Aberrant expression of E-cadherin in lobular carcinomas of the breast.
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.
Da Silva
Leonard
L
Molecular and Cellular Pathology, Mayne Medical School, University of Queensland, Brisbane, Australia.
Parry
Suzanne
S
Reid
Lynne
L
Keith
Patricia
P
Waddell
Nic
N
Kossai
Myriam
M
Clarke
Catherine
C
Lakhani
Sunil R
SR
Simpson
Peter T
PT
D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002278:Carcinoma in Situ / Q000175:diagnosis / Q000378:metabolism*; D044584:Carcinoma, Ductal / Q000175:diagnosis; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000175:diagnosis; D018275:Carcinoma, Lobular / Q000175:diagnosis / Q000378:metabolism*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D003937:Diagnosis, Differential; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000032:analysis; D017422:Sequence Analysis, DNA; D051899:Smad2 Protein / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D014408:Biomarkers, Tumor; D015820:Cadherins; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta