Clinical Biochemistry 48 (2015) 747–748
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Editorial
Lessons learned from thyroglobulin concentrations after total thyroidectomy and radioactive iodine ablation for differentiated thyroid cancer
Serum thyroglobulin (Tg) levels reflect the combination of three factors: the normal or “differentiated” neoplastic thyroid tissue volume, the degree of stimulation of the TSH receptor, and the effect of thyroid tissue injury [1]. It is precisely because of these properties that suppressed and stimulated (either with rhTSH or after thyroid hormone withdrawal) thyroglobulin (Tg) measurements in the absence of antiTg antibody interference are a routine part of the follow-up strategy of patients with papillary and follicular thyroid carcinoma (“differentiated” thyroid cancer). Also, the fact that Tg is released into the circulation after tissue injury implies that its concentrations should be carefully interpreted when measured close to the time of surgery and/or radioactive iodine ablation or treatment (RAI). Studies that have examined Tg disappearance kinetics in patients with differentiated thyroid cancer (DTC) treated with total or subtotal thyroidectomy have shown a mean Tg half-life ranging from approximately 28 h to 65 h [2,3]. Therefore, it would be expected that on average for individuals with the slowest clearance rates at least 25 days (t1/2 × 7–10) post-surgery is required to obtain Tg levels that reflect residual benign and/or malignant thyroid tissue. Given these important kinetic considerations, studies evaluating the prognostic value of postoperative pre-ablative Tg concentrations in patients with DTC, usually measure it at a minimum of 28 days after surgery [4–9]. Under these circumstances, Tg concentrations ranging from undetectably low to up to 5–10 μg/L are associated with a better prognosis, i.e., lower probability of metastatic disease and of persistent or recurrent disease. Indeed, patients with low-risk papillary thyroid cancer who do not receive RAI on the basis of postoperative stimulated Tg levels of b1 μg/L to up to b5 μg/L are unlikely to harbor persistent disease or to develop a recurrence after a mean follow-up of 6 years [10,11]. Six months to one year after total or subtotal thyroidectomy followed by RAI, stimulated Tg concentrations below the cut-off (usually b 1 μg/L) together with negative imaging studies identify patients who are free of disease, whereas those who do not meet these criteria may warrant further diagnostic and eventually therapeutic procedures [12,13]. Furthermore, suppressed and stimulated Tg concentrations measured during the first two years of follow-up after total thyroidectomy and RAI together with imaging studies, allow for a dynamic risk restratification approach that improves the risk estimates as provided by the American Thyroid Association (ATA) [13–16]. This ATA initial post-treatment risk recurrence classification relies on operative and surgical pathology findings as well as post-RAI scan findings but does not take into account Tg levels [13]. Typically, patients classified as “low risk” will have persistent or recurrent disease in approximately
9–22%, whereas those estimates increase to 43–48% in the “intermediate risk” category and to 68–69% in the “high-risk” category [17]. However, for patients that are re-stratified to the category of “excellent response to therapy” (stimulated Tg b1 μg/L without structural evidence of disease) the likelihood of persistent structural disease or recurrence is reduced to 14% in high-risk patients and to 2% in low and intermediate-risk patients [14]. Conversely, in patients with an “incomplete response to therapy” (stimulated Tg N 10 μg/L or suppressed levels N1 μg/L, rising Tg values, or structural disease) the likelihood of persistent structural disease or recurrence increases to 79% in high-risk patients, 41% in intermediate-risk patients, and 13% in low-risk patients [14]. In summary, the management and follow-up of patients with DTC rely on the initial risk stratification but it must be modified according to the structural and biochemical (stimulated and suppressed Tg levels in the absence of antibody interference) response to therapy [14,14a]. In this regard, Stevic et al. [18] explore the utility of measuring Tg levels in the absence of antibody interference at baseline (not stimulated), 2–3 days pre-RAI, 7 days post-RAI, and at 6 months of follow-up (stimulated) in patients with DTC treated with total thyroidectomy