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The Breast 23 (2014) 112e119

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The Breast

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Review

Intraoperative assessment of margins in breast conserving therapy:A systematic review

Kerryn Butler-Henderson a,*, Andy H. Lee a, Roger I. Price b,d, Kaylene Waring c

a School of Public Health, Curtin University, GPO Box U1987, Perth, Western Australia 6845, AustraliabMedical Technology & Physics, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australiac Patient Information Service, Armadale Health Service, PO Box 460, Armadale, Western Australia 6992, Australiad School of Physics, University of Western Australia, Nedlands, Western Australia 6009, Australia

a r t i c l e i n f o

Article history:Received 16 September 2013Received in revised form14 December 2013Accepted 5 January 2014

Keywords:IntraoperativeMarginBreast surgerySecond operationReview

* Corresponding author. Tel.: þ61 892667531, þ61 4892662958.

E-mail addresses: K.Butler-Henderson@curtin.edAndy.Lee@curtin.edu.au (A.H. Lee), Roger.Price@hKaylene.Waring@health.wa.gov.au (K. Waring).

0960-9776/$ e see front matter � 2014 Elsevier Ltd.http://dx.doi.org/10.1016/j.breast.2014.01.002

a b s t r a c t

Approximately one quarter of patients undergoing breast conserving therapy for breast cancer willrequire a second operation to achieve adequate clearance of the margins. A number of techniques toassess margins intraoperatively have been reported. This systematic review examines current intra-operative methods for assessing margin status. The final pathology status, statistical measures includingaccuracy of tumour margin assessment, average time impact on the procedure and second operationrate, were used as criteria for comparison between studies. Although pathological methods, such asfrozen section and imprint cytology performed well, they added on average 20e30 min to operationtimes. An ultrasound probe allows accurate examination of the margins and delivers results in a timelymanner, yet it has a limited role with DCIS where calcification is present and in multifocal cancer. Furtherresearch is required in other intraoperative margin assessment techniques, such as mammography,radiofrequency spectroscopy and optical coherence tomography.

� 2014 Elsevier Ltd. All rights reserved.

Introduction

With a high association between ductal carcinoma in situ (DCIS)and invasive ductal carcinoma (IDC), ensuring clear margins duringthe resection of DCIS is part of the recommendations made by theNational Breast Cancer Centre’s evidence-based clinical practiceguidelines [1]. Research has reported that 20e25% of patientstreated for breast cancer using breast conserving therapy (BCT) willrequire a second operation to obtain clear margins, with secondoperation rates as high as 72% being reported [1e3]. Optimal sur-gical margin distance also varies between and within countries,with most reporting between 2 mm and 10 mm as the optimalminimum margin width [3e5]. As BCT is the preferred surgicalmethod for patients who are not at high risk, the surgeon needs toaccurately assess the extent of disease and margin status duringsurgery to reduce the risk of needing a second operation. A methodthat is able to provide the surgeon with accurate informationintraoperatively about margin status would potentially reduce theneed for a second operation by confirming all the cancer has been

08956082 (mobile); fax: þ61

u.au (K. Butler-Henderson),ealth.wa.gov.au (R.I. Price),

All rights reserved.

removed. An intraoperative margin assessment (IMA) method isdefined for the purpose of this paper as a non-invasive methodapplied to the excised tissue or within the surgical cavity to pro-duce results about margin status during surgery to enable furthertissue shavings to be taken. The gold standard assessment will bedefined as pathology (histology or cytology), performed post-operatively, and hereby referred to as the standard assessment.

This review will systematically select and analyse the literatureto identify reported IMA methods in BCT for breast cancer. Theobjectives of this review are: (1) identify published academicliterature, using a systematic method, that reports the use of anintraoperative method to determine margin status in BCT; (2)examine the level of concordance in margin assessment betweenreported IMAmethods and standard assessment; (3) determine theaccuracy of such methods; and (4) ascertain the impact on secondoperation rates. The Preferred Reporting Items for Systematic Re-views andMeta-Analyses (PRISMA) guidelines are used to structurethe format and reporting of this review [6].

Methods

The databases Proquest, Medline, PubMed and Science Directwere searched on 3 June 2013 using the keywords: ‘breast’ AND‘surgery’ AND ‘intraoperative’. The inclusion criteria for articles

K. Butler-Henderson et al. / The Breast 23 (2014) 112e119 113

were those which (1) examined DCIS of the breast or invasivebreast cancer, (2) undertook an intraoperative assessment of thesurgical margins with the intention of immediate feedback on thestatus (with or without further excision), (3) human studies only,(4) written in the English language, (5) scholarly journal articlewith full text available, and (6) published between January 2000and May 2013. Articles were excluded from consideration if they:(1) used an additional shavings method to increase surgical mar-gins without IMA, (2) examined lesion size, lesion localisation orguidance or specimen orientation without margin assessment, and(3) investigated various cancers outside of the breast.

