Management of Ductal Carcinoma In Situ

Transcription

1 Management of Ductal Carcinoma In Situ Stella Hetelekidis, MD Stuart J. Schnitt, MD Monica Morrow, MD Jay R. Harris, MD Introduction Ductal carcinoma in situ (DCIS), also known as intraductal carcinoma, is a proliferation of presumably malignant epithelial cells within the mammary ductal system. Because there is no light-microscopic evidence of invasion through the basement membrane into the surrounding tissue, DCIS is best viewed as a preinvasive lesion. The increased use of screening mammography over the past two decades has led to a marked increase in the number of patients diagnosed with DCIS, and today, in many centers, one DCIS lesion is diagnosed for every two to three mammographically detected invasive breast cancers. Although patients with DCIS have been traditionally treated with mastectomy, this treatment approach has recently Dr. Hetelekidis is a Radiation Oncologist at the Joint Center for Radiation Therapy and the Brigham and Women s Hospital and Clinical Instructor at Harvard Medical School in Boston, Massachusetts. Dr. Schnitt is the Associate Director of Surgical Pathology at the Beth Israel Hospital and Associate Professor of Pathology at Harvard Medical School in Boston, Massachusetts. Dr. Morrow is the Director of the Lynn Sage Comprehensive Breast Center and Associate Professor of Surgery in the Department of Surgery of Northwestern University Medical School in Chicago, Illinois. Dr. Harris is the Clinical and Educational Director at the Joint Center for Radiation Therapy and Professor of Radiation Oncology at Harvard Medical School in Boston, Massachusetts. come under scrutiny for several reasons. First, many patients with invasive breast cancer are currently treated with breastconserving therapy, making it difficult to justify the generalized use of mastectomy for patients with DCIS. In addition, the natural history of DCIS is only partially understood, particularly for small, mammographically detected lesions. In this article, we will review current concepts regarding the diagnosis, natural history, and treatment of DCIS. Presentation Prior to the era of mammographic screening, patients with DCIS most often presented with a palpable breast mass or with nipple discharge. Technical improvements in mammography and the widespread use of screening mammography have led to the increased detection of smaller, clinically occult DCIS lesions. Mammographically, DCIS usually appears as clustered microcalcifications without a soft tissue abnormality, although these findings are not specific for DCIS and may be seen with benign lesions as well as with invasive cancers. In fact, most calcifications are indeterminate mammographically, resulting in biopsy yields of only 20 to 25 percent. The microcalcifications in DCIS are most often secondary to the calcification of necrotic cellular debris within the involved ducts, and their extent and characteristics are better defined with magnification views. Suspicious mammographic 244 Ca A cancer Journal for Clinicians

2 microcalcifications are generally differentiated from benign calcium deposits by their number, distribution, and appearance. Coarse granular or linear calcifications or clusters of variably-shaped calcifications are regarded as most suspicious (Figs. 1 and 2). DCIS can also occasionally be an incidental finding in breast tissue removed for an unrelated abnormality, such as fibroadenoma. Finally, some patients with DCIS present with Paget s disease of the nipple-areolar complex. Pathology DCIS is comprised of a heterogeneous group of histopathologic lesions that have been classified into several subtypes based primarily on architectural pattern. The most frequent subtypes are comedo, cribriform, papillary, micropapillary, and solid (Figs. 3 and 4). Any given DCIS lesion may consist of one or more of these subtypes. Comedo-type DCIS consists of cells that are cytologically malignant, showing pleomorphism and high-grade nuclei. Central areas of necrosis are present in the involved spaces. These lesions have a high proliferative rate, and they often show aneuploidy, overexpression of the HER2/NEU (c-erbb-2) oncogene, accumulation of p53 tumor suppressor gene protein product, and angiogenesis in the surrounding stroma. 