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2007;16:467-472. Published online March 2, 2007.Cancer Epidemiol Biomarkers Prev

Erin L. Ashbeck, Robert D. Rosenberg, Patricia M. Stauber, et al.

Breast CancerBenign Breast Biopsy Diagnosis and Subsequent Risk of

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Benign Breast Biopsy Diagnosis and SubsequentRisk of Breast Cancer

Erin L. Ashbeck, 1 Robert D. Rosenberg, 2 Patricia M. Stauber, 1 and Charles R. Key 31Epidemiology and Cancer Prevention, Cancer Research and Treatment Center and Departments of 2Radiology and3Pathology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico

Abstract

Background: We examine benign breast biopsy diagnosesas reported by community pathologists in New Mexicoand investigate associations with future breast cancerdevelopment.Methods: Using data collected between 1992 and 2000 by theNew Mexico Mammography Project and cancer data through2003 from the New Mexico Tumor Registry, we calculatedbreast cancer rates following 14,602 benign breast biopsiesfor women ages 30 to 89 years. For comparison, we alsocalculated the breast cancer rate following 215,283 normalscreening mammograms. Hazard ratios (HR) are presented.Results: We identified 480 subsequent breast cancer diagno-ses among 14,602 women with benign breast biopsies and4,402 breast cancer diagnoses among 215,283 women withmammograms assigned a negative or benign findingassessment. Histologic diagnoses in absence of atypia had anage-adjusted HR of 1.95 [95% confidence interval (95% CI),

1.77-2.15]. Among low-risk histologic diagnoses, the stron-gest associations with subsequent breast cancer developmentincluded adenosis, apocrine metaplasia, calcifications, andductal hyperplasia. Fibroadenoma, inflammation, and cystsdid not exhibit an association with breast cancer develop-ment. Women with low-risk diagnoses and breast tissuecharacterized as fatty or with scattered densities had a HR of2.09 (95% CI, 1.68-2.60), whereas women with low-riskhistologic diagnoses and dense breasts had a HR of 3.36(95% CI, 2.83-3.99).Conclusions: The observed breast cancer occurrence con-tributes to evidence of increased risk following benignbiopsy. The risk associated with histologic diagnoses inabsence of atypia was twice the risk experienced by womenwith normal mammogram evaluations and may be modifiedby breast density. (Cancer Epidemiol Biomarkers Prev2007;16(3):46772)

Introduction

Benign histologic diagnoses of breast biopsies are common andhave been associated with future development of breastcancer. Various pathologies are classified as benign, andalthough the risk increase associated with atypical hyperplasiahas been well established (1-6), more prevalent histologic

diagnoses have not been as extensively evaluated. The CancerCommittee of the College of American Pathologists updatedtheir 1985 Consensus statement in 1998, classifying ductalcarcinoma in situ , lobular carcinoma in situ , and atypicalhyperplasia as marked or moderate risk factors for futuredevelopment of invasive breast cancer, whereas the remaininglesions were classified as either slight or non risk factors (7, 8).However, Wang et al. (9) reported a statistically significantincreased risk associated with these lower category lesionsfrom the National Surgical Adjuvant Breast and BowelProjects Breast Cancer Prevention Trial. Hartmann et al.reported findings from the Mayo Clinic suggesting increasedrisk persisting for at least 25 years for women diagnosed with benign breast disease, in contrast to earlier findings (10, 11),although no increased risk was found specifically for women

with no family history and nonproliferative findings (12).Commonly diagnosed histologic features include adenosis,apocrine metaplasia, calcifications, cysts, fibroadenomas,fibrocystic changes, fibroses, ductal hyperplasia, and inflam-mation. Although a few studies (1, 3, 13-21) have investigated

some of these histologic diagnoses, the degree of riskassociation has not been as well established, and there is needto confirm the significance of these diagnoses when made bycommunity pathologists.

To address these questions, we examined clinical pathology

reports collected in New Mexico for 14,602 women with benign breast diagnoses. After a median of 6.8 years of follow-up time,480 women were diagnosed with breast cancer. We calculated breast cancer rates for women diagnosed with commonhistologic features and compared breast cancer risk for thesewomen with women with no known breast biopsy experienceand a normal mammogram.

