The Application Value And Influence Factors Of Contrast-enhanced Ultrasongrphy On Diagnosis Of Breast Lesions

Background and ObjectiveBreast cancer is the most common cancer in women all over the world,and it is also the main cause of cancer death in women.It is a highly heterogeneous disease associated with a variety of known immutable and changeable risk factors[1].In recent years,the incidence of breast cancer in China has been rising[2],which has brought huge economic and psychological trauma to patients.Early,timely and accurate diagnosis is very important for treatment and prognosis.The 2019 edition of "China female Breast Cancer screening Guide"[4]recommended mammography(MG)as the reference standard of breast cancer screening project,and emphasized the complementary role of ultrasound(US)to MG.US and MG are "golden partners" in breast screening and diagnosis,providing imaging support for early detection and treatment of breast cancer[5].Although the introduction of BI-RADS system provides a standardized classification for disease diagnosis,there are still some limitations in the application of MG and conventional US.The sensitivity of MG to dense breast is only 30-48%[5],and the false negative rate is relatively high[6].In China,49.49%of breast is dense[7],which limits the application of MG in China to some extent.US is more suitable for breast screening in Asian women with small and dense breasts,but its false positive diagnosis is high[8]The diagnosis of MG combined with US has the characteristics of high sensitivity and low specificity,which leads to many unnecessary biopsies.In addition,the diagnosis of US and MG is often inconsistent,which confuses clinicians and leads to correct clinical advice.There is an urgent need for an effective examination method to further evaluate the diagnostic results of MG+US.In the past two decades,contrast-enhanced ultrasound(CEUS)has been used in the differential diagnosis of breast lesions.It is a pure blood pool imaging technique,which can show not only the morphology of breast lesions,but also its microvascular architecture.Many studies have shown that CEUS can optimize BI-RADS classification,improve diagnostic efficiency and reduce unnecessary biopsies[9-11]CEUS is increasingly selected as an imaging method for further evaluation of US+MG results[11].However,CEUS not only requires additional time and cost,but also may cause complications.As an auxiliary tool of US and MG,there are still many problems to be discussed.First of all,so far,the application value of CEUS as an auxiliary means of US and MG to supplement CEUS in different types of diagnosis of US+MG is still controversial,and whether CEUS is an effective supplementary tool for inconsistent diagnosis of lesions between US and MG remains to be discussed[12].In addition,previous literatures have paid more attention to the contribution of CEUS in the differential diagnosis of breast lesions,but there are few studies on the limitations of CEUS diagnosis[19]Identifying the relevant factors that may lead to the misdiagnosis of CEUS will be helpful to the rational application of CEUS and the interpretation of its results.Finally,high-risk breast lesions have great heterogeneity in clinical,morphological and biological aspects[13].It is difficult to make early diagnosis in terms of family inheritance,gene sequencing,biochemical determination,clinical manifestations[14-16]or imaging examination[17].Studies have shown that the overall degree of vascularization of high-risk breast lesions is more obvious than that of non-high-risk lesions,and the number and density of blood vessels are proportional to the size and pathological severity of breast lesions[18].It is speculated that the evaluation of vascularization of benign lesions may be beneficial to the identification of high-risk lesions.Under the above background,this study intends to discuss from the following three aspects.The first part is to explore the supplementary application value of CEUS as an auxiliary means of MG and US in the diagnosis of US and MG in different situations.The second part discusses the limitations of CEUS in the diagnosis of breast lesions and clarifies the clinical,imaging and pathological features related to false positive and false negative diagnosis of CEUS.The third part is to explore the CEUS features of benign high-risk breast lesions and the diagnostic value of CEUS in high-risk breast lesions.Through the above three aspects of research,comprehensively evaluate the supplementary application value and limitations of CEUS in routine diagnosis of breast,and provide a basis for the rational