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Positive Predictive Value of Serum Thyroglobulin Levels, Measured during the First Year of Follow-Up after Thyroid Hormone Withdrawal, in Thyroid Cancer Patients

Departments of Nuclear Medicine and Endocrine Tumors, Surgery, Institut Gustave Roussy, Villejuif, France 94805

Address all correspondence and requests for reprints to: M. Schlumberger, Institut Gustave Roussy and University Paris-Sud, 39, Rue Camille-Desmoulins, 94 805 Villejuif Cedex, France. E-mail: schlumbg{at}igr.fr.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
The follow-up of patients with papillary and follicular thyroid carcinoma after thyroidectomy and radioiodine ablation is mainly based on serum thyroglobulin (Tg) level deter-mination.

The positive predictive value (PPV) of serum Tg level after thyroid hormone withdrawal, measured during the first 6–12 months of follow-up (initial off L-T₄ Tg), was studied in 256 consecutive differentiated thyroid cancer patients. All underwent a total thyroidectomy and 3.7 GBq ¹³¹I ablation; 37 patients had an elevated initial off L-T₄ Tg level. This study focuses on these 37 patients, 9 of whom had a clinical recurrence.

The present data confirm that in this selected cohort of patients, 74–185 MBq ¹³¹I-total body scan (TBS) has no clinical interest in the initial work-up and during the subsequent follow-up because it was negative in all patients, except in one with recurrent disease. The PPV of initial serum off L-T₄ Tg level above 5 ng/ml and 10 ng/ml was 42% and 53%, respectively; this PPV was only 50% at the time of recurrence or subsequent control. This relatively low PPV is related to the low recurrence rate in this series of patients, despite a prolonged follow-up, and to the subsequent decrease of serum Tg level in 14 of 37 (38%) patients in the absence of any further treatment. In contrast, the PPV of the increasing slope of serum Tg levels obtained after thyroid hormone withdrawal (83%) was excellent.

In conclusion, we confirm that ¹³¹I-TBS has a limited interest for the follow-up of thyroid cancer patients. Follow-up should rely on serum Tg level and prognostic parameters; however, initial serum Tg may be produced by thyroid tissues of various significance, an increase at two consecutive determinations indicating disease progression and a decrease being related to late effects of therapy. The best PPV is brought by the slope of serum Tg levels.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
TOTAL OR NEAR-TOTAL thyroidectomy is advocated in patients with papillary and follicular thyroid cancer larger than 1 cm in diameter and is followed by ¹³¹I ablation of residual thyroid in those patients with a high risk of recurrence and/or cancer-related death (1, 2, 3, 4). One goal of this approach is to optimize the diagnostic value of the two mainstays used during follow-up, i.e. serum thyroglobulin (Tg) measurement and ¹³¹I-total body scan (TBS; Refs. 1 , 4 , and5).

In a series of 256 consecutive patients who had no evidence of disease, we recently demonstrated that the control ¹³¹I-TBS with 74–185 MBq performed during the first year of follow-up has no diagnostic impact; no focus of uptake outside the thyroid bed was depicted in any patient, and the low thyroid bed uptake found in some patients could not be considered as the source of the serum Tg (6). This study suggested avoiding routine ¹³¹I-TBS and focusing on the predictive value of serum Tg level. This was confirmed by several studies comparing serum Tg level and ¹³¹I-TBS with a preparation by recombinant human TSH or thyroid hormone withdrawal (7, 8, 9, 10).

After total thyroid ablation, the sensitivity of serum Tg measurement is 80–100%, depending mainly on tumor burden, and is improved after thyroid hormone withdrawal (5, 11). We recently reported a 99% negative predictive value of undetectable serum Tg level obtained after thyroid hormone withdrawal during the first year of follow-up, and this was confirmed by other studies (7, 10). In this situation, serum Tg level was detectable in 15% of thyroid cancer patients who had no other evidence of disease, including a normal ¹³¹I-TBS performed with 74–185 MBq (2–5 mCi; Ref. 6). In previous studies, a ¹³¹I-TBS with 3.7 GBq (100 mCi) disclosed foci of uptake in about two thirds of those patients with a Tg level above some arbitrary level (>10 ng/ml; Refs. 12, 13, 14, 15). However, a recent study demonstrated a subsequent decrease of serum Tg level in some patients, even in the absence of any further treatment (16). This suggests that although a 100% specificity can be assigned to serum Tg level when measured with a modern immunoradiometric method, serum Tg may be produced by thyroid tissues of various significance, including normal residual thyroid, tumor thyroid tissue, or already irradiated normal or tumor thyroid tissue that will thereafter disappear without any further treatment.