Materials and Methods

Data Collection. Benign breast pathology reports werecollected and abstracted as part of the New Mexico Mammog-raphy Project. The New Mexico Mammography Project is amember of the Breast Cancer Surveillance Consortium, aNational Cancer Institutefunded project created to evaluatethe effectiveness of mammography screening (22). The benign breast data are linked with the New Mexico Tumor Registry toascertain the subsequent occurrence of breast cancer. The NewMexico Tumor Registry is a statewide, population-basedcancer registry and one of the National Cancer Institutefunded Surveillance, Epidemiology, and End Results registriesthat provide estimates of cancer incidence, treatment, andsurvival and mortality rates. The project was reviewed andapproved by the University of New Mexico Health SciencesCenter Human Research Review Committee.

New Mexico Tumor Registry staff abstracted pathologyreports using Systematized Nomenclature of Human andVeterinary Medicine codes. We grouped morphologic termsinto broader categories for the analysis. The atypical hyper-

plasia category includes both lobular and ductal forms. Theadenosis category includes adenosis, fibrosing adenosis, and

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Cancer Ep idemiol Biomarkers Prev 2 007;16(3). March 2007

Received 5/14/06; revised 12/6/06; accepted 12/19/06.Grant support: National Cancer Institute grant 5 U01 CA69976.The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.Requests for reprints: Robert D. Rosenberg, Department of Radiology, MSC10 5530, 1University of New Mexico, Albuquerque, NM 87131-0001. Phone: 505-272-0011;Fax: 505-272-5821. E-mail: [email protected]

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adenofibrosis. The cysts category includes cyst, epithelialinclusion cyst, apocrine cyst, and hemorrhagic cyst. Thefibroses category includes fibrosis, scar, diabetic fibrousmastopathy, and radial scar. The ductal hyperplasia categoryincludes intraductal hyperplasia, papillomatosis, and intra-ductal papilloma. The inflammation category includes inflam-mation not otherwise specified, acute inflammation, abscess,chronic inflammation, granulomatous inflammation, lipogra-nuloma, foreign body giant cell granuloma, granulation tissue,and inflammatory fat necrosis.

Population and Biopsy Selection. Women residing in NewMexico, ages 30 to 89 years, with a benign breast biopsy in ourdatabase between 1992 and 2000 were selected for analysis.Women with a known history of breast cancer, mastectomy, or breast implants at the time of biopsy were excluded. Startingwith a womans first breast biopsy report in the database, weidentified any subsequent breast biopsy that occurred within90 days and repeated the process until the 90 days followingthe last biopsy were biopsy-free, thus combining the results of all biopsies that occurred over a short period. The purpose of combining biopsy results clustered in time is to capture themost complete diagnosis available. Women diagnosed withductal carcinoma in situ or invasive breast cancer within 90days were excluded because we are only interested infollowing women with an entirely benign diagnosis. Follow-up time begins to accumulate on the 91st day after thediagnosis is complete.

For comparison, we identified women according to the sameselection and exclusion criteria with a screening mammogramassigned a negative or benign finding assessment, withno recommendations for additional evaluation, and with arecommendation to return for routine screening. Women witha known history of breast biopsy, breast cancer, mastectomy,or breast implants at the time of the mammogram wereexcluded. Women diagnosed with ductal carcinoma in situ orinvasive breast cancer within 90 days of the mammogram wereexcluded. Follow-up time begins to accumulate on the 91st dayafter the mammogram.

Statistical Analysis. The outcome, breast cancer, wasdefined as either ductal carcinoma in situ or invasive cancer.Breast cancer rates were calculated for each of the histologic

categories described previously. We generated Kaplan-Meierplots (SAS 8.2, LIFETEST procedure) to show the breast cancer

accumulation for each histologic group. We used Coxregression (SAS 8.2, PHREG procedure) to generate breastcancer hazard ratios (HR), and the women with negative and benign finding mammograms served as a reference group.Women in the reference group were censored at the time of any subsequent benign biopsies. If a woman initially receiveda negative mammogram diagnosis and later received a benign biopsy diagnosis, then she is included in both the benign biopsy group and the negative mammogram group, with herfollow-up time allocated accordingly.

