Pathologic Features of Breast Cancers in Women With Previous Benign Breast Disease

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1 Anatomic Pathology / BREAST CANCERS AFTER BENIGN BIOPSY DIAGNOSES Pathologic Features of Breast Cancers in Women With Previous Benign Breast Disease Timothy W. Jacobs, MD, 1 Celia Byrne, PhD, 2 Graham Colditz, MD, 2 James L. Connolly, MD, 1 and Stuart J. Schnitt, MD 1 Key Words: Benign breast disease; Breast cancer; Invasive carcinoma; Atypical hyperplasia Abstract To compare pathologic features of the cancers arising after different types of benign breast disease (BBD), we reviewed the invasive breast cancer slides of 169 women with a previous benign biopsy result. Lesions were categorized previously as nonproliferative, proliferative without atypia, or atypical hyperplasia. Pathologic features of the cancers were evaluated without knowledge of the previous BBD category. Estrogen and progesterone receptor immunohistochemistry was performed on available tissue blocks. The median times between a benign result and cancer were 100, 124, and 92 months for women with nonproliferative lesions, proliferative lesions without atypia, and atypical hyperplasia, respectively. Cancers in the 3 groups did not differ significantly in tumor size, axillary lymph node status, or histologic grade, and there was no significant difference in the distribution of histologic types of breast cancer. Lymphatic vessel invasion, extensive intraductal component, and hormone receptor status did not differ among BBD categories. The pathologic features of breast cancers that develop in women with a previous benign biopsy result do not vary according to the histologic category of the previous BBD. The results of several large population-based studies have indicated that among women who have had a previous breast biopsy with a benign result, the risk of subsequent breast cancer varies according to the histologic category of benign breast disease (BBD). 1-4 In particular, women whose benign breast biopsy results reveal proliferative lesions without atypia have a 1.5- to 2-fold greater breast cancer risk compared with women with nonproliferative lesions. Those who have atypical hyperplasia have a 3- to 5-fold higher risk than women with nonproliferative lesions. While the variation in breast cancer risk according to histologic type of BBD is generally acknowledged, the pathologic features of invasive breast cancers that develop in women with previous BBD have not been studied in detail. An understanding of the relationship between the pathologic characteristics of these cancers and the type of previous BBD could provide important information about the development of breast cancer. A linear stepwise progression of breast tumorigenesis has been postulated, from usual ductal hyperplasia through atypical hyperplasia, ductal carcinoma in situ (DCIS), and invasive carcinoma, analogous to the sequence of events in the development of colon cancer However, based on morphologic, immunophenotypic, and emerging genetic evidence, it is likely that at least 2 pathways for the development of invasive breast carcinoma exist. In the first of these pathways, low-grade invasive carcinoma is thought to arise from low-grade DCIS, which in turn is related closely to atypical ductal hyperplasia (ADH). In the second pathway, highgrade invasive carcinoma is thought to arise from high-grade DCIS, but the immediate precursor of high-grade DCIS is not clear. Examination of breast cancers that occur in women with previous BBD may be one method to provide insight into the validity of these proposed pathways. 362 Am J Clin Pathol 2001;115: American Society of Clinical Pathologists

2 Anatomic Pathology / ORIGINAL ARTICLE Therefore, we compared the pathologic features of invasive carcinomas that arose in women with different categories of previous BBD. This study was nested within the Nurses Health Study (NHS), a prospective cohort of US women with prospectively collected data on risk factors for breast carcinoma. Materials and Methods Study Population The NHS began in 1976 when 121,701 female registered nurses, born between 1921 and 1946, responded to a mailed questionnaire about potential breast cancer risk factors and medical history. Every 2 years, participants in the NHS are sent a questionnaire that updates this information. On all questionnaires, participants were asked about a past diagnosis of BBD that either required hospitalization or was confirmed with a breast biopsy. Eligible participants for this study had no previous diagnosis of cancer (other than nonmelanoma skin cancer) at the beginning of each follow-up cycle of the study and had reported a diagnosis of BBD with either hospitalization or biopsy confirmation on the baseline or subsequent questionnaires. Among these women, all who reported a breast cancer diagnosis (except lobular carcinoma in situ) at least 