Hindawi Journal of yroid Research Volume 2020, Article ID 8312628, 6 pages https://doi.org/10.1155/2020/8312628 Research Article Prognostic Significance of Thyroglobulin Antibodies in Differentiated Thyroid Cancer Jordi L. Reverter ,1,2 Irene Rosas-Allende,3 Carlos Puig-Jove,1,2 Carles Zafon,2,4 Ana Megia,2,5 Ignasi Castells,2,6 Eduarda Pizarro,2,7 Manel Puig-Domingo,1,2 and M. Luisa Granada2,3 1 Departments of Endocrinology and Nutrition, Germans Trias i Pujol Hospital and Research Institute, Universitat Autònoma de Barcelona, CIBERER (ISCIII), Barcelona, Spain 2 Consortium for the Study of Thyroid Cancer, CECAT, Barcelona, Spain 3 Clinical Biochemistry, Germans Trias i Pujol Hospital and Research Institute, Universitat Autònoma de Barcelona, CIBERER (ISCIII), Barcelona, Spain 4 Department of Endocrinology, Hospital Vall d’Hebron, Diabetes and Metabolism Research Unit, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona, CIBERDEM (ISCIII), Barcelona, Spain 5 Department of Endocrinology and Nutrition, Hospital Universitari Joan XXIII, Research Institute Pere Virgili, CIBERDEM (ISCIII), Tarragona, Spain 6 Endocrinology Service, Hospital General de Granollers, Barcelona, Spain 7 Endocrinology Service, Hospital de Mataró, Barcelona, Spain Correspondence should be addressed to Jordi L. Reverter; reverter.germanstrias@gencat.cat Received 4 December 2019; Revised 12 February 2020; Accepted 27 February 2020; Published 14 April 2020 Academic Editor: Massimo Tonacchera Copyright © 2020 Jordi L. Reverter et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To investigate whether variations in thyroglobulin autoantibodies (TgAb) are related to the recurrence or persistence of differentiated thyroid carcinoma (DTC) and may therefore be useful as surrogate tumor markers. Design and Methods. We retrospectively studied 98 subjects (83 women, 47 ± 15 years old) from an initial cohort of 1017 patients treated for DTC in five hospitals, with positive TgAb at any time during the follow-up. Patients presented five different patterns of evolution of serum TgAb concentrations: (1) stable positive TgAb, (2) de novo appearance, (3) an increase of more than 50%, (4) TgAb levels from positive to negative, and (5) a decrease of more than 50%. Results. In the group of 11 patients with stable TgAb, four cases presented persistence of the disease with structural incomplete response. In the group of 22 patients with sustained increasing trend rising more than 50% or de novo detectable TgAb levels, three patients were diagnosed with structural incomplete response. There was no evidence of recurrence or persistence of the disease in any of the 65 patients who showed a significant decrease in (n � 35) or disappearance of (n � 30) TgAb. Conclusions. Our results suggest that not only the appearance of a significant increase in TgAb but also stable concentrations of TgAb should be regarded as a sufficient risk condition for an active search for recurrent or persistent disease. Conversely, a significant decrease in TgAb levels can represent a good prognostic sign. 1. Introduction considered a highly sensitive and specific tumor marker for patients with DTC after removal of benign and malignant Differentiated thyroid carcinoma (DTC) has an excellent thyroid tissue by surgery and 131I ablation [2]. Thyroglobulin survival rate. Despite this, recurrences occur in 5%–20% of is usually measured by noncompetitive automated immu- patients, and because of its prevalence, DTC is the leading noassays using two monoclonal antibodies directed against cause of death among all endocrine tumors [1]. Serum two epitopes of the molecule. Over the years, advances in thyroglobulin (Tg) is produced and secreted exclusively by assay technologies have led to important improvements in benign or differentiated malignant thyroid cells, and it is the analytical performances of Tg immunometric assays 2 Journal of Thyroid Research (IMAs), with the sensitivity of detection increasing ten- obtained during reoperation. Patient characteristics (gender fold from 0.5–1.0 μg/L in the first-generation IMAs to and age), laboratory measurements (TSH, Tg, and TgAb 0.05–0.10 μg/L in the second-generation IMAs. However, levels), tumor characteristics (histological subtype: papillary the main limitation of determination of Tg is that it can be or follicular), and data regarding disease status during fol- modified by serum Tg autoantibodies (TgAb), which give low-up and duration of follow-up were also recorded. All falsely decreased results in IMA assays. Furthermore, this patients with at least one year of follow-up and at least two interference is variable among patients and only correlates determinations of Tg and TgAb, measured in a period of at with TgAb concentrations [3]. Therefore, the degree of least 6 months, were included in this study. Patients with interference cannot be predicted and an accurate Tg value TgAb levels below functional sensitivity of the assay in all the cannot be obtained. It should also be noted that any TgAb samples obtained during the follow-up were excluded. assay will detect only a subset of interfering TgAbs [4]. The study was conducted in accordance with the Dec- Serum TgAb are present in about 60% of patients with laration of Helsinki and was approved by the local Human autoimmune thyroid disease and are more frequent in fe- Research Ethics Committee of the Hospital Germans Trias i males [5]. It has been reported that approximately 20%–25% Pujol. Consent was obtained from each patient after full of patients are with DTC test positive for TgAb, depending on explanation of the purpose and nature of all procedures used. the specific assay used and the study population [6]. In pa- tients with DTC who test positive for TgAb, an undetectable 2.2. Laboratory Methods. Thyroglobulin determinations Tg cannot be judged as the absence of disease and such cases are classified as “indeterminate response” according to the ® were carried out by Elecsys electro chemiluminescent electromagnetic immunoassay (ICMA) (Roche Diagnos- American Thyroid Association (ATA) guidelines [7]. In these tics). TgAb were measured by chemiluminescent immu- patients, it has been suggested that the trend towards in- creasing TgAb concentration could reflect changes in thyroid ® noassay using either the Liaison system (DiaSorin, Saluggia, Italy) in one of the participating centers and the tissue mass [8]. The rationale behind TgAb measurement and the interpretation of results in DTC patients is based on the ® Immulite 2000 XPi analyzer (Siemens Healthcare Diag- nostics, Llanberis, UK) in the others. Functional sensitivity theory that the presence of an antigenic stimulus induced by (FS), defined as the lowest TgAb concentration that can be Tg is what drives TgAb production [9]. measured with an interassay coefficient of variation <20%, Various authors have suggested that TgAb can be used as was 10 UI/mL. A result was considered positive for TgAb if a surrogate tumor marker for disease recurrence during serum levels were ≥10 IU/mL (above FS) in samples mea- long-term follow-up in DTC [10–13]. However, this is a controversial issue, mainly because the presence of TgAb ® sured by the Liaison and ≥20 IU/mL in those measured may not be useful in a significant proportion of patients due ® with the Immulite 2000 XPi. Given that TgAb may rise transiently after surgery and its low prevalence [14], and also because there is as yet no 131 I ablation therapy, TgAb were measured at least 6 months clear definition of the magnitude of TgAb level variation and after these treatment procedures. the period of time over which it occurs that would be Based on TgAb presence and changes in serum TgAb necessary for it to be regarded as a significant trend in their concentrations, patients presented one of the five different concentrations. patterns: (1) stable positive TgAb concentrations with var- The aim of this study was to investigate the prevalence of iations less than 50% throughout follow-up, (2) increased TgAb in a large cohort of DTC patients and its potential levels of TgAb above functional sensitivity (de novo ap- usefulness as a surrogate tumor marker by evaluating whether pearance from negative to positive), (3) sustained increasing variations in TgAb levels are associated with disease activity. trend (increasing more than 50% in levels), (4) TgAb levels decreasing below FS with a shift in TgAb status from positive 2. Materials and Methods to persistently negative, or (5) levels of TgAb decreasing more than 50%. 2.1. Patients. We retrospectively studied patients treated for DTC between 2010 and 2016 at the Endocrinology De- partments of five hospitals in the region of Catalonia, Spain: 2.3. Imaging Modalities. Neck ultrasound was performed at the Germans Trias i Pujol University Hospital in Badalona, least yearly, and further imaging techniques (131Iodine, CT the Vall d’Hebron University Hospital in Barcelona, the Joan scan, MRI, 18-FDG PET/CT) were used if indicated. XXIII Hospital in Tarragona, the Granollers General Hos- pital in Granollers, and the Mataró Hospital in Mataró. 