followed by RAI. They noted that in patients without distant metastases and total resection of gross neck disease, Tg levels follow a generally predictable pattern: a transient early increase from baseline seven days after radioactive iodine (from a mean = 5.1 μg/L to a mean = 13.7 μg/L) followed by a decrease below baseline at 6 months (mean = 2.3 μg/L; all values b 10 μg/L and approximately 70% b 0.8 μg/L). None of the patients in this lower risk group had evidence of disease recurrence at 6-months. Conversely, in patients with incomplete macroscopic resection of the neck disease and/or distant metastases (higher risk group), pre-RAI levels (mean = 431.6 μg/L) were not statistically different than post-RAI levels (mean = 509.5 μg/L) and remained elevated (mean = 57.4 μg/L) at 6 months of follow-up. Not surprisingly, and in keeping with the tissue injury induced by radioactive iodine, the observations in the lower risk group support previous studies that show that serum Tg concentrations measured during the first week after RAI are higher than the matched pre-ablation Tg concentrations [8,19]. One could hypothesize that the reason the same phenomenon was not observed in the high-risk group is that perhaps this cohort included patients whose tumors under-express genes responsible for iodine uptake and metabolism. Indeed, it is now recognized that the more aggressive histologic papillary thyroid carcinoma subtypes, such as tall cell variants, and/or those PTCs with BRAFV600E show dedifferentiation that manifests in part by lower expression of genes governing iodine
http://dx.doi.org/10.1016/j.clinbiochem.2015.07.006 0009-9120/© 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
748
Editorial
metabolism [20]. Stevic et al. also provided further support for measuring Tg at 6 months post-radioactive iodine as they elegantly showed that Tg levels in lower risk patients are expected to become undetectable or below baseline at that time point whereas they will remain elevated in higher risk patients. It is noteworthy that their lower risk group had a median postoperative pre-RAI stimulated Tg of 13.7 μg/L, which is higher than the b10 μg/L that has been previously reported to be associated with better prognosis [4,6,9]. However, it should also be emphasized that post-operative Tg values are influenced by the extent of completeness of normal thyroid tissue resected. References [1] C.A. Spencer, J.S. Lopresti, Measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer, Nat. Clin. Pract. Endocrinol. Metab. 4 (2008) 223–233. [2] M. Hocevar, M. Auersperg, L. Stanovnik, The dynamics of serum thyroglobulin elimination from the body after thyroid surgery, Eur. J. Surg. Oncol. 23 (1997) 208–210. [3] L. Giovanella, L. Ceriani, M. Maffioli, Postsurgery serum thyroglobulin disappearance kinetic in patients with differentiated thyroid carcinoma, Head Neck 32 (2010) 568–571. [4] W.J. Oyen, C. Verhagen, E. Saris, W.J. van den Broek, G.F. Pieters, F.H. Corsten, Followup regimen of differentiated thyroid carcinoma in thyroidectomized patients after thyroid hormone withdrawal, J. Nucl. Med. 41 (2000) 643–646. [5] J.D. Lin, M.J. Huang, B.R. Hsu, T.C. Chao, C. Hsueh, F.H. Liu, et al., Significance of postoperative serum thyroglobulin levels in patients with papillary and follicular thyroid carcinomas, J. Surg. Oncol. 80 (2002) 45–51. [6] M. Toubeau, C. Touzery, P. Arveux, G. Chaplain, G. Vaillant, A. Berriolo, 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. 45 (2004) 988–994. [7] L. Giovanella, L. Ceriani, A. Ghelfo, F. Keller, Thyroglobulin assay 4 weeks after thyroidectomy predicts outcome in low-risk papillary thyroid carcinoma, Clin. Chem. Lab. Med. 43 (2005) 843–847. [8] M.O. Bernier, O. Morel, P. Rodien, J.P. Muratet, P. Giraud, V. Rohmer, et al., Prognostic value of an increase in the serum thyroglobulin level at the time of the first ablative radioiodine treatment in patients with differentiated thyroid cancer, Eur. J. Nucl. Med. Mol. Imaging 32 (2005) 1418–1421. [9] A. Polachek, D. Hirsch, G. Tzvetov, S. Grozinsky-Glasberg, I. Slutski, J. Singer, et al., Prognostic value of post-thyroidectomy thyroglobulin levels in patients with differentiated thyroid cancer, J. Endocrinol. Investig. 34 (2011) 855–860. [10] K. Gomez Hernandez, D. Etarsky, S. Orlov, P.G. Walfish, Stimulated thyroglobulin and neck ultrasonography facilitates postsurgical radioactive iodine remnant ablation selection in patients with low-risk well-differentiated thyroid carcinoma, Thyroid 22 (2012) 760–761.
