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Serum antithyroglobulin antibody levels are not a good predictive factor on detection of disease activity in patients with papillary thyroid carcinoma


 Department of General Surgery, Ankara Oncology Education and Research Hospital, Ankara, Turkey

Correspondence Address:
Sevim Turanli,
Department of General Surgery, Ankara Oncology Education and Research Hospital, 06200 Ankara
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_340_17

 > Abstract 


Objective: Thyroglobulin antibodies (TgAb) are detected in thyroid cancer patients up to 25%. We investigated the prognostic value of TgAb positivity in patients with papillary thyroid carcinoma (PTC) after initial therapy.
Patients and Methods: A database of 109 consecutive patients who underwent total thyroidectomy and therapeutic lateral neck dissection followed by remnant ablation for PTC between January 1989 and December 2014 was reviewed We recorded the patients' all serum Tg and TgAb levels over time to establish changing trends. Patients were classified as either positive or negative according to serum TgAb levels. The recurrence or persistence rates in both groups were compared.
Results: Of the 109 patients enrolled 14 patients had TgAb positivity. Thirty-two (29.3%) showed disease recurrence or persistent disease during 101 months of follow-up. Twenty-seven of 95 patients (28.4%) with negative TgAb had persistent or recurrent disease, whereas 5 of 14 patients (35.7%) with positive TgAb had persistence or recurrence (P = 0.57). No significant difference in disease-free survival (115.3 ± 10.8 vs. 224.1 ± 16.6 months, P = 0.78) and overall survival (P = 0.59) was observed between TgAb positive and TgAb negative patients.
Conclusions: TgAb status is not useful as a prognostic and predictive factor for clinical outcomes in patients with PTC in our experience.

Keywords: Antithyroglobulin antibody, recurrence, surrogate marker, thyroid papillary carcinoma



How to cite this URL:
Turanli S, Mersin HH. Serum antithyroglobulin antibody levels are not a good predictive factor on detection of disease activity in patients with papillary thyroid carcinoma. J Can Res Ther [Epub ahead of print] [cited 2019 Aug 23]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=263531




 > Introduction Top


Thyroglobulin (Tg) is produced in thyroid follicles as a precursor of thyroid hormones. Since the only source of Tg is thyroid tissue, serum Tg is an important tumor marker in the follow-up of differentiated thyroid cancer (DTC) patients after total thyroidectomy to detect residual or recurrent diseases. However, Tg antibodies (TgAb) are also produced in thyroid cancer patients up to 25% which is higher than in the normal population and can interfere with the Tg measurement.[1],[2],[3] Although radioimmunometric assays appear more resistant to TgAb interference than immunometric assays, the presence of TgAb may influence the serum Tg determination in both assays.[4] Even very low concentrations of TgAb can make the serum Tg levels unreliable and mask the recurrent or persistent disease. Therefore, measuring serum TgAb concentrations becomes important and current guidelines suggest simultaneous measurement of TgAb titers and serum Tg levels for a patient under thyroxine suppression.[5]

When the Tg cannot be used as a tumor marker because of the TgAb interference during follow-up in TgAb positive DTC patients, whether changes of TgAb levels could serve as a surrogate marker of Tg levels for the disease status is unclear. Although persistence or increase of the serum TgAb level may be related to residual or recurrent disease, there is no general acceptance of the use of TgAb levels in the prediction of recurrence and prognosis. A few previous studies have reported stable or increasing serum TgAb levels during follow-up probably indicates the presence of residual disease or possibly an increased risk of recurrence,[3],[6],[7],[8] but some other investigators did not find such correlations.[9],[10],[11]

In this study, we investigated whether changes in the serum TgAb level has a predictive value for disease recurrence and serve as a prognostic factor in patients who underwent total thyroidectomy and therapeutic lateral neck dissection followed by remnant ablation by 131 I for papillary thyroid carcinoma (PTC).


 > Patients and Methods Top


Study population and ethical consideration

In this retrospective study, a database of 139 consecutive adult patients who underwent total thyroidectomy and therapeutic lateral neck dissection followed by remnant ablation by 131 I for PTC between January 1989 and December 2014 was reviewed.

