Prognosis of High-Risk Papillary Thyroid Cancer Patients with Pre-Ablation Stimulated TG <1 NG/ML

Objective: The prevalence of undetectable pre-ablation stimulated thyroglobulin (s-Tg) and its clinical implications in high-risk papillary thyroid cancer (PTC) patients remain poorly described. We investigated the rate of tumor recurrence in PTC patients initially classified as high risk but with pre-ablation s-Tg <1 ng/mL and negative anti-Tg antibody (TgAb).Methods: In order to have a follow-up period of at least 5 years for each patient, PTC patients consecutively seen at our department from May 2008 to June 2013 with the following characteristics were selected: (i) classified as American Thyroid Association high risk on the basis of tumor histopathologic features; (ii) submitted to adjuvant ¹³¹I therapy after total thyroidectomy; (iii) a postoperative pre-ablation s-Tg <1 ng/mL and negative TgAb.Results: Among 767 high-risk PTC patients submitted to adjuvant ¹³¹I therapy, 69 patients met the inclusion criteria. Sixty-seven patients (97.1%) were diagnosed as classical PTC, and the remaining 2 patients (2.9%) were diagnosed as follicular variant PTC. When evaluated 9 to 12 months after ¹³¹I therapy, 67 patients (97.1%) were classified as excellent response. Two (2.9%) patients had an s-Tg >1 ng/mL (<3 ng/mL) in the absence of apparent disease, as detected by imaging methods (indeterminate response). During a median follow-up duration of 5.6 years, recurrence was observed in only 2 (2.9%) patients. The 67 (97.1%) patients without tumor recurrence were not submitted to any additional therapy, and all had a suppressed Tg <1 ng/mL in the last assessment.Conclusion: High-risk PTC patients with pre-ablation s-Tg <1 ng/mL and negative TgAb had a favorable prognosis.Abbreviations: CT = computed tomography; L-T4 = levothyroxine; PTC = papillary thyroid cancer; SPECT/CT = single photon emission computed tomography/computed tomography; s-Tg = stimulated thyroglobulin; T4 = thyroxine; TgAb = anti-thyroglobulin antibody; US = ultrasound     

Clinical Consequences of a Change in Anti-Thyroglobulin Antibody Assays During the Follow-up of Patients with Differentiated Thyroid Cancer

ObjectiveThyroglobulin (Tg) quantitation by immunometric assays is compromised by anti-thyroglobulin antibodies (TgAbs), potentially resulting in falsely low Tg concentrations. TgAb screening is recommended when measuring Tg, but current TgAb immunoassays do not detect all possible TgAbs in circulation. We assessed the impact of a change in TgAb assay on apparent disease status of patients with differentiated thyroid carcinoma (DTC).MethodsPatients seen at the Mayo Clinic, Rochester, Minnesota, for follow-up of DTC, who had been tested using 2 different TgAb assays (Beckman Access and Roche Elecsys) were identified. Electronic medical records were reviewed to evaluate any impact the change in TgAb assay had on clinical disease status assessment and follow-up.ResultsA total of 1,457 patients were tested using both assays. A change in TgAb status was found in 124 (8.5%) patients; a total of 117 patients who were TgAbnegative on the Beckman assay became TgAb-positive with the Roche assay. Additional testing was performed in 5 of these patients. Seven patients previously considered TgAb-positive were now TgAb-negative. In all 7 cases, physicians documented that they considered these patients now to be truly TgAb-negative and free of disease.ConclusionDiscrepancies in TgAb status are seen when using different TgAb assays. Relying on Tg and TgAb measurements to determine disease status may lead to underestimation of residual cancer. A multimodal (clinical, biochemical, and radiologic) approach to follow up on patients with DTC should be continued, pending the development of Tg quantitation methods that are highly sensitive and not affected by TgAb interference. (Endocr Pract. 2014;20:1032-1036)     

Urinary Iodine Concentration is Inversely Associated with Thyroglobulin Antibodies

Objective: Epidemiologic studies on the relationship between iodine and thyroid antibodies are inconsistent. Iodine nutrition, genetic, and environmental factors have been shown to modify the effects of iodine on thyroid autoimmunity. We investigated the relationship between urinary iodine concentration (UIC) and thyroglobulin antibodies (TgAbs) in individuals living in iodine-sufficient areas in this cross-sectional study.Methods: A total of 15,008 participants were recruited according to the age range of the population of China in our study. An oral questionnaire was administered to collect basic demographic information. Serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAbs), TgAbs, and UIC were measured, and thyroid ultrasonography was performed in all subjects. Participants were further divided according to the level of UIC and the status of TgAb, and logistic regression was applied to determine the relationship between UIC and TgAbs.Results: The median UIC of the study population was 205.23 (95% confidence interval &lsqb;CI], 65.7 to 537.67) μg/L. A total of 17.6% of participants had UIC <100 μg/L. With the increase in UIC, the prevalence of positive TgAbs decreased gradually. UIC level was lowest in subjects with high TgAb titer (median, 182.36 μg/L; 95% CI, 52.88 μg/L to 506.71 μg/L) and highest in the TgAb-negative group (median, 207.16 μg/L; 95% CI, 66.94 μg/L to 538.72 μg/L). Multilinear correlation analysis showed that gender (β = 37.632; P<.001), age (β = 0.467; P = .038), TSH (β = 13.107; P<.001), TPOAb (β = 1.150; P<.001), thyroid volume (β = 2.883; P<.001), and UIC (β = -0.047; P = .032) were independent predictors of TgAb variations. Low UIC (<100 μg/L) was associated with increased risk of positive TgAbs (adjusted odds ratio = 1.255 &lsqb;1.004 to 1.568]).Conclusion: Low UIC is an independent risk factor for positive TgAb in individuals living in iodine-sufficient areas.Abbreviations: CI = confidence interval; CV = coefficient of variation; FT3 = free triiodothyronine; FT4 = free thyroxine; OR = odds ratio; TgAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TSH = thyrotropin; UIC = urinary iodine concentration; USI = universal salt iodization     

Immunoglobulin Preparations Can Mislead Clinical Decision-Making in Follow-Up of Differentiated Thyroid Cancer

Objective: Intravenous and subcutaneous immunoglobulins are commonly used for immune substitution or as immune modulators in a variety of inflammatory and autoimmune disorders. Exogenous thyroid-specific thyroglobulin (Tg) antibodies present in the donor plasma may interfere with the interpretation of measurements of Tg autoantibodies (Tg-Abs) in the recipient’s plasma and potentially trigger an immune response in the recipient’s immune cells. Levels of antibodies causing bioassay interferences or those leading to clinically relevant changes in patient outcomes are not known. Tg is used as a biomarker in the long-term surveillance of patients with differentiated thyroid cancer (DTC) following total thyroidectomy and radioactive iodine ablation. However, the presence of Tg-Abs in the circulation interferes with Tg measurements. Assessment of levels of Tg-Abs is thus recommended as a part of standard follow-up of DTC together with Tg testing.Methods: To understand the potential mechanisms and pathophysiologic significance of possible interferences associated with administration immunoglobulin preparations and Tg measurement, we overview the current knowledge on interactions between Tg autoimmunity and immunoglobulin preparations and illustrate diagnostic challenges and perspectives for follow-up of patients with DTC treated with exogenous immunoglobulins.Results: In patients with DTC treated with immunoglobulin preparations, monitoring of thyroid cancer using Tg and Tg-Abs is challenging due to possible analytical interferences through passive transfer of exogenous antibodies from immunoglobulin preparations.Conclusion: Analytical interferences must be suspected when a discrepancy exists between clinical examination and diagnostic tests. Collaboration between endocrinologists, biologists, and pharmacologists is fundamental to avoid misdiagnosis and unnecessary medical or radiologic procedures.Abbreviations: CT = computed tomography; DTC = differentiated thyroid cancer; FNAB = fine-needle aspiration biopsy; HAb = heterophile antibody; IMA = immunometric assay; IVIg = intravenous immunoglobulin; RAI = radioactive iodine; RIA = radioimmunoassay; SCIg = subcutaneous immunoglobulin; Tg = thyroglobulin; Tg-Ab = thyroglobulin autoantibody; Tg-MS = thyroglobulin mass spectrometry; TPO-Ab = thyroid peroxidase autoantibody; TSHR-Ab = thyrotropin receptor autoantibody     

Clinical Features in Differentiated Thyroid Carcinoma Stratified By Lymph Node Status

Objective: Cervical lymph node (CLN) metastases (mets) often occur in differentiated thyroid cancer (DTC), especially in the central compartment, and are a major predictor of local recurrence. We examined clinical endpoints in three groups of patients based on status of lymph node involvement: those with definite lymph node involvement (N1), negative lymph nodes (N0), and no lymph nodes resected (Nx). We correlated these endpoints with clinical and pathologic features of these patients.Methods: Medical records of 261 patients with DTC who underwent thyroidectomy between 2006 and 2018 at our center were reviewed. Lymph node status of patients was categorized based on American Joint Committee on Cancer (AJCC) 8th edition criteria as N1, N0, and Nx. We performed statistical analysis to assess the differences among these groups, using one-way analysis of variance. When significant differences were found, pairwise comparisons were conducted among the three groups. Statistical significance was defined as 2-tailed P<.05 for all tests.Results: There were significant differences among the groups in tumor multicentricity, tumor category/size, AJCC stage, and the presence of thyroglobulin auto-antibodies (TgAbs). There were no difference in age, gender, or histopathology. N1 patients had a higher incidence of multicentricity, larger tumor sizes, and were more likely to have elevated TgAbs. There were no significant differences between the N0 and Nx groups.Conclusion: This study shows that larger and multi-centric tumors are associated with increased likelihood of CLN mets in DTC. We suggest increased vigilance for CLN mets in tumors >2 cm, multicentric tumors, and patients with elevated TgAbs.Abbreviations: AJCC = American Joint Committee on Cancer; CLN = cervical lymph node; DTC = differentiated thyroid cancer; FTC = follicular thyroid cancer; mets = metastases; N0 = no cancer in any lymph nodes; N1 = cancer in a lymph node; N1a = cancer in a central compartment lymph node; N1b = cancer in a lateral neck lymph node; Nx = lymph nodes not resected or examined; PTC = papillary thyroid cancer; TgAb = thyroglobulin auto-antibody     

A Study on Serum Antithyroglobulin Antibodies Interference in Thyroglobulin Measurement in Fine-Needle Aspiration for Diagnosing Lymph Node Metastasis in Postoperative Patients

Purpose

Thyroglobulin measurement in fine-needle aspiration washout fluid (FNA-Tg) is widely used for detection of lymph node metastasis (LNM) in patients with papillary thyroid cancer (PTC). Recent studies suggested that serum anti-thyroglobulin antibodies (TgAbs) could interfere with FNA-Tg. We evaluated whether TgAbs can affect FNA-Tg when diagnosing LNM in postoperative patients with PTC.

Methods

From November 2006 to June 2011, a total of 239 LNs from 201 patients who underwent bilateral thyroidectomy and radioactive iodine ablation therapy were included. The interactions between FNA-Tgs and serum TgAbs, and diagnostic performances between FNA with additional FNA-Tg and FNA alone according to the presence of serum TgAbs were evaluated using the generalized linear mixed model and the bootstrap method.

Results

From 106 (44.4%) malignant and 133 (55.6%) benign LNs, there were 32 (13.4%) LNs with detectable serum TgAb levels and 207 (86.6%) LNs with undetectable serum TgAb levels. In logistic regression analysis, a significant negative interaction was observed between FNA-Tgs and serum TgAbs (p = 0.031). In the absence of serum TgAbs, the diagnostic performances were superior in the FNA with FNA-Tg than in the FNA only. However, in the presence of serum TgAbs, the diagnostic performances of the FNA with FNA-Tg were not significantly different from the FNA only, even with a different cutoff value of FNA-Tg.

Conclusions

Serum TgAbs may interfere with FNA-Tg studies and caution is advised while analyzing FNA-Tg for detection of LNM in patients with PTC.     

Is it Worth Suppressing Tsh in low- and Intermediate-Risk Papillary Thyroid Cancer Patients Before the First Disease Assessment?

Objective: Guidelines recommend thyroid-stimulating hormone (TSH) suppression before the first response to treatment assessment in papillary thyroid cancer (PTC) patients. The aim of this study was to assess the rate of structural disease (SD) in low- and intermediate-risk PTC patients according to TSH levels measured 1 year after primary treatment.Methods: A consecutive, prospective series of low- and intermediate-risk PTC patients with 3-years follow-up was collected. TSH, thyroglobulin (Tg), antithyroglobulin antibodies (TgAb), and neck ultrasonography (US) 1 and 3 years after primary treatment were analyzed. Recurrence risk and disease status at 1 year were defined according to the American Thyroid Association (ATA) guidelines and as the presence or absence of SD after 3 years. Patients were grouped according to TSH level at 1 year: group 1, TSH <0.1 μUI/mL; group 2, TSH 0.1 to 0.5 μUI/mL; group 3, 0.5 to 2 μUI/mL; and group 4 >2 μUI/mL.Results: This study included 263 patients (70.9% female, median age 47.2 years) of whom the risk of recurrence was low in 170 (65%), intermediate-low in 63 (24%), and intermediate-high in 30 (11%). The response to initial treatment at 1 year was excellent in 149 (57%), biochemical incomplete in 18 (7%), indeterminate in 84 (32%), and structural incomplete in 12 (4%). Group 1 consisted of 53 (20%) patients, group 2 of 85 (32%), group 3 of 61 (23%), and group 4 of 64 (24%). The rate of SD at 1 and 3 years from primary treatment was not significantly different between TSH groups.Conclusion: TSH suppression before the first response to treatment assessment does not appear to influence the rate of SD evaluated 1 and 3 years after primary treatment.Abbreviations: ATA = American Thyroid Association; DTC = differentiated thyroid cancer; FTC = follicular thyroid cancer; LT4 = levothyroxine; PTC = papillary thyroid cancer; SD = structural disease; Tg = thyroglobulin; TgAb = antithyroglobulin antibodies; TSH = thyroid-stimulating hormone; US = ultrasonography     

Serial Neck Ultrasound is More Likely to Identify False-Positive Abnormalities than Clinically Significant Disease in Low-Risk Papillary Thyroid Cancer Patients

Objective: American Thyroid Association (ATA) low-risk papillary thyroid cancer (PTC) patients without structural evidence of disease on initial posttreatment evaluation have a low risk of recurrence. Despite this, most patients undergo frequent surveillance neck ultrasound (US). The objective of the study was to evaluate the clinical utility of routine neck US in ATA low-risk PTC patients with no structural evidence of disease after their initial thyroid surgery.Methods: We performed a retrospective review of 171 ATA low-risk PTC patients after total thyroidectomy, with or without radioactive iodine (RAI) ablation, who had a neck US without suspicious findings after therapy. The main outcome measure was a comparison of the frequency of finding false-positive US abnormalities and the frequency of identifying structural disease recurrence.Results: Over a median follow-up of 8 years, 171 patients underwent a median of 5 neck US (range 2–17). Structural recurrence with low-volume disease (≤1 cm) was identified in 1.2% (2/171) of patients at a median of 2.8 years (range 1.6–4.1 years) after their initial diagnosis. Recurrence was associated with rising serum thyroglobulin (Tg) level in 1 of the 2 patients and was detected without signs of biochemical recurrence in the other patient. Conversely, false-positive US abnormalities were identified in 67% (114/171) of patients after therapy, leading to additional testing without identifying clinically significant disease.Conclusion: In ATA low-risk patients without structural evidence of disease on initial surveillance evaluation, routine screening US is substantially more likely to identify false-positive results than clinically significant structural disease recurrence.Abbreviations:18FDG-PET = 18-fluorodeoxyglucose-positron emission testingAJCC = American Joint Committee on CancerATA = American Thyroid AssociationCT = computed tomographyETA = European Thyroid AssociationMRI = magnetic resonance imagingPTC = papillary thyroid cancerRAI = radioactive iodineTg = thyroglobulinTgAb = antithyroglobulin antibodiesTSH = thyroid-stimulating hormoneUS = ultrasound     

