Molecular alterations in columnar cell lesions of the breast

Abstract

Columnar cell lesions of the breast include a morphologic spectrum of simple columnar cell change, columnar cell hyperplasia, columnar cell hyperplasia with atypia and ductal carcinoma in situ of micropapillary/cribriform type. Invasive carcinomas of low grade are often seen in association with this spectrum. The biologic significance of these lesions that are commonly found on breast biopsies is unknown. Three cases of formalinfixed, paraffin-embedded breast tissues, each displaying the entire spectrum of columnar cell lesions through ductal carcinoma in situ and including foci of invasive carcinoma were microdissected at multiple sites to evaluate neoplasia progression. Minute tissue targets were microdissected (4-8/case) from unstained 4-lm thick recut paraffin sections and included non-neoplastic breast and sites of columnar cell change, hyperplasia, atypia, ductal carcinoma in situ and invasive carcinoma. Allelic imbalance for a broad panel of microsatellite markers in proximity to known tumor suppressor genes was quantitated using automated polymerase chain reaction/gel electrophoresis. Genomic loci evaluated 1p, 3p, 5q, 9p, 9q, 10q, 17p, 17q, 19q, 22q. The presence, topographic relationship and time course of mutational damage was correlated with columnar morphologic features. Detailed allelic imbalance information was obtained from each microdissection tissue target producing a detailed fingerprint of mutational damage in each case. Allelic damage was targeted predominately at 9q, 10q, 17p and 17q. Simple columnar cell change was without mutational changes and only present in one case of columnar cell hyperplasia. The remainder of the cases all show progressive accumulation of allelic damage in columnar cell changes with atypia, ductal carcinoma in situ and invasive carcinoma. The fractional mutation percentage increased progressively from columnar cell hyperplasia through invasive carcinoma. Low level of allelic imbalance was demonstrable in columnar cell lesions by the microdissection approach. A gradient of progressive mutational change could be delineated in each case manifesting allelic loss damage. Allelic loss damage appeared to preferentially target loci at 9q, 10q, 17p and 17q. The findings are consonant with the hypothesis that a select group of atypical columnar cell lesions are morphologic precursors to invasive carcinoma. Integrated molecular pathology analysis used here can help define the significance of columnar cell lesions and its role in breast cancer tumorigenesis on an individual patient basis.

Phosphatidylinositol-3-kinase pathway mutations are common in breast columnar cell lesions

“…[22][23][24][25][26][27][28] Previously, Moinfar et al 22 analyzed loss of heterozygosity in Ductal Intraepithelial Neoplasiaflat lesions, and found significant alterations, including changes in common with concurrent carcinoma; however, 9 of the 22 studied cases were 'pleomorphic' Ductal Intraepithelial Neoplasia-flat, equivalent to clinging carcinoma (high nuclear grade flat ductal carcinoma in situ). In a subsequent study using array comparative genomic hybridization Moinfar's group showed by that Ductal Intraepithelial Neoplasia low grade harbored changes common to lobular neoplasia, low nuclear grade ductal carcinoma in situ, and invasive carcinoma (loss of 16q, gain of 1q).…”

“…Recent loss of heterozygosity, comparative genomic hybridization, and immunohistochemical studies have suggested that columnar cell lesions, might represent the 'missing link' in low-grade breast cancer progression, as the earliest identifiable non-obligate precursor. 18,[22][23][24][25][26][27][28] In order to further address the pathogenetics of columnar cell lesions, we screened a cohort of columnar cell lesions, most with matched normal breast tissue and/or concurrent carcinoma, for a large panel of known activating point mutations, including PIK3CA and AKT1 mutations.…”

Is an Entropy-Based Approach Suitable for an Understanding of the Metabolic Pathways of Fermentation and Respiration?

“…For a description of the reasons at the basis of assumptions (1)- (5) see [36][37][38]. The RIEDP takes the form:…”

Digital mammography: more microcalcifications, more columnar cell lesions without atypia

“…8 Many studies have shown that there is an association between the presence of columnar cell lesions and ductal carcinoma in situ, atypical ductal hyperplasia or lobular neoplasia, and low-grade luminal type invasive carcinomas like tubular and lobular carcinomas. 2,4,[9][10][11][12][13][14][15] Moreover, protein expression as detected by immunohistochemistry is quite similar between columnar cell lesions and atypical ductal hyperplasia or ductal carcinoma in situ grade I. 8,15,16 Also, molecular studies provide evidence that atypical columnar cell lesions may be the 'missing link' between normal breast tissue and low-grade ductal carcinoma in situ and/or low-grade invasive carcinomas, 9,10,15,17,18 thereby being true precursors.…”