Differentiated thyrοid carcinoma (DTC) is the most common endocrine malignancy, generally associated with excellent long-term survival. Hοwever, a subset of patients develοps advanced disease (aDTC), particularly when refractοry to radioactive iodine (RAIR), which poses significant therapeutic challenges and wοrse outcomes. Accurate, individualized assessment οf treatment respοnse is essential for optimizing patient management. This review summarizes current principles fοr biοmarker- and imaging-based evaluation of aDTC. Serum thyroglobulin (Tg) and anti-thyroglobulin antibodies (TgAb), including their dynamic changes οver time, remain central biomarkers for detecting persistent, recurrent, or metastatic disease. Mοlecular profiling, including BRAF, TERT, and RAS mutatiοns, provides additional prognοstic and predictive information and guides the use of targeted therapies. Imaging modalities, including post-therapy radioiodine whole-body scans (WBS), single-phοton emission computed tomography/computed tomography (SPECT/CT), 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT), and emerging tracers such as 68Ga-DOTATATE and PSMA PET/CT, οffer complementary anatomical and functional data for respοnse assessment, particularly in RAIR or metabοlically active disease. Current guidelines recommend integrating biomarker trends with imaging findings within a dynamic risk stratification framework to guide individualized treatment decisiοns. Despite well-established recοmmendations, real-world application remains variable due to patient heterogeneity and center-specific resources. Emerging imaging modalities, quantitative PET metrics, and artificial intelligence (ΑΙ) –assisted approaches hold prοmise for enhancing prognostic accuracy and personalizing fοllow-up and therapy.

Cοnclusions: Integrating biomarkers, molecular profiling, and advanced imaging within a dynamic, patient-centered framework is essential for accurate response assessment and optimal management of advanced differentiated thyroid carcinoma.

Introduction

Differentiated thyroid carcinoma (DTC), is the most common endocrine malignancy, accounting for approximately 90–95% of thyroid malignancies, with papillary and follicular types comprising the major histological forms. While the long-term prognosis is excellent (10-year disease-specific survival >90%), when appropriate treatment is given, a subset of patients develops persistent, recurrent, or metastatic disease.1 Advanced DTC (aDTC), especially when refractory to radioactive iodine (RAIR) therapy, presents significant therapeutic challenges and worse outcomes.2 The incidence of advanced presentations is increasing—partly due to earlier detection of primary disease and longer survival of patients—thus leading to a growing number of individuals living with biochemically or structurally active disease and emphasising the need for accurate, personalized response-assessment strategies.3

During past decades, DTC management has undergone substantial evolution, with Nuclear Medicine (NM) maintaining a central role in diagnosis, therapy, and follow-up. The Society of Nuclear Medicine and Molecular Imaging (SNMMI)/ European Association of Nuclear Medicine (EANM) Practice Guideline for Nuclear Medicine Evaluation and Therapy of Differentiated Thyroid Cancer (2022) established an integrated, evidence-based framework covering individualized patient management and selection, patient preparation, radioiodine (RAI) therapy, post-treatment imaging and follow-up.4 The EANM perspective comparing this guideline with the European Thyroid Association (ETA) Consensus Statement details both alignment and differences between endocrine-oncology and nuclear-medicine approaches. These guidelines highlight key differences and emphasizes the identification of RAIR disease, individualized patient selection, post-therapy dosimetry, and the use of 18F-FDG PET/CT for response evaluation.5 However, real-world applicability of guidelines is variable: a recent study by our group found that strict guideline adherence may be limited by centre-specific resources and patient characteristics.6 The challenges and complexities of managing aDTC are underscored mainly by highlighting the limitations of static risk stratification (SRS) models. Complementary data on dynamic risk stratification (DRS) indicate that continuous reassessment based on biomarker and imaging response offers a more realistic surveillance model than static baseline classification.7 Taken together, this evidence reveals a fragmented landscape of recommendations which—while valuable—can present contradictions in terms of ablation indication, response criteria and follow-up intensity, particularly for aDTC patients. Harmonising these perspectives through evidence-based and practically applicable criteria is therefore essential. This review aims to synthesize response-evaluation principles in aDTC, integrating international guidelines with real-world experience and highlighting areas where further alignment and clarification are needed.

