Ductal invasive G2 and G3 carcinomas of the breast are the end stages of at least two different lines of genetic evolution.

Ductal invasive grade (G) 2 and G3 carcinomas represent the majority of invasive breast cancers. Previous morphological and cytogenetic studies have provided evidence that ductal invasive G2 carcinoma may originate from at least two different genetic pathways. The aim of this study was to evaluate further the heterogeneity of G2 breast cancer in comparison with G3 cancers by cytogenetic and quantitative analysis. To this end, 35 cases of ductal invasive G2 and 42 cases of ductal invasive G3 carcinomas were investigated by means of comparative genomic hybridization (CGH) and these findings were correlated with DNA ploidy status, mitotic activity index (MAI), mean nuclear area (MNA), volume per lumen (VPL), and clinico-pathological parameters. The findings of this study demonstrate that ductal invasive G2 carcinomas, in contrast to ductal invasive G3 carcinomas, have to be interpreted as the morphological end stage resulting from two different cytogenetic and morphological pathways; the loss of 16q material is the cytogenetic key event in the evolution of a subgroup of this entity. By correlating genetic alterations with DNA ploidy status, an extended morphology-based cytogenetic progression model is presented, with early and late genetic alterations in the pathogenesis of breast cancer. The correlation with MAI gives rise to the hypothesis that these different genetic pathways significantly differ in their proliferation rate. Further studies will be required to elucidate which genes contribute to an altered proliferation rate in these subgroups and to the associated prognosis.

Genetic relation of lobular carcinoma in situ, ductal carcinoma in situ, and associated invasive carcinoma of the breast.

AIMS: The mutual relation of lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS) of the breast, as accepted precursor lesions of invasive breast cancer, is controversial. Because they display genetic heterogeneity, it is not clear how genetically advanced these entities are and what causes the transition to an invasive carcinoma. METHODS: Six cases of LCIS, four of them with associated lobular invasive carcinoma, four cases of intermediately differentiated DCIS with an associated invasive lobular carcinoma, and nine cases of intermediately and poorly differentiated DCIS with associated ductal invasive carcinoma were investigated by means of comparative genomic hybridisation (CGH) after microdissection and immunohistochemical staining of E-cadherin. RESULTS: LCIS was characterised by a low average rate of copy number changes, no evidence of amplifications, and a high rate of gains and losses of chromosomal material at 1q and 16q, respectively. A high degree of genetic homology with well differentiated DCIS was obvious, as reported previously. The cases of intermediately differentiated DCIS with associated lobular invasive components and lobular differentiation revealed striking homologies, and a significant difference of E-cadherin expression. The comparison of preinvasive and invasive breast lesions, irrespective of differentiation within the same patient, revealed no specific alteration that might be associated with invasion. Genetic alterations seen in invasive carcinoma were not necessarily seen in the adjacent precursor lesions. CONCLUSIONS: These results provide strong evidence that invasive breast cancer is a disease with multiple cytogenetic subclones already present in preinvasive lesions. Moreover, specific CGH alterations associated with invasion were not observed. Furthermore, the close genetic association between well differentiated and a subgroup of intermediately differentiated DCIS and LCIS led to the hypothesis that LCIS and a subgroup of DCIS are different phenotypic forms of a common genotype.

Correlation of morphologic and cytogenetic parameters of genetic instability with chromosomal alterations in in situ carcinomas of the breast.

Classification of preinvasive breast disease could be better founded using biologic markers, thereby increasing reproducibility. We studied 57 breast ductal and lobular in situ carcinomas by means of comparative genomic hybridization and correlated these findings with quantitative features such as the mean nuclear area, mitotic index (MI), apoptotic index (AI), and the presence or absence of necrosis. Loss of 8p and gains of 8q and 6q were associated, respectively, with a significantly higher MI and AI, whereas loss of 16q was associated with a lower MI and AI. A significantly higher number of alterations per case were seen in tumors with gains of 6q, 8q, and 17q and tumors with loss of 13q. Loss of 16q and gain of 17q correlated with the absence or presence of necrosis, respectively. Our data clearly demonstrate that distinct cytogenetic changes correlate with phenotypic changes, proliferation, and apoptosis. These data may be used to refine existing classification schemes.