Mechanisms of Carcinogenesis

The vast array of histologic appearances of proliferative and atypical breast disease, as well as carcinomas, are the outward manifestations of the dozens or hundreds of biologic changes

taking place within these lesions and point to the complex and variable pathways to carcinogenesis. Indeed, not one common genetic or functional change can be found in every breast

cancer. Most reported changes occur in only a subset of carcinomas and usually in highly variable combinations with other changes.

A general model for carcinogenesis postulates that a normal cell must achieve seven new capabilities, including genetic instability, to become malignant [50] [51] (see Chapter 7 ) ( Fig. 23-

15 ). In hereditary carcinoma, one or more of these alterations is facilitated by the inheritance of germ-line mutations. Each of the new capabilities can be achieved by a change in one of

many genes. For example, changes in ER, EGF-R, RAS, or HER2/neu may result in self-sufficiency in growth signals. On the other hand, one cellular alteration (e.g., a change in a gene

such as p53 that has a central role in controlling the cell cycle, DNA repair, and apoptosis) can affect more than one of these capabilities.

The morphologic changes in the breast associated with the smallest increased risk of cancer are lesions with increased numbers of epithelial cells (proliferative changes). This suggests that

these early changes are related to evasion of growth-inhibiting signals, evasion of apoptosis, and self-sufficiency in growth signals. There is evidence that even at this early stage, there is

abnormal expression of hormone receptors and abnormal regulation of proliferation in association with hormone receptor positivity. [52]

Genetic instability, in the form of LOH, appears to be a later change, as it is rarely detected in proliferative changes but becomes more frequent in atypical hyperplasias and is almost

universally present in carcinoma in situ. Frank aneuploidy, as observed by nuclear enlargement, irregularity, and hyperchromasia, or image analysis to measure DNA content, is seen only

in high-grade DCIS and some invasive carcinomas. Limitless replicative potential is suggested by the ability of clonal populations of the cells of DCIS to completely fill a ductal system in

the breast. Increased angiogenesis is evident surrounding the basement membrane of some ducts that are involved by some types of DCIS. This might be due to direct stimulation by the

malignant cells, secondary stimulatory effects on stromal cells, or the loss of inhibition of angiogenesis by myoepithelial cells.

The morphologic and biologic features of carcinomas are usually established at the in situ stage, as in the majority of cases, the in situ lesion closely resembles the accompanying invasive

carcinoma. For example, lobular carcinomas are associated with LCIS, well-differentiated carcinomas with low-grade DCIS, and high-grade carcinomas with high-grade DCIS. Recurrent

carcinomas generally have the appearance of the original carcinoma. Breast carcinomas do not generally "dedifferentiate," or become more poorly differentiated over time.

This view of oncogenesis focuses on the malignant epithelial cell and does not take into account the other tissue components. The structure and function of the normal breast require

complex interactions between luminal cells, myoepithelial cells, and stromal cells. The same functions that allow for normal formation of new ductal branch points and lobules during

puberty and pregnancy—abrogation of the basement membrane, increased proliferation, escape from growth inhibition, angiogenesis, and invasion of stroma—can be co-opted during

carcinogenesis by abnormal epithelial cells, stromal cells, or both.[53] While the changes described above are accumulating in the luminal cells (or, less commonly, myoepithelial cells),

parallel changes also occur due to mutation or epigenetic changes (e.g., DNA methylation) or via abnormal signaling pathways in these other cell types, resulting in the loss of normal

cellular interactions and tissue structure. [54] Loss of these normal functions also occurs with age, and this loss might contribute to the increased risk of breast cancer in older women.

The final step of carcinogenesis, the transition of carcinoma limited by the basement membrane to ducts and lobules (carcinoma

Date: 2016-04-22; view: 739