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.

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.

Update on diagnosis and treatment of hyperthyroidism: ultrasonography and functional imaging.

Ultrasonography and radionuclide imaging using [99mTc]Pertechnetate or radioactive iodine isotopes are essential tools used during the diagnostic workup of hyperthyroidism with or without structural alterations of the thyroid. Color duplex sonography and ultrasound elastography may add important information to find the cause of the hormone excess. During the last few years, hybrid imaging using SPECT/-(CT) or PET-based methods, such as [124]Iodine-PET/CT or [124]Iodine-PET/ultrasound have been increasingly used, playing a role in the context of localizing ectopic thyroid tissue or in multinodular goiter. Recently, promising data has been published on the use of [99mTc]MIBI imaging in amiodarone induced hyperthyroidism.

Analysis of risk factors and prognosis in differentiated thyroid cancer with focus on minimal extrathyroidal extension.

AIMS: In contrast to all prior AJCC/TNM classifications for differentiated thyroid cancer (DTC) the 8th edition does not take minimal extrathyroidal extension (M-ETE) into consideration for local tumor staging. We therefore aimed to retrospectively assess the specific impact of M-ETE on the outcome of M-ETE patients treated in our clinic. METHODS: DTC patients with M-ETE and a follow-up time of ≥ 5 years were included and matched with an identical number of patients without M-ETE, but with equal histopathological tumor subtype and size. The frequency of initially metastatic disease among groups was compared using Fisher's exact test, the recurrence rate by virtue of log-rank test. Fisher's exact test and multivariate analysis were used to account for the presence of confounding risk factors. RESULTS: One hundred sixty patients (80 matching pairs) were eligible. With other confounding risk factors being equal, the prevalence of N1-/M1-disease at initial diagnosis was comparable among groups (M-ETE: 42.5 %; no M-ETE: 32.5 %; p = 0.25). No differences with regard to the recurrence rate were shown. However, M-ETE patients were treated with external beam radiation therapy more often (16.3 % vs. 1.3 %; p = 0.004) and received higher median cumulative activities of 131I (10.0 vs. 8.0 GBq; p < 0.001). DISCUSSION: Although having played a pivotal role for local tumor staging of DTC for decades M-ETE did not increase the risk for metastases at initial diagnosis and the recurrence rate in our cohort. Patients with M-ETE had undergone intensified treatment, which entails a possible confounding factor that warrants further investigation in randomized controlled trials.

Thyroid Related Quality of Life in Elderly with Subclinical Hypothyroidism and Improvement on Levothyroxine is Distinct from that in Young Patients (TSAGE).

The aim of this study was to investigate in a longitudinal approach whether levothyroxine (LT4) substitution has a different impact on quality of life (QoL) and thyroid related QoL in younger (<40 years) and older subjects (>60 years) with elevated thyroid-stimulating hormone (TSH) concentrations. The study included male and female patients with newly diagnosed, untreated subclinical hypothyroidism defined by TSH>8 mU/l. Patients were recruited throughout Germany from 2013-2016 and evaluated by clinical assessment, blood sampling and questionnaires for health related QoL and thyroid-disease thyroid-related QoL (ThyPRO) at time of diagnosis and six months after initiation of LT4 treatment. We found significantly lower QoL in both young and old patients with subclinical hypothyroidism compared to age-matched healthy individuals. Higher scores on follow-up were found in all patients irrespective of age, indicating better QoL on LT4 therapy. Analysis of the ThyPRO questionnaire showed that old patients experienced less Emotional Susceptibility, Tiredness, and Impaired Day Life on LT4, while young patients reported less Cognitive Complaints, Emotional Susceptibility, and Impaired Day Life compared to baseline assessment. Hypothyroidism with TSH concentrations>8 mU/l is associated with impairment in general and ThyPRO QoL in young and old age. Older patients benefited from LT4 therapy and remarkably show similar degree of improvement as younger patients, albeit with some thematic variation in ThyPRO QoL. Our data confirm current recommendations on initiation of LT4 substitution and suggest that this should not be withheld in elderly with TSH concentration above 8-10 mU/l.

Prognostic impact of incomplete surgical clearance of radioiodine sensitive local lymph node metastases diagnosed by post-operative (124)I-NaI-PET/CT in patients with papillary thyroid cancer.

