Track topics on Twitter Track topics that are important to you
Thyroidectomy followed by administration of large activities of 131-iodine (131I) is the treatment of choice for differentiated thyroid carcinoma (DTC). The serum thyroglobulin (Tg) measurement during hypothyroidism (offT4-Tg), just before radioiodine thyroid ablation, has proved to be effective for predicting persistent/recurrent disease. However, the Tg measurement cannot be used as a corresponding value for preablative offT4-Tg when rhTSH is used as stimulous before treatment. The present study was undertaken to evaluate if post-thyroidectomy Tg values, measured before rhTSH-stimulation and radioiodine administration, is of prognostic value in patients affected by DTC. We enrolled 28 patients with DTC and submitted to total thyroidectomy. Thyroxine (T4) treatment was started just after surgery to suppress TSH levels. Six to nine weeks later Tg levels were measured both basally (onT4-Tg) and after rhTSH (rhTSH-Tg) stimulation. Subsequently, T4 was stopped and serum Tg measured (offT4-Tg) just before 3700 MBq of 131I-iodide administration. A post-treatment whole body scan (PT-WBS) was performed and neck radioiodine uptake (RAIU) measured. A significant relationship was found between onT4-Tg and both rhTSH-Tg and offT4-Tg. The onT4-Tg levels of 0.2 ng/mL or higher predicted PT-WBS results with a 100% negative and 43% positive predictive values, respectively. Additionally onT4-Tg levels of 0.9 ng/mL or more predicts 12-months recurrences with 100% negative and 60% positive predictive value. In comparison, 1.0 ng/mL or higher offT4-Tg values predicted PT-WBS results and 12-months restaging with 94% and 100% negative and 45% and 27% positive predictive value, respectively. Basing on our data we conclude that preablative onT4-Tg may be of value as prognostic marker when rhTSH-aided radioiodine ablation is done. Additionally, the role of preblative onT4-Tg measurement as a yard-stick for radioiodine ablation should be further evaluate.
Introduction Total (or near-total) thyroidectomy followed by TSH-stimulated administration of large activities of 131-iodine (131I) is the treatment of choice for DTC [1-3]. The serum thyroglobulin (Tg) measurement during hypothyroidism, just before radioiodine thyroid ablation, has proved to be effective for predicting persistent/recurrent disease [4-8]. Recently recombinant human TSH (rhTSH) showed to be safely employed instead of thyroxine (T4) withdrawal (offT4) to prepare patients for radioiodine ablation [9-10]. However, the Tg level are measured 48 hours after radioiodine administration when rhTSH is used as stimulation . Consequently, due to the radioiodine-induced thyroid cells damage and Tg release, the Tg measurement would not have reliable predictive value in patients treated by rhTSH stimulation . The present study was undertaken to evaluate if preablativeTg measurement under T4 treatment is of prognostic value and serves as surrogate marker of offT4-stimulated preablative Tg.
Patients and methods
Patients selection We retrospectively enrolled 28 consecutive patients affected by histologically proven DTC (23 papillary, 5 follicular) submitted to total thyroidectomy and central compartment lymph-node dissection. Thyroxine (T4) treatment was started immediately after surgery to suppress TSH levels. Six to nine weeks later Tg levels were measured both basally (onT4-Tg) and after rhTSH (rhTSH-Tg) stimulation as previously described . Subsequently, T4 was stopped for 4 weeks and serum Tg measured (offT4-Tg) just before 3700 MBq of 131I-iodide administration. A post-treatment whole body scan (PT-WBS) with radioiodine uptake (RAIU) calculation was performed according to a previously described protocol . All non physiologic iodine uptake areas out of the thyroid bed were considered as positive findings [14, 15]. Patients with positive PT-WBS underwent specific treatment and personalized follow-up. Patients with negative PT-WBS immediately restarted T4 suppressive treatment. Final restaging was performed in all patients 12 months after the last treatment by neck ultrasound, onT4-Tg assay and both offT4-diagnostic WBS (DgWBS) and Tg assay (4 weeks T4 withdrawal; required TSH>30 mUI/L). Clinical and pathological characteristics of selected patients were summarized in the Table 1.
Serum Tg assay and screening for interferences Serum Tg was assayed in duplicate by a specific high-sensitive IRMA assay (DYNOtest® Tg-plus, BRAHMS Diagnostica GmbH, Berlin, Germany) according to the producer’ instructions. This method provided a sensitivity of 0.05 ng/mL and a functional sensitivity of 0.2 ng/mL [16, 17]. As previously published, preablative offT4 serum Tg values above 4.5 ng/mL and 3.2 ng/mL were considered as positive with respect to PT-WBS and 12 months restaging results, respectively . Otherwise, offT4-Tg values higher than 0.2 ng/ml measured 12 months after thyroid ablation were considered positive for persisting/relapsing disease. [18, 19]. The presence of anti-thyroglobulin antibodies (AbTg) was screened by a specific radioimmunoassay (DYNOtest® anti-TGn, BRAHMS Diagnostica GmbH, Berlin, Germany) and by recovery test with a specific Tg-recovery buffer provided by the producer. Sera showing AbTg levels more than 60 U/mL and/or recover less than 80% or more than 120% were excluded from the study. Quality control was ensured by assaying two levels of control sera in each series, by re-assessing all sera showing a coefficient of variation exceeding 10% and by a bimonthly partecipation in the European inter-laboratory control OncocheckTM.
Statistics Quantitative data are expressed as mean ± SD. Differences between groups were assessed by two-tailed unpaired t-test. The relationship between variables was assessed by linear regression analysis. In order to allow statistical analysis the value of undetectable serum Tg expressed as < 0.2 ng/nL was arbitrarily changed in 0.10 ng/mL. Statistical significance was defined by a p-value < 0.05.
Ethics All diagnostic and therapeutic procedures were performed according to the regulations of the local ethics committee. Informed consensus was obtained from each patient.
Results The overall results are summarized in the Table I. Relationship Between Post-surgery onT4-Tg, rhTSH-Tg and offT4-Tg A significant positive relationship was found between onT4-Tg and both rhTSH-Tg (p<.0001) and offT4-Tg (p<0.0001) (Figure 1, A-B-C) as well as between rhTSH and offT4-stimulated Tg (p<.0001).
Relationship Between Post-surgery Serum Tg and Thyroid Remnant Radioiodine Uptake (RAIU) Among 22 patients showing no DTC metastasis on PT-WBS the serum distribution of onT4-Tg, rhTSH-Tg and offT4-Tg was 0.342±0.402; 0.664±0.803 and 1.195±1.485 ng/mL respectively. Both rhTSH and offT4-stimulated Tg levels were related to RAIU (p <.05 and <.005, respectively) while no significant relationship was found between RAIU and onT4-Tg levels (Figure 1, D-E-F).
Relationship Between Post-surgery Serum Tg and PT-WBS results The patients with positive PT-WBS showed higher onT4-Tg (0.617±0.445 vs 0.341±0.402 ng/mL), rhTSH-Tg (2.150±1.249 vs 0.664±0.803 ng/mL) and offT4-Tg (4.417±2.136 vs 1.195±1.485 ng/mL) levels as compared with patients with negative scan. Among 14 patients with undetectable onT4-Tg (i.e. ≤0.2 ng/mL) none had positive PT-WBS neither recurrences at 12-months restaging. Additionally, none of these patients showed stimulated Tg values more than 0.4 ng/mL and 1.0 ng/mL after rhTSH stimulation and T4 withdrawal, respectively. Viceversa, among 14 patients with onT4-Tg levels more than 0.2 ng/mL, 6 had positive PT-WBS (onT4-Tg: 0.3 to 1.4 ng/mL) and 3 showed DTC recurrences at 12 months restaging (onT4-Tg: 0.9 to 1.7 ng/mL). Consequently, the onT4-Tg levels predicts PT-WBS results with a 100% negative and 43% positive predictive values, respectively. Additionally onT4-Tg levels of 0.9 ng/mL or more predicts 12-months recurrences with 100% negative and 60% positive predictive value. In comparison, 1.0 ng/mL or higher offT4-Tg values predicted PT-WBS results and 12-months restaging with 94% and 100% negative and 45% and 27% positive predictive value, respectively.
