Lobular carcinoma as a spectrum: resolving the gray zone between morphology, E-cadherin, and CDH1

Invasive lobular carcinoma (ILC) is characterized by E-cadherin loss resulting from CDH1 inactivation, but discordance among morphology, immunohistochemistry (IHC), and molecular findings can complicate diagnosis. We integrated histology, IHC, DNA sequencing, and whole-transcriptome sequencing (WTS) to clarify such discrepancies. Among 126 clinically sequenced breast cancers, 15 were selected based on ILC diagnosis or the presence of CDH1 mutation. WTS was performed on eight cases plus four ILCs with preserved E-cadherin and three normal breast tissues. Nine cases were histologically ILC, yet only one carried a CDH1 mutation by targeted sequencing, despite the E-cadherin loss in eight cases. Of seven CDH1 -mutant cases, six lacked lobular morphology and exhibited variable E-cadherin IHC. WTS classified four groups: group 1, CDH1 -mutant/non-lobular, confirmed concordant known variants; group 2, CDH1 -wild type/lobular, revealed previously undetected protein-altering mutations in three cases; group 3, lobular with preserved E-cadherin, showed missense variants in two cases; and group 4, normal breast, contained only non-coding variants. CDH1 expression was markedly reduced in Group 2, whereas CDH3 and CTNNB1 were downregulated across tumors but relatively preserved in Group 1. WTS identified pathogenic CDH1 mutations missed by targeted sequencing and revealed distinct CDH1/CDH3 / CTNNB1 expressions across subgroups, highlighting a diagnostic gray zone and suggesting that RNA-level profiling may further aid ILC classification.