2748 jcem.endojournals.org J Clin Endocrinol Metab, August 2012, 97(8):

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1 ORIGINAL Endocrine ARTICLE Care Long-Term Surveillance of Papillary Thyroid Cancer Patients Who Do Not Undergo Postoperative Radioiodine Remnant Ablation: Is There a Role for Serum Thyroglobulin Measurement? Cosimo Durante, Teresa Montesano, Marco Attard, Massimo Torlontano, Fabio Monzani, Giuseppe Costante, Domenico Meringolo, Marco Ferdeghini, Salvatore Tumino, Livia Lamartina, Alessandra Paciaroni, Michela Massa, Laura Giacomelli, Giuseppe Ronga, and Sebastiano Filetti, on behalf of the PTC Study Group Dipartimento di Medicina Interna e Specialità Mediche (C.D., T.M., L.L., A.P., G.R., S.F.) and Dipartimento di Scienze Chirurgiche (L.G.), Università di Roma Sapienza, Roma, Italy; Unità Operativa di Endocrinologia (M.A.), Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy; Unità Operativa di Endocrinologia (M.T., M.M.), Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Dipartimento di Medicina Interna (F.M.), Università di Pisa, Pisa, Italy; Dipartimento di Scienze della Salute (G.C.), Università di Catanzaro Magna Graecia, Catanzaro, Italy; Unità Operativa Semplice Dipartimentale di Endocrinologia (D.M.), Ospedale di Bentivoglio, Bologna, Italy; Dipartimento di Scienze Morfologico-Biomediche (M.F.), Università degli Studi di Verona, Verona, Italy; and Dipartimento di Scienze Mediche e Pediatriche (S.T.), Università di Catania, Catania, Italy Context: Serum thyroglobulin (Tg) assays are considered fundamental in postoperative surveillance of differentiated thyroid cancer (DTC) patients. However, the postsurgical profile of Tg levels has never been specifically investigated in patients who do not undergo radioiodine remnant ablation (RRA). Objectives: Our objective was to explore the evolution of Tg levels over time in DTC patients treated with total or near-total thyroidectomy without RRA. Design: We retrospectively analyzed 290 consecutively diagnosed cases of low-risk (American Thyroid Association criteria) DTC treated with thyroidectomy alone and followed yearly with neck ultrasonography and serum Tg assays. We compared final Tg values in this group and a matched group of 495 RRA-positive patients. Temporal trends of serial Tg levels were also analyzed in 78 of the RRA-negative patients monitored with a high-sensitivity immunoradiometric assay. Results: After follow-up of yr (median 5 yr), final Tg levels were undetectable ( 1 ng/ml) in 274 of 290 RRA-negative patients (95%) and 492 of 495 RRA-positive controls (99%). In the subset of 78 RRA-negative patients, undetectable Tg levels ( 0.2 ng/ml) were recorded in 60% at the first postoperative evaluation (3 12 months) and in 79% after 5 yr. Tg levels increased in the single patient who experienced disease recurrence during the observation period. Conclusion: In most RRA-negative patients, postoperative serum Tg values spontaneously drop to undetectable levels within 5 7 yr after thyroidectomy. Thus, in later phases, Tg assays may be a valuable tool for follow-up even in patients who do not undergo RRA. (J Clin Endocrinol Metab 97: , 2012) ISSN Print X ISSN Online Printed in U.S.A. Copyright 2012 by The Endocrine Society doi: /jc Received January 16, Accepted April 30, First Published Online May 7, 2012 Abbreviations: DTC, Differentiated thyroid cancer; RRA, radioiodine thyroid remnant ablation; Tg, thyroglobulin; US, ultrasonography; WBS, whole-body scan jcem.endojournals.org J Clin Endocrinol Metab, August 2012, 97(8):

2 J Clin Endocrinol Metab, August 2012, 97(8): jcem.endojournals.org 2749 Early detection of persistent/recurrent disease is the target of the surveillance program in differentiated thyroid cancer (DTC) patients. Serum thyroglobulin (Tg) assays and neck ultrasonography (US) are currently the mainstay of postoperative surveillance of patients with DTC (1). In the absence of residual thyroid tissue, measurement of Tg levels after endogenous or exogenous TSH stimulation is the most sensitive method for early detection of persistent/recurrent disease (1). This is one of the reasons that postsurgical radioiodine thyroid remnant ablation (RRA) has been considered an integral part of the initial treatment of DTC (1, 2). By eliminating all sources of Tg production, i.e. all residual thyroid tissue (normal and neoplastic), RRA zeroes the system, so that subsequent findings of detectable Tg production after TSH stimulation is a more reliable indicator of the presence of neoplastic thyroid cells somewhere in the body. More recent guidelines, however, advise a more selective use of RRA (1, 2). Evidence suggests that ablation is not warranted in cases characterized by a low to very low risk of recurrence, which represent an increasingly large proportion of the DTC being treated