Diagnostic, Theranostic and Prognostic Value of Thyroglobulin in Thyroid Cancer.

Thyroglobulin (Tg) is an iodinated glycoprotein, which is normally stored in the follicular colloid of the thyroid, being a substrate for thyroid hormone production. Since it is produced by well-differentiated thyroid cells, it is considered a reliable tumor marker for patients with differentiated thyroid carcinoma (DTC) during their follow-up after total thyroidectomy and radioiodine ablation. It is used to monitor residual disease and to detect recurrent disease. After total thyroid ablation, unstimulated highly sensitive Tg measurements are sufficiently accurate to avoid exogenous or endogenous thyrotropin (TSH) stimulation and provide accurate diagnostic and prognostic information in the great majority of DTC patients. Adopting sophisticated statistical analysis, i.e., decision tree models, the use of Tg before radioiodine theranostic administration was demonstrated to be useful in refining conventional, pathology-based risk stratification and providing personalized adjuvant or therapeutic radioiodine administrations. The follow-up of DTC patients aims to promptly identify patients with residual or recurrent disease following primary treatment. Our review paper covers the diagnostic, theranostic and prognostic value of thyroglobulin in DTC patients.

Thyroglobulin measurement is the most powerful outcome predictor in differentiated thyroid cancer: a decision tree analysis in a European multicenter series.

OBJECTIVES: An accurate prognostic assessment is pivotal to adequately inform and individualize follow-up and management of patients with differentiated thyroid cancer (DTC). We aimed to develop a predictive model for recurrent disease in DTC patients treated by surgery and 131I by adopting a decision tree model. METHODS: Age, sex, histology, T stage, N stage, risk classes, remnant estimation, thyroid-stimulating hormone (TSH), thyroglobulin (Tg), administered 131I activities and post-therapy whole body scintigraphy (PT-WBS) were identified as potential predictors and put into regression algorithm (conditional inference tree, c-tree) to develop a risk stratification model for predicting persistent/recurrent disease over time. RESULTS: The PT-WBS pattern identified a partition of the population into two subgroups (PT-WBS positive or negative for distant metastases). Patients with distant metastases exhibited lower disease-free survival (either structural, DFS-SD, and biochemical, DFS-BD, disease) compared to those without metastases. Meanwhile, the latter were further stratified into three risk subgroups based on their Tg values. Notably, Tg values >63.1 ng/mL predicted a shorter survival time, with increased DFS-SD for Tg values <63.1 and <8.9 ng/mL, respectively. A comparable model was generated for biochemical disease (BD), albeit different DFS were predicted by slightly different Tg cutoff values (41.2 and 8.8 ng/mL) compared to DFS-SD. CONCLUSIONS: We developed a simple, accurate and reproducible decision tree model able to provide reliable information on the probability of structurally and/or biochemically persistent/relapsed DTC after a TTA. In turn, the provided information is highly relevant to refine the initial risk stratification, identify patients at higher risk of reduced structural and biochemical DFS, and modulate additional therapies and the relative follow-up.

Theranostics of Thyroid Cancer.

Molecular imaging is pivotal in evaluating and managing patients with different thyroid cancer histotypes. The existing, pathology-based, risk stratification systems can be usefully refined, by incorporating tumor-specific molecular and molecular imaging biomarkers with theranostic value, allowing patient-specific treatment decisions. Molecular imaging with different radioactive iodine isotopes (ie, I131, I123, I124) is a central component of differentiated carcinoma (DTC)'s risk stratification while [18F]F-fluorodeoxyglucose ([18F]FDG) PET/CT is interrogated about disease aggressiveness and presence of distant metastases. Moreover, it is particularly useful to assess and risk-stratify patients with radioiodine-refractory DTC, poorly differentiated, and anaplastic thyroid cancers. [18F]F-dihydroxyphenylalanine (6-[18F]FDOPA) PET/CT is the most specific and accurate molecular imaging procedure for patients with medullary thyroid cancer (MTC), a neuroendocrine tumor derived from thyroid C-cells. In addition, [18F]FDG PET/CT can be used in patients with more aggressive clinical or biochemical (ie, serum markers levels and kinetics) MTC phenotypes. In addition to conventional radioiodine therapy for DTC, new redifferentiation strategies are now available to restore uptake in radioiodine-refractory DTC. Moreover, peptide receptor theranostics showed promising results in patients with advanced and metastatic radioiodine-refractory DTC and MTC, respectively. The current appropriate role and future perspectives of molecular imaging and theranostics in thyroid cancer are discussed in our present review.

Integrated Diagnostics of Thyroid Nodules.