The aim of the present study was to assess in our series of 256 consecutive patients (1) the spontaneous time course of serum Tg level and (2) the positive predictive value (PPV) of serum Tg level measured after thyroid hormone withdrawal during the first year of follow-up.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
A total of 256 consecutive patients who were initially treated between 1990 and 1997 and then followed at the Institut Gustave-Roussy (Villejuif, France) were included in the present study. They were 201 females and 55 males, ranging in age from 13–75 yr (mean age, 45 yr). Thyroid carcinomas were classified as papillary in 200 patients, well differentiated and minimally invasive follicular in 27, and poorly differentiated and widely invasive follicular carcinoma in 29 (17). The pathological tumor-node-metastasis (pTNM) classification of these 256 patients was: T1-N0, N1, or Nx in 30, 19, or 6 patients, respectively; T2-N0, N1, or Nx in 49, 36, or 8 patients, respectively; T3-N0, N1, or Nx in 12, 3, or 5 patients, respectively; T4-N0, N1, or Nx in 18, 51, or 10 patients, respectively; and Tx in 9 patients (18). They fulfilled the following criteria (6): 1) A near-total or total thyroidectomy was performed in all, with lymph node dissection in 225 patients. 2) One month after surgery, during which thyroid hormone treatment was withheld, 3.7 GBq (100 mCi) ¹³¹I were administered; at that time, the serum TSH level was above 30 µU/ml in all patients. A ¹³¹I-TBS was performed 4 d after the administration of ¹³¹I and showed uptake only in the thyroid bed, representing less than 2% of the administered activity; patients with uptake outside the thyroid bed were not included in the study because they required other therapeutic procedures (Refs. 1 and 4). 3) T₄ treatment was then initiated, with the aim of decreasing serum TSH to low levels (<0.1 µU/ml) without inducing a clinical thyrotoxicosis. This was controlled 3 months later by measuring serum free T₃ and TSH levels (Ref. 1). 4) A control ¹³¹I-TBS with 74–185 MBq (2–5 mCi) was performed 9 ± 3 months after initial treatment following thyroid hormone withdrawal and showed no uptake in 236 patients (92%) and only a low uptake in the thyroid bed in the other 20 (not measurable in 19 and equal to 1% in 1); serum TSH was above 30 µU/ml in all patients. A dual head -camera (DHD-SMV, Sopha Medical, Buc, France) equipped with high energy collimators and thick crystals was used at a constant low speed, over 30 min. 5) Serum Tg was measured during thyroid hormone treatment 3 months after initial treatment (initial on L-T₄ Tg), and again after thyroid hormone withdrawal, 6–12 months after initial thyroid surgery, at the time of the first control ¹³¹I-TBS (initial off L-T₄ Tg). A commercial kit (Dynotest Tg, BRAHMS, Berlin, Germany) with a functional sensitivity of 1 ng/ml was used in all patients (5). A recovery test was performed in all serum samples and did not show interference (recovery > 80%) in any sample. The eight patients with interference in the Tg assay were not included in the study.

Complete remission was defined as a normal clinical examination, a negative control ¹³¹I-TBS (i.e. no uptake outside the thyroid bed), and an undetectable Tg level after withdrawal of thyroid hormone treatment.

Follow-up

The first work-up was performed 6–12 months after initial treatment in all patients. The subsequent follow-up included a yearly clinical examination with serum TSH and Tg measurements. In patients with detectable serum Tg level during T₄ treatment, with serum Tg above 5 ng/ml after thyroid hormone withdrawal, or with any clinical abnormality, ultrasonography and chest x-rays were performed, and another ¹³¹I-TBS with 74–185 MBq and a serum Tg measurement were obtained after thyroid hormone withdrawal. In patients with a serum Tg above 10 ng/ml after thyroid hormone withdrawal, a ¹³¹I-TBS was performed with 3.7 GBq (100 mCi). Finally, in these patients, neck and lung computed tomography and bone scintigraphy were scheduled in case of negative 3.7 GBq ¹³¹I-TBS.

The PPV of the initial serum off Tg level, measured 6–12 months after thyroid surgery (initial off L-T₄ Tg) was studied, taking into account two cut-off levels, 5 and 10 ng/ml. The PPV of the subsequent control off L-T₄ Tg level (control off L-T₄ Tg) obtained more than 1 yr after thyroid surgery was also studied. Furthermore, the slope between initial and subsequent control off L-T₄ Tg levels was classified as increasing when control off L-T₄ Tg level was 50% or more above its initial value, as stable, or as decreasing when control off L-T₄ Tg level was 50% or less below its initial value. For each of these categories, the recurrence rate was assessed. No other therapeutic procedures were given between the initial and control off L-T₄ Tg measurements. The last off L-T₄ Tg level refers to a third serum Tg level obtained after thyroid hormone withdrawal at the end of the follow-up in patients without clinical disease. In five patients, another 3.7 GBq ¹³¹-I activity was given before the last off L-T₄ Tg levels were measured.

Statistics

Tg level PPV above 5 or 10 ng/ml was calculated as follows: the number of patients with demonstrated relapse or persistent disease and Tg levels above these two cut-off levels was divided by the total number of patients with Tg above these two cut-off levels during the same period of time. The 95% confidence intervals (95% CI) of PPV were calculated using binomial distribution.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Among the 256 patients, 37 (14%) had an initial off L-T₄ Tg level above 1 ng/ml, and they form the basis of this study. Thyroid carcinomas were classified as papillary in 32, well differentiated follicular carcinoma in 1, and poorly differentiated follicular carcinomas in 4. The pTNM classifications were: T1, N1 in 2 patients; T2, N0 or N1 in 4 or 6 patients, respectively; T3, N1 in 2 patients; and T4, N0, N1, or Nx in 4, 16, or 3 patients, respectively. After the control ¹³¹I-TBS at 6–12 months, these 37 patients were followed up for 3–154 months (mean, 69 months; median, 70 months), 34 at the Institut Gustave Roussy and the remaining 3 patients in other centers. These three patients had initial off L-T₄ Tg levels of 3, 6, and 7 ng/ml, respectively; at the end of the follow-up, they had no evidence of disease, and on L-T₄ Tg level was undetectable.

Diagnosis of persistent or recurrent disease (Table 1)

Clinical persistent or recurrent disease was diagnosed in 9 of these 37 patients (24%). As already reported, the initial control ¹³¹I-TBS performed with 74–185 MBq was negative in all of these 37 patients (6).

In six patients, recurrent disease was found more than 1 yr after thyroid surgery (range, 27–117 months). Clinical examination was normal in all six patients. A ¹³¹I-TBS performed with 3.7 GBq in six patients demonstrated uptake in neck lymph nodes in two patients, in the lung in one, and in neck lymph nodes and bone in another patient. In the other two patients, the 3.7-GBq ¹³¹I-TBS was negative; neck ultrasonography and lung CT scan demonstrated neck lymph node metastases and lung metastases in one and lung metastases in the remaining patient. Of note, ¹³¹I-TBS performed with 185 MBq was positive in only one of these six patients at the time of recurrence. The diagnosis of lymph node metastases was confirmed at surgery in the four patients.

In the other 28 patients, no evidence of disease was demonstrated after a median follow-up of 74 months (mean, 81 months; range, 6–154 months). In 5 of these 28 patients, a ¹³¹I-TBS obtained with 3.7 GBq did not demonstrate any evidence of disease. Eleven of these 28 patients achieved a complete remission at the end of the follow-up.

Initial and control off L-T₄ Tg levels (Table 2 and Fig. 1)

In the 37 patients, initial off L-T₄ Tg levels ranged from more than 1–5 ng/ml in 18, more than 5–10 ng/ml in 4, and more than 10 ng/ml in 15 patients (mean, 23 ng/ml; median, 6 ng/ml; range, 1.5–170 ng/ml). Initial on L-T₄ Tg level measured in 28 patients was undetectable in 23.

View larger version (20K): [in this window] [in a new window]   Figure 1. Evolution as a function of time of the initial and control serum Tg after thyroid hormone withdrawal in four groups of patients: A, 11 patients with only initial Tg measurements, including 3 patients with clinically persistent disease; B, 6 patients with increasing Tg slope, including 5 patients with clinically persistent or recurrent disease; C, 6 patients with stable Tg slope, including 1 patient with clinically recurrent disease; D, 14 patients with decreasing Tg slope, without clinical persistent or recurrent disease. Tgi, Initial off L-T4 Tg; Tgc, control off L-T4 Tg; Tgl, last off L-T4 Tg; open circle, patients without demonstrated disease; filled circle and arrows, patients with demonstrated disease; dashed line, patients retreated with 3.7 GBq 131I before the last off L-T4 Tg measurement.

A last off L-T₄ Tg measurement was obtained in 10 patients after a median time of 70 months after initial surgery (mean, 84 months; range, 43–149 months). The mean Tg level was 29 ng/ml (median, 3 ng/ml; range, 0–260 ng/ml). Elevated last off L-T₄ Tg levels ranged from more than 1–5 ng/ml in two patients and more than 5–10 ng/ml in one patient, and was more than 10 ng/ml in four patients. Interestingly, last off L-T₄ Tg level was undetectable in three patients who previously had a detectable off T₄ Tg level.

PPV of serum Tg level

Taking into account the 9 patients with clinical disease, the PPV of initial off L-T₄ Tg levels above 10 or 5 ng/ml were 53% (8 of 15 patients; 95% CI, 26–79%) and 42% (8 of 19 patients; 95% CI, 20–67%), respectively. One patient with clinically persistent disease had an initial off L-T₄ Tg level at 1.5 ng/ml.

