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Chapter 52

Breast: Stage Tis

David E. Wazer

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 in order 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 (89). The extent of involvement of the lobular lumen ranges from simple filling to moderate-to-severe distention with extension into the adjacent extralobular ducts (124). 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 (49,89,105,124).

LCIS has been reported to present with a multicentric distribution in up to 90% of mastectomy specimens, with bilateral involvement in 35% to 59% (89,105,124). LCIS cells are commonly estrogen-receptor positive, although overexpression of c-erbB-2 and p53 are uncommon (2,3,18,105). The loss of e-cadherin is often observed (2,64,129), and the absence of this adhesion molecule may explain the growth pattern seen with LCIS.

LCIS represents <15% of all noninvasive breast cancer (7,55,133). The majority of women are premenopausal at diagnosis, with an average age of 45 years (49,89,98). Risk factors for the development of LCIS correspond to those identified for invasive carcinoma (125). Because the male breast lacks lobular elements, this entity has not been described in men (49). As there are no clinical or mammographic indicators that are characteristic of LCIS, it is often detected as an incidental biopsy finding (89,105). In a minority of cases, LCIS can be detected with mammographic calcifications, but more commonly, calcifications are in adjacent tissue and are not histologically associated with LCIS (50,102,120). In excisional biopsy specimens, DCIS or invasive carcinoma are frequently identified even when LCIS is the sole histologic entity seen on core biopsy (24,47,74).

The presence of LCIS is considered a marker of increased risk for the subsequent development of invasive (usually ductal) carcinoma (7,49,55,98) that may be greatest for high-grade or more extensive lesions (86,89). This risk appears to be nearly equal for both breasts (22).

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 (60), whereas others have not (12). In an analysis of 182 patients with LCIS who were inadvertently enrolled on the National Surgical Adjuvant Breast and 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 (44). Nine IBTR (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.

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 (1,81,103). The effect that the presence of LCIS has on the outcome of conservative management of early-stage breast cancer

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has only recently been evaluated. The most widely accepted treatment approach is to manage the breast according to the dominant malignant histology (DCIS or invasive carcinoma) and disregard the presence of LCIS. In such circumstances, it is not necessary to pursue additional surgery to obtain clear margins for LCIS (1,12,81,103).

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 (46). The high frequency of contralateral breast involvement was subsequently used to justify contralateral biopsy and even bilateral mastectomy (46,98). 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 (7,49,55). 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 (7,44,49,55,133). 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% (40,128).

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 (90). Paget's disease of the nipple is characterized by the presence of Paget's cells that are located throughout the epidermis (76). 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 more than 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 (30,34).

Paget's disease is a rare entity representing <5% of all breast cancer cases (65,100) and is typically diagnosed in the fifth or sixth decade. Synchronous bilateral and male Paget's disease have been reported (30,57,77).

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 (100,130). Alternatively, Paget's disease can be asymptomatic and present as a pathologic finding after incidental surgical removal of the nipple–areolar complex (63). The differential diagnosis includes superficial spreading melanoma, pagetoid squamous cell carcinoma in situ, and clear cells of Toker (68,76). A palpable mass is detected in approximately 50% of patients at diagnosis; in more than 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 (21,30,100). Mammographic findings are frequent in the presence of a palpable mass, but normal mammograms are reported in as many as 50% of cases (61,100).

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 dependent 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 but this has been increasingly supplanted by breast-conserving treatment (8,91,136). The infrequent occurrence of this disease entity, the range of disease presentations (nipple involvement with/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% (32,39,48,70,94,126). 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 (121). 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 Organization 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% (16). 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 (78,93). 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

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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 is 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 (20,26,88,99). Axillary-node involvement is rare (0% to 5%) and most likely is associated with an undetected focus of invasive carcinoma (112). Risk factors for the development of DCIS are the same as those identified for invasive carcinoma (125) 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% (112).

With the increased use of mammography and as pathologists began to recognize DCIS as a pathologic entity, the incidence of DCIS has markedly increased (73,113,114). The incidence of DCIS in the United States rose from 4,800 cases in 1983 to now more than 50,000 cases annually, representing a 10-fold increase in only 20 years (19). Of the 215,990 new breast cancers diagnosed in 2004, 59,390 were noninvasive, of which 85% were DCIS (66). Of these, 90% are nonpalpable (34). Studies have shown that the rate of screen-detected DCIS increases with age despite the fact that it accounts for a progressively smaller proportion of the total breast cancers detected (33). 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 (33).

Mammography

Ninety-five percent of new cases of DCIS present with mammographic abnormalities, of which microcalcifications are most typical (123). 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%. 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 (Fig. 52.1, A and B) (31,58,96,135).

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 (58,104). Ultrasonography, digital mammography, and magnetic resonance imaging all have the potential to be helpful in the management of DCIS but have yet to be proven as an acceptable substitute for mammography in screening (106). In cases that present with nipple discharge and a negative mammogram, galactography may be helpful in determining the likelihood of underlying DCIS versus papilloma (Fig. 52.1C) (92). Magnetic resonance imaging has the potential to refine clinical decision-making and surgical planning in select cases.

Pathology and Biology

The histologic diversity of DCIS can lead to difficulty in distinguishing it from other pathologic entities (88,99). 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 (38). Traditionally, classification of DCIS has followed its architectural or morphologic appearance. The five subtypes of DCIS are comedo, solid, cribriform, micropapillary, and papillary (10,88,99) and it is common to encounter a mixture of subtypes within the same specimen (92). The characteristic features of each type are shown in Figure 52.2. Less common subtypes have been described and include apocrine, neuroendocrine, signet-cell cystic hypersecretory carcinoma, and clinging DCIS (71).

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 (26). 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 their 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 (97).

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 breast (51,84,85) (Fig. 52.3). 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. (84,85) 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 (84,85). Their proposed model for the development of widespread intraductal tumor extension within the breast is seen in Figure 52.4.

Faverly et al. (37) have described 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 more than 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 (less than 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

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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 (4). This 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 further supported by the recognized association between the presence of DCIS and the subsequent increased risk of developing an invasive breast cancer (19,95,122). In some series, a 10-fold risk of developing an invasive lesion has been reported. Most importantly, the presence of shared identical genetic abnormalities between DCIS and synchronous invasive breast cancer demonstrates a clonal relationship of biologic progression (19,83,95,122). The biologic evolution from benign breast cells to invasive breast cancer occurs through highly diverse genetic mechanisms.

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 (9,36,83,95,122).

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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 (83).

Molecular markers have been studied in DCIS and are found to have a heterogeneous distribution of expression (19). The estrogen receptor is present in 70% of DCIS but 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 (28), proliferation of fibroblasts, lymphocyte infiltration, and angiogenesis in the surrounding stromal tissues (52,53). 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 (5).

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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 DCIS has evolved (17,54,72,131).

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 cancer (115) 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 (69), those presenting with palpable masses or nipple discharge, and those with high-grade DCIS or comedonecrosis (92,107).

Natural History of DCIS

The overall incidence of DCIS in the general population is unclear. In an attempt to address this question, 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 used (6) 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%) (132). 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 more than 36% (13,25,80,101). Most of these subsequent malignancies occur within 10 years, although as many as one-third may develop after 15 years (13,101).

Women with DCIS in one breast are at risk for a second tumor (either invasive or in situ) in the contralateral breast (56); the rate at which such tumors develop is similar to that among women with primary invasive breast cancer, 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 (23). 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 DCIS

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

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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, this term 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 is a pressing clinical question. Attempts to resolve this issue have focused on the identification of risk factors for local recurrence after breast-conservation therapy for DCIS. With three exceptions (the prospectively randomized NSABP B-17, the EORTC 10853, and the United Kingdom Coordinating Committee on Cancer Research [UKCCCR] trials), all such studies have been retrospective in design. Nonetheless, a number of factors have been identified that may be important in defining local failure risk. These include symptomatic presentation (15,87,116), lesion size (108,116), histopathologic subtype (15), nuclear/cytologic grade (87,116,119), central necrosis (87,116,119), margin status (109,116,117), and patient age (15,42,117,127).

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.

Recent efforts to classify DCIS have been based primarily on the nuclear grade of the lesion and/or the presence or absence of necrosis. A number of 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 (87,116,119). 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 (109,116,117). 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 as 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. 52.5). The two modalities available to assess the size of the lesion are mammography 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. Pathologic assessment of lesion size also 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.

Mastectomy for DCIS

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% or less (111). 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 mastectomy (111) 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 trials (45) and large treatment registries (35) suggest that the rates of local or regional recurrence are significantly lower after mastectomy than after breast-conserving surgery, but 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 (35).

