Carcinoma in situ of the breast (CIS) comprise a heterogenous group of lesions, covering a wide spectrum of clinical conditions and histopathological changes. With respect to
biological behavior, CIS range from biologically aggressive lesions with a substantial risk of progression into invasive
carcinoma (IC), to lesions with a very low malignant potential. Two main types of CIS are described--
ductal carcinoma in situ (
DCIS) and
lobular carcinoma in situ (LCIS). Previous studies of CIS indicate that approximately a third will subsequently develop IC. Autopsy studies indicate that CIS is frequently occurring and it was estimated that about 20% of all women will develop CIS during lifetime. Only a minor fraction is ever diagnosed, although the incidence of
DCIS is increasing, especially related to mammography screening. The lack of knowledge about the
biological significance of the histopathological subtypes was the background of the present study. In 1982, a nationwide, prospective study of CIS (protocol DBCG 82-IS) was initiated by the Danish
Breast Cancer Cooperative Group (DBCG). From this protocol, the group of patients treated with breast conservation surgery (BCS) constituted the material for clinico-histological investigation. A total of 275 women were included in the period 1982-89. Follow-up studies showed that recurrence rate was significantly related to nuclear size of the primary lesion. Since nuclear changes might be related to
DNA content and, furthermore, many invasive
breast carcinomas were shown to be
DNA aneuploid, flow cytometric (FCM)
DNA ploidy analysis was performed in a series of
DCIS lesions. More than 80% of these lesions were
DNA aneuploid, with a distribution similar to that found in invasive
carcinomas. This finding raised the hypothesis that the
DNA pattern of an invasive
carcinoma was already established at the preinvasive stage of
DCIS. Therefore, FCM
DNA analysis was performed on a series of ICs with predominance of
DCIS. Partial or complete concordance in
DNA ploidy between
DCIS and IC within the individual case was found in most cases, except for the additional presence in the IC component of
DNA hyperdiploid clones that might possibly be of importance for the process of invasion. In order to further characterize CIS lesions and, possibly, to discriminate biologically different groups, immunohistochemical markers were investigated in a consecutive series of CIS and IC with predominance of
DCIS. The results were correlated to the histopathological and
DNA ploidy findings. In
DCIS, significant correlation was shown between large nuclear size and comedonecrosis, both of which showed also strong association to
DNA aneuploidy, high proliferation activity, low
steroid receptor content, and overexpression of c-erbB-2 and p53--factors that may indicate an aggressive behavior. Small nuclear CIS, whether LCIS or
DCIS, on the contrary, were
DNA diploid with low proliferation, and no cases showed overexpression of c-erbB-2 and p53. In IC, comparison of the
DCIS and the invasive component showed similar patterns. No significant differences, in neither morphology, immunohistochemistry, nor
DNA ploidy, were shown between
DCIS without and with invasion. These findings may indicate that none of the parameters in question may on its own be essential for the decisive event of invasive growth.