I WBS yields conflicting results, as summarized in

Table 1. Summary of articles comparing ¹²³I with diagnostic-dose ¹³¹I WBS.

Reference	Authors	Year	Nation	N of Patients	Conclusion	Concordance Rate (CR) (%)	Possible Bias	Design
[32]	Sarkar SD et al.	2002	USA	12	131I more sensitive than 123I	61.5%	Small sample size, no SPECT/CT acquisition	Retrospective
[33]	Mandel SJ et al.	2001	USA	14	123I more sensitive than 131I	91.4% *	Small sample size, no SPECT/CT acquisition	Prospective
[34]	Siddiqi A et al.	2001	UK	12	123I more sensitive than 131I	nd **	Selection bias: study reported just a representation of the not unusual possibility of false negative of 131I diagnostic scan	Prospective

* number of foci. ** they selected only patients with negative ¹³¹I scan.

. The study by Mandel et al. [31], which reported superior performance for ¹²³I, utilized an early acquisition time (5 h), potentially capitalizing on ¹²³I’s favorable early pharmacokinetics. In contrast, Sarkar et al. [30] used later acquisitions (24–96 h), which may disadvantage ¹²³I due to its physical short half-life. This highlights that the timing of image acquisition is a critical and often overlooked variable that significantly influences the perceived sensitivity of ¹²³I scintigraphy. In addition, there are specific limitations that affect both RAI WBS with diagnostic dose. These include the potential for restricted RAI uptake in small thyroid remnants, the high cost of ¹²³I, the possibility of misinterpretation of thyroid remnants as nodal metastases on planar images, and, finally, the limited sensitivity in the presence of unfavorable mutations (e.g., BRAF, TERT) [20].

4. ¹²³I Diagnostic Dose vs. ¹³¹I Therapeutic Dose Scintigraphies

Several studies have attempted to compare the diagnostic performance of ¹²³I WBS and ¹³¹I WBS after RAI therapy, reaching conflicting conclusions [35,36,37,38,39,40,41,42,43,44,45,46]. Most of the studies describe lower sensitivity of ¹²³I WBS, with the possibility of misrecognizing some RAI-avid lesions that are detectable with ¹³¹I WBS [35,37,38,39,42,44]. However, other studies do not confirm these findings [40,41,43,45,46] and report comparable sensitivities, albeit often with lower values for ¹²³I WBS than for ¹³¹I WBS. This would seem to confirm the latter’s slight superiority. Only one study described superiority of the ¹²³I scan [36].

Considering single study, Alzahrani AS et al. [35] performed a retrospective study which compared 238 diagnostic WBS performed 24 h after the oral administration of 185–555 MBq of ¹²³I with their corresponding ¹³¹I post-therapy WBS obtained 4–5 days after ¹³¹I therapy. They studied scans in three clinical situations: with the first ¹³¹I therapy, with the second ¹³¹I therapy, and in cases of elevated Tg levels and negative diagnostic scan. They found that 177 pairs were obtained with the first ¹³¹I therapy and showed concordance between pre-treatment and post-treatment scans in 166 pairs with a concordance rate (CR) of 93.8%: particularly, six post-treatment scans showed foci in thyroid bed and five in metastatic locations. Considering the second ¹³¹I therapy, 34 pairs were obtained and showed concordance in 28 pairs with a CR of 82.4%: particularly, in six cases, metastases were not detected with ¹²³I WBS. Finally, of twenty-seven pairs of scans in patients with elevated Tg levels and negative pre-treatment WBS, fifteen post-treatment scans remained negative, six showed an uptake in the thyroid bed, three showed benign lung uptake, and three showed definite uptake (in thyroid bed, in thyroid bed and lung, and in lymph nodes) which was also weakly detectable retrospectively in the ¹²³I WBS: CR in this setting was 55.6%.

Thomas DL et al. [36] retrospectively evaluated and compared pretherapy diagnostic ¹²³I scans with 7-day post-therapy ¹³¹I scans in detecting remnant thyroid disease as well as locoregional metastases in 53 patients. They found that ¹²³I scans performed 24 h after an oral administration of 1–1.6 mCi (37–59.2 MBq) were more sensitive and provided a better lesion-to-background ratio than ¹³¹I scans performed seven days after ¹³¹I oral administration. The study was probably affected by the late acquisition of the ¹³¹I WBS, and the authors acknowledge this in their conclusion.

