The two most common types of breast cancer are invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC), at 70-80% and 5-10% of cases respectively.  In IDC cords and nests of malignant cells display varying amounts of gland formation, whereas in ILC isolated or small clusters/ribbons of malignant cells show absent gland formation.  E-cadherin is a cell-to-cell adhesion molecule and its loss/reduced expression parallels cancer invasion and metastasis. E-cadherin immuno-staining is absent in most ILCs, but present in IDC.  Somatic mutations occur in the E-cadherin gene (CDH1) in ILCs but are rare in IDCs.   

 Loss of E-cadherin explains the divergent morphologic phenotype between ILC and IDC, and diffuse versus intestinal gastric cancer.  A better name for ILC might be ‘diffuse breast cancer’, one advantage being it avoids the misconception that ILC arises in breast lobules and IDC the ducts.  Germline CDH1 mutation carriers from Hereditary Diffuse Gastric Cancer (HDGC) kindred have a 60% risk of ILC by 80y, along with an 80% lifetime risk of stomach cancer.  Rare families with multiple ILCs but no gastric cancer have been identified with germline CDH1 mutation.

 There is no established model describing how loss of E-cadherin function might be related to initiation and/or progression in ILC, although one has been proposed in HDGC suggesting a long indolent phase for early stomach lesions. There are some similar themes in the natural history of ALH and LCIS, together referred to as lobular neoplasia (LN).  Whether LN is purely a marker of increased risk or the precursor lesion of ILC has been a controversial issue in breast pathology. Recent molecular evidence suggests it is both.

 This talk will address the main clinical conundrums which arise in the management of patients with LN, ILC and ILC risk in HDGC.  To illustrate some of these, results from a pilot study of pathological mapping of a mastectomy from a CDH1 mutation carrier will be presented: Mapping revealed 5 tumours, 11 foci of ALH and 16 foci of LCIS.