Thyroglobulin as specific tumor marker in differentiated thyroid cancer

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Thyroglobulin (Tg) is an iodoglycoprotein with a molecular mass of 660 kDa which is exclusively produced in thyrocytes or tumor cells of thyrocyte origin and which is necessary for the synthesis and storage of thyroid hormones. For a long time it was assumed that no secretion or leakage from the healthy thyroid occurs. In the 1960s, more-sensitive detection tools were developed: the specific hemagglutination-inhibition tests [34] and especially radioimmunoassays [65, 81]. Using these new tests, the detection sensitivity was sufficient to prove the presence of Tg also in the blood of healthy subjects. The reference range (95-percentile of the healthy population) extends to about 50 ng/ml, with quite a high interindividual variance. Some thyroid diseases release considerable amounts of Tg into the blood, particularly differentiated, follicular cell-derived thyroid cancer (DTC). However, also benign thyroid diseases may be associated with (highly) increased serum Tg levels (e.g., thyroid enlargement, thyroid nodules, hyperthyroidism, thyroiditis), and there is a very wide overlap between the serum Tg levels in benign or malignant disease. In Hashimoto's thyroiditis, for example, Tg values up to 22,000 ng/ml have been reported [52]. Like the glandular secretion, tumoral Tg secretion mostly displays a TSH dependency, because follicular-cell derived tumor tissue mostly preserves TSH receptors [72]. Consequently, Tg values measured under maximum TSH stimulation, obtained 3-4 weeks after levothyroxine or 2 weeks after triiodothyronine withdrawal ("off-Tg"), exceed Tg values under TSH suppression ("on-Tg") by one order of magnitude (in poorly differentiated tumors, less than factor 3, and in highly differentiated tumors, factor 10 and more [29, 30, 54, 57, 70, 75]). In an unpublished study of 356 patients in our department, a median stimulation factor of 8 was determined. In less-differentiated carcinomas, when TSH receptors are reduced, the stimulation factor can be much lower or absent. Even in healthy subjects without thyroid disease, circulating Tg displays a molecular heterogeneity, e.g., in respect of iodine content, which obviously depends on iodine alimentary support. Furthermore, structural distinctions between the predominant Tg forms in benign thyroid diseases and DTC have been detected, which are in part due to the process of release from the thyroid cell [17]. However, assays relying on those structural differences, which measure exclusively or at least preferably "malignant" Tg, are not available yet or in the foreseeable future. Thus, Tg can be used as a tumor marker only after total thyroidectomy - apart from a few exceptions. In the case of a carcinoma of unknown origin and proven distant metastases which might be thyroid cancer, the level of serum Tg may be a useful indicator. A high Tg value suggests thyroid cancer; a value in normal range nearly excludes at least a well-differentiated carcinoma derived from follicular cells [18]. Furthermore, Spencer et al. [75] proposed the measurement of serum Tg levels in all patients with DTC prior to surgery (in the presence of the primary tumor) in order to achieve information about the Tg secretion activity of the tumor. The specificity of Tg measurement in the follow-up of thyroid cancer is highest after thyroidectomy and adjuvant radioiodine ablation of the thyroid remnants. Corresponding to the serum half-life, on average 65 h [35], during the first days and weeks after thyroidectomy, still measurable but decreasing Tg values are expected. Thus, depending on the initial level of serum Tg, the full specificity and accuracy is established only several weeks after radioiodine ablation of the thyroid remnants [21]. Assuming the pretherapeutic serum Tg level to be 100 ng/ml arising from the benign thyroid or thyroid carcinoma, Tg might be measurable for approximately 4 weeks even after complete cure. In thyroid cancer patients with subtotal or "total" thyroidectomy but no radioiodine ablation, Van Wyngaarden and McDougall [82] detected persistent, measurable Tg values in 38% of the patients being judged tumor free, even under TSH-suppressive medication. The proportion of Tg-positive patients necessarily increases with the sensitivity of the Tg test used. In a group of 33 patients who were only thyroidectomized but had no radioiodine ablation, we found measurable serum Tg values under TSH suppression in 50% of the subjects using a test with a lower detection limit of 0.5 ng/ml and even in 100% using a test with a functional sensitivity of 0.03 ng/ml [31]. Nowadays, immunometric assays (IMAs; with isotope or nonisotope technique) are most frequently used for Tg measurement in Europe. Many of the commercialized kits offer a functional sensitivity of about 0.5 ng/ml. However, this lower limit is only a technical threshold and would lead to a high rate of false-positive findings if a single Tg value were to be assessed underlying such low value as cutoff. Therefore, arbitrary cutoff values are introduced intending to find an optimal compromise between diagnostic sensitivity and specificity. Often an arbitrary threshold of about 2 ng/ml is proposed [21, 29, 42, 84]. According to our experience, a significantly lower value can be used for the assessment of serial Tg measurement in the individual patient, if the performance of the Tg test is under permanent control. If the test is working perfectly, a newly detected measurable Tg value in the follow-up suggests recurrence. In their recent meta-analysis concerning the diagnostic value of serum Tg measurements in the follow-up of DTC, Eustatia-Rutten et al. [21] reported for IMAs an average diagnostic sensitivity of 0.778 ± 0.023 (mean ± SE), a specificity of 0.977 ± 0.005, and an accuracy of 0.933 ± 0.007 for on-Tg in patients with thyroid ablation (9 underlying series, with a total of 1,613 patients, median cutoff 2 ng/ml). The respective values for off-Tg were 0.961 ± 0.013, 0.947 ± 0.007,and 0.952 ± 0.006 (12 underlying series, with a total of 1,602 patients, median cutoff 3 ng/ml). © Springer-Verlag Berlin Heidelberg 2001, 2005.




Görges, R., & Bockisch, A. (2005). Thyroglobulin as specific tumor marker in differentiated thyroid cancer. In Thyroid Cancer (Second Edition) (pp. 221–237). Springer Berlin Heidelberg.

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