| Backgrond and objective:Breast cancer is a common malignant tumor in women,becoming the highest incidence of cancer in the world.Early stage breast cancer is considered curable.Surgical treatment combined with adjuvant systemic therapy is considered as the main treatment for early breast cancer.The surgical options included total mastectomy and local expanded breast conserving therapy（breast-conserving therapy BCT）.Breast conserving surgery has a small scope,which causes less trauma to patients.Meanwhile,the breast shape can be preserved,and the psychological burden of patients can be reduced while meeting the aesthetic needs of patients.In recent years,with the development of surgical techniques and systemic therapy,as well as clinical trial evidence,breast-conserving surgery combined with postoperative adjuvant radiotherapy for breast cancer has become the standard of choice for most early stage breast cancer.Risk factors for local recurrence after breast-conserving surgery include:no postoperative radiotherapy,positive surgical margin,negative estrogen receptor,high expression of Ki-67,overexpression of HER2,and young breast cancer patients.Positive surgical margin,as an important factor affecting local recurrence and prognosis of breast-conserving treatment.At present,the safe scope of breast-conserving surgery is still controversial.Negative margin is one of the key factors for the effect of breast-conserving surgery,so it is particularly important to look for predictors of positive margin.For patients with positive risk factors of surgical margin,appropriate increase of surgical resection range can benefit patients.Accurate and reliable margin assessment is also necessary in order to obtain negative margins.The sensitivity and specificity of the assessment methods are significant.A variety of intraoperative methods have been proposed to evaluate the specimen margins in order to improve the margin free rate at the initial stage of surgery and to avoid reoperation.At present,pathological diagnosis is still the gold standard.Routine pathology after surgery still cannot avoid the risk of reoperation,and appropriate intraoperative techniques are still needed.Intraoperative freezing section is the most reliable method for margin assessment;however,intraoperative freezing analysis has many limitations.It is time-consuming.For small tumors,too few tissues may not be able to fully evaluate specimens and obtain biomarkers,so this technique is prone to sampling errors.Therefore,a fast and accurate method of intraoperative margin evaluation to control the positive rate of surgical margin is still under study.Intraoperative specimen radiography,or intraoperative mammography,was originally used to assess calcification in patients and has been used more recently to determine surgical margins.Based on the current research status,this study is divided into two parts.The first part mainly collects the clinicopathological data of patients undergoing breast-conserving surgery in our center,analyzes the influence of these characteristics on the surgical margin of breast-conserving surgery,conducts univariate and multivariate analysis of different potential influencing factors,and establishes a positive prediction model of surgical margin.The purpose of this study was to evaluate the positive risk of surgical margin in different types of patients,so as to provide reference for the safe range of surgical margin in breast-conserving surgery.In the second part,we analyze the evaluation of intraoperative mammography technology on the state of incisor margin.Patients who underwent intraoperative mammography and breast-conserving surgery in our center were included in the study.The surgical margin of intraoperative mammography technology imaging was evaluated by blind method.The results of gold standard were compared to analyze the sensitivity,specificity,positive predictive value and negative predictive value of this technique.To analyze the feasibility and effectiveness of intraoperative mammography technique.The clinical case data of the patients were collected,and the clinicopathological characteristics of the included patients were sub-analyzed to analyze the influence of various factors on intraoperative mammography technology evaluation of surgical margin,so as to provide a basis for the feasibility and effectiveness of intraoperative mammography application of surgical margin evaluation in different types of patients.Methods:Part 1:Patients undergoing breast-conserving surgery admitted to our center between 1st July,2017 and 1st December,2020 were included.Collected the patient name and medical record number,age at operation,gender,doctor group of surgery,intraoperative frozen inspection time,intraoperative frozen result time,intraoperative frozen diagnosis report,routine postoperative pathological report,tumor histological type,tumor size,the molecular classification of breast cancer,hormone receptor（ER/PR）expression,HER-2 expression,expression of Ki-67,the WHO histological grade,tumor calcification and necrosis,lymph node metastasis,vascular invasion,whether with ductal carcinoma components,etc.Univariate