Three patients with aggressive variant of PTC (such as the insular and tall cell variant) and four patients who had distant metastases at the time of remnant ablation, two patients who had concurrent extrathyroid carcinoma, 14 patients who had histological evidence of lymphocytic thyroiditis at pathologic examination, and 7 patients who had no postoperative follow-up were excluded from the series. Permission was obtained from the Institutional Review Board of Ankara Oncology Education and Research Hospital, and the study was conducted in accordance with the Declaration of Helsinki.

Assays and evaluation of changes in thyroglobulin antibodies and thyroglobulin

During the study, Tg and TgAb measurements were completed using the Siemens Centaur XP immunoassay, a quantitative, chemiluminescent immunometric assay according to the manufacturer's recommendation and its cut-off value was 60 IU/mL. Serum TgAb values >60 IU/mL were considered positive.

Serum Tg, TgAb, and thyrotropin thyroid-stimulating hormone (TSH) were measured in all patients at the time of the radioiodine ablation treatment initially then every 3–6 months during thyroxine supplementation. We recorded the patients' all serum Tg and TgAb levels (on thyroxin therapy) over time to establish changing trends. Patients were classified as either positive or negative according to serum TgAb levels. Positive TgAb status included patients whose first postoperative TgAb level ≥60 IU and remained above this level during all period, and patients whose TgAb levels <60 IU initially then increase progressively during the follow-up period.

Follow-up

Serum-stimulated Tg, TgAb, and TSH was measured 1-month postoperatively without thyroxine treatment then 131 I remnant ablation was performed at most in 6 months postoperatively in all patients. After the radioiodine ablation, thyroxine supplementation was given. We followed the patients by conducting imaging studies such as neck ultrasonography, chest roentgenography as well as tomography, magnetic resonance imaging, fluorine-18 fluorodeoxyglucose positron emission or 131 I uptake on whole body scanning if indicated. Surveillance laboratory test consisted of serum Tg, TgAb, and TSH measurements every 3 to 6 months in first 2 years then annually based on the clinician's discretion. Recurrence was defined as any structural abnormality 1 year after complete ablation of thyroid remnants detected by imaging studies or positive cytological or surgical histopathological findings. Persistent disease was defined as the reappearance of disease within 1 year. Once recurrent lesions were suspected, radioiodine ablation and/or surgical excision were performed wherever appropriate. External beam radiation therapy was used in patients with advanced local disease or palliative intent for distant bony metastasis.

Statistical analysis

Demographic and clinical factors between patients without TgAb and those with TgAb were compared using Chi-squared or Fisher's exact tests, and continuous data were compared using a Student' t-test. In addition, Fisher exact test was used to determine an association between positive TgAb levels and persistent or recurrence disease. Lateral lymph node dissection was the starting point for disease-free survival and overall survival. Patients were followed up until either to death or to the last date the patient was known to be alive. Univariate survival curves for disease-free survival and death were estimated using the Kaplan–Meier method for the patients without persistent disease; group differences in survival time were tested by the log-rank test. All tests were two-tailed, and P values <0.05 were considered statistically significant. All statistical analyses were performed using the SPSS for Windows version 18.0 (SPSS Inc., Chicago, IL, USA).


 > Results Top


In this study, we enrolled 109 patients (66 women and 43 men) found to have PTC with clinical N1b lymph node metastasis who underwent total thyroidectomy and lateral lymph node dissection followed by immediate 131 I remnant ablation at tertiary referral center. Their median age was 48 years (18–74 years), and the histological subtypes were papillary carcinoma in 95, follicular variant in 14 patients. The median follow-up time was 101 months, with a range of 16–308 months.

The surge of the serum Tg Ab level in enrolled patients is given [Figure 1]. The cohort was stratified into TgAb negative (n = 95) and positive groups (n = 14). Of the 95 patients, 85 (78%) were negative for TgAb at remnant ablation and remained negative during follow-up, 10 (9.2%) patients had high TgAb levels initially but display a falling trend after the remnant ablation and had complete TgAb resolution in follow-up (TgAb negative group). Fourteen patients (12.8%) were positive for TgAb postoperatively, 8 (7.3%) of these patients continued to have persistently elevated TgAb levels until the last follow-up, and other 6 (5.5%) patients sustained rise of TgAb levels at any time (TgAb positive group).
Figure 1: The surge of the serum thyroglobulin antibodies level in enrolled patients