Cohen JB et al. [37] retrospectively compared 30 pre-therapy diagnostic ¹²³I scans performed 24 h after the administration of 74 MBq of ¹²³I with 30 post-therapy ¹³¹I scans performed 2–10 (mean 5.8) days after the administration of RAI in 29 patients. They found that WBS showed concordance in nineteen cases (63.3%), while in four cases (13.3%), ¹²³I WBS detected more lesions in the neck than ¹³¹I WBS. However, in seven cases (23.3%), ¹³¹I WBS were more sensitive than ¹²³I WBS, particularly in cases involving distant metastases.

Bravo PE et al. [38] retrospectively evaluated 342 individuals diagnosed with DTC, underwent RAI therapy, and performed a ¹²³I WBS one day before RAI administration and ¹³¹I WBS one week after RAI therapy. SPECT/CT acquisitions were also performed, and the administered ¹²³I activities were standardized: 1.5 mCi for patients treated with thyroid hormone withdrawal and 2.0 mCi for patients prepared with recombinant human TSH (rhTSH). The patients were divided into three groups: 311 patients RAI-naive without known distant metastatic disease, 23 patients with history of prior RAI and persistent disease, and 8 patients with known distant metastases. Their analysis showed that 22 patients (7%) in the first group had discordant scan findings but in only four cases did these discrepancies reflect actual disease. In the second and third groups, discordant scans were present in seven (30%) and five (62.5%) patients, respectively, with misinterpretation of metastatic disease at the ¹²³I WBS scan. Bravo PE et al. concluded that the sensitivity of ¹²³I WBS depends on the clinical setting.

Iwano S et al. [39] published a study evaluating 69 patients with DTC treated with RAI. They compared WBS images taken 24 h after the administration of 37 MBq of ¹²³I with images obtained 34 days after administration of 2.22–7.4 GBq (median 5.55 GBq) of ¹³¹I. They identified 108 sites of RAI uptake in the ¹³¹I WBSs, but only 77 of these were also detected with the ¹²³I, giving a CR of 71%. CR was higher for uptake in the thyroid bed (89%) and bone metastases (86%) but lower for lymph nodes (61%) and lung metastases (39%). The authors concluded that WBSs performed 24 h after the administration of 37 MBq of ¹²³I were not always predictive of the ¹³¹I WBS results.

Urhan M et al. [40] evaluated 292 ¹²³I WBS (dose administered: 50–111 MBq) with their corresponding post-treatment ¹³¹I images. All patients treated with RAI were in a hypothyroid state. They found that in 228 out of 263 patients with a positive diagnostic scan, ¹²³I and ¹³¹I WBS findings were concordant (CR 87%). However, 44 additional foci of abnormal uptake in 22 discordant cases were found in ¹³¹I WBS but with no impact on therapeutic management of the patients. In the other 13 patients, there was at least one new site on post-treatment images that had been missed on pre-treatment ¹²³I images. Finally, 29 patients with a negative diagnostic WBS were treated with ¹³¹I due to high Tg levels (range 11.3–480 ng/mL) with RAI uptake sites not detected with ¹²³I WBS seen in eight post-treatment ¹³¹I scans (CR 72%). The authors concluded that in DTC management pre-treatment, ¹²³I WBS is comparable to high-dose ¹³¹I post-treatment imaging, but data apparently do not support this conclusion: in fact, 43 of 292 WBS (14.7%) had at least an RAI-avid lesion not detected with ¹²³I WBS.

Gulzar Z et al. [41] prospectively evaluated 27 patients who underwent near total thyroidectomy and performed subsequent RAI therapy. They compared WBS obtained 4 and 24 h after the administration of 185 MBq ¹²³I, with WBS performed 5–7 days after administration of therapeutic dose of ¹³¹I. They found CR of 92.6% and 83.2%, respectively, for WBS performed after 4 and 24 h following ¹²³I administration compared with ¹³¹I WBS. Particularly, 7.8% of patients had at least one RAI-avid lesion that was not detected with the ¹²³I WBS.