Thyroid nodules are common findings, particularly in iodine-deficient regions. Our paper aims to revise different diagnostic tools available in clinical thyroidology and propose their rational integration. We will elaborate on the pros and cons of thyroid ultrasound (US) and its scoring systems, thyroid scintigraphy, fine-needle aspiration cytology (FNAC), molecular imaging, and artificial intelligence (AI). Ultrasonographic scoring systems can help differentiate between benign and malignant nodules. Depending on the constellation or number of suspicious ultrasound features, a FNAC is recommended. However, hyperfunctioning thyroid nodules are presumed to exclude malignancy with a very high negative predictive value (NPV). Particularly in regions where iodine supply is low, most hyperfunctioning thyroid nodules are seen in patients with normal thyroid-stimulating hormone (TSH) levels. Thyroid scintigraphy is essential for the detection of these nodules. Among non-toxic thyroid nodules, a careful application of US risk stratification systems is pivotal to exclude inappropriate FNAC and guide the procedure on suspicious ones. However, almost one-third of cytology examinations are rendered as indeterminate, requiring "diagnostic surgery" to provide a definitive diagnosis. 99mTc-methoxy-isobutyl-isonitrile ([99mTc]Tc-MIBI) and [18F]fluoro-deoxy-glucose ([18F]FDG) molecular imaging can spare those patients from unnecessary surgeries. The clinical value of AI in the evaluation of thyroid nodules needs to be determined.

Autoimmune Thyroid Diseases.

Autoimmune thyroid diseases (AITDs) include a wide spectrum of thyroid diseases affecting more commonly women than men. The most frequent forms are Graves' Disease (GD) and Hashimoto's thyroiditis / Autoimmune Thyroiditis (AIT), but there are also other immunogenic destructive forms of thyroiditis, that is, silent and postpartum thyroiditis. In the last decade, AITDs and other inflammatory thyroid diseases related to anti-tumor molecular drugs are more frequently seen due to the widespread use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICPIs). Autoimmune thyroiditis related to SARS-CoV-2 infection has been a novel entity in recent years. Graves' Disease and AIT may shift from hyperthyroidism to hypothyroidism, which may complicate the differential diagnosis and further treatment strategy. Moreover, all AITDs may manifest with thyrotoxicosis (a clinical condition marked with high serum levels of thyroid hormones) which has to be distinguished from hyperthyroidism (increased thyroid hormone production and secretion as a result of hyperfunctioning thyroid gland) due to different therapeutic approaches. Nuclear medicine techniques, such as radioiodine uptake (RAIU) and thyroid scintigraphy, using 99mTc- pertechnetate (Na[99mTc]TcO4) or 123-Iodine (Na[123I]I), have a crucial role in the differential diagnosis. Measurement of thyroid antibodies, e.g. thyroid peroxidase antibodies (TPO) and thyrotropin receptor antibodies (TRAb), as well as thyroid ultrasound, are complementary methods in the evaluation of thyroid disorders.

Molecular Theranostics in Radioiodine-Refractory Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) is the most common subtype of thyroid cancer and has an excellent overall prognosis. However, metastatic DTC in certain cases may have a poor prognosis as it becomes radioiodine-refractory. Molecular imaging is essential for disease evaluation and further management. The most commonly used tracers are [18F]FDG and isotopes of radioiodine. Several other radiopharmaceuticals may be used as well, with different diagnostic performances. This review article aims to summarize radiopharmaceuticals used in patients with radioiodine-refractory DTC (RAI-R DTC), focusing on their different molecular pathways. Additionally, it will demonstrate possible applications of the theranostics approach to this subgroup of metastatic DTC.

Thyroglobulin and thyroglobulin antibody: an updated clinical and laboratory expert consensus.

OBJECTIVE: Thyroglobulin measurement is the cornerstone of modern management of differentiated thyroid cancer, with clinical decisions on treatment and follow-up based on the results of such measurements. However, numerous factors need to be considered regarding measurement with and interpretation of thyroglobulin assay results. DESIGN: The present document provides an integrated update to the 2013 and 2014 separate clinical position papers of our group on these issues. METHODS: Issues concerning analytical and clinical aspects of highly-sensitive thyroglobulin measurement will be reviewed and discussed based on an extensive analysis of the available literature. RESULTS: Thyroglobulin measurement remains a highly complex process with many pitfalls and major sources of interference, especially anti-thyroglobulin antibodies, need to be assessed, considered and, when necessary, dealt with appropriately. CONCLUSIONS: Our expert consensus group formulated 53 practical, graded recommendations for guidance on highly-sensitive thyroglobulin and TgAb in laboratory and clinical practice, especially valuable where current guidelines do not offer sufficient guidance.

