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Comparison of Seven Serum Thyroglobulin Assays in the Follow-Up of Papillary and Follicular Thyroid Cancer Patients

Institut Gustave Roussy and University Paris Sud (M.S., F.Tr., S.K., M.R., E.B.), Villejuif, France; Centre Henri Becquerel (A.H.), Rouen, France; Hôpital Saint Louis (M.E.T., M.H.S.), Hôpital de la Pitié (L.L.), and Hôpital Cochin (F.Te.), AP-HP, Paris, France; Centre René Huguenin (C.C.), Saint Cloud, France; Hospices Civils de Lyon (F.C., F.B.-C.), Lyon, France; Hopital La Timone (D.T.), Marseille, France; Centre Georges François Leclerc (M.T.), Dijon, France; Institut Bergonié (F.Bo.), Bordeaux, France; Institut Jean Godinot (C.S.), Reims, France; Centre Jean Perrin (C.D.), Clermont Ferrand, France; Institut Paoli Calmettes (I.B.-R.), Marseille, France; Hôpital de San Giovanni Rotondo (M.T.), Italy; Centre François Baclesse (S.B.), Caen, France; Centre Lacassagne (F.Bu.), Nice, France; Hôpital Bretonneau (J.J.G.), Tours, France; Centre Paul Papin (O.M.), Angers, France; Centre Paul Strauss (O.S.), Strasbourg, France; Hôpital Hautepierre (J.L.S.), Strasbourg, France; Hôpital du Mans (A.P.), Le Mans, France; Hôpital de Thionville (D.S.), Thionville, France; and Hôpital de Limoges (F.A.), Limoges, France

Address all correspondence and requests for reprints to: Martin Schlumberger, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cédex, France. E-mail: schlumbg{at}igr.fr.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Background: Serum thyroglobulin (Tg) is the marker of differentiated thyroid cancer after initial treatment and TSH stimulation increases its sensitivity for the diagnosis of recurrent disease.

Aim: The goal of the study is to compare the diagnostic values of seven methods for serum Tg measurement for detecting recurrent disease both during L-T₄ treatment and after TSH stimulation.

Methods: Thyroid cancer patients who had no evidence of persistent disease after initial treatment (total thyroidectomy and radioiodine ablation) were studied at 3 months on L-T₄ treatment (Tg1) and then at 9–12 months after withdrawal or recombinant human TSH stimulation (Tg2). Sera with anti-Tg antibodies or with an abnormal recovery test result were excluded from Tg analysis with the corresponding assay. The results of serum Tg determination were compared to the clinical status of the patient at the end of follow-up.

Results: Thirty recurrences were detected among 944 patients. A control ¹³¹I total body scan had a low sensitivity, a low specificity, and a low clinical impact. Assuming a common cutoff for all Tg assays at 0.9 ng/ml, sensitivity ranged from 19–40% and 68–76% and specificity ranged from 92–97% and 81–91% for Tg 1 and Tg2, respectively. Using assays with a functional sensitivity at 0.2–0.3 ng/ml, sensitivity was 54–63% and specificity was 89% for Tg1. Using the two methods with a lowest functional sensitivity at 0.02 and 0.11 ng/ml resulted in a higher sensitivity for Tg1 (81% and 78%), but at the expense of a loss of specificity (42% and 63%); finally, for these two methods, using an optimized functional sensitivity according to receiver operating characteristic curves at 0.22 and 0.27 ng/ml resulted in a sensitivity at 65% and specificity at 85–87% for Tg1.

Conclusion: Using an assay with a lower functional sensitivity may give an earlier indication of the presence of Tg in the serum on L-T₄ treatment and may be used to study the trend in serum Tg without performing any TSH stimulation. Serum Tg determination obtained after TSH stimulation still permits a more reliable assessment of cure and patient’s reassurance.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
IN THYROID CANCER patients, the extent of neck recurrence or distant metastases has a major prognostic impact (1, 2). A cure is frequently obtained without significant morbidity in patients with a low tumor burden, but rarely in those with extensive disease, despite aggressive treatment modalities. Thus, highly sensitive tools should permit the early diagnosis of persistent and recurrent disease. Fortunately, recurrences are becoming less frequent due to earlier diagnosis of the disease and to more appropriate therapeutic modalities. Diagnostic tools should also be specific to avoid unnecessary treatment in the great majority of patients with no evidence of disease.

