Premalignant and In Situ Breast Disease: Biology and Clinical Implications

Breast cancer is currently the most common malignant disease affecting women in the United States. An estimated 211240 new cases and 40410 deaths from the disease will occur this year (1). Thus, understanding histopathologic changes that are associated with an increased probability of developing invasive breast cancer, and molecular changes that occur during early development of the disease, may enable more accurate assessment of risk, individualization of therapy, and most important, identification of specific defects that can be targeted therapeutically to prevent development and progression of the disease. Currently, the best-characterized premalignant lesions are atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), and lobular carcinoma in situ (LCIS). Two additional lesions, unfolded lobules and usual ductal hyperplasia, are sometimes considered to be early, premalignant epithelial abnormalities (2-5). Ductal carcinoma in situ (DCIS) is considered to be a preinvasive malignant lesion. Since simple cysts, uncomplicated fibroadenomas, stromal fibrosis, and sclerosing adenosis have not been consistently linked to a clinically significant increased risk for breast cancer, they will not be further discussed in our review, although they are common findings in breast biopsies. The major objectives of our review are to define which types of breast lesions represent premalignant disease and describe their biology, to describe the risk for invasive cancer in women with each type of premalignant breast lesion and explore whether there are predictors of progression to cancer, and to outline the clinical management of these lesions according to the available published evidence. Methods Identification of Published Reports We identified studies through a computerized search of the MEDLINE (1966-2005), CancerLit (1966-2005), and EMBASE (1990-2005) databases by using the following text words: premalignant lesions of the breast, atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), lobular neoplasia, unfolded lobules, or usual ductal hyperplasia. We limited the search to English-language articles on human research that were published between 1966 and February 2005. We also performed a computerized search of the proceedings of the annual meetings of the American Society of Clinical Oncology (ASCO) held between 1998 and 2004 to identify relevant studies published in abstract form. Finally, we screened all review articles and cross-referenced studies from retrieved articles for further pertinent articles. Quality Evaluation We divided studies according to the types of premalignant lesions and the nature of the study (molecular or laboratory research or clinical). Because some lesions included in our review are uncommon or difficult to study prospectively, most of the biological studies are retrospective analyses. For molecular studies, the relevance and reproducibility of the methods and findings and the number of samples analyzed in each study were the most important variables in evaluating the quality of the data. When possible, especially when addressing treatment and clinical management issues, we gathered data from large-scale randomized trials with clinically important end points (invasive breast cancer incidence and death) because these studies have the most rigorous designs and provide the most useful information. For clinical studies, we based quality on the sample size and the rigor of the study design. Role of the Funding Sources The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication. Evolutionary Progression of Breast Cancer Although considerable progress has been made in elucidating the genetic events in noninvasive and invasive breast cancer, the relationship between premalignant and in situ lesions and invasive cancer is not completely established. The currently favored working hypothesis of human breast cancer evolution suggests that breast cancer evolves in a linear progression through sequential stages of hyperplastic benign breast lesions with and without cellular atypia (ADH, ALH, and usual ductal hyperplasia); carcinoma in situ (DCIS and LCIS); and, ultimately, invasive carcinoma (6-8) (Table 1 and Figure). Support for this model comes from several lines of clinical and molecular research. Usual ductal hyperplasia, ADH, ALH, and in situ diseases are more frequent in breasts that contain invasive cancer, suggesting that they are precursors (21, 22). Also, epidemiologic studies demonstrate a stepwise, increasing risk for breast cancer associated with increasing morphologic changes of breast lesions (8, 10-12). Molecular studies have shown that many changes in the expression of cell cycle-related and apoptosis-related proteins found in invasive carcinoma are also found with increased frequency during progression in this proposed continuum (23-25). Invasive cancer and