Programmed Cell Death–Ligand 1 Overexpression in Thyroid Cancer

Objective: Programmed cell death–ligand 1 (PD-L1) expression on tumor tissue has been associated with favorable response to anti–programmed cell death–receptor 1/PD-L1 therapy in many human cancers. Studies have reported that PD-L1 is also expressed in thyroid cancer. The objective of this paper is to introduce the potential predictive and therapeutic values of PD-L1 in thyroid cancer.Methods: A literature search was conducted in the PubMed database using the terms “PD-L1,” “B7-H1,” and “thyroid cancer.” PD-L1 positivity was determined by immunohistochemical assay.Results: The frequency of PD-L1 positivity in different studies ranged from 6.1 to 82.5% in papillary thyroid cancer (PTC) patients and 22.2 to 81.2% in anaplastic thyroid cancer (ATC) patients. PD-L1 positivity rate was higher in ATC than in PTC within the same studies, and its expression intensity was significantly higher in tumor tissue than in the corresponding nontumor thyroid tissues. Moreover, PD-L1 expression was positively associated with the aggressiveness and recurrence of thyroid cancers and negatively associated with the differentiation status and outcomes. PD-L1 checkpoint pathway blockade may emerge as a promising therapeutic target in the treatment of thyroid cancers.Conclusion: PD-L1 is a potential biomarker to predict the recurrence and prognosis of thyroid cancers. It is also a novel immunotherapy target for optimizing the management landscape of radioiodine-refractory and ATCs.Abbreviations: ATC = anaplastic thyroid cancer; DTC = differentiated thyroid cancer; IHC = immunohistochemical; OS = overall survival; PD-1 = programmed cell death–receptor 1; PD-L1 = programmed cell death–ligand 1; PD-L2 = programmed cell death–ligand 2; PTC = papillary thyroid cancer; TNM = tumor-node-metastasis; Treg = regulatory T cell     

Proceedings of the Australasian Association of Clinical Biochemists’ 50th Annual Scientific Conference

Thyroglobulin (Tg) protein is synthesised uniquely by thyroid tissue and is measured as a post-operative differentiated thyroid cancer (DTC) tumour-marker. Tg autoantibodies (TgAb), present in ∼20 percent of DTC patients, interfere with Tg immunometric assay (IMA) measurements causing falsely low/undetectable serum Tg values. Tg radioimmunoassay (RIA) methodology appears resistant to such interferences but has limited availability, whereas new Tg mass-spectrometry methods have inferior sensitivity and unproven clinical value. When present, TgAb concentrations respond to changes in thyroid tissue mass. Thus, when Tg IMA measurements are compromised by the presence of TgAb the TgAb trend can serve as a surrogate DTC tumour-marker. Unfortunately, both physiologic and technical factors impact the interpretation of Tg and TgAb used as DTC tumour-markers.

Serum Tg Testing

Circulating Tg concentrations change in response to thyroid tissue mass, injury (surgery, biopsy or radioiodine) and the degree of TSH stimulation. Technical factors (Tg assay sensitivity, specificity and interferences) additionally impact the clinical utility of Tg testing. Specifically, new 2^nd generation Tg IMAs (functional sensitivities ≤ 0.1 μg/L) now mostly obviate the need for expensive recombinant human TSH(rhTSH)-stimulated Tg testing. Tg molecular heterogeneity remains responsible for two-fold between-method differences in Tg values that preclude switching methods and TgAb interference remains especially problematic.

Serum TgAb Testing

Reliable TgAb testing is critical for authenticating that Tg IMA measurements are not compromised by interference. Unfortunately, TgAb methodologies vary widely in sensitivity, specificity and the absolute values they report, necessitating that TgAb concentrations be monitored using the same method. Furthermore, adopting the manufacturer’s TgAb cut-off value to define a ‘detectable’ TgAb results in falsely classifying sera as TgAb-negative, because manufacturers’ cut-offs are set to diagnose thyroid autoimmunity and not to detect TgAb interference.

• Clin Biochem Rev. 2012 Nov; 33(4): S1–S53.
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S10 Lab Tests Online – Pathology Information for the People

B CampbellAuthor information Copyright and License information DisclaimerEditor, Lab Tests Online Australasia moc.liamg@rekwahdnallebpmacThe contents of articles or advertisements in The Clinical Biochemist – Reviews are not to be construed as official statements, evaluations or endorsements by the AACB, its official bodies or its agents. Statements of opinion in AACB publications are those of the contributors. Print Post Approved - PP255003/01665. Copyright © 2005 The Australasian Association of Clinical Biochemists Inc. No literary matter in The Clinical Biochemist – Reviews is to be reproduced, stored in a retrieval system or transmitted in any form by electronic or mechanical means, photocopying or recording, without permission. Requests to do so should be addressed to the Editor. ISSN 0159 – 8090     

Positive Thyroid Peroxidase Antibody and Thyroglobulin Antibody are Associated With Better Clinicopathologic Features of Papillary Thyroid Cancer