1 year after their first reported diagnosis of BBD and through June 1992 were considered as potential cases. Signed consent was sought from all identified participants to allow retrieval and review of the pathology information related to their breast cancer diagnosis and to review the slides from their first breast biopsy with a benign result. Benign Breast Disease There were 755 women with breast cancer with a previously reported benign breast biopsy result who were eligible for the present study. Of the women, 76% confirmed their previous benign biopsy result and provided permission for review of the pathology. We were unable to obtain consent and information about the benign biopsy result for the small number (20) of women who died shortly after the diagnosis of breast cancer. In response to our request, 53% of pathology departments sent some pathology material. The primary reasons for not sending the requested material was that material that old had been destroyed or the hospital no longer existed or had records for this patient (41.5%) or that it was against the pathology department policy to lend pathology material of any kind (5.5%). The overall success rate in obtaining slides from the initial benign breast biopsy was 40%. Histologic slides from biopsies with benign results performed at least 1 year before the cancer diagnosis were available for 273 participants. After review, the slides from 262 participants were classified as benign and as having suitable breast tissue. All pathology slides of breast biopsies with benign results collected for the present study were evaluated initially before November 1997 by 1 of 2 pathologists (J.L.C. or S.J.S.), who were blinded to whether breast cancer developed in those women. For participants who had bilateral biopsies that were both confirmed as benign, the side with the most severe histologic features was used for classification. When both sides were of equal severity, a side was selected randomly. Breast biopsies with benign results initially were categorized into 1 of the following 3 categories using the criteria outlined by Dupont and Page 1 and Page et al 24 : (1) nonproliferative (normal breast tissue, cysts, duct ectasia, apocrine metaplasia, and mild ductal hyperplasia), (2) proliferative without atypia (moderate to florid ductal hyperplasia, fibroadenoma, sclerosing adenosis, intraductal papilloma, and radial scar), or (3) atypical hyperplasia (of either ductal or lobular types). In keeping with recent data of Dupont et al 25 showing an increased risk of breast cancer among women with fibroadenoma compared with those without, fibroadenoma and fibroadenomatous change were classified as proliferative disease without atypia. Biopsy specimens revealing possible or definite atypical hyperplasia were reviewed later jointly by 2 pathologists (J.L.C. and S.J.S.), and a consensus reading was obtained. Previous analyses based on these classifications within the NHS demonstrated an increased risk of breast cancer for women with proliferative lesions without atypia and atypical hyperplasia compared with those with nonproliferative BBD. 3,26,27 Breast Cancer Of the 262 women who had a diagnosis of breast cancer and whose previous benign breast biopsy material had been reviewed, slides of the breast cancer (invasive or in situ) were obtained for 220 (84%). In the remaining cases, the pathology departments contacted indicated they never release material (2%), there was insufficient or no breast tissue available (2%), or the pathology material had been destroyed (5%). Only 5% of the pathology departments have not responded to requests, and insufficient information to request specimens was available for fewer than 2% of the cases. For the 220 women, 228 breast cancer specimens were obtained for the 220 women. Six women had bilateral breast biopsies, and 2 women had 2 separate lesions from 1 breast. Of the 228 specimens reviewed, 8 had no breast tissue on the slides provided for evaluation, 30 had DCIS only, 12 had lobular carcinoma in situ only, 5 had atypical hyperplasia, and 1 had Paget disease only, leaving 172 specimens with invasive breast cancer. These 172 specimens came from 169 women, 166 with single specimens, 1 with bilateral breast cancer, and 2 with multiple lesions in 1 breast. For the 3 American Society of Clinical Pathologists Am J Clin Pathol 2001;115:

