Breast Cancer: Stage Tis - Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Perez & Brady's Principles and Practice of Radiation Oncology (Perez and Bradys Principles and Practice of Radiation Oncology), 6 Ed.

Chapter 55. Breast Cancer: Stage Tis

David E. Wazer and Douglas W. Arthur

Noninvasive carcinoma of the breast (stage Tis) includes Paget’s disease of the nipple and two histopathologic entities that are distinct in both their clinical presentation and biologic potential: lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS). As a result of the increase in the use of mammography, these three histopathologic entities comprise a larger percentage of all breast cancer cases seen today. There remains considerable controversy regarding the optimal treatment approach and, as a consequence, treatment recommendations range from observation to breast conservation therapy to mastectomy. It is, therefore, important to understand the distinguishing pathologic appearances, biologic characteristics, and natural history of these three noninvasive breast disease entities to appropriately formulate coherent treatment recommendations.

LOBULAR CARCINOMA IN SITU

LCIS is characterized by multicentric breast involvement and consists of loose, discohesive epithelial cells that are large in size, variable in shape, and contain a normal cytoplasm to nucleus ratio.¹ The extent of involvement of the lobular lumen ranges from simple filling to moderate to severe distention with extension into the adjacent extralobular ducts.² As such, the lines of histologic delineation can become blurred between atypical ductal hyperplasia, LCIS, and, when ductal extension is seen, DCIS. This overlap of histologic morphology may complicate the interpretation of studies from different institutions.¹^–⁴

LCIS has been reported to present with a multicentric distribution in up to 90% of mastectomy specimens, with bilateral involvement in 35% to 59%.^5,⁶^–⁷ LCIS cells are commonly estrogen-receptor positive, although overexpression of c-erbB-2 and p53 are uncommon.⁴^,⁸^,⁹^–¹⁰ The loss of E-cadherin is often observed,⁸^,¹¹^,¹² and the absence of this adhesion molecule may explain the growth pattern seen with LCIS.

LCIS represents <15% of all noninvasive breast cancer.¹³^–¹⁵ The majority of women are premenopausal at diagnosis, with an average age of 45 years.¹^,³^,¹⁶ Risk factors for the development of LCIS correspond to those identified for invasive carcinoma.¹⁷ Because the male breast lacks lobular elements, this entity has not been described in men.³ As there are no clinical or mammographic indicators that are characteristic of LCIS, it is often detected as an incidental biopsy finding.¹^,⁴ In a minority of cases, LCIS can be detected with mammographic calcifications; however, more commonly, calcifications are in adjacent tissue and are not histologically associated with LCIS.¹⁸^–²⁰ In excisional biopsy specimens, DCIS or invasive carcinoma are frequently identified even when LCIS is the sole histologic entity seen on core biopsy.²¹^–²³

LCIS is considered a marker of increased risk for the subsequent development of invasive (usually ductal) carcinoma³^,¹³^,¹⁴^,¹⁶ that may be greatest for high-grade or more extensive lesions.¹^,²⁴ This risk appears to be nearly equal for both breasts.²⁵

The question as to whether LCIS can serve as a direct precursor lesion to the subsequent development of invasive lobular carcinoma is unresolved. Some studies have suggested a clonal link of synchronously detected LCIS and invasive lobular carcinoma,²⁶ whereas others have not.²⁷ In an analysis of 182 patients with LCIS who were inadvertently enrolled on the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17 trial for DCIS and treated with lumpectomy only, there was a 14.4% in-breast tumor recurrence (IBTR) rate and a 7.8% contralateral breast tumor recurrence rate after a median follow-up of 12 years.²⁸ Nine IBTRs (5% of the total cohort) were invasive carcinoma, and 17 (9% of the total cohort) were DCIS. Although the frequency of contralateral breast tumor recurrence rate was less than that of IBTR, the frequency of invasive contralateral breast tumor recurrence rate (5.6% of total cohort) was similar to invasive IBTR (5% of total cohort). Of note, all of the IBTR were documented to be at the site of the index lesion except for one, characterized as pure LCIS, that was found at a remote site.

The evidence associating LCIS with the subsequent development of invasive disease raises the question as to whether magnetic resonance imaging (MRI) would be a useful screening tool. Limited data exists to formulate a firm recommendation. In 2007, the American Cancer Society stated there was insufficient data; however, in 2009, the National Comprehensive Cancer Network published guidelines reflecting a panel consensus opinion that annual breast MRI should be considered in patients with LCIS. Since 2007, three studies have been published evaluating the role of MRI in patients with LCIS.²⁹^–³⁰^,³¹ Each document revealed a small but defined 3.8% to 4.5% breast cancer detection rate supporting consideration for an annual MRI in this subset of patients.

Management for LCIS depends on whether it is associated with another malignancy (DCIS or invasive carcinoma) or if LCIS is the sole histologic diagnosis. Approximately 10% of early-stage breast cancers have an associated component of LCIS.³²^–³⁴ The effect that LCIS has on the outcome of conservative management of early-stage breast cancer has only recently been evaluated. Limited studies suggest that the presence of LCIS should influence treatment approach³⁵; however, the most widely accepted treatment approach is to manage the breast according to the dominant malignant histology (DCIS or invasive carcinoma) and disregard the LCIS. In such circumstances, it is not necessary to pursue additional surgery to obtain clear margins for LCIS.²⁷^,³²^,³³^,³⁶^,³⁷

If LCIS is the sole histologic diagnosis, treatment recommendations range from conservative to radical. When first described as an entity, the significance of LCIS was unknown and mastectomy was often performed.³⁸ The high frequency of contralateral breast involvement was subsequently used to justify contralateral biopsy and even bilateral mastectomy.¹⁶^,³⁸ Observational studies after wide local excision alone have led to a better understanding of the natural history of this condition, and a more conservative approach is now commonly practiced.³^,¹³^,¹⁴ In patients with LCIS as the sole histologic diagnosis, the most widely accepted clinical practice is close observation with regular physical examination and mammographic surveillance.³^,¹³^–¹⁵^,²⁸ There is no role for radiotherapy in the management of LCIS. The fact that LCIS commonly involves both breasts makes treatment with unilateral mastectomy both inadequate and illogical. Bilateral prophylactic mastectomy is likely excessive in all but those patients believed to be at highest risk: young age, diffuse high-grade lesion, and significant family history. A less radical prophylactic approach in high-risk patients is to consider the use of tamoxifen. Tamoxifen has demonstrated efficacy in the prevention of invasive carcinoma and, in the context of LCIS, has been shown to reduce risk by 56%.³⁹^,⁴⁰

PAGET’S DISEASE

The clinical presentation of crusting and eczematous changes of the nipple–areola complex were first described in 1856. However, it was not until 1874 that the association with an underlying breast cancer was reported by Sir James Paget.⁴¹ Paget’s disease of the nipple is characterized by the presence of Paget’s cells that are located throughout the epidermis.⁴² Paget’s cells are large and have hyperchromatic, round to oval nuclei with abundant amphophilic to clear cytoplasm. Mitoses are commonly seen, and the cells can be found in clusters or individually in the basal layers. The fact that Paget’s disease is associated with an underlying malignancy in >95% of cases has generated discussion regarding the origin of these malignant cells. The epidermotropic theory appears to be the prevailing opinion, with the belief that the disease originates from the underlying in situ or invasive disease. This is supported by histologic evidence of intraepithelial extension, immunohistochemical studies, and evidence suggesting that the epidermal keratinocytes release a motility factor, heregulin-α, that results in the chemotaxis of Paget’s cells that migrate to the overlying nipple epidermis.⁴³^,⁴⁴

Paget’s disease is a rare entity representing <5% of all breast cancer cases⁴⁵^,⁴⁶ and is typically diagnosed in the fifth or sixth decade of life. Synchronous bilateral and male Paget’s disease have been reported.⁴³^,⁴⁷^,⁴⁸

Patients with Paget’s disease describe itching and burning of the nipple and areola. There is a slow progression toward a crusting eczematoid appearance that can extend to the periareolar skin. If neglected, bleeding, pain, and ulceration can occur.⁴⁶^,⁴⁹ Alternatively, Paget’s disease can be asymptomatic and present as a pathologic finding after incidental surgical removal of the nipple–areolar complex.⁵⁰ The differential diagnosis includes superficial spreading melanoma, pagetoid squamous cell carcinoma in situ, and clear cells of Toker.⁴²^,⁵¹ A palpable mass is detected in approximately 50% of patients at diagnosis; in >90% of cases, this will be an invasive carcinoma. In contrast, if no palpable mass is detected, 66% to 86% will have an underlying DCIS. These associated malignancies are usually located centrally, although they can occur elsewhere in the breast.⁴³^,⁴⁶^,⁵² Mammographic findings are frequent in the presence of a palpable mass; however, normal mammograms are reported in as many as 50% of cases.⁴⁶^,⁵³

At presentation, clinical evaluation includes bilateral breast examination, mammography, and biopsy to confirm the diagnosis of Paget’s disease and to fully evaluate the extent of the associated malignancy. The prognosis does not depend on the diagnosis of Paget’s disease but rather on the associated malignancy. Therefore, local treatment, as well as systemic and regional nodal disease risk management, should be based on the associated disease.

Management of Paget’s disease continues to evolve. Mastectomy was employed in the past, although this has been increasingly supplanted by breast-conserving treatment.⁵⁴^–⁵⁷ The infrequent occurrence of this disease entity, the range of disease presentations (nipple involvement with or without an underlying mass and association with invasive vs. noninvasive disease), and the variable extent of surgical resection has made the evaluation of treatment options difficult. Small series have described results with various forms of breast-conserving treatment, including wide local surgical resection alone, radiotherapy alone, and wide excision followed by whole-breast radiotherapy. Conservative surgery alone for Paget’s disease appears to be inadequate, with reported local recurrence rates of 25% to 40%.⁵^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶² The use of radiotherapy alone has been reported as achieving an 85% local control rate in a small series of patients with Paget’s disease of the nipple who presented without an associated palpable mass.⁶³ However, this approach has not been widely adopted because of the undefined histologic type and extent of the underlying disease leading to uncertainty in field design and total radiation dose.

