The prevalence of low-risk differentiated thyroid cancer (DTC) is increasing significantly, which mainly due to the early diagnosis of thyroid microcarcinoma (TMC) by using neck ultrasonography (US) (1–4). Optimal management of DTC usually requires inter-disciplinary cooperation, including surgery, risk-adapted postoperative radioactive iodine (RAI) therapy, individualized thyroid hormone therapy, and follow-up for the detection of patients with persistent or recurrent disease (5–7). Recently, considering factors such as the excellent prognosis of low-risk DTC (5, 8), absence of significant reduction in recurrence rate or disease-free survival in low-risk patients treated with RAI (9, 10), scarce evidence concerning the usefulness of RAI in improving disease-specific mortality in low-risk DTC (5), and potential side effects on RAI [e.g., chronic sialadenitis (11, 12), secondary malignancies (13, 14)], the 2015 American Thyroid Association (ATA) guidelines recommend performing conservative strategies, namely, total thyroidectomy (TT) or lobectomy without RAI ablation, for low-risk DTC patients (5). Thus, in China, TT or lobectomy without RAI ablation is becoming a common management for patients with low-risk DTC.

Although the above-mentioned conservative strategies are gradually becoming accepted, the assessment of response to therapy for these patients remains controversial. According to the 2015 ATA guidelines, periodic measurements of serum thyroglobulin (Tg) on thyroid hormone therapy and neck US should be considered during the follow-up of patients with low-risk DTC who underwent TT or lobectomy without RAI ablation (5), but the roles played by each of these methods are not specially defined. In 2016, Momesso et al. proposed a dynamic risk stratification method (mainly based on neck US findings and different suppressed serum Tg cutoff values, namely, Tg <0.2, 0.2–5, or >5 ng/mL for TT; Tg <30 or >30 ng/mL for lobectomy, to stratify assessments as excellent response, indeterminate response, biochemical incomplete response and structural incomplete response) to evaluate the response to initial surgery in low-risk DTC patients who did not undergo RAI therapy (15). However, since this evaluation system could be affected by the size of remnant tissue, the results vary significantly [e.g., excellent response, 94.1% as reported by Momesso et al. (15) versus 71.7% as reported by Park et al. (16)].

The current study attempted to use a dynamic evaluation strategy based on the trends of suppressed Tg, anti-thyroglobulin antibody (TgAb) levels and neck US findings to determine the response to therapy in Chinese low-risk DTC patients treated with surgery alone (TT or lobectomy) after a median follow-up of 51 months and identify risk factors associated with incomplete response.

In this study, we proposed and validated a new dynamic response to therapy assessment depending on trends of suppressed serum Tg, TgAb levels, and neck US findings in patients with low-risk DTC who underwent TT or lobectomy without RAI therapy. Response to therapy assessments were defined as excellent response, biochemical incomplete response, structural incomplete response, and indeterminate response, which mainly depended on the trends of suppressed serum Tg, TgAb levels and neck US findings without interference of the size of remnant tissue. Our findings show that, at the last follow-up, 95% of patients with low-risk DTC who underwent TT or lobectomy without RAI ablation therapy had excellent response. This rate in our cohort was similar to that (94.1%) reported by Momesso et al. (15), thus conforming the definition used in our study might be reasonable and reliable. Furthermore, the proportion of patients (97%) with excellent response among those who underwent TT in our study was similar to the proportion (98%) reported by Schlumberger et al. who performed a 5-year follow-up study of a randomized, phase 3, equivalence trial (ESTIMABL1, two thyrotropin-stimulation methods: thyroid hormone withdrawal versus the use of recombinant human TSH, and two RAI ablation doses:1.1 GBq versus 3.7 GBq) (20). Thus, our study provided further evidence to support no routine recommendation of RAI after surgery in low-risk DTC. The proportion of patients with biochemical incomplete response or indeterminate response in our study was in accordance with the 10-year recurrence rate of 1%–2%, which is expected for patients with low-risk DTC. During our follow-up, no patients had structural incomplete response, which may be explained by the aggressive prophylactic lymph node dissection and insufficient follow-up duration (21, 22).

According to the 2015 ATA guidelines, lobectomy may be sufficient for a unifocal intrathyroidal low-risk carcinoma sized <4 cm in diameter in patients with no prior head and neck radiation, familial thyroid cancer, or clinically detectable cervical LN metastases (5). In the present study, type of surgery was found to be a prognostic factor associated with incomplete response in low-risk DTC patients without RAI therapy at the last follow-up. Particularly, we found that the risk of biochemical incomplete response was significantly higher in patients who underwent lobectomy (seven and two patients due to increasing trends of suppressed serum Tg and TgAb levels, respectively), when compared to TT (two and one patients due to an increasing trend of suppressed serum Tg and TgAb levels, respectively). For low-risk DTC patients treated with lobectomy, an increase in Tg values over time suggested a growing thyroid tissue or tumor, and an increase in TgAb values suggested coexistent Hashimoto thyroiditis in residual thyroid tissues (especially in patients diagnosed with Hashimoto thyroiditis by surgical histopathology) or tumor relapse (5, 23–25).

The present study has several strengths. First, postoperative risk assessment, assessment of potential benefits and side effects of RAI therapy, and patients’ preferences and values had been adequately considered during post-operative management (observation and individualized thyroid hormone therapy without RAI ablation). Second, all the included patients underwent TT or lobectomy by experienced thyroid surgeons in our hospital who had more than 10 years of thyroidectomy experience. Third, all the serum Tg, TgAb, and TSH levels of all patients were measured by electrochemiluminescent immunoassay in our laboratory to ensure the accuracy and reliability. Finally, considering that neck US is operator-dependent, all high-resolution neck US scans were performed by experienced specialists to evaluate structural abnormalities to ensure the accuracy in our center. However, this study has several limitations. First, the 51-month (median) follow-up period chosen for this study might be suboptimal. Although most recurrences (80%) in low-risk DTC patients occurred during the first 3-5 years of follow-up, some recurrence or incomplete response might be missed (26, 27). Second, the single-institutional study design creates selection biases that are difficult to control. Third, this retrospective study enrolled a relatively small cohort of patients who underwent lobectomy.

In conclusion, our study validates that the newly proposed dynamic response to therapy assessment depending on trends of suppressed serum Tg, TgAb levels, and neck US findings could be an appropriate tool for postoperative follow-up in low-risk DTC patients without RAI therapy. Our findings provide further evidence to support no routine recommendation of RAI after surgery in low-risk DTC.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Institutional Research Ethics Committee of West China Hospital of Sichuan University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

PD, LW, RH and LL designed this research. PD, LW, LX and LY collected the data and performed the statistical analyses. PD, LW and RH reviewed the results, interpreted the data, and wrote the manuscript. PD, LW, RH and LL discussed and edited the paper. All authors contributed to the article and approved the submitted version.

This study was supported by the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYGD18016).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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