3 Jacobs et al / BREAST CANCERS AFTER BENIGN BIOPSY DIAGNOSES women with more than 1 breast cancer specimen, the information from the largest specimen was used for analyses. For the 169 women with confirmed invasive breast cancer, paraffin tissue blocks were obtained for 125 (74.0%). Therefore, the analyses in this study are based on the review of the H&E-stained slides of benign breast biopsy specimens and subsequent cancer from these 169 participants. Analysis of hormone receptor status was restricted to the 125 cases with available paraffin blocks. The pathology review of all breast cancer specimens was conducted by pathologists blinded to the preceding BBD category. The slides of invasive carcinoma for these 169 cases were reviewed initially by 1 pathologist (T.W.J.), and the following pathologic features were recorded: (1) tumor size, measured grossly (if available from the corresponding pathology report) and microscopically (the single largest dimension of invasive cancer measurable on a representative slide; a tumor present in multiple fragments was considered not measurable); (2) axillary lymph node status (derived from the pathology report and by review of available lymph nodes); (3) histologic type; (4) histologic grade, according to the Elston and Ellis modification of the Bloom-Richardson grading system 28 (a tumor was not graded if 1 or more of the 3 features necessary for a grading score [ie, tubule formation, nuclear pleomorphism, and mitotic count] were unevaluable); (5) the presence of lymphatic vascular invasion; and (6) the presence of an extensive intraductal component, as previously described. 29 For cases with equivocal histologic features, the relevant slides were reviewed by a second pathologist (S.J.S.), and a consensus was obtained. Hormone Receptor Status Assayed by Immunohistochemical Study Estrogen receptor (ER) and progesterone receptor (PR) status of the invasive carcinomas were assayed by immunohistochemistry in 125 cases for which formalin-fixed paraffin-embedded tissue blocks were available. Tissue sections, 4 to 5 µm thick, were cut from a representative paraffin block from each case. These sections then were deparaffinized in two 5-minute changes of xylene and were rehydrated through alcohols to distilled water. Endogenous peroxidase activity was blocked with 1% hydrogen peroxide in methanol for 10 minutes. Subsequently, sections were subjected to heat-induced epitope retrieval by heating in a microwave oven in citrate buffer (ph 6) for a total of 10 minutes (ie, two 5-minute periods with replacement of evaporated buffer between). ER Immunostaining Following heat-induced epitope retrieval, as described in the preceding section, the primary murine monoclonal antibody to ER protein (clone 1D5, DAKO, Carpinteria, CA) was applied overnight at 4 C at a 1:300 dilution. The slides then were sequentially incubated with biotinylated horse antimouse immunoglobulin (Vector, Burlingame, CA; 1:250 for 1 hour) and streptavidin-horseradish peroxidase (Vectastain Elite ABC, Vector; 1:200 for 1 hour). Following diaminobenzidine (DAB Plus, Zymed, San Francisco, CA), the slides were lightly stained with methyl green. PR Immunostaining The method was almost the same as that for the ER immunoassay, except the primary murine monoclonal antibody to PR protein (clone 1A6, DAKO) was applied for 1 hour at room temperature at a 1:100 dilution. For both ER and PR, a case was considered positive for the antigen if more than 10% of tumor cells showed distinct nuclear staining with the relevant antibody. A case was scored negative for the antigen if there was no staining of the tumor nuclei but normal breast epithelial nuclei (which served as an internal positive control) showed staining. A case was considered unevaluable if there was no staining of tumor nuclei and the normal breast epithelial nuclei also showed no staining with the respective antibody or if no normal breast epithelium was present. For both ER and PR assays, positive controls were included in each staining run and consisted of freshly cut cases known to express either ER or PR, as appropriate. Negative controls consisted of substituting mouse myeloma protein for ER or PR antibodies. All immunostains were scored jointly by 2 pathologists (T.W.J. and S.J.S.), and a consensus was obtained. Analytic Methods We used SAS PROC UNIVARIATE (SAS Institute, Cary, NC) to describe the distribution of breast cancer histologic characteristics by categories of past BBD. PROC ANOVA and NPAR1WAY (SAS Institute) for nonparametric analyses were used to test for differences in mean size of breast cancers and time between BBD and breast cancer diagnosis, across categories of past BBD. 30,31 A chi-square test of homogeneity was used in the comparison of frequency of breast cancer characteristics across stratum of previous BBD. Although age at breast cancer diagnosis was related to type of BBD, adjusting for age (age group categories of 34-39, 40-44, 45-49, 50-54, 55-59, 60-64, and years) did not materially change the associations between histologic features of previous BBD and the breast cancer characteristics. Since age adjustment did not affect the associations, unadjusted distributions and frequencies are presented. Results Previous benign biopsies revealed the following: nonproliferative disease, 38 women; proliferative disease 364 Am J Clin Pathol 2001;115: American Society of Clinical Pathologists

