TOTAL OR NEAR-TOTAL thyroidectomy is advocated in

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1 /03/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 88(3): Printed in U.S.A. Copyright 2003 by The Endocrine Society doi: /jc Positive Predictive Value of Serum Thyroglobulin Levels, Measured during the First Year of Follow-Up after Thyroid Hormone Withdrawal, in Thyroid Cancer Patients E. BAUDIN, C. DO CAO, A. F. CAILLEUX, S. LEBOULLEUX, J. P. TRAVAGLI, AND M. SCHLUMBERGER Departments of Nuclear Medicine and Endocrine Tumors, Surgery, Institut Gustave Roussy, Villejuif, France Abbreviations: CI, Confidence interval(s); PPV, positive predictive value; TBS, total body scan; Tg, thyroglobulin. The follow-up of patients with papillary and follicular thyroid carcinoma after thyroidectomy and radioiodine ablation is mainly based on serum thyroglobulin (Tg) level determination. 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-T 4 Tg), was studied in 256 consecutive differentiated thyroid cancer patients. All underwent a total thyroidectomy and 3.7 GBq 131 I ablation; 37 patients had an elevated initial off L-T 4 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, MBq 131 I -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-T 4 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 131 I-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. (J Clin Endocrinol Metab 88: , 2003) 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 131 I ablation of residual thyroid in those patients with a high risk of recurrence and/or cancer-related death (1 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 131 I-total body scan (TBS; Refs. 1, 4, and 5). In a series of 256 consecutive patients who had no evidence of disease, we recently demonstrated that the control 131 I-TBS with 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 131 I-TBS and focusing on the predictive value of serum Tg level. This was confirmed by several studies comparing serum Tg level and 131 I-TBS with a preparation by recombinant human TSH or thyroid hormone withdrawal (7 10). After total thyroid ablation, the sensitivity of serum Tg measurement is %, 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 131 I-TBS performed with MBq (2 5 mci; Ref. 6). In previous studies, a 131 I-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 ). 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. 1107

2 1108 J Clin Endocrinol Metab, March 2003, 88(3): Baudin et al. Tg Level Evolution in Differentiated Thyroid Cancer Patients and Methods 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 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) 131 I were administered; at that time, the serum TSH level was above 30 U/ml in all patients. A 131 I-TBS was performed 4 d after the administration of 131 I 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) T 4 treatment was then initiated, with the aim of decreasing serum TSH to low levels ( 0.1 U/ml) without inducing a clinical thyrotoxicosis. This was controlled 3 months later by measuring serum free T 3 and TSH levels (Ref. 1). 4) A control 131 I-TBS with 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 U/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-t 4 Tg), and again after thyroid hormone withdrawal, 6 12 months after initial thyroid surgery, at the time of the first control 131 I-TBS (initial off l-t 4 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 131 I-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 T 4 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 131 I-TBS with 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 131 I-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 131 I-TBS. The PPV of the initial serum off Tg level, measured 6 12 months after thyroid surgery (initial off l-t 4 Tg) was studied, taking into account two cut-off levels, 5 and 10 ng/ml. The PPV of the subsequent control off l-t 4 Tg level (control off l-t 4 Tg) obtained more than 1 yr after thyroid surgery was also studied. Furthermore, the slope between initial and subsequent control off l-t 4 Tg levels was classified as increasing when control off l-t 4 Tg level was 50% or more above its initial value, as stable, or as decreasing when control off l-t 4 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-t 4 Tg measurements. The last off l-t 4 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-t 4 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 Patients Among the 256 patients, 37 (14%) had an initial off l-t 4 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 131 I-TBS at 6 12 months, these 37 patients were followed up for 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-t 4 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-t 4 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 131 I-TBS performed with MBq was negative in all of these 37 patients (6). In three patients, persistent disease was diagnosed from 3 9 months after thyroid surgery. In one patient, neck lymph node metastases were clinically detected after a negative initial 131 I-TBS performed with 185 MBq and were subsequently confirmed at surgery. In the other two patients, clinical examination was normal, and a 131 I-TBS performed with 3.7 GBq demonstrated uptake in neck lymph nodes in two (that were confirmed at ultrasonography in one and at surgery in two). In six patients, recurrent disease was found more than 1 yr after thyroid surgery (range, months). Clinical examination was normal in all six patients. A 131 I-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 131 I-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, 131 I-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, months). In 5 of these 28 patients, a 131 I-TBS obtained with 3.7 GBq did not demonstrate any

3 Baudin et al. Tg Level Evolution in Differentiated Thyroid Cancer J Clin Endocrinol Metab, March 2003, 88(3): TABLE 1. Diagnostic modalities of persistent or recurrent disease in nine patients with demonstrated disease Patient no. Age yr/sex/pathology Time since surgery (months) Disease localization/ diagnostic standard Neck examination Neck ultrasonography On L-T 4 Tg initial/control Off L-T 4 Tg initial/control 131 I-TBS MBq/3.7 GBq 1 70/female/pap 3 node/ 131 I-TBS neg neg ND/NA 27/NA ND/pos 2 54/male/pap 3 node/pathology neg ND 6/NA 120/NA neg/pos 3 70/female/pap 9 node/pathology pos pos 2/NA 15/NA neg/neg 4 51/male/PDF 39 node/pathology neg pos 1/10 1.5/32 neg/pos 5 16/female/pap 69 node/pathology neg neg ND/8 69/173 neg/pos 6 54/female/pap 63 node-bone/pathology- 131 I-TBS neg pos 1/5 21/53 neg/pos 7 24/female/pap 62 lung/ 131 I-TBS neg ND 3/1 24/57 pos/pos 8 51/female/PDF 27 node-lung/pathologylung neg neg 56/ /800 neg/neg CT a 9 31/male/pap 117 lung/lung CT a neg neg 3/2.5 90/88 neg/neg pap, Papillary differentiated thyroid cancer; PDF, poorly differentiated follicular; neg, negative; pos, positive; ND, not determined; NA, not available in three patients with persistent disease at initial follow-up. a In these two patients, the lung metastasis diagnosis was performed at two consecutive computed tomography (CT) scans that visualized progressive lung metastases. evidence of disease. Eleven of these 28 patients achieved a complete remission at the end of the follow-up. Initial and control off L-T 4 Tg levels (Table 2 and Fig. 1) In the 37 patients, initial off l-t 4 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, ng/ml). Initial on l-t 4 Tg level measured in 28 patients was undetectable in 23. A subsequent control off l-t 4 Tg level was obtained in 26 of the 37 patients after a median time of 52 months after initial surgery (mean, 56 months; range, months). It was not performed in the other 11 patients, of whom 3 had persistent clinical disease, 3 were lost to follow-up, and 5 had initial off l-t 4 Tg levels below 5 ng/ml. The mean control off l-t 4 Tg level was 57 ng/ml (median, 10 ng/ml; range, ng/ ml). Control off l-t 4 level was undetectable in 8 patients, ranged from more than 1 5 ng/ml in 3 patients and more than 5 10 ng/ml in 3 patients, and was more than 10 ng/ml in 12 patients. Compared with initial off l-t 4 Tg levels, the control off l-t 4 Tg level was increased in 6 patients, was stable in 6 patients, and decreased or even normalized in 14 patients. A last off l-t 4 Tg measurement was obtained in 10 patients after a median time of 70 months after initial surgery (mean, 84 months; range, months). The mean Tg level was 29 ng/ml (median, 3 ng/ml; range, ng/ml). Elevated last off l-t 4 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-t 4 Tg level was undetectable in three patients who previously had a detectable off T 4 Tg level. PPV of serum Tg level Taking into account the 9 patients with clinical disease, the PPV of initial off l-t 4 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-t 4 Tg level at 1.5 ng/ml. Taking into account the 6 patients with clinical disease in whom a control off l-t 4 Tg measurement was available, the TABLE 2. Initial and control Tg levels measured after thyroid hormone withdrawal (off L-T 4 ), classified as a function of initial Tg levels and Tg slope Initial off L-T 4 Tg [ng/ml (n)] Off L-T 4 Tg slope (n) Follow-up: demonstrated disease (n) 1 yr 1 5 yr 5 yr 1 5 (18) Increasing (1) 1 Stable (1) (2/8) Not done (6) 5 10 (4) Increasing (0) Stable (2) (0/0) Not done (2) 10 (15) Increasing (5) Stable (3) 1 (1/3) Not done (3) 2 1 Total (37) PPV of control off l-t 4 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, %). No patient with a decreasing Tg slope and only one with a stable Tg slope had a clinical recurrence. Of note, on l-t 4 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-t 4 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-t 4 Tg slope but who had no other evidence of disease. Discussion 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 clin-

4 1110 J Clin Endocrinol Metab, March 2003, 88(3): Baudin et al. Tg Level Evolution in Differentiated Thyroid Cancer FIG. 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-T 4 Tg; Tgc, control off L-T 4 Tg; Tgl, last off L-T 4 Tg; open circle, patients without demonstrated disease; filled circle and arrows, patients with demonstrated disease; dashed line, patients retreated with 3.7 GBq 131 I before the last off L-T 4 Tg measurement. ical 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, 131 I-TBS with MBq has no clinical interest in the initial work-up and even during the subsequent followup, 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 131 I-TBS with 3.7GBq (19, 20). This may also explain the decrease or even the normalization of serum Tg levels after 131 I 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 131 I for Graves disease (21) and with the late achievement of complete remission in patients treated with 131 I 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-t 4 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-t 4 Tg levels. These data clearly confirm the poor sensitivity of serum Tg level when measured on l-t 4 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 10). We conclude that 131 I-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. Acknowledgments Received August 26, Accepted November 27, Address all correspondence and requests for reprints to: M. Schlumberger, Institut Gustave Roussy and University Paris-Sud, 39, Rue Camille-Desmoulins, Villejuif Cedex, France. schlumbg@ igr.fr. References 1. Schlumberger MJ 1998 Papillary and follicular thyroid carcinoma. N Engl J Med 338: Mazzaferri EL, Kloos RT 2001 Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 86: Grebe SK, Hay ID 1997 Follicular cell-derived thyroid carcinomas. In: Arnold A, ed. Endocrine neoplasms. Boston: Kluwer Academic Publishers; Wartofsky L, Sherman SI, Gopal J, Schlumberger M, Hay ID 1998 Therapeutic controversy: the use of radioactive iodine in patients with papillary and follicular thyroid cancer. J Clin Endocrinol Metab 83: Schlumberger M, Baudin E 1998 Serum thyroglobulin determination in the

