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

Abstract

Mixed ductal–lobular carcinomas (MDLs) show both ductal and lobular morphology, and constitute an archetypal example of intratumoural morphological heterogeneity. The mechanisms underlying the coexistence of these different morphological 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 clinicopathological analysis of a cohort of 82 MDLs, and found that: (1) MDLs more frequently coexist with ductal carcinoma in situ (DCIS) than with lobular carcinoma in situ (LCIS); (2) the E‐cadherin–catenin complex was normal in the ductal component in 77.6% of tumours; and (3) in the lobular component, E‐cadherin was almost always aberrantly located in the cytoplasm, in contrast to invasive lobular carcinoma (ILC), where E‐cadherin is typically absent. Comparative genomic hybridization and multiregion whole exome sequencing of four representative cases revealed that all morphologically distinct components within an individual case were clonally related. The mutations identified varied between cases; those associated with a common clonal ancestry included BRCA2, TBX3, and TP53, whereas those associated with clonal divergence included CDH1 and ESR1. Together, these data support a model in which separate morphological components of MDLs arise from a common ancestor, and lobular morphology can arise via a ductal pathway of tumour progression. In MDLs that present with LCIS and DCIS, the clonal divergence probably occurs early, and is frequently associated with complete loss of E‐cadherin expression, as in ILC, whereas, in the majority of MDLs, which present with DCIS but not LCIS, direct clonal divergence from the 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 intertumoural heterogeneity, and each case may have a unique molecular mechanism. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Mixed pleomorphic lobular and apocrine carcinoma of the breast: A case report suggesting pathogenesis

“…In ILC mixed with other types, as in the present case, however, it is more likely that the other component transitioned to ILC by loss of E‐cadherin via genetic or epigenetic change, rather than that each component was generated independently. Reed et al reported genome analysis data of mixed ductal‐lobular carcinoma of the breast suggesting that the lobular component can arise via a ductal pathway of tumor progression . The present case may suggest the existence of an oncogenic pathway similar to the ductal pathway in PLC via a transition from apocrine carcinoma.…”

“…This means aberrant expression of E‐cadherin protein that lost the functions of cell adhesion and anchoring P120 catenin. In mixed ductal‐lobular carcinomas, E‐cadherin was almost always aberrantly located in the cytoplasm in the lobular component, in contrast to the pure type of invasive lobular carcinoma, where E‐cadherin is mostly absent . There is little information on genetic changes involving aberrant expression of E‐cadherin in ILC, so that the molecular mechanism has not been clear.…”

Morphologic and Genomic Heterogeneity in the Evolution and Progression of Breast Cancer

“…In contrast to the above studies, where topographically defined regions were analysed, here morphologically defined populations of cells representing the different growth patterns (ductal and lobular, including associated pre-invasive lesions) were isolated by microdissection and analysed. In individual cases, all lesions shared precise genetic alterations as likely early events in tumour development; all cases also exhibited private mutations unique to a morphological lineage (e.g., TBX3), suggesting they may be important in the separate evolution from a common antecedent [42].…”

“…Mixed ductal lobular carcinomas are a unique histological subtype of breast cancer; like metaplastic breast cancers they elicit morphological evidence of intra-tumour heterogeneity, this time showing tumour regions with both ductal and lobular-like differentiation. Multi-region exome sequencing supplemented by copy number profiling of cases exhibiting distinct morphological components demonstrated these were clonally related tumour regions as opposed to being collision tumours [42]. In contrast to the above studies, where topographically defined regions were analysed, here morphologically defined populations of cells representing the different growth patterns (ductal and lobular, including associated pre-invasive lesions) were isolated by microdissection and analysed.…”

“…As these neoplastic cells can travel along ductal structures then this means invasion can occur at multiple sites giving rise to multifocal invasive disease (ILC, IC NST), which continues to undergo subclonal change. The individual components of this case were previously analysed by whole exome sequencing and all lesions were shown to be clonally related with early, common diver mutations identified in BRCA2 and TBX3, 'lobular' lineage-specific mutations including in CDH1 and 'ductal' lineage-specific mutations including in NF1 (see [42]). DCIS: ductal carcinoma in situ; LCIS: lobular carcinoma in situ; IC NST: invasive carcinoma no special type; ILC: invasive lobular carcinoma.…”