Small Beginnings: Do They Matter? The Importance of Lymphovascular Invasion in Early Breast Cancer

Extract

In the era of tailored therapy, the evaluation of systemic treatment of breast cancer has been increasingly dominated by consideration of biological features of the tumor and the host. Established breast cancer prognostic factors—those that determine natural history of breast cancer—include axillary nodal status, tumor size, histological grade, hormone receptor status, HER-2 expression, and presence of lymphovascular invasion. These factors often inform decisions about whether to use adjuvant systemic therapy. In contrast, predictive markers like expression of estrogen receptor (ER) alpha, progesterone receptor, and HER-2 protein are powerful tools to select certain types of therapy. Techniques to examine a myriad of genomic, transcriptional, or proteomic factors simultaneously, so-called ‘omics, currently dominate this field.

In this molecular age, it is important to reflect on the continuing importance of classic histopathology. One such feature is identification of lymphovascular invasion. Its importance in prognosis was suggested at the 2007 St Gallen consensus conference ( 1 ) when extensive lymphovascular invasion was identified as a factor to identify women with moderate risk as opposed to low risk for recurrence. These classic histological studies have been amplified by immunohistochemical analysis. For example, immunohistochemical studies of microvascular density assessed by vascular markers such as CD31 and CD34 antigens have usually shown an association between extent of staining and a greater likelihood of subsequent metastatic disease ( 2 ), shorter relapse-free interval, and reduced overall survival in patients with node-negative, ER-negative breast cancers ( 3 ). The presence of tumor in peritumoral small lymphatic spaces, independent of lymphovascular density, has been shown to play a fundamental role in tumor progression ( 4 ). D2-40 or podoplanin, a novel antibody, selectively stains the endothelium of lymphatic vessels. The utility of this antibody as a specific marker for detection of lymphovascular invasion in the routine pathological workup is evolving ( 5 , 6 ). Recent studies ( 7 , 8 ) have demonstrated a higher sensitivity for detection of lymphovascular invasion by D2-40 than by routine histological detection or CD31-detected vascular invasion. Controversy continues to exist with regard to the process whereby tumor cells gain access via preexisting lymphatics or via newly formed lymphatics at the invasive front of the tumor; D2-40–detected lymph channel invasion along with high CD31 microvessel density has been associated with outcome in breast cancer as shown in univariate and multivariable analyses.