5 Baudin et al. Tg Level Evolution in Differentiated Thyroid Cancer J Clin Endocrinol Metab, March 2003, 88(3): follow-up of patients with differentiated thyroid carcinoma. Eur J Endocrinol 138: Cailleux AF, Baudin E, Travagli JP, Ricard M, Schlumberger M 2000 Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid carcinoma? J Clin Endocrinol Metab 85: Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D, Pinchera A 2002 Diagnostic 131-iodine whole-body scan may be avoided in thyroid cancer patients who have undetectable stimulated serum Tg levels after initial treatment. J Clin Endocrinol Metab 87: Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham KE, Braverman LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri EL, Daniels GS, Ross DS, Luster M, Samuels MH, Becker DV, Maxon HR, Cavalieri RR, Spencer CA, McEllin K, Weintraub BD, Ridgway EC 1999 A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 84: Robbins RJ, Tuttle RM, Sharaf RN, Larson SM, Robbins HK, Ghossein RA, Smith A, Drucker WD 2001 Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma. J Clin Endocrinol Metab 86: Mazzaferri EL, Kloos RT 2002 Is diagnostic iodine-131 scanning with recombinant human TSH useful in the follow-up of differentiated thyroid cancer after thyroid ablation? J Clin Endocrinol Metab 87: Pacini F, Lari R, Mazzeo S, Grasso L, Taddei D, Pinchera A 1985 Diagnostic value of a single serum thyroglobulin determination on and off thyroid suppressive therapy in the follow-up of patients with differentiated thyroid cancer. Clin Endocrinol (Oxf) 23: Sherman SI, Tielens ET, Sostre S, Wharam Jr MD, Ladenson PW 1994 Clinical utility of posttreatment radioiodine scans in the management of patients with thyroid carcinoma. J Clin Endocrinol Metab 78: Pacini F, Lippi F, Formica N, Elisei R, Anelli S, Ceccarelli C, Pinchera A 1987 Therapeutic doses of iodine-131 reveal undiagnosed metastases in thyroid cancer patients with detectable serum thyroglobulin levels. J Nucl Med 28: Schlumberger M, Arcangioli O, Piekarski JD, Tubiana M, Parmentier C 1988 Detection and treatment of lung metastases of differentiated thyroid carcinoma in patients with normal chest x-rays. J Nucl Med 29: Pineda JD, Lee T, Ain K, Reynolds JC, Robbins J 1995 Iodine-131 therapy for thyroid cancer patients with elevated thyroglobulin and negative diagnostic scan. J Clin Endocrinol Metab 80: Pacini F, Agate L, Elisei R, Ceccarelli C, Lippi F, Molinaro E, Pinchera A 2001 Outcome of differentiated thyroid cancer with detectable serum Tg and negative diagnostic 131 I whole body scan: comparison of patients treated with high 131 I activities versus untreated patients. J Clin Endocrinol Metab 86: Hedinger C, Williams ED, Sobin LH 1988 Histological typing of thyroid tumours. International histological classification of tumours. World Health Organization, vol 11, ed 2. Berlin: Springer-Verlag Thyroid gland (ICD-OC73). In: Hermanek P, Sobin LH, eds. TNM classification of malignant tumors, 4th ed, 2nd revision. International union against cancer. Berlin: Springer-Verlag; Mc Dougall IR I treatment of 131I negative whole body scan, and positive thyroglobulin in differentiated thyroid carcinoma: what is being treated? Thyroid 7: Fatourechi V, Hay ID, Javedan H, Wiseman GA, Mullan BP, Gorman CA 2002 Lack of impact of radioiodine therapy in Tg-positive, diagnostic wholebody scan negative patients with follicular cell-derived thyroid cancer. J Clin Endocrinol Metab 87: Becker DV, Hurley JR 1982 Current status of radioiodine ( 131 I) treatment of hyperthyroidism. In: Freeman LM, Miller JM, eds. Nuclear medicine annual. New York: Raven Press; Schlumberger M, Challeton C, De Vathaire F, Travagli JP, Gardet P, Lumbroso JD, Francese C, Fontaine F, Ricard M, Parmentier C 1996 Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med 37: