The Study Of Conventional Ultrasound Combined With Molecular Markers In Predicting Lymph Node Metastasis In Central Cervical Area Of ??papillary Thyroid Carcinoma

Chapter 1 Conventional ultrasound,immunohistochemical factors and BRAF^V600E mutation in predicting central cervical lymph node metastasis of papillary thyroid carcinomaObjective The study was aimed at evaluating the correlation between central cervical lymph node metastasis?CLNM?in papillary thyroid carcinoma?PTC?patients and ultrasound?US?features,immunohistochemical factors and BRAF^V600E mutation.Methods A total of 225 consecutive patients?225 PTCs?who had undergone surgery were included.All PTCs were pre-operatively analyzed by US with respect to size,components,echogenicity,shape,margins,microcalcification,multiple cancers or not,internal vascularity and capsule contact or involvement.The presence of four immunohistochemical factors,including cytokeratin 19,human bone marrow endothelial cell 1,galectin-3 and thyroid peroxidase,and BRAF^V600E mutation was also evaluated.Univariate and multivariate analyses were performed to identify the risk factors for central CLNM,and a risk model was established.Receiver operating characteristic?ROC?curve was plotted to evaluate the best cutoff value and the area under the receiver operating characteristic?AUROC?.Results Pathologically,44%?99/225?of the PTCs had central CLNMs.Multivariate analysis revealed that size 10 mm,microcalcification,internal vascularity,capsule contact or involvement and BRAF^V600E mutation were independent risk factors for central CLNM.A multivariate logistic regression equation was performed with the significant predictive factors as listed below:P=1/{1+Exp?[-2.666+1.470�?if nodule size?10mm?+1.892�?if micro-calcification in nodule?+0.816�?if internal flow?+3.033�?if capsule contact or involvement?+1.495�(if BRAF^V600E mutation)]}.The risk score for central CLNM was calculated as follows:risk score=1.5�?if lesion size 10 mm?+1.9�?if microcalcification?+0.8�?if internal flow?+3.0�?if capsule con-tact or involvement?+1.5�(if BRAF^V600E mutation).The rating result was divided into six stages,and the relevant risk rates of central CLNM were 0%?0/1?,0%?0/22?,7.4%?4/54?,48.6%?34/70?,71.2%?42/59?and 100%?19/19?,respectively.Meanwhile,the ROC curve was plotted and the diagnostic value of 5independent risk factors as well as equation.The area under the ROC curves were0.572?95%CIs,0.497-0.647?,0.700?95%CIs,0.631-0.770?,0.599?95%CIs,0.523-0.647?,0.758?95%CIs,0.695-0.822?,0.572?95%CIs,0.947-0.646?and0.865?95%CIs,0.818-0.912?,respectively.The sensitivity and specificity were 74.8%and 39.7%,75.8%and 64.3%,40.4%and 79.4%,92.9%and 58.7%,92.9%and21.4%,and 73.0%and 87.9%,respectively.Conclusion PTC?10 mm,microcalcification,internal vascularity,capsule contact or involvement and BRAF^V600E mutation are risk factors for central CLNM.The risk model may be useful in treatment planning and management of patients with PTCs.Chapter 2 Prospective validation of a predictive model for central cervical lymph node metastasis in patients with papillary thyroid carcinomasObjective Conventional ultrasound?US?and BRAF^V600E mutation have been found to be associated with central cervical lymph node metastasis?CLNM?in patients with papillary thyroid carcinomas?PTCs?in our retrospective study in part one and a predictive model was established.This prospective study was aimed at validating the predictive power of the model for central CLNM in PTCs.Methods According to the predictive model in our retrospective study in part one,we assessed the US features of thyroid nodules?TNs?in these aspects: nodule size,micro-calcification,internal flow,and capsule contact or involvement.Afterwards,the suspicious nodules were subject to ultrasound-guided fine needle aspiration cytology?US-FNAC?and BRAF^V600E mutation analysis with FNAC specimen.All cases included in the study underwent surgery.220 patients?220 PTCs?were prospectively enrolled into the study with pathological examination as the reference standard.By applying the univariate and multivariate analyses to data,we further indentified the risk factors for central CLNM in PTCs.A new risk model was established.ROC curves were plotted with prospective cases in retrospective predictive model in part one and new risk model in this part.The area under two curves?AUROCs?was calculated.Finally,Z-test was performed to compare the two AUCs and validated the predictive model for central CLNM in PTCs.Results Central CLNMs were present in 40.9%?90/220?of 220 patients of PTCs.Multivariate analysis showed micro-calcification?OR = 3.433,95% CI : 1.210-9.742;P = 0.020?,internal flow?OR = 16.310,95% CI : 5.901-45.081;P < 0.001?,capsule contact or involvement?OR = 42.436,95% CI : 15.435-116.670;P < 0.001?,and BRAF^V600E mutation?OR = 5.545,95% CI : 1.325-23.196;P = 0.019?were independent risk factors for central CLNM.The new multivariate logistic regression model for predicting the present of central CLNM of PTCs was established as follows: P = 1/{1+exp ? [-4.306 + 1.233 �?if micro-calcification on US?+ 2.792 �?if internal flow on US?+ 3.748 �?if capsule contact or involvement?+ 1.713 �(if BRAF^V600E mutation)]}.In our previous predictive model,P = 1 / {1 + Exp ? [-2.666 + 1.470�?if nodule size ? 10mm?+ 1.892 �?if micro-calcification in nodule?+ 0.816 �?if internal flow?+ 3.033 �?if capsule contact or involvement?+ 1.495 �(if BRAF^V600E mutation)]}.According to the multivariate logistic regression models in prospective and retrospective study,two AUCs of ROC curves were 0.948?95% CI: 0.914-0.981?and 0.934?95% CI: 0.899-0.970?,respectively.The accuracy,sensitivity,specificity,positive predictive value?PPV?,and negative predictive value?NPV?of the present and new model were 92.3% and 90.0%,94.4% and 87.8%,90.8% and 91.5%,87.6% and 87.8%,and 95.9% and 91.5%,respectively.Z-test showed no significant difference between these two AUROCs?P = 0.572?.Conclusion The predictive model for central CLNM in PTC indicated no significant difference between prospective study in this part and previous prediction study in part one.They demonstrated strong agreement in the prediction for central CLNM in PTCs.Besides,the predictive model in this prospective study may be helpful in selecting appropriate treatment of patients with PTCs.