[11] S. Orlov, F. Salari, L. Kashat, J.L. Freeman, A. Vescan, I.J. Witterick, et al., Postoperative stimulated thyroglobulin and neck ultrasound as personalized criteria for risk stratification and radioactive iodine selection in low- and intermediaterisk papillary thyroid cancer, Endocrine (2015) Mar 20 [Epub ahead of print]. [12] E.L. Mazzaferri, R.J. Robbins, C.A. Spencer, L.E. Braverman, F. Pacini, L. Wartofsky, et al., A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma, J. Clin. Endocrinol. Metab. 88 (2003) 1433–1441. [13] American Thyroid Association Guidelines Taskforce on Thyroid N, Differentiated Thyroid C, D.S. Cooper, G.M. Doherty, B.R. Haugen, R.T. Kloos, et al., Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer, Thyroid 19 (2009) 1167–1214. [14] R.M. Tuttle, H. Tala, J. Shah, R. Leboeuf, R. Ghossein, M. Gonen, et al., Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system, Thyroid 20 (2010) 1341–1349. [14a] A.M. Sawka, J.D. Brierley, S. Ezzat, D.P. Goldstein, Managing newly diagnosed thyroid cancer, CMAJ. 186 (2014) 269–275. [15] F. Vaisman, H. Tala, R. Grewal, R.M. Tuttle, In differentiated thyroid cancer, an incomplete structural response to therapy is associated with significantly worse clinical outcomes than only an incomplete thyroglobulin response, Thyroid 21 (2011) 1317–1322. [16] F. Vaisman, D. Momesso, D.A. Bulzico, C.H. Pessoa, F. Dias, R. Corbo, et al., Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy, Clin. Endocrinol. (Oxf.) 77 (2012) 132–138. [17] D.P. Momesso, R.M. Tuttle, Update on differentiated thyroid cancer staging, Endocrinol. Metab. Clin. North Am. 43 (2014) 401–421. [18] I. Stevic, T.C. Dembinski, K.A. Pathak, W.D. Leslie, Transient early increase in thyroglobulin levels post-radioiodine ablation in patients with differentiated thyroid cancer, Clin. Biochem. 48 (2015) 658–661. [19] D. Taieb, F. Sebag, B. Farman-Ara, T. Portal, K. Baumstarck-Barrau, C. Fortanier, et al., Iodine biokinetics and radioiodine exposure after recombinant human thyrotropinassisted remnant ablation in comparison with thyroid hormone withdrawal, J. Clin. Endocrinol. Metab. 95 (2010) 3283–3290. [20] Cancer Genome Atlas Research N, Integrated genomic characterization of papillary thyroid carcinoma, Cell 159 (2014) 676–690.
Karen Gomez-Hernandez, M.D.⁎ Shereen Ezzat, M.D. Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario M5G 2N2, Canada ⁎Corresponding author.
Contents lists available at ScienceDirect
Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem
Editorial
Lessons learned from thyroglobulin concentrations after total thyroidectomy and radioactive iodine ablation for differentiated thyroid cancer
Serum thyroglobulin (Tg) levels reflect the combination of three factors: the normal or “differentiated” neoplastic thyroid tissue volume, the degree of stimulation of the TSH receptor, and the effect of thyroid tissue injury [1]. It is precisely because of these properties that suppressed and stimulated (either with rhTSH or after thyroid hormone withdrawal) thyroglobulin (Tg) measurements in the absence of antiTg antibody interference are a routine part of the follow-up strategy of patients with papillary and follicular thyroid carcinoma (“differentiated” thyroid cancer). Also, the fact that Tg is released into the circulation after tissue injury implies that its concentrations should be carefully interpreted when measured close to the time of surgery and/or radioactive iodine ablation or treatment (RAI). Studies that have examined Tg disappearance kinetics in patients with differentiated thyroid cancer (DTC) treated with total or subtotal thyroidectomy have shown a mean Tg half-life ranging from approximately 28 h to 65 h [2,3]. Therefore, it would be expected that on average for individuals with the slowest clearance rates at least 25 days (t1/2 × 7–10) post-surgery is required to obtain Tg levels that reflect residual benign and/or malignant thyroid tissue. Given these important kinetic considerations, studies evaluating the prognostic value of postoperative pre-ablative Tg concentrations in patients with DTC, usually measure it at a minimum of 28 days after surgery [4–9]. Under these circumstances, Tg concentrations ranging from undetectably low to up to 5–10 μg/L are associated with a better prognosis, i.e., lower probability of metastatic disease and of persistent or recurrent disease. Indeed, patients with low-risk papillary thyroid cancer who do not receive RAI on the basis of postoperative stimulated Tg levels of b1 μg/L to up to b5 μg/L are unlikely to harbor persistent disease or to develop a recurrence after a mean follow-up of 6 years [10,11]. Six months to one year after total or subtotal thyroidectomy followed by RAI, stimulated Tg concentrations below the cut-off (usually b 1 μg/L) together with negative imaging studies identify patients who are free of disease, whereas those who do not meet these criteria may warrant further diagnostic and eventually therapeutic procedures [12,13]. Furthermore, suppressed and stimulated Tg concentrations measured during the first two years of follow-up after total thyroidectomy and RAI together with imaging studies, allow for a dynamic risk restratification approach that improves the risk estimates as provided by the American Thyroid Association (ATA) [13–16]. This ATA initial post-treatment risk recurrence classification relies on operative and surgical pathology findings as well as post-RAI scan findings but does not take into account Tg levels [13]. Typically, patients classified as “low risk” will have persistent or recurrent disease in approximately
9–22%, whereas those estimates increase to 43–48% in the “intermediate risk” category and to 68–69% in the “high-risk” category [17]. However, for patients that are re-stratified to the category of “excellent response to therapy” (stimulated Tg b1 μg/L without structural evidence of disease) the likelihood of persistent structural disease or recurrence is reduced to 14% in high-risk patients and to 2% in low and intermediate-risk patients [14]. Conversely, in patients with an “incomplete response to therapy” (stimulated Tg N 10 μg/L or suppressed levels N1 μg/L, rising Tg values, or structural disease) the likelihood of persistent structural disease or recurrence increases to 79% in high-risk patients, 41% in intermediate-risk patients, and 13% in low-risk patients [14]. In summary, the management and follow-up of patients with DTC rely on the initial risk stratification but it must be modified according to the structural and biochemical (stimulated and suppressed Tg levels in the absence of antibody interference) response to therapy [14,14a]. In this regard, Stevic et al. [18] explore the utility of measuring Tg levels in the absence of antibody interference at baseline (not stimulated), 2–3 days pre-RAI, 7 days post-RAI, and at 6 months of follow-up (stimulated) in patients with DTC treated with total thyroidectomy followed by RAI. They noted that in patients without distant metastases and total resection of gross neck disease, Tg levels follow a generally predictable pattern: a transient early increase from baseline seven days after radioactive iodine (from a mean = 5.1 μg/L to a mean = 13.7 μg/L) followed by a decrease below baseline at 6 months (mean = 2.3 μg/L; all values b 10 μg/L and approximately 70% b 0.8 μg/L). None of the patients in this lower risk group had evidence of disease recurrence at 6-months. Conversely, in patients with incomplete macroscopic resection of the neck disease and/or distant metastases (higher risk group), pre-RAI levels (mean = 431.6 μg/L) were not statistically different than post-RAI levels (mean = 509.5 μg/L) and remained elevated (mean = 57.4 μg/L) at 6 months of follow-up. Not surprisingly, and in keeping with the tissue injury induced by radioactive iodine, the observations in the lower risk group support previous studies that show that serum Tg concentrations measured during the first week after RAI are higher than the matched pre-ablation Tg concentrations [8,19]. One could hypothesize that the reason the same phenomenon was not observed in the high-risk group is that perhaps this cohort included patients whose tumors under-express genes responsible for iodine uptake and metabolism. Indeed, it is now recognized that the more aggressive histologic papillary thyroid carcinoma subtypes, such as tall cell variants, and/or those PTCs with BRAFV600E show dedifferentiation that manifests in part by lower expression of genes governing iodine
http://dx.doi.org/10.1016/j.clinbiochem.2015.07.006 0009-9120/© 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.
748
Editorial
metabolism [20]. Stevic et al. also provided further support for measuring Tg at 6 months post-radioactive iodine as they elegantly showed that Tg levels in lower risk patients are expected to become undetectable or below baseline at that time point whereas they will remain elevated in higher risk patients. It is noteworthy that their lower risk group had a median postoperative pre-RAI stimulated Tg of 13.7 μg/L, which is higher than the b10 μg/L that has been previously reported to be associated with better prognosis [4,6,9]. However, it should also be emphasized that post-operative Tg values are influenced by the extent of completeness of normal thyroid tissue resected. References [1] C.A. Spencer, J.S. Lopresti, Measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer, Nat. Clin. Pract. Endocrinol. Metab. 4 (2008) 223–233. [2] M. Hocevar, M. Auersperg, L. Stanovnik, The dynamics of serum thyroglobulin elimination from the body after thyroid surgery, Eur. J. Surg. Oncol. 23 (1997) 208–210. [3] L. Giovanella, L. Ceriani, M. Maffioli, Postsurgery serum thyroglobulin disappearance kinetic in patients with differentiated thyroid carcinoma, Head Neck 32 (2010) 568–571. [4] W.J. Oyen, C. Verhagen, E. Saris, W.J. van den Broek, G.F. Pieters, F.H. Corsten, Followup regimen of differentiated thyroid carcinoma in thyroidectomized patients after thyroid hormone withdrawal, J. Nucl. Med. 41 (2000) 643–646. [5] J.D. Lin, M.J. Huang, B.R. Hsu, T.C. Chao, C. Hsueh, F.H. Liu, et al., Significance of postoperative serum thyroglobulin levels in patients with papillary and follicular thyroid carcinomas, J. Surg. Oncol. 80 (2002) 45–51. [6] M. Toubeau, C. Touzery, P. Arveux, G. Chaplain, G. Vaillant, A. Berriolo, 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. 45 (2004) 988–994. [7] L. Giovanella, L. Ceriani, A. Ghelfo, F. Keller, Thyroglobulin assay 4 weeks after thyroidectomy predicts outcome in low-risk papillary thyroid carcinoma, Clin. Chem. Lab. Med. 43 (2005) 843–847. [8] M.O. Bernier, O. Morel, P. Rodien, J.P. Muratet, P. Giraud, V. Rohmer, et al., Prognostic value of an increase in the serum thyroglobulin level at the time of the first ablative radioiodine treatment in patients with differentiated thyroid cancer, Eur. J. Nucl. Med. Mol. Imaging 32 (2005) 1418–1421. [9] A. Polachek, D. Hirsch, G. Tzvetov, S. Grozinsky-Glasberg, I. Slutski, J. Singer, et al., Prognostic value of post-thyroidectomy thyroglobulin levels in patients with differentiated thyroid cancer, J. Endocrinol. Investig. 34 (2011) 855–860. [10] K. Gomez Hernandez, D. Etarsky, S. Orlov, P.G. Walfish, Stimulated thyroglobulin and neck ultrasonography facilitates postsurgical radioactive iodine remnant ablation selection in patients with low-risk well-differentiated thyroid carcinoma, Thyroid 22 (2012) 760–761.
[11] S. Orlov, F. Salari, L. Kashat, J.L. Freeman, A. Vescan, I.J. Witterick, et al., Postoperative stimulated thyroglobulin and neck ultrasound as personalized criteria for risk stratification and radioactive iodine selection in low- and intermediaterisk papillary thyroid cancer, Endocrine (2015) Mar 20 [Epub ahead of print]. [12] E.L. Mazzaferri, R.J. Robbins, C.A. Spencer, L.E. Braverman, F. Pacini, L. Wartofsky, et al., A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma, J. Clin. Endocrinol. Metab. 88 (2003) 1433–1441. [13] American Thyroid Association Guidelines Taskforce on Thyroid N, Differentiated Thyroid C, D.S. Cooper, G.M. Doherty, B.R. Haugen, R.T. Kloos, et al., Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer, Thyroid 19 (2009) 1167–1214. [14] R.M. Tuttle, H. Tala, J. Shah, R. Leboeuf, R. Ghossein, M. Gonen, et al., Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system, Thyroid 20 (2010) 1341–1349. [14a] A.M. Sawka, J.D. Brierley, S. Ezzat, D.P. Goldstein, Managing newly diagnosed thyroid cancer, CMAJ. 186 (2014) 269–275. [15] F. Vaisman, H. Tala, R. Grewal, R.M. Tuttle, In differentiated thyroid cancer, an incomplete structural response to therapy is associated with significantly worse clinical outcomes than only an incomplete thyroglobulin response, Thyroid 21 (2011) 1317–1322. [16] F. Vaisman, D. Momesso, D.A. Bulzico, C.H. Pessoa, F. Dias, R. Corbo, et al., Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy, Clin. Endocrinol. (Oxf.) 77 (2012) 132–138. [17] D.P. Momesso, R.M. Tuttle, Update on differentiated thyroid cancer staging, Endocrinol. Metab. Clin. North Am. 43 (2014) 401–421. [18] I. Stevic, T.C. Dembinski, K.A. Pathak, W.D. Leslie, Transient early increase in thyroglobulin levels post-radioiodine ablation in patients with differentiated thyroid cancer, Clin. Biochem. 48 (2015) 658–661. [19] D. Taieb, F. Sebag, B. Farman-Ara, T. Portal, K. Baumstarck-Barrau, C. Fortanier, et al., Iodine biokinetics and radioiodine exposure after recombinant human thyrotropinassisted remnant ablation in comparison with thyroid hormone withdrawal, J. Clin. Endocrinol. Metab. 95 (2010) 3283–3290. [20] Cancer Genome Atlas Research N, Integrated genomic characterization of papillary thyroid carcinoma, Cell 159 (2014) 676–690.
Karen Gomez-Hernandez, M.D.⁎ Shereen Ezzat, M.D. Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario M5G 2N2, Canada ⁎Corresponding author.