PURPOSE: Nodal involvement is an independent risk factor of recurrence in papillary thyroid cancer (PTC). Neither the international guidelines nor the recently introduced ongoing risk adaptation concept consider the extent of initial surgical clearance of radioiodine sensitive lymph node metastases in their stratification systems. We investigated the prognostic relevance of incomplete initial surgical clearance in patients with purely lymphogeneous metastatic PTC (pN1 M0) despite successful radioiodine therapy. Accurate assessment of pre-ablative nodal status was attempted using PET/CT studies with both (124)I-NaI and (18)F-FDG along with high-resolution cervical ultrasound. METHODS: Sixty-five patients with histologically diagnosed lymph node metastases (pN1 M0) were retrospectively analyzed. Patients with iodine-negative lymph node metastases diagnosed by (18)F-FDG PET/CT or distant metastases were excluded from the analysis. The association of disease recurrence with the pre-ablative nodal status, as well as other baseline characteristics, were examined applying nonparametric tests for independent samples and multiple regression analysis. Patients with persistent lymph node metastases in (124)I-NaI PET/CT were further divided according to the additional presence or absence of FDG-uptake in (18)F-FDG PET/CT. Survival analyses were performed using Kaplan-Meier curves and the Cox proportional hazards model for uni- and multivariate analyses to assess the influence of prognostic factors on progression free survival (PFS). RESULTS: Incomplete metastatic lymph node resection captured by (124)I-NaI PET/CT (n = 33) was an independent risk factor for recurrence (61 % vs 25 %, p = 0.006) and shorter PFS (46 months vs not reached, HR 4.0 [95 %-CI, 1.7-9.2], p = 0.001). Ultrasound could detect lymph node metastases only in 19/33 patients (58 %). Among patients with positive nodal status, FDG-avidity of metastatic iodine positive lymph nodes worsened the outcome (16 vs 69 months, p = 0.047). From all other investigated factors including age, N-stage (N1a vs N1b), and T-Stage (T4 vs T1-3), only large tumor size (pT4) had a significant impact on PFS (HR 2.9 [95 %-CI, 1.3-6.4], p = 0.007). CONCLUSIONS: Incomplete initial surgical clearance of lymph node metastases even after successful radioiodine therapy may increase the chances of recurrence and is an independent risk factor for impaired survival of patients with PTC. Pre-ablative (dual tracer PET/CT) imaging with (124)I-Na and (18)F provides a prognostic tool for these patients and may considerably complement the current risk stratification systems.

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.

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.

Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled Trials.

CONTEXT: Few meta-analyses on incidence of endocrine immune-related adverse effects (eirAEs) have been published and many trials have been published since. OBJECTIVE: We performed a comprehensive meta-analysis with updated literature to assess risk and incidence of eirAEs of any grade and grade 3 to 5 by immune checkpoint inhibitor (ICI) monotherapy or combination therapy in solid tumors. METHODS: An electronic search using PubMed/Medline, Embase, and the Cochrane Library was performed. Randomized controlled studies (RCTs) assessing eirAEs under ICI monotherapy or ICI combination therapy were selected. Stata software (v17) was used for statistical analyses and risk of bias was evaluated using Review Manager version 5.3. RESULTS: A total of 69 RCTs with 80 independent reports, involving 42 886 patients, were included in the study. Meta-analysis revealed the following pooled estimates for risk ratio and incidence, respectively: for any grade hypothyroidism 7.81 (95% CI, 5.68-10.74, P < .0001) and 7.64% (95% CI, 6.23-9.17, P < .0001); significantly increased also for hyperthyroidism, hypophysitis/hypopituitarism, and adrenal insufficiency; and for insulin-dependent diabetes mellitus 1.52 (95% CI, 1.07-2.18, P = .02), and 0.087% (95% CI, 0.019-0.189, P = .0006), respectively. Meta-regression showed that combination of ICIs (nivolumab plus ipilimumab; durvalumab plus tremelimumab) is an independent risk factor for any grade hypophysitis/hypopituitarism, and that ICI agent is an independent factor of risk for adrenal insufficiency, but that cancer type is not an independent risk factor for eirAEs. CONCLUSION: We showed that risk, independent from cancer type, and incidence of eirAEs are substantially increased with ICI therapy. Combination of ICIs increases risk for eirAEs, especially for hypophysitis/hypopituitarism.

Diagnostic accuracy of Afirma gene expression classifier, Afirma gene sequencing classifier, ThyroSeq v2 and ThyroSeq v3 for indeterminate (Bethesda III and IV) thyroid nodules: a meta-analysis.