Fig. 1 presents the process for study selection. In the first stagearticles were extracted based on the search strategy outlined above.Article titles were reviewed by order of publication date (newest tooldest), blinding for author, journal, institution and country wherethe research was conducted. Articles were discarded if the titleindicated the study clearly was not relevant to the purpose of thisreview. Potential titles were then compared to already selectedarticles for duplication and removed if appropriate. Next, the ab-stracts of selected papers were assessed against the eligibilitycriteria listed above, with blinding. Finally, full text articles werethen assessed against the eligibility criteria listed above, withblinding. Reason for rejection was also documented.

A quality assessment tool to assess the strength of each articlewas developed based on the Strengthening the Reporting ofObservational Studies in Epidemiology (STROBE) checklist forcohort, caseecontrol and cross-sectional studies (combined) [7].Weighting was applied for each area according to the level ofimportance to give an overall quality assessment score (QAS) out of20. The tool was initially tested by three reviewers on the first tenarticles, and subsequently applied to all articles by the primaryreviewer (first author) who solely performed the systematic review.Data items were then highlighted and extracted into result tables.

The principal summary measures to meet the objectives of thisreview are (1) IMA methods, (2) level of significance betweenreported IMA methods and standard assessment, (3) accuracy ofIMA methods, or if unavailable the sensitivity and specificity, and(4) second operation rates, taking optimal margin width and studymethodology into account. Only when the accuracy, sensitivityand specificity were not provided but the number of positive andnegative cases by IMA and standard assessment were reported,the data were further analysed to estimate the accuracy, sensi-tivity, specificity, positive and negative predictive values. Becausethese studies varied in optimal margin width and detailed infor-mation was seldom provided, a meta-analysis of pooled data wasnot performed and risk of bias across studies could not becalculated.

Results

Study characteristics

As shown in Fig. 1, 27 studies were included in this review.Table 1 summarises the characteristics of these studies. The meanQAS was 12.19 (standard deviation [SD] 3.13) and ranged from 5.75to 17.75. The studies varied greatly on their presentation of results,which impacted on the overall QAS assigned during the evaluationprocess.

One third (9/27) of the studies recruited subjects prospectivelybut did not act on results from IMA, i.e. prospective observational.About 40% (11/27) of studies also recruited prospectively and actedon IMA results, i.e. prospective experimental, whereas theremaining (7/27) studies were retrospective chart reviews. Optimalmargin width ranged from zero to 5 mm (not reported in four

studies), with five studies using�0 mm, seven using�1 mm, sevenusing �2 mm and four using �5 mm.

Most studies (20/27) used the IMA on the excised specimen,with five studies also examining within the surgical cavity. Themajority of studies did not discuss methods for assessing multifocalcancers, with 8 (29.6%) studies analysing results by tumour insteadof by case. Only two studies examined in the surgical cavity but notthe excised specimen. Half (14/27) of the studies were undertakenin the United States of America (USA) and the majority of studies(21/27) were undertaken at one institutional site. Very few studies(3/27) reported the number of surgeons or users of the IMAmethod; consequently it is not feasible to comment on the risk ofinter-operator variability.

Themean age of patients, where reported, were similar betweenstudies, ranging from 55 to 60 years. Histological information,namely, type, grade and tumour size, were extracted to assesswhether study populations were comparable. Most studies (19/22)reported that the majority of cases were invasive ductal carcinoma,while three studies recruited only DCIS cases. Although the caseswere predominantly classified as grade II, there was little differencein the number of cases reporting grade I or grade III disease. Thegreatest variation in study characteristics was found in tumour size,withmany studies (12/15) reporting amean tumour size between 1and 2 cm.

Table 2 and Table 3 present the reported summary measures.Data were analysed by study methodology as further shavingsbased on IMA findings were taken in prospective experimentalstudies, impacting on the final pathology margin status and secondoperation rates.

Prospective experimental studies

Based on the reported level of concordance, where the IMAmethod was compared to the standard assessment (pathology), theradiofrequency spectroscopy probe performed the best [10,22].However, the 2-view specimen mammography and the macro-scopic margin assessment technique, which had the largest optimalmargin distance of �5 mm, reported the lowest second operationrates of 5% and 7.3%, respectively. The reporting of time differencewas not reliable because comparisons were made against differentprocedures. The intraoperative digital specimen mammography(IDSM) reduced operation times by on average 19 min whencompared to standard specimenmammography (SSM) [28]. 2-viewspecimen mammography reported an average 15 min increase inoperation time when compared to the standard assessment [30].Ultrasound could reduce operation time by 1 min [32] to15 min [34], whereas frozen section increased operation time by27 min on average [4].

Overall accuracy of IMA in prospective experimental studies wasonly reported for frozen section [11] (98.3%) and touch smearcytology [17] (93.8%). Sensitivity and specificity rates were given inhalf of the prospective experimental studies, with frozen section[11] reporting the highest sensitivity (91.1%) and specificity (100%).Interestingly, the other two studies which produced good sensi-tivity and specificity were also intraoperative pathological assess-ments. Touch smear cytology [17] reported 70% sensitivity and97.1% specificity based on a sample size of 160 patients. Macro-scopic margin assessment [29] reported sensitivity and specificityrates of 73% and 88%, respectively, in 220 cases.