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[Table 1] summarizes the patients and tumor characteristics between positive and negative TgAb groups. There was no statistically significant difference between positive and negative TgAb groups according to the clinicopathological features except postoperative stimulated Tg level. Mean first stimulated Tg levels before the remnant ablation was lower in TgAb positive group compared with TgAb negative groups (P = 0.006).
Table 1: Patients and tumor characteristics

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During the study period, 32 of the 109 patients (29.3%) showed disease recurrence or persistent disease. Among the 95 patients in the TgAb negative group, 27 patients (28.4%) were confirmed to have recurrent or persistent disease whereas 5 of 14 patients (35.7%) in the TgAb positive group had recurrent or persistent disease. The rate of disease recurrence or persistence was not statistically different between the TgAb positive and negative groups (P = 0.57). Out of the 32 patients who have recurrent or persistent disease 30 patients had high Tg levels, 5 of whom had also high TgAb levels. Only two patients with recurrence or persistence had both low Tg and TgAb level and hence, it could not be possible to predict recurrence or persistence biochemically for these patients.

In this study, Tg level had a 93.7% sensitivity and 89.6% specifity for identifying patients with recurrence or persistence on follow-up whereas those of TgAb were 15.6% and 88.3%, respectively. The positivity of TgAb displayed positive predictive value for recurrent disease of 35%, while the negative predictive value of low TgAb level was 71%.

Furthermore, TgAb status could not predict the prognosis of patients with PTC in the study cohort. No significant difference in disease-free survival (115.3 ± 10.8 vs. 224.1 ± 16.6 months, P = 0.78), and overall survival (P = 0.59) was observed between TgAb positive and TgAb negative groups.


 > Discussion Top


Although Tg is an important tumor marker to detect recurrence or persistence and monitoring of papillary thyroid cancer after total thyroidectomy, presence of circulating TgAb makes the Tg unreliable and needs a surrogate marker of carcinoma recurrence. Therefore, identification of whether TgAb positivity irrespective of Tg levels was a predictive marker in the surveillance of homogeneous group of patients with PTC is important. In the present study, we studied whether TgAb positivity can predict recurrent or persistent disease in patients with PTC following total thyroidectomy and lateral lymph node dissection and 131 I remnant ablation therapy. The rate of TgAb positivity in our cohort was 12.8% which was similar to those reported values of 10%–25% range in the literature.[1],[2][3],[10] The presence of circulating TgAb makes the Tg unreliable as a tumor marker and needs a surrogate marker of carcinoma recurrence.[12] TgAb may be used for this purpose, but previous studies on this role of TgAb in patients with DTC are open to dispute.

In a recent study of 226 DTC patients with undetectable Tg levels, Chung et al. found a higher rate of recurrence in patients with TgAb positive and Tg negative than those with TgAb and Tg negative.[6] A similar study of 824 patients by Kim et al. confirmed the finding of higher rate of recurrence in patients with TgAb positive and Tg negative at 6–12 months after ablation therapy and additionally reported that the change in TgAb levels between the time remnant ablation and 6–12 months thereafter may be predictive value for recurrence.[3]

Actually, transient elevation of TgAb level may be observed in patients with PTC following surgery or ablation therapy.[13] However, eradication of follicular cells by surgical resection or ablation leads to progressive decrease in TgAb levels and ultimately their complete disappearance in patients who achieve complete remission. In contrary, persistently elevated TgAb or progressive increase in serum TgAb level which was decreased following initial therapy could be evidence of the continued presence of functional thyroid cells in residual thyroid tissue or recurrence of disease. Consequently, it is concluded that changes in postoperative TgAb levels may serve as a surrogate marker in PTC patients who had undetectable Tg in several recent reports.[7],[14],[15]