De Geus-Oei LF et al. [42] studied 55 patients who had been treated with ¹³¹I (1.85–5.55 GBq) and had previously undergone diagnostic ¹²³I WBS (111–370 MBq). They compared WBS obtained 24 h after ¹²³I administration with WBS obtained 3–15 days (median 8.6 days) after ¹³¹I administration in the 36 patients for whom these data were available. They found that more lesions were visible on the post-therapeutic ¹³¹I WBS than on the corresponding diagnostic ¹²³I scan in thirteen patients; in two patients, ¹²³I WBS appeared more sensitive; and in twenty-one, the findings were equal (CR 58.3%).

Ali N et al. [43] retrospectively evaluated 58 patients who underwent at least two ¹³¹I therapy and made a comparison between a 20 min scintigraphy obtained 2 and 24 h after the administration of ¹²³I 185–270 MBq and a 10–12 min scintigraphy obtained 4–7 days after the administration of 5.55 GBq of ¹³¹I. The study, which initially included 135 patients, showed that despite a high complete response rate (94.8%), more lesions were visible on the post-therapeutic ¹³¹I WBS than on the corresponding diagnostic ¹²³I scan. Notably, in three patients, the ¹²³I WBS was negative while the ¹³¹I scan was positive. In one patient, ¹²³I scintigraphy detected an uptake that was not seen on the ¹³¹I scan; however, a subsequent scan performed after the third ¹³¹I therapy eventually revealed it.

Siddiqi A et al. [34], as previously reported, prospectively evaluated 12 patients with DTC previously treated with thyroidectomy and RAI and with negative ¹³¹I diagnostic scan and raised Tg levels (>2.5 pg/L): in these patients, a diagnostic ¹²³I WBS was performed 2 h and 24 h after administration of ¹²³I tracer dose 185 MBq and 4–7 days after ¹³¹I therapy dose 5.55 GBq. They performed a total of 18 ¹²³I scans and found 16 positive ¹²³I WBS with corresponding 14 positive ¹³¹I WBS: in the two cases of discordance, one was a false negative uptake; in the second one, the Tg levels decreased after therapy; and no imaging or histopathological confirmation of the bone uptake at ¹²³I scan was performed. In two cases, ¹³¹I WBS detected thyroid bed uptakes not revealed by ¹²³I. The primary limitation of the study—aside from the small sample size and the absence of SPECT/CT images—was the patient selection criterion, which included only patients with a negative ¹³¹I diagnostic WBS.

Schoelwer MJ et al. [44] retrospectively evaluated 33 pediatric patients who performed total thyroidectomy, diagnostic scintigraphy, and RAI therapy for DTC. Thirty-seven pairs of scans with different iodine isotopes were performed. For diagnostic scanning, five received 74 MBq of ¹³¹I, twenty-one received 74 MBq of ¹²³I, and eleven received 111 mCi of ¹²³I; images were acquired 24 h after RAI administration. Therapeutic dose of ¹³¹I was variable (27–190 mCi) and images acquired after 7 days. Of the 31 ¹³¹I scans considered, 24/31 were concordant with ¹³¹I therapeutic scans (CR 77%), particularly in two cases with missing mediastinal uptake and four cases with missing lung uptake (false negative ¹²³I rate: 19.4%). One case was represented by a false positive ¹³¹I finding.

Yaakob W et al. [45] retrospectively evaluated 13 patients with DTC who underwent thyroidectomy and were given ¹²³I whole-body scans 24 h after receiving 0.8–1.0 mCi of ¹²³I. All patients then received a therapeutic dose of ¹³¹I (29.9–250 mCi), after which a WBS was performed 7–10 days later. Excluding one patient with a false positive ¹²³I WBS scan, the authors found excellent correlation between scans in 11 out of 12 patients, particularly in the case where ¹²³I underestimated the lung burden (CR 91.7%).