1-5 Using standard two-view mammography, there is a high correlation between the histologic extent of the lesion and the extent of the calcifications on mammogram. 6 Some investigators group the remaining subtypes of DCIS together as non-comedo lesions, based on the perception that these other types are often composed of cytologically bland cells with low-grade nuclei and a low proliferative rate. In fact, this dichotomous classification system is an oversimplification. Some DCIS lesions with low-grade nuclei may show necrosis, while others with cribriform, micropapillary, papillary, or solid architectural patterns may be composed of cytologically malignant cells with high-grade nuclei. In addition, some DCIS lesions have nuclei that are of intermediate grade. To overcome the limitations of traditional pathologic classification systems, which are based on architectural pattern, a number of alternative classification schemes have recently been proposed that emphasize nuclear grade as the most important histopathologic factor. 7-9 Estrogen- and progesterone-receptor proteins are seen in some cases of DCIS, more frequently in non-comedo types. 10 However, their importance in the management of patients with DCIS has not been established. In most cases, the diagnosis of DCIS is straightforward. However, in some cases, diagnostic problems do occur. At one end of the spectrum, it may be difficult to distinguish examples of low-grade DCIS from atypical ductal hyperplasia. At the other end, the distinction between pure DCIS and DCIS with microinvasion or even frankly invasive cancer may be problematic. Finally, the distinction between DCIS and lobular carcinoma in situ (LCIS) is sometimes difficult. The distribution of DCIS in the breast is of considerable interest. Several prior studies suggested that DCIS is frequently a multicentric disease. However, recent studies using more meticulous pathologic/mammographic correlative technique have shown that these additional foci are almost always present in relation to the index lesion (multifocal spread) and that true multicentricity is uncommon. 6 Most cases of DCIS show a segmental pattern of involvement in the breast. These observations have implications for the management of patients with DCIS and indicate that breast-preserving procedures may be feasible in many patients. About one percent of all patients with the diagnosis of DCIS are found to Vol. 45 No. 4 July/august

3 M a n a g e m e n t o f D u c t a l C a r c i n o m a i n s i t u have axillary lymph node involvement, a potential consequence of undetected stromal invasion. The frequencies of both microinvasion and axillary lymph node involvement are related to the extent of the DCIS lesion. Lagios 11 reviewed 111 cases of DCIS treated with mastectomy and found no evidence of occult invasion when the extent of DCIS was less than 2.5 cm, whereas 12 of 25 lesions (48 percent) larger than 5.5 cm were found to have microinvasion. Two instances of lymph node involvement occurred in association with microinvasion. Silverstein et al 12 have recently reviewed their experience with axillary dissection in 189 patients with DCIS, and no cases of lymph node involvement were found. Fig. 1. Craniocaudal-view mammogram shows numerous pleomorphic microcalcifications, many of which are arrayed along the course of ducts. The calcifications are varied in size and shape, but are predominantly rounded. Malignant Potential A critical but as yet unresolved issue concerning DCIS is its potential to progress to invasive breast cancer. Because DCIS was historically treated with mastectomy, little information on the risk of progression to invasive disease is available. In particular, the natural history of the Fig. 2. (A) Craniocaudal-view mammogram shows a focus of microcalcifications in the lateral aspect of the breast. (B) Magnification view better defines the extent of the microcalcifications and more clearly shows their linear characteristics. (C) Specimen mammogram shows removal of the microcalcifications seen in 2A and 2B. 246 Ca A cancer Journal for Clinicians

