Most cases of in-situ and invasive lobular carcinoma (ILC) show absence of E-Cadherin immunoreactivity. In this image, the ILC component is negative where as the entrapped benign ducts show strong membrane staining and serve as an internal positive control. It must be noted that aberrant staining for E-Cadherin is seen in about 16% of cases and does not exclude the diagnosis of ILC if the H&E features are diagnostic. The lack of E-Cadherin is due to biallelic loss of expression of a tumor suppressor gene CDH1 on chromosome 16q. E-Cadherin is a calcium-dependent transmembrane protein that plays a key role in cell-cell adhesion. As a result, the tumors like ILC that lack E-Cadherin are discohesive and frequently consist of single cells infiltrating through the breast parenchyma. Image courtesy of: Jian-Hua Qiao, MD, FCAP, Los Angeles, CA, USA.