The Value of Diagnostic Whole-Body Scanning and Serum Thyroglobulin in the Presence of Elevated Serum Thyrotropin During Follow-Up of Anti-Thyroglobulin Antibody–Positive Patients with Differentiated Thyroid Carcinoma Who Appeared to Be Free of Disease After Total Thyroidectomy and Radioactive Iodine Ablation

Introduction

S erum thyroglobulin (Tg) is the most common follow-up test in patients with well-differentiated thyroid cancer (DTC). After total thyroidectomy followed by ablation of remnant tissue with ¹³¹I, ∼95% of patients without anti-Tg antibodies (TgAb) have serum Tg <1 ng/mL at a time when they are taking levo-thyroxine (L-T4) therapy (Tg-on-T4) (1,2). In these patients, repeat measurement of serum Tg when serum thyroid stimulating hormone (TSH) concentrations are greater than 30 mIU/L, achieved by either thyroid hormone withdrawal or administration of recombinant human TSH (rhTSH), referred to here as “stimulated Tg,” is recommended. Stimulated Tg is sometimes combined with whole-body scanning (WBS) by using a low activity of ¹³¹I or ¹²³I (diagnostic WBS [DxWBS]) (3 –5). In about 20% of patients whose serum Tg-on-T4 is <1 ng/mL, stimulated Tg values increase to >1 ng/mL (1,6 –8) and, if a DxWBS is performed, there is the occasional revelation of ectopic uptake due to metastases (8 –10).

In the presence of TgAb, which occurs in up to 25% of patients with DTC (11), serum Tg concentrations might be underestimated when measured by immunometric assays (11,12), currently the most widely used Tg assays. Therefore, adopting the proposal of Mazzaferri (13), the American Thyroid Association (4) does not recommend stimulated Tg (or DxWBS) in patients who have Tg-on-T4 values of <1 ng/mL if they have TgAb. Almost all follow-up studies of patients with DTC exclude those with TgAb. In the few that do not make this exclusion, the number of patients is small (8). We sought, therefore, to determine in patients with DTC who appeared to be free of disease after surgery and ablative treatment with radioactive iodine, but who had positive tests for serum TgAb, the value during follow-up of performing DxWBS and of obtaining stimulated Tg.

Patients and Methods

The study was approved by the Research Ethics Committee of our institution. A total of 136 consecutive patients (121 women and 15 men; age: 13–74 years, mean: 49 years) with DTC (papillary cancer in 125 and follicular cancer in 11) seen at our institution (Santa Casa de Belo Horizonte), who met the following criteria, were selected for the study. They included those who had undergone total thyroidectomy followed by remnant ablation with ¹³¹I (1.1–5.5 GBq [30–150 mCi]), those in whom apparently complete tumor resection at surgery was achieved, and those in whom post ¹³¹I-therapy WBS (RxWBS) showed no ectopic ¹³¹I uptake. To be eligible, patients also had to have a normal clinical exam, Tg-on-T4 of <1 ng/mL and a positive test for TgAb on assessment at 8–12 months (mean: 10 months) after ¹³¹I ablation. The tumor-node-metastasis (TNM) stage (14) of patients in the study was T1N0, T1N1, T2N0, T2N1, T3N0, and T3N1 in 28, 15, 23, 20, 25, and 25 patients, respectively.

Stimulated Tg (measured after L-T4 withdrawal for 4 weeks or administration of rhTSH), neck ultrasound (US), and DxWBS were obtained from all patients. Patients with stimulated Tg >1 ng/mL without disease on US and DxWBS were evaluated by other imaging methods (chest and mediastinal computed tomography [CT], WBS with ^99mTc-MIBI, RxWBS, and fluorodeoxyglucose positron emission tomography [FDG-PET]).

Results

TgAb titers ranged from 65 to 2845 IU/mL. Stimulated Tg was >1 ng/mL in 10/136 patients (7.3%). DxWBS revealed metastases in two of these patients (pulmonary and mediastinal). In eight patients with negative DxWBS, other imaging methods showed lymph node metastases in one, pulmonary metastases in one, and bone metastases in another patient. Five patients had no apparent disease, but their stimulated Tg was >1 ng/mL.

Stimulated Tg was <1 ng/mL in 126 patients. DxWBS revealed metastases in three of these patients (pulmonary metastases in one and lymph node metastases in two). US detected lymph node metastases in 4 of the 123 patients with a negative DxWBS. The remaining 119 patients had no apparent DTC.

Table 1 presents information for TgAb titers, stimulated Tg values, and imaging studies in patients with stimulated Tg >1 ng/mL and patients with stimulated Tg <1 ng/mL whose imaging studies were consistent with metastatic DTC. Five (41.6%) of the 12 patients with apparent metastases as judged by imaging studies had stimulated Tg >1 ng/mL. Regarding the imaging methods, five patients had a positive DxWBS, US revealed lymph node metastases in six (50%), and both exams were negative in two patients but DTC was detected by FDG-PET. Therefore, determination of stimulated Tg combined with DxWBS changed patient management in 13 of 136 patients (9.5%) and detected metastases in 8 (6%). Even when excluding patients with a positive neck US (n=6), DxWBS revealed metastases in four patients, and stimulated Tg values of >1 ng/mL led to the detection of disease by other imaging methods in two additional cases and to a different follow-up than would have otherwise been performed in five other cases.

