MTC is a rare carcinoma which is more aggressive than differentiated thyroid carcinoma (DTC). MTC cells do not concentrate radioactive iodine and are not sensitive to thyrotropin-suppressive therapy, which is different from DTC. Although the proportion of MTC in thyroid cancer had declined in recent years, it caused a disproportionately high rate of thyroid-related death.2-6The survival rate for the MTC is significantly lower than of DTC.10,17According to our results, 6.6% (56/852) of MTC patients had distant metastases, and the 5- and 10-year cumulative CSS rate of these patients were 44% and 22%, respectively. The decrease of distant metastasis might be related to the early diagnosis of MTC in recent years. The cumulative survival rate obtained in our study was lower than previous studies, this reason might be explained by selection bias.
Several studies have already identified survival prognostic factors for MTC, includingage, primary tumor size, initial stage, extrathyroidal extension, lymph node metastasis and initial distant metastasis.2,3,5,8,10,11However, distant metastasis is the strongest predictor of OS and progression-free survival.8The most common metastatic sites of MTC are the lung, bone and liver.11-16 Lung metastases general present as multiple micronodular in most patients.11 For bone metastases, the lesions are mostly multifocal and preferentially occur in the spine, pelvis and ribs, and the most common morphologies of bone metastases are osteolytic and osteogenic.22,23Moreover, liver metastases are often multiple, and disseminated throughout the parenchyma.24,25The most common causes of death from distant metastases are complications from the progression of distant metastases, chemotherapy-related complications, and airway obstruction from tracheal invasion.11
The recent application of RET-specific inhibitors (selpercatinib and pralsetinib) has provided an effective and promising option for systemic treatment in RET-mutant MTC patients with metastatic and progressive diseases.18,19 However, the high cost of imaging techniques screening for distant metastases reduces the initiative for monitoring, and these techniques still have the possibility of false negatives, which may delay the timing of treatment in patients with advanced MTC. It is of great clinical significance to evaluate the independent risk factors for distant metastasis and further establishment a clinical prediction model in MTC.
According to the 8th edition of the AJCC staging system,the TNM classification lacks important prognostic factors such as gradations of age in patients with MTC.20 In addition, the lymph node metastases classifications for MTC in this staging system are just according to the location of nodes, regardless of the number or the rate of lymph nodes metastases.5,26-29
Increased age was associated with higher disease specific mortality and worse survival in MTC patients.2,10,30-32 The cut-off value analyzed by X-tile software for the relationship between age and the CSS was 67 years (Supplementary Materials Figure 2).21While, referring to previous study by A. Kotwal et al., the cut-off value for age was 55 years.10In univariate logistic regression analyses, age>55 and>67 years were all statistically significantfor distant metastasis (OR=2.815, 95%CI: 1.609-4.928, P<0.001; OR=2.002, 95%CI: 1.075-3.728, P=0.029, respectively). According to the calculated OR values, we selected 55 years as the preferred cut-off value for age.
In our study, the optimal cut-off value for the relationship between LNR and the CSS was 0.3. Previous studies found that highermetastatic lymph node ratio predict poorer survival in MTC.5,28,29 The cut-off values for the metastatic lymph node ratio previously selected were 0.1 and 0.5.28,33Different from previous studies, our study was based on all adult MTC patients who underwent total thyroidectomy and neck lymph nodes dissection. Therefore, 0.3, as our cut-off value, is more clinically applicable than previous studies.In addition to predicting survival, the lymph node ratio can potentially predict recurrence and distant metastases in MTC.10,34We came to similar conclusion, LNR>0.3 (OR=2.075, 95%CI:1.030-4.181, P=0.041) was a significant predictor of distant metastasis.
Our study also confirmed that N1 stage (OR=5.527, 95%CI: 1.495-20.433, P=0.010) and gross ETE (OR = 2.941, 95%CI: 1.580-5.474, P=0.001) were found to be independent predictors of distant metastases, which was consistent with the literature reports.10,15,26Tumor size>40 mm (OR=5.060, 95%CI: 2.161-11.848, P<0.001) was an independent risk factor for distant metastasis in our study. A. Kotwal et al. found that tumor size could significantly predict distant metastasis in univariate analysis, but it lost significance in multivariate analysis,10 further research is needed to confirm.
Univariate analysis in our study showed thatmale sex (OR=2.622, 95%CI: 1.491-4.612, P=0.001) was a potential risk factor for distant metastasis in MTC, but it lost significance in the subsequent multivariate analysis,which was similar to the finding of A. Kotwal et al.10
We developed the nomogram for distant metastasis based on the five independent predictors mentioned above, including age, N1 stage, tumor size, gross ETE and LNR. To our knowledge, this is a very rare nomogram with good predictive performances to predicted distant metastasis of MTC patients who undergone total thyroidectomy and neck lymphnodes dissection.In this model, the C-index and AUC values of the nomogram prediction model were both 0.874, and the C-index value of bootstrapping validation was 0.861, indicated that the model had good predictive ability. The calibration curve suggested that the actual probability of distant metastasis corresponded closely with the predicted probability of distant metastasis in MTC patients.
The predictive model can help clinicians to screen patients at high risk of distant metastasis in MTC. Through the implementation of close postoperative monitoring of these people, timely treatment if necessary, and ultimately improve the poor prognosis of these patients.
The limitation of our study was its retrospective design, small sample size and lacking external validation. Moreover, there was a lack of evaluation of genetic status, calcitonin in our study. Despite these limitations, we verified that age>55 years and LNR>0.3 were significant predictors of poor CSS and distant metastasis, and N1 stage, tumor size>40 mm andgross ETE were significant predictors of distant metastasis. We further established a nomogram model for predicting distant metastasis in MTC patients. For these MTC patients at high risk of distant metastasis, we recommend close monitoring of whole-body imaging procedures after surgery.