application and further promotion of CEUS.Part I:Breast Non-mass Lesions on Contrast-enhanced Ultrasonography:Feature Analysis and BI-RADS Classification AssessmentObjects:To evaluate the supplementary value of contrast-enhanced ultrasonography(CEUS)in routine diagnosis of breast lesions,and to compare the complementary value of CEUS under different conditions of mammography(MG)and conventional ultrasound(US),and to explore the reasonable application of CEUS.Methods:The diagnostic results of 349 cases of breast lesions confirmed by pathology were analyzed by US,MG and CEUS examination in our hospital from January 2017 to June 2020.Firstly,the diagnostic efficacy of US,MG,US+MG,US+CEUS and US+CEUS+MG in all lesions was evaluated by ROC curve,and the sensitivity,specificity,accuracy,positive predictive value(PPV),negative predictive value(NPV),false positive(FP),false negative(FN)and area under the curve(AUC)were calculated.Then,according to the BI-RADS classification results of US+MG combined diagnosis,349 lesions were divided into possible benign group(1-3 category)and possible malignant group(4 and 5 category).The diagnostic sensitivity,specificity,accuracy,PPV,NPV and AUC were compared between the two groups before and after supplementary CEUS examination.Finally,349 lesions were divided into consistent group and inconsistent group according to the diagnosis of US and MG.The clinical and pathological features of patients with consistent and inconsistent US and MG were compared,and the diagnostic sensitivity,specificity,accuracy,PPV,NPV and AUC were compared between the two groups before and after supplementary CEUS.Statistical analysis was carried out by SPSS22.0 software(SPSS,Chicago,IL,USA).The qualitative index was expressed by frequency(percentage),the difference between groups was compared by χ2test,the quantitative index was expressed by mean ±standard deviation,and the difference between groups was compared by t test.McNemar test was used to compare the sensitivity and specificity of different examination methods,and Z test was used to compare the AUC of different methods.The PPV and NPV of different methods are compared with the fractional statistics of the same distribution as the chi-square statistics proposed by Leisenring et al.The expression of P<0.05 was statistically significant.Results:Of all the 349 breast lesions,205 were benign and 144 were malignant.In the diagnosis of all lesions,the sensitivity,specificity,accuracy,PPV,NPV,FP and FN of US+CEUS+MG in the diagnosis of breast lesions were 97.92%,69.27%,81.95%,69.12%,98.12%,30.73%and 2.08%respectively.The specificity,accuracy and AUC were significantly higher than those of US+MG,and the false positive decreased.Among the 349 breast lesions,80 may be benign and 269 may be malignant diagnosed by US+MG.In the potentially benign group,the sensitivity,specificity,accuracy,PPV,NPV and AUC of US+CEUS+MG were 71.42%,98.63%,92.5%,83.33%,97.30%,0.850.The sensitivity was higher than that of US+MG,but there was no significant difference in specificity,accuracy,NPV and AUC.In the possible malignant group,the sensitivity,specificity,accuracy,PPV,NPV and AUC of US+CEUS+MG were 98.54%,53.78%,76.58%,68.88%,97.26%and 0.758.The specificity,accuracy,PPV and AUC were higher than those of US+MG,and the sensitivity had no significant difference.Among the 349 breast lesions,178 were consistent in US and MG diagnosis,and 171 were inconsistent.The main reason for the inconsistency between US and MG diagnosis in the pathologically benign group was the false positive of US examination(69.44%),while in the malignant group,the main reason was that MG was false negative(92.06%).Breast cancer with young women,small lesions,dense breast and negative lymph nodes was more common in the inconsistent group(P=0.008,0.013,0.023 and 0.000,respectively).There was no significant difference in different pathological grades between the two groups.In the consistent diagnosis group,the sensitivity,specificity,accuracy,PPV,NPV and AUC of US+CEUS+MG were 97.53%,58.76%,76.40%,66.39%,96.61%and 0.781,respectively.All the indexes were higher than those of US+MG,but there was no statistical difference.In the inconsistent diagnosis group,the sensitivity,specificity,accuracy,PPV,NPV and AUC of US+CEUS+MG were 92.06%,85.19%,87.72%,69.05%,94.85%and 0.886,respectively.The specificity,accuracy,PPV and AUC were higher than those of US+MG and there was no statistical difference in sensitivity and NPV.Conclusion:The supplementary application of CEUS is of great value in the further evaluation of the diagnostic results of US+MG,which can improve the diagnostic