Columnar cell lesions of the breast: clinical significance and molecular background

Abstract

Columnar cell lesions (CCLs) of the breast have since long been regarded as possible precursor lesions of breast cancer. CCLs are cystically dilated ducts lined by columnar cell epithelium, with or without atypia. Intraluminal secretions and microcalcifications are frequently seen and the microcalcifications characterize the CCLs at mammography. On the 31st of January 2012, Anoek H.J. Verschuur-Maes defends her PhD-thesis ‘Columnar cell lesions of the breast: clinical significance and molecular background’ at University Utrecht under supervision of promotor P.J. van Diest, MD, PhD, and co-promotor dr. P.C. de Bruin, MD, PhD. Data has shown that CCLs have been diagnosed more frequently since the introduction of digital mammography compared to screen-filmed mammography. This seems to be related to a higher number of core needle biopsies taken for microcalcifications. However, in terms of percentage, the same percentage of columnar cell lesions with atypia were found during the full-field digital mammography period as in the screen-filmed mammography period (1.8%) and significantly more columnar cell lesions without atypia (8.2% and 2.8%, respectively). Since we questioned whether it is relevant to find CCLs in core needle biopsies, we investigated the progression risk of CCLs. In addition a systematic review was performed to provide more evidence based advice for the best treatment. Overall, a relatively high pooled underestimation risk was found for (in situ) carcinomas for all patients initially diagnosed with CCL with atypia (9%). Therefore, this seems to support the indication for surgical (‘mini’) excision. For CCLs without atypia, the underestimation and progression rates seem to be limited and only follow-up is advised. Different studies applying molecular techniques have demonstrated that CCLs with atypia exhibit increasing genetic alterations from normal breast epithelium to CCL with atypia to DCIS and invasive cancer. During tumour development, DNA promoter hypermethylation (further denoted “methylation”) is also considered to be an early event. We found that the cumulative methylation increased significantly from normal breast tissue through CCL, towards ductal carcinoma in situ and invasive carcinoma. For some genes, the epigenetic abnormalities that were seen in invasive cancer were already present in CCLs, suggesting that methylation increases stepwise in the progression to invasive cancer via CCL. In another study, copy number changes of 17 genes, located on chromosome 8 and 17 in particular, were studied. It seemed that these alterations mostly occur at a stage later than CCL in the progression to invasive cancer. Then, we studied the mucinous variant of CCLs in 4164 breast core needle biopsies and we found an incidence of 0.5% of the mucinous CCL. Also, significantly more mucinous CCLs were present in mucinous carcinoma than in ductal carcinoma cases. This supports a possible role of mucinous CCLs in the developmental pathway towards mucinous carcinoma. Then, by studying 89 male breast cancer specimens, it seems that CCLs do not exist in the male breast and that there is no role for CCLs in male breast carcinogenesis. In conclusion, more evidence is provided for CCLs, with atypia being a possible precursor lesion of female breast cancer and thus needing treatment.