2.4. Recurrent or Persistent Disease. Recurrence or persis- Patients were treated with complete thyroidectomy, addi- tence of the disease had to be proven by cytology, histology, tional lymph node dissection if indicated, suppressive lev- or positive post-131I therapy scan. In this study, the ATA othyroxine treatment, and postoperative remnant ablation management guidelines criteria for recurrence and persis- with 131I according to ATA guidelines [7]. Laboratory tence of the disease were used [7]. evaluation consisted of taking measurements of serum Tg, TgAb, and TSH at least once every year. Recurrence was defined as detection of structural disease by ultrasound or 2.5. Statistical Analysis. Descriptive statistics were applied to other image explorations, whole-body scan, or presence of all collected variables expressed as frequencies for cate- malignant cells in a fine-needle aspiration biopsy or in tissue gorical data or mean values ± standard deviations for Journal of Thyroid Research 3 continuous data. Group comparisons were carried out using Table 1: Patient demographics and characteristics. the chi-square test. A p value less than 0.05 was considered significant. Statistical analysis was performed using the IBM Sex (M/F) 15/83 ® SPSS Statistics 24 software package (IBM Corp., Armonk, NY, USA). Mean age, years (SD) 47 (±15) Family history neoplasia, n 39 Family history thyroid disease, n 29 3. Results Prior neck irradiation, n 8 Histologic subtype, n 3.1. Patients. From an initial cohort of 1017 patients with Classical papillary 80 DTC, 98 (n � 83 females, 47 ± 15 y), representing 9.5%, Tall cell 1 presented positive TgAb at some point during follow-up. Sclerosing 4 Table 1 shows the characteristics of these patients. This Hürthle 1 group included papillary thyroid cancer (n � 86) and fol- Follicular 12 licular thyroid carcinoma (n � 12). Patient’s initial Tg levels Mean size, cm (SD) 2.3 (±1.7) were 0.75 ± 1.3 ng/mL. In terms of TgAb status, 11 patients Multifocality, n 33 had stable positive TgAb concentrations, 16 patients had de Extrathyroidal extension, n 23 Lymphovascular invasion 17 novo appearance, and 6 patients had a significant increase in TgAb. On the other hand, in 65 patients, TgAb levels de- TNM classification, n T1 38 creased above FS (n � 35) or >50% (n � 30) during follow-up. T2 22 Figure 1 represents a flowchart of the results. T3 28 T4 10 3.2. Relationship between TgAb and Recurrence or Persistence N1 48 of the Disease. Table 2 shows the characteristics of the 7 M1 10 patients with disease recurrence according to TgAb levels Stage, n during the follow-up. In the group of 11 patients with stable Stage I 56 Stage II 2 TgAb, the mean follow-up period was 78.9 ± 9.0 months, and Stage III 18 four cases presented persistence of the disease with struc- Stage IVA 13 tural incomplete response. In only one of the 6 patients with sustained increasing trend rising more than 50% was re- currence detected. Sixteen patients presented de novo de- persistence; this group was strongly represented as it cor- tectable TgAb levels and two of these patients were responded to 65 out of the 98 patients. And finally, the cases diagnosed with structural incomplete response. The mean with active disease were detected in patients with stable follow-up period in the group of increasing or de novo levels of a significant increase in or de novo appearance of appearance TgAb was 75.7 ± 10.1 months. TgAb, thus supporting the usefulness of the measurement of There was no evidence of recurrence or persistence of the TgAb as a surrogate marker of active disease in DTC [17]. disease in any of the 65 patients who showed a significant From a clinical point of view, these results suggest that decrease in (n � 35) or disappearance of (n � 30) TgAb after a only a minority of cases of DTC show positive TgAb during mean follow-up of 65 ± 10.9 months. follow-up. This low prevalence of TgAb, together with the When patients with pattern type 1 (increase) were fact that in more than half of cases, TgAb disappear or compared with those in pattern type 2 (decrease), no sig- decrease during follow-up, raises the question of whether its nificant differences were observed regarding persistence or measurement would be of major utility in daily clinical recurrence of the disease (p < 0.2). The relative risk of having practice. The prevalence reported in various studies on this active disease was higher but not significantly different in topic is not only higher (25%) than in the general population patients with stable TgAb with respect to those with de novo (10%) but also higher than that seen in our results [4, 16]. appearance (p � 0.3) or a significant increase (p � 0.2). Based on our data, the actual impact on DTC populations Patients with positive TgAb presented a highly significant RR may be limited. As the prevalence of positive TgAb in our of persistent or recurrent disease (not quantifiable due to the DTC population was 10% and the probability of recurrence absence of cases with active disease in the group of patients of disease in papillary