Selecting Patients for Breast-Conserving TherapyThe Importance of Lobular Histology

Monica Morrow, M.D.1

Kristine Keeney, M.D.2

Denise Scholtens, Ph.D.3

Janet Wei, B.S.2

Jennifer Steel, B.S.2

Seema A. Khan, M.D.2

1 Department of Surgical Oncology, Fox ChaseCancer Center, Philadelphia, Pennsylvania.

2 Lynn Sage Breast Program, Feinberg School ofMedicine, Northwestern University, Chicago, Illi-nois.

3 Department of Preventive Medicine, FeinbergSchool of Medicine, Northwestern, University, Chi-cago, Illinois.

Address for reprints: Monica Morrow, M.D., De-partment of Surgical Oncology, Fox Chase CancerCenter, 333 Cottman Avenue, Philadelphia, PA19111-2497; Fax: (215) 214-4035; E-mail:Monica.Morrow@fccc.edu

Received November 11, 2005; revision receivedJanuary 20, 2006; accepted February 2, 2006.

BACKGROUND. Concerns exist regarding the ability to select patients with lobular

carcinoma for breast-conserving therapy (BCT) using mammography. The purpose

of this study was to compare the conversion rate from BCT to mastectomy among

patients with lobular (ILC) and ductal carcinoma (IDC), and to compare the

number of resections needed to obtain negative margins.

METHODS. In all, 349 patients with pure or mixed ILC were identified from a

database and 318 were successfully matched to 2 controls with IDC on the basis of

year of diagnosis, menopausal status, and stage of disease. Conditional logistic

regression was used to control for matching.

RESULTS. Patients with ILC were older, had larger tumors (2.6 vs. 2.1 cm; P�.001),

and were more likely to have contraindications to BCT (25% vs. 20%). In patients

thought to be candidates for BCT, no difference in success rate was noted on the

basis of histologic type after controlling for age and stage. In those undergoing

BCT, no difference in the number of procedures was seen on the bases of histology

after adjustment for age and stage.

CONCLUSIONS. Patients with ILC are not more likely to fail BCT than those with

IDC, nor do they require more operations to obtain negative margins. These results

do not support the use of more extensive preoperative evaluation such as magnetic

resonance imaging in patients with ILC. Cancer 2006;106:2563– 8.

© 2006 American Cancer Society.

KEYWORDS: lobular carcinoma, breast-conserving therapy, margins, reexcision.

Breast-conserving therapy (BCT) is an established treatment forwhich the contraindications are well defined. Improvements in

imaging, in the extent of pathologic evaluation of lumpectomy spec-imens, and the routine use of adjuvant systemic therapy for themajority of breast cancer patients have resulted in a decrease in localrecurrence rates in the preserved breast.1 Local recurrence rates inpatients who received systemic therapy in a series of National SurgicalAdjuvant Breast and Bowel Project (NSABP) trials were less than 5% at10 years of follow-up.2 In spite of this, concern has persisted regardingthe use of BCT in patients with infiltrating lobular carcinoma (ILC),which is perceived as more difficult to treat surgically than breastcarcinomas of other types due to its propensity for multifocality.3–5

Several recent studies have indicated that preoperative magneticresonance imaging (MRI) in women with ILC identifies more exten-sive disease than anticipated based on the results of mammographyand physical examination and detects unsuspected multifocal cancerin 25% to 50% of cases.6,7 These observations are difficult to reconcilewith the low rates of local failure observed after BCT, and may be areflection of biased selection of patients for MRI evaluation ratherthan characteristic of the entire spectrum of patients with lobular

2563

© 2006 American Cancer SocietyDOI 10.1002/cncr.21921Published online 8 May 2006 in Wiley InterScience (www.interscience.wiley.com).

carcinoma. Given the possibility that the extent of ILCis less reliably assessed by physical examination andconventional imaging than the extent of invasive duc-tal carcinoma (IDC), we hypothesized that the rate ofreexcision for positive surgical margins and the con-version rate from BCT to mastectomy would be higherin women with ILC than in those with IDC.

To test this hypothesis, we performed a retrospec-tive study of a matched group of patients with ILC andIDC and assessed clinical outcome data to determinewhether the ability to select patients for breast con-servation and the number of excisions needed to ob-tain negative margins differs between patients withILC and IDC.

MATERIALS AND METHODSStudy PopulationPatients diagnosed with ILC of pure or mixed typebetween 1995 and 2004 were identified in a prospec-tively maintained database of the Lynn Sage Compre-hensive Breast Care Center at Northwestern MemorialHospital after study approval by the NorthwesternUniversity Institutional Review Board. Each ILC pa-tient was matched to 2 IDC patients by menopausalstatus, year of diagnosis, and pathologic stage. Dataregarding demographics, presentation, pathology, andsurgical procedures were obtained from the database.Medical records were used to resolve incomplete orconflicting data. Patients who received preoperativechemotherapy, those who did not undergo a surgicalprocedure at Northwestern Memorial Hospital, andthose with a preoperative diagnosis of AJCC Stage IIIor Stage IV disease were excluded from the study.

The contraindications to BCT described by thejoint committee of the American College of Surgeons,American College of Radiology, and College of Amer-ican Pathologists were used to select patients for mas-tectomy.8 Absolute contraindications included a his-tory of prior irradiation to the breast field, diagnosisduring the first or second trimester of pregnancy, theinability to obtain negative surgical margins, and thepresence of diffuse indeterminate calcifications onmammogram. Relative contraindications were a largetumor size relative to the size of the breast and activecollagen vascular disease.

If excisional biopsy was performed for diagnosisthis was classified as the first surgical procedure, andany subsequent excisions were classified as reexci-sions. A positive surgical margin was defined as tumorcells touching an inked surface of the specimen. Allpatients with positive margins underwent reexcision.Reexcision was selectively undertaken in patients withmore than microscopic foci of tumor at a distance of�2 mm from an inked margin. This was performed at

the discretion of the attending physician based on theextent of margin involvement, the amount of remain-ing breast tissue in the area of the involved margin,and the size of the patient’s breast. The same defini-tion of a positive and negative margin was used forpatients with IDC and ILC.

The decision to convert from BCT to mastectomywas made on the basis of multiple clinical factorsincluding the size of the patient’s breast, number ofinvolved margins, extent of margin involvement, andthe patient’s acceptance of the possibility of multipleadditional surgical procedures if further reexcisionswere attempted. No arbitrary number of attempts atexcision was used to define the need for mastectomy.Failure of breast conservation was defined as the per-formance of a mastectomy in a patient in whom BCThad been attempted.

Statistical MethodsSummary comparisons between the lobular and duc-tal groups for age, tumor dimension on pathology,race, number of affected first-degree relatives, exten-sive intraductal component, palpable mass, numberof positive lymph nodes, and tumor grade were madeusing univariate conditional logistic regression modelsto control for matching. All reported P-values were2-sided. Summary statistics were calculated for all ILCand IDC patients, and for the subgroup of matchedtriplets in which all 3 were eligible for and elected toundergo BCT.

For formal evaluation of within-strata differencespertaining to failure of BCT, we used conditional lo-gistic regression models restricted to the subset of 119lobular-ductal triplets in which all 3 were deemed tobe candidates for BCT and elected to undergo theprocedure. Age was adjusted for as a continuous vari-able. The linearity assumption for age was tested bydividing age into 10-year groups (ages 20-29 years,ages 30-39 years, etc.), estimating separate beta coef-ficients for each age category, and checking for aroughly linear trend of the estimated coefficients. Inaddition to adjusting for age, we also explored furtheradjustments for pathologic tumor dimension, treatedas a continuous variable. Linearity of the tumor di-mension relation was tested in a similar manner to theage relation, and it was determined that a log trans-formation was needed to adequately satisfy this as-sumption. In this model, 1 ductal patient had missingdata for pathologic tumor size and therefore was notincluded.

We also used conditional logistic regression toformally evaluate within-strata differences pertainingto number of excisions, restricted to the subset of 81lobular-ductal triplets in which all 3 patients were

2564 CANCER June 15, 2006 / Volume 106 / Number 12

deemed eligible for BCT, elected to undergo the pro-cedure, and ultimately experienced successful BCT.The number of excisions was treated as 2 differentcategories: 1 or 2-3. We again adjusted for age as acontinuous variable, checking the linearity assump-tion in the same manner as the failure of BCT analysis.We also evaluated the same adjustment for tumordimension measured by pathological review (logtransformed).

In addition to the adjustments previously men-tioned for both models, we also explored extendedmodels including tumor dimension measured by clin-ical examination, mammography, and ultrasound.

RESULTSA total of 349 cases with a primary diagnosis of ILC ormixed ILC/IDC were identified, 24 of which were ex-cluded for the inability to match 2 women with IDC.Of the remaining 325 patients who were successfullymatched with 2 IDC patients, the pathologic diagnosisof ILC could not be verified in 7 cases (coded as ILC inthe database, but chart review revealed a differenthistology), and these were excluded, resulting in afinal sample of 318 lobular patients with 636 matchedwomen with IDC. The final pathologic stage distribu-tion of the lobular cancer patients was 138 patientswith Stage I disease, 150 patients with Stage II disease,27 patients with Stage III disease, and 3 patients withStage IV disease. The 3 patients with Stage IV diseasewere believed to have Stage II disease at the time ofsurgical therapy but were found to have metastasesduring metastatic workups performed before the ini-tiation of systemic treatment.

Characteristics of patients with ILC and IDC arecompared in Table 1. Patients with ILC were signifi-cantly older than their counterparts with IDC, and hadsignificantly larger tumors (2.6 cm vs. 2.1 cm), in spiteof being matched for stage and menopausal status.Palpable tumors were present in 175 of 318 of the ILCgroup (55%) versus 386 of 634 of the IDC group (61%)(P�.06). Needle localization was performed beforelumpectomy for the 45% of nonpalpable tumors in thelobular group and the 39% of tumors in the ductalgroup that were not palpable (P�.06). Palpable tu-mors were not wire localized and intraoperative ultra-sound was not used to direct the excision. The mam-mogram was negative in 54 of the 196 patients withILC with mammogram data (28%) versus 43 of 434patients with IDC (10%) with mammogram data(P�.001). Similarly, carcinoma could not be detectedby ultrasound in 50 of 221 ILC patients (23%) withultrasound data versus 33 of 394 IDC patients (8%)with ultrasound data (P�.001).

Of the 954 patients originally included in the anal-

ysis, 206 were not believed to be candidates for BCT,including 81 of the 318 patients with ILC (25%) and125 of the 636 patients with IDC (20%). The greaterpercentage of ILC patients who were ineligible for BCTis consistent with the larger size of tumors in thelobular group. Of the patients believed to be medicallyeligible for BCT, 79 chose to undergo mastectomy.This included 24 of 38 ILC patients and 55 of 636 IDCpatients (7.5% vs. 8.6%; P�.62). Because of thematched nature of the study design, all lobular-ductaltriplets for whom at least 1 patient was either ineligi-ble for BCT or chose mastectomy as initial treatmentwere excluded from the subsequent analyses. This left119 matched triplets for the analysis of the success ofBCT according to histologic type. The characteristics

TABLE 1Patient and Tumor Characteristics for All Lobular and DuctalPatients

Variable Lobular (n � 318) Ductal (n � 636) P*

Mean age atdiagnosis, y

(SD) 59.31 (11.39) 56.27 (12.54) �.001Mean tumor

dimension(pathologic) 2.632 (2.219) 2.055 (1.517) �.001†

(SD) (n � 315) (n � 628)Race (%)White 263 (82.7) 492 (77.4)Nonwhite 55 (17.3) 144 (22.6) .054No. of first-degree

relatives withbreast cancer(%)

0 258 (81.1) 499 (78.5)1� 60 (18.9) 137 (21.5) .350Extensive

intraductalcomponent (%)

No 264 (83.0) 473 (74.4)Yes 54 (17.0) 163 (25.6) .003No. of positive

lymph nodes(%)

0 211 (66.3) 377 (59.3)1-3 64 (20.1) 173 (27.2) .0024-9 23 (7.2) 57 (9.0) .05910� 20 (6.3) 29 (4.6) .740Grade (%)1 139 (43.8) 93 (14.7)2 135 (42.6) 206 (32.6) �.0013 43 (13.5) 332 (52.6) �.001

(n � 317) (n � 631)

SD: standard deviation.

* P values were derived from univariate conditional logistic regression models.† Tumor dimension was log transformed in a conditional logistic regression model to satisfy the

linearity assumption.

Breast Conservation for Lobular Carcinoma/Morrow et al. 2565

of the patients included in this analysis are summa-rized in Table 2. The analysis for the number of exci-sions needed to achieve negative surgical margins waslimited even further to the 81 lobular-ductal triplets inwhich all 3 patients eventually achieved successfulBCT.

BCT was successful in 100 of the 119 ILC patients(84.0%) who chose this option compared with 208 of238 IDC patients (87.4%). In a conditional logisticregression model adjusting for age and pathologic tu-mor dimension, no significant difference in the failurerate of BCT was observed between patients with ILCand IDC (Table 3). The number of excisions requiredto achieve negative surgical margins was analyzed inthe 243 patients (81 lobular/ductal triplets) who un-derwent successful BCT. A total of 155 patients re-quired a single excision, 85 underwent 2 excisions, and

3 underwent 3 excisions. The conditional logistic re-gression model incorporating age, number of exci-sions, and tumor dimension is shown in Table 4. Nosignificant difference in the number of required exci-sions was observed based on histology adjusted forage and tumor size, although a trend toward moreexcisions was noted in the lobular group (odds ratio of1.58; 95% confidence interval, 0.89-2.79).

We also compared outcomes between patientswith pure lobular carcinoma and those with mixedlobular-ductal histology. Of the original 318 lobularpatients, there were 155 patients with pure lobularcarcinoma and 163 with mixed histology. Forty-onepatients with pure lobular carcinoma were ineligiblefor BCT (26.5%), compared with 40 patients withmixed tumors (24.5%). Mastectomy was selected by 13patients with pure lobular carcinoma and 11 withmixed lobular carcinoma. Breast conservation wassuccessful in 85 of 101 of patients with pure lobularcarcinoma in whom the procedure was attempted(84.1%) compared with 97 of 112 patients with mixedductal and lobular carcinoma(86.6%). There were nosignificant differences in BCT outcome noted on thebasis of pure or mixed lobular histology (P�.85, by theFisher exact test).

DISCUSSIONProspective randomized trials with long-term fol-low-up have demonstrated that survival after BCTand mastectomy is equivalent.9,10 Using clinical ex-amination and diagnostic mammography, candi-

TABLE 2Patient and Tumor Characteristics for Triplets in Which All 3 WereEligible For and Elected to Undergo BCT

Variable Lobular (n � 119) Ductal (n � 238) P*

Mean age atdiagnosis, y

(SD) 60.7 (10.9) 57.4 (12.6) �.001Mean tumor

dimension(pathologic) 2.01 (1.74) 1.54 (0.97) .028†

(SD) (n � 119) (n � 237)Race (%)White 97 (81.5) 186 (78.2)Nonwhite 22 (18.5) 52 (21.8) .46No. of first-degree

relatives withbreast cancer (%)

0 98 (82.4) 190 (79.8)1� 21 (17.6) 48 (20.2) .57Extensive

intraductalcomponent (%)

No 95 (79.8) 173 (72.7)Yes 24 (20.2) 65 (27.3) .14No. of positive

lymph nodes (%)0 92 (77.3) 172 (72.6)1-3 18 (15.1) 48 (20.3) .094-9 6 (8.4) 13 (5.5) .3710� 3 (2.5) 5 (2.1) .75Grade (%)1 58 (48.7) 45 (19.0)2 49 (41.2) 86 (36.3) �.0013 12 (10.1) 106 (44.7) �.001

(n � 119) (n � 237)

BCT: breast-conserving therapy; SD: standard deviation.

* P values were derived from univariate conditional logistic regression models.† Tumor dimension was log transformed in a conditional logistic regression model to satisfy the

linearity assumption.

TABLE 3Failure of BCT: Lobular Versus Ductal Carcinoma

Variable Odds Ratio (95% CI)* P

BCT yes (vs. no) 1.42 (0.694–2.92) .330Age (per 10 y) 1.58 (1.20–2.07) �.001Tumor dimension (per 1 log(cm)) 1.47 (0.99–2.15) .051

BCT: breast-conserving therapy; 95% CI: 95% confidence interval.

*Odds ratios were derived from conditional regression models.

TABLE 4Number of Excisions to Negative Surgical Margins for PatientsAchieving Successful BCT: Lobular Versus Ductal Carcinoma

Variable Odds Ratio (95% CI) P

No. of excisions 2-3 (vs. 1) 1.58 (0.89–2.79) .120Age (per 10 y) 1.51 (1.08–2.11) .017Tumor dimension on pathology

(per 1 log(cm)) 1.35 (0.83–2.18) .220

BCT: breast-conserving therapy; 95% CI: 95% confidence interval.

2566 CANCER June 15, 2006 / Volume 106 / Number 12

dates for BCT can be identified with greater than95% accuracy.11 Local recurrence rates in patientsreceiving adjuvant systemic therapy are reported tobe �5% at 10 years in multiinstitutional studies inwhich surgery is performed by surgeons with diverseinterests and volumes of breast cancer patients.2