analysis was carried out for different clinicopathological characteristics of patients with positive surgical margin as the analysis object.Chi-square test was carried out for the variable groups that were significant in univariate analysis,and odds ratio（OR）,relative patio（RR）and the corresponding 95%confidence intervals（CI）were calculated.At the same time,Binary Logistic Multivariate Regressive Analysis was performed on the significant variables in univariate analysis.The significance of univariate significant variables in multivariate analysis,OR and corresponding 95%confidence intervals were analyzed.A multivariate regression model with positive margins was established.To study the risk and protective factors of positive margin in breast-conserving surgery.Part 2:Patients admitted to our center between 1st July,2017 and 1st December,2020 who underwent intraoperative mammography during breast conserving surgery were included.Collected the patient name and medical record number,age at operation gender,intraoperative mammography images,intraoperative frozen inspection time,intraoperative frozen result time,routine pathology,intraoperative frozen diagnosis report,routine postoperative pathological report,tumor histological type,tumor size,the molecular classification of breast cancer,hormone receptor（ER/PR）expression and its HER-2 expression,expression of Ki-67,the WHO histological grade,tumor calcification and necrosis,lymph node metastasis,vascular invasion.The intraoperative mammograph images were interpreted by the experienced imaging teachers of our center in a blind way,and the incisive edge was described,and the incisive edge was defined as positive,negative and suspicious positive.The sensitivity,specificity,positive predictive value and negative predictive value were compared between the intraoperative frozen section results and the postoperative routine pathological results.Subgroup analysis of clinicopathological characteristics of patients was conducted,and sensitivity,specificity,positive predictive value and negative predictive value were calculated for different subgroups.Chi-square test was performed to compare sensitivity and specificity,and odds ratio（OR）,relative patio（RR）and the corresponding 95%confidence intervals（CI）were calculated.Results:Part 1:A total of 665 patients receiving breast conserving therapy in our center were enrolled,and the breast conserving rate in our center was 42.6%.The mean age of patients was 52.65 years old,the median age was 51 years old.The lesion size was mainly less than 2cm,with a mean lesion size of 1.68cm and a median lesion size of1.5cm.A total of 117 patients were found to have positive surgical margins by intraoperative frozen sections or postoperative routine pathology,among which 103patients were found to have positive surgical margins by intraoperative frozen sections,and the final surgical margins were negative by routine pathology after extensive resection.The intraoperative frozen sections of 2 patients showed negative incised margins,while the routine pathology after surgery indicated positive margins.Twelve patients did not receive intraoperative frozen section detection,and conventional pathology indicated positive incisional margin.The overall positive rate of initial surgical margin（including frozen sections）was 17.6%,and the positive rate of final surgical margin indicated by routine pathology was 2.1%.The surgical range selected by the surgeons in our center was complete resection of the tumor tissue,with the surgical margin 2mm-5mm away from the primary lesion.There were differences in the judgment of tumor tissue boundary and resection range among doctors in different surgical groups.19 of the 75 patients who received neoadjuvant chemotherapy achieved Pathologic Complete Response（p CR）with a Miller-Payne rating of 5,with a p CR rate of 25.3%.Univariate analysis showed statistically significant differences among surgeons,age,histological types and molecular types of breast cancer（p<0.1）,among which surgeons had a more significant influence（p=0.01）.The number of patients undergoing breast-conserving surgery in surgeon groups A,B,C,D and E was205,151,120,83,106,respectively;The positive rates of surgical margins were 18.5%,26.3%,15.0%,6.3%and 20.8%,respectively.Different surgical groups were inconsistent in the determination of the minimum margin,which led to the difference in the positive rate of margin.For age group（p=0.100）,the positive rates of surgical margins in<40,40-60 and≥60 groups were 24.7%,15.5%,and 19.3%,respectively.For histologically invasive ductal carcinoma,invasive lobular carcinoma,DCIS,DCISM,and special type of invasive carcinoma,the positive rates of incisional margin were16.7%,46.2%,30.0%,20.8%,and 13.7%,respectively,and the overall group significance was 0.054.In the molecular classification of breast cancer,the positive rates of surgical margins in patients with Luminal A,Luminal B,HER-2 negative,triple negative（TNBC）,HER-2 positive hormone receptor negative,and HER-2 positive hormone receptor positive were 15.0%,21.8%,19.7%,11.1%,and 25.8%,respectively.The whole p=0.090.Chi-square test within the