Discussion Many reports indicate the usefulness of Tg concentration measurement before radioiodine treatment to early detection of DTC relapse or metastasis [4-8, 20, 21]. Three factors determine Tg concentration in most clinical situations: thyroid cell mass, thyroid cell damage and activation of TSH receptors . When Tg is measured before radioiodine ablation the effects of surgical damage are generally vanished and endogenous TSH levels are increased in all patients: consequently the thyroid remnant mass is the major determinant of the serum Tg concentrations . However, the rhTSH-stimulated Tg cannot be used instead of preablative offT4-Tg when rhTSH is employed to prepare radioiodine ablation . Therefore we evaluated the role of post-surgery onT4-Tg as surrogate prognostic marker. We choiced to suppress TSH levels in order to normalize the effect of TSH stimulation on thyroid remnants. Clearly, the TSH suppression reduced Tg levels: however, the high-sensitive Tg assays provide a good distinction between the lower limit of the euthyroid reference range and the functional sensitivity limit detecting small amounts of thyroid tissue even in the TSH-suppressed state (22, 23). We showed a significant positive relationship between post-surgery Tg measured during T4 treatment and after TSH stimulation. No relationship was found between RAIU (i.e. expression of remnant mass) and onT4-Tg, probably due the clustering of all Tg levels lower than 0.2 ng/mL (see statistics paragraph). However, undetectable onT4-Tg after surgery identifies patients free of metastasis at PT-WBS and without late recurreces during early 12-months follow-up. None of these patients showed a significant increase in both rhTSH and offT4-stimulated Tg before radioiodine ablation. This seems to indicate that the relationship between Tg expression and thyroid tissue mass is manteined even in TSH suppression state: Therefore undetectable serum onT4-Tg really identifies patients without significant thyroid tissue amount as well as stimulated Tg. All patients performed extracapsular total thyroidectomy in a dedicated thyroid surgery unit and the thyroid remnant, expressed as RAIU, was lower in our series than in others. This means that our data cannot directly translated to patients treated by more limited surgery. Globally, basing on our data we conclude that preablative onT4-Tg may be of value as prognostic marker when rhTSH-aided radioiodine ablation is done. Additionally, the role of preblative onT4-Tg measurement as a yard-stick for radioiodine ablation should be further evaluate.
1. Schlumberger MJ. Medical progress: papillary and follicular thyroid carcinoma. N Engl J Med 1998; 338: 297-306.
2. Pacini F. Follow-up of differentiate thyroid cancer. Eur J Nucl Med 2002; 29(S2): 492-6.
3. Klain M, Richard M, Leboulleux S et al. Radioiodine therapy for papillary and follicular thyroid carcinoma. Eur J Nucl Med 2002; 29(S2): S479-85.
4. Ronga G, Filesi M, Ventroni G et al. Value of the first serum thyroglobulin level after total thyroidectomy for the diagnosis of metastasis from differentiated thyroid carcinoma. Eur J Nucl Med 1999; 26(11): 1448-52.
5. Grünwald F, Menzel C, Fimmers R et al. Prognostic value of thyroglobulin after thyroidectomy before ablative radioiodine therapy in thyroid cancer. J Nucl Med 1996; 37(12): 1962-4.
6. Lin JD, Huang MJ, Hsu BR, Chao TC, Hsueh C, Liu FH et al. Significance of postoperative serum thyroglobulin levels in patients with papillary and follicular thyroid carcinomas. J Surg Oncol 2002; 80: 45-51.
7. Kim TY, Kim WB, Kim ES, Ryu JS, Yeo JS, Kim SC et al. Serum thyroglobulin levels at the time of 131I remnant ablation just after thyroidectomy are useful for early prediction of clinical recurrence in low-risk patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 2005; 90: 1440-5.
