The Prospective Clinical Validation Study Of Internal Mammary Sentinel Lymph Node Biopsy In Breast Cancer

Objective In addition to axillary lymph node(ALN),internal mammary lymph node(IMN)is another important nodal drainage of the breast.The combination of ALN and IMN stage can provide a more reliable standard for the clinical-pathological stage,and the determination of postoperative therapy.Recently,many studies presented positive impact of IMN radiation on the survival of breast cancer patients.With the development of sentinel lymph node biopsy(SLNB),internal mammary sentinel lymph node biopsy(IM-SLNB)is expected to be a minimally invasive diagnostic technique for assessing IMN status.However,IM-SLNB is far behind that of the axilla for the low visualization rate of internal mammary sentinel lymph node(IM-SLN)with the traditional radiotracer injection technique.A modified radiotracer injection technique(periareolar intraparenchymal,high volume and ultrasound guidance)is first produced in our institution.Previous studies have proved that the modified injection technique significantly improves the IM-SLN visualization rate and IM-SLNB guided by this technology has a high success rate.The relatively high visualization rate of IM-SLN laid the foundation for the further study and clinical application of IM-SLNB.In anatomical aspect,our previous results have demonstrated the concept of IM-SLN.In clinical aspect,high success rate and low false-negative rate are prerequisites for the widespread development of SLNB.The current study is needed to confirm whether IM-SLNB has a low false-negative rate.The study is designed as a clinical verification of the accuracy of IM-SLNB in patients with ALN positive breast cancer.Methods From August 2017 to August 2020,211 patients scheduled for mastectomy with the preoperative pathology confirmed invasive breast cancer and positive ALNs were involved in the study.The research protocol had been registered on the US Clinicaltrials.gov website.The study was approved by the ethics committee of each center and each patient provided informed consent.The radiotracer 99mTc-sulfur colloid was prepared in the department of nuclear medicine.The boiling time of sulfur colloid was 3～4 mins.The modified injection technique was used to inject radiotracer.The radiotracer(1.0～2.0ml 18.5～70.3MBq 99mTc-sulfur colloid)was injected into the mammary gland layer at 6 and 12 o’clock around the areola under the ultrasound guidance.The methylene blue was used as the dye tracer.After the general anesthesia and 10～15 minutes before the operation,2ml of methylene blue was injected subcutaneously around the areola of the patient,and the remaining 2ml was injected into the glandular layer around the areola area.SPECT/CT lymphoscintigraphy imaging was recommended 30 minutes before surgery.After the procedure of the mastectomy,IM-SLNB was performed under the guidance of intraoperative gamma detector in patients with radioactive IM-SLNs detected by preoperative lymphography imaging and/or gamma detector.Then,the lymph nodes of the internal mammary region were dissected and the pleura was preserved.Three sections H&E stained routine pathological examination from each node was perform for the pathological diagnosis of IM-SLNs and IMNs.The main objective of the study was to evaluate the accuracy of IM-SLNB under the guidance of the modified technique.Meanwhile,many other exploratory analysis were conducted,including the exploratory analysis on the cut-off value of the procedure of IM-SLNB guided by the isotope;the clinical value of blue dye in IM-SLNB;the exploratory analysis of the proportion of patients whose pN stages and adjuvant treatment plans were changed after IM-SLNB;the positive rate of IM-SLNs and its risk factors;the positive rate of IM-nSLNs and its related factors;the intercostal distribution of IM-SLNs,et alResults A total of 211 patients from 6 centers planned to participate in this study,and 148 patients with the visualization of IMN were actually enrolled.The visualization of IMN was 70.1%.All 148 patients successfully performed IM-SLNB→IMN dissection with a success rate of 100%.Complications occurred in 5 cases.Among the 148 patients,61 were IMN-positive patients,with a positive rate of 41.2%.There were 2 false negative cases,yielding the false-negative rate of IM-SLNB 3.3%(2/61),the accuracy 98.7%(146/148)and the sensitivity 96.7%(59/61).The positive IM-SLNs of 52.5%patients were the only positive IMNs identified.The study tried to apply the 10%cut-off value of the axillary SLNB guided by the isotope to the procedure of IM-SLNB and analyzed its possibility,and the false-negative rate increased to 9.8%.A total of 287 IM-SLNs were obtained from 148 patients,and 85 IM-SLNs of 46 patients had blue dye staining.All blue-stained IM-SLNs were detected by the intraoperative gamma detector,rather than obtained by dissecting the blue-stained lymphatics to the stained lymph nodes.The accuracy of IM-SLN reflecting the status of IMN is 98.7%.IM-SLNB can change the pN stages of 39,9%patients.The study evaluated the number of patients who needed IMN radiation under the guidance of different guidelines:the NCCN guideline/German Society of Radiation Oncology guideline/the guideline of Department of Health,Ireland 148 cases,the UK Royal College of Radiologists guideline 89 cases,and the UK National Institute for Health and Care Excellence guideline 102 cases,respectively.The proportion of patients who can avoid radiation based on the negative result of IM-SLN after IM-SLNB were:the NCCN guideline/German Society of Radiation Oncology guideline/the guideline of Department of Health,Ireland 58.8%,the UK Royal College of Radiologists guideline 48.3%,and the UK National Institute for Health and Care Excellence guideline 52.9%,respectively.Taking the NCCN guidelines as an example,according to different pN stages,the number and the proportion of patients who can be exempted from IMN radiation based on the negative IM-SLN results were 28 cases/42.4%with pN1 and 59 cases/72.0%with pN2～3,respectively.Among the 148 patients,59 were IM-SLN positive,with a positive rate of 39.9%.Univariate analysis showed that the positive rate of IM-SLN was significantly related to the pathological size(P=0.001),the location of tumor(P=0.005)and the number of metastatic ALNs(P=0.002).Multivariate analysis showed that the pathological size(P=0.007),the location of the tumor(P=0.004),and the number of metastatic ALNs(P=0.003)were all the independent risk factors for IM-SLN metastasis.A novel nomogram was constructed based on the pathological size,the location of the tumor,and the number of metastatic ALNs.The nomogram had an AUC value of 0.783,which was significantly better than the probability based on the number of metastatic ALNs alone according to the current guidelines(AUC=0.651,P<0.001).Among 59 patients with positive IM-SLNs,27 were IM-nSLN positive,with a positive rate of 45.8%.Univariate analysis showed that positive rate of IM-nSLN was significantly related to the pathological size(P=0.001),the histological grade(P=0.001)of the tumor,the number of positive IM-SLNs(P=0.024),and the number of negative IM-SLNs(P=0.015).Multivariate analysis showed that the pathological size of the tumor(P=0.020),the number of positive IM-SLNs(P=0.024),and the number of negative IM-SLNs(P=0.004)were the independent risk factors for IM-nSLN metastasis.A novel nomogram was constructed based on the pathological size of the tumor,the number of positive and negative IM-SLNs,with an AUC value of 0.875.The IM-SLNs in the 1st,2nd,3rd and 4th intercostal space were 95,117,67,and 8,respectively.The metastatic IM-SLNs in the 1st,2nd,3rd and 4th intercostal space were 20,33,17,and 2,respectively.The 1st to the 3rd I intercostal space was the main intercostal space for IMN drainage and metastasis.Conclusions The clinical verification study confirmed that IM-SLNB based on the novel injection technique has a high accuracy and a low false-negative rate.It can lay a foundation for the clinical application of IM-SLNB minimally invasive diagnosis.It is not recommended to use the 10%cut-off value of the axillary SLNB guided by the isotope to IM-SLNB,and it is recommended that all IMNs with any radioactivity count be regarded as IM-SLNs.The clinical value of blue dye is only limited to providing visual aid to the procedure of IM-SLNB guided by the isotope.Based on the operating process in this study,the IM-SLNB operating specifications guided by the novel injection technique have been established.IM-SLNB guided by the modified radiotracer injection technique can obtain the histological diagnosis of IMN and serve as an important basis for individualized IMN radiation.It can prevent IM-SLN negative patients from IMN radiation and the heart and lung toxicity caused by the radiation.At the same time,it can warrant IM-SLN positive patients receive IMN radiation,which increases local control and survival benefits.For patients with positive IM-SLNs,radiation of the 1st to the 3rd intercostals of the internal mammary area should be performed.If there is metastatic IM-SLN in the other intercostal space,it is recommended to enclose this intercostal space in the target area of radiation to avoid insufficient treatment.A nomogram predicting IM-SLN metastasis based on the pathological size,the location of the tumor,and the number of metastatic ALNs can be used to assess the probability of IM-SLN positive in patients with metastatic ALNs,which is better than the current guidelines.For those hospitals that cannot carry out IM-SLNB,this model can be used to guide IMN radiation.For patients whose tumors are located in the lateral quadrant and undergo breast-conserving surgery,patients who do not need to undergo a separate incision for IM-SLNB can be screened out to increase the cosmetic effect.A nomogram constructed to predict IM-nSLN metastasis based on the pathological size of the tumor,the number of positive and negative IM-SLNs can predict populations with positive IM-SLN and negative IM-nSLN,as these patients can avoid IMN radiation.Currently,theories that IMN radiotherapy can be tailored and balanced on basis of IM-SLNB have been established.