4 small, mammographically detected lesions seen with increasing frequency today is largely unknown. There have been three studies in which retrospective reviews of benign breast biopsies have identified small numbers of patients with DCIS who received no treatment beyond diagnostic biopsy Page et al 13 found progression to invasive disease in seven (28 percent) of 25 patients at intervals from three to 10 years (mean, 6.1 years). Rosen et al 14 noted progression in eight of 15 patients; however, an additional 15 patients had been lost to follow-up. Eusebi et al 15 noted that two of 28 patients with DCIS developed ipsilateral invasive breast carcinoma (mean follow-up, 16.7 years). In addition, Alpers and Wellings 16 reported that of 44 patients with invasive carcinoma of the breast undergoing bilateral mastectomy, 21 (48 percent) were found to have DCIS of the contralateral breast. This is in contrast to the rate of development of contralateral invasive breast cancer, which is about 10 to 15 percent over 20 years. Therefore, it appears that some, but not all, DCIS lesions will progress to invasive carcinoma. Options for Treatment The treatment of patients with DCIS with mastectomy is associated with cure rates approaching 100 percent However, mastectomy has been viewed by some clinicians as a prophylactic treatment because it is used to prevent the development of an invasive breast cancer. With the increasing use of breast-conserving treatment for patients with invasive breast carcinoma, the routine use of mastectomy for patients with DCIS has been questioned, particularly for small, lowgrade lesions. Several investigators have examined the results of breast-conserving treatment of DCIS using surgical resection alone (Table 1). 2,7,20-24 Lagios et al 7 reported the results in 79 women with DCIS measuring 25 mm or less (mean size, 6.8 mm) treated with wide excision alone. With a mean of 124 months of follow-up, 13 local recurrences (16 percent) have been noted (personal communication, March 1995). Six of these recurrences were invasive carcinomas, and seven were DCIS. The recurrence rate was 33 percent (12/36) in patients with high-grade DCIS containing comedo-type necrosis versus two percent (1/43) in patients with intermediate- or low-grade DCIS. Schwartz et al 20 similarly examined the treatment results for 70 patients with DCIS lesions measuring 2.5 cm or less. All patients underwent re-excision of the surgical bed, achieving negative margins of resection. Eleven patients (15 percent) experienced local recurrence (mean follow-up, 49 months). Here, too, the risk of local recurrence varied greatly with histologic subtype: 12 (32 percent) of 38 patients with comedo histology experienced local recurrence while only one (three percent) of 32 patients with non-comedo histology had a recurrence. In both of these series, careful histopathologic and mammographic techniques were used to assess the adequacy of the resection. Other investigators have reported on the use of excision and radiation therapy for DCIS (Table 2) ,25-29 Hiramatsu et al 25 recently reviewed the outcome of 76 patients treated with excision and radiation therapy (median follow-up, 74 months). The five- and 10-year local recurrence rates were four percent and 15 percent, respectively. Four of the seven recurrences were invasive, and three were DCIS. Solin et al 26 reported the results of 172 patients treated at multiple institutions. With a mean follow-up period of 84 months, 16 recurrences (nine percent) were found, and almost half of these were invasive. The presence of comedo-type DCIS plus nuclear grade 3 was a significant predictor for local recurrence, but not for overall survival. The median time to recurrence was 62 months, with a Vol. 45 No. 4 July/august

5 M a n a g e m e n t o f D u c t a l C a r c i n o m a i n s i t u A Fig. 3. Cribriform-type (low-grade) ductal carcinoma in situ. (A) Low-power photomicrograph demonstrates several spaces involved with a fenestrated proliferation of ductal carcinoma in situ cells. Rare psammoma-type calcifications are present (arrows). (B) High-power view demonstrates cytologic detail. The intraductal carcinoma cell nuclei are small and relatively uniform in appearance. There is no evidence of mitotic activity. A psammoma-type calcification is present in the center of the field. B A B Fig. 4. Comedo-type (high-grade) ductal carcinoma in situ. (A) Low-power photomicrograph of an involved space shows in situ carcinoma cells at the periphery and large central area of necrosis (N) which is focally calcified (arrow). (B) High-power view shows cytologically malignant cells with nuclear pleomorphism and variably prominent nucleoli. A mitotic figure is evident (arrow). range of 19 to 119 months. Silverstein et al 30 initially found that among patients treated with excision and radiation therapy, a higher local recurrence rate was observed for patients with the comedo subtype (11 percent) compared with the non-comedo subtypes (two percent) (median follow-up, 45 months). However, an update of this study revealed that this difference was no 248 Ca A cancer Journal for Clinicians