Berbano R et al. [46] conducted a study involving 16 patients with DTC treated with RAI. They compared whole-body scans performed 24 h after administration of 10 mCi (370 MBq) of ¹²³I with images acquired 5–7 days after ¹³¹I administration (dose range: 75–200 mCi). They observed concordant findings in 15 of the 16 scans (CR 93.8%), with a single discordant case in which the ¹²³I WBS failed to detect a lung lesion.

Most of the studies were affected by the limitation of the absence of SPECT/CT images, resulting in low diagnostic performance of the scintigraphic images. Furthermore, some studies [34,38,41,44,45,46] had a small sample size (<30 patients). Another possible source of bias is the heterogeneity in the ¹²³I scintigraphy protocol, including the administered dose and timing of image acquisition. A similar problem is also present for ¹³¹I scintigraphy after a therapeutic dose. Finally, excluding the paper by Gulzar Z et al. [41], most studies had a retrospective design.

Table 2. Summary of articles that comparing ¹²³I scintigraphy with therapeutic-dose ¹³¹I WBS.

Reference	Authors	Year	Nation	N of Patients	Conclusion	CR (%)	Possible Bias	Design
[34]	Siddiqi A et al.	2001	UK	12 *	123I comparable with 131I	nd	Selection bias. Absence of SPECT/CT. Small sample size.	Prospective
[35]	Alzahrani AS et al.	2001	Saudi Arabia	238	131I more sensitive than 123I	93.8 in first RAI therapy; 82.4 in second RAI therapy; 55.6 in patients with high Tg and negative pre-treatment WBS	Different doses of 123I and 131I administered. Absence of SPECT/CT	Retrospective
[36]	Thomas DL et al.	2009	USA	53	123I more sensitive than 131I	26.4	Late acquisition of 131I WBS. Different doses of 131I administered. Absence of SPECT/CT	Retrospective
[37]	Cohen JB et al.	2004	USA	29	131I more sensitive than 123I	63.3%	Different doses of 131I administered. Absence of SPECT/CT. Small sample size.	Retrospective
[38]	Bravo PE	2013	USA	342	131I more sensitive than 123I	93% in the first RAI therapy; 70% in patients previously treated and with persistent disease; 37.5% in patients with known M1	/	Retrospective
[39]	Iwano S et al.	2009	Japan	69	131I more sensitive than 123I	71%	Different doses of 131I administered. Low dose of 123I administered. Absence of SPECT/CT	Retrospective
[40]	Urhan M et al.	2007	USA	292	123I comparable with 131I **, but data suggest 131I more sensitive than 123I	85.3%	Different doses of 123I and 131I administered. Absence of SPECT/CT	Retrospective
[41]	Gulzar Z et al.	2001	USA	27	123I comparable with 131I **	92.6% in images after 24 h; 85.2% in images after 4 h	Different doses of 131I administered. Absence of SPECT/CT. Small sample size.	Prospective
[42]	De Geus-Oei LF et al.	2002	The Netherlands	55 ***	131I more sensitive than 123I	58.3%	Different doses of 131I administered. Absence of SPECT/CT. Small sample size.	Retrospective
[43]	Ali N et al.	2006	UK	58 ****	123I comparable with 131I **	94.8%	Retrospective nature of the study	Retrospective
[44]	Schoelwer MJ et al.	2015	USA	33 *****	131I more sensitive than 123I	77%	Different doses of 131I administered. Absence of SPECT/CT. Small sample size	Retrospective
[45]	Yaakob W et al.	1999	USA	13	123I comparable with 131I **	91.7%	Different doses of 131I administered. Absence of SPECT/CT. Small sample size.	Retrospective
[46]	Berbano R et al.	1998	USA	16	123I comparable with 131I **	93.8%	Different doses of 131I administered. Absence of SPECT/CT. Small sample size.	Retrospective

* 12 patients but 18 ¹²³I and ¹³¹I WBS performed. ** Authors’ conclusion, but data may suggest ¹³¹I little better than ¹²³I. *** Comparison between ¹²³I and ¹³¹I WBS were available for 36 patients. **** Study enrolled 135 patients, but only 58 were retreated with ¹³¹I. ***** 33 patients enrolled, 37 WBS performed, but 5 excluded because of performed with ¹³¹I diagnostic dose and one because of false positive ¹²³I result.

summarizes the findings of the studies reported in the comparison of ¹²³I diagnostic scintigraphy and scintigraphy performed after a therapeutic dose of ¹³¹I.

The bulk of evidence from Table 2 indicates that post-therapeutic ¹³¹I WBS detects a higher number of RAI-avid lesions than pre-therapeutic ¹²³I WBS. The concordance rates are generally high in treatment-naïve patients with low tumor burden but drop significantly in the setting of persistent or metastatic disease. The most common sites for ¹²³I false negatives are lymph nodes and pulmonary metastases, likely due to lower lesion uptake and poorer count statistics compared to the high activity used in therapy. Therefore, a negative ¹²³I scan in a high-risk patient, particularly one with elevated Tg levels, should be interpreted with caution, as it does not definitively exclude the presence of RAI-avid disease. Figure 1 shows an example of WBSs confrontation in a patient who was treated for metastatic DTC.

5. ¹²³I Scan and Thyroglobulin Level

Tg is a protein produced only by follicular thyroid cells. After thyroidectomy and, in particular, RAI ablation, it represents a fundamental tumor marker for the management and follow-up of DTC [47]. Its level and/or rising trend are well known to be associated with disease recurrence, as reported in the ATA 2025 guidelines. They defined dynamic risk stratification classes according to the response to therapy and the Tg levels. This includes, other than an excellent response (ER) and a structural incomplete response (SIR), an indeterminate response (IR) in the presence of a basal Tg (bTg) range of 0.2–1.0 ng/mL and a biochemically incomplete response (BIR) in the presence of a bTg range of 1.0–10.0 ng/mL, which is associated with an increased risk of structural recurrence of the disease. In this context, some studies have analyzed the usefulness of ¹²³I scintigraphy in relation to Tg levels [48,49,50,51].

Campennì et al. [48] conducted a retrospective evaluation of 124 patients with DTC who underwent thyroidectomy and RAI therapy during follow-up. The study focused on the utility of the ¹²³I scan. They found that the diagnostic performance of ¹²³I WBS SPECT/CT significantly increased in patients with basal Tg values of at least 0.39 ng/mL.

Sol B et al. [49] retrospectively evaluated 40 patients with DTC who had undergone total thyroidectomy, focusing on 24 patients with undetectable basal Tg level determined with a highly sensitive Tg assay (below 0.1 ng/mL) six months after thyroidectomy. They found that none of these patients had stimulated Tg level above 1 ng/mL or a remnant on the ¹²³I WBS after one year of follow-up. They concluded that ¹²³I scintigraphy is unnecessary in this patient group.

Again, Campennì et al. [50] retrospectively evaluated 241 low- to intermediate-risk patients with histologically confirmed DTC and negative Tg antibodies (AbTg) all treated with total thyroidectomy and RAI therapy. During the follow-up 8–12 months after RAI, a ¹²³I WBS was performed in 51 patients, particularly in 16 patients without excellent response. They found that seven out of sixteen (43.7%) DTC patients with IR (mean stimulated Tg = 4.5 ng/mL) and/or BIR (mean stimulated Tg = 13.5 ng/mL) ¹²³I WBS and SPECT/CT were able to identify five local and two locoregional lymph-node metastases.

Villani MF et al. [51] evaluated 55 pediatric patients with DTC, and, particularly, they considered 41 scans performed after ¹²³I administration with rhTSH and before RAI therapy. They found that thyroglobulin alone apparently was not a good predictor for staging modification (AUC = 0.6855 in ROC analysis), while ¹²³I WBS modified staging in 12/41 (29%): in 3/12 (25%) for the presence of lung metastases and in 9/12 (75%) for lymph node involvement. In all these patients, the therapeutic management were modified.

Table 3. Summary of articles evaluating the relationship between ¹²³I scintigraphy and Tg levels.