8. Giovanella L, Ceriani L, Ghelfo A, Keller F. Thyroglobulin assay 4 weeks after thyroidectomy predicts outcome in low-risk papillary thyroid carcinoma.Clin Chem Lab Med 2005;43: 843-7.
9. Barbaro D, Boni G, Meucci G, Simi U, Lapi P, Orsini P et al. Recombinant human thyroid-stimulating hormone is effective for radioiodine ablation of post-surgical thyroid remnants. Nucl Med Commun. 2006; 27(8):627-32.
10. Pacini F, Ladenson PW, Schlumberger M, Driedger A, Luster M, Kloos RT et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J Clin Endocrinol Metab. 2006; 91: 926-32.
11. Robbins RJ, Svrivastava S, Shaha A, Ghossein R, Larson SM, Fleischer M et al. Factors influencing the basal and recombinant human thyrotropin-stimulated serum thyroglobulin in patients with metastatic thyroid carcinoma. J Clin Endocrinol Metab. 2004; 89: 6010-6.
12. Taieb D, Lussato D, Guedj E, Roux F, Mundler O. Early sequential changes in serum thyroglobulin after radioiodine ablation for thyroid cancer: possible clinical implications for recombinant human thyrotropin-aided therapy. Thyroid 2006; 16: 177-9.
13. Mazzaferri E, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L 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 2003; 88: 1433-41.
14. Giovanella L, Ceriani L, Ghelfo A, Keller F, Sacchi A, Maffioli M et al. Thyroglobulin assay during thyroxine treatment in low-risk differentiated thyroid cancer management: comparison with recombinant human thyrotropin-stimulated assay and imaging procedures. Clin Chem Lab Med 2006; 44:248-52.
15. Reiners C, Luster M, Lassman M. Clinical experience with recombinant human thyroid-stimulating hormone (rhTSH): whole-body scanning with iodine-131. J Endocrinol Invest 1999; 22(S11):17-24.
16. Giovanella L, Ceriani. High-sensitivity human thyroglobulin (hTG) immunoradiometric assay in the follow-up of patients with differentiated thyroid carcinoma. Clin Chem Lab Med 2002; 40(5): 480-4.
17. Morghentaler NG, Froelich J, Rendl J, Willnich M, Alonso C, Bergmann A et al. Technical evaluation of a new immunoradiometric and a new immunoluminometric assay for thyroglobulin. Clin Chem 2002; 48(7): 1077-83.
18. Iervasi A, Iervasi G, Carpi A, Zucchelli GC. Serum thyroglobulin measurement: clinical background and main methodological aspects with clinical impact. Biomed Pharmacother. 2006; 60: 414-24
19. Sahlmann CO, Schreivogel I, Angerstein C et al. Clinical evaluation of a new thyroglobulin immunoradiometric assay in the follow-up of differentiated thyroid carcinoma. Nuklearmedizin 2003; 42: 71-7.
20. Makarewicz J, Adamczewski Z, Knapska-Kucharska M, Lewinski A. Evaluation of the diagnostic value of first thyroglobulin determination in detecting metastases after differentiated thyroid carcinoma surgery. Exp Clin Endocrinol Diabetes 2006; 114: 485-9.
21. de Rosario PW, Guinaraes VC, Maia FF, Fagundes TA, Purisch S, Padrao EL et al. Thyroglobulin before ablation and correlation with posttreatment scanning. Laryngoscope 2005; 115: 264-7.
22. Spencer CA, LoPresti JS, Fatemi S, Nicoloff JT. Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid 1999; 9: 435-41.
23. Wunderlich G, Zophel K, Crook L, Smith S, Smith BR, Franke WG. A high-sensitivity enzyme-linked immunosorbent assay for serum thyroglobulin. Thyroid 2001; 11: 819-24.
