Identification of Circulating Tumor Cell Phenotype in Differentiated Thyroid Carcinoma

Objective: Circulating tumor cells (CTCs) have been considered as the origin of tumor metastasis and recurrence, which always indicate a poor prognosis. There are three phenotypes of CTCs according on different epithelial-to-mesenchymal transition (EMT) markers, including epithelial, mesenchymal, and epithelial/mesenchymal (mixed phenotypic) CTCs. We intended to explore the relationship among CTC phenotypes and the clinicopathological characteristics of patients with differentiated thyroid carcinoma (DTC). Methods: Peripheral blood samples from 58 patients with DTC were collected, and CTCs were isolated by cell sizes. To identify phenotypes of CTCs, branched DNA signal amplification technology was adopted to capture and amplify target sequences, and then multiplex RNA-in situ hybridization (RNA-ISH) assay was used to identify CTC phenotypes depended on epithelial-mesenchymal transition (EMT) markers. Results: The positive rate of CTCs was 77.59% in 58 DTC patients. Totally, 488 CTCs with detective phenotype were found. Among them, there were 121 (24.80%) epithelial CTCs, 67 (13.72%) mesenchymal CTCs, and 300 (61.48%) mixed phenotypic CTCs. An obvious increased epithelial CTCs was observed in male patients compared with female. Notably, CTCs were more prevailing in younger male patients with ETI and bilateral focus. Conclusions: The CTCs are common in DTC patients, and mixed phenotypic is the major phenotype, indicating that EMT is prevalent in DTC even though its prognosis was better than other epithelial tumors. Detection of CTC and its phenotypes might independently predict the prognosis of DTC.

C-X-C Chemokine Receptor Type 4 (CXCR4) and Programmed Death-Ligand 1 (PD-L1) Expression are Prognostic Biomarkers for Papillary Thyroid Carcinoma

Chemokines and immunomodulatory factors involve in tumor development. Papillary thyroid carcinoma (PTC) is considered to start from dendritic cell infiltration and then produce immunomodulatory factors. In this study, CXCR4 and PD-L1 biomarkers were used to explore their prognostic role in PTC survival. Confocal microscopy detected the transfection efficiency in tumor cells. 42 PTC patients and thyroiditis patients (control) were enrolled to measure the expressions of CXCR4 and PD-L1. Multi-factor analysis analyzed the effect of combined CXCR4 and PD-L1 expression on ROC. The two groups had no differences in the baseline characteristics. CTXCR4 and PD-L1 level in PTC patients was significantly higher than control. CXCR4 was lowly expressed in thyroid cancer tissue and PD-L1 was highly expressed in serological samples. Compared with single measurement, the combined detection of CXCR4 and PD-L1 showed more ROC area. In conclusion, reduced CXCR4 and increased PD-L1 level is found in thyroid cancer and their level might be used as predictive markers for PTC to improve the curative effect.

Predictive Factors for Skip Lymph Node Metastasis and Their Implication on Recurrence in Papillary Thyroid Carcinoma

Skip lymph node (LN) metastases in papillary thyroid carcinoma (PTC) belong to N1b classification in the absence of central neck LN involvement. This study aimed to evaluate the predictive factors of skip metastases and their impact on recurrence in PTC patients with pN1b. A total of 334 PTC patients who underwent total thyroidectomy with LN dissection (central and lateral neck compartment) followed by radioactive iodine ablation were included. Patients with skip metastases tended to have a small primary tumor (≤1 cm) and single lateral neck level involvement. Tumor size ≤ 1 cm was an important predictive factor for skip metastases. Univariate analysis for recurrence showed that patients with a central LN ratio > 0.68, lateral LN ratio > 0.21, and stimulated thyroglobulin (Tg) levels > 7.3 ng/mL had shorter RFS (recurrence-free survival). The stimulated Tg level was associated with shorter RFS on multivariate analysis (>7.3 vs. ≤7.3 ng/mL; hazard ratio, 4.226; 95% confidence interval, 2.226−8.022; p < 0.001). Although patients with skip metastases tended to have a small primary tumor and lower burden of lateral neck LN involvement, there was no association between skip metastases and RFS in PTC with pN1b. Stimulated Tg level was a strong predictor of recurrence.

Optimal Surgical Extent in Patients with Unilateral Multifocal Papillary Thyroid Carcinoma

Multifocality increases the risk of recurrence in patients with papillary thyroid carcinoma (PTC); however, it is unclear whether multifocality justifies more extensive or aggressive surgical treatment. Here, we evaluated the effect of the operative extent on the recurrence-free survival (RFS) of patients with multifocal PTC. Between 2010 and 2019, 718 patients with unilateral multifocal PTC were enrolled; 115 patients (16.0%) underwent ipsilateral thyroid lobectomy, and 606 patients (84.0%) underwent total thyroidectomy. With a mean follow up of 5.2 years, RFS was comparable between the total thyroidectomy and lobectomy groups (p = 0.647) after adjusting for potential confounders. Multivariable Cox regression analysis also demonstrated that the operative extent was not an independent predictor of recurrence (HR 1.686, 95% CI: 0.321–8.852). Subgroup analyses further indicated that both total thyroidectomy and thyroid lobectomy resulted in comparable RFS for multifocal PTC patients with other high-risk factors, including tumor size > 1 cm (p = 0.711), lymph node metastasis (p = 0.536), and intermediate ATA risk of recurrence (p = 0.682). In conclusion, thyroid lobectomy was not associated with the risk of recurrence in patients with multifocal PTCs. Multifocality in PTC may not always require aggressive surgery.