thyroid carcinoma (PTC) has been whose TgAb decreased significantly or disappeared). reported to reach 20% at some point during the patient’s lifetime, the combined probability of recurrence in patients 4. Discussion with positive TgAb is 2 out of every 100 DTC patients. In connection with this, two long-term retrospective studies, First, in this study involving a relatively large cohort of covering follow-up periods of 12 to 29 years, detected only patients with DTC and positive TgAb at some point during 2.5 patients per year with positive TgAb [11, 18]. Population follow-up, the prevalence of positive TgAb was relatively factors may be at the root of this difference in TgAb low, less than 10%, with respect to previous reports [14–16]. prevalence [19]. Second, a decrease in TgAb to undetectable levels below the Independent of its prevalence, in those patients showing FS of the method or a significant decrease >50% identified positive TgAb, who are considered a diagnostic challenge, those cases with no evidence of disease recurrence or serum levels of TgAb have been proposed as a surrogate 4 Journal of Thyroid Research Initial cohort (n = 1017) Negative TgAb (n = 920) Positive TgAb at any time during follow-up (n = 98) Stable or increasing TgAb Decreasing TgAb Stable >50% increase Negative to positive Positive to negative >50% decrease (n = 11) (n = 6) (n = 16) (n = 35) (n = 30) 4 rec/per 1 rec/per 2 rec/per 0 rec/per 0 rec/per TgAb: thyroglobulin auto antibodies rec/per: thyroid carcinoma recurrence or persistence Figure 1: Flow chart of the study population and results. Table 2: Characteristics of the patients with disease recurrence according to thyroglobulin autoantibodies levels during the follow-up. TgAb Stable >50% increase de novo appearance Sex (M/F) M F F F F F F Age (years) 50 73 38 52 77 70 75 Histology Papillary Papillary Papillary Papillary Papillary Papillary Papillary Initial TNM T3N1M0 T4N1M0 T2N1M0 T4N1M1 T4N1M0 T4N1M0 T3N1M0 Diagnostic procedure PET/TC PET/TC Ultrasound PET/TC PET/TC Ultrasound Ultrasound Recurrence location Lung M1 Lung M1 Neck N1 Lung M1 Lung M1 Neck N1 Neck N1 Recurrence time (months) 12 14 7 23 36 48 23 Tg (ng/ml) Initial 0.2 5.8 0.4 0.2 0.2 176 0.2 Recurrence 0.1 0.6 0.1 0.2 0.2 19 0.3 TgAb (IU/ml) Initial 128 3000 81 900 221 Negative Negative Recurrence 83 2500 71 700 2500 63 172 PET/TC: 18F-fluorodeoxyglucose positron emission tomography/computed tomography; Tg: thyroglobulin; TgAb: thyroglobulin autoantibodies; N1: lymph node metastasis; M1: distant metastasis. tumor marker [10, 11, 15, 16]. Our results are in accordance with borderline TgAb (3.2%) during follow-up. However, with the ATA guidelines statement [7], which indicates that patients with borderline TgAb were more likely to progress a decline in TgAb levels over time is considered a good to elevated TgAb, and this event was significantly associated prognostic sign [20], while rising antibody levels, in the with recurrence [22]. absence of an acute injury to the thyroid, significantly in- The interference of TgAb in Tg determinations is an issue crease the risk of persistent or recurrent thyroid cancer [21]. that has not yet been resolved in the clinical assessment of Specifically, recurrent or progressive disease should be thyroid carcinoma patients classified as “undetermined re- suspected in those patients initially positive for TgAb that sponse.” In the absence of alternative methods, neck ultra- then become negative but subsequently show rising levels of sound and other image explorations have become the basis of TgAb [7]. In our study, all patients with persistent or re- risk stratification [7]. Some studies have proposed that TgAb current disease had de novo appearance of TgAb or a sig- persistence suggests persistence or recurrence of the disease nificant >50% increase during follow-up, but also no active [20, 21] even when limiting the time frame to the first year after DTC was observed in any patient in whom TgAb levels treatment in TgAb positive PTC patients [23]. Our study does became undetectable or decreased significantly over time. not support these findings. In our cohort, the pattern depicting These results agree with a previous prospective study of 576 the persistence of stable levels or increase in TgAb throughout patients with DTC, which found no statistically significant follow-up is associated with active disease. However, other difference in recurrence development between patients with studies have found no correlation between persistent TgAb and persistent undetectable TgAb (2.6%) compared with those higher frequency of recurrence or mortality [24]. Journal of Thyroid Research 5 An important point to consider is the need to establish spite of this, the limits of quantification of the different clear definitions for trends in TgAb levels and the level at assays and the discriminant values that each manufacturer which the TgAb is considered as positive. In this regard, recommends considering that a sample contains antibodies reports of the cutoff point of serum TgAb levels are scarce against Tg can vary by a factor of up to 200. The hetero- and inconsistent [25]. Some authors have used the reference geneity of the epitopes to which the antibodies are directed range provided by the manufacturer as a limit, but this and their recognition in different TgAb assays is a known specific value was established to identify autoimmune thy- cause of variation [26]. In this regard, patients with DTC roid disease and not to define interference with Tg [16]. We with restriction of the TgAb epitope similar to Hashimoto’s consider, according to other authors [11], that TgAb levels disease have a higher rate of disease recurrence or persis- “positive” or “negative” depend on the functional sensitivity tence than in patients with nonspecific reactivity, which of the assay since interference can occur at detectable TgAb suggests that TgAb epitope specificities may have prognostic concentrations below the reference limit (borderline TgAb). value [27]. In addition, the quantification of TgAb levels allows the The main strengths of our study are the strict follow-up evaluation of variations over time, which is also very im- during an average period of four years, the precise analytical portant for defining the trend pattern of an individual pa- determinations, and the homogeneity of the sample of DTC tient [8]. Some of the reasons for the discrepancies between patients coming from the same geographical area of studies may be related to some selection bias or differences in Northeastern Spain. The data presented in this study are not study design. new in themselves but, in our opinion, they broaden the base Another potential source of discrepancy is the two of scientific knowledge on a controversial topic of clinical different methods used to analyze TgAb in our study. In this significance. In addition, thyroid autoimmunity has a sense, despite being standardized according to the same multifactorial etiology with a complex interaction of envi- World Health Organization International Standard 65/93, ronmental factors in genetically susceptible individuals. these two tests give different numerical results. To validate Therefore, the influence of thyroid autoimmunity in patients our results, we made a previous comparison of the results with thyroid cancer could be significantly different obtained by these two trials in a sample of 80 subjects, depending on the populations studied, and providing data in showing that they had a high level of correlation (r � 0.92, our area is a contribution that we consider valuable. Among p < 0.001) with proportional differences (slope � 0.70), the weaknesses is the retrospective design. which indicates that the results obtained by Immulite In conclusion, from a clinical perspective, our results (Siemens) were consistently higher than those obtained with show a low prevalence of TgAb in CDT patients. When TgAb Liason (DiaSorin) (data not shown). is detected in a given patient, temporally close follow-up is The presence of endogenous TgAb may interfere in Tg mandatory for the definition of any TgAb temporal variation measurements, resulting in falsely high (in competitive pattern, thus suggesting that not only the appearance of radioimmunoassays) or falsely low (with current immu- TgAb or significant increase in TgAb but also stable TgAb nometric assays) results. The cutoff level is used to determine concentrations should be considered a warning sign. In these the qualitative status of TgAb (positive or negative), and cases, active search for recurrent or persistent disease by therefore, the interference of the Tg assays has been means of highly sensitive image scans is warranted. By established as the functional sensitivity of the tests based on contrast, a significant decline in or stable persistence of TgAb the ratio Tg-IMA to Tg-RIA. It has been shown that when the levels can be considered a good prognostic sign. manufacturer’s recommended cutoff point (used to detect thyroid autoimmunity) was used to determine the presence of TgAb, some samples showing interference were falsely Data Availability classified as negative for TgAb and this lowered the limit of The clinical and analytical data used to support the findings detection of TgAb. Functional sensitivity minimizes false of this study are available upon request to the corresponding negative ratings. 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