Role of Preablative Stimulated Thyroglobulin in Prediction of Nodal and Distant Metastasis on Iodine Whole-Body Scan

Abstract

Background:

Preablative stimulated thyroglobulin (ps-Tg) is an important investigation in the follow-up of patients with Differentiated thyroid cancer(DTC) after surgery. Levels of ps-Tg >2–10 ng/ml have been suggested to predict metastasis to cervical and extracervical sites. There is still debate on the need for routine iodine whole-body scan (¹³¹I WBS) in the management of low-to-intermediate-risk DTC patients.

Objective:

We analyzed our data of patients with DTC who underwent total thyroidectomy to discuss the predictability of ps-Tg on metastatic disease on the ¹³¹I WBS.

Materials and Methods:

Retrospective analysis of patient records.

Results:

One hundred and seventeen patients with DTC (95 papillary thyroid cancer [71 had classic histology, 8 had tall cell variant, 16 had follicular variant] and 22 follicular thyroid cancer [18 minimally invasive, 2 hurtle cell, and 2 widely invasive cancers]) had undergone total thyroidectomy. All these patients underwent ps-Tg assessment and an ¹³¹I WBS. About 65% of them went on to have radioiodine ablation along with a posttherapy ¹³¹I WBS. We divided the cohort into four groups based on their ps-Tg levels: Group 1 (ps-Tg <1), Group 2 (ps-Tg 1–1.9), Group 3 (ps-Tg 2–5), and Group 4 (ps-Tg >5). None of the patients in Group 1, 7% of those combined in Groups 2 and 3 (2 out of 28 patients), and 26% (12 out of 47) of those in Group 4 had either cervical or extracervical metastasis. Those with extracervical metastatic disease to lungs and bones had a mean (standard deviation) ps-Tg value of 436 (130) and median of 500 ng/ml and those with cervical metastatic disease had a mean Tg value of 31 (64) and median 6.6 ng/ml.

Conclusions:

A ps-Tg value in the absence of anti-Tg antibodies <1 ng/ml reliably excludes metastatic disease in DTC, while a value >5 ng/ml has a 26% risk of having either cervical or extracervical metastasis.

Introduction

Differentiated thyroid carcinoma (DTC), arising from the thyroid follicular epithelial cells, accounts for the vast majority of thyroid cancers. Of the DTCs, papillary thyroid cancer (PTC) comprises about 85% of cases compared to about 12% that have follicular histology. Overall treatment outcome regarding DTC is excellent, and the 10-year survival rate is about 90%; the rate of persistent or recurrent cases is 23–30%.[1] Surgery, selective postoperative radioactive iodine (RAI) therapy, and thyroid-stimulating hormone (TSH) suppressive therapy are the primary treatment modalities for DTC. Postoperative serum thyroglobulin (Tg) on thyroid hormone therapy or after TSH stimulation (preablative stimulated thyroglobulin [ps-Tg]) can help in predicting the presence of metastatic disease outside the thyroid bed on the iodine whole-body scan (¹³¹ I WBS), predicting potential future disease recurrence, guide need for radioiodine treatment.[1] However, the predictive value of the postoperative Tg value will be significantly influenced by a wide variety of factors including the presence of antithyroglobulin antibodies (anti-Tg Ab), the amount of residual thyroid cancer and/or normal thyroid tissue, the TSH level at the time of Tg measurement, the functional sensitivity of the Tg assay, the Tg cutoff used for analysis, the individual risk of having RAI-avid locoregional or distant metastasis, the time elapsed since total thyroidectomy, and/or the sensitivity of the posttherapy scanning technique (single-photon emission computed tomography [CT]/CT vs. planar imaging). No uptake outside the thyroid bed was identified in 132 low-risk patients with a ps-Tg of <1 ng/mL.[2,3,4,5,6,7,8,9,10,11] However, RAI-avid metastatic foci outside the thyroid bed were detected in 6.3% of intermediate-/high-risk patients with a ps-Tg of <2 ng/mL.[12] The American Thyroid Association (ATA) guideline concludes stating that the likelihood of finding RAI-avid metastatic disease on the posttherapy scan is substantially lower (2.8%) if the postoperative Tg is undetectable in three different Tg assays than if it is undetectable only in a single assay (30%).[1] Conversely, the likelihood of identifying either locoregional or distant metastases on the posttherapy scan increases as ps-Tg values rise above 5–10 ng/mL.[5,13,14,15] While a ps-Tg of <1 ng/mL may not completely eliminate the possibility of identifying a metastatic foci outside the thyroid bed on a posttherapy RAI scan, ps-Tg values >5–10 ng/mL increase the likelihood of identifying RAI-avid metastatic disease on the posttherapy scan. ps-Tg values <1–2 ng/mL are strong predictors of remission, while ps-Tg values >10–30 ng/mL increase the likelihood of having persistent or recurrent disease, failing initial RAI ablation, having distant metastases, and dying of thyroid cancer.[1] Postoperative diagnostic RAI WBSs may be useful when the extent of the thyroid remnant or residual disease cannot be accurately ascertained from the surgical report or neck ultrasonography and when the results may alter the decision to treat or the activity of RAI that is to be administered. The ps-Tg value along with the ¹³¹ I WBS is likely to be helpful in identifying patients that may benefit from RAI ablation.

Aims

We analyzed our data of patients with DTC who underwent total thyroidectomy to discuss the predictability of ps-Tg and on metastatic disease on the ¹³¹ I WBS.

Settings and design

This was a retrospective study of health records.

Materials and Methods

We retrospectively studied 117 patients who underwent total thyroidectomy and had a ps-Tg assessment and a diagnostic ¹³¹ I WBS. The study was conducted from January 2015 to January 2016 at Narayana Health City, Bangalore, after approval by the Institutional Review Board. All 117 patients had undergone total thyroidectomy by a team of high-volume thyroid surgeons (authors NHC, VP, VS, MAK, and BV). Levels of Tg and anti-Tg Ab were determined using electrochemiluminescence immunoassay, and TSH level was determined using chemiluminescence immunoassay. The functional sensitivity of the Tg assay was <1 ng/ml, and values of anti-Tg Ab >100 IU/L were considered as positive anti-Tg Ab. Patient details were noted including age, sex, histology subtypes, lymph node metastasis, distant metastasis (bone/lung/others), findings on diagnostic ¹³¹ I WBS, serum TSH, ps-Tg, and anti-Tg Ab levels. These patients underwent ¹³¹ I WBS after levothyroxine (LT4) withdrawal and a low-iodine diet for 2–6 weeks when serum TSH >30 μIU/mL. Patients received ¹³¹ I at a dose that varied from 30 mCi (1.1 GBq) to 200 mCi (7.4 GBq) according to their ATA recurrence risk stratification. Posttherapy WBS was performed after 48 h and compared with the pretherapy WBS to assess if there was any alteration in the disease stage. We divided the cohort into four groups based on their ps-Tg levels – Group 1 (ps-Tg <1), Group 2 (ps-Tg 1–1.9), Group 3 (ps-Tg 2–5), and Group 4 (ps-Tg >5) – and analyzed the predictability of ps-Tg value on findings on the ¹³¹ I WBS.

Approval

The study was approved by our hospital's ethics committee.

Statistical analysis used

Results on continuous measurements are presented as mean (standard deviation [SD]) and median, and results on categorical measurements are presented as percentages (%). P < 0.05 was considered statistically significant. Mean (SD) and median Tg level were calculated for each of the four groups as described above.

