Ductal carcinoma in situ (DCIS) represents a proliferation of malignant epithelial cells within the ducts of the breast, without invasion through the basement membrane. It is assumed that all invasive carcinomas of the breast are preceded by DCIS; however, it is not known what proportion of DCIS, if left untreated, will progress to invasive carcinoma. Before the introduction of population-based mammographic screening, most cases of DCIS were detected by clinical symptoms, including palpable mass, nipple discharge, or Paget's disease of the nipple. At mammography, DCIS is usually detected by typical patterns of microcalcifications . The incidence of carcinoma in situ (including DCIS and lobular carcinoma in situ, LCIS) of the breast accounts for approximately 20% of screen-detected breast cancers, compared to 3-5% of all symptomatic cancers before the period of population-based mammographic screening . The spread of DCIS through the ductal system is segmental, continuous, and often extensive at the time of diagnosis . When symptomatic disease led to the diagnosis of DCIS, the treatment of choice was usually mastectomy. Mastectomy often represents overtreatment for nonsymptomatic screen-detected DCIS, especially since breast-conserving treatment has become a generally accepted alternative to mastectomy in early invasive breast cancer. Moreover, not all cases of DCIS progress to invasive carcinoma within the lifetime of the patient. It is not possible, however, to reliably predict the biological behavior of DCIS. DCIS is a heterogeneous spectrum of lesions, varying in morphology, extent and clinical presentation, and it is evident that the degree of cytonuclear differentiation of DCIS corresponds with the malignancy grade of its invasive recurrence . The risk of recurrence, however, does not differ much between well-differentiated DCIS and poorly differentiated DCIS . Assessment of the risk factors associated with histopathologic characteristics and, more recently, genetic alterations in DCIS have become an important research area in recent years. Table 5.1 (randomized clinical trials in DCIS) depicts the results from four randomized clinical trials demonstrating that breast-conserving treatment followed by radiotherapy is a good alternative to mastectomy [51, 60, 66]. Although not designed to define subgroups with varying risks for recurrence, most of these studies reported that young age (less than 40 years), involved margins, decreasing width of tumor-free margins, and poorly differentiated DCIS were associated with increased risk. Still, a reliable assessment of risk in individual cases is not possible. (Table presented) The impact of treatment of DCIS on breast-cancer-specific survival is not clear yet. Thus far, randomized studies suggest an equal survival after local surgery alone or surgery followed by radiotherapy, although recurrence rates differ. The incidence of metastatic disease and death after breast-conserving therapy is comparable with that after mastectomy, in general less than 2%. Taking the risk of a delayed (salvage) mastectomy for recurrent tumor may therefore be an acceptable alternative for immediate mastectomy. However, it will be of great clinical benefit if histological or genetic factors can be identified that accurately predict which cases of DCIS are likely to progress to metastasizing invasive breast cancer in order to use these markers to tailor treatment. It should be remembered that it is difficult for the surgeon to identify the resection margins for DCIS; evaluation of the margins by the pathologist requires sampling guided by the microcalcifications. In one study of 469 patients with DCIS it was demonstrated that radiation therapy did not lower the recurrence rate when the DCIS was excised with margins of 10 mm or more. In addition, among patients with margin widths of 1 to < 10 mm there was no statistically significant benefit from postoperative radiation therapy. There was a statistically significant benefit from radiation among patients in whom margin widths were less than 1 mm . It has been commented, however, that this study lacked a multivariate analysis and that longer follow-up and confirmation in independent patient series is required [57, 150]. The management of DCIS is currently directed mainly by histological classification, which is discussed in section 5.2 of this chapter. Section 5.3 summarizes what is known about the genetic alterations in DCIS. Based on current knowledge, we propose a multistep model for the progression of breast cancer (section 5.4), which may provide insight into the molecular mechanisms underlying breast carcinogenesis. And finally, in section 5.5, future directions for genetic research into DCIS are discussed.