4 Anatomic Pathology / ORIGINAL ARTICLE without atypia, 98 women; and atypical hyperplasia, 33 women. Of women with atypical hyperplasia, 14 had ADH, 12 had atypical lobular hyperplasia (ALH), and 7 had both ADH and ALH. The median time between the benign breast biopsy result and the subsequent invasive carcinoma was 100, 124, and 92 months for women with nonproliferative disease, proliferative disease without atypia, and atypical hyperplasia categories, respectively (P =.238 across categories). Tumor size, measured either grossly (from the description in the pathology report) or by microscopic review, did not differ significantly across categories of previous BBD Table 1. Axillary lymph node status, determined by pathology report or by microscopic examination of available lymph nodes, also was similar across groups Table 2. The histologic types of invasive carcinoma did not differ significantly according to previous BBD category Table 3. In particular, infiltrating ductal carcinomas were present in 58%, 67%, and 61% of women with previous benign biopsy specimens categorized as nonproliferative disease, proliferative disease without atypia, and atypical hyperplasia, respectively. There was no preponderance of special types of cancers in any of the 3 groups. Similarly, the histologic grade of the invasive carcinomas was not significantly different between categories Table 4. Specifically, the women with Table 1 Tumor Size of Invasive Carcinomas Categorized According to Histologic Subtype of Previous Benign Breast Disease * Tumor Size Nonproliferative (n = 38) Proliferative Without Atypia (n = 98) Atypical Hyperplasia (n = 33) Gross size (mm) No. of cases evaluable Mean Median Range Microscopic size (mm) No. of cases measurable Mean Median Range * Number of cases in each size group does not equal the total number of cases in the categories since size data were not always available. For 7 tumors, the microscopic size was not evaluable. P =.234 for nonparametric test of differences in mean size across categories of benign breast disease. P =.440 for nonparametric test of differences in mean size across categories of benign breast disease. Table 2 Axillary Lymph Node Status of Invasive Carcinomas Categorized According to Histologic Subtype of Previous Benign Breast Disease * Axillary Lymph Node Status Nonproliferative (n = 38) Proliferative Without Atypia (n = 98) Atypical Hyperplasia (n = 33) By pathology report No. of cases with lymph nodes No. (%) node-positive 8 (42) 15 (48) 8 (44) By microscopic review No. of cases with lymph nodes No. (%) node-positive 4 (36) 15 (58) 5 (38) * P =.905 for differences in proportion with positive lymph nodes from pathology report across categories of benign breast disease. P =.359 for differences in proportion with positive lymph nodes by microscopic review across categories of benign breast disease. Table 3 Histologic Type of Invasive Breast Carcinoma Categorized According to Histologic Subtype of Previous Benign Breast Disease * Histologic Type of Invasive Carcinoma Nonproliferative (n = 38) Proliferative Without Atypia (n = 98) Atypical Hyperplasia (n = 33) Infiltrating ductal 22 (58) 66 (67) 20 (61) Infiltrating lobular 8 (21) 12 (12) 7 (21) Mixed ductal and lobular 6 (16) 14 (14) 4 (12) Medullary 0 (0) 1 (1) 0 (0) Mucinous 1 (3) 4 (4) 1 (3) Tubular 1 (3) 1 (1) 1 (3) * Data are given as number (percentage). Percentages may not sum to 100% owing to rounding. Overall, P =.931 for differences in histologic types by category of benign breast disease. P =.534 for differences across infiltrating ductal vs all other categories by benign breast disease status. American Society of Clinical Pathologists Am J Clin Pathol 2001;115:

5 Jacobs et al / BREAST CANCERS AFTER BENIGN BIOPSY DIAGNOSES previous atypical hyperplasia did not have more low-grade invasive carcinomas than did the other 2 categories (36% compared with 37% and 31% for nonproliferative and proliferative without atypia, respectively). The proportion of cases with lymphatic vascular invasion or with an extensive intraductal component was similar in all groups Table 5. We also analyzed the histologic type and grade of invasive carcinoma in relation to the type of atypical hyperplasia. These analyses are limited by the small number of cases in the various subgroups. Of note, the proportion of infiltrating ductal carcinomas was similar in women with ADH (71%) and in those with ALH (75%). While the proportion of infiltrating lobular carcinomas was higher in women with both ADH and ALH than with either ADH and ALH alone, these results should be interpreted cautiously since only 7 women had both ADH and ALH Table 6. The histologic grade of the subsequent carcinomas did not differ among women with ADH alone, ALH alone, or both ADH and ALH Table 7. Of 125 total cases with available tissue blocks, 109 (87.2%) were evaluable for ER and 105 (84.0%) were evaluable for PR. ER and PR status did not