Metaplastic breast carcinoma: tumour histogenesis or dedifferentiation?

Global gene expression profiling studies have classified breast cancer into molecular classes, some of which show similarity to normal mammary cells (ie luminal and basal subtypes) with a subsequent histogenetic implication that reinforced the perception that the phenotype of breast cancer reflects the cell of origin. However, it remains to be determined whether phenotypic changes are the result of malignant transformation of particular cancer stem cells (histogenesis) or specific genetic hits occurring at various stages of carcinogenesis (dedifferentiation). We sought to test the hypothesis that dedifferentiation may be the more likely explanation using in vivo clinical data. Our findings support the hypothesis that at least some metaplastic carcinomas are derived from phenotypic transition from conventional mammary adenocarcinoma either at the in-situ, primary invasive stage or at a distant metastatic site. This observation argues against the cell of origin theory (histogenesis) for breast carcinogenesis and favours the concept of tumour dedifferentiation at later stages.

The biological and clinical characteristics of breast carcinoma with mixed ductal and lobular morphology.

UNLABELLED: Although invasive ductal (IDC) and lobular (ILC) breast carcinomas are well characterised in the literature, the biological and clinical significance of mixed tumours with both ductal and lobular components has not been investigated. In the current study, we have examined a well-characterised series of breast carcinoma with a long term follow-up that comprised 140 mixed tumours, 2170 IDC and 380 pure ILC. RESULTS: Mixed tumours constituted 3.6% of all cases. The majority (59%) of the mixed tumours were grade 2 compared to 33% in IDC and 88% in ILC. Positive lymph nodes (LN) were found in 41% and definite vascular invasion (VI) in 26% of the cases. DCIS was detected in 123 (89%) and LCIS in 43 (31%) (both DCIS and LCIS were found in 39 cases). The majority of tumours were predominantly (>50 of tumour area) of ductal type (57%). When compared to pure IDC, mixed tumours showed an association with lower grade, ER positivity and lower frequency of development of distant metastases. When compared to pure ILC, mixed tumours showed an association with higher grade, positive LN metastasis, VI and development of regional metastasis. After adjustment for grade most of these differences were no longer apparent. There was an association between histologic type of carcinoma in LN metastasis and the predominant histologic type of the primary tumour. Mixed tumours showed metastatic patterns similar to that of ILC with frequent metastasis to bone. No clinically meaningful differences in survival were found between these mixed carcinomas and pure IDC or ILC of the breast or between mixed tumours with predominantly ductal or lobular phenotype.

Improved methods of detection of lymphovascular invasion demonstrate that it is the predominant method of vascular invasion in breast cancer and has important clinical consequences.

The presence of vascular invasion (VI), encompassing both lymphovascular invasion (LVI) and blood vascular invasion (BVI), in breast cancer has been found to be a poor prognostic factor. It is not clear, however, which type of VI plays the major role in metastasis. The aims of this study were to use an endothelial subtype specific immunohistochemical approach to distinguish between LVI and BVI by comparing the differential expression of blood vascular (CD34 and CD31) and lymphatic markers (podoplanin/D2-40) to determine their prognostic role in a well-characterized group of breast cancer patients with known long-term follow-up. Sections from 177 consecutive paraffin-embedded archival specimens of primary invasive breast cancer were stained for expression of podoplanin, D2-40, CD31, and CD34. BVI and LVI were identified and results were correlated with clinicopathologic criteria and patient survival. VI was detected in 56/177 specimens (31.6%); 54 (96.4%) were LVI and 2 (3.5%) were BVI. The presence of LVI was significantly associated with the presence of lymph node metastasis, larger tumor size, development of distant metastasis, regional recurrence and worse disease-free interval and overall survival. In multivariate analysis, LVI retained significance association with decreased disease-free interval and overall survival. In conclusion, VI in breast cancer is predominantly of lymph vessels and is a powerful independent prognostic factor, which is associated with risk of recurrence and death from the disease. The use of immunohistochemical staining with a lymphendothelial specific marker such as podoplanin/D2-40 increases the accuracy of identification of patients with tumor associated LVI.