Objective: The management of thyroid nodules with indeterminate cytology (ITN) is still a challenge. To evaluate the performance of commercial molecular tests for ITN, we performed this comprehensive meta-analysis. Methods: We performed an electronic search using PubMed/Medline, Embase, and the Cochrane Library. Studies assessing the diagnostic accuracy of Afirma gene expression classifier (GEC), Afirma gene sequencing classifier (GSC), ThyroSeq v2 (TSv2), or ThyroSeq v3 (TSv3) in patients with ITN (only Bethesda category III or IV) were selected; Statistical analyses were performed by using Stata. Results: Seventy-one samples (GEC, n = 38; GSC, n = 16; TSv2, n = 9; TSv3, n = 8) in 53 studies, involving 6490 fine needle aspirations (FNAs) with ITN cytology with molecular diagnostics (GEC, GSC, TSv2, or TSv3), were included in the study. The meta-analysis showed the following pooled estimates: sensitivity 0.95 (95% CI: 0.94-0.97), specificity 0.35 (0.28-0.43), positive likelihood ratio (LR+) 1.5 (1.3-1.6), and negative likelihood ratio (LR-) 0.13 (0.09-0.19), with the best performance for TSv3 (area under the ROC curve 0.95 (0.93-0.96), followed by TSv2 (0.90 (0.87-0.92)), GSC (0.86 (0.82-0.88)), and GEC (0.82 (0.78-0.85)); the best rule-out property was observed for GSC (LR-, 0.07 (0.02-0.19)), followed by TSv3 (0.11 (0.05-0.24)) and GEC (0.16 (0.10-0.28), and the best rule-in was observed for TSv2 (LR+, 2,9 (1.4-4.6)), followed by GSC (1.9 (1.6-2.4)). A meta-regression analysis revealed that study design, Bethesda category, and type of molecular test were independent factors. Conclusion: We showed that in patients with ITN, TSv3 has the best molecular diagnostic performance, followed by TSv2, GSC, and GEC. As regards rule-out malignancy, GSC, and rule-in, TSV2 is superior to other tests.

Correct and Incorrect Recommendations for or against Fine Needle Biopsies of Hypofunctioning Thyroid Nodules: Performance of Different Ultrasound-based Risk Stratification Systems.

PURPOSE: To evaluate the recommendations for or against fine needle biopsy (FNB) of hypofunctioning thyroid nodules (TNs) using of five different Ultrasound (US) -based risk stratification systems (RSSs). METHODS: German multicenter study with 563 TNs (≥ 10 mm) in 534 patients who underwent thyroid US and surgery. All TNs were evaluated with ACR TI-RADS, EU-TIRADS, ATA, K-TIRADS 2016 and modified K-TIRADS 2021. A correct recommendation was defined as: malignant TN with recommendation for FNB (appropriate) or benign TN without recommendation for FNB (avoided). An incorrect recommendation was defined as: malignant TN without recommendation for FNB (missed) or benign TN with recommendation for FNB (unnecessary). RESULTS: ACR TI-RADS demonstrated the highest rate of correct (42.3 %) and lowest rate of incorrect recommendations (57.7 %). The other RRSs showed similar results for correct (26.5 %-35.7 %) and incorrect (64.3 %-73.5 %) recommendations. ACR TI-RADS demonstrated the lowest rate of unnecessary (73.4 %) and the highest rate of appropriate (26.6 %) FNB recommendation. For other RSSs, the rates of unnecessary and appropriate FNB were between 75.2 %-77.1 % and 22.9 %-24.8 %. The lowest rate of missed FNB (14.7 %) and the highest rate of avoided FNB (85.3 %) was found for ACR TI-RADS. For the other RSSs, the rates of missed and avoided FNB were between 17.8 %-26.9 % and 73.1 %-82.2 %. When the size cutoff was disregarded, an increase of correct recommendations and a decrease of incorrect recommendations was observed for all RSSs. CONCLUSION: The RSSs vary in their ability to correctly recommend for or against FNB. An understanding of the impact of nodule size cutoffs seems necessary for the future of TIRADS.

Thyroid Imaging Reporting and Data Systems: Applicability of the "Taller than Wide" Criterium in Primary/Secondary Care Units and the Role of Thyroid Scintigraphy.

