Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. Surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy are the standard TC treatment modalities. However, recurrence or tumor metastasis remains the main challenge in the management of anaplastic thyroid cancer (ATC) and radioiodine (RAI) radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Several multi-tyrosine kinase inhibitors (MKIs), or immune checkpoint inhibitors in combination with MKIs, have emerged as novel therapies for controlling the progression of DTC, medullary thyroid cancer (MTC), and ATC. Here, we discuss and summarize the molecular basis of TC, review molecularly targeted therapeutic drugs in clinical research, and explore potentially novel molecular therapeutic targets. We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.

Cervical lymph node metastases are very common in papillary thyroid cancer (PTC), and typically spread in a predictable stepwise fashion in clinical practice. However, lateral lymph node metastasis (LLNM) without central lymph node metastasis (CLNM) as skip metastasis is not rare in PTC. The aim of this study was to investigate the incidence, risk factors and pattern of skip metastasis in PTC. A total of 271 patients with PTC and suspicious LLN diagnosed by pre-operation examinations who underwent total thyroidectomy and central lymph node dissection plus lateral lymph node dissection between January 2008 and December 2011 were enrolled in this study. Clinicopathological features were collected, and the pattern of cervical lymph node metastasis and skip metastasis were analyzed. The LLNM rate was 74.9% (203/271, diagnosed by postoperative pathology examination) and significantly associated with extrathyroid extension (ETE), primary tumor located at the upper pole, and CLNM (p < 0.05). The skip metastasis rate was 14.8% (30/203) and was more frequently found in microcarcinoma patients, especially when the primary tumor size was ≤0.5 cm (p = 0.001 OR = 12.9). However, skip metastasis was unrelated to the remaining factors examined. Small cancers with a pre-operation diagnosis of LLNM are more likely to have skip metastases, especially when the primary tumor size is less than 0.5 cm in diameter; however, this type of metastasis appears to develop in a random fashion. Thus, additional research is needed to identify potential predictive factors, such as a primary tumor located at the upper pole.

There are about half of papillary thyroid carcinoma (PTC) patients with the experience of central lymph node metastasis (CLNM), while the model to predict high-risk groups of CLNM from PTC patients is uncertain. The aim of this study was to evaluate candidate risk factors of CLNM and identify risk factors of recurrence to guide the postoperative therapeutic decision and follow-up for physicians and patients.A total of 4107 patients(4884 lesions) who underwent lymph node dissection in two hospitals from 2005 to 2014 were evaluated. CLNM risk was stratified and a risk-scoring model was developed on the basis of the identified independent risk factors for CLNM. Cox’s proportional hazards regression model was used to investigate the risk factors for recurrence.CLNM was proved in 37.96% (1559/4107) of patients and 33.96% (1659/4884) of lesions. In the multivariate analysis, Male, Age ≤35 years, Tumor size >0.5 cm,Lobe dissemination (+), Psammoma body (+), Multifocality and Capsule invasion (+) were independent risk predictors of CLNM (P < 0.01). A 14-point risk-scoring model was built to predict the stratified CLNM in PTC patients and the area under receiver operating characteristic curve of the model for the prediction of CLNM was 0.672 (95% CI: 0.656–0.688) (P < 0.01). COX regression model showed that Tumor size >0.5 cm, Lobe dissemination (+), Multifocality and CLNM were significant risk factors associated with poor outcomes. The research suggested that prophylactic CLN dissection could be performed in patients with total score ≥4 according to the risk-scoring model, and more aggressive treatment and more frequent follow-up should be considered for patients with Tumor size >0.5 cm, Lobe dissemination (+), Multifocality and CLNM.

This study aims to evaluate candidate risk factors for lateral lymph node metastasis (LLNM) and develop a predictive model to identify high-risk groups among patients with papillary thyroid carcinoma (PTC). Additionally, we identified risk factors for recurrence to inform postoperative therapeutic decisions and follow-up for physicians and patients. A total of 4107 patients (4884 lesions) who underwent lymph node dissection at our hospital from 2005 to 2014 were evaluated. LLNM risk was stratified, and a risk-scoring model was developed based on identified independent risk factors for LLNM. Cox’s proportional hazards regression model was used to investigate the risk factors for recurrence. Lateral Lymph Node (LLN) metastasis was observed in 10.49% (431/4107) of patients. Multivariate analysis identified the following independent risk predictors for LLN metastasis: Age ≤ 35 years (P = 0.002), tumor size > 1.0 cm (P = 0.000), lobe dissemination (+) (P = 0.000), and CLNM (+) (P = 0.000). A 12-point risk-scoring model was constructed to predict stratified LLNM in PTC patients, with an area under the receiver operating characteristic curve (AUROC) of 0.794 (95% CI: 0.774–0.814) (P < 0.01). The Cox regression model indicated that tumor size > 1.0 cm, lobe dissemination (+), multifocality, Central Lymph Node Metastasis (CLNM), and LLNM were significant risk factors associated with poor outcomes. Based on the risk scoring model, additional investigations and comprehensive considerations are recommended for patients with a total score greater than 5, and prophylactic cervical lymph node dissection is performed if necessary. Additionally, more aggressive treatment and more frequent follow-ups should be considered for patients with tumor size > 1.0 cm, lobe dissemination (+), multifocality, CLNM, and LLNM.