Since the beginning of the eighties, follow-up strategies have combined the use of total body scan with ¹³¹I radioiodine (¹³¹I-TBS) and serum thyroglobulin (Tg) determination. Serum Tg is an excellent tumor marker with conventional assays with a functional sensitivity at 1.0 ng/ml. Serum Tg during L-T₄ treatment is higher than this cutoff in more than 95% of patients with distant metastases; however, it is lower than this cutoff in 20% of patients with isolated lymph node metastases (3, 4), and this proportion is likely to increase with the routine use of neck ultrasonography (US). Disease detection with serum Tg measurement is improved when it is performed after either withdrawal of L-T₄ or im injections of recombinant human TSH (rhTSH) (3, 4, 5). Under such conditions, false negative serum Tg determinations are observed mostly in patients with isolated small lymph node metastases that can be evidenced on neck US (6, 7, 8, 9). In addition, ¹³¹I-TBS appeared less sensitive than neck US for the detection of neck recurrences, and uptake at distant sites was demonstrated with a diagnostic or a high activity only in patients with detectable serum Tg after TSH stimulation (7, 8, 9, 10, 11). This was the basis for two recent consensus reports, according to which, when there is no evidence of disease at 9–12 months after initial treatment with neck US and serum Tg determined after TSH stimulation, routine diagnostic ¹³¹I-TBS can be avoided at least in low-risk patients (12, 13). When this early evaluation does not show any evidence of disease, the risk of subsequent recurrence is low (10, 11).

In these studies, the functional sensitivity of serum Tg assays was around 1 ng/ml, and the availability of kits with an improved functional sensitivity raised the possibility that measuring serum Tg during L-T₄ treatment might permit the early detection of persistent or recurrent disease without the need for any TSH stimulation (14, 15, 16, 17). Indeed, the functional sensitivity of each assay is an important characteristic because it gives a measure of the reproducibility of a measurement. It is the concentration derived from the 20% between-run coefficient of variation that is determined in human serum over a period of at least 6 months, using at least two different lots of reagents and two different instrument calibrations during the testing period (17). It gives the value above which any concentration can be considered detectable in clinical practice.

The objective of the present study was to estimate the diagnostic accuracy of seven Tg assays in a large series of patients with papillary and follicular thyroid cancer who had no evidence of disease. Patients were prospectively studied according to the recommended follow-up protocol (12, 13). Serum Tg measurement was obtained at 3 months after ablation on L-T₄ treatment, and at 9–12 months at the time of a control ¹³¹I-TBS, after withdrawal of either L-T₄ or rhTSH. Either complete remission or persistent/recurrent disease was assessed at the 9–12 month study and during subsequent follow-up.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

Patients with papillary and follicular thyroid carcinoma were enrolled if they were treated in the following manner: 1) they underwent a total thyroidectomy and, depending on local protocols, central neck lymph node dissection resulting in apparent complete resection of neoplastic foci. 2) Postoperatively, they received ¹³¹I for thyroid remnant ablation [1.1–3.7 GBq (30–100 mCi)], and no focus of uptake was detected outside the thyroid bed on the TBS performed 3–5 d after ¹³¹I therapy. 3) They then received L-T₄ treatment, and were seen 3–4 months later so that the adequacy of the L-T₄ dose could be monitored.

Study protocol

Patients were enrolled in the study at the 3- to 4-month examination, after obtaining their informed consent. The study protocol consisted first in obtaining a serum Tg1 sample at 3–4 months after the initiation of L-T₄ treatment when serum TSH was less than 0.5 µU/ml. Patients with serum TSH more than 0.5 µU/ml had a 25-µg increase in the daily dose of L-T₄, and further serum TSH and Tg1 samples were obtained 3 months later that were used in the study. Second, at 9–12 months after the initiation of L-T₄ therapy and after TSH stimulation, a second serum sample (Tg2) and a ¹³¹I-TBS were obtained. At that time, TSH stimulation was achieved either by withdrawing L-T₄ treatment for 4–5 wk until serum TSH exceeded 30 µU/ml, or through injections of rhTSH (0.9 mg im for 2 consecutive days). The method chosen for TSH stimulation was at the local doctors’ discretion. The Tg2 sample was obtained on the day of ¹³¹I administration in case of withdrawal (the sample was also used for TSH measurement) or 1–3 d after the second injection in case of rhTSH stimulation.

Between June 2000 and October 2003, 968 patients from 27 centers were enrolled in the study. Data obtained for each patient included: age, gender, date and extent of surgery, histological type of the primary thyroid tumor, pathological tumor node metastasis classification (18), date of ¹³¹I ablation and results of postablation TBS, and the dates of Tg1 and Tg2 sampling. Serum Tg1 and Tg2 samples were aliquoted and stored frozen in a central laboratory at –80 C until use. The method used for TSH stimulation, the serum TSH levels corresponding to Tg1 and Tg2, and the date of the ¹³¹I-TBS were also recorded. At the time of the protocol initiation, neck US was not a routine procedure in many centers; however, it was routinely performed during the subsequent follow-up in the majority of patients.

Then, patients were followed up according to local procedures, and outcome was recorded annually. However, because annual follow-up of all thyroid cancer patients was not the policy in several participating centers, follow-up data were not available for a number of patients. At each evaluation, the results of each test were recorded and patients were classified as without or with evidence of disease. In the latter case, the site of recurrence was recorded. When results were doubtful, for instance ¹³¹I uptake in the neck that seemed to be located outside the thyroid bed, every attempt was made during the subsequent follow-up to classify patients as free of disease or exhibiting persistent or recurrent disease.

The protocol was approved by the Ethics Committee at Bicêtre Hospital, France and by the local Clinical Research committee of each participating center. All patients gave their written informed consent before participating in the study.

Control ¹³¹I-TBS at 9–12 months

TBS was performed with a standard protocol, 2 d after the administration of 148–185 MBq (4–5 mCi) ¹³¹I and consisted in a TBS (scanning with a double-head -camera at low speed for a minimum of 30 min or at least 140,000 counts) with spot images (scanning for a minimum of 10 min or for at least 60,000 counts) in any doubtful region. Pregnancy was excluded before each administration of radioiodine. Iodine contamination was prevented by careful instructions and was sought by interviewing the patient and, when doubt persisted, by urinary iodine measurement.

Ten sessions were organized during which all ¹³¹I-TBS images were blindly reviewed by a panel of at least 10 experts, endocrinologists or nuclear medicine physicians, participating in the study. A consensus was obtained for each TBS and was recorded. Foci of uptake outside the thyroid bed in the neck and at distant sites were recorded. Foci of uptake in the neck were classified as suspicious when they were located near the thyroid bed or the salivary glands and confirmation was sought in all patients with other imaging modalities, including neck US and by fine needle aspiration biopsy when abnormalities were observed at neck US. Similarly, distant sites with uptake were submitted to other imaging procedures, including computed tomography scan of the chest, computed tomography scan or magnetic resonance imaging for bone foci, and fluorodeoxyglucose positron emission tomography scan.

Assays

Once the study was completed, aliquots of each sample of Tg1 and Tg2 were sent to one of the three participating laboratories (Lyon, Saint-Louis, and Institut Gustave Roussy). Serum Tg measurement was performed in duplicate for all samples with each of the seven kits. A given kit was used to measure all samples in a given laboratory according to the manufacturer’s instructions. Results were reported as the average value of the duplicates.