BACKGROUND: To examine the applicability of the "taller than wide" (ttw) criterium for risk assessment of thyroid nodules (TNs) in primary/secondary care units and the role of thyroid scintigraphy therein. METHODS: German bicenter study performed in a setting of primary/secondary care. Patient recruitment and analysis in center A was conducted in a prospective manner. In center B, patient data were retrieved from a database that was originally generated by prospective data collection. TNs were assessed by ultrasound and thyroid scans, mostly fine needle biopsy and occasionally surgery and others. In center A, only patients who presented for the first time were included. The inclusion criterion was any TN ≥ 10 mm that had at least the following two sonographic risk features: solidity and a ttw shape. In center B, consecutive patients who had at least ttw and hypofunctioning nodules ≥ 10 mm were retrieved from the above-mentioned database. The risk of malignancy was determined according to a mixed reference standard and compared with literature data. RESULTS: In center A, 223 patients with 259 TNs were included into the study. For further analysis, 200 nodules with a reference standard were available. The overall malignancy rate was 2.5% (upper limit of the 95% CI: 5.1%). After the exclusion of scintigraphically hyperfunctioning nodules, the malignancy rate increased slightly to 2.8% (upper limit of the 95% CI: 5.7%). Malignant nodules exhibited sonographic risk features additional to solidity and ttw shape more often than benign ones. In addition to the exclusion of hyperfunctioning nodules, when considering only nodules without additional US risk features, i.e., exclusively solid and ttw-nodules, the malignancy rate decreased to 0.9% (upper limit 95% CI: 3.7%). In center B, from 58 patients, 58 ttw and hypofunctioning TNs on thyroid scans with a reference standard were available. Malignant nodules from center B were always solid and hypoechoic. The overall malignancy rate of hypofunctioning and ttw nodules was 21%, with the lower limit of the 95% CI (one-sided) being 12%. CONCLUSIONS: In primary/secondary care units, the lowest TIRADS categories for indicating FNB, e.g., applying one out of five sonographic risk features, may not be appropriate owing to the much lower a priori malignancy risk in TNs compared to tertiary/quaternary care units. Even the combination of two sonographic risk features, "solidity" and "ttw", may only be appropriate in a limited fashion. In contrast, the preselection of TNs according to hypofunctioning findings on thyroid scans clearly warranted FNB, even when applying only one sonographic risk criterion ("ttw"). For this reason, thyroid scans in TNs may not only be indicated to rule out hyperfunctioning nodules from FNB but also to rule in hypofunctioning ones.

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.

Predictive value of highly sensitive basal versus stimulated thyroglobulin measurement in long-term follow-up of thyroid cancer.

Objective: Recurrence of differentiated thyroid cancer (DTC) is associated with reduced quality of life, and therefore, early identification of patients at risk is urgently needed.Here we investigated the predictive power of various cut-off values of single stimulated thyroglobulin (s-Tg) and single highly sensitive measured, unstimulated thyroglobulin (u-hsTg) measurements close to the end of primary therapy for recurrence-free survival (RFS) in long-term follow-up (>10 years) of patients with DTC. Methods: In DTC patients with adjuvant radioiodine therapy, we assessed retrospectively u-hsTg (6 ± 3 months before s-Tg measurement) and s-Tg measurements (≤24 months after last radioiodine therapy). Positive predictive (PPV)/negative predictive values (NPV) of various cut-off values (s-Tg: 0.5/1.0 ng/mL; u-hsTg: 0.09/0.2 ng/mL) for patient outcomes as well as additional factors associated with disease development were analyzed. Results: In total, 175 patients were retrospectively reviewed (tumor recurrence: n = 14/complete remission: n = 161). Examined cut-off values for s-Tg and u-hsTg showed significant predictive power for RFS (log-rank: all P < 0.001). NPV/PPV for s-Tg were 98.6%/36.4%, respectively (0.5 ng/mL cut-off) and 96.7%/42.9%, respectively (1.0 ng/mL cut-off); those for u-hsTg were 97.3%/35.7%, respectively (0.09 ng/mL cut-off) and 95.2%/85.7%, respectively (0.2 ng/mL cut-off). U-hsTg (P < 0.001) and patient age (P < 0.05) were significantly associated with tumor recurrence. One-third of patients with tumor recurrence in the course initially showed undetectable u-hsTg after completion of primary therapy. Conclusion: With >10 years of follow-up, both s-Tg and u-hsTg have a comparably high predictive power for RFS, while only u-hsTg was significantly associated with a recurrence event.Serial u-hsTg measurements seem warranted since patients with tumor recurrence during follow-up may have an undetectable tumor marker at baseline.

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.