efficiency and reduce unnecessary biopsies.The application value of CEUS is different in different US and MG diagnosis situations.CEUS is an effective supplementary method in the diagnosis of malignant lesions diagnosed by US+MG and inconsistent diagnosis between US and MG,which can improve the efficiency of differential diagnosis and reduce unnecessary biopsies.In the patients with possible benign diagnosis of US+MG and those with the same diagnosis of US and MG,the supplementary application of CEUS has no significant effect on the diagnostic efficiency,but it can enhance the confidence of benign diagnosis and exclude the lesions from further diagnosis.This may provide a reference for the reasonable application of CEUS.Part Ⅱ:Application of contrast-enhanced ultrasound in differential diagnosis of breast lesions:factors related to false negative and false positive resultsObjective:By comparing the diagnostic results of contrast-enhanced ultrasonography(CEUS)with pathological findings of breast lesions,to explore the clinical,imaging and pathological features related to false positive and false negative diagnosis of CEUS,and the influence of these features on the diagnostic efficiency of CEUS.Methods:349 breast lesions confirmed by pathology from January 2017 to June 2020 were included.All lesions were examined by mammography,routine ultrasound and CEUS before biopsy or surgical resection.The results of CEUS were compared with pathological results,and the results were divided into four groups:CEUS diagnosed as possible benign and pathological confirmed as benign lesions were true negative;CEUS diagnosed as possible malignant and pathological confirmed as benign lesions were false positive;CEUS diagnosed as possible malignant and pathological confirmed as malignant lesions were true positive;CEUS diagnosed as possible benign and pathological conffrmed malignant lesions were false negative.The measurement data of correct diagnosis group and wrong diagnosis group were expressed by mean ±standard deviation,independent sample t test was used for comparison between the two groups,frequency(percentage)was used for counting data,and χ2 test was used for comparison between the two groups.The factors with statistical differences in univariate analysis were analyzed by multivariate Logistic regression analysis,and the odds ratio(OR)and 95%confidence interval(95%CI)were used to evaluate the factors related to CEUS diagnostic errors(false positive and false negative).The OR of different factors to the diagnostic efficacy of CEUS was analyzed.Results:There were 349 breast lesions in 349 patients,including 205 benign and 144 malignant,with an average age of(45.2±14.1)years.Among the 349 lesions,the sensitivity of CEUS diagnosis was 88.19%(127/144),the specificity was 73.17%(150/205),and the accuracy was 79.36%(277/349).The false positive rate of benign lesions(55/205,26.83%)was higher than that of malignant lesions(17/144,11.81%).In benign lesions,high-risk lesions(20/55,36.36%)and inflammatory lesions(11/55,20.00%)were the main causes of false positive.In the malignant breast lesions,the false-negative rate in the in-situ group(7/47,14.89%)was slightly higher than that in the infiltrating group(10/97,10.31%),but there was no statistical significance(χ2=0.497,P=0.481).The false-negative rate in the special type of breast cancer was 50.00%for both intra cystic papillary carcinoma and mucinous carcinoma.Compared with true negative lesions,the patients with false positive lesions were younger(P=0.031),the distance from nipple to nipple(DtP)was shorter(P=0.048),and the proportion of patients with high risk lesions was higher(P=0.000).Stratified analysis showed that the false positive rate of age≤45 years old was higher than that of age>45 years old(OR=3.748,P=0.001).The false positive rate of DtP≤20mm was higher than that of DtP>20mm(OR=2.747,P=0.010).The false positive rate in high-risk group was higher than that in non-high-risk group(OR=7.857,P=0.000).Multivariate analysis showed that age,DtP and pathological grouping were significantly correlated with false positive CEUS results(OR=2.284,1.285,1.895;P=0.002,0.048,0.035,respectively).Compared with true positive lesions,the patients with false negative lesions were younger(P=0.046),and the maximum diameter of lesions(LMD)was smaller(P=0.000).Stratified analysis showed that the false negative rate of age≤45 years old was higher than that of age>45 years old(OR=3.581,P=0.014).The false negative rate of LMD≤10mm was higher than that of LMD>10mm(OR=12.527,P=0.000).Multivariate analysis showed that age and LMD were significantly correlated