The seven kits used in the study were Tg-Kryptor (B.R.A.H.M.S., Berlin, Germany), Immulite TG (Diagnostic Products Corporation, Los Angeles, CA), Thyro (Cis Bio International, Gif-sur-Yvette, France), Tg Advantage (Nichols Institute Diagnostics, San Clemente, CA), DYNOtest Tg-Plus (B.R.A.H.M.S.), Tg Access (Beckman-Coulter, Fullerton, CA), and e-Iason TgCa (Iason, Graz-Seierberg, Austria). Functional sensitivity, described by the manufacturers is 0.9 ng/ml for three assays (Tg Kryptor, Immulite Tg, and Thyro), 0.3 ng/ml for Tg Advantage, 0.2 ng/ml for Dynotest Tg-Plus, 0.11 ng/ml for Tg Access, and 0.02 ng/ml for e-Iason TgCa.

Calibration of each kit was controlled by using an international Tg standard (single lot number, CRM 457; BCR, Brussels, Belgium) (19) at eight known Tg values spiked into human Tg free sera obtained during L-T₄ treatment from a patient who had no evidence of disease for 10 yr and undetectable serum Tg after L-T₄ withdrawal with the Tg Access kit, and by measuring these samples with all assays (20). Results in Table 1 clearly demonstrate the method-to-method variability. In fact, six of the seven manufacturers claimed CRM-457 standardization, but apart from Immulite TG and Tg Access methods, the other four methods (Tg-Kryptor, Dynotest Tg-Plus, Tg Advantage, and e-Iason TgCa) involve an adjustment factor of around 2 for corresponding to the expected values.

Tests and standards

For Tg1, the results were not available for 2–9% of patients, including for 14 patients for whom no Tg1 sample was available for any assay. For Tg2, the results were not available for 7–15% of patients, including for 60 (5%) patients for whom no Tg2 sample was available for any assay.

The results of serum Tg determinations were reported blindly from the clinical status of the patients. The reference standard used in the study was a combination of the ¹³¹I-TBS at 9–12 months and the subsequent clinical and imaging follow-up. The results of the blinded TBS review were taken into account. Neck recurrence was confirmed by a fine needle biopsy or surgical biopsy, and ¹³¹I uptake or typical imaging features confirmed distant metastases. Follow-up of patients consisted in a clinical examination with serum Tg determination under L-T₄ treatment on a yearly basis in all patients, and according to local practice, in neck US in most patients, and in a control diagnostic ¹³¹I-TBS and serum Tg determination after TSH stimulation in a few patients. Serum Tg was measured in each center with the locally used method. Data on follow-up are still being collected annually. According to the protocol, patients who were not seen on a yearly basis will be evaluated again in the center at 5 yr after initial treatment.

Statistical analysis

Sample size. While designing the study, it was estimated that a total of 200 patients with a positive TBS would be required to estimate a sensitivity approximating 85% with 5% accuracy for a Tg assay. The probability of recurrence was estimated from historical series at around 20%, and 1000 patients were included in the study (3, 21).

Diagnostic accuracy. We used classical criteria to assess the clinical performance of each assay: 1) the sensitivity is the percentage of patients with recurrent disease during follow-up who had a positive Tg determination; 2) the specificity is the percentage of patients who had no evidence of disease during follow-up and who had a negative Tg determination.

Sensitivity and specificity were calculated for each assay using the aforementioned reference standard. These calculations were performed with three cutoff levels (positive or negative) for both Tg1 and Tg2: 1) a single common cutoff equal to 0.9 ng/ml for all kits; 2) for the four assays with a lower functional sensitivity, the functional sensitivity reported by the manufacturers; and 3) for the two most sensitive assays, the cutoff maximizing the sum of sensitivity plus specificity deduced from the receiver operating characteristic (ROC) (Fig. 1).

View larger version (15K): [in this window] [in a new window]   FIG. 1. ROC curves used to determine the Tg level that maximizes the sum sensitivity plus specificity for the Tg Access and for the e-Iason TgCa assays.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

A total of 968 patients from 27 centers were enrolled in the study (Table 2). Twenty-four patients did not complete the study. Among the 944 patients who completed the study and who were followed up, 504 received rhTSH injections and, in 440, L-T₄ was withdrawn for Tg2 determination and ¹³¹I-TBS. Patient clinical characteristics are reported in Table 2 according to the TSH stimulation method (rhTSH or withdrawal of L-T₄). The percentage of women (79% and 76%), mean age at diagnosis (47 yr), and the pathological tumor classification and the histological type (88% and 87% of papillary carcinomas) were similar between the two groups; a slightly greater number of pN1 patients were in the rhTSH group (30%) than in the withdrawal group (24%) (P = 0.06). In accordance with inclusion criteria, no patient had known local and regional tumor foci or distant metastases at the time of inclusion.

As described above, the reference standard used was a combination of the control ¹³¹I-TBS performed 9–12 months after ablation and clinical and imaging data obtained over a mean follow-up of 28 months (range: 8–50 months).

Recurrent disease was evidenced in 30 patients, in the thyroid bed (n = 5); in neck lymph nodes (n = 16); in lungs (n = 4); in bones (n = 1); in neck lymph nodes and lungs (n = 1); in bones and lungs (n = 1); in neck lymph nodes, lungs, and bones (n = 1); and in neck lymph nodes and skin (n = 1) (Table 3).

The ¹³¹I-TBS performed 9 months after ablation did not show any significant uptake in the thyroid bed in 91% of the patients after rhTSH stimulation and in 81% of the patients after withdrawal (Table 4). It showed visible but low (<0.1%) uptake in the thyroid bed in 8 and 18% of the patients after rhTSH and withdrawal, respectively, and uptake in the thyroid bed greater than 0.1% of the administered activity in 1% of the patients of each group (Table 4).

Based on these findings, the results of the control ¹³¹I-TBS when compared with the patient’s clinical status at the end of the follow-up can be classified as true positive in seven, false negative in 23, false positive in 16, and true negative in 898 patients, leading to 23% sensitivity, 98% specificity, with a clinical impact in only seven (0.7%) among 944 patients.

Serum Tg determination

Serum Tg was obtained 3 d after the second rhTSH injection in 427 patients and 1 or 2 d after the second injection in 77 patients. After withdrawal, mean serum TSH was 87 µU/ml (SD=49).

Results of serum Tg determinations (Tg1 and Tg2)

Using a common cutoff at 0.9 ng/ml, the proportion of patients with detectable Tg1 was similar with each of the seven methods in the rhTSH group (3–14%) and in the withdrawal group (4–13%). In contrast, the proportion of detectable Tg2 was higher after withdrawal (16–33%) than after rhTSH (8–23%), with each of the seven methods (P < 10^–4). However, the number of recurrences was similar in each group (14 in the withdrawal group and 16 in the rhTSH group).

Tg2 was not significantly different among patients with either no detectable uptake in the thyroid bed, detectable but low uptake (<0.1%), or with uptake greater than 0.1% on the control ¹³¹I-TBS (data not shown).

Diagnostic values of the seven methods (Table 5)

Tg1 and Tg2 results were compared with the clinical status of patients at the end of the study, and the sensitivity and specificity of each assay were calculated. Tg2 obtained either after withdrawal or rhTSH were pooled for this analysis.

Sensitivity and specificity were then studied according to functional sensitivity values provided by the manufacturers. With a functional sensitivity at 0.3 and 0.2 ng/ml (Tg Advantage and Dynotest Tg-Plus kits), sensitivity of Tg1 improved to 63% and 54%, respectively, and specificity was 89% for both assays. With the lowest functional sensitivity (0.02 ng/ml for e-Iason TgCa and 0.11 ng/ml for Tg Access kit), the sensitivity was even higher for both Tg1 (81% and 78%) and for Tg2 (95% and 92%), but at the expense of a considerable loss in specificity for both Tg1 (42% and 63%) and for Tg2 (23% and 44%).