The EANM guideline on radioiodine therapy of benign thyroid disease.

This document provides the new EANM guideline on radioiodine therapy of benign thyroid disease. Its aim is to guide nuclear medicine physicians, endocrinologists, and practitioners in the selection of patients for radioiodine therapy. Its recommendations on patients' preparation, empiric and dosimetric therapeutic approaches, applied radioiodine activity, radiation protection requirements, and patients follow-up after administration of radioiodine therapy are extensively discussed.

Thyroid Hormone Withdrawal versus Recombinant Human TSH as Preparation for I-131 Therapy in Patients with Metastatic Thyroid Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Differentiated thyroid carcinoma (DTC) is characterized by an excellent prognosis with a 10-year survival rate > 90%. However, when DTC develops in a metastatic form, it has been shown to significantly impact patient survival and quality of life. Although I-131 has been shown to be an effective therapy in patients with metastatic DTC, whether its efficacy after recombinant human TSH (rhTSH) is comparable to endogenous TSH stimulation by thyroid hormone deprivation (THW) is still debated. Our present study was prompted to compare clinical results obtained in metastatic DTC by I-131 administered after rhTSH and THW stimulation protocols, respectively. METHODS: A systematic search on PubMed, Web of Science, and Scopus was performed from January to February 2023. Pooled risk ratios with 95% CI were determined for evaluating the initial response after to I-131 therapy after preparation with rhTSH or THW and the disease progression. To track the accumulation of evidence and reduce type I errors because of small data, a cumulative meta-analysis was performed. A sensitivity analysis was also performed to examine the impact of individual studies on overall prevalence results. RESULTS: Ten studies were included with a total of 1929 patients pre-treated with rhTSH (n = 953) and THW (n = 976), respectively. The cumulative data of our systematic review and meta-analysis showed an increase in the risk ratio over the years without any change in favour of a pre-treatment or the other on the effectiveness of I-131 therapy of metastatic DTC. CONCLUSIONS: Our data suggest that pretreatment with rhTSH or THW has no significant impact on the effectiveness of I-131 therapy for metastatic DTC. This implies that concerns about the use of one or the other pretreatment should be deferred to clinical evaluations made considering patient characteristics and reduction in side effects.

Postoperative thyroglobulin as a yard-stick for radioiodine therapy: decision tree analysis in a European multicenter series of 1317 patients with differentiated thyroid cancer.

PURPOSE: An accurate postoperative assessment is pivotal to inform postoperative 131I treatment in patients with differentiated thyroid cancer (DTC). We developed a predictive model for post-treatment whole-body scintigraphy (PT-WBS) results (as a proxy for persistent disease) by adopting a decision tree model. METHODS: Age, sex, histology, T stage, N stage, risk classes, remnant estimation, TSH, and Tg were identified as potential predictors and were put into regression algorithm (conditional inference tree, ctree) to develop a risk stratification model for predicting the presence of metastases in PT-WBS. RESULTS: The lymph node (N) stage identified a partition of the population into two subgroups (N-positive vs N-negative). Among N-positive patients, a Tg value > 23.3 ng/mL conferred a 83% probability to have metastatic disease compared to those with lower Tg values. Additionally, N-negative patients were further substratified in three subgroups with different risk rates according to their Tg values. The model remained stable and reproducible in the iterative process of cross validation. CONCLUSIONS: We developed a simple and robust decision tree model able to provide reliable informations on the probability of persistent/metastatic DTC after surgery. These information may guide post-surgery 131I administration and select patients requiring curative rather than adjuvant 131I therapy schedules.

Bone health evaluation in primary hyperparathyroidism using dual-energy X-ray absorptiometry and trabecular bone score.

Bone involvement in primary hyperparathyroidism (PHPT) is characterized by reduced bone mineral density (BMD) using dual X-ray absorptiometry (DXA). A hallmark of PHPT is BMD loss at cortical sites while trabecular bone remains relatively preserved. PHPT is associated with increased fracture risk at both trabecular and cortical skeletal sites, which cannot be explained based on BMD values alone. The application of the trabecular bone score (TBS), an index of the lumbar spine DXA bone microarchitecture, showed lower TBS values and increased risk of fractures in PHPT patients, independent of BMD. Although further prospective studies are needed, promising data have been published with the use of TBS and some advanced DXA-based imaging modalities in patients with PHPT.

Accuracy of papillary thyroid cancer prognostic nomograms: a systematic review.

