Ruling Out 131 I Ablation in Low-Risk Differentiated Thyroid Carcinoma Basing on Thyroglobulin Measurement

1. Although Rosario et al. in their series show that measurement of serum Tg levels at the time of ¹³¹I remnant ablation was able to predict early and long-term outcome of patients, discrepancies between undetectable Tg levels and residual ¹³¹I uptake on a posttreatment whole-body scan (PT-WBS) have been reported by other groups (2,3). Rosario et al. stressed that high-risk patients (i.e., those with poorly differentiated tumors, incomplete tumor resection, and high risk of recurrence, or those undergoing previous treatment with ¹³¹I) were not included in their study; in a comparable study by Park et al., however, 57.7% of patients with undetectable Tg and positive PT-WBS were stage III or IV. In their study, Park et al. also found regional and distant metastases in 42.3% patients at lower risk (2).

2. In the study by Phan et al. (3), which specifically analyzed low-risk patients with undetectable Tg at ablation, none of the patients had metastases on initial PT-WBS. In contrast, thyroid remnants were found in 100% of their patients; Rosario et al., in agreement with Phan et al., report that 95.2% of patients without metastases at PT-WBS show a thyroid remnant, all with ¹³¹I uptake values <2%. The definition for an insignificant thyroid remnant employed by Rosario et al. in this context is debatable. The 2% cutoff was previously obtained in a series of DTC patients treated with ¹³¹I ablation and was shown to be an indicator for a significantly higher chance of successful ablation, wherein successful ablation was defined as TSH-stimulated Tg <5 ng/mL and an ¹³¹I uptake <0.5% on diagnostic whole-body scintigraphy (dxWBS) (4). In many other studies, however, significantly lower cutoff levels are suggested for both TSH-stimulated Tg (<1–2 ng/mL or simply undetectable) and ¹³¹I uptake (<0.1%) with regard to the definition of successful thyroid remnant ablation (5). Further, in their study, Rosario et al. have simply omitted ¹³¹I dxWBS in their evaluation of successful ablation, making it impossible for the reader to judge the efficacy of the strategy proposed with regard to small thyroid remnants, which thyroid ultrasound is often not able to detect reliably. This is all the more disturbing when considering that Rosario et al. performed their staging with PT-WBS exclusively recorded as planar images. In fact, single-photon emission computed tomography (SPECT)/computed tomography (CT) examination of the neck and mediastinum modifies the planar scan interpretation in up to 40% patients, detecting regional nodal metastases and clarifying equivocal focal neck uptakes and, even of more importance, significantly altering the initial estimated risk of recurrence in 6.4% of postsurgical patients (6,7). Especially, in the central compartment (where the ultrasound accuracy is low and thyroid remnants may obscure pathologic uptake foci on planar imaging), lymph node metastases cannot be excluded with certainty using planar PT-WBS and ultrasonography.

3. Different technical problems still affect Tg measurement and need to be considered before authenticating the use of serum Tg as a marker for the presence of thyroid tissue. Interference from TgAb compromises the use of serum Tg as a tumor marker in up to 20% DTC patients by reducing Tg measurement results in immunometric methods, regardless of the serum concentrations of either Tg or TgAb (8). Although the role of recovery testing remains debatable, international guidelines call for a negative TgAb measurement using specific immunoassays before authentication of any Tg measurement (9). Krahn et al., however, recently compared different TgAb immunoassays in patients with DTC showing a very poor agreement with regard to both the qualitative aspect (whether TgAb were present at all) and the quantitatively determined TgAb levels. This inability to agree on what constitutes the presence or absence of TgAb greatly detracts from any study that purports to screen antibody interferences in Tg measurement, thus gravely reducing the role of TgAb measurement in validating the Tg results (10). Additionally, interferences by heterophilic antibodies and the so-called “high-dose hook effect” may rarely also lead to reporting of inappropriately normal or low serum Tg values in sera with high Tg concentrations (8). Finally, a decrease in immunological reactivity or changes of the structural conformation of the Tg molecule in thyroid cancer can make the serum Tg levels undetectable or detectable in different immunoassays (11). We recently showed that problems of various natures may occur with Tg measurements at the time of ablation in up to one-sixth of patients, most of whom had stage I-II DTC. Despite extensive laboratory work-up (i.e., retesting using different Tg and TgAb immunoassays, recovery test, heterophilic antibodies screening) and significant ¹³¹I residual uptake in PT-WBS, Tg was undetectable in about one-fifth of patients (12).

4. Although in itself we applaud the proposition of the algorithm proposed by Rosario et al. in Figure 1, and we certainly agree that it is likely that it is possible to omit ¹³¹I ablation in patients who had excellent surgery, which was able to remove all thyroid tissue, it might be a bit too early to put this algorithm into practice. As Shattuck et al. (13) were able to show, 50% of multifocal thyroid carcinomas are of independent clonal origin (i.e., they have arisen separately). It is therefore conceivable that nonablated thyroid remnants may once again give rise to the formation of thyroid carcinoma. Rosario et al., however, based their algorithm on the excellent results at follow-up of patients with Tg <1 ng/mL and negative ultrasound of the neck who nonetheless received a full-activity ¹³¹I ablation, which might have considerably improved prognosis.