Although ILC is the second most common histo-logic type of breast carcinoma, it accounts for only 5%to 10% of all breast cancer cases.12,13 As a result, rel-atively few patients with ILC were included in therandomized trials of BCT. In addition, ILC is moredifficult to identify mammographically than IDC andaccounts for a higher proportion of mammographi-cally occult carcinomas.14 –16 This, coupled with thepropensity of ILC to grow in a multifocal and multi-centric pattern more frequently than other histologicsubtypes17–19 suggests that patients with ILC might bepoor candidates for BCT. This impression is confirmedby studies of MRI in women with ILC (Table 5). Thesereports indicate that MRI identified additional diseasethat was not apparent by physical examination ormammography in 20% to 50% of women withILC.6,7,20 –22 Quan et al.20 reported that 38 of 62 pa-tients with ILC had suspicious ipsilateral or contralat-eral findings on MRI. Nineteen of the 51 ipsilateralfindings were biopsied and 22% revealed carcinoma.Similarly, Weinstein et al.6 observed that 50% of 32patients with ILC had more extensive disease detectedwith MRI. These studies would suggest that without apreoperative MRI, patients with ILC who are suitablefor BCT cannot be reliably identified.

The findings of the current study do not supportthe idea that ILC is more difficult to treat surgicallythan IDC. As in previous reports, ILC was less likely tobe visualized by both mammography and ultrasoundthan IDC.14 –16 Even in a population of patients diag-nosed since 1995 and subjected to diagnostic imagingby mammography specialists, 28% had tumors thatwere mammographically occult and 23% were notidentified by ultrasound. We also observed that pa-tients with ILC were more likely to have contraindica-

tions to BCT than those with IDC (25% vs. 20%, re-spectively), identified by clinical evaluation,mammography, and ultrasound. Arpino et al.23 foundthat patients with ILC were slightly less likely to un-dergo BCT than those with IDC (9.5% vs. 12.7%) intheir study of 4140 ILC cases and 45,169 IDC cases.However, their study was unable to distinguish be-tween patients undergoing mastectomy due to medi-cal contraindications to BCT and patients choosing tohave a mastectomy. In addition, the extremely lowoverall rate of BCT in their study raises questionsregarding its relevance to practice today. Yeatman etal.24 also observed a higher mastectomy rate in pa-tients with ILC. Of note, these authors reported thatpatients with ILC who were believed to be candidatesfor BCT were 2.5 times more likely to require imme-diate conversion from lumpectomy to mastectomydue to the finding of unexpectedly extensive tumorthan those with IDC (17.5% vs. 6.9%; P�.018). How-ever, no adjustment was made for the significantlylarger tumors that were present in the patients withILC. In contrast, after adjustments for tumor dimen-sion and patient age, both factors that differed be-tween patients with IDC and ILC in the current study,we found no difference in the success rate of BCT onthe basis of histology in a conditional logistic regres-sion model when patients with ILC were comparedwith those with IDC matched for stage, menopausalstatus, and year of treatment. This was true in spite ofthe fact that our 16% failure rate for BCT in patientswith ILC was virtually identical to the 17.5% failurerate reported by Yeatman et al.24

We also did not identify any significant differencesin the number of excisions required to obtain negativesurgical margins on the basis of tumor histology, al-though a trend toward more excisions was observed inthe lobular group. This finding was based on a condi-tional logistic regression model that included age andtumor dimension. In contrast, Santiago et al.25 notedthat reexcision was required in 73% of 55 patients withILC compared with 50% of those with IDC. Molland etal.26 also observed a higher rate of positive surgicalmargins in patients with ILC in whom lumpectomywas attempted compared with their counterparts withIDC. However, these studies did not adjust for othervariables that might influence the likelihood of nega-tive surgical margins.

The findings of the current study suggest that thelarger size at presentation of ILC compared with IDCmay be responsible for the perceived surgical difficul-ties in BCT. A higher proportion of patients are ini-tially recognized as ineligible for BCT, but in the groupof patients believed to be candidates for the proce-dure, differences in rates of conversion to mastectomy

TABLE 5Impact of MRI on the Management of Lobular Carcinoma

Reference No. of PatientsPercent Change inManagement

Weinstein et al.6 32 60Kneeshaw et al.22 21 24Schelfout et al.21 26 50Quan et al.20 59 61 (22 biopsy proven)Munot et al.7 14 50

MRI: magnetic resonance imaging.

Breast Conservation for Lobular Carcinoma/Morrow et al. 2567

or the number of excisions needed to obtain negativesurgical margins were not observed. These results,coupled with the observations of others that localcontrol rates do not differ between patients with IDCand ILC,25,27,28 do not provide a justification for theroutine use of MRI in the breast cancer patient newlydiagnosed with ILC. We believe that the routine incor-poration of MRI into surgical treatment planningawaits the demonstration in a prospective random-ized trial of a decrease in the rate of local recurrenceafter BCT or a reduction in the number of surgicalprocedures needed to complete local therapy.

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