group for the variables p<0.1 in the univariate analysis showed that the positive rate of incisions in surgeon group D was significantly lower than that in the other four groups.There are significant differences between the subtypes of invasive lobular carcinoma and the specific types of invasive ductal carcinoma.It is suggested that lobular subtype is a high risk factor for positive margin in invasive breast cancer.For the age group,there was significant difference between the 40-60 years old group and the<40 years old group subgroup,while there was no significant difference between the patients and the≥60 years old group,suggesting that younger age were related to the increased positive rate of surgical margin.In terms of molecular typing of breast cancer,this study showed no significant difference between Luminal A type and Luminal B HER-2 negative type,suggesting that the expression of Ki-67 did not significantly affect the status of surgical margin.The expression of HER-2（p=0.445）suggested that the overexpression of HER-2 would not significantly increase the possibility of positive surgical margin.However,the positive rate of surgical margin of patients with positive HER-2 hormone receptor was significantly different from that of patients with Luminal A（p=0.019）,but not statistically different from that of patients with Luminal B（p=0.615）.For patients with positive HER-2 hormone receptor negative type,the positive rate of surgical margin of patients with positive HER-2 hormone receptor was significantly lower than that of patients with positive type（p=0.036）.It suggested that HER-2,hormone receptor（HR）and Ki-67 may have certain correlation on the effect of surgical margin,and that overexpression of HER-2 and high expression of Ki-67 or positive hormone receptor were potential risk factors.In the binary logistics multivariate regression,no significant difference was found when the four groups of variables were tested according to the established subgroup distribution.It suggested that there was a correlation among the four groups of variables,which did not independently affect the positive margin.Possibly because each variable is grouped more,there is an influence between each other.For each group of variables is used to detect the binary classification,regrouping according to the variable chi-square test results between groups,tips and other all or there are significant differences of two or more subgroups of the group as a set of independent,the rest for the other groups,reduce variable subgroups in order to reduce the correlation between variables,and then to regression analysis.The results of multivariate regression after the re-dichotomization of the four groups of variables showed significant differences（p<0.05）.Univariate analysis was conducted again,and there were also statistical differences.Surgeon variables and age variables were independent predictors of margin positivity,with ORs less than 1 indicating that surgeon group D and age between 40 and 60 years were independent protective factors for margin positivity.Histological type group p=0.035,OR value 3.441（95%CI:1.112-10.652,）,molecular typing p=0.016,OR=1.181,95%CI=1.032-1.352.These results indicated that molecular type and histological type were also independent predictors of margin positivity,with OR values greater than 1,indicating that invasive lobular carcinoma and breast cancer patients with positive HER-2 positive hormone receptor were independent risk factors of margin positivity.Part 2:A total of 329 breast-conserving patients who underwent intraoperative mammography were enrolled,with a mean age of 51.7 years and a median age of 51years.The size of the lesions ranged less than 2cm,with an average size of 1.43cm.Intraoperative mammography images of 329 enrolled patients with patient information removed were presented to two imaging teachers for blind review.The sensitivity of the two teachers was 20.0%and 48.7%respectively.The specificity was 98.8%and 57.2%.The positive predictive values were 62.5%and 13.3%,respectively.The negative predictive values were 92.5%and 89.2%,respectively.The results of 169 patients evaluated by two teachers were consistent,and the sensitivity,specificity,positive predictive value and negative predictive value of this part were 17.6%,98.0%,50.0%and 91.4%,respectively.For the patient images with inconsistent reading results,the review results were handed over to the third teacher,and the review results were determined as described above.The sensitivity,specificity,positive predictive value and negative predictive value after review were 33.3%,94.6%,46.4%and 91.0%.To group of patients with clinical and pathological characteristics analysis of sensitivity and specificity,age,focal size,histological type,neoadjuvant,necrosis and calcification,the WHO classification,vascular invasion situation,its HER-2 expression,lymph node is for sensitivity and specificity were no significant effect,molecular classification for the sensitivity and specificity p values are less than 0.1.There was no significant difference in specificity among the subtypes.For sensitivity,Luminal A patients had A significantly