these days (3, 4). As more and more patients enter follow-up with remnants of normal thyroid tissue, it is reasonable to wonder whether serum Tg is destined to play a less important role as a biochemical marker of tumor burden. The question is also important from an economic point of view; the growing number of patients being treated for low-risk DTC makes it imperative that the follow-up protocols for these cases be as cost-effective as possible. Surprisingly, however, although various studies have confirmed the value of neck US for detecting local metastases in patients who do not receive RRA (5, 6), fewer attempts have been made to elucidate the Tg assays in the follow-up of these patients. Indeed, the most recent American Thyroid Association (ATA) guidelines recommend only that periodic serum Tg measurements and cervical US be considered in the follow-up of patients who undergo less than total thyroidectomy or total thyroidectomy not followed by RRA (1). The present study was conducted to shed light on this critical aspect of the postsurgical management of this rapidly expanding subpopulation of patients with DTC. Patients and Methods Study design A retrospective multicenter study was conducted with institutional review board approval in all participating centers to investigate temporal trends in serum Tg levels from RRA ( ) DTC patients, i.e. those whose thyroidectomy was not followed by RRA. We adopted a multilevel approach, which began with the analysis of final Tg values (i.e. measured at the time of the last follow-up visit) in RRA ( ) and RRA ( ) cohorts with similar postoperative staging results. Next, we analyzed final serum Tg levels for possible correlation with final TSH values and with patient exposure to low-level radioiodine activity during diagnostic 131 I whole-body scan (WBS). The final phase entailed analysis of serial Tg measurements obtained with the same assay in a subset of cases. Patients, therapy, and follow-up strategies The study cohort comprised 290 individuals consecutively diagnosed with DTC in eight thyroid cancer referral centers in Italy (six thyroid clinics and two nuclear medicine units), with 160 of these patients having been analyzed in a previous report (6). All 290 were treated with total or near-total thyroidectomy without RRA. Almost 80% (234 of 290) of the cases had been discovered incidentally after surgery for large, multinodular goiters. The remaining 56 had been diagnosed preoperatively by fine-needle aspiration cytology. All patients were at low risk for persistent/recurrent disease based on the 2009 ATA risk stratification system (1), thus including small intrathyroidal tumors, no clinical or histological evidence of disease inside or outside the neck, and no aggressive histotypes or vascular invasion). Primary tumors were classified as T1a ( 1 cm) in 287 cases, T1b ( 1 and 2 cm) in two cases, and T2 ( 2 and 4 cm) in one case; six patients had multifocal disease. Thirty-five patients underwent prophylactic central neck dissection, and all lymph nodes removed were negative. All 290 were Tg antibody negative. After primary treatment, all patients were followed for at least 2.5 yr or until exitus with visits at least once a year (physical examination; serum Tg, Tg antibody, and TSH assays; and cervical US). In a subset of patients (n 19) followed in a nuclear medicine unit, the initial postoperative examination also included a diagnostic WBS performed after thyroid hormone withdrawal or stimulation with recombinant human TSH. For comparison purposes, we also collected demographic and clinical data on 495 other low-risk DTC patients (controls) whose initial treatment had included postsurgical RRA. With this exception, all RRA ( ) controls met the criteria listed above for the RRA ( ) cohort. Methods For each RRA ( ) and RRA ( ) case analyzed, we recorded demographic data, thyroid cancer features (patient age at onset, histology, and tumor staging), treatment (surgery, RRA, and levothyroxine therapy), and findings at the last follow-up visit (laboratory findings, cervical US findings, and outcome). The primary analysis of Tg data involved comparison of basal values measured at the final follow-up visit in RRA ( ) and RRA ( ) patients. To characterize the evolution of this marker over time, we also analyzed yearly basal Tg levels in a subset of 78 RRA ( ) patients whose assays had all been done in the same laboratory with the same method. Patients were classified as disease free when there was no clinical evidence of recurrent/persistent tumor, no sonographic evidence of abnormal residual tissues or metastatic lymph nodes (7), and negative serum Tg assays. Negativity was defined as undetectable levels ( 1 ng/ml) under basal and/or TSH-stimulated conditions in RRA ( ) patients and levels that remained stable or decreased over time in those who were RRA ( ). When suspicious lymph nodes were detected, they were subjected to fine-needle aspiration cytology with measurement of Tg levels in