Risk stratification and advanced differentiated thyroid cancer criteria

Advanced disease accounts for 13%–15% of DTCs and is characterized by a worse prognosis and more challenging management.8 Accurate risk stratification is fundamental for identifying patients with aDTC and guiding personalized management approaches. High-risk disease is generally defined according to the 2015 American Thyroid Association (ATA) guidelines as tumors with extrathyroidal extension, aggressive histology, large-volume nodal or distant metastases, or incomplete response to initial therapy.9 This classification is crucial for tailoring surveillance intensity and therapeutic interventions, including the use of adjuvant radioiodine therapy and consideration of systemic therapies in refractory cases.

Although, aDTC is a term used to describe aggressive tumors, there is significant variability of its accurate definition among specialties. In general, surgeons define advanced thyroid cancers as tumors that are surgically unresectable, endocrinologists use the term to describe RAIR disease, and oncologists apply it when distant metastases are present.10 A recent consensus statement by the American Head and Neck Society (AHNS) Endocrine Surgery Section and International Thyroid Oncology Group defined advanced thyroid cancer according to four categories. The structural/surgical category includes the following: (1) bulky, invasive, or inoperative locoregional disease; (2) recurrence; (3) distant metastases; (4) gross residual neck disease without option for reoperation; (5) rapid progression on imaging; and (6) imminent threat posed by tumor burden. The biochemical category encompasses: tumors refractory to RAI -including disease that either fails to uptake RAI initially or loses this ability after prior therapy, as well as patients who have received high cumulative doses (e.g., >600 mCi) with minimal benefit from further RAI -, unresponsive to thyroid-stimulating hormone (TSH) suppression, and rapid calcitonin, carcinoembryonic antigen, or thyroglobulin doubling times. The histologic/molecular category includes findings such as poorly differentiated or other aggressive histology components, high Ki67 index, high mitotic count or tumor necrosis, and all anaplastic thyroid carcinoma.11 Molecular and genetic features further refine the identification of aDTC, with BRAF V600E mutations associated with decreased RAI avidity and poorer outcomes, and TERT promoter or TP53 alterations correlating with more aggressive tumor behavior.12 RET and NTRK rearrangements may inform potential targeted therapy options.13 Finally, tumors can be categorized as advanced thyroid cancer at the discretion of the treating physician if there are features that portend aggressive tumor behavior.

These criteria help identify patients likely to experience more aggressive disease, guiding both imaging, follow-up and therapeutic decisions. The integration of molecular, imaging, and RAI responsiveness data is therefore essential for individualized patient selection and therapeutic planning. Collectively, these features delineate the subset of DTC patients in whom standard approaches are insufficient, highlighting the need for continuous risk reassessment, dynamic response evaluation, and tailored interventions. This framework naturally sets the stage for biomarker-based assessment, which is discussed in the following section.

Biomarker based evaluation of aDTC

Serum thyroglobulin

Biomarkers play a central role in the assessment and management of aDTC, providing dynamic insights into disease burden, response to therapy and prognosis. Serum thyroglobulin (Tg) remains the cornerstone biomarker, especially after total thyroidectomy and radioiodine ablation, providing critical information on persistent, recurrent, or metastatic disease. Multiple studies have demonstrated that elevated postoperative Tg levels following total thyroidectomy and radioactive iodine (RAI) remnant ablation are strongly associated with higher risk of recurrence and advanced disease. Specifically, a TSH-stimulated Tg exceeding 1–2 ng/mL at the time of ablation has been consistently identified as an independent predictor of persistent or recurrent disease, with risk escalating alongside increasing Tg concentrations.14 Other data suggest that postoperative Tg values in the range of 20–30 ng/mL optimize sensitivity and specificity for predicting disease recurrence.15 High postoperative Tg values (>10–30 ng/mL) are additionally associated with poorer survival. On the other hand, Tg values below 1–2 ng/mL strongly predict remission, even among ATA low- and intermediate-risk patients who did not receive RAI ablation9. Elevated or rising Tg levels indicating persistent or recurrent disease, should always be assessed in patients with negative anti-thyroglobulin antibodies (anti-TgAb) and post-thyroidectomy status. The utility of Tg must be interpreted in the context of RAI treatment history and imaging findings, as low or undetectable Tg levels may not reliably exclude disease in patients with poorly differentiated or RAI-refractory tumors. Therefore, dynamic risk stratification, both post-ablative and during long-term follow-up, is of great importance not only for the detection of advanced disease but also for its appropriate management and monitoring.

Beyond absolute Tg levels, dynamic changes over time—particularly Tg doubling time (Tg-DT), provide additional prognostic granularity. While DTC often has an indolent course, recurrences occur in up to 20% of patients, with 10% potentially resulting in mortality.6 Tg-DT offers independent predictive value for loco-regional recurrence, distant metastases, and overall survival, supplementing traditional prognostic indicators such as TNM stage, age, and gender. A Tg-DT shorter than 1 year consistently correlates with higher recurrence rates and disease progression, whereas longer doubling times generally reflect more favorable outcomes.16 Furthermore, Tg-DT has been shown to predict findings on 18F-FDG PET/CT in patients with detectable Tg but negative radioiodine scans, aiding in the detection of clinically significant disease that may otherwise remain occult.17 Together, postoperative Tg levels and Tg-DT provide a complementary framework for refining risk stratification in advanced DTC, guiding patient-specific decisions on imaging, RAI therapy, and ongoing surveillance. Their integration into dynamic risk assessment models enhances the ability to predict treatment response, identify persistent or recurrent disease, and personalize management strategies in complex cases of advanced DTC.

In recent years another prognostic indicator, the thyroglobulin-to-thyrotropin (Tg/TSH) ratio, has been increasingly explored. Several studies have suggested that this ratio may refine patient stratification and optimize post-thyroidectomy management by identifying those less likely to achieve successful ablation. In their study, Trevizam and colleagues challenged the hypothesis that both serum Tg and the Tg/TSH ratio could reliably predict the therapeutic success of RAI ablation in DTC patients, proposing cut-off values of 4.41 ng/mL for Tg and 0.093 for the Tg/TSH ratio. After multivariate adjustment, only Tg retained independent prognostic significance for ablation outcomes, suggesting limited incremental value of the ratio itself under certain clinical conditions.18 Subsequent investigations, however, have provided complementary evidence supporting the Tg/TSH ratio as an independent determinant of ablation success. Lin et al. identified the Tg/TSH ratio as a predictive factor for treatment failure in DTC patients, emphasizing its clinical utility as an easily calculable and cost-effective variable during TSH stimulation protocols, to early detect advanced disease.19 Collectively, these findings suggest that the Tg/TSH ratio may serve as a complementary biomarker to Tg in anticipating ablation outcomes, particularly in patients at intermediate risk, though further prospective validation is warranted before its integration into standardized response-assessment algorithms.

Anti-thyroglobulin antibodies as surrogate tumor markers

Another fundamental biomarker for the evaluation of advanced disease and assessment of therapeutic response in differentiated thyroid carcinoma is the presence and behavior of TgAb.20 It not only is a critical marker in the biochemical evaluation of DTC, but can also markedly influence the interpretation of serum Tg levels.21 Their presence interferes with most immunometric Tg assays, often producing spuriously low or undetectable Tg values that may obscure evidence of persistent or recurrent disease.22 Consequently, the 2015 American Thyroid Association (ATA) guidelines emphasize that Tg should only be used as a reliable biomarker for disease monitoring in patients with negative TgAb, while TgAb themselves should be measured concurrently at every follow-up and interpreted as an independent surrogate marker of disease activity.9 Fluctuations in TgAb titers have been shown to correlate with disease status: stable, rising or de novo appearance of serum TgAb concentrations may indicate persistent or recurrent disease even when Tg is undetectable and prompts additional investigations.23 Spencer et al. demonstrated that TgAb persistence beyond 1 year post-thyroidectomy is associated with an increased likelihood of structural disease detection on imaging.21

