References and Supplementary Text

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  7. The framework has been adapted from the teaching of Dr. James Wheeler at the University of Pennsylvania and has been useful for teaching observers with little training in normal histology to recognize diagnostic patterns. One usefulness of the framework is that it permits testable hypotheses to be developed. More important for the purpose of this article, this framework and the few assumptions about the nature of increasing fitness permit accurate diagnosis, reproducing the pure pattern recognition approaches found in most textbooks.
    There are important differences between evolution in community-level biology, and evolution in development of cancer. One simplifying feature is that only one "species" (ductal cells in this case) evolves while the other "species" are constrained by a static (predictable) genotype. On the other hand, Darwin never had to face the conceptual problem of his finches "differentiating" into the trees that provided their niche.
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  15. In addition to the evidence for trophic interactions between ductal cells and the basal lamina micro environment, there is considerable histologic evidence that the ductal/myoepithelial compartment can interact with the stromal compartment, particularly the so-called specialized perilobular fibroblasts. A mutually beneficial interaction between these fibroblasts and the apparently mutually dependent ductal/myoepithelial population has been proposed by Rosai(24) to produce phyllodes tumors (a relative of a fibroadenoma): Phyllodes tumors can be viewed as benign neoplasms of perilobular fibroblasts which induce the non-neoplastic ductal/myoepithelial compartment to expand, possibly because the presence of ductal/myoepithelial cells improves the growth of the fibroblasts. The development of papillomas also appears to display a trophic interaction between ductal/myoepithelial cells and periductal fibroblasts. In this case, however, the neoplastic population has been shown to be the ductal/myoepithelial cells.
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  17. Some ductal carcinomas in situ occasionally may have aligned nuclei, but the alignment in the cancer cells is different from the alignment in the benign cells. In benign lesions, the long axes of the nuclei tend to point along the same line as the long axis of a bridge of cells (the pattern is described as being like a "school of fish"), whereas, malignant cells' long axes may occasionally and stochastically point perpendicular to the bridge of cells, (like a "picket fence").
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  21. It is virtually certain that other pathways for breast cancer development exist, other than via the lesions described in this article. Azzopardi (2) tried to argue strongly for the existence of a distinct type of DCIS he termed "clinging" carcinoma, in which the ductal cells did not necessarily become multilayered. Diagnostic reproducibility of this and other potential precursors is the obstacle to accepting these as DCIS, however, and the concept of DCIS without multilayering (except in the relatively unusual and possibly arbitrary setting of a papillary lesion) has been abandoned. Fibroadenomas and sclerosing adenosis both are associated with a slightly increased relative risk of developing invasive breast cancer(25,26). However, since there is no morphologic spectrum linking these lesions to invasive cancer, rather than being a step in the development of ductal cancer, they are probably only associated with other carcinogenic factors that may lead to breast cancer. A practical point for researchers studying human samples is that the "normal" breast tissues that they receive for study from pathologists may contain non-conventional neoplastic ductal proliferations.
  22. Werb Z. Stromelysin-1 as a regulator of stromal-epithelial interactions during mammary gland development, involution and carcinogenesis. http://mammary.nih.gov/reviews/stromelysin1_(Werb).html
  23. Fischer AH, Chaddee DN, Wright JA, Gansler TS, Davie JR. Oncogenes affect nuclear morphology: Inferences about the structural basis, functional correlates, and signal transduction pathway for the altered morphology. Submitted for publication to Acta Cytologica
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  26. Jensen RA, Page DL, Dupont WD, and Rogers LW. Invasive breast cancer risk in women with sclerosing adenosis. Cancer 64:1977-1983, 1989

Acknowledgments: Thanks to Valerie Weaver at the Life sciences Division, University of California, Berkeley (valerie_weaver@macmail3.lbl.gov) for helpful perspectives and comments. Thanks to Panya Taysavang at Emory University Department of Pathology for his expertise in scanning slides and helpful feedback.

Andrew Fischer, M.D. (afische@emory.edu)
Department of Pathology
H176 Emory University Hospital
1364 Clifton Road NE
Atlanta, GA 30322

Visit The Emory Pathology department at: http://www.emory.edu/PATHOLOGY/