ObjectiveTo compare the thyroid autoantibody status of patients with papillary thyroid cancer (PTC) and benign nodular goiter as well as possible associations between thyroid autoantibodies and clinicopathologic features of PTC.MethodsA total of 3934 participants who underwent thyroidectomy were enrolled in this retrospective study. Patients were divided into PTC and benign nodule groups according to pathological diagnosis. Based on the preoperative serum antibody results, PTC patients were divided into thyroid peroxidase antibody (TPOAb)-positive, thyroglobulin antibody (TgAb)-positive, dual TPOAb- and TgAb-positive, or antibody-negative groups.ResultsOf the 3934 enrolled patients, 2926 (74.4%) were diagnosed with PTC. Multivariate regression analyses suggested that high thyroid-stimulating hormone levels (adjusted odds ratio [OR] = 1.732, 95% CI [1.485-2.021], P < .001), positive TgAb (adjusted OR = 1.768, 95% CI [1.436-2.178], P < .001), and positive TPOAb (adjusted OR = 1.452, 95% CI [1.148-1.836], P = .002) were independent risk factors for predicting malignancy of thyroid nodules. Multinomial multiple logistic regression analyses indicated that positive TPOAb alone was an independent predictor of less central lymph node metastasis in PTC patients (adjusted OR = 0.643, 95% CI [0.448-0.923], P = .017), whereas positive TgAb alone was significantly associated with less extrathyroidal extension (adjusted OR = 0.778, 95% CI [0.622-0.974], P = .028). PTC patients with dual-positive TPOAb and TgAb displayed a decreased incidence of extrathyroidal extension (adjusted OR = 0.767, 95% CI [0.623-0.944], P = .012) and central lymph node metastasis (adjusted OR = 0.784, 95% CI [0.624-0.986], P = .037).ConclusionAlthough preoperative positive TPOAb and TgAb are independent predictive markers for PTC, they are also associated with better clinicopathologic features of PTC.     

Unfavorable Responses to Radioiodine Therapy in N1b Papillary Thyroid Cancer: A Propensity Score Matching Study

Objective: Regional nodal metastases carry prognostic significance in papillary thyroid cancer (PTC). However, whether different locational nodal metastases correlate with different therapeutic responses remains controversial. We innovatively applied the response to therapy restratification system to evaluate the dynamic disease status after surgery and radioactive iodine (RAI) therapy in PTC patients with different locational nodal metastases.Methods: A total of 585 nondistant-metastatic PTC patients who underwent total thyroidectomy and RAI therapy were retrospectively enrolled. Patients with nodal metastases were categorized into N1a and N1b groups. Propensity score matching was used to balance the bias between the 2 groups. Therapeutic responses were dynamically evaluated, and responses to RAI therapy were classified into excellent (ER), indeterminate (IDR), biochemical incomplete (BIR) and structural incomplete response (SIR).Results: N1b group patients showed a significantly higher pre-ablation stimulated thyroglobulin (Ps-Tg) level than N1a group patients (7.4 ng/mL versus 3.2ng/mL, P<.001). After RAI therapy, N1b group patients took a longer time to achieve ER (9.86 months versus 3.29 months, P<.001) and exhibited a higher proportion of non-ER (IDR, BIR, and SIR) (39.15% versus 17.46%, P<.001) compared to N1a group patients. In logistic regression, N1b and Ps-Tg ≥10 ng/mL were confirmed to be independent factors predicting non-ER (odds ratio: 2.591, and 9.196, respectively). In Cox regression, patients with N1b disease and Ps-Tg ≥10 ng/mL showed significantly lower hazards for achieving ER (hazard ratio: 0.564, and 0.223, respectively).Conclusion: N1b PTC patients showed inferior responses to surgery and RAI therapy compared to N1a patients. N1b was confirmed to be an independent factor predicting unfavorable responses to RAI therapy.Abbreviations: AJCC = American Joint Committee on Cancer; ATA = American Thyroid Association; BIR = biochemical incomplete response; BRAF^V600E = proto-oncogene B-Raf V600E mutation; CI = confidence interval; CT = computed tomography; DNA = deoxyribonucleic acid; DTC = differentiated thyroid cancer; ER = excellent response; ETE = extrathyroidal extension; HR = hazard ratio; IDR = indeterminate response; LNM = lymph node metastasis; N1a = central cervical LNM; N1b = lateral cervical LNM; OR = odds ratio; PSM = propensity score matching; Ps-Tg = pre-ablation stimulated thyroglobulin; PTC = papillary thyroid cancer; RAI = radioactive iodine; SIR = structural incomplete response; Tg = thyroglobulin; TgAb = thyroglobulin antibody; TSH = thyroid-stimulating hormone     

Clinical significance of serum thyroglobulin and antithyroglobulin antibody in differentiated thyroid cancer after thyroid ablation

Serum thyroglobulin (Tg) is a suitable marker for differentiated thyroid carcinoma following total thyroid ablation. Between 1998 and 2003, serum samples from 715 papillary and 179 follicular tumor patients treated with total/nearly total thyroidectomy and radioiodine ablation therapy were collected. According to the "Guidelines for Oncotherapy in Hungary", serum Tg, antithyroglobulin antibody (TgAb), TSH and FT4 levels were measured in periods of 3 months following the first treatment and of 6 months after 2 years. In the present work the prognostic value of Tg and TgAb data of cancer patients with hormone substitution therapy were evaluated individually and retrospectively. Serum Tg and TgAb concentrations were measured with a highly sensitive immunoradiometric (IRMA) method, and with a second generation, broad epitope specificity competitive radioimmunoassay, respectively. TSH levels determined by fourth generation LIAISON kit were in a range of 0.05-0.10 mIU/L. Accuracy of measuring of Tg <1 ng/ml made it possible to select the low cut-off level (Tg <2 ng/ml) following total thyroidectomy. In the predominant part of TSH-suppressed patients (746/774, 96%) the serum Tg concentration was below the cut-off level of 2 ng/ml. The sensitivity of Tg determination in 59 TSH-suppressed thyroid cancer patients with lung and bone metastases was as high as 86 to 100%. On the contrary, the number of false negative data was high in cases with lymph node metastases of papillary cancer, and sensitivity did not exceed 62%. Specificity and sensitivity of Tg in TgAb negative patients were 91 to 100%. Based on our results it could be concluded that measuring of Tg and TgAb, using a current IRMA method and a second generation RIA kit, proved to be effective tools for the postoperative monitoring of differentiated thyroid tumours. It has to be noted that determination of TgAb is highly recommended for the adequate interpretation of serum Tg levels. Persistently high and/or increasing serum TgAb concentration with low Tg result had a diagnostic value during the follow-up and can be connected with the recurrence or persistence of the differentiated thyroid cancer.     

Cancer thyroïdien de souche folliculaire avec persistance d’anticorps antithyroglobuline : signification pronostique et apport de la TEP/TDM au F-FDG

Aim

To investigate the rate of persistence or/and recurrence of follicular cell-derived thyroid cancer with elevated serum antithyroglobulin antibody (TgAb) one year after ablative therapy. We also evaluated the predictive factors of persistence or/and recurrence and the clinical impact of PET/CT with FDG.

Methods

This retrospective study involved 154 TgAb+ patients. PET/CT was performed in 22 patients with a pejorative anatomo-clinical type. The results of the PET/CT were compared with histology and clinical follow-up.

Results

In 23 cases, thyroglobulin (Tg) was positive (14% of TgAb+ Tg+) while in other 131 cases, stimulated Tg was negative (86% of TgAb+ Tg−). Twenty-nine patients (18%) were finally diagnosed with persistent or recurrent disease during follow-up. Independent predictive factors were: age higher than 60 years, Tg+, increase of TgAb concentration in the first year following surgery, and T3/T4/N1 status. PET/CT showed sensitivity of 66% and specificity of 90%. Positivity of PET/CT was significantly associated with a poor prognosis.

Discussion and conclusion

There is no significant association between persistence of TgAb and persistent/recurrent disease when stimulated Tg is negative. An increase of TgAb concentration in the first year of follow-up is an important prognostic indicator. PET/CT with FDG seems to be very useful in the therapeutic management of differentiated thyroid cancer, especially for the patients with pejorative anatomo-clinical types.     

Prognostic Value of Lymph Node Uptake on Pretreatment F-18 FDG PET/CT in Patients with N1B Papillary Thyroid Carcinoma

Objective: The aim of this study was to investigate the prognostic value of metabolic characteristics of metastatic lymph node (LN) using pretreatment F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for patients with papillary thyroid carcinoma (PTC) and metastatic lateral LN (N1b).Methods: Ninety-six PTC patients (female:male = 72:24; median age, 44.5 years) with pathologic N1b who underwent pretreatment FDG PET/CT, total thyroidectomy, and radioactive iodine ablation were retrospectively reviewed. To predict responses to initial therapy and recurrence, clinicopathologic factors and metabolic parameters were reviewed, such as sex, age, tumor size, extranodal extension, number and ratio of metastatic LNs, serum thyroglobulin, and maximum standardized uptake value (SUVmax).Results: Among the 96 PTC patients, 81 (84.4%) were classified into the acceptable response (58 excellent; 23 indeterminate) and 15 (15.6%) into the incomplete response (8 biochemical incomplete; 7 structural incomplete) by the 2015 American Thyroid Association management guideline for differentiated thyroid carcinoma. The multivariate analysis showed that SUVmax of N1b (P = .018), pre-ablation stimulated thyroglobulin level (P = .006), and the ratio of metastatic LNs (P = .018) were related to incomplete response. The cutoff value of each variable was determined by receiver operating characteristic analysis. Nine (9.4%) patients experienced recurrences (median follow-up: 50 months). The Kaplan-Meier analysis revealed that SUVmax of N1b (cutoff value: 2.3; P = .025) and ratio of metastatic LNs (cutoff value: 0.218; P = .037) were significant prognostic factors for recurrence.Conclusion: High SUVmax of N1b cervical LN on pretreatment FDG PET/CT could predict incomplete responses to initial therapy and recurrence in patients with N1b PTC.Abbreviations: ATA = American Thyroid Association; DTC = well-differentiated thyroid carcinoma; FDG = F-18 fluorodeoxyglucose; IQR = interquartile range; LN = lymph node; N1b = metastatic lateral cervical lymph node; PET/CT = positron emission tomography/computed tomography; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; ROC = receiver operating characteristic; SUVmax = maximum standardized uptake value; Tg = thyroglobulin; USG = ultrasonography     

Lymphocytic Thyroiditis is Associated with Increased Number of Benign Cervical Nodes and Fewer Central Neck Compartment Metastatic Lymph Nodes in Patients with Differentiated Thyroid Cancer