6 longer apparent with longer follow-up. 21 Others have also found no effect of the histologic subtype alone on the recurrence rates after irradiation. 26 Two studies from the National Surgical Adjuvant Breast and Bowel Project (NSABP) have been reported on treatment outcome in patients with DCIS. Protocol B-06 was a prospective, randomized study designed to examine the outcome in patients with invasive breast carcinoma treated with mastectomy, lumpectomy alone, or lumpectomy and irradiation. 31 Upon retrospective review of pathologic materials, 78 patients were found to have had DCIS alone. 32 Only one of these patients presented with a mammographically detected lesion, and the mean size for the 71 lesions in which pathologic dimensions were available was 2.2±1.3 cm. Updated results on 76 patients are available. 22 With a follow-up of 83 months, two (seven percent) of 27 patients treated with irradiation experienced local recurrence, while none of the 28 patients treated with mastectomy recurred locally (one patient died of metastatic disease without a local recurrence). In contrast, nine (43 percent) of the 21 patients treated with lumpectomy alone had local failures. Although analysis was limited by the small number of patients, no difference in overall survival was observed among the three groups. The results of the first prospective, randomized study examining the role of radiation therapy in breast-conserving treatment of DCIS were recently reported by the NSABP (Protocol B-17). 23 In this study, 818 women with DCIS were randomly assigned to either lumpectomy alone or lumpectomy followed by breast irradiation. Histologically negative surgical margins were a study requirement. With a median follow-up of 43 months, event-free survival was found to be higher in women treated with breast irradiation (84 percent versus 74 percent), and this was primarily due to fewer ipsilateral breast recurrences developing in the irradiated group. Sixty-four ipsilateral breast recurrences (16 percent) occurred in the group treated with lumpectomy alone, while 28 (seven percent) developed in the patients treated with lumpectomy and irradiation. The greatest reduction was seen in the subsequent development of ipsilateral invasive carcinoma. The fiveyear cumulative incidence of invasive breast cancers was 10.5 percent with lumpectomy alone, compared with 2.9 percent with the addition of radiation therapy. The reduction in the recurrence of DCIS was also statistically significant, but not as striking, with a cumulative incidence of 10.4 percent at five years with lumpectomy alone and 7.5 percent with lumpectomy and irradiation. Most of the recurrences were seen at or near the primary site. Other events, such as the development of contralateral breast cancer, were similar in the two groups. A recent analysis of the significance of pathologic findings of the NSABP B- 17 protocol showed the only statistically significant independent predictors for ipsilateral breast recurrence to be the presence of comedo-type necrosis and involved/uncertain margins. 33 Although the addition of radiation therapy reduced the risk of recurrence in all subgroups, the difference was greatest in those patients whose DCIS lesions showed moderate to marked comedo necrosis. Nonetheless, several questions remain unanswered from this single, randomized study. Accurate determination of the extent of DCIS lesions is often difficult, and the sizes of the lesions from Protocol B-17 were not systematically recorded in all patients. Another limitation is the relatively short follow-up period (mean, 43 months). Increasing recurrence rates are observed with follow-up beyond five years. 21,25 Whether the rates of local recurrence for the two groups will continue to diverge over time remains to be seen. The most recent NSABP study investigated the potential role of tamoxifen in patients with DCIS treated with exci- Vol. 45 No. 4 July/august