Taking into account the 6 patients with clinical disease in whom a control off L-T₄ Tg measurement was available, the PPV of control off L-T₄ Tg levels above 10 or 5 ng/ml were 50% (6 of 12 patients; 95% CI, 21–79%).

Finally, the PPV of an increasing Tg slope was 83% (5 of 6 patients; 95% CI, 36–100%). No patient with a decreasing Tg slope and only one with a stable Tg slope had a clinical recurrence.

Of note, on L-T₄ Tg levels were detectable (>1 ng/ml) in eight of the nine patients at the time of disease discovery. At their last visit, on L-T₄ Tg level was undetectable in 27 of the other 28 patients, and ranged 18 ng/ml in the remaining patient with an increasing off L-T₄ Tg slope but who had no other evidence of disease.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The follow-up of patients with papillary and follicular thyroid carcinoma is mainly based on serum Tg determination. The predictive value of serum Tg, measured during the first year follow-up and after thyroid hormone withdrawal, was studied in 256 consecutive patients with a normal clinical examination, among whom 37 had an elevated serum Tg level after withdrawal of thyroid hormone treatment.

The present data confirm that, in this selected cohort of patients, ¹³¹I-TBS with 74–185 MBq has no clinical interest in the initial work-up and even during the subsequent follow-up, because it was negative in all but one patient with clinical persistent or recurrent disease. Also, clinical examination appeared to be poorly sensitive; neck ultrasonography was the most sensitive tool for localizing neoplastic foci and should be routinely performed during the follow-up of thyroid cancer patients.

The PPV of initial serum Tg level above 5 ng/ml and 10 ng/ml obtained after thyroid hormone withdrawal was 42% and 53%, respectively; this PPV was only slightly improved (i.e. 50%) at the time of the subsequent control or recurrence. This relatively low PPV may be related to the low recurrence rate in this series of patients, despite a prolonged follow-up, and also to the significance of serum Tg obtained only some months after initial treatment. In fact, the PPV of the increasing slope of serum Tg levels obtained after thyroid hormone withdrawal was 83%.

In clinical practice, these results indicate that an initial elevated serum Tg level after thyroid hormone withdrawal, even above 10 ng/ml, should not be considered as specific of persistent or recurrent disease, and thus should not be used alone for indicating further imaging modalities. This may explain discrepancies among series of patients with detectable serum Tg level who underwent various diagnostic modalities, including a ¹³¹I-TBS with 3.7GBq (19, 20). This may also explain the decrease or even the normalization of serum Tg levels after ¹³¹I therapy reported in some patients, in the absence of detectable uptake.

In fact, another determination of serum Tg should be obtained during the subsequent years, after an interval of time depending on prognostic indicators. Our study shows that serum Tg levels will decrease in 38%, becoming undetectable in 30% (11 of 37 patients), and this was observed in the absence of any further treatment in 9 patients. This suggests that irradiated thyroid cells can still produce Tg in the serum and respond to TSH stimulation for months or even years, and that they will disappear thereafter. This is in accordance with the late occurrence of hypothyroidism in patients treated with ¹³¹I for Graves’ disease (21) and with the late achievement of complete remission in patients treated with ¹³¹I for distant metastases from papillary and follicular thyroid carcinoma (22). This biological observation, together with the low rate of recurrences, may explain the low PPV of initial serum Tg level obtained after withdrawal of thyroid hormone treatment. We thus confirm in a homogenous group of patients treated and followed up with a standard protocol, in whom Tg was obtained at the same period of time and measured with the same method, the recent observation of Pacini et al. (16).

At the time of recurrent disease, serum Tg on L-T₄ treatment was detectable in the eight patients in whom it was measured. It was, however, previously undetectable in that situation in at least 2 of these patients, and was also undetectable at the end of the follow-up in 27 of the 28 patients with no evidence of disease, among whom 17 had still detectable off L-T₄ Tg levels. These data clearly confirm the poor sensitivity of serum Tg level when measured on L-T₄ treatment.

The use of recombinant human TSH will facilitate repeated determinations of stimulated Tg level in patients considered at high risk of recurrence because of detectable stimulated Tg level, without the inconvenience of prolonged thyroid hormone withdrawal (8, 9, 10).

We conclude that ¹³¹I-TBS has a limited interest for the follow-up of thyroid cancer patients. Follow-up should rely on serum Tg level, an increase at two consecutive determinations indicating a disease progression, and a decrease suggesting a late effect of therapy. The best Tg PPV is brought by the slope of Tg levels.

	Footnotes

 
Abbreviations: CI, Confidence interval(s); PPV, positive predictive value; TBS, total body scan; Tg, thyroglobulin.

Received August 26, 2002.

Accepted November 27, 2002.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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