| BackgroundAxillary staging is important for the correct staging of breast cancer, guiding the subsequent surgical and adjuvant therapy since invaded axillary lymph nodes is one of the strongest prognostic factors for breast cancer. Sentinel lymph node biopsy (SLNB) is part of the standard approach for axillary staging. SLNB is usually performed first because it is less morbid than axillary lymph node dissection (ALND). Therefore, patients with negative SLNB may avoid unnecessary ALND and its complications such as upper extremity edema and shoulder joint movement disorders. However, the SLNB technique is associated with a false negative rate of 5 to 10%. This high false negative rate is of clinical concern, and thus new approaches to axillary lymph node staging are clearly needed to address this issue.Identification and sampling of suspicious axillary lymph nodes (SALN) using ultrasound has been proposed in order to improve axillary staging without the necessity to perform an ALND. Indeed, a number of recent studies used ultrasound to identify SALN and to sample them, either using fine needle aspiration (FNA) and/or core needle biopsy, and showed relatively good predictive value for axillary status. However, most of these studies tested the use of ultrasound-guided SALN biopsy (USALNB) instead of SLNB, and the use of USALNB alone is associated with highly variable false positive rates that may impair its use in a clinical setting. Nevertheless, the use of ultrasound to detect the SALN was shown to reduce the reoperation rate.Indeed, the currently accepted concept of lymphatic of drainage of the breast is that a specific lymph node chain drains a specific area of the breast. Therefore, free cancer cells will first invade the sentinel lymph node, and then invade the lymph nodes of the chain one after the other. However, a lymph node may be invaded without displaying gross ultrasound characteristics of invasion on ultrasound. At the same time, SLNB has been shown to suffer from some technical issues that may be involved in its false negative rate.Therefore, the present study suggests a new approach for axillary staging using both SLNB and USALNB by wire localization. The aim of the present study was to compare SLNB alone with SLNB+USALNB in the prediction of the axillary status, using ALND as the gold standard.MethodsPatientsBetween January 2010 and July 2013,216 consecutive patients were enrolled at the Department of Breast and Thyroid Surgery, Qianfoshan Hospital, Shandong University. Inclusion criteria were:(1) women with clinical stage I or II breast cancer according to the AJCC TNM version 6.0; (2) a single primary breast tumor; (3) no distant metastases; and (4) no history of surgery or radiotherapy on the same side as the cancer. Exclusion criteria were:(1) neoadjuvant chemotherapy; (2) neoadjuvant endocrine therapy; (3) local resection surgery performed before axillary staging; or radiotherapy on the same side as the cancer. Diagnosis was confirmed by the pathological examination of percutaneous breast biopsies.The study was approved by the Medical Ethics Committee of the Qianfoshan Hospital affiliated to Shandong University (20110133), and written informed consent was obtained from each participant. Study designThis was a cohort study aiming to determine the predictive value of the axillary status in early breast cancer using SLNB alone and SLNB+US ALNB compared with axillary dissection as the gold standard. All patients underwent, in order: ultrasound-guided wire localization of the suspicious lymph node, SLNB, US ALNB, and ALND.Lymph node samplingB-mode ultrasound (Logiq 9, GE Healthcare, Waukesha, WI, USA) was conducted to determine the axillary lymph node that was the most likely to arbor a breast cancer metastasis. Because there is no generally accepted definition of suspicious lymph nodes under ultrasound, a suspicious lymph node was defined in the present study as a lymph node>0.5 cm in diameter, a length/width ratio<1.7, absence of hilum, heterogeneous thickening of the cortex, and increased peripheral blood flow. Lymph nodes showing these features were present in almost all patients. Therefore, after a careful examination of each lymph node, the most suspicious lymph node was selected for sampling. A hook wire (US Biopsy Breast Location Needle, Promex Technologies LLC, Franklin, IN, USA) was used to identify the one or two most suspicious lymph nodes under ultrasound guidance. If two lymph nodes were very close, the lymph nodes were identified with a single hook wire. On the other hand, if the lymph nodes were distant from each other or could not be observed in one ultrasonic range, two hook wires were used.Two radiologists including one chief and one senior attending doctor were asked to identify the suspicious lymph nodes. Disagreements were discussed and resolved by consensus.SNLB was performed 2-3 hours after ultrasound. A subcutaneous injection of methylthioninium chloride (4 ml,40 mg; Jiangsu Jumpcan Pharmaceutical Group Co.,Ltd., China) was performed at the surface of the tumor. Methylene blue was used instead of isosulfan or isotopes because of the limited availability of these products. The skin and subcutaneous tissues were incised 10 min later, and skin flaps were isolated routinely. Adipose connective tissues were incised parallel to the outer edge of the pectoralis major muscle. After identification of the blue-stained lymphatic vessels, dissection of the tissues was performed along the lymphatic vessels to find and resect blue-stained lymph nodes. The resected blue-stained lymph nodes were labeled as the sentinel lymph nodes for pathological examinations. Thereafter, the nodes identified using ultrasound were removed along the wire. During SLNB, the consistency between the nodes identified by SLNB and those identified using ultrasound was examined. The two methods were considered consistent when the nodes identified by ultrasounds were found to be stained blue and inconsistent when nodes other than the ones identified by ultrasound were stained blue. The ultrasound-suspicious lymph nodes were all removed with the hook wire, regardless of SLNB results. Lymph nodes identified by hook wires were considered as suspicious lymph nodes, while blue-stained ones were considered as SLNs.Suspicious lymph nodes and SLNs were examined using frozen sections. Axillary lymph nodes may be divided according to the outer, rear, and inner sides of the pectoralis minor muscle groups, according to the conventional surgical grouping criteria of axillary lymph nodes. Level Ⅱ or Ⅲ ALND was performed regardless of the results of SLNB and USALNB. Breast-conserving surgery or mastectomy was then performed, based on the decision reached by the patient following discussion with the surgeon. Adjuvant chemotherapy, radiotherapy, hormonal therapy, and biological therapy were administered post-operation according to each cancer, in a standard manner.All lymph nodes sampled were subjected to standard pathological examination, including hematoxylin & eosin (H&E) staining, and estrogen receptor, progesterone receptor and HER2 immunohistochemistry. Cytokeratins were not evaluated in the lymph nodes due to the limited amount of available tissues. H&E staining were considered as the gold standard to assess sensitivity and false negative rate. Pathologists were blind regarding the origin of the lymph nodes. All researchers were blind to the pathological results. Follow-upAll patients were followed up after treatments were completed. Follow-up was performed every 6 months by plain X-ray of the chest, bone scanning, ultrasound examination of the liver, thoracic wall and breasts, and axillary ultrasound examination, according 174 to the NCCN guidelines. Statistical analysisData are presented as mean ± standard deviation (SD), absolute numbers and percentages. Variables within the contingency tables were analyzed using the x 2 or the Fisher exact test, as appropriate. SPSS 16.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. P-values<0.05 were considered statistically significant.ResultsResults Patients’characteristicsAge ranged from 26 to 68 years old. All patients were without clinically palpable nodes before surgery. There were 76 patients clinical stage I breast cancer (according to the AJCC TNM,6th edition) and 140 with clinical stage II. Tumor was found in the 186 upper outer quadrant in 96 cases, in the lower outer quadrant in 54 cases, in the upper inner quadrant in 12 cases, in the lower inner quadrant in 10 cases, and in the central quadrant in 44 cases. Of these cases,196 underwent modified radical mastectomy, and 20 underwent breast-conserving surgery. Most tumors were invasive ductal carcinomas (85.2%). Tumor grade was I in 10.2% of cases, II in 83.3% and Ⅲ in 6.5%. Tumors were hormone receptor-positive in 66.2% of cases, HER2-positive in 19.4%, and 68.1% showed a Ki-67 index>14%. Lymph node statusSLNB using the methylene blue dye technique was successful in 99.1% of patients. A mean of 2.3 (range:1-5) SLNs were excised, with 1 SLN in 54 patients,2 SLNs in 78 patients,3 SLNs in 60 patients, and >3 SLNs in 22 patients. A mean of 1.3 (range 1-2) SALN were identified by ultrasound and excised, including 1 SALN in 150 patients and 2 SALNs in 64 patients. A mean of 20.3 (range:12-36) lymph nodes were excised by ALND.Postoperative pathological examination of axillary lymph nodes obtained by ALND showed that 143 cases were negative, and that 71 cases were positive. Among these 71 positive cases, SLNB alone indicated that 63 were node-positive. Ultrasound indicated suspicious lymph nodes in 35 patients. Therefore, using the combination of SLNB and USALNB,69 cases were node-positive. Sentinel lymph node biopsy aloneThe predictive value of SLNB alone. Using ALND results as the gold standard, sensitivity was 88.7%, specificity was 100%, false negative rate was 11.3% and false positive rate was 0%. Sentinel lymph node biopsy and ultrasound-suspicious lymph node biopsyThe predictive value of SLNB+USALNB. Using ALND results as the gold standard, sensitivity was 97.2%, specificity was 100%, false negative rate was 2.8% and false positive rate was 0%. Using SLNB results as the gold standard, compared with SLNB alone, SLNB+USALNB had a better false negative rate (2.8% vs.11.3%, P=0.031).Follow-up dataDuring follow-up, only two patients were found with distant metastases.The first patient was a 65-year-old female patient with grade II invasive ductal carcinoma (left breast,4 cm). She underwent a level II ALND, and all sampled lymph nodes were negative. Tumor immunohistochemistry revealed a triple-negative breast cancer, P53-positive, and the Ki-67 index was<40%. She received four cycles of docetaxel and cyclophosphamide. Pulmonary and bone metastases were found one year after surgery.The second patient was a 31-year-old female patient with grade II invasive ductal carcinoma (left breast,1.7 cm). She underwent level II ALND and all sampled lymph nodes were negative. She received epirubicine,5-fluorouracil and cyclophosphamide for 6 cycles, followed by 2 months of oral toremifene. The patient stopped her hormonal therapy by herself, and thoracic vertebral metastases were found two years after surgery. |
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