Objective: Current staging and risk-stratification systems for predicting survival or recurrence of patients with differentiated thyroid carcinoma may be ineffective at predicting outcomes in individual patients. In recent years, nomograms have been proposed as an alternative to conventional systems for predicting personalized clinical outcomes. We conducted a systematic review to evaluate the predictive performance of available nomograms for thyroid cancer patients. Design and methods: PROSPERO registration (CRD42022327028). A systematic search was conducted without time and language restrictions. PICOT questions: population, patients with papillary thyroid cancer; comparator prognostic factor, single-arm studies; outcomes, overall survival, disease-free survival, cancer-specific survival, recurrence, central lymph node metastases, or lateral lymph node metastases; timing, all periods; setting, hospital setting. Risk of bias was assessed through PROBAST tool. Results: Eighteen studies with a total of 20 prognostic models were included in the systematic review (90,969 papillary thyroid carcinoma patients). Fourteen models were at high risk of bias and four were at unclear risk of bias. The greatest concerns arose in the analysis domain. The accuracy of nomograms for overall survival was assessed in only one study and appeared limited (0.77, 95% CI: 0.75-0.79). The accuracy of nomograms for disease-free survival ranged from 0.65 (95% CI: 0.55-0.75) to 0.92 (95% CI: 0.91-0.95). The C-index for predicting lateral lymph node metastasis ranged from 0.72 to 0.92 (95% CI: 0.86-0.97). For central lymph node metastasis, the C-index of externally validated studies ranged from 0.706 (95% CI: 0.685-0.727) to 0.923 (95% CI: 0.893-0.946). Conclusions: Our work highlights the extremely high heterogeneity among nomograms and the critical lack of external validation studies that limit the applicability of nomograms in clinical practice. Further studies ideally using commonly adopted risk factors as the backbone to develop nomograms are required. Significance statement: Nomograms may be appropriate tools to plan treatments and predict personalized clinical outcomes in patients with papillary thyroid cancer. However, the nomograms developed to date are very heterogeneous, and their results seem to be closely related to the specific samples studied to generate the same nomograms. The lack of rigorous external validation procedures and the use of risk factors that sometimes appear to be far from those commonly used in clinical practice, as well as the great heterogeneity of the risk factors considered, limit the ability of nomograms to predict patient outcomes and thus their current introduction in clinical practice.

Free thyroxine measurement in clinical practice: how to optimize indications, analytical procedures, and interpretation criteria while waiting for global standardization.

Thyroid dysfunctions are among the most common endocrine disorders and accurate biochemical testing is needed to confirm or rule out a diagnosis. Notably, true hyperthyroidism and hypothyroidism in the setting of a normal thyroid-stimulating hormone level are highly unlikely, making the assessment of free thyroxine (FT4) inappropriate in most new cases. However, FT4 measurement is integral in both the diagnosis and management of relevant central dysfunctions (central hypothyroidism and central hyperthyroidism) as well as for monitoring therapy in hyperthyroid patients treated with anti-thyroid drugs or radioiodine. In such settings, accurate FT4 quantification is required. Global standardization will improve the comparability of the results across laboratories and allow the development of common clinical decision limits in evidence-based guidelines. The International Federation of Clinical Chemistry and Laboratory Medicine Committee for Standardization of Thyroid Function Tests has undertaken FT4 immunoassay method comparison and recalibration studies and developed a reference measurement procedure that is currently being validated. However, technical and implementation challenges, including the establishment of different clinical decision limits for distinct patient groups, still remain. Accordingly, different assays and reference values cannot be interchanged. Two-way communication between the laboratory and clinical specialists is pivotal to properly select a reliable FT4 assay, establish reference intervals, investigate discordant results, and monitor the analytical and clinical performance of the method over time.

Evolution of thyroid cancer biomarkers: from laboratory test to patients' clinical management.

Over the past three decades, laboratory medicine has significantly evolved thanks to technological advances made possible by new materials and evidence. Clinicians' ongoing requests for powerful, rapid, and minimally invasive tests has led manufacturers to develop rapid, accurate, and sensitive tests that can increase diagnostic accuracy and improve follow-up, bringing laboratory medicine ever closer to personalized medicine. The aim of this study was to critically review the main problems of the current Tg and CT biomarkers for the diagnosis/monitoring of DTC and MTC, respectively, and to identify the advantages and challenges of using the new laboratory biomarkers in the clinical management of patients with differentiated and medullary thyroid cancer. Insufficient harmonization of Tg and CT assays and lack of interchangeability of laboratory results and cutoff values pose challenges for comparability and standardization of procedures and methods. New diagnostic and monitoring approaches such as PCT or the Tg doubling time have proven to be effective. Close collaboration between clinicians and laboratory specialists remains essential to translate the advantages and limitations of current assays into appropriate clinical interpretation criteria. Over the years, the journal Clinical Chemistry and Laboratory Medicine (CCLM) has taken many steps to develop advanced research and technology in the diagnosis and monitoring of tumor cancer and to help clinicians translate it into clinical practice.

