Background Several studies have demonstrated that extranodal extension (ENE) is associated with prognosis in breast cancer. Whether this association should be described in pathological reports warrants further investigation.Objective In this research, we evaluated the predictive value of ENE in axillary lymph nodes (ALNs) in invasive breast cancer and explored the feasibility of employing ENE to predict clinicopathological features, nodal burden, disease recurrence-free survival (DRFS) and overall survival (OS) in clinical practice. In addition, the cutoff values of perpendicular diameter (PD-ENE) and circumferential diameter (CD-ENE) of ENE were investigated.Methods A total of 402 cases of primary invasive breast cancer were extracted from Fudan University Shanghai Cancer Center; these patients underwent axillary lymph node dissection (ALND) between 2010 and 2015. ENE in the axillary lymph node (ALN) was defined as the tumor cells breaking through the lymph node capsule into peripheral adipose tissue and causing connective tissue reactions. Relationships between ENE and clinicopathological features, nodal burden, disease recurrence-free survival (DRFS) and overall survival (OS) were analyzed. PD-ENE was defined by measuring from the point where tumor tissue broke the node capsule to the highest point of the tumor cells in the perinodal adipose tissue. The average PD-ENE was 1.8 mm; therefore, we divided ENE-positive patients into two groups: PD-ENE no greater than 2 mm and PD-ENE greater than 2 mm. CD-ENE was defined as measuring along the nodal capsule as the distance between peripheral edges of the ENE area. According to the average circumferential diameter (CD-ENE), we classified ENE-positive patients into two groups: CD-ENE no greater than 3 mm and CD-ENE greater than 3 mm. Correlations between ENE cutoffs and prognosis were analyzed.Results In this cohort of patients, 158 (39.3%) cases were positive for ENE in ALN.98 (24.4%) cases had PD-ENE no larger than 2 mm, and 60 (14.9%) cases had PD-ENE larger than 2 mm. Also, 112 (27.9%) cases had CD-ENE no larger than 3 mm, and 46 (11.4%) cases had CD-ENE larger than 3 mm. Statistical analysis indicated that histological grade, N stage, and HER2 overexpression subtype were associated with ENE. The presence of ENE had significant statistical correlations with nodal burden, including N stage, median metastatic tumor diameter and peri-lymph node vascular invasion (p < 0.001, p < 0.001, p = 0.001, respectively). Cox regression analysis demonstrated that patients with ENE exhibited significantly reduced DRFS in both univariate analysis (HR 2.126, 95% CI 1.453 - 3.112, p < 0.001) and multivariate analysis (HR 1.745, 95% CI 1.152 - 2.642, p = 0.009) compared with patients without ENE. For overall survival (OS), patients with ENE were associated with OS in univariate analysis (HR 2.505, 95% CI 1.337 - 4.693, p = 0.004) but not in multivariate analysis (HR 1.639, 95% CI 0.824 - 3.260, p = 0.159). Kaplan–Meier curves and log-rank test showed that patients with ENE in ALN had lower DRFS and OS (for DRFS: p < 0.0001; and for OS: p = 0.002, respectively). However, neither the PD-ENE group (divided by 2 mm) nor the CD-ENE group (divided by 3 mm) exhibited significant differences regarding nodal burden and prognosis.Conclusions Our study indicated that ENE in the ALN was a predictor of prognosis in breast cancer. ENE was an independent prognostic factor for DRFS and was associated with OS. ENE in the ALN was associated with a higher nodal burden. The size of ENE, which was classified by a 3-mm (CD-ENE) or 2-mm (PD-ENE) cutoff value, had no significant prognostic value in this study. Based on our findings, the presence of ENE should be included in routine pathological reports of breast cancers. However, the cutoff values of ENE warrant further investigation.

Background The precise stage of lymph node (LN) metastasis is a strong prognostic factor in breast cancer, and sentinel lymph node (SLN) is the first station of nodal metastasis, whereas the clinical value of extranodal extension (ENE) in SLN are still in exploration.Objective Our study aimed to evaluate the predictive and prognostic values of ENE in SLN and to investigate the feasibility of ENE to predict non-SLN metastasis, disease free survival (DFS) and overall survival (OS) in clinical practice.Methods 183 cases of primary invasive breast cancer (cT1-2N0 breast cancer with 1-2 positive SLNs) underwent SLN biopsy and axillary lymph node dissection (ALND) between 2008 and 2015 were extracted from the pathology database of Fudan University Shanghai Cancer Center. Sections were reviewed for the microscopic features of SLN, including the number and pattern of SLN metastasis, SLNs positive ratio, nodal vascular invasion (NVI), and ENE. The associations between tumor features including ENE and non-SLN metastasis, DFS and OS were analyzed. Moreover, ENE was subclassified into circumferential (CD-ENE) and perpendicular (PD-ENE) and set a threshold as 2mm or 3mm to evaluate the prognostic value of ENE.Results 73/183 (39.9 %) cases were positive for ENE in SLN. Logistic regression analysis indicated that ENE, the number and pattern of SLN involvement, SLN positive ratio, and NVI were significantly associated with the presence of non-SLN metastasis in univariate analysis. ENE, higher number of SLN involvement, SLN macrometastasis, and NVI were significantly associated with a higher rate of non-SLN metastasis in multivariate analysis. Cox regression analysis showed ENE in SLN was associated with DFS and OS in univariable analysis, but not in multivariable analysis. Whereas the size of ENE (CD-ENE and PD-ENE) subdivided by 3mm (or 2mm) cutoff values were not found as strongly prognostic factors of DFS and OS as well.Conclusions Our study indicated that ENE in SLN was a predictor for non-SLN metastasis in breast cancers, patients with ENE in SLN had a higher rate of non-SLN metastasis. ENE in SLN was associated with DFS and OS in univariable analysis, but not in multivariable analysis. The size of ENE (CD-ENE and PD-ENE) which was classified by a 3mm (or 2mm) cutoff value had no significant prognostic values in this study. The prognostic value of ENE in SLN and the cutoff values of ENE in SLN in breast cancers need further investigation.