Update on Calcitonin Screening for Medullary Thyroid Carcinoma and the Results of a Retrospective Analysis of 12,984 Patients with Thyroid Nodules.

BACKGROUND: We provide an update on calcitonin (Ctn) screening for the early detection of medullary thyroid carcinoma (MTC) and present the results of a large single-center analysis evaluating sex-specific cut-off-levels and long-term courses. METHODS: A total of 12,984 consecutive adult patients (20.1% male and 79.9% female) with thyroid nodules who had undergone routine Ctn measurement were retrospectively analyzed. Patients with confirmed suspicious Ctn values were referred for surgery. RESULTS: Ctn measurements were elevated in 207 (1.6%) patients, with values below twice the sex-specific reference limit in 82% of these cases. Further clarification was possible in 124/207 cases, of which MTC could be ruled out in 108 cases. Histopathological assessment confirmed MTC in 16/12,984 patients. CONCLUSIONS: Our extrapolated MTC prevalence of 0.14% is significantly lower than that described in early international screening studies. The stimulation test can usually be dispensable when using a decision-making concept based on sex-specific basal Ctn cut-off values. Ctn screening is recommended even in patients with very small thyroid nodules. High quality standards in pre-analytics, laboratory measurements, and the interpretation of data must be ensured, as well as close interdisciplinary cooperation between medical disciplines.

¹8F-FDG PET/CT changes therapy management in high-risk DTC after first radioiodine therapy.

PURPOSE: Advanced tumour stage and initial metastases are associated with reduced general and tumour-free survival in patients with differentiated thyroid carcinoma. Optimal initial therapy is mandatory for a positive patient outcome, but can only be performed if all non-iodine-avid tumour lesions are known before planning treatment. We analysed the benefit of (18)F-FDG PET/CT at initial diagnosis in patients with high-risk differentiated thyroid carcinoma and determined whether the (18)F-FDG PET/CT results led to a deviation from the standard procedure, which consists of two consecutive radioiodine treatments with thyroid hormone suppression in between and no additional imaging, with individual patient management. METHODS: The study group comprised 90 consecutive patients with either extensive or metastasized high-risk differentiated thyroid carcinoma who received (18)F-FDG PET/CT after the first radioiodine treatment approximately 4 weeks after thyroidectomy under endogenous TSH stimulation. We carried out PET/CT imaging with low-dose CT without contrast medium, which we only used for attenuation correction of PET images. RESULTS: (18)F-FDG PET/CT was positive in 26 patients (29%) and negative in 64 patients (71%). Compared to the results of posttherapeutic (131)I whole-body scintigraphy, the same lesions were PET-positive in 7 of the 26 patients, different lesions were PET-positive in 15 patients, and some PET-positive lesions were the same and some were different in 4 patients. TNM staging was changed due to the PET results in 8 patients. Management was changed in 19 of the 90 patients (21%), including all patients with only FDG-positive lesions and all patients with both FDG-positive and iodine-positive lesions. Age was not a predictive factor for the presence of FDG-positive lesions. FDG-positive and iodine-positive lesions were associated with high serum thyroglobulin. However, at low serum thyroglobulin values, tumour lesions (iodine- and/or FDG-avid) were also diagnosed. Thus, the serum thyroglobulin value prior to the first radioiodine treatment cannot be used as a predictor of the presence of FDG-positive lesions. CONCLUSION: (18)F-FDG PET/CT resulted in a change of therapeutic procedure in 11 of 90 patients and in a change of patient management through additional diagnostic measures in 8 of 90 patients, and is consequently very helpful in initial staging. At our hospital, (18)F-FDG PET/CT in high-risk patients with differentiated thyroid carcinoma has been established as an initial staging modality.

The role of thyroglobulin doubling time in differentiated thyroid cancer: a meta-analysis.