Optimized thresholds were then determined for these two kits, according to ROC curves (Fig. 1): for Tg Access kit, it was equal to 0.27 and 1.2 ng/ml for Tg1 and Tg2, respectively, and for e-Iason TgCa kit, the corresponding thresholds were 0.22 and 0.97 ng/ml, respectively. At these optimized thresholds for Tg1, the sensitivity was 65% for both assays, and specificity was 85% and 87%.

Using a kit with a lower functional sensitivity resulted in a lower clinical impact of TSH stimulation (Table 6).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

Indeed we have been faced with missing data, but their low numbers both for Tg1 and Tg2 are unlikely to change significantly the conclusions of this study.

Persistent or recurrent disease was demonstrated in 30 patients (<3%) with a mean follow-up of 28 months, with two thirds of recurrences occurring in the thyroid bed or in neck lymph nodes. Neck US was not performed on a routine basis at 9–12 months, because it was not routinely used at the time of the study initiation, but previous studies on similar patients have shown that the risk of subsequent recurrence is small (0.5% at 10 yr) when neck palpation and control diagnostic TBS are normal and serum Tg remains undetectable after TSH stimulation (10, 11). In the remaining nine patients, distant metastases could already be suspected in seven, with the increased Tg1 as shown with all kits.

The present study confirms that a single radioiodine ablation is successful in 99% of patients, as shown by no detectable uptake in the thyroid bed and when present, less than 0.1% of the administered activity on a control ¹³¹I-TBS (7, 8, 9, 10, 11). When persistent uptake was present in the thyroid bed, it did not appear to be clinically relevant and was not related to the serum Tg level either during L-T₄ treatment or after TSH stimulation. TBS revealed suspicious foci of uptake in only seven of the 30 patients with persistent/recurrent disease, but demonstrated suspicious foci of uptake in other 16 patients, that were finally related to normal thyroid remnants, salivary glands, or artifacts. The poor interest of routine diagnostic ¹³¹I-TBS during follow-up is in accordance with recent consensus reports, but ¹³¹I-TBS performed with a large activity may provide diagnostic information in selected patients with other imaging abnormalities or elevated serum Tg levels (12, 13).

Discrepancies between methods for direct determination of anti-Tg antibodies or recovery tests are obvious, demonstrating a method-to-method variability despite standardization against the WHO standard. Many researchers advocate direct quantitative determination of anti-Tg antibodies (20, 22, 23). Serum Tg determination may be unreliable in patients with anti-Tg antibodies, and neck US and possibly ¹³¹I-TBS should be used for follow-up.

Tg assays should be standardized against the Tg international reference preparation (CRM 457), but this is not the only source of between-assay variability (19, 20). We analyzed the results without correction for two main reasons: first, our results can be readily applied in routine practice, and second, an even larger number of samples would have been below the level of functional sensitivity after correction, and this would not have improved the sensitivity of the method. For the same reason, we decided to exclude sera with detectable anti-Tg antibodies or with incorrect recovery from serum Tg determination with the corresponding assay.

Although the standard procedure for Tg measurement is 72 h after the second rhTSH injection, peak rhTSH stimulated Tg occurs earlier (24–48 h after the second injection) in 32% of patients (11). Thus, all serum Tg determinations were taken into account.

Determining a cutoff value for each assay seems to be particularly relevant for each preparation method, withdrawal or rhTSH, if we assume that there may be wide discrepancies between different methods for serum Tg determination. However, the limited number of events prohibited such determination and we focused on the diagnostic values of each assay. Using a common cutoff at 0.9 ng/ml, the percentage of patients with detectable serum Tg was 2-fold higher after withdrawal of L-T₄ therapy than after rhTSH, and this is consistent with the more intense stimulation induced by withdrawal as opposed to rhTSH (5). However, the percentage of recurrences was similar in the two groups of patients, and the great majority of patients with detectable serum Tg had no other evidence of disease, and this will be discussed below.