Molecular Imaging and Theragnostics of Thyroid Cancers.

Molecular imaging plays an important role in the evaluation and management of different thyroid cancer histotypes. The existing risk stratification models can be refined, by incorporation of tumor-specific molecular markers that have theranostic power, to optimize patient-specific (individualized) treatment decisions. Molecular imaging with varying radioisotopes of iodine (i.e., 131I, 123I, 124I) is an indispensable component of dynamic and theragnostic risk stratification of differentiated carcinoma (DTC) while [18F]F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) helps in addressing disease aggressiveness, detects distant metastases, and risk-stratifies patients with radioiodine-refractory DTC, poorly differentiated and anaplastic thyroid cancers. For medullary thyroid cancer (MTC), a neuroendocrine tumor derived from thyroid C-cells, [18F]F-dihydroxyphenylalanine (6-[18F]FDOPA) PET/CT and/or [18F]FDG PET/CT can be used dependent on serum markers levels and kinetics. In addition to radioiodine therapy for DTC, some theragnostic approaches are promising for metastatic MTC as well. Moreover, new redifferentiation strategies are now available to restore uptake in radioiodine-refractory DTC while new theragnostic approaches showed promising preliminary results for advanced and aggressive forms of follicular-cell derived thyroid cancers (i.e., peptide receptor radiotherapy). In order to help clinicians put the role of molecular imaging into perspective, the appropriate role and emerging opportunities for molecular imaging and theragnostics in thyroid cancer are discussed in our present review.

An essential practice summary of the new EANM guidelines for parathyroid imaging.

Parathyroid imaging is essential for the detection and localization of hyperfunctioning parathyroid tissue in patients with primary hyperparathyroidism (pHPT). Surgical treatment of pHPT mainly consists of minimally invasive parathyroidectomy (MIP), as a single adenoma represents the most common cause of this endocrine disorder. Successful surgery requires an experienced surgeon and relies on the correct preoperative detection and localization of hyperfunctioning parathyroid glands. Failure to preoperatively identify the culprit parathyroid gland by imaging may entail a more invasive surgical approach, including bilateral open neck exploration, with higher morbidity compared to minimally invasive parathyroidectomy. Parathyroid imaging may be also useful before surgery in case of secondary hyperparathyroidism (sHPT) or hereditary disorders (MEN 1, 2, 4) as it enables correct localization of typically located parathyroid glands, detection of ectopic as well as supernumerary glands. It is now accepted by most surgeons experienced in parathyroid surgery that preoperative imaging plays a key role in their patients' management. Recently, the European Association of Nuclear Medicine (EANM) issued an updated version of its Guidelines on parathyroid imaging. Its aim is to precise the role and the advantages and drawbacks of the various imaging modalities proposed or well established in the preoperative imaging strategy. It also aims to favor high performance in indicating, performing, and interpreting those examinations. The objective of the present article is to offer a summary of those recent EANM Guidelines and their originality among other Guidelines in this domain issued by societies of nuclear medicine physicians or other disciplines.

Functional and molecular thyroid imaging.

Nuclear medicine methods were introduced in the 1940s for thyroid disease diagnosis and therapy. They is still a crucial part of thyroid nodules work-up. Thyroid imaging with iodine or iodine-analog isotopes is widely employed in patients with thyrotoxicosis and remains the only examination able to prove the presence of autonomously functioning thyroid tissue, which excludes malignancy with a high probability. In addition, technetium-99m-methoxyisobutylisonitrile ([99mTc]Tc-MIBI) scintigraphy and positron emission tomography/computed tomography (PET/CT) with 18F-fluoro-2-deoxy-d-glucose ([18F]FDG) are able to avoid unnecessary surgical procedures for cytologically inconclusive thyroid nodules, as confirmed by meta-analysis and cost-effectiveness studies. All considered thyroid molecular imaging allows functional characterization of different thyroid diseases, even before clinical symptoms become manifest, and remains integral to the management of such conditions. This paper summarizes main concepts of thyroid scintigraphy and its clinical use. In addition, it elaborates development of thyroid scintigraphy, as well as thyroid molecular imaging in patients with thyroid nodules and thyrotoxicosis.