In the present study, we used a moderately large sample size to investigate the clinical and molecular imaging characteristics of RR-DTC patients and the ability of these characteristics to predict RR-DTC, with the overall aim of establishing an effective multivariable prediction model for RR-DTC; such a model may prove valuable in further optimizing the treatment strategy in the early stages of metastatic DTC. Our study found that nine predictors were significantly related to RR-DTC based on univariate analyses. In addition, four independent predictors of RR-DTC were confirmed in multivariate logistic regression analysis: age at diagnosis ≥ 48 years, recurrence between the operation and iodine-131 treatment, the uptake of 18F-FDG, and the site of metastasis. According to the ORs, different scores were assigned to predictors that were positively correlated with RR-DTC, and we then established a 52-point scoring system. Finally, we determined that 10 was the optimal score for predicting RR-DTC, and the associated AUC was 0.898. The scoring system has higher predictive value than any other single independent predictor; its sensitivity, specificity, and Youten index were 76.0%, 93.0%, and 0.69, respectively.
There have been many studies on the prognostic factors associated with RR-DTC; however, the identification of predictors of RR-DTC rather than pure prognostic factors may be helpful in changing prognostic strategies and outcomes . In a previous study, Li et al. explored RR-DTC predictors and found that certain factors were highly correlated with RR-DTC, including smoking, tumor type, extrathyroid extension, pN stage, and number and rate of lymph node metastasis . However, in view of the latest advances in genetic analysis of thyroid tumors, including molecular methods, we have incorporated molecular imaging characteristics into our prediction model for RR-DTC.
In our study, 55.2% (223/404) of patients developed RR-DTC, and 28.7% (116/404) had distant metastasis, which is consistent with the literature reporting that 7–23% DTC have distant metastasis . However, 77.6% (90/116) of patients with distant metastases developed RR-DTC in our study, which is higher than previous work showing 25–50% of patients with distant metastases developing RR-DTC . One explanation is that our study only comprised patients with metastatic DTC who had undergone PET/CT imaging, the use of which depends on the judgment of their physician; meanwhile, patient decisions were also an important factor, which may not fully reflect the true clinical features of metastatic DTC.
Using univariate analysis, our study found age to be a predicting factor. Prior studies have shown that the adverse effect of age on prognosis gradually increases with each decade, especially after 40–45 years [16, 17]. Different studies use different cut-off values; in this study, the cut-off age was 48 years. In the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system, an age threshold of 45 years is one of the main criteria . It is inferred from this that the older the age, the greater the possibility of RR-DTC, leading to an increased risk of death . The cut-off point value of diagnostic age was changed from 45 years to 55 years in the 8th edition of the AJCC TNM staging system. Wassermann et al. showed that age ≥ 60 years old significantly affected a patient's cancer-specific survival after the detection of RR-DTC . Studies have shown that some elderly men have more advanced disease, lower disease-free survival, and higher mortality than female patients [20, 21]. However, whether sex can predict the occurrence of RR-DTC is unknown; our results showed that sex was not a statistically significant factor. Operation frequency was another predictive factor. Cervical scar adhesion, unclear anatomical level, recurrent external invasion of residual cancer after the initial operation, and the incidence of complications reduce the possibility of complete resection of the tumor, thus increasing the risk of RR-DTC. Some studies have suggested that some pathological subtypes of thyroid cancer are more likely to develop into RR-DTC, such as follicular thyroid cancer, Hürthle cell carcinoma, and poorly differentiated thyroid cancer (PDTC) [22, 23]. One meta-analysis also confirmed that the pathological subtype was a predictor of RR-DTC . However, our results showed that histological subtype was not a statistically significant factor, although there were a relatively low proportion of adverse pathological subtypes in our study, which may explain this finding.
Next, we discuss the conclusions of the molecular imaging in RR-DTC. In our study, 18F-FDG uptake was a predictor for RR-DTC, whereas iodine uptake was not. This is consistent with a study of Kang et al., who showed that RAI uptake of metastasis was not correlated with RR-DTC, but FDG uptake was negatively correlated with RR-DTC . Previous studies have shown that despite repeated RAI treatment, more than 50% of patients eventually show disease progression and are ultimately considered refractory to RAI . Moreover, more courses of prior TSH stimulation before iodine-131 administration, as well as more administration of probably overused iodine-131, possibly lead to a higher tumor burden [25–27]. Therefore, they may be of great value in the early identification of RR-DTC patients and combination with other therapeutic modalities [27, 28]. Early 18F-FDG imaging can not only predict the occurrence of RR-DTC but also predict the prognosis because RR-DTC is closely related to iodine treatment response. When FDG PET is used in conjunction with RAI whole body scan (WBS), we can obtain the metabolic information of the two radioactive tracers and infer the differentiation status of thyroid carcinoma at the same time. Many studies have shown that regardless of the affinity of iodine-131, FDG uptake is an adverse prognostic factor [10, 29, 30]. Incidentally, thyroglobulin response can also predict RR-DTC , but it lags behind molecular imaging, so it was not included in our prediction model. However, the advantage of 18F-FDG PET/CT lies in its ability to identify and locate tumor lesions.
In univariate analysis, some variables could not be used as independent factors of the disease. Therefore, multivariate analysis was conducted, and several scoring systems for predicting disease-specific mortality based on clinical and pathological prognostic factors were developed . This research may help establish a predictive scoring system for RR-DTC that incorporates molecular imaging.
Currently, the diagnosis of RR-DTC takes a long time because it relies on the trend of thyroglobulin (Tg) and WBS after multiple RAI treatments, combined with relevant imaging examination results. If the development of RR-DTC is determined according to the normal procedures, it required 4–77 months in our study, with a median of 6 months. However, using our scoring system, the prediction can be made at the first appointment of RAI therapy, and the time is significantly shorter than 6 months. The disadvantage is that patients with metastatic DTC need to undergo whole body PET/CT examination at the first RAI therapy, which has a high cost. However, our research is worthwhile because it proves that FDG PET/CT is a powerful early predictor. If FDG PET/CT is examined early after treatment initiation, it can avoid adverse reactions and costly treatment for patients who are unlikely to benefit from it.
There are some limitations to this study. Given that this study used a retrospective design, it is inherent to selection bias. Second, due to clinical limitations, few metastases could be confirmed pathologically. This is a problem that we need to solve when we study tumor metastasis. Third, we did not validate the scoring system in the current study. Many prospective cohorts need to be further validated. Lastly, genetic status was not included at the very beginning of the research. Some studies have shown that molecular markers provide useful insight into the role of predicting the occurrence of RR-DTC, and this is an area for future research efforts.