lower sensitivity than patients with positive HER-2 and HR（p=014,RR=0.123,corresponding 95%confidence interval 0.017-0.872）.There was no significant difference among other groups.It is suggested that the overexpression of HER-2 is beneficial to enhance the sensitivity of intraoperative molybdenum and palladium technique in patients with HR positive and Ki-67 low expression.Due to the high specificity of intraoperative molybdenum target technique,it can be used as a screening standard for negative surgical margin.No need to wait for freezing.According to the statistics of the freezing time required for the cutting edge of breast cancer conserving surgery in our center from submission to removal of the film,the longest freezing time was 1 hour and 29 minutes,while the shortest was 15 minutes.The average freezing time of the film was 42 minutes and the median freezing time was 39 minutes.Clinical application of intraoperative molybdenum target technology can save an average of 39minutes of anesthesia and waiting time for patients with negative incisive margin.After rereading the frozen sections with positive margins,54.8%of them were found to be positive at one end,indicating the potential importance of edge localization analysis.Conclusions:Part 1:The overall positive rate of primary surgical margin（including intraoperative frozen section positive and routine pathological positive）in breast cancer conserving surgery in our center was controlled at 17.6%,and the positive rate of final surgical margin indicated by routine pathology was 2.1%.Multivariate analysis indicated that the positive rate of surgical margin was significantly higher when the age was less than 40 years old or≥60 years old,and the age of 40-60 years old was an independent protective factor for positive surgical margin.The positive rate of surgical margin in the surgery group of D was significantly lower than that in the other groups.The choice of margin range varies among surgeons.For invasive carcinoma,lobular subtype is invasive lobular carcinoma.Due to its pathological characteristics,breast-convalescent therapy is more difficult,and the positive rate of incision margin is significantly increased,which is an independent risk factor affecting the incision margin.Expression of HER-2,expression of Ki-67,and HR status did not independently affect the outcome of surgical margin,but there was a potential correlation.Both positive HER-2 and HR（HER-2 positive hormone receptor positive molecular typing）were independent risk factors for positive surgical margin.Part 2:Compared with the gold standard pathological results,intraoperative mammography technology has strong specificity and obviously insufficient sensitivity in the assessment of surgical margin in breast-conserving surgery.It is not suitable for the diagnosis of positive surgical margin,and the high rate of misdiagnosis and missed diagnosis is not conducive to improving the detection rate of positive surgical margin in patients,thus reducing the positive rate of surgical margin and the risk of local recurrence.However,its specificity is relatively prominent,and it can be used as the exclusion criteria for positive surgical margin.In other words,the intraoperative assessment of mammography in the patient is negative for the surgical margin,that is,there is no need to wait for the freezing result,the operation is ended,the anesthesia time of the patient is shortened,and the waiting time for the operation is reduced.Due to the low positive rate of margin in breast-conserving surgery in our center,intraoperative mammography technology,as a fast,convenient and low-cost technology,has great application value for margin assessment.Two teachers independent reading differences as a result,two teachers read consistent results,and the third teacher to review the revised results specificity stable at more than 90.0%,prompt a patient’s mammography imaging teachers suggest two or more,or to evaluate clinical surgeons at the same time,in order to eliminate subjective,improve the negative detection rate.The average duration of freezing in the center was 39 minutes,and the application of mammography technology as the positive exclusion criteria could reduce the time cost of the operation.The clinicopathological characteristics of the patients had no significant difference in sensitivity and specificity of intraoperative mammography.The overexpression of HER-2 may be beneficial to enhance the intraoperative mammography sensitivity of patients with HR positive and Ki-67 low expression.After rereading the frozen sections with positive margins,54.8%of them were found to be positive at one end,indicating the potential importance of edge localization analysis.Among the 39 patients with positive frozen surgical margins,only 2 patients remained positive after reexpansion,and both of the two patients had sporadic positive initial surgical margins.It is suggested that there may be discontinuity of tumor cells in patients with scattered positive lesions,resulting in relatively diffuse lesion sites,and it is difficult to determine the surgical margin. |
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