It is generally accepted that DCIS and LCIS are precursor lesions of invasive breast cancer, both probably originating in the terminal ductal lobular unit. Nonetheless, distinguishing between both entities is sometimes difficult. This raised the question of whether these two tumour entities might have a common precursor.9
For many years, DCIS was seen as a uniform tumour group. However, clinical and molecular cytogenetic investigations revealed that DCIS might consist of different subgroups, which would justify a more detailed classification.2,7,10
We were able to demonstrate two different pathways, with the loss of chromosomal material of 16q as a central event in well differentiated and intermediately differentiated DCIS.2
These results show a high degree of genetic homology between LCIS and well differentiated DCIS and, at least in part, confirm the results of Lu et al
Nevertheless there are controversial results such as the gain of 6q and the loss of 16p material. How far the use of a polymerase chain reaction based DNA enrichment technique (DOP-PCR) contributes to this remains unclear. We interpret our results as important evidence in favour of the hypothesis that LCIS and well differentiated DCIS reflect two closely related neoplastic lesions evolving from one neoplastic cell. The loss of E-cadherin expression probably represents a molecular switch to the loosely cohesive growth pattern of LCIS, with a similar cell morphology to that seen in well differentiated DCIS.
Against the background of a postulated progression from well differentiated DCIS to intermediately differentiated DCIS,2
one could expect that there might be rare cases supporting the hypothesis that intermediately differentiated DCIS and invasive lobular carcinoma have a stem cell in common. In four cases of lobular invasive carcinoma, one of them of the pleomorphic subtype, we were able to show that there is a common stem cell origin for the invasive and preinvasive tumour components. This was further substantiated by the fact that lobular invasive carcinoma and intermediately differentiated DCIS show a high degree of genetic homology.11,12
Immunohistochemical staining for E-cadherin in the DCIS component was noteworthy in that it showed a classic membrane bound staining pattern, whereas the invasive part showed a weak, diffuse, intracytoplasmic reaction. In addition, immunohistochemical investigations regarding p53 and HER-2/neu, as well as ploidy studies using flow cytometry, suggest that a subgroup of non-high grade DCIS cases share other genetic homologies with lobular invasive carcinoma.7,13
Comparisons of cumulative data from DCIS, LCIS, and invasive breast cancer have yielded that gains of 6q and Xq are associated with intralobular and intraductal growth, respectively.3,6
Allelic imbalances of 11q13 associated with a more aggressive phenotype have been described in DCIS and LCIS.2,14,15
Nevertheless, these alterations are not indicative of invasion because they were shown to be present in precursor lesions. Comparing preinvasive and invasive tumour components with CGH within one patient,2,3
heterogeneous findings were seen. Our investigations demonstrate that, by using CGH as a screening technique for chromosomal copy number changes, the step from intraductal to invasive breast cancer should not be seen as part of a linear progression. With DCIS showing, in some cases, fewer alterations than in invasive breast cancer, we have to postulate DCIS as a clonal proliferation with different cytogenetic subclones. This is in agreement with microsatellite analysis studies demonstrating a clear genetic diversity in preinvasive stages of breast cancer development and, furthermore, less intratumor diversity in carcinomas than in their preinvasive components.16
The same mechanism can be demonstrated in LCIS, with a loss of the X chromosome in one case of LCIS and a normal CGH ratio profile in the adjacent lobular invasive carcinoma, as shown in fig 1A. It seems unlikely that in LCIS the X chromosome is lost and is gained again during invasion. Therefore, it might be speculated that one of these subclones became invasive while one or more other subclones progressed intraductally. Therefore, progression to invasiveness cannot be attributed to a specific alteration, which is why further research on a sub-CGH level is needed. Interestingly, in one case, a 16q loss has been detected in a poorly differentiated DCIS, whereas the associated ductal invasive grade 3 carcinoma did not show any alterations in the CGH profile for this chromosome. This could be interpreted to mean that 16q losses in poorly differentiated breast lesions might be a secondary genetic event, as postulated earlier.12
Evidence exists that the overwhelming number of morphological forms of invasive breast cancer is reflected by specific genetic features. As a result of this, we propose a hypothetical progression model (fig 2). The underlying mechanism for the coexistence of ductal and lobular preinvasive and invasive tumours seems to be a proliferation of a single cell clone with two different forms of morphological appearance. Further studies will need to show whether transition from LCIS towards ductal invasive carcinoma or from DCIS towards lobular invasive carcinoma is possible. How far this hypothesis can be transferred to poorly differentiated tumours with mixed differentiation also remains a subject for intense investigation.
Hypothetical model of the pathogenesis of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS).