Elsevier

Human Pathology

Volume 33, Issue 7, July 2002, Pages 715-722
Human Pathology

Original Contributions
Molecular and genetic abnormalities in radial scar*,**

https://doi.org/10.1053/hupa.2002.125375Get rights and content

Abstract

Hyperplasia of usual type (HUT) may be an early precursor of breast carcinoma and has been shown to contain molecular and genetic abnormalities previously seen in more advanced breast lesions, such as allelic imbalance (AI) and coexpression of estrogen receptor-alpha (ER) and the proliferation marker Ki67. We have examined hyperplastic and other areas from within radial scar (RS) for such abnormalities, to explore whether such regions of RS are similar at the molecular and genetic level to histologically similar lesions found independent of RS. Abnormal expression of ER and Ki67 in hyperplastic foci and other histologically distinct areas within RS was detected by dual-label immunofluorescence. Subtle differences in expression patterns were seen compared to similar lesions outside RS, with a lower overall level of ER overexpression in HUT within RS (P = 0.0012) and less evidence of the abnormal ER association with Ki67 (P = 0.004). AI of chromosome 16q and 8p was detected in RS, indicating that at least some areas of RS are clonal and neoplastic, but no clear relationship to ER dysregulation was found. Different genetic losses seen in microdissected areas of the same RS indicated clonal differences between these areas. The role of RS as a marker of malignancy and relative risk of breast cancer remains uncertain. Nonetheless, here we provide evidence that some molecular and genetic changes that occur to a greater degree in breast cancer and some premalignant breast lesions are present in a minority of RS. HUM PATHOL 33:715-722. Copyright 2002, Elsevier Science (USA). All rights reserved.

Section snippets

Histology and immunostaining

Blocks and slides of 17 patients with RS were retrieved from the files of the Pathology Department of the Royal Liverpool University Hospital, spanning an 11-year period. Slides stained with hematoxylin and eosin were reviewed to identify foci of different histologies within and outside RS. Cases that contained invasive or in situ carcinoma were excluded from the study. The cases of RS selected were from patients age 40 to 67 years.

For immunostaining, tissue samples were processed and stained

Distribution of ER+ cells in HUT

Seventy-one foci of HUT within RS (mean, 4.2 per patient; range, 1 to 11) were studied by a dual-labeled immunofluorescent technique, using ER and Ki67 antibodies. Like HUT foci outside RS, reported earlier,11 the staining pattern was heterogeneous (Table 1) and ER expression was positively correlated with age (Spearman's rho, r = 0.34, P = 0.001).

. ER, Ki67 and dual staining of HUT within and outside of RS

HUT SubgroupN (%)% ER+: Mean (SD)% Dual+ Cells: Mean (SD)
Dual+ER+HUTHUT in RSHUTHUT in RSHUT

Discussion

In the current study we looked at the same molecular markers in HUT foci within RS as we previously studied in HUT independent of RS11 and additional markers of AI at 2 loci implicated in breast tumorigenesis. The RS identified and selected for the study were of larger size to allow for both microdissection and for counting of sufficient numbers of epithelial cells, but did not show any concurrent malignant component. Such lesions are associated with a higher relative risk of malignancy.6, 7

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      As previously mentioned, Jacobs et al12 reported similarities in the expression of factors involved in vascular stroma formation between the two lesions, suggesting similarities in the stromal–epithelial balance between them. Iqbal et al21 reported molecular and genetic changes in a minority of radial scars similar to those seen in breast carcinomas. The finding in follow-up studies of radial scars that subsequent malignancy is just as likely to occur in the contralateral as in the ipsilateral breast, and the conclusion of Sanders et al17 in the largest study to date of its kind that there is little increased risk of subsequent carcinoma above that of the background proliferative disease (typical or atypical), argues against radial scars being precursors to carcinoma.

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    *

    Supported in part by a Clatterbridge Cancer Research Trust Mavis Horwich Fellowship.

    **

    Address correspondence and reprint request to Michael P.A. Davies, MD, Clatterbridge Cancer Research Trust, J.K. Douglas Laboratories, Clatterbridge Hospital, Bebington, CH63 4JY, UK.

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