Aberrant expression of E-cadherin in lobular carcinomas of the breast

Am J Surg Pathol. 2008 May;32(5):773-83. doi: 10.1097/PAS.0b013e318158d6c5.

Abstract

Invasive lobular carcinoma (ILC) and lobular carcinoma in situ characteristically show loss of E-cadherin expression and so immunohistochemistry for E-cadherin is being increasingly used as a tool to differentiate between lobular and ductal lesions in challenging situations. However, misinterpretation of "aberrant" positive staining may lead some to exclude a diagnosis of lobular carcinoma. E-cadherin and beta-catenin immunohistochemistry was analyzed in 25 ILCs. E-cadherin "positive" ILCs were subjected to molecular analysis including comparative genomic hybridization. Different morphologic components of case 25, showing heterogenous E-cadherin expression, were analyzed by E-cadherin gene sequencing, methylation, and DASL gene expression profiling. Four ILCs were positive for E-cadherin, but each also had neoplastic cells with aberrant staining. Two of these ILCs were positive for beta-catenin, again with some aberrantly stained neoplastic cells, and 2 were negative. The solid component of case 25 was positive for E-cadherin whereas the classic and alveolar areas were negative. All components harbored an in-frame deletion in exon 7 (867del24) of the E-cadherin gene and loss of the wild type allele. Comparative genomic hybridization demonstrated evidence of clonal evolution from E-cadherin-positive to E-cadherin-negative components. E-cadherin down-regulation seems to be through transcriptional repression via activation of transforming growth factor-beta/SMAD2 rather than methylation. Positive staining for E-cadherin should not preclude a diagnosis of lobular in favor of ductal carcinoma. Molecular evidence suggests that even when E-cadherin is expressed, the cadherin-catenin complex maybe nonfunctional. Misclassification of tumors may lead to mismanagement of patients in clinical practice, particularly in the context of in situ disease at margins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / metabolism*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Carcinoma in Situ / diagnosis
  • Carcinoma in Situ / metabolism*
  • Carcinoma, Ductal / diagnosis
  • Carcinoma, Intraductal, Noninfiltrating / diagnosis
  • Carcinoma, Lobular / diagnosis
  • Carcinoma, Lobular / metabolism*
  • DNA Methylation
  • DNA, Neoplasm / analysis
  • Diagnosis, Differential
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunohistochemistry
  • Loss of Heterozygosity
  • Nucleic Acid Hybridization
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / analysis
  • Sequence Analysis, DNA
  • Smad2 Protein / biosynthesis
  • Transforming Growth Factor beta / biosynthesis

Substances

  • Biomarkers, Tumor
  • Cadherins
  • DNA, Neoplasm
  • RNA, Messenger
  • RNA, Neoplasm
  • SMAD2 protein, human
  • Smad2 Protein
  • Transforming Growth Factor beta