Mixed ductal-lobular carcinomas: evidence for progression from ductal to lobular morphology

Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are an archetypal example of intra-tumour morphological heterogeneity. The mechanisms underlying coexistence of these different morphologic entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinico-pathological analysis of a cohort of 82 MDLs and found: i) MDLs more frequently co-exist with ductal carcinoma in situ (DCIS) than lobular carcinoma in situ (LCIS); ii) the E-cadherin-catenin complex was normal in the ductal component in 77.6% of tumours; iii) in the lobular component, E-cadherin was almost always aberrantly located to the cytoplasm in contrast to Invasive Lobular Carcinoma (ILC), where E-cadherin is typically absent. Comparative Genomic Hybridisation (CGH) and multi-region whole exome sequencing (WES) of four representative cases revealed that all morphologically distinct components within an individual case were clonally related. Mutations identified varied between cases; those associated with common clonal ancestry included BRCA2, TBX3, TP53, while those associated with clonal divergence included CDH1, ESR1. Together, these data support a model in which separate morphological components of MDLs arise from a common ancestor, and that lobular morphology can arise via a 'ductal' pathway of tumour progression. In MDLs that present with LCIS and DCIS, the clonal divergence likely occurs early, and is frequently associated with complete loss of E-cadherin expression, as in ILC. While in the majority of MDLs, which present with DCIS but not LCIS, direct clonal divergence from ductal to the lobular phenotype occurs late in tumour evolution and is associated with aberrant expression of E-cadherin. The mechanisms driving the phenotypic change may involve E-cadherin-catenin complex deregulation, but are yet to be fully elucidated, as there is significant inter-tumour heterogeneity and each case may employ unique molecular mechanisms