Objective: Whether or not autoimmune thyroid disease influences the progression of differentiated thyroid cancer (DTC) remains controversial. Findings of previous studies are influenced by lead time bias and/or procedure bias selection. These biases can be reduced by studying a single-institution patient population that underwent a similar extent of surgical resection.Methods: From a cohort of 660 patients with DTC who underwent thyroidectomy, we retrospectively studied 357 patients who underwent total thyroidectomy and central compartment node dissection (CCND) for DTC between 2003 and 2013.Results: Forty-one percent (140/345) of study patients had lymphocytic thyroiditis (LT), and 30% (91/301) had serum positive for thyroglobulin antibody (TgAb). LT was reported in 78% of the TgAb-positive cases. Sixty percent (213/357) of cases had metastatic thyroid carcinoma in 1 or more neck lymph nodes (55% [198/357] central compartment, and 22% [77/356] lateral compartment). Patients with LT had fewer metastatic cervical lymph nodes than those with no LT (2.7 ± 4.7 vs 3.5 ± 4.8, respectively, P = .0285). Patients with positive TgAb and thyroiditis had a larger number of benign cervical lymph nodes removed than those with negative TgAb or no LT. No significant difference was observed in age, tumor size, multifocality, extrathyroidal extension, vascular invasion, or frequency of cervical lymph node metastasis between TgAb-negative and -positive cases or between cases with and without LT.Conclusion: Lymphocytic thyroiditis is associated with fewer central neck compartment metastatic lymph nodes and a larger number of excised reactive benign cervical lymph nodes. Whether this association indicates a protective role of thyroid autoimmunity in lymph node spreading remains unclear.Abbreviations:CCND = central compartment node dissectionDTC = differentiated thyroid cancerHT = Hashimoto thyroiditisLT = lymphocytic thyroiditisTgAb = thyroglobulin antibodyTPO = thyroid peroxidase     

The Correlation Between Metabolic Disorders And Tpoab/Tgab: A Cross-Sectional Population-Based Study

Objective: Studies have shown that metabolic abnormalities influence the immune system. Because the prevalence of metabolic and autoimmune thyroid diseases has increased synchronously, the correlation between them was worth exploring. The study objective was to investigate the relationship between metabolic disorders and thyroid auto-antibodies in euthyroid subjects.Methods: Data were obtained from the Thyroid Diseases and Diabetes Mellitus project survey of 55,891 subjects from 31 provinces in China. The body mass index (BMI), waist circumference (WC), blood pressure, thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibodies (TgAbs), thyroid-stimulating hormone (TSH), urinary iodine concentration, blood glucose, lipid profile, and uric acid levels were evaluated. Free thyroxine and free triiodothyronine levels were measured in patients with abnormal serum TSH levels.Results: In males, the BMI, WC, systolic blood pressure (SBP), diastolic blood pressure (DBP), and 2-hour post-glucose oral glucose tolerance test results of the TPOAb-/TgAb-positive group were significantly higher than those of the TPOAb-/TgAb-negative group. In females, the BMI, WC, SBP, DBP, total cholesterol, and low-density-lipoprotein cholesterol (LDL-C) in the TPOAb-/TgAb-positive group were significantly increased compared to the TPOAb-/TgAb-negative group. Multivariate analysis showed that in males, the odds ratio (OR) of positive TgAbs in the abdominal obesity group was 1.175 (95% confidence interval [CI], 1.016 to 1.359; P = .03), and the OR of positive TPOAbs in the hyperuricemia group was 1.195 (95% CI, 1.041 to 1.372; P = .011). In females, the OR of positive TgAbs was 1.19 (95% CI, 1.068 to 1.326; P = .002) in the high LDL-C group.Conclusion: Obesity, high LDL-C, and hyperuricemia were positively correlated with the prevalence of positive thyroid autoantibodies in euthyroid subjects in a gender-dependent manner. This cross-sectional survey showed that metabolic disorders are associated with increased positive thyroid autoantibody levels in euthyroid subjects in a gender-dependent manner.Abbreviations: AIT = autoimmune thyroiditis; BMI = body mass index; CI = confidence interval; DBP = diastolic blood pressure; FPG = fasting plasma glucose; FT3 = free triiodothyronine; FT4 = free thyroxine; HbA1c = glycated hemoglobin; HDL-C = high-density-lipoprotein cholesterol; LDL-C = low-density-lipoprotein cholesterol; OGTT2hPG = oral glucose tolerance test 2-hours post-glucose; OR = odds ratio; SBP = systolic blood pressure; TC = total cholesterol; TG = triglycerides; TgAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TSH = thyroid-stimulating hormone; UA = uric acid; WC = waist circumference     