3 2750 Durante et al. Serum Tg in Patients Who Do Not Undergo RRA J Clin Endocrinol Metab, August 2012, 97(8): the needle washout fluid. In some patients, aspirates were also assayed for Tg/TSH mrna (8). Computed tomography, magnetic resonance imaging, and positron emission tomography were performed only when extracervical tumor spread was suspected. Cervical US examinations were performed by experienced operators using color Doppler scanners with multifrequency probes ( Mhz). Serum Tg levels were measured with various immunoradiometric assays with functional sensitivities of approximately 1 ng/ml. In the patient subset analyzed to identify Tg level trends over time, all values had been obtained with the DYNOtest Tg-plus assay (BRAHMS Diagnostica GmbH, Berlin, Germany), which was carried out according to the manufacturer s instructions and has a functional sensitivity of 0.2 ng/ml (9). Diagnostic 131 I WBS were performed with a -camera with two detectors equipped with high-energy collimators and thick crystals. The detection speed was 5 cm/sec with a total count of at least 140,000 cycles/min. Statistical analysis Median values and ranges were calculated for continuous variables, and differences between medians were evaluated with the independent-samples t test. Differences between categorical variables were assessed with the Fisher exact test. P values 0.05 were considered statistically significant. All analyses were performed with StatView version software (SAS Institute Inc., Cary, NC). Results Characteristics of the study population Table 1 displays the characteristics of the RRA ( ) and RRA ( ) cohorts and the outcomes recorded at the last follow-up visit. As expected, tumors in the RRA ( ) group were smaller (median diameter, 4 vs. 12 mm) than those in the RRA ( ) group. All patients in both groups had lowrisk thyroid cancer, so it was not surprising that there were no thyroid cancer-related deaths during follow-up. All the RRA ( ) patients and 289 (99.6%) of the 290 in the RRA ( ) group remained disease free for the duration of follow-up and required no further treatment. Only one RRA ( ) patient (0.4%) developed cervical recurrence, which was managed with surgery and radioiodine therapy. Tg levels at the end of follow-up period As shown in Table 1, Tg levels assessed at the end of the follow-up period were undetectable (i.e. Tg 1.0 ng/ml) in 492 (99%) of the 495 RRA ( ) patients (median followup, 6 yr; range, yr) and 273 (95%) of the 290 in the RRA ( ) group (median follow-up, 5 yr; range, yr). The other 17 patients from the latter group (5%) had final Tg levels ranging from (median, 2.68 ng/ml). Thus far, only one of the Tg-positive patients has had any clinical or sonographic evidence of recurrent disease. After the early postsurgery decline, Tg levels stabilized within the detectable range, and there were no further increases over the course of the study. (None of the patients developed anti-tg antibodies during the follow-up.) Interestingly enough, final Tg status (i.e. 1 vs. 1 ng/ml) in the RRA ( ) cohort was unrelated to final TSH values (Table 2) or to the presence/absence of residual thyroid tissue on the initial neck US and/or WBS (data not shown). We also analyzed the final Tg status in a subgroup of 58 RRA ( ) patients recruited in a single nuclear medicine unit, 19 (33%) of whom had had a diagnostic WBS (median cumulative 131 I dose was 5 mci; range, mci). The percentage of patients with detectable serum Tg levels was identical in the 131 I scan (one of 19, 5%) and 131 I scan-naive (two of 39, 5%) subgroups. Temporal trends in serum Tg during follow-up In the subgroup of RRA ( ) patients (n 78) with serial serum Tg levels measured with a highly sensitive immunoradiometric assay (functional sensitivity 0.2 ng/ ml), 47 (60%) of the patients had undetectable levels at the first postoperative examination (3 12 months) (Fig. 1A). This group increased over time and included 79% of the patients after 5 yr of follow-up (Fig. 1A). In 77 (98.7%) cases, the Tg values remained stable or declined sponta- TABLE 1. Study population characteristics and case outcomes Patient characteristics RRA ( ) group, n 290 RRA ( ) group, a n 495 P value Sex n (%) Male 251 (86.5) 411 (83) 0.19 Female 39 (13.5) 84 (17) Age at diagnosis (yr) median (range) 47 (17 81) 46 (12 77) Tumor size (mm) median (range) 4 (0.5 25) 12 (0.5 40) Length of follow-up (yr) median (range) 5 (2.5 22) 6 (2.5 25) Final serum Tg level n (%) 1 ng/ml 273 (95) 492 (99) ng/ml 17 (5) 3 (1) Disease status n (%) Persistence/recurrence 1 (0.4) 0 (0) 0.19 Remission 289 (99.6) 495 (100) a Median radioactive iodine dose was 80 mci (range mci).