Observational Model: Defined Population, Observational Model: Natural History, Time Perspective: Longitudinal, Time Perspective: Retrospective/Prospective
Differentiated Thyroid Carcinoma
Oncology Institute of Southern Switzerland
Published on BioPortfolio: 2014-07-23T21:30:06-0400
This is a prospective, multicenter, open label Phase II Clinical Trial. 30 advanced poorly differentiated thyroid carcinoma patients who were histopathologically confirmed inoperable were ...
A multi-center , opened, Phase II study to assess the efficacy and safety of Sulfatinib 300 mg Sulfatinib in advanced Medullary Thyroid Carcinoma ( MTC) and iodine-refractory differentiate...
The purpose of the study is to evaluate the concordance between the 18F-PET/CT under thyrotropin stimulation and the diffusion-weighted Magnetic Resonance Imaging, in the detection of resi...
Thyroid carcinoma is the common endocrine system malignant neoplasm. At present it has become the malignant neoplasm of fastest growing incidence rate. More than 90% thyroid carcinoma is t...
Due to arguments showing that angiogenesis could be involved in progression of metastatic thyroid carcinoma and to objective response during previous studies with sunitinib (an angiogenic ...
Thyroid fine-needle aspiration cytology (FNAC) is one of the most performed medical procedures worldwide. It is used as a diagnostic test to separate benign thyroid nodules (colloidal and hyperplastic...
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy in children and adolescents. Infrequently, children with PTC may present with or develop disease not amenable to surgery or radi...
This article provides suggestions to help clinicians implement important changes in the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiat...
Radioiodine treatment (RAI-T) of differentiated thyroid carcinoma (DTC) is important to avoid disease progression, in particular in pediatric patients. For these reasons, a diagnostic scan may be usef...
ID genes have an important function in the cell cycle, and ID proteins may help identify aggressive tumors, besides being considered promising therapeutic targets. However, their role in thyroid tumor...
An aggressive THYROID GLAND malignancy which generally occurs in IODINE-deficient areas in people with previous thyroid pathology such as GOITER. It is associated with CELL DEDIFFERENTIATION of THYROID CARCINOMA (e.g., FOLLICULAR THYROID CARCINOMA; PAPILLARY THYROID CANCER). Typical initial presentation is a rapidly growing neck mass which upon metastasis is associated with DYSPHAGIA; NECK PAIN; bone pain; DYSPNEA; and NEUROLOGIC DEFICITS.
A carcinoma composed mainly of epithelial elements with little or no stroma. Medullary carcinomas of the breast constitute 5%-7% of all mammary carcinomas; medullary carcinomas of the thyroid comprise 3%-10% of all thyroid malignancies. (From Dorland, 27th ed; DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p1141; Segen, Dictionary of Modern Medicine, 1992)
A homeobox protein and transcription factor that localizes to the cell nucleus where it activates expression of thyroid specific genes such as THYROGLOBULIN and the THYROTROPIN RECEPTOR. It is critical for maintaining thyroid tissue in a differentiated state and also plays a role in lung development. Mutations in the NKX2-1 gene are associated with CHOREA, BENIGN HEREDITARY.
A transplantable, poorly differentiated malignant tumor which appeared originally as a spontaneous breast carcinoma in a mouse. It grows in both solid and ascitic forms.
A thyroid neoplasm of mixed papillary and follicular arrangement. Its biological behavior and prognosis is the same as that of a papillary adenocarcinoma of the thyroid. (From DeVita Jr et al., Cancer: Principles & Practice of Oncology, 3d ed, p1271)
The thyroid is a butterfly-shaped gland in the neck, just above thecollarbone and is an endocrine gland that make hormones. These Thyroid hormones control the rate of many activities in the body, including how fast the body burns calories and how fast th...
Surgery is a technology consisting of a physical intervention on tissues. All forms of surgery are considered invasive procedures; so-called "noninvasive surgery" usually refers to an excision that does not penetrate the structure being exci...
Radiology is the branch of medicine that studies imaging of the body; X-ray (basic, angiography, barium swallows), ultrasound, MRI, CT and PET. These imaging techniques can be used to diagnose, but also to treat a range of conditions, by allowing visuali...