7 M a n a g e m e n t o f D u c t a l C a r c i n o m a i n s i t u Table 1 Studies of Ductal Carcinoma In Situ Treated with Wide Excision Alone Mean Number of Follow-up Recurrence Invasive Reference Patients (months) No. (percent) (percent) Arnesson et al (13) 40 Carpenter et al (18) 20 Lagios et al (16) 46 Schwartz et al (15) 27 Silverstein et al (8) 50 Fisher et al 22 (B-06) (43) 56 Fisher et al 23 (B-17) (16) 50 sion and breast irradiation (Protocol B- 24). In an attempt to further reduce the local recurrence rate and possibly decrease the rate of contralateral breast cancer development, patients were randomized to treatment for five years with tamoxifen or with placebo. This study had no specific limits on the size of the intraductal lesion, and negative resection margins were not mandatory for entry. Additionally, postsurgical mammograms were not required, and women with additional areas of microcalcifications were not excluded. A number of European trials are also investigating the roles of radiation therapy and tamoxifen in combination with limited surgery. Approach to Management Given the heterogeneous nature of these lesions, the uncertainty about natural history, and the paucity of long-term results with breast-conserving therapy, the treatment of DCIS has become one of the most controversial areas in the field of breast disease. Some clinicians believe mastectomy should be offered to all patients with DCIS because of its high degree of effectiveness. Other clinicians believe the small, mammographically detected tumors commonly diagnosed today do not require mastectomy given the uncertain risk of progression and the effectiveness of breast-conserving therapy. The NSABP B-17 results suggest that many patients with DCIS may be treated with excision and irradiation, but it is unclear, at present, how this treatment compares to mastectomy. In addition, it is likely that some patients with DCIS may be treated by excision alone, but it is unclear how to best identify them. In the absence of prospective, randomized trials comparing mastectomy and breast-conserving treatment, several outcomes of treatment should be considered in assessing the available data. These outcomes include the risk of recurrence, the risk of invasive breast cancer, the risk of dying of breast cancer, and the psychologic and physical implications of mastectomy. Current data on breast-conserving treatment with radiation therapy 250 Ca A cancer Journal for Clinicians

8 Table 2 Studies of Ductal Carcinoma In Situ Treated with Excision and Radiation Therapy Mean Number of Follow-up Recurrence Invasive Reference Patients (months) No. (percent) (percent) Hiramatsu et al (9) 57 McCormick et al (18) 30 Ray et al (9) 20 Silverstein et al (10) 50 Solin et al (9) 44 Stotter et al (9) 100 Fisher et al 22 (B-06) (7) 50 Fisher et al 23 (B-17) (7) 40 show recurrence rates of 10 to 15 percent at 10 years. Because about half of these recurrences are invasive, the risk of invasive breast cancer is about five to seven percent. Assuming that with close follow-up after treatment of DCIS, these invasive lesions would be detected early, then the risk of ultimately dying of breast cancer can be estimated to be about two to three percent. This compares with a risk of about one to two percent after mastectomy. If we consider that women with LCIS, who develop invasive breast cancer at a rate of about one percent per year (or 10 percent at 10 years), are typically managed with observation alone, then breast-conserving therapy for patients with DCIS seems a reasonable option. Is there a subset of patients that can be treated with excision alone? Retrospective data indicate that patients with small DCIS lesions, particularly of the non-comedo subtypes, may be adequately treated with lumpectomy alone if attention is given to the histologic resection margins and there is verification of complete tumor removal by postoperative mammogram. The only results available from a prospective study at this time are those from the NSABP Protocol B Additional prospective studies looking at excision alone for selected patients with DCIS are still needed. Treatment Recommendations Most patients with DCIS have nonpalpable, mammographically detected lesions, and careful mammographic and pathologic evaluation is necessary for formulating treatment recommendations. Patients who are found to have suspicious calcifications on screening mammography should have magnification views performed to clearly define the full extent of the calcifications. Needle localization should be used to guide the biopsy, and if the calcifications are extensive, bracketing wires are often used to aid in complete excision. Specimen mammography and postexcision mammograms are useful to confirm the removal of all suspicious calcifications. On pathologic evaluation, the speci- Vol. 45 No. 4 July/august