The combination of limited surgical resection and postoperative radiotherapy appears to be the most practical breast-conserving approach. Two studies have evaluated the combined use of surgery and radiotherapy in Paget’s disease of the nipple. The European Organisation for Research and Treatment of Cancer (EORTC) Study 10873 was a multi-institutional registry trial that reported a 5-year local recurrence rate of 5.2%.⁶⁴ In this study, a complete excision with tumor-free margins of the nipple–areolar complex and underlying breast tissue was followed by whole-breast radiotherapy. The median follow-up was 6.4 years, and the majority of these patients were found to have an underlying DCIS without a palpable mass. A separate study consisted of a seven-institution collaborative review of 36 patients with Paget’s disease without a palpable mass or mammographic density.⁶⁵^,⁶⁶ Patient follow-up was a median of 9.4 years. The extent of surgical resection varied as patients underwent complete (69%) or partial (25%) excision of the nipple–areolar complex and underlying breast tissue, with 6% reported as biopsy only. The final margin status was documented as negative in 56%, positive in 6%, and unknown in 39%. All received whole-breast irradiation, and most received an additional boost dose to the tumor bed. The actuarial rate of local failure as the only site of first recurrence was 9% at 5 years and 13% at both 10 and 15 years. Two additional patients recurred in the treated breast simultaneously with regional and distant metastasis at 69 and 122 months. Despite the differences in clinical, pathologic, and treatment factors, statistical evaluation did not identify any factors that significantly predicted for risk of local recurrence.

Current data suggest that a combined-modality approach that conserves the breast is an appropriate alternative to mastectomy in properly selected patients with underlying noninvasive or invasive carcinoma of limited extent. As with any breast-conserving approach, patients with multicentric disease extension should be excluded. Surgical resection should include the nipple–areolar complex with microscopically clear margins surrounding both the Paget’s disease and the associated malignancy. Whole-breast radiotherapy is delivered with standard techniques. Management of regional nodes and the risk of systemic disease are dictated by the associated malignancy.

DUCTAL CARCINOMA IN SITU

Clinical Presentation and Epidemiology

DCIS is a neoplastic process that is confined to the ductal system of the breast and lacks histologic evidence of invasion. These cells neither disrupt the basement membrane nor involve the surrounding breast stroma. This entity lacks the ability to metastasize and is confined to the breast.⁶⁷^–⁷⁰ Axillary node involvement is rare (0% to 5%) and most likely is associated with an undetected focus of invasive carcinoma.⁷¹ Risk factors for the development of DCIS are the same as those identified for invasive carcinoma,¹⁷ including family history, reproductive events such as delayed age of first live birth and nulliparity, history of benign breast biopsy, and dietary factors such as alcohol consumption. Before the use of screening mammography, DCIS typically presented as a palpable mass or nipple discharge. An invasive component commonly was found, and pure DCIS rarely was encountered. The widespread use of mammography now routinely detects DCIS <1 cm in diameter and results in breast cancer–free survival rates that approach 100%.⁷¹

With the increased use of mammography and as pathologists began to recognize DCIS as a pathologic entity, the incidence of DCIS has markedly increased.⁷²^–⁷⁴ The incidence of DCIS in the United States rose from 4,800 cases in 1983 to >50,000 cases in 2004, representing a 10-fold increase in only 20 years.⁷⁵ Of the nearly 290,000 new breast cancers that occur annually, approximately 58,000 are anticipated to be noninvasive, of which 85% will be DCIS.⁷⁶Of these, 90% are expected to be nonpalpable.⁴⁴ Studies have shown that the rate of screen-detected DCIS increases with age despite that it accounts for a progressively smaller proportion of the total breast cancers detected.⁷⁷ The rate of DCIS detection has been reported to increase from 0.56 per 1,000 mammograms among women aged 40 to 49 years to 1.07 per 1,000 mammograms among women aged 70 to 84 years.⁷⁷

Imaging

Ninety-five percent of new cases of DCIS present with mammographic abnormalities, of which microcalcifications are most typical.⁷⁸ Noncalcified mammographic abnormalities make up the remaining findings, with asymmetric densities identified in 10%, dominant masses in 8%, and abnormal galactograms (performed for evaluation of nipple discharge) in 6%. Amorphous, coarse, fine pleomorphic, and fine linear are all forms of calcifications that that can be related to DCIS. Linear and segmental calcifications are considered suspicious distribution and can be associated with DCIS in up to 80% of cases.⁷⁹ Linear and branching calcifications frequently are associated with high-grade DCIS and necrosis, whereas fine and granular calcifications are associated more commonly with low-grade DCIS^80–⁸³ (Fig. 55.1A,B).

Initial evaluation should include magnification views that allow for complete characterization of mammographic findings and determination of the need for biopsy. The extent of the lesion as determined mammographically may be used as a guide for excision; however, the size typically is underestimated by 1 to 2 cm when compared with pathologic measurements.⁸¹^,⁸⁴^,⁸⁵ Prior to 2000, MRI was not considered a useful imaging modality for DCIS. However, change in MRI imaging acquisition and an improved understanding of non-masslike malignant lesion imaging characteristics now has MRI considered a valuable imaging tool for DCIS.⁸⁶ MRI now presents as the imaging modality with the highest sensitivity to detect DCIS, particularly high-grade DCIS. MRI has additionally been shown to better establish the extent of DCIS, thus aiding treatment planning.⁸⁷ In cases that present with nipple discharge and a negative mammogram, galactography may be helpful in determining the likelihood of underlying DCIS versus papilloma⁸⁸ (Fig. 55.1C).

Pathology and Biology

The histologic diversity of DCIS can lead to difficulty in distinguishing it from other pathologic entities.⁶⁹^,⁷⁰ The spectrum of DCIS extends from noncomedo, low-grade DCIS that can be similar in appearance to atypical ductal hyperplasia to comedo, high-grade DCIS. In addition, DCIS can extend into lobules, making it difficult to distinguish from LCIS.⁸⁹ Traditionally, classification of DCIS has followed its architectural or morphologic appearance. The five subtypes of DCIS are comedo, solid, cribriform, micropapillary, and papillary,⁶⁹^,⁷⁰^,⁹⁰ and it is common to encounter a mixture of subtypes within the same specimen.⁸⁸ The characteristic features of each type are shown in Figure 55.2. Less common subtypes have been described and include apocrine, neuroendocrine, signet-cell cystic hypersecretory carcinoma, and clinging DCIS.⁹¹

In 1997, a consensus conference committee was convened to reach an agreement on the pathologic classification of DCIS and the identification of specific features that may convey prognostic significance.⁶⁸ Methods of processing and evaluating the pathologic specimen were also addressed. Rather than endorsing any specific classification system, the committee recommended and described features that should be documented for each case of DCIS, thus separating out important pathologic components and providing a comprehensive evaluation of the pathologic findings. These features include nuclear grade, presence of necrosis, polarization, and architectural pattern(s). The committee extended its recommendations to include margin status, lesion size, extent of microcalcifications, and correlation between specimen x-ray and mammographic findings. The DCIS Working Party of the EORTC arrived at similar conclusions and emphasized the importance of cytonuclear and architectural differentiation.⁹²

Three-dimensional examination and reconstruction techniques have resulted in a better understanding of the enormously complex structure of the mammary duct–lobular system and the patterns by which DCIS can spread within the breast⁶^,⁸⁴^,⁹³ (Fig. 55.3). Knowledge of the anatomy and distribution of DCIS within the mammary ductal tree can be useful in selecting patients for breast conservation and assuring maximal surgical clearance of the lesion while preserving an acceptable cosmetic result. For example, Ohtake et al.⁶^,⁸⁴ studied the duct–lobular system with computer graphic reconstruction and found that the breast consists of 16 to 24 duct–lobular systems, each culminating in a corresponding collecting duct at the nipple. They also identified ductal anastomoses that established a connection between the various ductal–lobular units and provided a potential pathway for tumor extension and subsequent diffuse involvement.⁶^,⁸⁴ Their proposed model for the development of widespread intraductal tumor extension within the breast is seen in Figure 55.4.

Faverly et al.⁹⁴ have described the DCIS growth pattern within the ductal tree and the implications for surgical excision. The growth patterns documented include unicentric (one area only), multicentric (two distinct areas separated by >4 cm), continuous (extension along ductal system without gaps), and discontinuous or multifocal (two or more areas separated by <4 cm). They found that in mammographically detected DCIS, a multicentric growth pattern was rare (<2%), with most cases showing an even distribution between discontinuous and continuous growth patterns. Of cases with a discontinuous growth pattern, 63% had foci separated by gaps that measured <5 mm, 83% had foci separated by <10 mm, and only 8% had foci separated by >10 mm. There was a correlation between differentiation and growth pattern such that 90% of poorly differentiated DCIS showed a continuous growth pattern, whereas 70% of well-differentiated DCIS had a discontinuous growth pattern. Based on these findings, the authors concluded that a 1-cm margin of normal tissue around the lesion would lead to complete surgical clearance of histologically evident DCIS in 90% of cases. DCIS is a precursor lesion to invasive ductal carcinoma and exists along an evolutionary continuum that starts with benign breast tissue and ends with an invasive breast carcinoma.⁹⁵This concept has been validated in several ways. For years, pathologists have recognized and documented confirmation of a histologic progression from benign breast cells to invasive breast cancer. The evolutionary concept is supported by the recognized association between the presence of DCIS and the subsequent increased risk of developing an invasive breast cancer.⁷⁵^,⁹⁶^,⁹⁷ In some series, a 10-fold risk of developing an invasive lesion has been reported. At the biologic and molecular level, many studies have demonstrated that DCIS and invasive breast cancer are highly similar at the cellular and molecular levels.⁹⁵^,⁹⁸^–¹⁰⁰^,¹⁰¹^–¹⁰² These similarities have now been shown to extend to global gene expression profiles as DCIS has been classified under luminal, basal, and erbB2 intrinsic molecular subtypes.⁹⁸^,¹⁰³ Additionally, these shared identical genetic abnormalities between DCIS and synchronous invasive breast cancer demonstrate a clonal relationship of biologic progression.⁷⁵^,⁹⁶^,⁹⁷^,¹⁰⁴ The biologic evolution from benign breast cells to invasive breast cancer occurs through highly diverse genetic mechanisms.