4 J Clin Endocrinol Metab, August 2012, 97(8): jcem.endojournals.org 2751 TABLE 2. Distribution of Tg values in the RRA ( ) group (n 290) according to final TSH levels Tg values (ng/ml) <0.1, n , n 84 >0.4 1, n 63 >1, n 71 P value NS NS, Not significant. TSH values (mu/liter) neously over time, and all of these patients remained disease free (Fig. 1, A and B). The last patient in this subgroup (mentioned above) is the only one in the entire study who developed recurrent disease. Figure 2 summarizes the evolution of this case and the temporal trends of the US and serum Tg findings. Discussion Detection of small papillary thyroid cancers has increased markedly over the past decade, and as a result, clinicians are now following an increasing number of low- or verylow-risk DTC patients, who, in accordance with current practice guidelines (1, 2), have not received RRA after thyroidectomy. Most recurrences in these patients occur within the first 3 5 yr after surgery, but late relapses have been described that were diagnosed up to 10 yr after the initial treatment (10). For this reason, it has been suggested that even patients with low-risk DTC require lifelong surveillance (11). According to the 2009 ATA guidelines, periodic serum Tg assays and neck US should both be considered during the follow-up of these RRA ( ) patients (1), although the roles played by each of these methods are not specifically defined. Our goal in the present study was to address the question of whether serum Tg assays have any A N. of pts Years Serum Tg (ng/ml) Mean values Detectable serum Tg (%) Rates Tg (ng/ml) B st Follow-up Last Follow-up FIG. 1. Evolution of serum basal Tg levels after thyroidectomy without RRA. Trend of serial basal Tg determination during the first 7 yr after surgery in a subset of patients (n 78) who did not receive RRA. All measurements were obtained using the same highly sensitive immunoradiometric assay (functional sensitivity, 0.2 ng/ml) over the entire follow-up period. A, The bar graph displays the rate of patients with detectable Tg levels at each follow-up time point. The line graph shows the mean Tg levels over time in 31 of 78 patients who had still detectable Tg values at the first postoperative evaluation. B, The line graphs show the individual levels of detectable serum Tg at the first postoperative evaluation and at the time of the last visit. pts, Patients. value in the follow-up of DTC patients who do not undergo postoperative RRA. We have already suggested that neck US and Tg measurements play different roles in this setting (12). Cervical US has displayed higher diagnostic accuracy than either Tg or diagnostic 131 I WBS for detection of residual/recurrent disease in low-risk DTC populations (5). Its higher sensitivity (compared with Tg assay) has also been documented in higher-risk thyroid cancer patients who did not undergo RRA (13). Furthermore, negative findings at the initial postoperative scan are highly predictive of a favorable long-term outcome, particularly in cases that meet the criteria for very low/low risk (6, 13). In contrast, the results of serum Tg assays are difficult to interpret in RRA ( ) patients, where it is frequently difficult to tell whether detectable serum levels of Tg reflect production by malignant tissue or benign thyroid remnants or both (5, 6, 14). After a median follow-up of 5 yr, we found that basal Tg values had dropped below the detection limit ( 1 ng/ ml) in 95% (274 of 290) of the RRA ( ) patients, a rate that is very similar to that observed among controls who did undergo RRA (99%; 492 of 495). Undetectable levels were observed even in the presence of unsuppressed TSH levels (Table 2), and the decline showed no relation to the patient s previous exposure to 131 I for diagnostic purposes. It probably reflects the spontaneous impairment of the normal thyroid cell functional activity remaining after surgery. When we restricted our analysis to a subgroup of RRA ( ) patients with serial Tg measurements obtained during follow-up with the same high-sensitivity assay (functional sensitivity 0.2 ng/ ml), we observed a postoperative drop in Tg levels that was often fairly rapid. At the first postsurgical evaluation (i.e months after thyroidectomy), almost 60% of these patients had undetectable levels ( 0.2 ng/ml) in the absence of TSH suppression. In the remaining cases, detectable Tg levels were present at the first visit, but they decreased spontaneously over time, and by the fifth year, the percentage of

