Despite the long name, this is the most common type of breast carcinoma. It includes a heterogenous group of tumours that have no specific distinguishing features on macroscopic or microscopic appearance. These tumours tend to have a worse prognosis than the 'special types' of breast carcinoma.
Tumour Features
Macroscopic
Macroscopically these tumours vary in colour from white, tan or yellow and are often heterogeneous. Cystic areas are rare. Necrosis is not commonly seen but may be associated with haemorrhagic areas. The classical features include a very firm, gritty texture that is partly due to the microcalcifications and dense stromal reactions seen in the tumour. The borders of the tumour may be infiltrative, speculated or pushing.
Microscopic
The malignant cells can range significantly in appearance, both between cells and with regards to the overall architecture. Cells are typically large and may have pleomorphic nuclei; the degree of pleomorphism is an important part of the grading system for ductal carcinoma. The architecture is similarly important, with well differentiated tumours showing overt glandular differentiation and tubule formation. Poorly differentiated tumours may show minimal or no tubule formation and simply form sheets of malignant cells. The number of mitoses per high power field is also important in grading.
Grading
The most commonly used grading system in Australia seems to be the Modified Bloom Richardson system, which combines three factors (tubule formation, nuclear pleomorphism and mitotic rate) to give a grade of 1 to 3.
- Tubules
- 1: >75% tubule formation
- 2: 10-75% tubule formation
- 3: < 10% tubule formation
- Nuclear Pleomorphism
- 1: Nuclei are similar size to normal duct cells
- 2: Nuclei are of intermediate size
- 3: Nuclei are very large, often with vesicular nuclei
- Mitotic Rate per 10 high power fields
- 1: 0-7 mitoses
- 2: 8-14 mitoses
- 3: 15 or more mitoses
Immunohistochemistry
Immunohistochemistry has both diagnostic and management implications in breast cancer.
- Hormonal receptors (the oestrogen and progesterone receptors) are both detectable with immunohistochemistry. As well as assisting in the diagnosis of breast cancer, the presence of these receptors has important implications for the aggressiveness of the disease (no receptors = bad) and the treatment of the disease (receptors = able to receive endocrine therapy)
- ERBB2 or HER2 staining is often performed, but accurate results depend on in situ hybridisation techniques
- Ki-67, which stains for the product of the MKI67 gene that is only found in cells undergoing the cell cycle, is an important proliferative marker that can be used to gauge how many cells are participating in the cell cycle. High levels of MKI67 expression are thought to be related to more aggressive malignancies.
- E-cadherin, a cell binding molecule, is usually positive in invasive ductal carcinoma of no special type, allowing differentiation from invasive lobular carcinoma.
- p63 is a myoepithelial marker that can be used to determine the presence of invasion when there is concern over DCIS (p63 is absent from invasive cancers)
Genetics
The development of DNA/RNA microarrays has assisted in the classification of invasive ductal carcinoma of no special type into several categories. They are named based upon their gene expression patterns; and the genes can be broadly grouped into four categories:
- Luminal genes (i.e. those expressed by the cells that line the lumen of normal breast ducts): These include CK8, CK18 and hormone receptor genes
- HER2 gene: The ERBB2 gene is amplified in a number of breast cancers, often detected through SISH of FISH techniques
- Proliferation gene cluster: These are genes associated with cellular proliferation, such as EGFR, Wnt etc.
- Basal gene cluster: These are genes typically expressed by the basal epithelial layer of normal breast tissue, including a different set of cytokeratins
There are four commonly seen combinations of the these gene clusters:
- Luminal A (luminal +, others -) malignancies typically express oestrogen and progesterone receptors, show no overexpression of ERBB2, and have cytokeratins that match the normal luminal cells of the ducts. This group accounts for about half of ductal carcinoma of NST.
- Luminal B (luminal +, HER2 +/-, proliferation +, basal -) malignancies are often 'triple positive', with hormone receptors preserved as well as overexpression of ERBB2. These tumours are of higher grade and show improved outcomes with chemotherapy. They are associated with worse prognosis.
- Basal-like (luminal -, HER2 -, proliferation +, basal +) malignancies, often called 'triple negative', have no evidence of OR/PR expression and no overexpression of ERBB2. They stain positively for cytokeratins that match the myoepithelial and basal cells of the normal ducts. These are aggressive tumours and chemotherapy often plays an important role due to the lack of endocrine targets
- HER2 or ERBB2 positive malignancies show amplification of the ERBB2 gene and amplification of proliferation pathways. TP53 is often frequently mutated in this group and overall the prognosis is poor without ERBB2 targeted therapy (eg. trastuzumab)
The significance of these gene profiles is controversial. While they are associated with poorer prognosis, they are also expensive to carry out as a routine procedure. Whether they add a significant level of benefit above classifying tumours as ER/PR +/-, HER2 +/-, and Ki67 is unknown.
Some gene expression tools (OncoType DX and the Amsterdam 70 gene test) utilise patterns of gene expression to make estimates of prognosis or response to therapy.
- The OncoType DX utilises the expression of 16 genes compared to five 'control' genes in early stage, hormone positive patients without lymph node metastases. It predicts for a survival benefit with the use of chemotherapy versus endocrine therapy alone, and has been validated in independent data sets. It is the subject of an ongoing randomised trial to determine its efficacy in the prospective setting. Importantly, it does not require fresh tissue for analysis to take place.
- The Amsterdam 70-gene profile compares the expression of seventy genes known to predict for poor prognosis. Unlike the OncoType DX, it has no role in evaluating effect of cytotoxic therapy but instead gives a prognostic score only. It is more controversial, having initially been validated in the population from which the data was derived. It is also expensive, and difficult to arrange, as it requires fresh frozen tissue for analysis; the need for the Amsterdam test may not be known until after surgery has taken place.