Results

One hundred and seventeen patients with DTC (95 PTC [71 had classic histology, 8 had tall cell variant, and 16 had follicular variant] and 22 follicular thyroid cancer [18 minimally invasive, 2 hurtle cell, and 2 widely invasive cancers]) had undergone total thyroidectomy, and they underwent ps-Tg assessment before their ¹³¹ I WBS. About 74% were females and mean (SD) age was 41 (15) years. About 65% of them went on to have radioiodine ablation (RIA) at our institution along with a posttherapy ¹³¹ I WBS. Among those who did not undergo RAI, 32% had no uptake on ¹³¹ I WBS. None of the patients had an upstaging of their disease on the posttherapy scan. There were 34 patients (29%) in Group 1; of them, six patients were excluded as their anti-Tg antibody titers were >100 IU/L and five patients did not have any demonstrable uptake on their WBS and did not undergo RIA. Group 2 had 12 patients (10%); among them, three of them had anti-Tg >100 IU/L (excluded from analysis), none had extracervical metastatic disease, and only one patient had ipsilateral cervical metastasis picked up on the WBS. Group 3 had 19 patients (16%); among them, none had positive anti-Tg antibodies, two patients had no uptake on WBS, none had extracervical metastatic disease, and only one patient had ipsilateral cervical metastasis picked up on the WBS. Group 4 had 52 patients (45%); among them, five patients had anti-Tg >100 IU/L (excluded from analysis), two patients had no uptake on WBS, five patients had extracervical metastasis (four had bone and lung metastasis, two had concurrent lymph node metastasis, and one had isolated lung metastasis), and seven patients had cervical lymph node metastasis as diagnosed by the ¹³¹ I WBS. Among those in Group 4, 32 patients (62%) underwent RIA and no additional sites of metastatic disease were noted in them. Fourteen patients (12%) had anti-Tg antibody titers >100 IU/L (median titers 219 IU/L); among them, three had cervical nodal metastasis, one had lung metastasis, and one had bone metastasis. While those with extracervical metastatic disease to lungs and bones had a mean (SD) ps-Tg value of 436 (130) ng/ml and median of 500 ng/ml, those with cervical metastatic disease had a mean Tg value of 31 (64) ng/ml and median 6.6 ng/ml. These results of the Tg and the WBS results are shown in Tables 1a–d. A ps-Tg value in the absence of anti-Tg antibodies <1 ng/ml reliably excludes metastatic disease in DTC, while a value >5 ng/ml has a 26% risk of having either cervical or extracervical metastasis [Figure 1].

Table 1a.

Details of patients with preablative stimulated thyroglobulin <1 μg/L

Table 1d.

Details of patients with pre-ablative stimulated Tg >5

Figure 1.

Scatter plot between Tg levels and findings as per I¹³¹ whole-body scan. The Tg data have been reproduced in logarithmic scale

Table 1b.

Details of patients with preablative stimulated thyroglobulin 1-1.9 μg/L

Table 1c.

Details of patients with preablative stimulated thyroglobulin 2-5 μg/L

Discussions

Our study reaffirms the value of ps-Tg in terms of predicting the staging of the disease on the ¹³¹ I WBS. This can help tailoring RIA, using it routinely for those with ps-Tg >5 ng/ml, individualizing for those with ps-Tg between 1 and 5 ng/ml, and avoiding in those with ps-Tg <1 ng/ml, provided there is no antibody interference to Tg measurement. In one of the prospective studies with a follow-up of 6 years, patients with ps-Tg <1 μg/L did not receive RAI, while those with ps-Tg >5 μg/L routinely did and those with ps-Tg 1–5 μg/L received RAI on the basis of several clinical risk factors.[16] In this study, 116 (90%) patients in this cohort have not received RAI therapy with no evidence of residual/recurrent disease, whereas among the 13 patients who received RAI, 1 (8%) had pathologic residual/recurrence disease.

Surgical remnant and laboratory techniques can significantly affect serum Tg and anti-Tg levels. The limitations include the absence of posttherapy WBS data in 35% of patients, staging of the disease was done at the time of initial assessment, and long-term follow-up data of this cohort are not available at the time of submission.

Conclusions

A ps-Tg value in the absence of anti-Tg antibodies <1 ng/ml reliably excludes metastatic disease in DTC, while a value >5 ng/ml has a 26% risk of having either cervical or extracervical metastasis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.