We had to consider that a single pathology report often listsmultiple histologic features and calculated Pearson correlationcoefficients to evaluate the association among histologicdiagnoses. Because atypical hyperplasia, cytologic atypia,and lobular carcinoma in situ diagnoses are well documentedin the literature in terms of their association with elevated risk,we separated any diagnosis that included one of these high-risk histologies and refer to the remaining as low-riskhistologic diagnoses. Existing literature does not providesufficient guidance for further hierarchical classificationamong the low-risk histologic diagnoses. Therefore, althoughthe group of women classified as high risk are mutuallyexclusive of the women in the low-risk groups, we did not usea hierarchical classification scheme for the low-risk diagnoses,and the specific low-risk groups are not mutually exclusive of each other. For example, if a woman has an initial diagnosis,including both adenosis and calcifications, she is included inthe rates and HRs for adenosis and for calcifications. However,if her initial diagnosis also includes atypical hyperplasia, she isclassified as high risk and only included in the analysis foratypical hyperplasia and not in the analyses of adenosis orcalcifications. Each diagnosis group was examined individu-ally; for example, in the analysis of adenosis, women with alow-risk diagnosis that includes adenosis were compared withwomen with a negative/benign mammogram in a Cox model.The first HR in Table 3 is adjusted for age in deciles. Thesecond HR is further adjusted by including indicator variablesfor concurrent diagnoses of apocrine metaplasia, calcifications,cysts, fibroadenoma, fibroses, ductal hyperplasia, and inflam-mation. Analyses of other specific low-risk diagnoses aresimilarly adjusted for concurrent low-risk diagnoses.

We investigated breast density, approximate menopausal

status, and family history of breast cancer as modifiers of theassociation between benign histologic diagnoses and future

Table 1. Patient characteristics

Women withhigh-risk histologic

diagnoses, n = 532 (%)

Women withlow-risk histologic

diagnoses, n = 14,070 (%)

Women withnegative/benign

mammograms, n = 215,283 (%)

Age, y30-39 40 (8) 2,474 (18) 23,391 (11)40-49 168 (32) 5,160 (37) 78,595 (37)50-59 158 (30) 3,274 (23) 50,892 (24)60-69 94 (18) 2,010 (14) 35,881 (17)70-79 56 (11) 986 (7) 21,222 (10)80-89 16 (3) 166 (1) 5,302 (2)

Race/ethnicityAmerican Indian 19 (4) 435 (3) 15,299 (7)Hispanic 165 (31) 4,193 (30) 65,614 (30)Non-Hispanic White 324 (61) 8,571 (61) 123,455 (57)Other 8 (2) 209 (1) 3,152 (1)Missing 16 (3) 662 (5) 7,763 (4)

Breast densityFatty/scattered densities 119 (22) 3,171 (23) 83,074 (39)Dense 182 (34) 4,404 (31) 57,868 (27)Missing 231 (43) 6,495 (46) 74,341 (35)

Family history of breast cancerNo 328 (62) 8,023 (57) 146,894 (68)Yes 48 (9) 1,097 (8) 17,793 (8)Missing 156 (29) 4,950 (35) 50,596 (24)

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breast cancer development and also adjusted for these factors,age and race/ethnicity, as potential confounders whenpossible, depending on the availability of data.

Results

Benign breast biopsies were identified for 14,602 women, andscreening mammograms with a negative or benign findingassessment were identified for 215,283 women. Eighty-fivepercent of the pathology reports resulted from surgical biopsies, predominantly excisional and core biopsies, whereasthe remaining 15% of the pathology reports were from fine-needle aspirations. Five hundred thirty-two of the 14,602women with benign breast biopsies received a high-riskdiagnosis. Among the women with benign breast biopsies,93% had only one biopsy to consider, whereas 6.2% had two biopsies in a short period, and 0.4% had three or four biopsiesin the diagnostic series. The maximum duration from first tolast biopsy in the diagnostic series was 145 days.

Baseline characteristics, including age, race/ethnicity, breastdensity, and family history of breast cancer in a first-degreerelative, are presented in Table 1, stratified into three groups,including women with high-risk histologic diagnoses, womenwith low-risk histologic diagnoses, and women with screeningmammograms assigned a negative or benign finding assess-ment. The age distributions among the three groups were

similar, although women with high-risk histologic diagnoseswere slightly older. Although the racial/ethnic distributionswere also similar among the three groups, Non-HispanicWhite women had a higher representation in the benign biopsy groups compared with the negative mammogram

group. Despite considerable missing data for breast density(from 35-46%), the available data suggest highest breastdensity among women with high-risk histologic diagnosesfollowed by women with low-risk histologic diagnoses and thelowest breast density among the negative mammogram group.We also see a slightly higher proportion of women with afamily history of breast cancer among women with high-riskhistologic diagnoses, although the availability of data waslimited (24-35% missing).