In the context of advanced aDTC, TgAb monitoring remains clinically valuable, particularly in patients with RAIR disease where Tg may not accurately reflect tumor burden. Serial TgAb trends, when interpreted alongside imaging modalities such as 18F-FDG PET/CT, can assist in detecting subclinical disease progression or therapeutic response.24 Moreover, TgAb kinetics have been proposed as a biomarker of immune and tumor dynamics, offering complementary information to Tg and imaging-based findings. In a pivotal study, Morbelli and colleagues provided novel insights into the biological significance of TgAb behavior, demonstrating that patients with increasing TgAb titers over time exhibited greater tumor glucose metabolism as measured by 18F-FDG PET/CT. Significantly higher TgAb concentrations were observed in individuals with both radioiodine- and FDG-avid lesions, suggesting that persistent or rising antibody levels may reflect ongoing Tg secretion from metabolically active tumor tissue. Conversely, iodine-refractory patients with FDG-avid but non–iodine-avid disease did not exhibit higher TgAb titers compared to patients with no evidence of disease, indicating a possible link between TgAb production and the maintenance of some degree of tumor differentiation. Accordingly, TgAb kinetics may serve as a valuable adjunct for monitoring disease progression in RAIR DTC—particularly in patients where Tg measurements are unreliable—providing a biochemical correlate to metabolic imaging findings.25

Molecular and genomic biomarkers: BRAF, TERT, RAS, and emerging predictive mutational signatures

Recent advances in molecular oncology have broadened the biomarker landscape of DTC beyond traditional serum markers. Somatic mutations in BRAF, TERT, and RAS genes have been extensively investigated for their prognostic and predictive implications, particularly in advanced and RAIR disease.26 The coexistence of BRAF, V600E and TERT promoter mutations has been associated with a synergistic effect, conferring more aggressive biological behavior, increased risk of recurrence, and reduced overall survival.27 Similarly, RAS mutations, often linked to follicular-patterned or poorly differentiated variants, have been correlated with distinct molecular phenotypes and therapeutic vulnerabilities.28 These molecular alterations not only inform disease biology but also guide the application of targeted systemic therapies. In RAIR-DTC, identification of BRAF or RET/PTC alterations may predict sensitivity to multikinase inhibitors such as sorafenib29 and lenvatinib30 whereas NTRK and RET fusions can direct the use of highly selective inhibitors with durable response profiles.31 Furthermore, recent studies have demonstrated that dynamic biomarker assessment—integrating molecular signatures, Tg/TgAb trends, and metabolic imaging—enables a comprehensive evaluation of therapeutic response, particularly in patients undergoing targeted or immunotherapeutic interventions.32 Combining Tg/TgAb trends with molecular profiling and 18F-FDG PET/CT uptake allows clinicians to identify RAIR phenotypes at an earlier stage, predict outcomes more accurately, and guide individualized follow-up schedules or therapeutic escalation. Early detection of molecularly aggressive clones can inform decisions regarding the timing of targeted therapy or enrollment in clinical trials, thereby optimizing patient-centered care in aDTC.33 Consequently, the integration of traditional and molecular biomarkers provides a multidimensional framework for response assessment, facilitating early detection of disease evolution, optimization of therapy intensity, and real-time personalization of patient management in aDTC.

Imaging based evaluation of aDTC

Anatomical and functional imaging is fundamental for the evaluation and longitudinal management of aDTC, complementing biochemical and molecular biomarkers. Nuclear medicine imaging remains pivotal, particularly through post-therapy RAI scans and 18F-FDG PET/CT, enabling assessment of residual thyroid tissue, metastatic spread, and identification of RAIR disease. Post-therapy RAI scans provide both functional and semi-quantitative information on iodine-avid lesions, guiding decisions on subsequent RAI therapy and long-term surveillance. In contrast, 18F-FDG PET/CT is particularly valuable in patients with elevated Tg or TgAb but negative RAI scans, as it detects metabolically active, dedifferentiated lesions that may not concentrate iodine, thereby identifying high-risk phenotypes and guiding targeted interventions.4,9