9 M a n a g e m e n t o f D u c t a l C a r c i n o m a i n s i t u men should be carefully oriented and inked, with particular attention given to the nuclear grade, the architectural subtype, the correlation of microcalcifications with DCIS, the extent of disease, and the distance between the DCIS and the resection margins. Evidence of microinvasion should be noted. It is recommended that biopsy tissue without a discernible mass not be sent for biochemical analysis of estrogen-receptor proteins as small areas of invasion may be inadvertently missed. Once DCIS is diagnosed, treatment options should be discussed with the patient, considering the various outcomes and risks described above. Breast-conserving treatment should require removal of all microcalcifications (as seen on specimen mammography or magnification views) and negative microscopic margins of resection; re-excision is often necessary to achieve this. If a patient wishes to have breast-conserving therapy and is an appropriate candidate, entry onto a protocol should be encouraged. Not every patient with DCIS who desires breast-conserving treatment will be an appropriate candidate. In general, simple mastectomy is recommended for women in whom the DCIS is too extensive to be adequately removed. This in turn may be determined not only by the extent of the disease, but also by the size of the breast, the histopathology (e.g., margins), and the cosmetic result that is acceptable to each patient. Axillary dissection is not routinely performed; however, a limited dissection is commonly performed in patients with extensive lesions, particularly if these are high-grade. In patients treated with mastectomy, reconstruction using tissue flaps or implants is done based on each patient s desires. Hormonal therapy for DCIS is currently not indicated except on study protocols. Future Studies Additional information is needed from clinical trials and laboratory studies to improve the management of patients with DCIS. The results of the NSABP B-24 trial and others will provide important information about the utility of tamoxifen. The optimal histologic classification of DCIS is still in evolution, and further work is needed in correlating histology with clinical outcome. Whether new classification systems that emphasize nuclear grade of DCIS will be of prognostic significance and aid in the selection of patients for various treatments remains to be seen. Research is needed to identify factors associated with the development of invasive disease. Work is currently under way examining genetic changes, angiogenesis, and cellular growth factors as prognostic markers. 4,5,34,35 Finally, long-term results from clinical trials are needed to provide patients more accurate estimates of outcome based on treatment choice. CA References 1. Meyer JS: Cell kinetics of histologic variants of in situ breast carcinoma. Breast Cancer Res Treat 1986;7: Carpenter R, Boulter PS, Cooke T, Gibbs NM: Management of screen detected ductal carcinoma in situ of the female breast. Br J Surg 1989;76: van de Vijver MJ, Peterse JL, Mooi WJ, et al: Neu-protein overexpression in breast cancer: Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. N Engl J Med 1988;319: Poller DN, Roberts EC, Bell JA, et al: p53 protein expression in mammary ductal carcinoma in situ: Relationship to immunohistochemical expression of estrogen receptor and c-erbb-2 protein. Hum Pathol 1993;24: Guidi AJ, Fischer L, Harris JR, Schnitt SJ: Microvessel density and distribution in ductal carcinoma in situ of the breast. J Natl Cancer Inst 1994; 86: Holland R, Hendriks JH, Vebeek AL, et al: Extent, distribution, and mammographic/histological correlations of breast ductal carcinoma in situ. Lancet 1990;335: Ca A cancer Journal for Clinicians

