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.

A Novel Metastasis-related Genes Based Signature for Predicting the Progression-free Interval of Patients With Papillary Thyroid Carcinoma

Background: We aimed to build a novel model with metastasis-related genes (MTGs) signature and relevant clinical parameters for predicting progression-free interval (PFI) after surgery for papillary thyroid carcinoma (PTC).Methods: We performed a bioinformatic analysis of integrated PTC datasets with the MTGs to identify differentially expressed MTGs (DE-MTGs). Then we generated PFI-related DE-MTGs and established a novel MTGs based signature. After that, we validated the signature on multiple datasets and PTC cell lines. Further, we carried out uni- and multivariate analysis to identify independent prognostic characters. Finally, we established a signature and clinical parameters-based nomogram for predicting the PFI of PTC. Results: We identified 155 DE-MTGs related to PFI in PTC. The functional enrichment analysis showed that the DE-MTGs were associated with an essential oncogenic process. Consequently, we found a novel 10-gene signature and could distinguish patients with poorer prognoses and predicted PFI accurately. The novel signature had a C-index of 0.76 and the relevant nomogram had a C-index of 0.80. Also, it was closely related to pivotal clinical characters of datasets and invasiveness of cell lines. And the signature was confirmed a significant independent prognostic factor in PTC. Finally, we built a nomogram by including the signature and relevant clinical factors. Validation analysis showed that the nomogram's efficacy was satisfying in predicting PTC’s PFI. Conclusions: The MTG signature and nomogram were closely associated with PTC prognosis and may help clinicians improve the individualized prediction of PFI, especially for high-risk patients after surgery.

Effectiveness of Lymphatic Contrast Enhanced Ultrasound in the diagnosis of Cervical Lymph node metastasis from papillary thyroid carcinoma

Cervical lymph node metastasis (CLNM) is common in patients with papillary thyroid carcinoma (PTC), which is responsible for tumor staging and surgical strategy. The accurate preoperative identification of CLNM is essential. In this study, twenty consecutive patients with PTC received a parenchyma injection of Sonazoid followed by contrast enhanced ultrasound (CEUS) to identify CLNM. The specific lymphatic CEUS (LCEUS) signs for diagnosing CLNM were summarized, which were further compared with the resected specimens to get the pathological basis. After the injection of contrast agent, lymphatic vessel and lymph node (LN) could be exclusively displayed as hyperperfusion on LCEUS. The dynamic perfusion process of contrast agent in CLNM over time can be clearly visualized. Perfusion defect and interruption of bright ring were the two characteristic LCEUS signs in diagnosing CLNM. After comparing with pathology, perfusion defect was correlated to the metastatic foci in medulla and interruption of bright ring was correlated to the tumor seeding in marginal sinus (all p values < 0.001). The diagnostic efficacies of these two signs were high (perfusion defect vs. interruption of bright ring: AUC, 0.899, 95% CI 0.752–1.000 vs. 0.904, 0.803–1.000). LCEUS has advantages in identifying CLNM from PTC. The typical LCEUS signs of CLNM correlated with pathology.