Anatomical imaging modalities

Anatomical imaging modalities, including high-resolution ultrasound (US), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI), complement functional imaging by providing precise lesion localization, characterization, and measurement for treatment planning. Their integration is critical for accurate staging, response assessment, and therapeutic decision-making in complex aDTC cases. Neck US remains the first-line modality for the diagnosis of (a)DTC, for detecting persistent disease or loco-regional recurrences, particularly in cervical lymph nodes. According to the ATA Guidelines, following surgery, cervical US to evaluate the thyroid bed and central and lateral cervical nodal compartments should be performed at 6–12 months and then periodically. In cases where advanced disease is identified, whether in the context of persistent disease or de novo recurrence, the disease burden should be thoroughly assessed in combination with other biomarkers, as discussed, and always within the framework of DRS. This approach ensures that individualized therapeutic decisions are made appropriately. For example, if a positive finding would alter management, ultrasonographically suspicious lymph nodes ≥8–10 mm in the smallest diameter should be biopsied for cytology, with concomitant thyroglobulin measurement in the needle washout fluid.9 At this point, we will not elaborate on the broad and well-established role of US in the diagnostic work-up of thyroid nodules and the preoperative assessment of thyroid cancer. It is well recognized that US, with its high spatial resolution, provides detailed visualization not only of the thyroid gland itself but also of all cervical lymph node compartments and adjacent structures. This allows for both accurate diagnosis and, to some extent, initial staging of the disease. Using TIRADS criteria, elastography, and Doppler techniques, ultrasound yields valuable, precise, and reproducible information without exposing the patient to ionizing radiation or invasive procedures. Since the present section focuses on the response assessment of aDTC, we will not further discuss these diagnostic features of ultrasound but will instead examine the other imaging modalities that contribute to this clinical objective.

Cross-sectional imaging is essential for evaluating mediastinal, pulmonary, and osseous disease. ATA guidelines strongly recommend that they should be considered (i) in the setting of bulky and widely distributed recurrent nodal disease where US may not completely delineate disease, (ii) in the assessment of possible invasive recurrent disease where potential aerodigestive tract invasion requires complete assessment, (iii) when neck US is felt to be inadequately visualizing possible neck nodal disease (high Tg, negative neck US), (iv) in high risk DTC patients with elevated serum Tg (generally >10 ng/ mL) or rising Tg antibodies with or without negative RAI imaging or (v). Imaging of other organs including MRI brain, MR skeletal survey, and/or CT or MRI of the abdomen should be considered in high-risk DTC patients with elevated serum Tg (generally >10 ng/mL) and negative neck and chest imaging who have symptoms referable to those organs or who are being prepared for TSH-stimulated RAI therapy (withdrawal or rhTSH) and may be at risk for complications of tumor swelling.9 The TENIS syndrome—i.e., elevated serum thyroglobulin with negative iodine scintigraphy—represents the principal indication for performing cross-sectional imaging, according to the SNMMI/EANM guidelines. In investigating the pathophysiology and clinical implications of this syndrome, the authors propose that the development of an appropriate treatment plan should be guided by four sequential steps: (1) ruling out false-negative whole-body scans (WBS) and false-positive thyroglobulin results; (2) re-stratifying patient risk; (3) obtaining non-radioiodine imaging; and (4) individualizing management based on the location and burden of metastatic disease.4 Consequently, it is evident that cross-sectional imaging is primarily indicated for advanced disease and not for low- or intermediate-risk DTC patients. Importantly, both the decision to perform CT or MRI and the interpretation of these results to guide appropriate therapeutic strategies must always be contextualized alongside biomarker data and the overall disease trajectory, within a continuous, dynamic risk stratification framework.

Functional imaging modalities

Current guidelines emphasize a risk-adapted, multimodality imaging strategy, recommending imaging selection and timing based on disease stage, prior treatment history, and Tg/TgAb trends. The 2022 SNMMI/EANM Practice Guideline4 advises post-therapy RAI scans for all RAI-treated patients, while ATA guidelines9 substantially restrict its application. Specifically, routine Whole Body Scan (WBS) is not recommended for low- and intermediate-risk patients with undetectable Tg, negative anti-Tg antibodies, and a negative neck ultrasound—essentially the majority of DTC cases—being reserved only for selected high- or intermediate-risk individuals where persistent disease is suspected. This restriction markedly reduces the role of nuclear medicine in the longitudinal assessment of a large proportion of patients, potentially overlooking subclinical disease which may lead to advanced disease and limiting opportunities for early intervention. In this context, the EANM declined to endorse these recommendations, citing their inherent limitations, while numerous studies have highlighted the potential risks associated with omitting whole-body scintigraphy during follow-up—even in patients with low- or intermediate-risk disease. 34 Indeed, it is not uncommon for cases initially classified as indolent to be recharacterized or to evolve into aDTC, a development often unveiled through the use of WBS, in the context of DRS.35