Assuming a common cutoff at 0.9 ng/ml, the sensitivity of serum Tg determination for tumor detection ranged from 19–40% during L-T₄ treatment and rose to 68–76% after TSH stimulation, whereas specificity was high in both conditions. This indeed is consistent with multiple previous reports, and clearly confirms the interest of TSH stimulation when using such kits and that serum Tg level is an excellent marker when obtained after TSH stimulation (4). Lowering the functional sensitivity of the method to 0.2–0.3 ng/ml improved its sensitivity for tumor detection during L-T₄ treatment to 54–65%, whereas specificity remained high. This was observed with two kits, using the functional sensitivity provided by the manufacturers and with the other two kits, using optimized functional sensitivity. Using lower functional sensitivity further improved sensitivity but at the expense of a decreased specificity. The clinical impact of Tg determination obtained after TSH stimulation, in terms of disease detection decreases with improved sensitivity of the assay. In that condition, the optimized thresholds were similar to those of the less-sensitive kits, around or above 0.9 ng/ml.

A large number of these low detectable Tg levels did not correspond to any demonstrable disease at the time of the study. Using a method with a low functional sensitivity, a recent report demonstrated a significant relationship between the level of Tg during L-T₄ treatment and the level reached after rhTSH stimulation (17), a finding that was confirmed by our study. In that study (17), much of the testing was performed several years after the initial therapy and cannot provide any real insight into the value of this Tg method at the 9–12 month evaluation. Low serum Tg levels could thus be related to normal residual thyroid tissue or to neoplastic foci that are too small to be imaged rather than to nonspecific effects in the assay, such as heterophilic antibody interference (24). Recent studies showed that two thirds of patients with detectable serum Tg after TSH stimulation at 9–12 months had lower or undetectable serum Tg after TSH stimulation a few months or years later, even without any further treatment (25, 26, 27). Indeed, these patients are being followed up and this will distinguish small tumor foci with an increasing trend in serum Tg level from irradiated cells that will disappear without any further treatment with a decreasing trend. In the present study, few patients with detectable Tg1 had lower Tg2, and this may be related to measurement or sampling errors or to a spontaneous decrease in Tg production between the time of Tg1 and Tg2 samplings.

In conclusion, the use of an assay with an improved functional sensitivity may indicate earlier the presence of Tg in the serum on L-T₄ treatment, and may then be used to study the trend of serum Tg by repeated serum Tg determinations during L-T₄ treatment without performing any TSH stimulation. This was observed with a functional sensitivity at 0.2–0.3 ng/ml without significant decrease in specificity. Using methods with a lower functional sensitivity will further improve the sensitivity but at the cost of a decreased specificity. The follow-up of these patients will permit to assess the significance of these detectable but low Tg levels. Serum Tg determination obtained after TSH stimulation at 9–12 months still permits a more reliable assessment of cure. In turn, the certainty of cure permits patient’s reassurance, decreased daily dose of L-T₄ treatment that will avoid subclinical thyrotoxicosis, and limitation of follow-up to an annual clinical examination on L-T₄ treatment with serum TSH and Tg determinations. It should be kept in mind that the rate of recurrence is low in this population, and the majority of patients will have negative test with any method, and thus the relative medico-economic values for these methods should be evaluated.

	Footnotes

 
This study was partially supported by an unrestricted grant from Genzyme France. Kits for measuring Tg were kindly provided by the manufacturers.

Author Disclosure Summary: M.S. received lecture fees from Genzyme. The other authors have nothing to declare.

First Published Online April 10, 2007

Abbreviations: rhTSH, Recombinant human TSH; ROC, receiver operating characteristic; TBS, total body scan; Tg, thyroglobulin; US, ultrasonography.

Received April 4, 2006.

Accepted March 30, 2007.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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