Preoperative Evaluation Of Sentinel Lymph Node Metastasis By Percutaneous Contrast-enhanced Ultrasound In Early Breast Cancer

Background and AimsSentinel lymph node(SLN)refers to the first station lymph node receiving breast cancer lymph reflux,which represents the metastatic status of axillary lymph nodes(ALN).Accurate assessment of SLN is essential for clinical decision making.At present,the identification and diagnosis of SLN are performed during operation.Traditional imaging methods cannot accurately identify SLNs before surgery,and have difficulty in direct evaluation of SLNs.Percutaneous contrast enhanced ultrasound(CEUS)uses a percutaneous injection of the contrast agent to display the lymphatic channels and SLN in real-time,which was confirmed to be a safe and effective preoperative SLN identification method.Only locating SLN cannot solve the problem of preoperative diagnosis and staging of lymph nodes.Previous studies showed that the enhancement pattern of SLN enables the preliminary diagnosis of SLN metastatic status before surgery,but shows the lower specificity.The classification of CEUS enhancement patterns is rough,and the same enhancement pattern can occur in both benign and malignant SLNs with a great overlap.There are few studies on axillary metastatic burden,and the diagnostic value of CEUS combined with traditional ultrasound characteristics for SLN metastatic burden is not clear.With the extensive development of early diagnosis of breast cancer,the lymph node metastasis rate of patients with early breast cancer is only 20-30%.Therefore,a new concept of axillary surgery for breast cancer has been proposed in recent years:early breast cancer patients with low risk of lymph node metastasis can be exempted from axillary surgery.Preoperative analysis of the relationship between CEUS enhancement pattern and SLN metastasis status is conducive to the individualized treatment plans and the optimization of clinical flow.Therefore,this study is intended to recruit early cT1-2N0 invasive breast cancer patients to perform percutaneous CEUS,(1)to construct a nomogram based on lymphatic US findings of SLNs to predict high(≥3 metastatic SLNs)or low(<3 metastatic SLNs)tumor burden preoperatively in early breast cancer;(2)to further summarized the enhancement pattern of SLN and explore the diagnostic value of CEUS for axillary negative SLN.MethodsPart Ⅰ:Patients from Peking Union Medical College Hospital(Center 1)were grouped into the development and internal validation cohorts at a ratio of 2:1 according to the enrollment time from June 2020 to June 2021.The external validation cohort from the Third Affiliated Hospital of Peking University(Center 2)was constructed between November 2017 and December 2020.The enhancement patterns of the SLNs were classified into three patterns:homogeneous,inhomogeneous and no enhancement.The cortical morphology of SLN was classified into four types:the thin hypoechoic cortex,diffuse thickening cortex,focal eccentric cortex and round hypoechoic node with no hilum.With the results of intraoperative SLN biopsy as the gold standard,the Univariate and Multivariate Logistic regression analysis was performed on the clinical information,ultrasound characteristics of SLN and pathological results of primary breast cancer to conduct the modal to predict the axillary tumor burden in early breast cancer.The diagnostic performance of the model was evaluated by receiver operating characteristic(ROC)area under the curve(AUC)and calibration curve.Part Ⅱ:We prospectively recruited consecutive patients with clinically node-negative early breast cancer from July 2021 to October 2021 in Peking Union Medical College Hospital.All patients underwent conventional US and percutaneous CEUS examinations.The CEUS of SLNs were classified into four enhancement patterns:homogeneous,featured inhomogeneous,focal defect,and no enhancement.The featured inhomogeneous enhancement includes cribriform,half-moon,and ring enhancement.The diagnostic performance of conventional ultrasound and CEUS for SLN metastasis was assessed by receiver operating characteristic(ROC)curves and decision curves,the effect of CEUS on reclassification value in patients with axillary negative SLN was evaluated.Conclusions and resultsPart I:A total of 179,90 and 197 women formed the development and internal and external validation cohorts,respectively.By univariate and multivariate logistic regression analysis,the US findings of enhancement pattern and cortical morphology were independently associated with≥3 metastatic ALNs.The diagnostic model of predicting≥3 metastatic ALNs was constructed by ultrasound characteristics,and the nomogram showed an AUC of 0.87,0.90 and 0.91 in the development,internal,and external validation groups,respectively.The calibration slope of 1.0(P=0.80-0.81;Brier=0.066-0.067)in the validation cohorts in predicting≥3 metastatic ALNs.Percutaneous CEUS can accurately identify SLN before surgery,and can stratify patients with clinical T1-2N0 invasive breast cancer based on the enhancement pattern and cortical morphology.Our nomogram could aid in multidisciplinary treatment decision-making.Part Ⅱ:A total of 78 women were enrolled in this study,including 55,18,and 5 patients with negative axilla,1-2,and≥3 metastatic SLNs pathologically,respectively.The identification rate of SLNs by CEUS was 100%.Patterns Ⅰ and Ⅱcan select 91.7%(44/48)of patients with disease-free axilla,while patterns Ⅲ andⅢ had higher percentages of metastasis(65.2%,P<0.001 and 57.1%,P<0.002,respectively).For the SLN metastatic burden,100%(48/48)of patients with patternⅠ/Ⅱ had≤2 metastatic SLNs.Compared with conventional US,the CEUS enhancement patterns showed significant improvement in diagnosing metastatic SLNs(0.813 vs 0.601,P<0.001).CEUS had greater clinical benefits and could correctly reclassify 48%of metastatic SLNs(P<0.001)without sacrificing the classification accuracy of negative SLNs(P=0.25),and could improve predicted accuracy by 0.42(P<0.001).CEUS demonstrated better diagnostic performance and greater clinical benefits than conventional US for the preoperative diagnosis of SLN,which showed the potential of CEUS to select candidates for precluding axillary surgery in early breast cancer.In summary,for the preoperative evaluation of axillary SLN metastatic status in early breast cancer,we conducted a clinical study to recruit early breast cancer patients with negative clinical axillary palpation and evaluate the value of CEUS for SLN metastatic status.On the one hand,we constructed a diagnostic model to predict≥3 metastatic lymph nodes by combining CEUS and traditional ultrasound characteristics,and achieved the stratification of preoperative metastatic burden of axillary lymph nodes;On the other hand,we reanalyzed and summarized the enhancement pattern of SLN.The specific CEUS signs significantly improved the diagnostic accuracy of SLN.CEUS enhancement pattern has higher clinical benefit for axillary-negative patients,which is expected to become an effective preoperative method for screening patients to exempt axillary surgery in the future.