In our opinion, post-therapy 131I WBS remains fundamental in the assessment of aDTC, providing an initial evaluation of disease distribution and identifying iodine-avid metastases. WBS provides a global functional overview of RAI uptake, enabling the detection of previously unknown metastatic foci and informing subsequent management decisions. However, planar WBS has intrinsic limitations, including suboptimal anatomical localization and difficulty differentiating physiologic from pathologic uptake, which can hinder accurate response assessment in patients with complex or extensive disease. Single-photon emission computed tomography/computed tomography (SPECT/CT), as an extension of WBS, overcomes many of these limitations by integrating functional and anatomical information in a single examination. This hybrid modality allows precise localization of metastatic lesions, particularly in the cervical and mediastinal regions, and distinguishes true disease from non-specific uptake or physiologic activity. Several studies have demonstrated that post-therapy 131I SPECT/CT improves lesion detection rates, alters clinical management in a significant proportion of patients, and enhances response evaluation in aDTC. Heinrich et al. showed that post-therapy 131I SPECT/CT provides prognostic information regarding lymph node metastases and can influence management decisions, including early surgical interventions or targeted therapy selection.36 Wong et al. reported that SPECT/CT significantly improves detection and characterization of metastatic lymph nodes and distant metastases, facilitating personalized treatment strategies.37 Additional studies confirm that SPECT/CT enhances lesion detection, informs therapeutic response assessment, and enables dynamic monitoring of iodine-refractory disease.38 Importantly, SPECT/CT is particularly valuable when serum thyroglobulin or TgAb levels indicate persistent or recurrent disease, providing a biochemical–imaging correlation that supports dynamic risk stratification and personalized treatment planning, making it indispensable for comprehensive response assessment in patients with advanced or RAI-refractory thyroid cancer.

Although 18F-FDG PET/CT is not the imaging modality of choice for the initial evaluation or routine follow-up of DTC, it has emerged as a pivotal imaging modality for evaluating treatment response of aDTC, particularly in cases exhibiting RAIR characteristics. While traditional imaging techniques, such as CT, primarily assess anatomical changes, 18F-FDG PET/CT provides functional insights by detecting metabolic activity indicative of viable malignant tissue. 18F-FDG-PET/CT imaging is particularly useful not only for identification and localization of non_iodine avid disease, but has also for predicting the course of disease, as aggressive or indolent. It has demonstrated prognostic value for survival in metastatic DTC predicting survival disadvantage for patients with positive PET as compared with those with a negative PET scans.39 Clinical studies have demonstrated that 18F-FDG PET/CT provides superior prognostic information compared to morphological imaging in patients with RAIR DTC undergoing tyrosine kinase inhibitor (TKI) therapy, such as lenvatinib. Ahmaddy et al. (2021) reported that metabolic response assessed via 18F-FDG PET/CT was more closely correlated with progression-free survival (PFS) and disease-specific survival (DSS) than morphological response assessed by CT, highlighting its utility in monitoring therapeutic efficacy in this patient cohort.40 Furthermore, semiquantitative parameters derived from 18F-FDG PET/CT, including standardized uptake values (SUVmax, SUVmean), total metabolic tumor volume (tMTV), and total lesion glycolysis (tTLG), have been identified as significant prognostic factors in RAIR DTC. Phuong et al. (2024) found that elevated SUVmax (>6.39 g/ml), SUVmean (>3.68 g/ml), tMTV (>1.24 cm³), and tTLG (>4.23 cm³) were associated with poorer PFS, underscoring the importance of these metrics in risk stratification and treatment planning.41