10 7. Lagios MD, Margolin FR, Westdahl PR, Rose MR: Mammographically detected duct carcinoma in situ: Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer 1989;63: Holland R, Peterse JL, Millis RR, et al: Ductal carcinoma in situ: A proposal for a new classification. Semin Diagn Pathol 1994;11: Poller DN, Silverstein MJ, Galea M, et al: Ductal carcinoma in situ of the breast: A proposal for a new simplified histological classification association between cellular proliferation and c-erbb-2 protein expression. Mod Pathol 1994;7: Bur ME, Zimarowski MJ, Schnitt SJ, et al: Estrogen receptor immunohistochemistry in carcinoma in situ of the breast. Cancer 1992;69: Lagios MD: Ductal carcinoma in situ: Pathology and treatment. Surg Clin North Am 1990;70: Silverstein MJ, Gierson ED, Waisman JR, et al: Axillary lymph node dissection for T1a breast carcinoma: Is it indicated. Cancer 1994;73: Page DL, Dupont WD, Rogers LW, Landenberger M: Intraductal carcinoma of the breast: Follow-up after biopsy only. Cancer 1982;49: Rosen PP, Braun DW Jr, Kinne DE: The clinical significance of preinvasive breast carcinoma. Cancer 1980;46(suppl 4): Eusebi V, Foschini MP, Cook MG, et al: Longterm follow-up of in situ carcinoma of the breast with special emphasis on clinging carcinoma. Semin Diagn Pathol 1989;6: Alpers CE, Wellings SR: The prevalence of carcinoma in situ in normal and cancer-associated breasts. Hum Pathol 1985;16: Ashikari R, Huvos AG, Snyder RE: Prospective study of non-infiltrating carcinoma of the breast. Cancer 1977;39: Sunshine JA, Moseley HS, Fletcher WS, Krippaehe WW: Breast carcinoma in situ: A retrospective review of 112 cases with a minimum 10 year follow-up. Am J Surg 1985;150: Farrow JH: Current concepts in the detection and treatment of the earliest of the early breast cancers. Cancer 1970;25: Schwartz GF, Finkel GC, Garcia JC, Patchefsky AS: Subclinical ductal carcinoma in situ of the breast: Treatment by local excision and surveillance alone. Cancer 1992;70: Silverstein MJ, Cohlan BF, Gierson ED, et al: Duct carcinoma in situ: 227 cases without microinvasion. Eur J Cancer 1992;28: Fisher ER, Leeming R, Anderson S, et al: Conservative management of intraductal carcinoma (DCIS) of the breast. J Surg Oncol 1991;47: Fisher B, Costantino J, Redmond C, et al: Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med 1993;328: Arnesson LG, Smeds S, Fagerberg G, Grontolt O: Follow-up of two treatment modalities for ductal cancer in situ of the breast. Br J Surg 1989;76: Hiramatsu H, Bornstein BA, Recht A, et al: Outcome and risk factors for local failure after conservative surgery and radiotherapy for ductal carcinoma in situ, The Cancer Journal from Scientific American in press. 26. 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. Cancer 1993;71: McCormick B, Rosen P, Kinne D, et al: Duct carcinoma in situ of the breast: An analysis of local control after conservation surgery and radiotherapy. Int J Radiat Oncol Biol Phys 1991;21: Ray GR, Adelson J, Hayhurst E, et al: Ductal carcinoma in situ of the breast: Results of treatment by conservative surgery and definitive irradiation. Int J Radiat Oncol Biol Phys 1994;28: Stotter AT, McNeese M, Oswald MJ, et al: The role of limited surgery with irradiation in primary treatment of ductal in situ breast cancer. Int J Radiat Oncol Biol Phys 1990;18: Silverstein MJ, Waisman JR, Gamagami P, et al: Intraductal carcinoma of the breast (208 cases): Clinical factors influencing treatment choice. Cancer 1990;66: Fisher B, Redmond C, Poisson R, et al: Eightyear results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320: Fisher ER, Sass R, Fisher B, et al: Pathologic findings from the National Surgical Adjuvant Breast Project (Protocol 6): I. Intraductal carcinoma (DCIS). Cancer 1986;57: Fisher ER, Costantino J, Fisher B, et al: Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17: Intraductal carcinoma. Cancer 1995;75: Simpson JF, O Malley F, Dupont WD, Page DL: Heterogeneous expression of nm23 gene product in noninvasive breast carcinoma. Cancer 1994;73: Normanno N, Giordino T, Smith K, et al: Expression of amphiregulin, cripto-1 and heregulin alpha in primary human breast carcinomas. Proc Annu Meet Am Assoc Cancer Res 1994;35:A76. Abstract. Vol. 45 No. 4 July/august