FIGURE 55.1. A: Linear and branching calcifications frequently associated with high-grade ductal carcinoma in situ (DCIS). B: Fine and granular calcifications commonly associated with low-grade DCIS. C: Galactogram with the multiple filling defects associated with DCIS.

FIGURE 55.2. A: Comedo ductal carcinoma in situ (DCIS) characterized by central necrosis, large cells, and poorly differentiated nuclei. B: Solid DCIS characterized by ductal spaces filled with neoplastic cells with limited necrosis. C: Cribriform DCIS characterized by microlumens and fenestrations. D:Micropapillary DCIS characterized by intraluminal projections with no fibrovascular core. E: Papillary DCIS characterized by intraluminal projections with a fibrovascular core.

Genetic and molecular differences have been documented that differentiate DCIS from normal breast tissue. Genetic alterations have been evaluated with an analysis of loss of heterozygosity that has demonstrated gain or loss of multiple loci.⁹⁶^,⁹⁷^,¹⁰⁴^–¹⁰⁶ Loss of heterozygosity is not seen in normal breast tissue. The frequency of loss of heterozygosity correlates with histologic progression of breast tissue from benign to malignant. Loss of heterozygosity is seen in approximately 50% of atypical ductal hyperplasia. Among specimens harvested from cancerous breasts, 77% of noncomedo and 80% of comedo DCIS lesions share loss of heterozygosity with the synchronous invasive lesion in at least one locus.¹⁰⁴

Molecular markers have been studied in DCIS and are found to have a heterogeneous distribution of expression.⁷⁵ The estrogen receptor is present in 70% of DCIS; however, the rate of expression is higher in low-grade lesions (90%) than in high-grade lesions (25%). This association with histologic grade is reversed for the rate of overexpression of HER2/neu proto-oncogene and the p53 tumor suppression gene. Approximately 50% of all DCIS lesions have overexpression of HER2/neu, and in 25% the p53 tumor suppressor gene is also detected. Both of these molecular markers are noted in <20% of low-grade lesions but are present in approximately two-thirds of high-grade lesions.

Alterations in the surrounding breast parenchyma may also be seen with DCIS. High-grade DCIS, in particular, has been associated with the breakdown of the myoepithelial cell layer and basement membrane surrounding the ductal lumen,¹⁰⁷ proliferation of fibroblasts, lymphocyte infiltration, and angiogenesis in the surrounding stromal tissues.¹⁰⁸^,¹⁰⁹ Whether these stromal changes reflect important steps that facilitate primary tumor transformation or secondary alterations in response to ductal epithelium that is being transformed is unknown. Quantitative changes in the expression of genes related to cell motility, adhesion, and extracellular-matrix composition—all of which may be related to the acquisition of invasiveness—occur as DCIS evolves into invasive carcinoma.¹¹⁰

Data suggest that DCIS represents a stage in the development of breast cancer in which most of the molecular changes that characterize invasive breast cancer are already present, although the lesion has not yet assumed a fully malignant phenotype. A final set of events, which probably includes gain of function by malignant cells and loss of function and integrity by surrounding normal tissues, is associated with the transition from a preinvasive DCIS lesion to invasive cancer. Most, if not all, clinically relevant features of breast cancer, such as hormone-receptor status, the level of oncogene expression, and histologic grade, are probably determined by the time that DCIS has evolved.¹¹¹^–¹¹⁴

An occult microinvasive tumor (one that does not exceed 0.1 cm in diameter) may be seen with some cases of DCIS. Such cases are classified as microinvasive breast cancer¹¹⁵ and are generally treated according to the guidelines for invasive disease. Occult microinvasive tumors are most common in patients with DCIS lesions that are >2.5 cm in diameter,¹¹⁶ those presenting with palpable masses or nipple discharge, and those with high-grade DCIS or comedonecrosis.⁸⁸^,¹¹⁷

FIGURE 55.3. All ducts and their branches in an autopsy breast, viewed en face. Each Roman numeral refers to a different independent duct system. (From Going JJ, Moffat DF. Escaping from flatland: clinical and biological aspects of human mammary duct anatomy in three dimensions. J Pathol2004;203:538–544. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

FIGURE 55.4. Models for the formation of widespread intraductal tumor extension over multiple mammary duct–lobular systems. Narrow line, normal mammary duct–lobular systems; bold line, intraductal tumor extension; closed circle, invasive tumor foci. Left: Multicentric development. Middle:Unicentric development with continuous intraductal tumor extension. Right: Unicentric development with continuous intraductal tumor extension through ductal anastomoses connecting adjacent duct–lobular systems. (From Ohtake T, Abe R, Kimijima I, et al. Intraductal extension of primary invasive breast carcinoma treated by breast-conservation surgery. Cancer 1995;76:32–45, with permission. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Natural History of Ductal Carcinoma in Situ

The overall incidence of DCIS in the general population is unclear. In an attempt to address this incidence, a small number of autopsy studies have been reported. One series examined 185 randomly selected breasts from 101 women in which a subgross sampling technique was used¹¹⁸ and one or more foci of DCIS were found in 6% of cases. A review of seven autopsy series of women not known to have breast cancer during life showed a median prevalence of DCIS of 8.9% (range, 0% to 14.7%).¹¹⁹ The fact that some autopsy series document a greater incidence of DCIS in asymptomatic women than most clinical series suggests either the possibility that DCIS is either underdiagnosed or that many cases are not clinically significant.

A primary consideration in the natural history of DCIS is the risk of progression to invasive carcinoma. The published evidence on the clinical course of untreated DCIS is sparse because it has been recognized as a distinct entity for only a relatively brief period, having been considered rare before the widespread use of mammography and having been treated most frequently by mastectomy. Those cases for which long-term follow-up data are available were grossly palpable DCIS—a form that may not be equivalent to the mammographic DCIS that is seen more commonly today. The few published long-term follow-up studies of DCIS after only biopsy document an overall incidence of subsequent invasive carcinoma of >36%.⁷^,¹²⁰^–¹²² Most of these subsequent malignancies occur within 10 years, although as many as one-third may develop after 15 years.⁷^,¹²⁰

Women with DCIS in one breast are at risk for a second tumor (either invasive or in situ) in the contralateral breast¹²³; the rate at which such tumors develop is similar to that among women with primary invasive breast cancer at approximately 0.5% to 1% per year.

DCIS is a part of the breast/ovarian cancer syndromes defined by BRCA1 and BRCA2, with mutation rates similar to those found for invasive breast cancer.¹²⁴ These findings suggest that patients with DCIS with an appropriate personal or family history of breast and/or ovarian cancer should be screened and followed according to the same high-risk protocols as developed for invasive breast cancer.

Treatment Options for Ductal Carcinoma in Situ

Prognostic Factors and Their Interpretation

The goal of treatment with DCIS is prevention of local recurrence, with particular emphasis on the prevention of invasive breast cancer. Treatment decisions are largely based on information provided by mammography and, most especially, pathologic evaluation of the biopsy specimen. As such, in the consideration of treatment options, it is important for the clinician to be aware of some of the technical limitations associated with the clinical and histopathologic assessment of DCIS.

Studies performed during the past two decades clearly have suggested that DCIS is not a single disease. Rather, DCIS encompasses a diverse group of lesions that differ with regard to their clinical presentation, mammographic features, extent and distribution within the breast, histologic characteristics, and biologic markers. Moreover, clinical follow-up studies have indicated that these lesions vary in their propensity to recur or progress to invasive breast cancer. As a consequence, a significant proportion of patients diagnosed with DCIS can be treated adequately with breast-conserving therapy (i.e., excision with or without radiation therapy). Which patients with DCIS can be treated safely with excision alone and which patients require radiation therapy after excision are pressing clinical questions. Attempts to resolve this issue have focused on the identification of risk factors for local recurrence after breast-conservation therapy for DCIS. Through multiple retrospective studies, several factors have been identified that may be important in defining local failure risk. These include symptomatic presentation,¹²⁵^,¹²⁶^–¹²⁷ lesion size,¹²⁷^,¹²⁸histopathologic subtype,¹²⁵ nuclear/cytologic grade,¹²⁶^,¹²⁷^,¹²⁹ central necrosis,¹²⁶^,¹²⁷^,¹²⁹ margin status,¹²⁷^,¹³⁰^,¹³¹ and patient age.¹²⁵^,¹³¹^,¹³²^,¹³³

The relative importance of any histopathologic factor in predicting the probability of local recurrence and, in turn selecting the appropriate therapeutic option for a given patient, is unclear. This is partly the result of the inherent difficulty associated with the establishment of standardized and reproducible systems of pathologic classification, including such apparently straightforward assessments of grade, margin width, and lesion size.

Efforts to classify DCIS have been based primarily on the nuclear grade of the lesion and/or the presence or absence of necrosis. Several studies have shown that there is an association between high nuclear grade and/or necrosis and the risk of local recurrence and progression to invasion.¹²⁶^,¹²⁷^,¹²⁹ Although the criteria for histologic grading systems have been published, there are limited data regarding the ability of pathologists to apply them in a reproducible manner.

Several studies have shown that the status of the microscopic margins appears to be important in predicting the likelihood of recurrence in the breast for patients with both invasive breast cancer and DCIS treated with breast-conserving therapy.¹²⁷^,¹³⁰^,¹³¹ However, there are numerous technical problems in the evaluation of margins of breast-excision specimens. First, if a specimen is removed in more than one fragment, the margins cannot be evaluated. Second, there is no standardized method for sampling or reporting margins, and this process is subject to sampling error. Finally, it is often difficult to provide an accurate assessment of the margin width for patients who undergo a re-excision because the initial biopsy site can be eccentrically located in the surgical specimen.

Most DCIS lesions present as a nonpalpable, grossly inapparent mammographic abnormality, which can make accurate determination of the size or extent of the lesion difficult (Fig. 55.5). The modalities available to assess the size of the lesion are mammography, MRI, and pathologic examination. Mammography frequently will underestimate the pathologic extent of DCIS, particularly for well-differentiated lesions in which substantial areas of the tumor may not contain microcalcifications. MRI has been demonstrated to more accurately estimate the disease extent; however, it should be recognized that pathologic assessment of lesion size can be difficult. Macroscopic examination of a specimen containing DCIS rarely reveals a grossly evident tumor that can be measured. Therefore, the assessment of the size of the lesion must be estimated from histologic sections.