The pathology diagnosis was characterized by a singlehistologic category for 45% of the women, whereas theremaining 55% was characterized by two or more histologiccategories. Calcifications exhibited the strongest correlationwith other histologic categories, including ductal hyperplasia(0.22), adenosis (0.20), atypical hyperplasia (0.16), and fibro-cystic changes (0.16). Fibrocystic changes were positivelycorrelated with ductal hyperplasia (0.15) and calcifications(0.16). Apocrine metaplasia was also correlated with hyperpla-sia, not otherwise specified (0.15), and ductal hyperplasia wascorrelated with adenosis (0.14). The strongest negative corre-lations include fibrocystic changes with fibroadenoma ( 0.15),

Figure 1. Cumulative incidence of breast cancer following benign breast diagnosis.

Table 2. Breast cancer rates following benign biopsy

Breast cancers(in situ /invasive)

Women at risk Breast cancersper 100,000 woman-years

Negative/benign mammograms 4,402 (710:3,692) 215,283 266Atypical hyperplasia 17 (5:12) 319 1,148Cytologic atypia 4 (1:3) 111 770Lobular carcinoma in situ 8 (4:4) 115 899Low-risk histologic diagnoses 451 (82:369) 14,070 466

Adenosis 36 (8:28) 1,182 541Apocrine metaplasia 45 (5:40) 1,127 748Calcifications 67 (13:54) 2,094 604Cysts 25 (4:21) 1,096 398Fibroadenoma 54 (11:43) 2,943 273Fibrocystic breast changes 217 (48:169) 6,128 515Fibroses 68 (11:57) 2,418 473Hyperplasia, ductal 74 (15:59) 2,279 563Inflammation 18 (10:8) 1,006 305

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fibroses ( 0.14), inconclusive ( 0.13), negative ( 0.21), andother ( 0.13). Negative results were also negatively correlatedwith fibroadenomas ( 0.15). The absolute value of the cor-relation coefficient between all other pairs of histologiccategories was V 0.11 and in most cases


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Figure 2 examines the low-risk histology diagnoses individ-ually over time. We only display curves for groups with largersample sizes and restrict our interpretation to the first several

years, as the curves become erratic due to limited sample sizeafter 4 to 5 years. Women diagnosed with apocrine metaplasia,adenosis, calcifications, ductal hyperplasia, fibroses, and cystsexperienced more breast cancer diagnoses than those withnormal mammograms. Women diagnosed with inflammationand fibroadenomas did not experience more breast cancerdiagnoses than women with normal mammograms.

The age-adjusted HRs and 95% confidence intervals (95%CI) for atypical hyperplasia, cytologic atypia, and lobularcarcinoma in situ were 4.40 (2.73-7.09), 3.58 (1.34-9.52), and 3.20(1.60-6.40), respectively, compared with women with screeningmammograms with negative or benign finding assessments(Table 3). The remaining low-risk histologic diagnoses had anage-adjusted HR of 1.95 (95% CI, 1.77-2.15). The termfibrocystic breast changes was broadly applied by clinical

pathologists, as 44% of the low-risk diagnoses included asimilar term (6,128 women with fibrocystic breast changes of the 14,070 women with low-risk diagnoses; Table 2), eitheralone or in conjunction with other descriptors, with an age-adjusted HR of 2.07 (95% CI, 1.80-2.37). Specific low-riskhistologic diagnoses with the strongest associations withsubsequent breast cancer development included adenosis,apocrine metaplasia, calcifications, and ductal hyperplasia(Table 3). After adjustment for concurrent low-risk diagnoses,the HRs increased for adenosis, apocrine metaplasia, andductal hyperplasia, whereas they decreased for other low-riskdiagnoses. Cysts were significantly associated with subsequent breast cancer development before adjustment for concurrentdiagnoses with HR of 1.64 (95% CI, 1.11-2.43), whereas afteradjustment, the HR attenuated and was no longer significantwith a HR of 1.28 (95% CI, 0.74-2.21). Fibroadenoma andinflammation diagnoses did not exhibit a notable magnitude of effect or a statistically significant association with subsequent breast cancer development.