Prophylactic Central Neck Dissection for cN1b Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis

BackgroundThe value of prophylactic central neck dissection (PCND) for papillary thyroid carcinoma (PTC) with clinically evident lateral cervical lymph node metastases (cN1b) remains unclear. Therefore, a systematic review and meta-analysis was conducted to assess the efficacy and safety of PCND.MethodsA comprehensive systematic search was conducted on PubMed, Web of Science, Cochrane library and Embase databases up to September 2021 to identify eligible studies. Controlled clinical trials assessing therapeutic effects and safety of PCND for cN1b PTC patients were included. The risk of bias for each cohort study was assessed using the Newcastle-Ottawa Scale (NOS). The primary outcomes were indexes related to the locoregional recurrence (LRR) and surgical complications. Review Manager software V5.4.0 was used for statistical analysis. A fixed effects model was adopted for the data without heterogeneity, otherwise a random effects model was used.ResultsWe included 4 retrospective cohort studies, which comprised 483 PTC patients. There was no statistically significant difference in the central neck recurrence (CNR) (10.2% vs. 3.8%, relative risk (RR) = 1.82; 95%CI 0.90–3.67; P = 0.09), lateral neck recurrence (LNR) (5.1% vs. 7.7%, RR = 0.47; 95% CI 0.13–1.74; P = 0.26), and overall recurrence (OR) (18.9% vs. 16.9%, RR = 0.77; 95%CI 0.34–1.76; P = 0.54), between LND + PCND group and LND group. Simultaneously, PCND increased the risk of permanent hypoparathyroidism (11.4% vs. 4.5%, RR = 2.70, 95%CI 1.05–6.94; P = 0.04) and overall complications (17.0% vs. 5.3%, RR = 3.28; 95%CI 1.37–7.86; P = 0.008).ConclusionsThis meta-analysis showed that PCND did not have any advantage in preventing LRR for cN1b PTC. Meanwhile, PCND may result in the increased rate of surgical complications. However, the current evidence is limited and more clinical trials are still needed to further clarify the true role of PCND.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, CRD42021281825.

Value of Contrast-Enhanced Ultrasound in the Preoperative Evaluation of Papillary Thyroid Carcinoma Invasiveness

ObjectiveTo evaluate the diagnostic performance of preoperative contrast-enhanced ultrasound (CEUS) in the detection of extracapsular extension (ECE) and cervical lymph node metastasis (LNM) of papillary thyroid carcinoma (PTC) and the added value of CEUS in the evaluation of PTC invasiveness to conventional ultrasound (US).Materials and MethodsA total of 62 patients were enrolled retrospectively, including 30 patients with invasive PTCs (Group A, ECE or LNM present) and 32 patients with non-invasive PTCs (Group B). All patients underwent US and CEUS examinations before surgery. US and CEUS features of PTCs and lymph nodes were compared between groups. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of US, CEUS, and the combination of the two in the detection of ECE and LNM of PTCs were calculated. Logistic regression was used to analyze relationships between variables.ResultsThe PTC size was larger in group A on both US and CEUS (P = 0.001, P = 0.003). More PTCs showed hyper-enhancement in group A (P = 0.013) than in group B. More PTCs had &gt;25% contact between PTC and the thyroid capsule and discontinued capsule on US and CEUS (all P &lt; 0.05) in group A than in group B. More absent hilum and calcification of lymph nodes were observed in group A (both P &lt; 0.05) than in group B on US. More centripetal perfusion and enlarged lymph nodes were observed in group A (both P &lt; 0.05) than in group B on CEUS. CEUS alone and US combined with CEUS manifested higher diagnostic accuracy (79.0%) than US alone (72.6%) in the detection of ECE. The combination of US and CEUS manifested the highest diagnostic accuracy (95.2%) than CEUS alone (90.3%) and US alone (82.2%) in the detection of LNM. Diagnoses of ECE and LNM by the combination of US and CEUS were independent risk factors for PTC invasiveness [odds ratio (OR) = 29.49 and 97.20, respectively; both P = 0.001].ConclusionCEUS or US combined with CEUS is recommended for the detection of PTC ECE, while the combination of US and CEUS is most recommended for LNM detection. CEUS plays an essential role in the preoperative evaluation of PTC invasiveness.