FIGURE 55.5. Extensive ductal carcinoma in situ (DCIS) in a mastectomy breast sectioned in the coronal plane. Every parenchymal structure (duct or lobule) within the marked perimeter is colonized by DCIS; outside that boundary there is none. (From Going JJ, Moffat DF. Escaping from flatland: clinical and biological aspects of human mammary duct anatomy in three dimensions. J Pathol 2004;203:538–544. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)

Mastectomy for Ductal Carcinoma in Situ

Mastectomy was the standard treatment of DCIS through the first four decades of its recognition as a distinct histopathologic entity. Mastectomy is a highly effective treatment for DCIS, with a locoregional control rate of 96% to 100% and cancer-specific mortality rates of ≤4%.¹³⁴ No randomized study has compared mastectomy with breast-conservation treatment for DCIS. Therefore, the relative outcomes for mastectomy and breast-conservation treatment can be estimated only by reviewing nonrandomized, retrospective studies. Local treatment failure after mastectomy¹³⁴ may occur because of unrecognized invasive carcinoma that results in local recurrence or distant metastasis, or it may be the result of incomplete removal of breast tissue with the subsequent formation of a new primary tumor.

Data from some surgical trials¹³⁵ and large treatment registries¹³⁶ suggest that the rates of local or regional recurrence are significantly lower after mastectomy than after breast-conserving surgery, although there have been no significant differences in overall survival. Metastatic breast cancer can follow the recurrence of an invasive tumor or the development of cancer in the contralateral breast. However, death related to breast cancer within 10 years after the diagnosis of DCIS occurs in only 1% to 2% of all patients, irrespective of whether mastectomy or breast-conserving surgery was performed.¹³⁶

The role of postmastectomy chest wall radiation following mastectomy or skin-sparing mastectomy and close pathologic margins has been debated in the literature but is not presently considered the standard of care. Some studies show an increased risk of chest wall failure in selected cases of high-grade DCIS undergoing mastectomy with pathologic margins <1 mm, leading to a routine recommendation of postmastectomy radiation in these cases.¹³⁷ The empiric use of a close or positive margins as a trigger for postmastectomy radiation has been challenged, providing a strong argument against postmastectomy radiation.¹³⁸ This retrospective review evaluated the risk of chest wall recurrence following mastectomy, specifically looking at skin-sparing mastectomy and high-risk features of high-grade and close margins. In this series, the overall risk of chest wall recurrence was rare at 1.7% and only 3.3% for high-grade DCIS. Margins <5 mm were not at increased risk. It was concluded that the chest wall failure rate was sufficiently low that a routine recommendation of postmastectomy radiation DCIS with high-risk features was not warranted.

Breast Conservation for Ductal Carcinoma in Situ

Four prospective randomized studies of excision only versus excision plus breast irradiation for DCIS have been performed with reported results, and all have shown that the rate of local recurrence was reduced with the addition of radiation (Table 55.1). The NSABP B-17 trial¹³⁹^–¹⁴¹ consisted of 813 patients who were stratified by age (≤49 years vs. >49 years), DCIS versus DCIS plus LCIS, method of detection, and whether an axillary dissection was performed. Tumor size was determined by mammogram, gross pathologic measurement, or clinical examination. Of the patients enrolled, 83% had nonpalpable tumors. The 17.5-year rate of local recurrence was 19.8% with radiation and 35.9% without radiation. The average annual incidence rates of ipsilateral noninvasive recurrences and ipsilateral invasive recurrences were reduced with breast irradiation by 47% and 52%, respectively.¹⁴¹ An analysis of clinical variables showed that microcalcifications extending beyond a maximum dimension >1 cm were associated with an elevated risk of breast recurrence. A central pathology review was performed, including a multivariate analysis of histopathologic variables (Table 55.2). Comedonecrosis in patients treated on NSABP B-24 did not correlate with an increased risk of IBTR; however, comedonecrosis did relate to the risk of DCIS-IBTR. The prognostic value of margin status (free vs. unknown/involved) depended on the treatment group and was greater among those treated with lumpectomy and radiotherapy alone as compared to those that also received tamoxifen.¹³²^,¹⁴⁰^,¹⁴¹

The EORTC 10853 trial¹⁴²^,¹⁴³ randomly allocated 1,010 patients with ≤5 cm DCIS and negative margins to excision versus excision plus breast irradiation. Lesions were nonpalpable in 79% of patients, and the mean maximal tumor diameter was approximately 2 cm. The 10-year rate of local recurrence was 15% for patients treated with radiation, as compared with 25% for patients treated without radiation (p <.0001). At a median follow-up of 10.2 years, radiation therapy resulted in risk reduction for both invasive and noninvasive breast relapse of 42%. As with the NSABP B-17 study, a central pathology review was performed.¹²⁵^,¹⁴² In a multivariate analysis, factors associated with an increased risk of local recurrence were ≤40 years of age, clinically symptomatic presentation (nipple discharge or palpable mass), intermediate or poorly differentiated DCIS, solid/comedo and cribriform histologic growth pattern, involved or uncertain margins, and treatment by local excision alone. The risk of DCIS recurrence was documented to be less following treatment of well-differentiated DCIS as compared to intermediate and poorly differentiated DCIS; however, there was no difference seen in invasive recurrence. Although early publications suggested a relationship between histologic type and risk of distant metastasis and death, with additional follow-up no statistically significant relationship is now appreciated.

The EORTC 10853 trial did not allow the identification of an appropriate margin width for treatment with or without radiotherapy because the eligibility criteria did not require reporting of the margin status. Nonetheless, the central review of cases did provide some information regarding the relative importance of surgical margin as related to local failure risk. A recurrence rate of 24% at 4 years was observed in cases with close/involved margins after excision alone. Radiotherapy was not adequate to compensate for involved margins because even with the application of irradiation, the recurrence rate was 20% in this group. These data and others¹²⁷^,¹²⁸^,¹³⁰^,¹³¹ are strongly suggestive that obtaining a microscopic complete excision is essential for optimal local control in breast-conserving therapy for DCIS. Of further note, even in the group of DCIS cases for which margins could be considered optimal (i.e., those patients who underwent a surgical re-excision in which no residual DCIS was found), a 4-year local recurrence rate of 18% was observed when these patients were treated with surgery alone.¹²⁵

TABLE 55.1 LUMPECTOMY VERSUS LUMPECTOMY AND WHOLE-BREAST RADIOTHERAPY: RANDOMIZED CLINICAL TRIALS FOR DUCTAL CARCINOMA IN SITU

TABLE 55.2 HAZARD RATIOS FOR INVASIVE IPSILATERAL BREAST TUMOR (I-IBTR) RECURRENCE OR DUCTAL CARCINOMA IN SITU (DCIS-IBTR) BASED ON COMEDONECROSIS AND MARGIN STATUS ADAPTED FROM NSABP B-17 AND B-24

The United Kingdom, Australia, and New Zealand (UK/ANZ) DCIS trial is a randomized trial investigating the role of adjuvant radiotherapy.¹⁴⁴^,¹⁴⁵ With a 2 × 2 factorial protocol design, the aim of this study was to compare excision alone versus excision plus tamoxifen versus excision plus radiotherapy versus excision plus radiotherapy and tamoxifen. Tamoxifen was prescribed as 20 mg per day, and radiotherapy was delivered through whole-breast tangential fields to a total dose of 50 Gy. Boost was not recommended, and elective decision to withhold or provide one of the treatments was permitted. Data has been reported with a median follow-up of 12.7 years. The addition of radiotherapy was demonstrated to reduce the risk of IBTR. Of the 1,030 patients randomized between no radiotherapy versus radiotherapy, ipsilateral IBTR was 19.4% versus 7.1%, respectively (p <.0001). The addition of tamoxifen offered no benefit toward overall ipsilateral local control when administered in addition to radiotherapy; however, tamoxifen did appear to reduce the ipsilateral recurrence rate of DCIS (but not invasive carcinoma) in the absence of radiotherapy.¹⁴⁴^,¹⁴⁵

The Swedish Breast Cancer Group SweDCIS study was a randomized trial that enrolled 1,067 patients from 1987 to 1999, with 1,046 of these patients followed for a mean of 8 years. Patients were randomized between lumpectomy followed by radiotherapy and lumpectomy only for treatment of DCIS.¹⁴⁶ Following a sector resection, microscopic clear resection was not required, and 50 Gy in 25 fractions to the whole breast was delivered in the majority of patients. A split course, 54 Gy in 2-Gy fractions, delivered in two treatment series separated by a 2 week break was allowed. No boost dose was delivered. The in-breast failure risk reduction is reported as 16% at 10 years (95% confidence interval [CI] 10.3% to 21.6%) with a relative risk of 0.40 (95% CI 0.30 to 0.54). Detailed analysis did not identify any patient or tumor characteristic subgroups that did not benefit in risk reduction from the addition of postoperative radiotherapy. Additionally, despite combining factors entailing a low risk of recurrence without radiotherapy, a low-risk group that did not significantly benefit from the addition of radiotherapy could not be identified.

A meta-analysis was completed utilizing the individual patient data from each of the four randomized trials mentioned, and an overview of results was reported by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).¹⁴⁷ With a total of 3,729 women eligible for analysis, it was demonstrated that radiotherapy reduced the absolute 10-year risk of any ipsilateral breast event (recurrent DCIS or invasive disease) by 15.2% (standard error [SE] 1.6%, 12.9% vs. 28.1%, 2 p <.00001). This analysis further establishes strong and consistent evidence that the addition of radiotherapy following breast-conserving surgery for DCIS approximately reduces the risk of IBTR by 50%. Subgroup analyses from these randomized trials have demonstrated that the absolute benefits of radiotherapy are greater in women at increased risk for tumor recurrence, such as women with involved surgical margins (identified on retrospective pathologic review), younger women, and those with tumors that have high-grade or comedonecrotic features.¹²⁵^,¹³⁹^,¹⁴⁰^,¹⁴²^,¹⁴⁷ However, this meta-analysis confirms that no matter what the underlying rate of ipsilateral IBTR is within subgroups evaluated, the risk reduction of approximately 50% remained. This was demonstrated across categories defined by patient age, type of excision, use of tamoxifen, method of detection, margin status, tumor focality, and histologic or nuclear grade. There was little impact of radiotherapy on contralateral or distant events and a difference in the risk of death from breast cancer was not appreciated.

Patient age is an important prognostic variable for local recurrence after breast conservation for DCIS.¹²⁵^,¹³¹^,¹³²^,¹³³ In younger patients, DCIS more frequently contains adverse prognostic pathologic features and extends over a greater distance in the breast than in older patients.¹³³ In series with adequate follow-up, younger patients treated with lumpectomy and radiation therapy had a significantly higher rate of local recurrence than older patients, especially for invasive local recurrences.¹³³ Some studies have suggested that careful attention to margin status and excising larger volumes of tissue can reduce this difference substantially.¹³¹^,¹³³ No available data show that younger patients have better long-term cancer-free survival rates if treated by mastectomy rather than lumpectomy and radiation therapy. Successful treatment of younger patients with DCIS with lumpectomy and radiation therapy requires careful attention to patient evaluation, selection, and surgical technique. When this is done, age at diagnosis should not be a contraindication to breast-conserving therapy.

The randomized trials discussed were designed and conducted over a decade ago. Since then, imaging technology, surgical techniques, and pathologic evaluation have continued to advance, suggesting that the patients encountered with DCIS presently may represent a group a patients with smaller, less extensive disease that is better surgically cleared as compared to those included in the randomized trials. As a result, the value of adjuvant radiotherapy has been hypothesized to be lower than indicated in previous trials. However, it should be noted that the tumor characteristics of those included in the randomized trials represented limited and mammographically detected disease. Despite this, several recent studies have attempted to identify and treat patients with highly selected favorable tumor characteristics with excision alone (i.e., without whole-breast irradiation) and report 10-year local failure rates of 3% to 25%.¹³⁰^,¹³⁴ One of these studies¹²⁸ has proposed a scoring system using histopathologic features including tumor size, grade, and margin width in an attempt to stratify patients according to local failure risk after excision plus or minus whole-breast irradiation. Each variable was assigned a score of 1 to 3, and the sum total defined the Van Nuys Prognostic Index. Although appealingly simple, this scheme¹²⁸ is drawn from the retrospective analysis of a patient cohort in which there exist several methodologic shortcomings, and it has not been independently validated.¹⁴⁸

Wong et al.¹⁴⁹ performed a prospective study that attempted to identify patients with “low-risk” DCIS who can be spared whole-breast radiation therapy. This trial enrolled 158 patients with lesions that were mostly grade 1 or 2 and with a mammographic extent of ≤2.5 cm who were treated with wide excision, with final margins of ≥1 cm or a re-excision without residual DCIS. Tamoxifen was not permitted. The median age was 51 years. The most recent data, with a median follow-up of 10 years,¹⁵⁰ reports an estimated annual percentage rate of 2.1% local recurrence. Of those with an IBTR, 68% had a DCIS recurrence and 32% experienced recurrence with invasive carcinoma. These data provide prospective evidence that despite margins of >1 cm, the local recurrence rate is substantial even in patients with small grade 1 or 2 DCIS following treatment with wide excision alone.

In an intergroup trial run by the Eastern Cooperative Oncology Group and North Central Cancer Treatment Group, wide excision only in a population of conservatively selected patients with DCIS was evaluated.¹⁵¹ Eligibility included patients with low- or intermediate-grade DCIS measuring ≤2.5 cm or high-grade DCIS measuring ≤1 cm. Microscopic margin width was required to be ≥3 mm with no residual calcifications on postoperative mammograms. The majority of these patients had a more favorable profile than that reflected by the eligibility criteria with median lesion size of 6 mm and the majority having margins >5 mm. Additionally, after 2000, patients had the choice of taking tamoxifen, potentially impacting recurrence rates and/or time to recurrence intervals. In the study, 565 patients were evaluable, and with a median follow-up of 6.2 years, the 5-year rate of ipsilateral in-breast failure was 6.1% in the low-intermediate grade group and 15.3% in the high-grade group. Whether this identifies the low-intermediate grade group as a group that could avoid radiotherapy remains to be demonstrated, as this may represent a group with a delayed IBTR pattern. The Radiation Therapy Oncology Group conducted a prospective randomized trial to further assess the need for radiotherapy in low-risk DCIS. Following lumpectomy with ≥3-mm clear margins of resection, patients were stratified according to age (<50 vs. ≥50 years), tumor size (≤1 vs. >1 to 2.5 cm), margin status (negative re-excision vs. 3 to 9 mm vs. ≥10 mm), grade, and the use of tamoxifen (at the discretion of the managing physician). Following stratification, patients were randomized to whole-breast irradiation versus observation. This trial closed early due to accrual rate, enrolling 636 of the planned 1,800 patients. Meaningful results may be possible but have not yet been presented to date. The NSABP and Radiation Therapy Oncology Group have jointly launched a phase III accelerated partial-breast irradiation trial that randomly allocates patients between standard whole-breast irradiation following lumpectomy versus accelerated partial-breast irradiation to determine if in-breast control rates are comparable. As the in-breast failure patterns for DCIS suggest that treatment directed to the primary lesion plus a 2-cm margin should achieve local control rates that equate to whole-breast treatment approaches, patients with pure DCIS or DCIS and LCIS are eligible for stratified randomization.

Follow-Up and Management of Recurrence

Ipsilateral tumor recurrences in patients with DCIS are usually detected on surveillance mammography, although one-quarter may be detected on the basis of changes on physical examination of the breast or chest wall.¹⁵²^,¹⁵³ For this reason, patients should be scheduled for a baseline mammogram 6 to 12 months after initial therapy and at least annually thereafter. Distant breast cancer metastases in the absence of regional recurrence are unusual. Local recurrences after breast-conserving surgery and radiotherapy are generally treated with mastectomy. Selected patients with local recurrences who have not previously received radiotherapy may be candidates for local excision and radiotherapy. The clinical outcome of ipsilateral tumor recurrence is governed by the nature of the recurrence. Patients with recurrent DCIS have an excellent prognosis, with <1% risk of further recurrence after salvage mastectomy. Patients with invasive recurrence after breast-conserving surgery for DCIS have a prognosis similar to those with early-stage breast cancer, with a 15% to 20% risk of metastatic recurrence at 8 years.¹⁵³

TABLE 55.3 TAMOXIFEN VERSUS NO TAMOXIFEN: RANDOMIZED CLINICAL TRIALS FOR DUCTAL CARCINOMA IN SITU

The Role of Tamoxifen for Ductal Carcinoma in Situ

The use of tamoxifen in the treatment of DCIS has been studied; however, results have been conflicting. Therefore, its role is not yet clearly defined. Additional studies are being conducted evaluating the role of aromatase inhibitors,¹⁵⁴^,¹⁵⁵ and Her2Neu targeted treatment is presently being investigated in the NSABP B-43 trial. In this prospective randomized trial, patients with Her2Neu-positive DCIS are treated with postlumpectomy radiotherapy and randomized between herceptin or observation. The NSABP B-24 trial¹³²^,¹⁴¹ compared excision plus radiotherapy to excision, radiotherapy, and tamoxifen. Patients who received tamoxifen had a decreased incidence of breast cancer events (invasive or noninvasive ipsilateral or contralateral breast cancer) compared with patients who did not receive tamoxifen. With a median follow-up of 163 months, the addition of tamoxifen translated into a significant 32% reduction in invasive IBTR (9.0% vs. 6.6%, p = .025), a nonsignificant 16% reduction in DCIS-IBTR (7.6% vs. 6.7%, p = .33), and a 32% reduction in contralateral breast cancer (8.1% vs. 4.9%, p = .023); however, no survival benefit was found (Table 55.3). Positive tumor margins were significantly associated with breast recurrence. The 15-year cumulative incidence of invasive IBTR was reduced from 17.4% in patients with positive margins to 11.5% with the addition of tamoxifen. In those with tumor-free margins, tamoxifen did not improve in-breast disease control with a 7.4% and 7.5% incidence of invasive IBTR with and without tamoxifen, respectively.

In contrast to the findings of the NSABP B-24 trial, the UK/ANZ DCIS trial found that tamoxifen had no effect in reducing local recurrence rate when combined with whole-breast radiation therapy (Table 55.3). When used as single agent without radiation therapy after lumpectomy, tamoxifen had no effect on the incidence of invasive recurrence but did show a statistically significant reduction in the risk of DCIS recurrence (10.4% vs. 7.4%, p =.04).¹⁴⁴^,¹⁴⁵ As such, the role of tamoxifen for DCIS in the absence of whole-breast radiotherapy remains to be defined.

Because DCIS is a precursor to invasive breast cancer and shares many biologic features of invasive carcinoma, it is increasingly recognized as a target for preventive measures. In the largest trials of the prevention of primary breast cancer among women at high risk for breast cancer by virtue of age, family history, or prior benign breast disease, tamoxifen reduced the risk of DCIS by 50% to 70%.³⁹^,¹⁵⁶

A Decision Tree for Ductal Carcinoma in Situ

The management of DCIS requires the coordinated, multidisciplinary interaction of radiologists, surgeons, pathologists, and oncologists. Patients are first assessed to determine if they are candidates for breast-conserving surgery. Women with multicentric DCIS, as defined by the presence of two or more tumors in separate quadrants of the breast, and those with extensive or diffuse DCIS or suspicious-appearing microcalcifications throughout the breast are candidates for mastectomy, as are women in whom negative margins or acceptable cosmesis cannot be achieved with the use of breast-conserving surgery. Some women may prefer mastectomy to breast conservation to minimize the chance of ipsilateral recurrence or for other reasons.

Patients deemed to be appropriate candidates for breast conservation require complete surgical excision of the affected area. The extent of DCIS in the breast and the existing margin determine the likelihood of identifying residual disease on re-excision. Nearly half of patients with margins <1 mm have residual DCIS on re-excision.³⁷ However, the optimal margin width for the management of DCIS is not known. At a minimum, there should be no tumor at the margin.