differ between categories Table 8. Of note, 85.3% of all cases were ER-positive and 81.9% of all cases were PR-positive. Fifteen women had bilateral previous biopsies that revealed BBD. One of these women had 2 histologically distinct synchronous carcinomas in the same breast. Five women had bilateral breast carcinomas. Discussion Previous studies have demonstrated clearly that the subsequent risk of breast cancer varies according to the histologic category of BBD. 1-3,25,26,32 However, the results of the present study suggest that the pathologic features and hormone receptor status of invasive breast cancers that Table 4 Histologic Grade of Invasive Breast Carcinomas Categorized According to Histologic Subtype of Previous Benign Breast Disease * Histologic Grade Nonproliferative (n = 38) Proliferative Without Atypia (n = 98) Atypical Hyperplasia (n = 33) I 14 (37) 30 (31) 12 (36) II 13 (34) 32 (33) 12 (36) III 10 (26) 33 (34) 9 (27) Not evaluable 1 (3) 3 (3) 0 (0) * Histologic grade according to the Elston and Ellis modification of the Bloom-Richardson grading system. Data are given as number (percentage). Percentages may not sum to 100% owing to rounding. P =.883 for differences in histologic grade across categories of benign breast disease. A case was not graded if 1 or more of the 3 features necessary for grading (tubule formation, nuclear pleomorphism, and mitotic count) were unevaluable. Table 5 Presence of Lymphatic Vascular Invasion (LVI) and an Extensive Intraductal Component (EIC) in Invasive Carcinomas Categorized According to Histologic Subtype of Previous Benign Breast Disease * Nonproliferative (n = 38) Proliferative Without Atypia (n = 98) Atypical Hyperplasia (n = 33) LVI present 5 (13) 15 (15) 3 (9) EIC positive 5 (13) 18 (18) 7 (21) * Data are given as number (percentage). P =.630 for differences in the presence of LVI across categories of benign breast disease. P =.651 for differences in the presence of EIC across categories of benign breast disease. Table 6 Histologic Type of Invasive Breast Carcinoma Categorized According to Subtype of Atypical Hyperplasia * Histologic Type of Atypical Ductal Atypical Lobular Atypical Ductal Hyperplasia and Atypical Invasive Carcinoma Hyperplasia (n = 14) Hyperplasia (n = 12) Lobular Hyperplasia (n = 7) Infiltrating ductal 10 (71) 9 (75) 1 (14) Infiltrating lobular 2 (14) 1 (8) 4 (57) Mixed ductal and lobular 1 (7) 2 (17) 1 (14) Mucinous 1 (7) 0 (0) 0 (0) Tubular 0 (0) 0 (0) 1 (14) * Data are given as number (percentage). Percentages may not sum to 100% owing to rounding. Overall, P =.075 for differences in histologic types by type of atypical hyperplasia. P =.030 for differences in proportion of infiltrating lobular carcinoma vs all other types of invasive carcinoma by type of atypical hyperplasia. P =.018 for differences of infiltrating ductal vs all other types of invasive carcinoma by type of atypical hyperplasia. Present in the same previously benign breast biopsy specimen. 366 Am J Clin Pathol 2001;115: American Society of Clinical Pathologists

6 Anatomic Pathology / ORIGINAL ARTICLE Table 7 Histologic Grade of Invasive Breast Carcinomas Categorized According to Type of Previous Atypical Hyperplasia * Atypical Ductal Hyperplasia and Histologic Grade Atypical Ductal Hyperplasia (n = 14) Atypical Lobular Hyperplasia (n = 12) Atypical Lobular Hyperplasia (n = 7) I 6 (43) 3 (25) 3 (43) II 5 (36) 5 (42) 2 (28) III 3 (21) 4 (33) 2 (28) * Histologic grade according to the Elston and Ellis modification of the Bloom-Richardson grading system. Data are given as number (percentage). Percentages may not sum to 100% owing to rounding. A case was not graded if 1 or more of the 3 features necessary for grading (tubule formation, nuclear pleomorphism, and mitotic count) were unevaluable. P =.874 for differences in histologic grade across type of atypical hyperplasia. Present in the same previously benign breast biopsy specimen. Table 8 Hormone Receptor Status of Invasive Carcinomas by Immunohistochemical Study Categorized According to Histologic Subtype of Previous Benign Breast Disease * Hormone Receptor Status Nonproliferative Proliferative Without Atypia Atypical Hyperplasia Estrogen receptor No. of evaluable cases No. (%) of positive cases 17 (77) 58 (89) 18 (82) Progesterone receptor No. of evaluable cases No. (%) of positive cases 19 (83) 52 (87) 15 (68) * P =.342 for differences in proportion of estrogen receptor positive cases across categories of benign breast disease. P =.156 for differences in proportion of progesterone receptor positive cases across categories of benign breast disease. develop in women with a previous breast biopsy with a benign result do not vary according to BBD status. In particular, breast cancers that arise in women with previous atypical hyperplasia do not have distinctive features and do not seem to be primarily low grade. There are few available data about the