Lymphovascular invasion (LVI), the presence of malignant cells within lymphovascular channels, is a crucial step in the invasion-metastasis cascade. LVI, when identified morphologically in the peritumoural area, is regarded as an indicator of metastatic potential and is strongly associated with a poor prognosis in many solid tumours, including breast cancer (BC). Although molecular mechanisms associated with the development of LVI have been extensively studied, details of driver genes, and molecular pathways and mechanisms involved in its development in BC, remain poorly defined. Although invasive BC cells have the ability to invade surrounding stroma, only those that can interact with endothelial cells, penetrate the vascular wall and withstand the intravascular stress will develop LVI and complete metastatic dissemination. Identification of additional molecular events associated with LVI in the primary tumour and characterisation of the contribution of the tumour micro-environment to modulating biological processes leading to LVI in BC remain a challenging task. This stems not only from the complexity of the molecular alterations in the primary tumour and the interactions with different components of its micro-environment but also from the subjective nature of LVI assessment in human BC. In this review, we discuss the clinicopathological features and the current knowledge of the molecular mechanisms underlying LVI in BC.

BackgroundAlthough the prognostic value of Ki67 in breast cancer is well documented, using optimal cut-points for patient stratification, reproducibility of the scoring and interpretation of the results remains a matter of debate particularly when using tissue microarrays (TMAs). This study aims to assess Ki67 expression assessed on TMAs and their matched whole tissue sections (WTS). Moreover, whether the cut-off used for WTS is reproducible on TMA in BC molecular classes and the association between Ki67 expression cut-off, assessed on TMAs and WTS, and clinicopathological parameters and patient outcome were tested.MethodA large series (n = 707) of primary invasive breast tumours were immunostained for Ki67 using both TMA and WTS and assessed as percentage staining and correlated with each other, clinicopathological parameters and patient outcome. In addition, MKI67 mRNA expression was correlated with Ki67 protein levels on WTS and TMAs in a subset of cases included in the METABRIC study.ResultsThere was moderate concordance in Ki67 expression between WTS and TMA when analysed as a continuous variable (Intraclass correlation coefficient = 0.61) and low concordance when dichotomised (kappa value = 0.3). TMA showed low levels of Ki67 with mean percentage of expression of 35 and 22% on WTS and TMA, respectively. MKI67 mRNA expression was significantly correlated with protein expression determined on WTS (Spearman Correlation, r = 0.52) and to a lesser extent on TMA (r = 0.34) (p < 0.001). Regarding prediction of patient outcome, statistically significant differences were detected upon stratification of patients with tumours expressing Ki67 at 10, 15, 20, 25 or 30% in TMA. Using TMA, ≥20% Ki67 provided the best prognostic cut-off particularly in triple-negative and HER2-positive classes.ConclusionKi67 expression in breast cancer can be evaluated using TMA although different cut-points are required to emulate results from WTS. A cut-off of ≥20% for Ki67 expression in BC provides the best prognostic correlations when TMAs are used.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-017-4270-0) contains supplementary material, which is available to authorized users.