When we stratified the data at age 55 years as anapproximation for menopausal status, the HRs were consis-tently higher in the group presumed to be postmenopausal(Table 4). Women with a low-risk histologic diagnosis whowere 55 y Fatty/scattered densities Dense

Negative/benign mammograms 1.00 x 1.16 (1.04-1.30) 1.00k 2.02 (1.86-2.18)Low-risk histologic diagnoses 1.87 (1.64-2.13) 2.39 (2.02-2.83) 2.09 (1.68-2.60) 3.36 (2.83-3.99)

Adenosis 2.51 (1.38-4.57) 3.53 (1.87-6.66) 4.28 (1.90-9.66) 4.63 (2.10-10.19)Apocrine metaplasia 3.36 (1.93-5.84) 3.68 (2.11-6.42) 4.38 (1.93-9.93) 7.58 (3.93-14.64)Calcifications 2.16 (1.34-3.50) 2.31 (1.45-3.69) 3.15 (1.48-6.74) 3.12 (1.48-6.60)Cysts 1.16 (0.59-2.27) 1.70 (0.85-3.39) 0.38 (0.05-2.92) 3.26 (1.69-6.31)Fibroadenoma 1.23 (0.86-1.75) 1.09 (0.61-1.97) 1.49 (0.80-2.78) 1.58 (0.87-2.88)Fibroses 1.52 (0.99-2.33) 2.45 (1.66-3.63) 1.78 (1.00-3.18) 3.10 (1.83-5.24)Hyperplasia, Ductal 2.13 (1.38-3.29) 2.58 (1.75-3.80) 2.36 (1.34-4.18) 3.86 (2.24-6.65)Inflammation 1.09 (0.51-2.31) 1.39 (0.55-3.50) 1.90 (0.60-6.05) 3.16 (1.30-7.68)

*HRs (95% CI) are adjusted for age in deciles.c HRs for specific low-risk diagnoses are adjusted for concurrent low-risk diagnoses seen in this list.b HRs stratified by breast density are calculated from a subset of women with available breast density scores.xWomen with negative/benign mammograms ages V 55 y are the reference group in all models stratified by approximate menopausal status.kWomen with negative/benign mammograms with fatty/scattered breast densities are the reference group in all models stratified by breast density.

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slightly modified the association between low-risk histologicdiagnosis and breast cancer development in our data, thoughthe extent of missing data limits our ability to evaluateinteractions.

The results of these analyses must be considered in thecontext of several limitations. We did not attempt todistinguish between markers of elevated overall breast cancerrisk and lesions with increased risk of local breast canceroccurrence. We did not have complete information about all of the known epidemiologic breast cancer risk factors availablefor evaluating potential confounders and effect modifiers, aswe could not dictate what information was collected by thefacilities. The histologic terms were abstracted from clinicalpathology reports, meaning each diagnosis was not the resultof a consistent team of pathologists working with strictlydefined criteria and an algorithm to resolve disagreements, asused in other studies. Furthermore, poor agreement amongpathologists about the distinction between low-grade ductalcarcinoma in situ and atypical ductal hyperplasia in theabsence of a strictly controlled protocol has been discussedelsewhere (29-31). Pathologists also differ in the level of detailthey specify on a clinical report, and some may report only theprimary histologic feature, whereas others may report multiplefeatures. Whereas some investigators have chosen to compare

with the overall population (12), we used women with anormal mammogram as our reference population. Womenreceiving regular health care, such as mammography or benign breast biopsies, will have a higher chance of cancerdiagnosis than those not receiving regular health care. Clearly,the choice of control group could alter the HR estimates.

Physicians who make decisions about patient care andadvise patients about the importance of any pathologydiagnosis do so based on clinical pathology reports. Althoughthis analysis does not constitute biological evidence of therisk of a particular histologic feature, this analysis is useful asit evaluates the association between actual informationprovided to practicing physicians and subsequent breastcancer diagnosis.

AcknowledgmentsWe thank William C. Hunt and Deirdre Hill for helpful comments onan earlier version of this manuscript.

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