Objective: In patients with differentiated thyroid cancer (DTC), recurrences may occur in up to 20% and may have a fatal outcome in 10% of cases. Thyroglobulin doubling time (Tg-DT) values may contribute to predict response to treatment and disease recurrence in DTC patients. This study aimed to address the following questions: (1) Are Tg-DT values indicative of response to treatments in patients with DTC (i.e. 'treatment monitoring')?; (2) Is Tg-DT predictive of 2-[18F]fluoro-2-deoxy-d-glucose (2-[18F]FDG) PET/CT in patients with DTC?; (3) Are Tg-DT values predictive of DTC prognosis (i.e. 'prediction')? Design: Systematic review and meta-analysis. Methods: Methodology was registered in the PROSPERO database (CRD42021257947). A systematic search was carried out in PubMed, Web Of Science, and Scopus from June to August 2021 without time and language restrictions. Results: Eleven studies were included for a total of 1421 patients. Positive association between Tg-DT < 1 year and recurrence or disease progression was observed. Tg-DT was found to be related with (2-[18F]FDG) PET/CT results in patients with DTC. The area under the curve was 0.86 (95% CI: 0.83-0.89), sensitivity was 0.84 (0.64;0.94), specificity was 0.71 (0.35; 0.92), DOR was 13.1 (3.1; 55.0), LR+ was 2.9 (1.0; 8.1), LR- was 0.22 (0.1; 0.5). For patients with Tg-DT < 1 year (n = 247), the survival risk ratio was 2.09 (95% CI: 1.49; 2.94). Conclusions: Tg-DT values are valuable in predicting response to treatment and disease recurrence in patients with DTC, as well as their overall survival. In addition, Tg-DT significantly increases the detection rate of 2-[18F]-FDG PET/CT.

Diagnostic Performance of 99mTc-Methoxy-Isobuty-Isonitrile (MIBI) for Risk Stratification of Hypofunctioning Thyroid Nodules: A European Multicenter Study.

99mTc-MIBI (MIBI) imaging is able to exclude malignancy of hypofunctioning thyroid nodules (TNs) with high probability but false positive results are frequent due to low specificity. Therefore, pre-test selection of appropriate TNs is crucial. For image evaluation visual and semiquantitative methods (Washout index, WOInd) are used. Aim of this study was to evaluate the diagnostic performance of MIBI imaging in hypofunctioning TNs with indeterminate fine-needle aspiration cytology results in a multicentric European setting. Patients with hypofunctioning TNs, EU-TIRADS 4 or 5, Bethesda III/IV and MIBI imaging were included. For visual evaluation the intensity of MIBI uptake in the TN was compared to normal thyroid tissue. 358 patients with 365 TNs (n = 68 malignant) were included. Planar imaging (SPECT) showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 96% (94%), 21% (22%), 22% (15%), 96% (96%), and 35% (32%). The WOInd (38.9% of all cases, optimal cutoff: -19%) showed a sens 100% (spec 89%, PPV 82%, NPV 100%, ACC 93%). For hypofunctioning TNs at intermediate or high risk with indeterminate cytology, a MIBI negative result on visual evaluation is an effective tool to rule-out thyroid malignancy. The semi-quantitative method could considerably improve overall diagnostic performance of MIBI imaging.

Distribution of Functional Status of Thyroid Nodules and Malignancy Rates of Hyperfunctioning and Hypofunctioning Thyroid Nodules in Germany.

AIM: Thyroid scintigraphy enables the depiction of the functional status of thyroid nodules (TNs) with both, 99mTc-pertechnetate and 123Iodine. The functional status is relevant for diagnostic procedures for the differentiation of benign and malignant TNs. The aim of this study was to examine the current frequencies of hyper-, hypo- and isofunctioning TNs in Germany and to estimate the risk of malignancy with regard to functional status. METHODS: In 11 study centers, a minimum of 100 nodules per center were consecutively enrolled between July 2019 and April 2020. Inclusion criteria were: newly diagnosed nodule, nodule' size of 10 mm or more, thyroid scintigraphy. Exclusion criteria were: completely cystic TNs, patients with prior radioiodine therapy or thyroid surgery. The risk of malignancy was estimated for hyper- and hypofunctioning TNs. RESULTS: Overall, 849 patients (72 % women) with 1262 TNs were included. Patients' age ranged from 18 to 90 years. Most TNs were hypofunctioning (n=535, 42%) followed by isofunctioning TNs (n=488, 39%) and hyperfunctioning TNs (n=239, 19%). When only TNs with a maximum size of 2 cm or more were considered the rate of hyperfunctioning and hypofunctioning TNs increased (to 27% and 49%) while isofunctioning TNs decreased. Only one of all hyperfunctioning TNs was malignant. In hypofunctioning nodules, the malignancy rate was estimated at 10%. CONCLUSION: In Germany, the proportion of hyperfunctioning TNs is approximately 20% and increases in larger TNs to up to 27%. Due to the low risk of malignancy in hyperfunctioning TNs, no further procedures to rule out malignancy are necessary. The risk of malignancy of hypofunctioning TNs is significantly higher. Thus, a thyroid scintigraphy is a useful diagnostic tool in Germany.