Breast Conservation for DCIS

Three prospective randomized studies of excision only versus excision plus breast irradiation for DCIS have been performed, and all have shown that the rate of local recurrence was reduced with the addition of radiation (Table 52.1). The NSABP B-17 trial (41,43) consisted of 818 patients who were stratified by age (49 years of age or younger vs. older than 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 12-year rate of local recurrence was 15.7% with radiation and 31.7% without radiation (p <.000005) (Fig. 52.6). The average annual incidence rates of all ipsilateral breast tumor recurrences, ipsilateral noninvasive recurrences, and ipsilateral invasive recurrences were reduced with breast irradiation by 59%, 47%, and 71%, respectively. An analysis of clinical

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variables showed that microcalcifications extending beyond a maximum dimension of >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 52.2), that revealed only moderate/marked comedonecrosis as being significantly associated with local failure risk. Margin status (free vs. unknown/involved) was of borderline significance.

The EORTC 10853 trial (14,67) randomly allocated 1,010 patients with 5 cm or smaller 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 (14,15). In a multivariate analysis (Table 52.3), factors associated with an increased risk of local recurrence were age 40 years or younger, clinically symptomatic presentation (nipple discharge or palpable mass), intermediate or poorly differentiated DCIS, solid and cribriform histologic growth pattern, involved or uncertain margins, and treatment by local excision alone. The risk of invasive recurrence was not related to histologic type of DCIS, but the risk of distant metastasis was significantly higher in poorly differentiated DCIS compared with well-differentiated DCIS.

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 others (108,109,116,117) 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 (15).

The UKCCCR DCIS Working group has also conducted a randomized trial investigating the role of adjuvant radiotherapy (59). 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. A total of 1,030 patients were enrolled. When reported with 4.38 year follow-up, the crude incidence of local recurrence was 14% of the patients who were treated with excision only and 6% when the excision was followed by radiotherapy. 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 (59).

Subgroup analyses from 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 (14,15,41,43). However, radiotherapy lowers the incidence of recurrence among all subgroups, regardless of the baseline risk.

Patient age is an important prognostic variable for local recurrence after breast conservation for DCIS (15,42,117,127). In younger patients, DCIS more frequently contains adverse prognostic pathologic features and extends over a greater distance in the breast than in older patients (127). In series with

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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 (127). Some studies have suggested that careful attention to margin status and excising larger volumes of tissue can reduce this difference substantially (117,127). 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.

A number of 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% (109,111). A scoring system has been proposed (108) 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 scheme (108) is drawn from the retrospective analysis of a patient cohort in which there exist a number of methodologic shortcomings and it has not been independently validated (29).

Wong et al. (134) 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

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residual DCIS. Tamoxifen was not permitted. The median age was 51 years and the median follow-up was 40 months. The rate of ipsilateral local recurrence was 2.4% per patient-year, corresponding to a 5-year rate of 12%. Nine patients (69%) experienced recurrence of DCIS and four (31%) 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.

Presently, the Radiation Therapy Oncology Group is conducting 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 are 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 vs. ≥10 mm), grade, and the use of tamoxifen (at the discretion of the managing physician). Following stratification, patients are randomized to whole-breast irradiation versus observation. 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 will be 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 (75,118). 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 less than a 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 (118).

The Role of Tamoxifen for DCIS

The NSABP B-24 trial (42) 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 (8.2% vs. 13.4% at 5 years, respectively; p = .0009), but no survival benefit was found. Tamoxifen therapy resulted in a 44% reduction in the risk of subsequent invasive tumor recurrence but had no significant effect on ipsilateral noninvasive breast recurrence (Table 52.4). Positive tumor margins were significantly associated with breast recurrence, and tamoxifen reduced ipsilateral breast failure by 22% with negative margins and 44% in cases with positive or unknown margins.

In contrast to the findings of the NSABP B-24 trial, the UKCCCR trial found that tamoxifen had no effect in reducing local recurrence rate when combined with whole-breast radiation therapy (Table 52.4). 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% vs. 6%; p = .03) (59). 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% (27,40).

A Decision Tree for DCIS

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 in order to minimize the chance of ipsilateral recurrence or for other reasons. At present, there is no established role for the use of magnetic resonance imaging in screening patients for DCIS in determining whether breast-conserving surgery is an option.

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 reexcision. Nearly half of patients with margins that are <1 mm have residual DCIS on re-excision (82). However, the optimal margin width for the management of DCIS is not known. At a minimum, there should be no tumor at the margin.

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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 (110). 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 (62). 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 (79).

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 (11), 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, but 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:

• 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.
• 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 52.5.