|Year : 2017 | Volume
| Issue : 3 | Page : 68-71
Is measurement of serum thyroglobulin at the time of 131I remnant ablation after thyroidectomy useful for early prediction of recurrence of differentiated thyroid carcinoma?
Intidhar El Bez, Taieb Ben Ghachem, Aida Mhiri, Mohamed Faouzi Ben Slimène, Ihsen Slim
Department of Nuclear Medicine, Salah Azaiez Institute, Tunis, Tunisia
|Date of Web Publication||26-Dec-2017|
Dr. Intidhar El Bez
Department of Nuclear Medicine, Boulevard 9 Avril, Bab Saâdoun, 1006, Tunis
Source of Support: None, Conflict of Interest: None
Context: The follow-up of differentiated thyroid cancer (DTC) after total thyroidectomy is commonly based on serum Tg determination, 131-iodine ((131)I) diagnostic whole-body scan (WBS) and neck ultrasound (n-US). Aims: Assess the frequency and risk factors for recurrence and persistent disease in patients with both undetectable serum Tg level and normal post ablation WBS at the time of ablation. Settings and Design: We conducted a retrospective study of 500 consecutive DTC patients, treated with I-131 between January 2000 and January 2009. Methods and Materials: Patients were treated in all cases with a 131-I activity. Serum Tg level was measured on the day of I-131 administration. A neck scintigraphy was performed in all patients. Statistical Analysis Used: It included a descriptive study with, for qualitative variables, a calculation of absolute and relative frequencies. Quantitative variables were expressed as averages, medians, and standard deviations with extreme values. Results: Among 500 patients ablated, 100 consecutive patients were included. The WBS was abnormal in 5 and n-US abnormal in 1. Among 95 patients with a normal WBS, Tg/TSH 6-18 months after ablation was undetectable. n-US was normal in 92 and falsely positive in 3. After a mean follow-up of 5 years, recurrence occurred in 2 cases, both with an aggressive histological variant. Conclusions: Our data suggest that the presence of undetectable levels of serum Tg/TSH at the time of the first control WBS after initial treatment, is highly predictive of complete and persistent remission. The control WBS has never given information that could influence the following therapeutic strategy. On this basis, we propose that the diagnostic (131) I WBS may be avoided in patients with undetectable levels of Tg/TSH in the absence of TgAb at the time of ablation.
Keywords: Iodine, scintigraphy, thyroglobulin, thyroid cancer
|How to cite this article:|
El Bez I, Ghachem TB, Mhiri A, Ben Slimène MF, Slim I. Is measurement of serum thyroglobulin at the time of 131I remnant ablation after thyroidectomy useful for early prediction of recurrence of differentiated thyroid carcinoma?. Libyan J Med Sci 2017;1:68-71
|How to cite this URL:|
El Bez I, Ghachem TB, Mhiri A, Ben Slimène MF, Slim I. Is measurement of serum thyroglobulin at the time of 131I remnant ablation after thyroidectomy useful for early prediction of recurrence of differentiated thyroid carcinoma?. Libyan J Med Sci [serial online] 2017 [cited 2018 Oct 16];1:68-71. Available from: http://www.ljmsonline.com/text.asp?2017/1/3/68/221492
| Introduction|| |
According to the recent American Thyroid Association recommendations, radioactive iodine (I-131) administration after total thyroidectomy for differentiated thyroid cancer (DTC) is indicated in patients with moderate to high risk of recurrence, based on age, tumor size, lymph node status, extrathyroidal extension, histological type of the thyroid tumor and thyroid-stimulating hormone (TSH) stimulated serum thyroglobulin (Tg) level, 6–18 months after ablation.,,, However, stimulated serum Tg level at the time of ablation is not taken into account for this indication.
The aims of this study were to assess the frequency and risk factors for recurrence and persistent disease in patients with both undetectable serum Tg level and normal postablation whole-body scintigraphy (WBS) at the time of ablation.
| Subjects and Methods|| |
This was a single center retrospective study, in our institute. Files of consecutive patients treated with I-131 between January 2000 and January 2009 were reviewed. Inclusion criteria were as follows: (i) patients with DTC; (ii) confirmed pathological diagnosis of malignancy; (iii) first I-131 treatment given after total thyroidectomy with or without neck lymph node dissection; (iv) undetectable serum-stimulated Tg level (Tg <1 ng/mL) in the absence of thyroglobulin autoantibody (TgAb) on the day when 131-I was given in case of ablation performed after thyroid hormone withdrawal (THW); and (v) a serum TSH level above 35 mUI/L.
Records of 500 consecutive DTC patients were reviewed. Overall 100 patients (20%) met the inclusion criteria and formed the basis of this report.
Patients were treated after THW in all cases with a 131-I activity of 100 mCi (3700 MBq) in 10 cases, 30 mCi (1233 MBq) in 90 cases. Serum Tg level was measured on the day of I-131 administration, the serum TSH level being above 35 mU/L. A neck scintigraphy was performed in all patients. In case of foci of I-131 uptake outside the thyroid bed, classified as persistent disease, specific therapeutic procedures were performed. WBS was classified as normal or abnormal in case of iodine uptake outside the thyroid bed. Tg measurement was performed by radioimmunoassay. The Tg level was considered to be not accurately measured in the presence of Tg antibodies. In patients without detectable I-131 uptake outside the thyroid bed on the postablation WBS, L-T4 treatment was initiated with the aim of decreasing TSH to low levels (<0.1 mUI/L) without inducing clinical thyrotoxicosis. Six to 18 months later, TSH stimulated serum Tg was measured and neck ultrasonography was performed. Patients with undetectable Tg/TSH (<1 ng/mL) and normal neck ultrasonography were subsequently followed up at yearly intervals with clinical examination and serum Tg measurement on L-T4 treatment at a replacement dose (serum TSH level between 0.5 and 1 mUI/L). Recurrence was suspected in patients with an increase in serum Tg level (≥1 ng/mL), and/or abnormal neck ultrasonography. In patients with detectable Tg/TSH and/or abnormal clinical examination or neck ultrasonography, morphological evaluation or chest computed tomography were performed. When recurrence was documented, specific treatments were given.
| Results|| |
The clinical characteristics of the 100 patients (88 females and 12 males), mean age 40 years, (range: 23–72) are reported in [Table 1]. The cancer was papillary in 81 cases (81%), follicular in 15 cases (15%), and an association of both papillary and follicular in four (4%) cases. Aggressive subtypes of DTC were found in two cases: tall cell cancer in 1 case (1%) and diffuse sclerosing variant in one case (1%). Initial treatment consisted in total thyroidectomy in all cases. Twenty (20%) patients did not undergo any neck dissection. Mean size of the primary thyroid tumor was 25 mm (range: 1–30, median: 9 mm). According to the 2010 pTNM scoring system, tumors were classified as pT1a in 42 (42%) cases, pT1b in 16 (16%) cases, pT2 in 25 (25%) cases, and pT3 in 17 (32%) cases. Lymph node metastases were present in two (2%) cases (pN1), absent in 63 (63%) cases (pN0) and lymph node status was unknown in 35 (35%) cases (pNx). Median interval of time between surgery and I-131 ablation was 100 days (range: 60–150 days).
WBS was abnormal in five cases (5%), disclosed foci of uptake outside the thyroid bed that were considered to be abnormal in three cases and suspicious in one case.
All abnormal foci of iodine uptake were located in the neck. They were located in the central compartment in three cases and in the lateral neck compartment in two cases. N-US, performed in all cases, were normal in 96 and falsely positive in three. A second I-131 treatment was administered after THW in all patients with abnormal postablative WBS. The second WBS was normal in four cases and showed persistent, abnormal foci of iodine uptake in the neck in one case. All patients were then followed up on L-T4 treatment, and after a median follow-up of 9 years (range: 5–13), one patient experienced a lung recurrence, 1 year after initial treatment. This patient had a pT2N1 tumor, an abnormal second WBS and an undetectable Tg level on L-T4 treatment at the time of recurrence.
Suspicious foci of I-131 uptake were located in the lung. A second I-131 treatment was administered. No recurrence occurred after a median follow-up of 5 years.
All patients with abnormal WBS or abnormal neck US had lymph node metastases.
Among the 95 patients with a normal postablative WBS, follow-up (>5 years) was available for 80 patients. TSH stimulated serum Tg level at 6–18 months after ablation was measured in all patients, after THW. It was undetectable in the absence of TgAb in 93 (98%) cases. Neck US performed 6–18 months after ablation in all patients, was normal in 92 (97%), falsely positive in three (3%).
During the follow-up, the patient with positive TgAb remained with a stable level of TgAb, undetectable serum Tg and normal neck US.
Among the two patients, recurrence occurred in two cases. Both had an aggressive variant of DTC.
| Discussion|| |
Postoperative administration of radioactive iodine allows to perform a highly sensitive WBS that may detect persistent disease by evidencing iodine uptake outside the thyroid bed. Furthermore, it facilitates follow-up by improving the specificity of serum Tg measurement by destroying the thyroid remnants, the normal source of Tg. Some studies reported a benefit of postoperative radioactive iodine therapy for recurrence-free survival in patients with tumors larger than 1 or 1.5 cm, or with neck lymph node metastases, or with aggressive pathological variants of DTC.,,, However, the efficacy of adjuvant radioactive iodine therapy for improving survival and recurrence-free survival is still controversial in low-risk patients, and only nonrandomized studies are available.,,,
The definition of cure at 9–12 months after postoperative radioactive iodine treatment is based on an undetectable stimulated serum Tg level with a normal neck US, therefore the usefulness of radioactive ablation in patients that have already an undectectable postoperative stimulated serum Tg level and a normal neck US can be questioned.,,,,
The negative predictive value of an undetectable stimulated Tg level at 6–18 months after ablation is very high, reaching 97% or more.,,,, Persistent disease in patients with undetectable stimulated serum Tg level is mostly due to the presence of small lymph node metastases, mainly found at neck US. Detectable postoperative Tg level at the time of ablation may be related to the presence of persistent disease or normal thyroid remnant.,,, Recent studies have, however, reported postoperative undetectable stimulated serum Tg level in up to 30% of the patients at the time of radioactive remnant ablation.
In this study, we only found abnormal WBS and abnormal neck US in patients with lymph node metastases, which is, therefore, a major risk factor of abnormal WBS and neck US.
Furthermore, proven recurrence during follow-up was rare (1%) and only found in patients with aggressive histological variants. Whether this low risk is linked to intrinsic cancer characteristics or to the beneficial effect of adjuvant radioactive iodine therapy cannot be determined because our study was retrospective and all patients were given 131-I. It can only be noted that in both cases, Tg level was elevated at the time of recurrence and that aggressive histological variants are known to respond poorly to 131-I treatment. A point worthy of note is that, in one case, one patient was classified as suspicious for the recurrent disease because of TgAb appearing during follow-up and no recurrence has been identified yet, most probably due to a change in the TgAb assay, emphasizing the importance of using the same assays over time.,
These results suggest that when postoperative stimulated Tg level is undetectable and neck US is normal, 131-I ablation could be avoided in patients without lymph node metastasis and in the absence of an aggressive histological variant of DTC. These results are in accordance with those that found radioactive iodine beneficial only for tumors with neck lymph node metastases or aggressive variants of DTC.,,, They suggest a tailoring of 131-I administration, not only on pTNM staging and histological subtypes but also on postoperative stimulated Tg level, and they emphasize the importance of lymph node staging for the determination of 131-I indications.
As expected, a postoperative undetectable stimulated Tg level with a normal neck US has a high negative predictive value both postoperatively and when performed 6–18 months after ablation. We also found that despite a mean interval of time of 87 days between surgery and ablation, neck US was informative as long as strict ultrasound criteria are used for the suspicion of malignancy. False positive neck US were more frequent than true positive, most probably due to this short postoperative delay and a high frequency of postoperative lymphocele or inflammatory hypervascularized hypertrophic lymph nodes.
Finally, we found that there was no need for repeating stimulated serum Tg measurement 6–18 months after ablation when it was already undetectable at the time of ablation. These results are in accordance with the previous series that reported a limited value of repeated rhTSH/Tg measurement in patients with previously negative rhTSH-stimulated Tg.,
| Conclusion|| |
Undetectable postoperative stimulated serum Tg level in the absence of TgAb at the time of ablation is frequent. In these patients, the stimulated Tg months after ablation does not add any further information. The study results suggest that I-131 ablation indications could be tailored to levels of postoperative stimulated serum Tg level and may be avoided in the absence of lymph node metastases in patients without an aggressive histological variant of TC.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al.
2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 2016;26:1-33.
Frasoldati A, Toschi E, Zini M, Flora M, Caroggio A, Dotti C, et al.
Role of thyroglobulin measurement in fine-needle aspiration biopsies of cervical lymph nodes in patients with differentiated thyroid cancer. Thyroid 1999;9:105-11.
Pacini F, Molinaro E, Castagna MG, Agate L, Elisei R, Ceccarelli C, et al.
Recombinant human thyrotropin-stimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma. J Clin Endocrinol Metab 2003;88:3668-73.
Torlontano M, Crocetti U, Augello G, D'Aloiso L, Bonfitto N, Varraso A, et al.
Comparative evaluation of recombinant human thyrotropin-stimulated thyroglobulin levels, 131I whole-body scintigraphy, and neck ultrasonography in the follow-up of patients with papillary thyroid microcarcinoma who have not undergone radioiodine therapy. J Clin Endocrinol Metab 2006;91:60-3.
Sobin LH, Gospodarowicz M, Wittekind C, editors. UICC TNM Classifi cation of Malignant Tumors. 7th ed. Wiley-Blackwell Publishing; 2011. p. 58-62.
DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990;71:414-24.
Mazzaferri EL. Thyroid remnant 131I ablation for papillary and follicular thyroid carcinoma. Thyroid 1997;7:265-71.
Taylor T, Specker B, Robbins J, Sperling M, Ho M, Ain K, et al.
Outcome after treatment of high-risk papillary and non-Hurthle-cell follicular thyroid carcinoma. Ann Intern Med 1998;129:622-627.
Jung TS, Kim TY, Kim KW, Oh YL, Park DJ, Cho BY, et al.
Clinical features and prognostic factors for survival in patients with poorly differentiated thyroid carcinoma and comparison to the patients with the aggressive variants of papillary thyroid carcinoma. Endocr J 2007;54:265-74.
Samaan NA, Schultz PN, Hickey RC, Goepfert H, Haynie TP, Johnston DA, et al.
The results of various modalities of treatment of well differentiated thyroid carcinomas: A retrospective review of 1599 patients. J Clin Endocrinol Metab 1992;75:714-20.
Sanders LE, Cady B. Differentiated thyroid cancer: Reexamination of risk groups and outcome of treatment. Arch Surg 1998;133:419-25.
Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Dvorak CE, Gorman CA, et al.
Papillary thyroid carcinoma managed at the Mayo clinic during six decades (1940-1999): Temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 2002;26:879-85.
Kim S, Wei JP, Braveman JM, Brams DM. Predicting outcome and directing therapy for papillary thyroid carcinoma. Arch Surg 2004;139:390-4.
Cailleux AF, Baudin E, Travagli JP, Ricard M, Schlumberger M. Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer? J Clin Endocrinol Metab 2000;85:175-8.
Mazzaferri EL, Kloos RT. 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 2002;87:1490-8.
Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D, Pinchera A, et al.
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 2002;87:1499-501.
Torlontano M, Attard M, Crocetti U, Tumino S, Bruno R, Costante G, et al.
Follow-up of low risk patients with papillary thyroid cancer: Role of neck ultrasonography in detecting lymph node metastases. J Clin Endocrinol Metab 2004;89:3402-7.
Toubeau M, Touzery C, Arveux P, Chaplain G, Vaillant G, Berriolo A, et al.
Predictive value for disease progression of serum thyroglobulin levels measured in the postoperative period and after (131)I ablation therapy in patients with differentiated thyroid cancer. J Nucl Med 2004;45:988-94.
Bachelot A, Cailleux AF, Klain M, Baudin E, Ricard M, Bellon N, et al.
Relationship between tumor burden and serum thyroglobulin level in patients with papillary and follicular thyroid carcinoma. Thyroid 2002;12:707-11.
Grünwald F, Menzel C, Fimmers R, Zamora PO, Biersack HJ. Prognostic value of thyroglobulin after thyroidectomy before ablative radioiodine therapy in thyroid cancer. J Nucl Med 1996;37:1962-4.
Ronga G, Filesi M, Ventroni G, Vestri AR, Signore A. Value of the first serum thyroglobulin level after total thyroidectomy for the diagnosis of metastases from differentiated thyroid carcinoma. Eur J Nucl Med 1999;26:1448-52.
Oyen WJ, Verhagen C, Saris E, van den Broek WJ, Pieters GF, Corsten FH, et al.
Follow-up regimen of differentiated thyroid carcinoma in thyroidectomized patients after thyroid hormone withdrawal. J Nucl Med 2000;41:643-6.
Tala Jury HP, Castagna MG, Fioravanti C, Cipri C, Brianzoni E, Pacini F, et al.
Lack of association between urinary iodine excretion and successful thyroid ablation in thyroid cancer patients. J Clin Endocrinol Metab 2010;95:230-7.
Spencer CA, Wang CC. Thyroglobulin measurement. Techniques, clinical benefits, and pitfalls. Endocrinol Metab Clin North Am 1995;24:841-63.
Schlumberger M, Hitzel A, Toubert ME, Corone C, Troalen F, Schlageter MH, et al.
Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients. J Clin Endocrinol Metab 2007;92:2487-95.
Bonnet S, Hartl D, Leboulleux S, Baudin E, Lumbroso JD, Al Ghuzlan A, et al.
Prophylactic lymph node dissection for papillary thyroid cancer less than 2 cm: Implications for radioiodine treatment. J Clin Endocrinol Metab 2009;94:1162-7.
Kloos RT, Mazzaferri EL. A single recombinant human thyrotropin-stimulated serum thyroglobulin measurement predicts differentiated thyroid carcinoma metastases three to five years later. J Clin Endocrinol Metab 2005;90:5047-57.
Castagna MG, Brilli L, Pilli T, Montanaro A, Cipri C, Fioravanti C, et al.
Limited value of repeat recombinant human thyrotropin (rhTSH)-stimulated thyroglobulin testing in differentiated thyroid carcinoma patients with previous negative rhTSH-stimulated thyroglobulin and undetectable basal serum thyroglobulin levels. J Clin Endocrinol Metab 2008;93:76-81.