5 2752 Durante et al. Serum Tg in Patients Who Do Not Undergo RRA J Clin Endocrinol Metab, August 2012, 97(8): Serum Tg (ng/ml) Post-operative serum Tg level Diagnosis of disease recurrence by FNAC Treatment Years FIG. 2. Postoperative serum Tg levels in the single study patient who developed recurrent disease during follow-up. The initial follow-up examination (10 months after surgery) revealed detectable Tg levels (as expected) and a tiny (maximum diameter 5 mm), round hypoechoic area to the left of the trachea (too small to biopsy), and the follow-up frequency was increased to every 6 months. At the 16-month postoperative visit, Tg levels were undetectable, and the suspicious area was only slightly larger than it had been on the previous sonogram ( 0.5 mm). It continued to grow slowly, although Tg levels remained undetectable. After 4.5 yr of follow-up, there was a sudden rise in serum Tg, and the lesion had become large enough to biopsy (6.7 mm). US-guided fine-needle aspiration for cytology and measurement of Tg in the needle washout revealed malignancy. Lesion growth and Tg levels continued to increase until yr 6, when surgery was performed. It revealed a microscopic focus of residual primary tumor, which was subsequently treated with radioactive iodine administration. No further follow-up data were available at the time of study data lock. FNAC, Fine-needle aspiration cytology. patients with undetectable levels had climbed to 79%. With one exception, none of the patients had any evidence of recurrent/residual disease during the study period. Like all retrospective multicenter studies, our study has several limitations. The patients were followed at different centers and during different time periods. Consequently, the serum Tg values analyzed in the entire cohort were measured with different immunoradiometric assays. Nonetheless, all of these assays had functional sensitivities of approximately 1 ng/ml. As for the patient subset in which we analyzed yearly Tg determinations, all obtained with the same high-sensitivity assay, the maximum follow-up in this group was 7 yr. This is probably a long enough interval to provide us with a reasonable picture of the Tg trend, but some of the patients in this subset had shorter follow-ups (Fig. 1A). Finally, we were unable to analyze possible correlations between the Tg status and the size of the thyroid remnants, because this data could not be retrospectively ascertained in all cases. Nevertheless, the presence or absence of residual thyroid tissue on neck US showed no relation at all to the final Tg status. On the whole, our findings provide new and important insight into the natural history of benign Tg production by postoperative thyroid remnants that have not been ablated with radioactive iodine. As expected, 25 40% of the RRA ( ) patients whose yearly Tg levels we analyzed had detectable levels during the first 5 yr of follow-up, and this undeniably reduces the validity of Tg as a marker of residual/recurrent thyroid cancer during this phase (where the risk of such outcomes is at its highest). However, this production spontaneously declines over time and in most cases reaches undetectable levels after the first 5 7 yr of follow-up, thereby mimicking the situation achieved with RRA. After this zero-production point has been established, our experience and several reports confirm that the reappearance of detectable Tg levels can be considered reliable evidence of probable disease recurrence (15 17). The ATA guidelines advise using serial Tg assays and neck US in the postoperative surveillance of RRA ( ) populations (1), but they do not specify how or when these methods should be used. The exceedingly low recurrence rates in the low-risk population we are considering makes it very difficult to draw any firm conclusions on the specific role of Tg measurement in predicting persistent or recurrent disease in these patients. During the initial postoperative assessment, when the chance of persistent/recurrent disease is highest (10, 18, 19), we consider neck US indispensable because of its excellent negative predictive value for thyroid cancer recurrence (6). For an RRA ( ) patient, it is difficult to consider Tg assays anything more than a complementary tool during this phase; if US findings are negative, detectable Tg levels in these patients are clearly a less reliable marker of ectopic thyroid tissue. If, however, as the ATA guidelines recommend (1), the lowrisk patient is going to undergo extended follow-up, the need to identify the more cost-effective of these two methods becomes more important. In this setting, the basal serum Tg assay has certain obvious advantages over cervical US, including simplicity, lower cost, wider availability, and lower operator dependence. Given the slow progression of these tumors, it seems unlikely that omitting routine US in this phase will delay the detection of recurrence to an extent that would affect patient survival (20). These conclusions, however, must be confirmed in longterm prospective studies. Hopefully, our findings will serve as a springboard for ad hoc efforts of this type aimed specifically at better defining optimal long-term management strategies for the growing population of low-risk DTC patients. Acknowledgments Members of the PTC Study Group are Davide Bianchi (Bentivoglio, Bologna); Dario Tumino (Catania); Carmelo Capula

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