Reference	Authors	Year	Nation	N of Patients	Design	Possible Bias	Conclusion
[48]	Campennì et al.	2023	Italy	124	Retrospective	Retrospective nature of the study	123I scintigraphy diagnostic value appeared higher in patients with bTg > 0.39 ng/mL
[49]	Sol B et al.	2021	Belgium	24 *	Retrospective	Small sample size, retrospective nature of the study	123I scintigraphy is not useful in patients with undetectable bTg (<0.1 ng/mL) 6 months after thyroidectomy
[50]	Campennì et al.	2021	Italy	16 **	Retrospective	Retrospective nature of the study	123I scintigraphy use appears very useful during follow-up of patients with DTC and BIR or IR
[51]	Villani MF et al.	2018	Italy	41 ***	Retrospective	Retrospective nature of the study	Tg alone give no strength information in staging modification prior to RAI therapy. 123I appears useful in the definition of therapeutic management of patients with DTC prior to RAI.

* 24 Patients with ER were selected from a sample of 40 patients. ** 16 Patients without ER were selected from a sample of 51 patients. *** 40 Patients who performed a WBS with 123I before RAI therapy were selected on a sample of 55 patients.

summarizes the findings of the studies reported.

6. Discussion

¹²³I scintigraphy remains a key tool in the management of DTC, in particular in the diagnostic setting during the follow-up, especially in patients with IR and/or BIR as reported by Campennì A et al. [48,50], although its sensitivity is limited [35,38]. Its possible utility in performing it after total thyroidectomy and prior to RAI therapy has also been reported [29,30,31,51]. Execution of ¹²³I diagnostic images allows the assessment of metastatic DTC localization or can underline the presence of unexpected alterations of radioiodine distribution in several cases [28]. These findings can help to define the appropriate RAI dose, if indicated, or can modify the therapeutic approach to these subjects: this applies to both initial therapy after total thyroidectomy and follow-up therapy.

In contrast with its utility in cases of dosable bTg, the absence of incremental diagnostic value in the presence of negative bTg was also described in one study. Particularly, the study of Sol B et al. [49] reported that the presence of bTg < 0.1 ng/mL during the early follow-up after initial therapy apparently made unuseful the ¹²³I scintigraphy. These data appear to agree with the literature and particularly with the high negative predictive value of the bTg data [52,53]. Therefore, there is no benefit in routinely performing 123I WBS during the follow-up of patients with ER.

It is important to highlight that studies comparing ¹²³I and ¹³¹I scintigraphy reported in the literature describe an apparent superiority of the ¹²³I diagnostic scan over the ¹³¹I scan [33,34], while ¹³¹I scans performed after RAI therapy appear to be more sensitive than ¹²³I diagnostic WBS scans [35,37,38,39,42,44]. Studies reporting comparable diagnostic values for ¹³¹I WBS after RAI therapy and ¹²³I diagnostic WBS mostly describe a slight superiority of the former. In particular, few patients in these studies had a DTC lesion missing on the ¹²³I WBS that was subsequently detected with the ¹³¹I. Urhan et al. [40] reported this to be 14.7%, Gulzar et al. [41] 7.8%, Ali et al. [43] 5.2%, Yaakob et al. [45] 8.3%, and Berbano et al. [46] 6.2%. Given that the presence of metastases is one of the few factors that can significantly affect outcomes in patients with DTC [54], the possibility of missing them in 5.2–14.7% of cases warrants caution when using ¹²³I diagnostic scintigraphy during follow-up. In summary, ¹²³I WBS scintigraphy appears to provide useful information when positive results are reported. However, a negative result could not exclude the presence of a RAI-avid lesion in a few cases, despite its good sensitivity. In conclusion, the ¹³¹I WBS performed after the administration of therapeutic activity remains the gold standard for evaluating RAI avidity in the localization of DTC disease.

It is important to emphasize that no clear standardization protocol on ¹²³I dose or acquisition time were described for patient dosimetry, even though diagnostic practice studies reported the administration of different ¹²³I doses. Almost all these studies agreed on acquiring images 24 h after administration, whereas the utility of an earlier acquisition is still being debated. In the same context, no studies focused on comparing preparation with hormone withdrawal in relation to rhTSH were found in the literature. This lack of standardized protocols requires an expert consensus to establish a well-known and widely utilized practice, especially considering the large number of studies reported in the literature. Standardization of ¹²³I WBS dosimetry and diagnostic protocols, including the dose, timing, and patient preparation, could provide a basis for further studies evaluating its usefulness and enabling better comparison.

Furthermore, it is fundamental to highlight that the choice of imaging in DTC is not merely between ¹²³I and ¹³¹I, and performing an RAI WBS does not necessarily conclude the diagnostic process. In this setting, ¹⁸F-FDG PET/CT has a well-established role in RAI refractory DTC where lesions lose the ability to concentrate iodine [55,56]. A key clinical challenge is identifying which patients could benefit from ¹⁸F-FDG PET/CT and where ¹²³I can serve as a triage tool. Considering patients with BIR, a positive scan confirms the presence of RAI-avid lesions and guides therapy, albeit with some limitations, while a negative scan should prompt investigation for iodine-refractory disease with ¹⁸F-FDG PET/CT. Similarly, in patients with known SIR, the possibility to evaluate both the RAI and FDG uptake in every single metastases could guide the therapeutic choice. Possible roles of the ¹²³I scintigraphy in the management of DTC are highlighted in Figure 2.

Finally, beyond conventional planar or SPECT-based approaches, it is important to acknowledge the additional contribution that PET imaging can offer in the evaluation of iodine-avid disease. In this context, ¹²⁴I PET/CT provides superior sensitivity and true quantitative capabilities, enabling improved detection of small-volume lesions—particularly cervical lymph node involvement and micronodular pulmonary metastases—and offering a more accurate basis for patient-specific dosimetry. Several studies [57,58,59] have demonstrated that ¹²⁴I PET outperforms ¹²³I scintigraphy in lesion conspicuity and may better predict post-therapeutic ¹³¹I uptake, supporting its potential role in treatment planning. Nevertheless, its routine clinical use remains limited by restricted availability and higher costs.

We can actually suggest the use of ¹²³I scintigraphy for pre-ablation assessment in cases of unclear RAI indication, IR, BIR, and SIR, bearing in mind its limited sensitivity. This can be followed by an ¹⁸F-FDG PET/CT scan if the WBS is negative. Finally, ¹²³I should be used for dosimetry when required.

The review has several limitations. Firstly, most of the studies appeared quite old and lacked SPECT/CT image acquisition, which is actually the gold standard for managing DTC as recommended by several international guidelines, including the recent SNMMI/EANM 2022 and ATA 2025 guidelines [20,60]. This could lead to an underestimation of the sensitivity of the two tracers considered. Secondly, the absence of standardization in administration and acquisition protocols resulted in heterogeneous use of dosage and acquisition time in ¹²³I diagnostic scintigraphy. Similarly, significant heterogeneity in the ¹³¹I therapeutic dose administered to patients, as well as in the timing and acquisition protocol of the scintigraphic images, was reported. This heterogeneity makes it difficult to compare individual studies and surely affects the sensitivity of scintigraphic studies. Thirdly, most of the studies considered were designed with retrospective analyses. Finally, another important possible limitation is represented by the small sample size of some studies considered.

Further studies with a large sample size and a prospective design should be desirable to define the real discrepancy between ¹²³I and ¹³¹I scintigraphy after RAI therapy. Other variable such as ¹⁸F-FDG PET/CT, Tg levels, the staging, the risk factor, etc., should be also considered in the analysis. This approach could confirm whether the latter is superior and identify patients in whom the possibility of a false negative result with ¹²³I is present.

7. Conclusions

In conclusion, ¹²³I scintigraphy represents a valuable diagnostic tool in the management of DTC in specific settings, particularly in cases of raised Tg levels (IR and/or BIR), patients with SIR, and for dosimetry in metastatic disease. Instead, its role in pre-ablation assessment is still debated. Moreover, it is fundamental to highlight its possible lower sensitivity compared to post-therapeutic ¹³¹I scans. The development of standardized protocols for administered activity and acquisition timing is needed. Future prospective, multi-center studies with large sample sizes, standardized ¹²³I protocols, and mandatory SPECT/CT are essential to definitively establish its sensitivity and integrate it into a cost-effective, patient-tailored diagnostic algorithm.