Neither dissection of axillary lymph nodes nor mapping of sentinel lymph nodes is routinely warranted in patients with DCIS because of the very low incidence of axillary metastases.¹⁵⁷ Three to 13% of patients with DCIS, and a slightly greater percentage with DCIS and microinvasion, have isolated tumor cells in sentinel axillary lymph nodes.¹⁵⁸ The prognostic significance of these cells is not clear. Clinical experience suggests that patients have a much better outcome than would be predicted by such rates of nodal metastases, and most instances represent micrometastases of unclear metastatic potential. However, sentinel lymph node mapping may be used in selected patients with a higher likelihood of occult invasive cancer—those with extensive, high-grade DCIS or palpable masses—and those undergoing mastectomy as sentinel node mapping cannot be performed afterward if invasive tumor is identified.¹⁵⁹

After breast-conserving surgery, radiotherapy is administered using tangential fields to the whole breast with a standard dose of 45 to 50 Gy delivered in daily fractions of 180 to 200 cGy. On the basis of extrapolation from data on the treatment of invasive breast cancer,¹⁶⁰ a radiation boost to the tumor bed may be added to whole-breast treatment, particularly for women with close surgical margins, although the benefit of a boost in the management of DCIS is not established. There is no role for postmastectomy or nodal irradiation in the treatment of DCIS.

It is not yet possible to prospectively identify women who are at sufficiently low risk that radiotherapy may not be of some clinical advantage in preventing recurrences. After discussing the various options, patients may elect not to receive radiation treatment; however, they must understand and accept the increased risk of recurrence that this choice probably entails.

In summary, despite considerable advances in our clinical knowledge base, the answer to the question “when should radiotherapy be used for DCIS?” remains complex and surrounded by considerable controversy. Two fundamental considerations must be emphasized:

1. A primary goal of breast-conserving therapy for DCIS is to achieve the best possible cosmetic outcome. Attempts to obtain wide surgical margins through deforming, large-volume breast excisions represent cosmetic failures and defeat the purpose of breast conservation.

2. Breast irradiation reduces the risk of subsequent invasive or noninvasive carcinoma in the treated breast and thus reduces the risk of the ultimate cosmetic failure— mastectomy.

According to prospectively randomized trials of breast-conserving therapy for DCIS, radiotherapy reduces subsequent breast recurrence in all patient groups irrespective of prognostic risk factors. That is not to say, however, that radiotherapy must be used for all patients with DCIS. In all cases, a realistic and balanced discussion of the relative risks and benefits of treatment options should be presented to the patient. Reasonable estimates of breast recurrence during the ensuing decade with or without radiotherapy are available based on level I evidence from prospective clinical trials. A decision tree to assist in the selection of treatment options is presented in Table 55.4.

TABLE 55.4 MANAGEMENT SCHEME FOR DUCTAL CARCINOMA IN SITU

REFERENCES

1. Page DL, Kidd TE, Dupont WD, et al. Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease. Hum Pathol 1991;22:1232–1239.

2. Tavassoli FA. Lobular neoplasia. In: Tavassoli FA. Pathology of the breast, 2 nd ed. New York: Elsevier, 1999:373–400.

3. Frykberg ER, Bland KI. In situ breast carcinoma. Adv Surg 1993;26:29–72.

4. Schnitt SJ, Morrow M. Lobular carcinoma in situ: current concepts and controversies. Semin Diagn Pathol 1999;16:209–223.

5. Lagios MD, Westdahl PR, Marye RR, et al. Paget’s disease of the nipple. Cancer 1984;54:545–551.

6. Ohtake T, Abe R, Kimijima I, et al. Intraductal extension of primary invasive breast carcinoma treated by breast—conservation surgery. Cancer 1995;76:32–45.

7. Sanders ME, Schuyler PA, Dupont WD, et al. The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer 2005;103:2481–2484.

8. Acs G, Lawton TJ, Rebbeck TR, et al. Differential expression of E-cadherin in lobular and ductal neoplasms of the breast and its biologic and diagnostic implications. Am J Clin Pathol 2001;115:85–98.

9. Albonico G, Querzoli P, Ferretti S, et al. Biological profile of in situ breast cancer investigated by immunohistochemical technique. Cancer Detect Prev 1998;22:313–318.

10. Bur ME, Zimarowski MJ, Schmitt SJ, et al. Estrogen receptor immunohistochemistry in carcinoma in situ of the breast. Cancer 1992;69:1174–1181.

11. Jacobs TW, Pliss N, Kouria G. Carcinomas in situ of the breast with indeterminate features. Am J Surg Pathol 2001;25:229–236.

12. Vos CB, Cleton-Jansen AM, Verx G, et al. E-cadherin inactivation in lobular carcinoma in situ of the breast: an early event in tumorigenesis. Br J Cancer 1997;76:1131–1133.

13. Andersen JA. Lobular carcinoma in situ of the breast—an approach to rational treatment. Cancer 1977;39:2597–2602.

14. Haagensen CD, Bodian C, Haagensen DE. Lobular neoplasia (lobular carcinoma in situ). Breast carcinoma: risk and detection. Philadelphia, PA: WB Saunders, 1981:238–292.

15. Wheeler JE, Enterline HT, Roseman JM, et al. Lobular carcinoma in situ of the breast—long term follow-up. Cancer 1974;34:554–563.

16. Rosen PP, Kosloff C, Lieberman PH, et al. Lobular carcinoma in situ of the breast. Detailed analysis of 99 patients with average follow-up of 24 years. Am J Surg Pathol 1978;2:225–251.

17. Trentham-Dietz A, Newcomb PA, Storer BE, et al. Risk factors for carcinoma in situ of the breast. Cancer Epidemiol Biomarkers Prev 2000;9:697–703.

18. Georgian-Smith D, Lawton TJ. Calcifications of lobular carcinoma in situ of the breast: radiologic-pathologic correlation. Am J Roentgenol 2001;176:1255–1259.

19. Sapino A, Frigerio A, Peterse JL, et al. Mammographically detected in situ lobular carcinomas of the breast. Virchows Arch 2000;436:421–430.

20. Sonnenfeld MR, Frenna TH, Weidner N, et al. Lobular carcinoma in situ: mammographic-pathologic correlation of results of needle-directed biopsy. Radiology 1991;181:363–367.

21. Cohen MA. Cancer upgrades at excisional biopsy after diagnosis of atypical lobular hyperplasia or lobular carcinoma in situ core-needle biopsy: some reasons why. Radiology 2004;231:617–621.

22. Foster MC, Helvie MA, Gregory NE, et al. Lobular carcinoma in situ or atypical lobular hyperplasia at core-needle biopsy: is excisional biopsy necessary? Radiology 2004;231:813–819.

23. Liberman L, Sama M, Susnik B, et al. Lobular carcinoma in situ at percutaneous breast biopsy: surgical biopsy findings. Am J Roentgenol 1999;173:219–299.

24. Ottesen GL, Graversen HP, Blichert-Toft M, et al. Carcinoma in situ of the female breast. 10 year follow-up results of a prospective nationwide study. Breast Cancer Res Treat 2000;62:197–210.

25. Chuba PJ, Hamre MR, Yap J, et al. Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of surveillance, epidemiology, and end results data. J Clin Oncol 2005;23:5534–5541.

26. Hwang ES, Nyante SJ, Chen YY, et al. Clonality of lobular carcinoma in situ and synchronous invasive lobular carcinoma. Cancer 2004;100:2562–2572.

27. Ben-David MA, Kleer CG, Paramagul C, et al. Is lobular carcinoma in situ as a component of breast carcinoma a risk factor for local failure after breast-conserving therapy? Cancer 2006;106:28–34.

28. Fisher ER, Land SR, Fisher B, et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project—twelve-year observations concerning lobular carcinoma in situ. Cancer2004;100:238–244.

29. Friedlander LC, Roth SO, Gavenonis SC. Results of MR imaging screening for breast cancer in high-risk patients with lobular carcinoma in situ. Radiology 2011;261(2):421–427.

30. Port ER, Park A, Borgen PI, et al. Results of MRI screening for breast cancer in high risk patients with LCIS and atypical hyperplasia Ann Surg Oncol 2007;14:1051–1057.

31. Sung JS, Malak SF, Bajaj P, et al. Screening breast MR imaging in women with a history of lobular carcinoma in situ. Radiology 2011;261(2):414–420.

32. Abner AL, Connolly JL, Recht A, et al. The relationship between the presence and extent of lobular carcinoma in situ and the risk of local recurrence for patients with infiltrating carcinoma of the breast treated with conservative surgery and radiation therapy. Cancer 2000;88:1072–1077.

33. Moran M, Haffty B. Lobular carcinoma in situ as a component of breast cancer: the long-term outcome in patients treated with breast-conservation therapy. Int J Radiat Oncol Biol Phys 1998;40:353–358.

34. Sasson AR, Fowble B, Hanlon AL, et al. Lobular carcinoma in situ increases the risk of local recurrence in selected patients with stages I and II breast carcinoma treated with conservative surgery and radiation. Cancer2001;91:1862–1869.

35. Jolly S, Kestin LL, Goldstein NS, et al. The impact of lobular carcinoma in situ in association with invasive breast cancer on the rate of local recurrence in patients with early-stage breast cancer treated with breast-conserving therapy Int J Radiat Oncol Biol Phys 2006;66:365–371.

36. Ciocca RM, Li T, Freedman GM, et al. Presence of lobular carcinoma in situ does not increase local recurrence in patients treated with breast-conserving therapy. Ann Surg Oncol 2008;15:2263–2271.

37. Neuschatz AC, DiPetrillo T, Steinhoff M, et al. The value of breast lumpectomy margin assessment as a predictor of residual tumor burden in ductal carcinoma in situ of the breast. Cancer 2002;94:1917–1924.

38. Foote FW, Stewart FW. Lobular carcinoma in situ—a rare form of mammary cancer. Am J Pathol 1941;17:491–495.

39. Fisher B, Costantino J, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 1998;90:1371–1388.

40. Vogel VG, Costantino JP, Wickerham DL, et al. National Surgical Adjuvant Breast and Bowel Project update: prevention trials and endocrine therapy of ductal carcinoma in situ. Clin Cancer Res2003;9:495 S–501 S.