The EANM/SNMMI guidelines advocate for the use of 18F-FDG PET/CT in patients with TENIS syndrome, as it facilitates the detection of recurrent or metastatic disease that may be missed by conventional imaging. Additionally, these guidelines suggest that 18F-FDG PET/CT can be instrumental in assessing treatment response, particularly in the context of RAIR DTC, by providing functional imaging that complements anatomical findings.4 The 2015 ATA guidelines explicitly recommend consideration of 18F-FDG PET/CT in patients with rising or persistently elevated serum Tg and negative RAI imaging, particularly when Tg elevation is substantial and the result would alter management. The ATA also recognizes FDG positivity as a marker of more aggressive, less iodine-avid disease and as a prognostic indicator in metastatic DTC.9 In practice, many authors and guideline summaries note that an approximate Tg threshold (commonly cited ∼10 ng/mL, though exact cut-offs vary by context and assay) may be used to increase the diagnostic yield of PET/CT in the workup of suspected occult disease.42 Taken together, the societies converge on the principal indication (TENIS), but differ in emphasis: SNMMI/EANM emphasize the routine availability and utility of FDG PET/CT within a nuclear-medicine–driven algorithm for RAIR disease, whereas the ATA frames PET/CT use more selectively — as an investigation to be pursued when PET findings would change patient management and when biochemical (Tg/TgAb) and clinical features support its yield. In conclusion, 18F-FDG PET/CT serves as an invaluable tool in the response assessment of aDTC, offering functional imaging capabilities that enhance prognostication and inform therapeutic decision-making. Its integration into clinical practice, alongside traditional imaging modalities, is essential for the comprehensive management of patients with aDTC.

Νon-radioiodine, non-18F-FDG molecular imaging agents have expanded the armamentarium for assessing treatment response in aDTC. Somatostatin-receptor (SSTR) PET (e.g., 68Ga-DOTATATE/68Ga-DOTANOC) can detect SSTR-expressing thyroid lesions and may be useful for lesion localization and for selecting patients amenable to peptide-receptor radionuclide therapy (PRRT) in selected cases where conventional imaging is inconclusive.43 Recent series and reviews indicate that SSTR-PET may complement 18F-FDG by identifying a distinct biologic subset of lesions with preserved receptor expression and potentially different therapeutic options.44 Furthermore, other investigations, such as the study by Vrachimis et al., demonstrated the superiority of 18F-FDG PET/CT οver conventional imaging modalities like MRI in the assessment of RAIR-DTC. Specifically, 18F-FDG PET/CT exhibited higher sensitivity, particularly for detecting pulmonary metastases, where its metabolic imaging capability provided a significant diagnostic advantage. When evaluating extrapulmonary disease, 68Ga-DOTATATE PET/MRI appeared more sensitive, while 18F-FDG PET/CT retained greater specificity, suggesting complementary rather than competitive roles for these two modalities. Nοtably, diffusion-weighted MRI (DWI) offered no incremental diagnostic value and could not substitute for 18F-FDG PET/CT in postoperative monitoring of patients with suspected or established RAIR-DTC.45

Similarly, prοstate-specific membrane antigen (PSMA) PET/CT and fibroblast-activation protein inhibitor (FAPI) PET tracers have shown promising performance in aDTC. 68Ga-PSMA PET/CT has identified lesiοns not always seen on FDG or RAI scans and has, in individual cases, directed consideration of 77Lu-PSMA therapy.46 TENIS patients seem to have been benefited mostly by PSMA-targeted imaging and radionuclide therapy.47 Other tracers such as 18F-DOPA have an established role in medullary disease and occasional utility in selected DTC biology, but evidence in aDTC is limited compared with the above agents.48 These tracers should be considered when conventional iodine and FDG imaging are non-diagnostic, when tracer biology may alter management (e.g., eligibility for PRRT or PSMA-directed therapy), or when enhanced lesion detection would change the therapeutic plan. Current guidelines and recent literature recommend a tailored, multidisciplinary approach—integrating tracer selection with Tg/TgAb trends, prior RAI response, and molecular profile—to maximize the clinical yield of advanced PET/SPECT imaging in response assessment of aDTC.

Response criteria and real-world applicability in aDTC

The management and assessment of aDTC present unique challenges due tο disease heterogeneity, variable iοdine avidity, and the emergence of RAIR and metastatic phenotypes. In such contexts, conventional biochemical and structural parameters may lose prognostic precision, necessitating the integration of molecular imaging, dοsimetric, and targeted therapeutic data into the response evaluation framework.

It is beyond the scope of the present article to catalog here the already established response-to-therapy criteria as proposed by the ATA9, ETA5, and EANM/SNMMI4. Considering these criteria as well known, we will limit ourselves to highlighting the following points: Despite their widespread adoption, the response classification systems encounter limitations in the setting of aDTC:

• •

  Many patients with RAIR-DTC present with metabοlic disease detected via 18F-FDG PET/CT rather than classical iodine avid lesions, complicating the structural incomplete vs biochemical incomplete categorization.

• •

  Real-world practice may diverge frοm guideline thresholds (e.g., Tg cut-offs, imaging timing) due to assay variability, availability of imaging modalities, and centre-specific workflows.

• •

  Dynamic risk stratification (DRS) toοls, which integrate response categories with ongoing surveillance data, may offer superior prognostic discrimination compared with static initial risk stratification alone.49

Given the rapid therapeutic evolution in advanced DTC (targeted therapies, immunotherapy, dosimetric approaches), response classification systems must remain adaptable and must be interpreted within the broader context of patient-specific disease biology and treatment trajectory.

Future directions

The management of aDTC is evοlving rapidly, driven by the integration of novel imaging modalities, molecular biomarkers, and computational tools aimed at enhancing risk-adapted surveillance and individualized therapy. Emerging strategies focus on leveraging multi-dimensional data to improve early detection of progression, optimize therapy selection, and predict response in RAIR and metabolically active disease.

Beyοnd conventional 131I and 18F-FDG PET/CT, new radiotracers are being investigated for their capacity to detect DTC lesions that are poοrly iodine-avid or FDG-avid, offering complementary prognostic information. Furthermore, hybrid imaging approaches and the application of quantitative PET parameters, including total lesion glycolysis and SUV metrics, enhance risk stratification and guide the timing and intensity of systemic or locoregional interventions.50

Machine learning and AI-assisted algorithms are increasingly applied to integrate imaging, molecular, and biochemical data, aiming to predict therapeutic response and personalize follow-up protocols. Early studies suggest that AI-based models can outperform traditional risk stratification in identifying patients at high risk for progression or recurrence, particularly in RAIR-DTC.51 Such predictive tools may also assist in optimizing the timing of repeat radioiodine therapy versus systemic interventions and in guiding individualized dosimetry planning.

Conclusions

Biomarker- and imaging-based assessment remains central tο the management of aDTC. Serum Tg and TgAb, particularly their dynamic trends, provide critical prognostic and predictive information, complementing structural imaging findings and guiding clinical decision-making. Integratiοn of molecular and genomic markers, including BRAF, TERT, and RAS mutations, οffers further potential to persοnalize risk stratification and therapy selection, particularly in radioiodine-refractory disease. Despite well-established guidelines from the ATA, ETA, and EANM/SNMMI, real-world applicability remains variable, particularly for high-risk or refractory cases, due to center-specific resources, patient characteristics, and heterogeneity in follow-up protocols. Prοspective, multicenter studies are needed to validate and refine current response criteria, integrating dynamic biοmarkers, advanced imaging, and molecular profiling to optimize individualized surveillance and therapeutic strategies.

In conclusion, dynamic, patient-centered evaluatiοn combining serοlogic, imaging, and mοlecular data is essential fοr accurate response assessment in aDTC. The οngoing challenge is tο harmonize guideline recοmmendations with real-world clinical practice, while leveraging emerging biomarkers and imaging techniques to improve prognostic precisiοn and inform therapy in this cοmplex patient pοpulation.

CRediT authorship contribution statement

Savvas Frangos: Writing – original draft, Writing – review & editing. Evanthia Giannoula: Writing – original draft, Writing – review & editing. Ioannis Iakovou: Writing – original draft, Writing – review & editing.

Declaration of competing interest

We declare the use of generative AI in the manuscript preparation process.