Update in lobular breast lesions: Pathological diagnosis in the molecular era

Lobular breast carcinoma has been recognized as a distinct entity for over 80 years, and the clinicopathologic features of classic cases are familiar. However, the repertoire of morphologic variants, intersection of contemporary immunophenotyping (E-cadherin, catenins), and genomic studies (CDH1, loss of heterozygosity, alterations in other cell adhesion pathway genes), provides opportunity to critically revisit diagnostic challenges and update criteria. Judicious application of well validated E-cadherin immunostaining with careful interpretation to distinguish strong membrane pattern from aberrant staining (discontinuous or weak membrane, granular, cytoplasmic, dot-like) can aid in diagnostic reproducibility; p120 and β-catenin immunohistochemistry provides further confirmation, with similar caveats. Nevertheless, with increasing application of immunohistochemistry, 'lobular' cancers with intact E-cadherin expression are increasingly encountered. CDH1, encoding E-cadherin, harbors pathogenic mutations in 65-70 % of lobular carcinomas, as one facet of biallelic inactivation. As with immunohistochemistry, CDH1 mutations are not universal, such that lobular carcinoma defies classification as a purely molecular entity at present. In addition to solidifying contemporary criteria for lobular carcinoma, there is a need to reset the terminology used for 'mixed' or 'uncertain' ductal-lobular carcinomas, as prior studies in the literature have been inconsistent in nomenclature and definitions. Recent studies provide insight into invasive lobular carcinoma with tubular elements associated with cadherin switching (P-cadherin upregulation) in tubular areas. Lobular-like invasive mammary carcinoma is another term recently applied to morphologically lobular carcinomas with membranous E-cadherin and p120 expression. These studies further understanding of the biologic spectrum of lobular carcinoma, yet salient morphologic, immunophenotypic, and molecular questions remain.