Clinical significance of extranodal extension in sentinel lymph node positive breast cancer

The precise stage of lymph node (LN) metastasis is a strong prognostic factor in breast cancers, and sentinel lymph node (SLN) is the first station of nodal metastasis. A number of patients have extranodal extension (ENE) in SLN, whereas the clinical values of ENE in SLN in breast cancers are still in exploration. The aim of our study was to evaluate the predictive and prognostic values of ENE in SLN in breast cancers, and to investigate the feasibility of ENE to predict non-SLN metastasis, nodal burden, disease free survival (DFS) and overall survival (OS) in clinical practice. 266 cases of primary invasive breast cancer (cT1-2N0 breast cancer) 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. ENE in SLN was defined as extension of neoplastic cells through the lymph-nodal capsule into the peri-nodal adipose tissue, and was classified as no larger than 2 mm and larger than 2 mm group. The associations between ENE and clinicopathological features, non-SLN metastasis, nodal burden, DFS, and OS were analyzed. In the 266 patients with involved SLN, 100(37.6%) were positive for ENE in SLN. 67 (25.2%) cases had ENE no larger than 2 mm in diameter, and 33(12.4%) had ENE larger than 2 mm. Among the clinicopathological characteristics, the presence of ENE in SLN was associated with higher pT and pN stages, PR status, lympho-vascular invasion. Logistic regression analysis indicated that patients with ENE in SLN had higher rate of non-SLN metastasis (OR4.80, 95% CI 2.47-9.34, P<0.001). Meanwhile, in patients with SLN micrometastasis or 1-2 SLNs involvement, ENE positive patients had higher rate of non-SLN metastasis, comparing with ENE negative patients (P<0.001, P=0.004 respectively). The presence of ENE in SLN was correlated with nodal burden, including the pattern and number of involved SLN (P<0.001, P<0.001 respectively), the number of involved non-SLN and total positive LNs (P<0.001, P<0.001 respectively). Patients with ENE had significantly higher frequency of pN2 disease (P<0.001). For the disease recurrence and survival status, Cox regression analysis showed that patients with ENE in SLN had significantly reduced DFS (HR 3.05, 95%CI 1.13-10.48, P=0.008) and OS (HR 3.34, 95%CI 0.74-14.52, P=0.092) in multivariate analysis. Kaplan-Meier curves and log-rank test showed that patients with ENE in SLN had lower DFS and OS (for DFS: P<0.001; and for OS: P<0.001 respectively). Whereas no significant difference was found in nodal burden between ENE<less than or equal to>2 mm and>2 mm groups, except the number of SLN metastasis was higher in patients with ENE>2 mm. Cox regression analysis, Kaplan-Meier curves and log-rank test indicated that the size of ENE was not an independent factor of DFS and OS. Our study indicated that ENE in SLN was a predictor for non-SLN metastasis, nodal burden and prognosis in breast cancers. Patients with ENE in SLN had a higher rate of non-SLN metastasis, higher frequency of pN2 disease, and poorer prognosis. Patients with ENE in SLN may benefit from additional ALND, even in SLN micrometastasis or 1-2 SLNs involvement patients. The presence of ENE in SLN should be evaluated in clinical practice. Size of ENE which was classified by a 2 mm cutoff value had no significant predictive and prognostic values in this study. The cutoff values of ENE in SLN need further investigation.