No Benefit of Dedicated Thyroid Nodule Screening in Patients with Acromegaly

Objective: Acromegaly results from the excessive production of growth hormone and insulin-like growth factor-1. While there is up to a 2-fold increased prevalence of thyroid nodules in patients with acromegaly, the incidence of thyroid cancer in this population varies from 1.6 to 10.6% in several European studies. The goal of our study was to determine the prevalence of thyroid nodules and thyroid cancer among patients with acromegaly at a large urban academic medical center in the United States (U.S.).Methods: A retrospective chart review was performed of all patients with acromegaly between 2006–2015 within the University of California, Los Angeles health system. Data were collected regarding patient demographics, thyroid ultrasounds, thyroid nodule fine needle aspiration (FNA) biopsy cytology, and thyroid surgical pathology.Results: In this cohort (n = 221, 49.3% women, mean age 53.8 ± 15.2 &lsqb;SD] years, 55.2% Caucasian), 102 patients (46.2%) underwent a thyroid ultrasound, from which 71 patients (52.1% women, mean age 52.9 ± 15.2 &lsqb;SD] years, 56.3% Caucasian) were found to have a thyroid nodule. Seventeen patients underwent a thyroid nodule FNA biopsy and the results revealed 12 benign biopsies, 1 follicular neoplasm, 3 suspicious for malignancy, and 1 papillary thyroid cancer (PTC), from which 6 underwent thyroidectomy; PTC was confirmed by surgical pathology for all cases (8.5% of all nodules observed).Conclusion: In this sample, the prevalence of thyroid cancer in patients with acromegaly and coexisting thyroid nodules is similar to that reported in the general U.S. population with thyroid nodules (7 to 15%). These findings suggest that there is no benefit of dedicated thyroid nodule screening in patients newly diagnosed with acromegaly.Abbreviations: AACE = American Association of Clinical Endocrinologists; ATA = American Thyroid Association; DTC = differentiated thyroid cancer; FNA = fine needle aspiration; GH = growth hormone; IGF-1 = insulin-like growth factor-1; PTC = papillary thyroid cancer; U.S. = United States     

The Relationship of BrafV600E Mutation Status to FDG PET/CT Avidity in Thyroid Cancer: A Review and Meta-Analysis

Objective: Papillary thyroid cancer (PTC) harboring a BRAF^V600E gene mutation has been shown to exhibit aggressive tumor behavior and carries higher risks of recurrence and disease-specific death. In this systematic review and meta-analysis, we examined published evidence related to the accuracy of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in detection of residual disease in patients with BRAF^V600E mutated thyroid cancer.Methods: We extracted data from PUBMED/MEDLINE and EMBASE published between January 1995 and March 2017. We included studies that compared FDG PET standardized uptake values (SUVs) between BRAF^V600E-positive and BRAF^V600E-negative subjects, as well as those that evaluated the odds of having FDG avidity between BRAF^V600E-positive and -negative patients with thyroid cancer.Results: There were a total of 12 studies in the systematic review. Seven studies qualified for the analysis for calculating the pooled odds ratio (OR). The pooled cohort with binary data had 1,144 patients out of which 843 were BRAF^V600E positive and 301 were BRAF^V600E negative. Those with a BRAF^V600E mutation had a significantly greater likelihood of having FDG-avid lesions. The pooled OR was 2.12 (confidence interval &lsqb;CI] 1.53–3.00, P<.01). The pooled mean SUV (cohort of 315 patients) was significantly higher in BRAF^V600E-positive compared to BRAF^V600E negative patients, with a pooled mean difference of 5.1 (CI 4.3–5.8).Conclusion: Our meta-analysis shows that presence of BRAF^V600E mutation in PTC confers a higher likelihood of FDG PET avidity and is associated with higher SUV uptake values compared to BRAF^V600E-mutation negative status.Abbreviations: BRAF = B-Raf proto-oncogene, serine/threonine kinase; CI = confidence interval; CT = computed tomography; DTC = differentiated thyroid cancer; FDG = fluorodeoxyglucose; PET = positron emission tomography; PTC = papillary thyroid cancer; SUV = standardized uptake value     

The Association Between Tumor Tissue Calcification,Obesity, and Thyroid Cancer Invasiveness In A Cohort Study

Objective: We examined the relationships between tumor tissue calcifications of papillary thyroid cancer (PTC), body mass index (BMI), and tumor invasiveness.Methods: This was a retrospective analysis of 13,995 patients with PTC. Comparisons were made between the clinical and pathologic features of the tumor tissue calcifications group and non–tumor tissue calcifications group. Odds ratios (ORs) of tumor tissue calcifications, BMI, and tumor invasiveness features were calculated using a binary logistic regression model. We analyzed the relationship between tumor tissue calcifications and certain characteristics of thyroid cancer based on the pathologic findings.Results: BMI was positively correlated with tumor tissue calcifications in patients with PTC (OR, 1.015; P = .011), and obesity increased the risk of tumor tissue calcifications (OR, 1.374; P = .038). Calcifications were positively correlated with T-size (OR, 1.899; P<.001), multifocality (OR, 1.217; P<.001), extrathyroidal extension (ETE) (OR, 1.287; P<.001), high T-stage (OR, 1.765; P<.001), N+ (OR, 1.763; P<.001), and a higher number of lymph node metastases (OR, 1.985; P<.001). Compared with normal-weight patients with tumor tissue calcifications, obese patients with tumor tissue calcifications had an increased risk of ETE (OR_obesity, 1.765 vs. OR_normal, 1.300) and N+ (OR_obesity, 1.992 vs. OR_normal, 1.784).Conclusion: Tumor tissue calcifications are positively correlated with the invasiveness of PTC. Obesity further promotes the risk of tumor invasiveness in PTC combined with tumor tissue calcifications. These findings suggest that more comprehensive evaluations by trained pathologists may help physicians identify the optimal therapeutic regimens in the postoperative period.Abbreviations: BMI = body mass index; CI = confidence interval; ETE = extrathyroidal extension; FT3 = free triiodothyronine; OR = odds ratio; PTC = papillary thyroid carcinoma; RET = rearranged during transfection; TTC = tumor tissue calcification; US = ultrasonography; USC = ultrasonography calcification; WHO = World Health Organization