41. Paget J. On the disease of the mammary areola preceding cancer of the mammary gland. St Bartholomew Hosp Rep 1874;10:87–89.

42. Lloyd J, Flanagan AM. Mammary and extramammary Paget’s disease. J Clin Pathol 2000;53:742–749.

43. Desai DC, Brennan EJ, Carp NZ. Paget’s disease of the male breast. Am Surg 1996;62:1068–1072.

44. Ernster VL, Barclay J, Kerlikowske K, et al. Incidence of and treatment for ductal carcinoma in situ of the breast. JAMA 1996;275:913–918.

45. Jamali FR, Ricci A, Deckers PJ. Paget’s disease of the nipple-areola complex. Surg Clin North Am 1996;76:365–381.

46. Sakorafas GH, Blanchard K, Sarr MG, et al. Paget’s disease of the breast. Cancer Treat Rev 2001;27:9–18.

47. Hayes R, Cummings B, Miller RAW, et al. Male Paget’s disease of the breast. J Cutan Med Surg 2000;4:208–212.

48. Markpoulos CH, Gogas H, Sampalis F, et al. Bilateral Paget’s disease of the breast. Eur J Gynaecol Oncol 1997;18:495–496.

49. Ward KA, Burton JL. Dermatological diseases of the breast in young women. Clin Dermatol 1997;15:45–52.

50. Inwang ER, Fentiman IS. Paget’s disease of the nipple. Br J Hosp Med 1990;44:392–395.

51. Kohler S, Rouse RV, Smoller BR. The differential diagnosis of pagetoid cells in the epidermis. Mod Pathol 1998;11:79–92.

52. Chaudary MA, Millis RR, Lane B, et al. Paget’s disease of the nipple: a ten year review including clinical, pathological, and immunohistochemical findings. Breast Cancer Res Treat 1986;8:139–146.

53. Ikeda DM, Helvie MA, Frank TS, et al. Paget disease of the nipple: radiologic-pathologic correlation. Radiology 1993;189:89–94.

54. Ashikari R, Park K, Huvos AG, et al. Paget’s disease of the breast. Cancer 1970;26:680–685.

55. Kawase K, DiMaio DJ, Tucker SL, et al. Pagets disease of the breast: there is a role for breast conserving therapy Ann Surg Oncol 2005;12:1–7.

56. Paone JF, Baker RR. Pathogenesis and treatment of Paget’s disease of the breast. Cancer 1981;48:825–829.

57. Yim JH, Wick MR, Philpott GW, et al. Underlying pathology in mammary Paget’s disease. Ann Surg Oncol 1997;4:287–292.

58. Dixon AR, Galea RR. Pathogenesis and treatment of Paget’s disease of the breast. Cancer 1981;48:825–829.

59. Fischer B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med2002;347:1233–1241.

60. Fourquet A, Campana F, Vielh P, et al. Paget’s disease of the nipple without detectable breast tumor: conservative management with radiation therapy. Int J Radiat Oncol Biol Phys 1987;13:1463–1465.

61. Polgar C, Orosz Z, Kovacs T, et al. Breast-conserving therapy for Paget disease of the nipple. Cancer 2002;94:1904–1905.

62. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of randomized study comparing breast-conserving surgery with radical (Halstead) mastectomy for early breast cancer. N Engl J Med2002;347:1227–1232.

63. Stockdale AD, Brierly JD, White WF, et al. Radiotherapy for Paget’s disease of the nipple: a conservative alternative. Lancet 1989;2:664–666.

64. Bijker N, Rutgers EJT, Duchateau L, et al. Breast-conserving therapy for Paget disease of the nipple. Cancer 2001;91:472–477.

65. Marshall JK, Griffith KA, Haffty BG, et al. Conservative management of Paget disease of the breast with radiotherapy. Cancer 2003;97:2142–2149.

66. Pierce LJ, Haffty BG, Solin LJ, et al. The conservative management of Paget’s disease of the breast with radiotherapy. Cancer 1997;80:1065–1072.

67. Catzavelos C. Part III. The pathobiology of ductal carcinoma in situ. Curr Probl Cancer 2000;24:125–140.

68. Consensus conference on the classification of ductal carcinoma in situ. Cancer 1997;80:1798–1802.

69. Page DL, Anderson TJ. Diagnostic histopathology of the breast. Edinburgh, Scotland: Churchill Livingstone, 1987.

70. Rosen PP. Rosen’s breast pathology. Philadelphia, PA: Lippincott Raven; 1997:237–245.

71. Silverstein MJ. Current management of noninvasive (in situ) breast cancer. Adv Surg 2000;34:17–41.

72. Lenhard RE. Cancer statistics, a measure of progress. CA Cancer J Clin 1996;46:3–7.

73. Simon MS, Lemanne D, Schwartz AG, et al. Recent trends in the incidence of in situ and invasive breast cancer in the Detroit Metropolitan area (1975–1988). Cancer 1993;71:769–774.

74. Simon MS, Schwartz AG, Martino S, et al. Trends in the diagnosis of in situ breast cancer in the Detroit Metropolitan area, 1973 to 1987. Cancer 1992;69:466–469.

75. Burstein HJ, Polyak K, Wong JS, et al. Ductal carcinoma in situ of the breast. N Engl J Med 2004;350:1430–1441.

76. American Cancer Society. Cancer facts and figures. Atlanta, GA: American Cancer Society, 2011.

77. Ernster VL, Ballard-Barbash R, Barlow WE, et al. Detection of ductal carcinoma in situ in women undergoing screening mammography. J Natl Cancer Inst 2002;94:1546–1554.

78. Tabar L, Gad A, Parsons WC, et al. Mammographic appearances of in situ carcinomas. In: Silverstein MJ, ed. Ductal carcinoma in situ of the breast. Baltimore, MD: Williams & Wilkins, 1997:413–420.

79. D’Orsi CJ. Imaging for the diagnosis and management of ductal carcinoma in situ. J Natl Cancer Inst Mongr 2010;2010(4):214–217.

80. Dinkel H-P, Gassel AM, Tschammler A. Is the appearance of microcalcifications on mammography useful in predicting histological grade of malignancy in ductal cancer in situ? Br J Radiol 2000;73:938–944.

81. Holland R, Hendriks J, Verbeek A, et al. Extent, distribution and mammographic/histological correlations of breast ductal carcinoma in situ. Lancet 1990;335:519–522.

82. Recht A, Rutgers EJ, Fentiman IS, et al. The fourth EORTC DCIS consensus meeting (Chateau Marguette, Heemskerk, The Netherlands 23–24 January 1998)—conference report. Eur J Cancer1998;34:1664–1669.

83. Wright B, Shumak R. Part II. Medical imaging of ductal carcinoma in situ. Curr Probl Cancer 2000;24:112–124.

84. Ohtake T, Kimijima I, Fukushima T, et al. Computer-assisted complete three-dimensional reconstruction of the mammary ductal/lobular systems. Cancer 2001;91:2263–2272.

85. Satake H, Shimamoto K, Sawaki A, et al. Role of ultrasonography in the detection of intraductal spread of breast cancer: correlation with pathologic findings, mammography and MR imaging. Eur Radiol2000;10:1726–1732.

86. Lehman CD. Magnetic resonance imaging in the evaluation of ductal carcinoma in situ. J Natl Cancer Inst Monogr 2010;(4):214–217.

87. Berg WA, Gutierrez L, Nessairer MS, et al. Diagnositic accuracy of mammography, US, and MR imaging in preoperative assessment of breast cancer. Radiology 2004;133:830–849.

88. Patchefsky AS, Schwartz GF, Finkelstein SD, et al. Heterogeneity of intraductal carcinoma of the breast. Cancer 1989;63:731–741.

89. Fechner RE. Epithelial alterations in the extralobular ducts of breasts with lobular carcinoma. Arch Pathol 1972;93:164–171.

90. Azzopardi JG. Problems in breast pathology. Philadelphia, PA: WB Saunders, 1983.

91. Lagios MD. Ductal carcinoma in situ: controversies in diagnosis, biology, and treatment. Breast J 1995;1:68–78.

92. Recht A, van Dongen JA, Fentimen IS, et al. Third meeting of the DCIS Working Party of the EORTC (Fondazione Cini, Isola s. Giorgio, Venezia, 28 February 1994)—conference report. Eur J Cancer1994;30 A:1895–1901.

93. Going JJ, Moffat DF. Escaping from Flatland: clinical and biological aspects of human mammary duct anatomy in three dimensions. J Pathol 2004;203:538–544.

94. Faverly DRG, Burgers L, Bult P, et al. Three dimensional imaging of mammary ductal carcinoma in situ; clinical implications. Semin Diagn Pathol 1994;11:193–198.

95. Allred DC, Mohsin SK, Fuqua SAW. Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer 2001;8:47–61.

96. Radford DM, Phillips NHJ, Fair KL, et al. Allelic loss and the progression of breast cancer. Cancer Res 1995;55:5180–5183.

97. Stratton MR, Collins N, Lakhani SR, et al. Loss of heterozygosity in ductal carcinoma in situ of the breast. J Pathol 1995;175:195–201.

98. Allred DC. Ductal carcinoma in situ: terminology, classification and natural history. J Natl Cancer Inst Monogr 2010;2010(41):134–138.

99. Hannemann J, Velds A, Halfwerk JB, et al Classification of ductal carcinoma in situ by gene expression profiling. Breast Cancer Res 2006;8(5):R61.

100. Kuerer HM, Albarracin CT, Yang WT, et al. Ductal carcinoma in situ: state of the science and roadmap to advance the field. J Clin Oncol 2009;27:279–288.

101. Ma XJ, Salunga R, Tuggle JT, et al. Gene expression profiles of human breast cancer progression. Proc Natl Acad Sci U S A. 2003;100(10):5974–5979.

102. Porter D, Lahti-Domenici J, Keshaviah A, et al. Molecular markers in ductal carcinoma in situ of the breast. Mol Cancer Res 2003;1(5):362–375.