In contrast to these studies, we did not find a relationship between TgAb positivity and cancer recurrence and survival in patients with PTC following total thyroidectomy and lateral lymph node dissection and ablation therapy. In our study population, TgAb positivity had no predictive value for persistence or recurrence in patients with PTC. The different findings between current and above-mentioned studies might be attributed to several points. First, unlike above-mentioned studies, our study includes both positive and negative TgAb patients irrespective of Tg levels. We intended to evaluate the predictive role of TgAb levels in the entire patients of follow up. However, all of these previous studies were limited to subsets of patients who had positive TgAb with undetectable Tg values and therefore are subject to considerable selection bias. Second, there are variations in the timing of the TgAb measurement between studies. The prevalence of circulating TgAb in patients who underwent total thyroidectomy followed by remnant ablation might be affected by the timing of TgAb measurement. There might be different reasons of TgAb positivity other than the recurrences of thyroid cancer, especially at early postoperative period. Even if the serum TgAb level could be falsely high in early postoperative period, continuously decreased in most patients by time. Most of the above studies have evaluated the TgAb level measured at 6–12 months after remnant ablation or 1–2 years after thyroidectomy. These durations are relatively short to assess the real TgAb status. Although the median half-life of TgAb was 10 weeks,[15] Chiovato et al. reported that the median disappearance time of TgAb was 3 years after complete ablation of thyroid tissue by thyroidectomy or radioactive iodine treatment.[16] Therefore, sequential measurements in serum TgAb levels during follow-up rather than only initial or isolated TgAb level at any time may reflect the TgAb trends more reliable and are useful for prediction of recurrence or persistence in TgAb positive PTC patients.[13] Since we evaluated the changing trend in serum TgAb level and identified the status of TgAb after the resolution period was completed in current study, our cohort did not include patients with false positive serum TgAb level. Third, different TgAb immunoassays methods have been used for TgAb measurement among studies. There are inherent variations of current TgAb assays. They have different sensitivity limits and the cutoff values that manufacturers recommend to define positive TgAb.[4] In addition, TgAb detected one method may not be detected by another method.[17],[18],[19] Eventually, the serum of one patient produces different TgAb numeric results with different methods.[17],[18],[19],[20],[21] This makes the comparison of TgAb values difficult between assays. In current study, serum Tg and TgAb have been measured consistently using same quantitative, chemiluminescent immunometric assay throughout the study. However, it was prone to interference which might cause an underestimation of serum Tg levels. Nevertheless, serum Tg levels maintain importance for prediction of recurrence or persistence in TgAb positive PTC patients in our series.

On the other hand, there are several recent studies suggested positive serum TgAb is not a predictive factor for recurrence and is not associated with prognosis of PTC patients, as similar with our study. In one of them, Smooke-Praw et al. reported that neither absolute TgAb level nor TgAb trends had predictive value in the surveillance of patients with PTC. They concluded that the follow-up of TgAb positive patients should rely on high-quality imaging until a valid alternative serum marker for Tg is identified.[9] In the more recent study of 247 patients with thyroid cancer and TgAb measured preoperatively, Xu et al. also reported that both preoperative TgAb positivity and persistently elevated TgAb levels after initial therapy were not associated with recurrence.[10] Another recent study of 1206 PTC patients by Kuo et al. which used the competitive radioimmunoassay was concordant in finding no predictive value of TgAb in the surveillance of patients with PTC.[11]

The results of above and current studies have raised doubts regarding the prognostic value of the TgAb status as a surrogate marker in the surveillance of Tg negative patients with PTC. Although thyroid tissue is intact, TgAb level does not elevate in normal population or all thyroid cancer patients preoperatively. Similarly, TgAb might not elevate in all patients with residual thyroid tissue or thyroid carcinoma recurrence, as shown in the present study. Therefore, whether TgAb level reflects the thyroid tissue mass remains doubtful.

However, the current study was limited by a relatively small number of patients from single institution. Only 14 of our 95 patients had TgAb positivity, which might be insufficient to identify significant differences in prognostic outcome between TgAb positive and TgAb negative patients. In addition, we have no data regarding the preoperative TgAb status of study patients, which would help to interpret more reliably about postoperative changing patterns of TgAb. Furthermore, this was a retrospective study with consequent methodological limitations.


 > Conclusions Top


TgAb status does not seem to be associated with prognosis in patients with PTC after initial treatment. Data from the current study suggest that both persistently elevated TgAb levels and increasing trends in TgAb levels might not be considered as a predictive indicator of persistent or recurrent disease. It should be noticed that this study consist of small number of patients. Considering the previous studies and our study, the role of TgAb as a surrogate serum marker for Tg has to be validated with further studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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Spencer CA, LoPresti JS, Fatemi S, Nicoloff JT. Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid 1999;9:435-41.  Back to cited text no. 1
    
2.
Spencer CA. Clinical review: Clinical utility of thyroglobulin antibody (TgAb) measurements for patients with differentiated thyroid cancers (DTC). J Clin Endocrinol Metab 2011;96:3615-27.  Back to cited text no. 2
    
3.
Kim WG, Yoon JH, Kim WB, Kim TY, Kim EY, Kim JM, et al. Change of serum antithyroglobulin antibody levels is useful for prediction of clinical recurrence in thyroglobulin-negative patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 2008;93:4683-9.  Back to cited text no. 3
    
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Spencer C, Fatemi S. Thyroglobulin antibody (TgAb) methods-strengths, pitfalls and clinical utility for monitoring TgAb-positive patients with differentiated thyroid cancer. Best Pract Res Clin Endocrinol Metab 2013;27:701-12.  Back to cited text no. 4
    
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Tsushima Y, Miyauchi A, Ito Y, Kudo T, Masuoka H, Yabuta T, et al. Prognostic significance of changes in serum thyroglobulin antibody levels of pre- and post-total thyroidectomy in thyroglobulin antibody-positive papillary thyroid carcinoma patients. Endocr J 2013;60:871-6.  Back to cited text no. 7
    
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Durante C, Tognini S, Montesano T, Orlandi F, Torlontano M, Puxeddu E, et al. Clinical aggressiveness and long-term outcome in patients with papillary thyroid cancer and circulating anti-thyroglobulin autoantibodies. Thyroid 2014;24:1139-45.  Back to cited text no. 8
    
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Smooke-Praw S, Ro K, Levin O, Ituarte PH, Harari A, Yeh MW. Thyroglobulin antibody levels do not predict disease status in papillary thyroid cancer. Clin Endocrinol (Oxf) 2014;81:271-5.  Back to cited text no. 9
    
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Xu J, Bergren R, Schneider D, Chen H, Sippel RS. Thyroglobulin antibody resolution after total thyroidectomy for cancer. J Surg Res 2015;198:366-70.  Back to cited text no. 10
    
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Kuo SF, Chao TC, Chang HY, Hsueh C, Lin CL, Chiang KC, et al. Prognosis of papillary thyroid cancers with positive serum thyroglobulin antibody after total thyroidectomy. Asian J Surg 2017;40:186-92.  Back to cited text no. 11
    
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Spencer CA, Takeuchi M, Kazarosyan M, Wang CC, Guttler RB, Singer PA, et al. Serum thyroglobulin autoantibodies: Prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998;83:1121-7.  Back to cited text no. 12
    
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Görges R, Maniecki M, Jentzen W, Sheu SN, Mann K, Bockisch A, et al. Development and clinical impact of thyroglobulin antibodies in patients with differentiated thyroid carcinoma during the first 3 years after thyroidectomy. Eur J Endocrinol 2005;153:49-55.  Back to cited text no. 13
    
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Hsieh CJ, Wang PW. Sequential changes of serum antithyroglobulin antibody levels are a good predictor of disease activity in thyroglobulin-negative patients with papillary thyroid carcinoma. Thyroid 2014;24:488-93.  Back to cited text no. 14
    
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Yamada O, Miyauchi A, Ito Y, Nakayama A, Yabuta T, Masuoka H, et al. Changes in serum thyroglobulin antibody levels as a dynamic prognostic factor for early-phase recurrence of thyroglobulin antibody-positive papillary thyroid carcinoma after total thyroidectomy. Endocr J 2014;61:961-5.  Back to cited text no. 15
    
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Chiovato L, Latrofa F, Braverman LE, Pacini F, Capezzone M, Masserini L, et al. Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens. Ann Intern Med 2003;139:346-51.  Back to cited text no. 16
    
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La'ulu SL, Slev PR, Roberts WL. Performance characteristics of 5 automated thyroglobulin autoantibody and thyroid peroxidase autoantibody assays. Clin Chim Acta 2007;376:88-95.  Back to cited text no. 17
    
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Taylor KP, Parkington D, Bradbury S, Simpson HL, Jefferies SJ, Halsall DJ. Concordance between thyroglobulin antibody assays. Ann Clin Biochem 2011;48:367-9.  Back to cited text no. 18
    
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Pickett AJ, Jones M, Evans C. Causes of discordance between thyroglobulin antibody assays. Ann Clin Biochem 2012;49:463-7.  Back to cited text no. 19
    
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Spencer CA, Bergoglio LM, Kazarosyan M, Fatemi S, LoPresti JS. Clinical impact of thyroglobulin (Tg) and tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas. J Clin Endocrinol Metab 2005;90:5566-75.  Back to cited text no. 20
    
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