Discussion

Up to 25% of patients with DTC have positive tests for TgAb (11). Unfortunately, the presence of these antibodies in the circulation may underestimate serum Tg levels as measured by immunometric assays (11,12). Two management approaches are recommended in the literature for patients with positive tests for TgAb who do not have apparent disease based on the impression of complete tumor resection at initial thyroid surgery, an RxWBS without metastases, a normal clinical exam, and Tg-on-T4 values of <1 ng/mL when their assessment is complete after initial surgery and radioactive iodine treatment. The recent North American guidelines and an invited prospective (4,13) does not recommend stimulated Tg and DxWBS, whereas some investigators propose the measurement of stimulated Tg and DxWBS (3,5,8,17,18). Knowledge about the proportion of patients with DTC who have no apparent residual disease after initial treatment (complete tumor resection at initial thyroid surgery, an RxWBS without metastases, a normal clinical exam, and Tg-on-T4 values of <1 ng/mL), who have stimulated Tg values of >1 ng/mL, and in whom metastases are revealed on imaging studies is fundamental to define the value of obtaining stimulated Tg.

In the current study, 5/12 (41.6%) patients with apparent disease based on imaging studies had stimulated Tg >1 ng/mL, demonstrating that even in the presence of TgAb, some patients with metastases have detectable Tg. Notably, TgAb do not always sufficiently interfere with serum Tg so that the latter becomes undetectable (12,19,20), especially in cases in which this protein is abundantly secreted such as patients with distant metastases (12,20). In the current study, a relevant proportion of patients with Tg-on-T4 <1 ng/mL (7.3%) converted to levels >1 ng/mL after TSH stimulation despite the presence of circulating TgAb. Concordantly, stimulated Tg levels >1 ng/mL were observed in 7/48 (14.6%) patients with Tg-on-T4 <1 ng/mL in previous studies (8,17). Therefore, measurement of stimulated Tg seem to be useful during the first year after initial therapy in patients with DTC who have no apparent residual disease after initial treatment and Tg-on-T4 <1 ng/mL even in the presence of TgAb.

The positive predictive value (PPV) of detectable levels of Tg was 50% in the current study, and this value could be even underestimated considering that recurrences may be identified during long-term follow-up. Other studies also demonstrated the elevated PPV of Tg in patients with circulating TgAb (17,19 –21). In patients with stimulated Tg >1 ng/mL after TSH stimulation in the presence of circulating TgAb without disease on US and DxWBS, other imaging methods (CT and FDG-PET) are indicated. When metastases are not readily detected, it is recommended that these patients be maintained under TSH suppression, Tg and neck US monitoring be performed more frequently, and a new Tg stimulation and DxWBS be performed after 1–2 years because of the higher risk of subsequent detection of metastases (3).

Employing the same preparation as that used for the measurement of stimulated Tg, DxWBS revealed ectopic uptake (metastases) in 5/136 (3.7%) patients, with neck US showing no anomalies in 4. Other studies also demonstrated the value of DxWBS in patients with TgAb (8,18,20,22). One limitation of DxWBS, the so-called stunning effect, can be prevented with the use of ¹²³I or of a tracer activity that does not exceed 2 mCi ¹³¹I (4,5).

Taken together, the results showed that measurement of stimulated Tg combined with DxWBS was clearly useful in 13/136 (9.6%) patients with Tg-on-T4 <1 ng/mL and positive TgAb on assessment after initial therapy (positive DxWBS and/or stimulated Tg >1 ng/mL). Even when excluding cases with positive US, these procedures changed patient management in 11/130 (8.5%) cases. If Tg stimulation and DxWBS were not performed as proposed by some investigators (4,13), the diagnosis would not have been established initially in 6/12 patients with metastases, including 4 with distant metastases. In these cases, the diagnosis would only be established if TgAb titers doubled or Tg-on-T4 would eventually become detectable (4,13), or disease would become clinically apparent, indicating progression, with the risk of a poor prognosis and lower chance of cure (23). One limitation, that is, the need for L-T4 withdrawal (associated with iatrogenic hypothyroidism), can be resolved by preparation with rhTSH. If Tg continues to be <1 ng/mL after TSH stimulation and US and DxWBS are negative, then subsequent follow-up can be done by periodic evaluation of Tg-on-T4, TgAb, and neck US (4,13). The last method is able to detect most cases of late recurrence (24). If US does not reveal anomalies but TgAb titers progressively increase, other imaging methods, especially CT and FDG-PET (18,19), are indicated.

In conclusion, measurement of stimulated Tg and DxWBS (using the same preparation) seems to be useful during the first year after initial therapy in patients with TgAb without apparent disease and Tg-on-T4 <1 ng/mL, even when neck US is negative.