with false negative CEUS results(OR=1.718,2.173;P=0.047,0.031,respectively).Age,LMD and DtP have significant influence on the diagnostic efficiency of CEUS.The diagnostic efficacy of CEUS for lesions with age>45 years old,LDM>10mm and DtP>20mm was higher than that of lesions with age≤45 years old(OR=2.620),LDM≤10 mm(OR=2.391)and DtP≤20 mm(OR=2.309),respectively.Conclusion:CEUS has its limitations in the diagnosis of breast lesions,and a variety of clinical,pathological and imaging features of breast lesions are related to misdiagnosis.Younger age is related to false positive and false negative diagnosis,shorter DtP,high-risk lesions are related to false positive diagnosis,and smaller LMD is related to false negative diagnosis.To clarify the factors related to the false positive and false negative diagnosis of CEUS,we can properly use CEUS in the diagnosis of breast lesions and choose available alternatives to improve the diagnostic accuracy of breast lesions.Part Ⅲ:Contrast-enhanced ultrasound of benign high-risk breast lesions:features analysis and diagnostic value evaluation Object:To explore the contrast-enhanced ultrasound(CEUS)features of benign high-risk breast lesions and to evaluate the value of CEUS in the diagnosis of high-risk breast lesions.Materials:Conventional ultrasound(US),mammography(MG)and CEUS were performed in our hospital from January 2017 to June 2020,and the diagnostic results of US,MG and CEUS in 205 cases of benign breast lesions confirmed by pathology(including 34 cases of high-risk lesions and 171 cases of non-high-risk lesions)were analyzed.Conventional US and MG were classified according to BI-RADS.The CEUS of 205 lesions were analyzed qualitatively and quantitatively,and scored according to the five-point system proposed by Luo Baoming et al(1-3 for non-high-risk lesions and 4-5 for high-risk lesions).Then the initial US classification was adjusted according to the CEUS score,and the adjusted classification results were taken as the joint diagnosis results of US+CEUS.The final result of the combined diagnosis of US+MG and US+CEUS+MG was that the patients with high classification were regarded as the final result.0,1,2 and 3 categories were non-high risk lesions,while 4 and 5 categories were high-risk lesions.The qualitative index was expressed by frequency(percentage),the difference between groups was compared by χ2 test,the quantitative index was expressed by mean ±standard deviation,and the difference between groups was compared by t test.ROC curve was used to evaluate the diagnostic efficacy of US,MG,US+MG,CEUS,US+CEUS and US+CEUS+MG in high-risk lesions.Z test was used to compare the area under the curve.Results:There were 205 cases of benign breast lesions,including 171 cases of non-high-risk and 34 cases of high-risk lesions.There were differences in many CEUS qualitative and quantitative indexes between them.Among the qualitative indexes,the proportion of high enhancement(P=0.000),fast forward(P=.000),unclear edge(P=0.004),irregular enhancement(P=0.000),increased range after enhancement(P=0.000),annular enhancement(P=0.000)and radial perfusion(P=0.000)in high-risk lesions were higher than those in non-high-risk lesions.There was no difference between the two groups in the homogeneity of enhancement(P=0.269),centripetal enhancement(P=0317),and the proportion of perfusion defect(P=0.436).Among the quantitative indexes,the peak intensity(PI)and relative peak intensity(△PI)of high-risk lesions were higher than those of non-high-risk lesions(P=0.026 and 0.018,respectively),and the relative initial enhancement time(△AT)was longer than that of non-high-risk lesions(P=0.001).The sensitivity,specificity and accuracy of US+CEUS+MG diagnosis were 94.11%,81.87%,83.90%,0.877,respectively,which were higher than US(AUC=0.411,P=000),MG(AUC=0.665,P=0.030),US+MG(AUC=0.437,P=0.000)and CEUS(AUC=0.689,P=0.009),and there was no significant difference between US+CEUS and US+CEUS(AUC=0.871,P=0.780).Conclusion:CEUS can evaluate the difference of vascularization degree between benign high-risk lesions and non-high-risk lesions,and there are statistical differences in many CEUS qualitative and quantitative indexes between the two groups.Compared with non-high-risk lesions,high-risk lesions began to enhance earlier,faster,higher intensity,abnormal perfusion and a larger proportion of lesions.Supplementing CEUS on the basis of US and MG can not only improve the detection of high-risk lesions,avoid treatment delay caused by underestimation,but also reduce unnecessary biopsies of benign non-high-risk lesions,providing a basis for further clinical treatment.