premalignant lesions have also been demonstrated to share several genetic alterations (2, 5, 26-28) (Table 2). These progressive molecular changes occur slowly, and overall, the journey from normal epithelium to invasive breast cancer is thought to take many years or even decades, thus providing a large window of opportunity for intervention. Table 1. Evidence Supporting the Hypothesis That Invasive Breast Cancer Arises from Premalignant Lesions Figure. Proposed histologic evolution of breast cancer. Table 2. Biological Features of Premalignant Breast Lesions Although this multistep model of human breast cancer evolution has been useful as a framework for translational molecular research and has aided in understanding the pathogenesis and cause of human breast cancer, it may oversimplify a very complex process. The conceptual evolutionary tree that has been presented may contain many branches and dead ends, and some lesions may arrest or even regress. In fact, the histologic appearance of premalignant lesions within specific categories is similar regardless of whether they progress or stabilize, suggesting that there may be morphologically silent molecular differences that result in progression, regression, or stabilization of these preneoplastic lesions. Early Events: The Normal Breast, Unfolded Lobules, and Usual Ductal Hyperplasia The duct system of the breast is a branching structure with its base at the nipple and branches extending outward, supported by a vascularized fibrofatty stroma. The most distal structures are designated as terminal duct lobular units. Terminal duct lobular units are the normal functional unit of the breast and consist of an intralobular terminal duct and several blindly ending tubular structures, termed ductules or acini, arranged around the duct like a cluster of grapes. Structurally, the terminal duct lobular units have a round or lobulocentric arrangement and are lined by 2 cell layers (Figure): an outer myoepithelial layer that has contractile properties and an inner luminal epithelial component. Cells in the terminal duct lobular units make up the most rapidly proliferative compartment of the ductal tree (50, 51) and are thought to be the precursor cells of breast cancer. Unfolded lobules are architecturally distorted terminal duct lobular units, where the ductules and intralobular terminal duct progressively dilate, enlarge, and coalesce (Figure). Over time, these dilated structures separate, resulting in spherical cysts that may be progenitors of epithelial cysts, apocrine cysts, usual and atypical epithelial hyperplastic lesions, and carcinoma in situ (51). As with other stages of epithelial hyperplasia, increased architectural and cytologic atypia within unfolded lobules confer an increased risk for breast cancer (52). Hyperplastic lesions result from proliferation of the epithelial component within terminal duct lobular units. Usual ductal hyperplasia is the most common type of hyperplasia observed in the breast, present in about 25% of benign biopsy specimens (12, 53). According to Page and Dupont (53), usual ductal hyperplasia lesions can be subdivided into mild, moderate, and florid subtypes, reflecting increasing cellular proliferation within and filling the duct spaces. Histologically, these cells are heterogeneous, in contrast to ADH, which has a more monotonous cell population. Although the epithelial cells in unfolded lobules and usual ductal hyperplasia resemble those in terminal duct lobular units, their proliferation rates substantially differ. In unfolded lobules and usual ductal hyperplasia, the epithelial proliferation rates average about 5%, which is 2- to 3-fold higher than that in normal terminal duct lobular units (Table 2) (29, 30). Estrogen receptor (ER) is relatively overexpressed in usual ductal hyperplasia lesions compared with normal epithelium; up to 60% of usual ductal hyperplasia lesions express ER in most cells (29, 30, 35, 36) compared with 25% to 30% in normal epithelium (Table 2). Estrogen receptor is a central component of pathways promoting growth and proliferation of breast epithelial cells and may play a partial role in driving progression. Several studies have evaluated loss of heterozygosity in premalignant lesions, such as usual ductal hyperplasia lesions, to identify alterations that might be important in the progression to invasive disease (54-59). To identify genetic changes that may be important in the early development of precursor lesions and their progression to invasive disease, O'Connell and colleagues (5) analyzed 399 precursor lesions (211 usual ductal hyperplasia lesions, 51 ADH lesions, 81 noncomedo DCIS lesions, and 56 comedo DCIS lesions) for loss of heterozygosity at 15 genetic loci known to exhibit high rates of loss in invasive breast cancer. Among specimens harvested from cancerous breast lesions, 37% of usual ductal hyperplasia, 45% of ADH, 77% of noncomedo DCIS