Pitfalls in the histological diagnosis of morphologic variants of invasive lobular carcinoma of the breast

Invasive lobular carcinoma (ILC) is the second most frequent histological type of breast cancer and the most frequent special type. Disruption of cell-to-cell adhesion, caused most often by E-cadherin loss of function, results in the distinctive histomorphology of ILC which is characterized by single threads of monotonous, dyscohesive neoplastic epithelial cells infiltrating the breast parenchyma with little or no stromal reaction, referred to as classic ILC. In the past four decades, ILC variants that differ from classic ILC with regard to architectural, cytological, and/or nuclear features have been described. The recognition and correct characterization of ILC, including its variant forms, is essential to avoid misdiagnosis and its possible treatment implications. Some ILC variants may be associated with more aggressive clinical behavior as compared to classic ILC, independent of standard predictive and prognostic parameters. Additionally, the distinctive biological and clinical features of ILC are increasingly being investigated as therapeutic targets in ILC-tailored clinical trials. In this manuscript, we have undertaken an in-depth review of the current state of knowledge about ILC variants. Evidence gained from molecular analysis of ILC and its microenvironment suggests that ILC variants are biologically distinct from classic ILC. However, this conclusion is undermined by the imprecise histopathological identification of ILC variants. In the absence of standardized and simplified criteria for the diagnosis of ILC, under-recognition of ILC variants may translate into missed opportunities for tailored treatment of ILC patients. Therefore, we propose steps toward the development of a roadmap that will ultimately lead to a more reproducible classification of ILC variants and improve our knowledge of these challenging tumors.