103. Allred DC, Wu Y, Mao S, et al. Ductal carcinoma in situ and the emergence of diversity during breast cancer evolution. Clin Cancer Res 2008;14:370–378.

104. O’Connell P, Pekkel V, Fuqua SA, et al. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 1998;90:697–703.

105. Aubele MM, Cummings MC, Mattis AE, et al. Accumulation of chromosomal imbalances from intraductal proliferative lesions to adjacent in situ and invasive ductal breast cancer. Diagn Mol Pathol2000;9:14–19.

106. Farabegoli F, Champeme MH, Bieche I, et al. Genetic pathways in the evolution of breast ductal carcinoma in situ. J Pathol 2002;196:280–286.

107. Damiani S, Ludvikova M, Tomasic G, et al. Myoepithelial cells and basal lamina in poorly differentiated in situ duct carcinoma of the breast: an immunocytochemical study. Virchows Arch1999;434:227–234.

108. Guidi AJ, Fischer L, Harris JR, et al. Microvessel density and distribution of ductal carcinoma in situ of the breast. J Natl Cancer Inst 1994;86:614–619.

109. Guidi AJ, Schnitt SJ, Fischer L, et al. Vascular permeability factor (vascular endothelial growth factor) expression and angiogenesis in patients with ductal carcinoma in situ of the breast. Cancer1997;80:1945–1953.

110. Allred DC, Wu Y, Tsimelzon A, et al. The progression of DCIS to IBC: a cDNA expression microarray study [abstract]. Breast Cancer Res Treat 2002;76(Suppl 1):S81.

111. Buerger H, Otterbach F, Simon R, et al. Different genetic pathways in the evolution of invasive breast cancer are associated with distinct morphological subtypes. J Pathol 1999;189:521–526.

112. Gupta SK, Douglas-Jones AG, Fenn N, et al. The clinical behavior of breast carcinoma is probably determined at the preinvasive stage (ductal carcinoma in situ). Cancer 1997;80:1740–1745.

113. Lampejo OT, Barnes DM, Smith P, et al. Evaluation of infiltrating ductal carcinomas with a DCIS component: correlation of the histologic type of the in situ component with grade of the infiltrating component. Semin Diagn Pathol 1994;11:215–222.

114. Warnberg F, Nordgren H, Bergkvist L, et al. Tumour markers in breast carcinoma correlate with grade rather than with invasiveness. Br J Cancer 2001;85:869–874.

115. Singletary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 2002;20:3628–3636.

116. Lagios MD, Margolin FR, Westdahl PR, et al. Mammographically detected duct carcinoma in situ: frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer1989;63:618–624.

117. Silver SA, Tavassoli FA. Mammary ductal carcinoma in situ with microinvasion. Cancer 1998;82:2382–2390.

118. Alpers C, Wellings S. The prevalence of carcinoma in situ in normal and cancer associated breast. Hum Pathol 1985;16:796.

119. Welch HG, Black WC. Using autopsy series to estimate the disease “reservoir” for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med 1997;11:1023–1028.

120. Betsill WL, Rosen PP, Lieberman PH, et al. Intraductal carcinoma: long-term follow-up after treatment by biopsy alone. JAMA 1978;239:1863–1867.

121. Collins LC, Tamimi RM, Baer HJ, et al. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy: results from the Nurses’ Health Study. Cancer 2005;103:1778–1784.

122. Millis RR, Thynne GSJ. In situ intraduct carcinoma of the breast: a long-term follow-up study. Br J Surg 1975;62:957–962.

123. Habel LA, Moe RE, Daling JR, et al. Risk of contralateral breast cancer among women with carcinoma in situ of the breast. Ann Surg 1997;225:69–75.

124. Claus EB, Petruzella S, Matloff E, et al. Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. JAMA 2005;293:553–554.

125. Bijker N, Peterse JL, Duchateau L, et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol 2001;19:2263–2271.

126. Ottesen GL, Graversen HP, Blichert-Toft M, et al. Ductal carcinoma in situ of the female breast: short-term results of a prospective nationwide study—the Danish Breast Cancer Cooperative Group. Am J Surg Pathol1992;16:1183–1196.

127. Sneige N, McNeese MD, Atkinson EN, et al. Ductal carcinoma in situ treated with lumpectomy and irradiation: histopathological analysis of 49 specimens with emphasis on risk factors and long term results. Hum Pathol1995;26:642–649.

128. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer 1996;77:2267–2274.

129. Solin LJ, Yeh IT, Kurtz J, et al. Ductal carcinoma in situ (intraductal carcinoma) of the breast treated with breast-conserving surgery and definitive irradiation: correlation of pathologic parameters with outcome of treatment. Cancer 1993;71:2532–2542.

130. Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 1999;340:1455–1461.

131. Solin LJ, Fourquet A, Vicini FA, et al. Long-term outcome after breast-conservation treatment with radiation for mammographically detected ductal carcinoma in situ of the breast. Cancer2005;103:1137–1146.

132. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet 1999;353:1993–2000.

133. Vicini FA, Recht A. Age at diagnosis and outcome for women with ductal carcinoma-in-situ of the breast: a critical review of the literature. J Clin Oncol 2002;20:2736–2744.

134. Silverstein MJ. Van Nuys experience by treatment. In: Silverstein MJ, Lagios MD, Poller DN, et al., eds. Ductal carcinoma in situ of the breast. Philadelphia, PA: Williams & Wilkins, 1997:443–447.

135. Fisher ER, Leeming R, Anderson S, et al. Conservative management of intraductal carcinoma (DCIS) of the breast. J Surg Oncol 1991;47:139–147.

136. Ernster VL, Barclay J, Kerlikowske K, et al. Mortality among women with ductal carcinoma in situ of the breast in the population-based Surveillance, Epidemiology and End Results program. Arch Intern Med 2000;160:953–958.

137. Carlson G, Page A, Johnson E, et al. Local recurrence of ductal carcinoma in situ after skin-sparing mastectomy. J Am Col Surg 2007;204:1074–1078.

138. Chan LW, Rabban JR, Hwang ES, et al. Is radiation indicated in patients with ductal carcinoma in situ and close or positive mastectomy margins. Int J Rad Onc Biol Phys 2011;80:25–30.

139. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 1998;16:441–452.

140. Fisher B, Land S, Mamounas E, et al. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol 2001;28:400–418.

141. Wapnir IL, Dignam JJ, Fisher B, et al Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 2011;103:478–488.

142. Bijker N, Meijnen PH, Bogaerts J, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ (DCIS): ten-year results of European organization for research and treatment of cancer (EORTC) randomized trial 10853. J Clin Oncol 2006;24:3381–3387.

143. Julien JP, Bijker N, Fentiman IS, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. Lancet 2000;355:528–533.

144. Cusck J, Sestak I, Pinder SE, et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term resulrs from the UK/ANZ DCIS trial Lancet Oncol2011;12:21–29.

145. Houghton J, George WD, Cuzick J, et al. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomized controlled trial. Lancet2003;362:95–102.

146. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast J Clin Oncol2008;26:1247–1252.

147. Early Breast Cancer Trialists’ Collaborative Group, Correa C, McGale P, Taylor C, et al. Overview of the randomized trials of radiotherapy in dictal carcinoma in situ of the breast. J Natl Cancer Inst Mongr 2010;(41):162–167.

148. De Mascarel I, Bonichon F, MacGrogan G, et al. Application of the Van Nuys Prognostic Index in a retrospective series of 367 ductal carcinomas in situ of the breast examined by serial macroscopic sectioning: practical considerations. Breast Cancer Res Treat 2000;61:151–159.

149. Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol 2006;24:1031–1036.

150. Wong JS, Smith BL, Troyan SL, et al. Eight-year update of a prospective study of wide excision alone for ductal carcinoma in situ of the breast. Int J Radiat Oncol Biol Phys 2011;81:S31.

151. Hughes LL, Wang M, Page DL, et al. Local excision alone without irradiation for ductal carcinoma in situ of the breast: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009;27:5319–5324.

152. Liberman L, Van Zee KJ, Dershaw DD, et al. Mammographic features of local recurrence in women who have undergone breast-conserving therapy for ductal carcinoma in situ. Am J Roentgenol1997;168:489–493.

153. Solin LJ, Fourquet A, Vicini FA, et al. Salvage treatment for local recurrence after breast-conserving surgery and radiation as initial treatment for mammographically detected ductal carcinoma in situ of the breast. Cancer2001;91:1090–1097.

154. U.S. National Institutes of Health. Anastrozole or tamoxifen in treating postmenopausal women with ductal carcinoma in situ who are undergoing lumpectomy and radiation therapy. ClinicalTrials.gov.Available at: http://clinicaltrials.gov/ct2/show/NCT00053898?term = NCT00053898&rank =1. Accessed October 11, 2011.

155. U.S. National Institutes of Health. Adjuvant tomoxifen compared with anastrozole in treating postmenopausal women with ductal carcinoma in situ (IBIS-II DCIS). ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT00072462?term = IBIS+II&rank = 2. Accessed October 11, 2011.

156. Cuzick J, Forbes J, Edwards R, et al. First results from the International Breast Cancer Intervention Study (IBIS-I): a randomised prevention trial. Lancet 2002;360:817–824.

157. Silverstein MJ, Rosser RJ, Gierson ED, et al. Axillary lymph node dissection for intraductal breast carcinoma—is it indicated? Cancer 1987;59:1819–1824.

158. Intra M, Veronesi P, Mazzarol G, et al. Axillary sentinel lymph node biopsy in patients with pure ductal carcinoma in situ of the breast. Arch Surg 2003;138:309–313.

159. McMasters KM, Chao C, Wong SL, et al. Sentinel lymph node biopsy in patients with ductal carcinoma in situ: a proposal. Cancer 2002;95:15–20.

160. Bartelink H, Horiot J-C, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345:1378–1387.

161. Schwartz GF, Solin LJ, Olivotto IA, et al. Consensus conference on the treatment of in situ ductal carcinoma of the breast, April 22–25, 1999. Cancer 2000;88:946–954.

Page

Contents

If you find an error or have any questions, please email us at admin@doctorlib.org. Thank you!