pathologic features of breast cancers in women with previous (not concurrent) biopsy-proven BBD categorized according to the criteria of Dupont and Page 1 and Page et al. 24 In a smaller study, Page and coworkers 24 reported on the histologic type of invasive cancer in women with previous atypical hyperplasia. Of 150 women with ADH, 18 (12.0%) developed invasive carcinoma, 11 of which were the not otherwise specified type, 4 had infiltrating ductal carcinoma with more than 60% DCIS, and 1 each was mucinous, tubular, or invasive cribriform. Of 126 women with ALH, 16 (12.7%) developed invasive carcinoma, of which 8 were the not otherwise specified type, 3 had more than 60% in situ carcinoma, 2 were infiltrating lobular, 1 was mixed-type invasive lobular, and 1 was atypical medullary carcinoma. However, in the 34 cases, these authors did not report other pathologic features or hormone receptor status. Importantly, information about the pathologic features of the cancers was provided only for women with a previous benign biopsy that revealed atypical hyperplasia, and subsequent carcinomas in women with previous nonproliferative disease or proliferative disease without atypia were not included in the analysis. Interestingly, the proportion of invasive carcinomas in our study that were ER-positive (overall 85.3%) is higher than the published range of 60% to 70%. 33 The observation may have important implications for breast cancer prevention strategies, particularly in view of the recent findings from the National Surgical Adjuvant Breast Project Breast Cancer Prevention Trial (P1), which indicate that the use of tamoxifen significantly reduced the risk of ER-positive cancers, including those in women with benign breast lesions such as atypical hyperplasia. 34 The results of our study also support the notion that atypical hyperplasias represent markers of generalized increased breast cancer risk, since the histologic features of cancers in women with atypical hyperplasia do not seem to be distinctive. However, the possibility that at least some atypical hyperplasias represent direct precursor lesions cannot be excluded, particularly in view of emerging genetic evidence (including data from microdissection and comparative genomic hybridization studies) 15,16,19-23,35 linking atypical hyperplasias and low-grade DCIS and, in turn, low-grade DCIS with certain types of invasive breast cancers. These theories are not mutually exclusive, because at the time of original benign breast biopsy, residual BBD (ipsilateral and/ or bilateral) might have remained and, therefore, could have been a true precursor lesion to the invasive carcinoma. Although the number of cases for an analysis of the type of atypical hyperplasia in relation to subsequent carcinoma was American Society of Clinical Pathologists Am J Clin Pathol 2001;115:

7 Jacobs et al / BREAST CANCERS AFTER BENIGN BIOPSY DIAGNOSES limited in our study, the patients with previous benign biopsies showing both ADH and ALH had a higher proportion of invasive lobular carcinomas, while those with only ADH or ALH had similar proportions of subsequent invasive ductal carcinomas. Although these data would support the notion that atypical hyperplasias are generalized risk factors for subsequent cancer (irrespective of histologic lineage), this warrants further investigation, in the light of new data about the possible genetic associations between ALH, lobular carcinoma in situ, and subsequent invasive carcinomas with similar cytologic features of individual tumor cells. 17,18 Analyses of the type of DCIS in relation to the category of previous BBD and the type of BBD and DCIS present concurrently with the invasive carcinomas in these patients should further help to elucidate the relationship between BBD and evolution of subsequent invasive cancer, and such analyses are in progress. Our data suggest that the pathologic features and hormone receptor status of breast cancers that develop in women with a previous breast biopsy with a benign result do not vary according to the type of previous BBD. Furthermore, breast cancers that arise in patients with atypical hyperplasia do not seem to have distinctive features and, specifically, do not seem to be primarily low grade. From the 1 Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; and the 2 Channing Laboratory, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA. Supported by grants CA and CA from the National Institutes of Health, Bethesda, MD. Presented in part at the United States and Canadian Academy of Pathology annual scientific meeting, San Francisco, CA, March 1999, and at the 22nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December Address reprint requests to Dr Jacobs: Dept of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA References 1. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. 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