Prospective observational studies and retrospective chart reviews

Several IMA methods performed well based on the reportedlevel of concordance. Ultrasound [16,19] showed no significantdifference (p < 0.05) to standard assessment, which supported the

Fig. 1. Flow diagram of article selection strategy.

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findings of the two prospective experimental studies [32,34]. Aretrospective review of IDSM [8] (p ¼ 0.012) also found no differ-ence between IDSM and SSM, consistent with the prospectiveexperimental study [28]. However, all three IMA pathologicalmethods resulted in significant concordance levels: the combineduse of gross tissue inspection and specimen radiology [31]

(p < 0.001), imprint cytology [15] (p < 0.001) and frozen section[21] (p ¼ 0.002).

With respect to second operation rate, frozen section had thelargest difference between study and control rates [12,21]. Grosstissue inspection with specimen radiography similarly reported asignificant difference (p ¼ 0.029) [31]. No significant difference in

Table 1Characteristics of selected studies on intraoperative margin assessment (IMA) methods.

Articleno.

Referenceno.

Year QAS IMA method Specimen,cavity or both

Study methodology Optimalmargins

Sample size Country No. ofhospital sites

Age: Mean ormedian years (SD)

1 8 2013 14 Intraoperative DSM Specimen Retrospective >1 mm 201 (96 study; 105control)

Canada 1 Study 59.5 (9.6)Control 59.6 (10.1)

2 9 2013 14.5 Ultrasound Both Prospective observational >2 mm 223 Spain 1 59.5 (11.1)3 10 2012 7 RF spectroscopy probe Specimen Prospective experimental >1 mm 596 (298 study; 298

control)USA 21 Not reported

4 11 2012 10 Frozen section Specimen Prospective experimental >2 mm 369 (181 study; 188control)

USA 1 Study 58.1 (11.6)Control 57.6 (12.2)

5 12 2012 11 Frozen section Specimen Retrospective >2 mm 549 (278 study; 271control)

USA 1 Study 56.8Control 58.0

6 13 2011 5.75 RF spectroscopy probe Cavity Prospective observational >5 mm 22 Germany 3 Not reported7 14 2011 16.5 Ultrasound Specimen Prospective experimental >2 mm 45 Israel 1 Not reported8 15 2011 6.25 Imprint cytology Specimen Prospective observational >0 mm 29 USA 1 Not reported9 16 2011 11.5 Ultrasound Both Prospective observational Not reported 17 USA 1 Not reported10 17 2010 12 Touch smear cytology Specimen Prospective experimental >0 mm 160 Japan 1 58.111 18 2009 11 Optical coherence

tomographySpecimen Prospective observational >2 mm 33 (18 study; 15

control)USA 1 Study 66

Control 6212 19 2009 15.5 Ultrasound Specimen Prospective observational >1 mm 155 (96 study; 59

control)USA 1 Study 59

Control 5613 20 2009 13.25 Frozen section Specimen Prospective observational >2 mm 186 Turkey 1 4914 21 2008 17.75 Frozen section Specimen Retrospective >1 mm 111 (78 study; 33

control)Switzerland 1 Study 59.6

Control 57.515 22 2008 14 RF spectroscopy probe Specimen Prospective experimental >1 mm 293 (143 study; 150

control)Israel 11 Study 59

Control 6016 23 2008 11 Gamma camera & probe Both Prospective observational >5 mm 42 Spain 1 59 (7.8)17 24 2007 9 Gamma probe Cavity Prospective experimental >0 mm 23 Brazil 1 51.3 (11.7)18 25 2007 14 RF spectroscopy probe Specimen Prospective observational >1 mm 57 Israel 2 Not reported19 26 2007 16.5 Frozen section Specimen Retrospective Not reported 290 USA 1 5620 27 2007 17.25 Gross tissue inspection &

SRSpecimen Retrospective >2 mm 251 USA 1 IDC 60

DCIS 5821 28 2007 12 Intraoperative DSM Specimen Prospective experimental Not reported 79 USA 1 Not reported22 29 2004 12.75 Macroscopic margin

assessmentSpecimen Prospective experimental �5 mm 220 Ireland 1 59

23 30 2004 10.25 2-view specimenmammography

Specimen Prospective experimental Not reported 93 USA 1 Not reported

24 31 2003 10.75 Gross tissue inspection &SR

Specimen Retrospective >5 mm 109 USA 1 55 (10)

25 32 2002 10.5 Ultrasound Both Prospective experimental �1 mm 49 (27 study; 22control)

Netherlands 2 Not reported

26 33 2002 11.75 Imprint cytology Specimen Retrospective >0 mm 137 USA 1 5827 34 2001 13.5 Ultrasound Specimen Prospective experimental >0 mm 51 (27 study; 24

control)USA Not reported Not reported

DCIS ¼ ductal carcinoma in situ; DSM ¼ digital specimen mammography; IDC ¼ invasive ductal carcinoma; IMA ¼ intraoperative margin assessment; mm ¼ millimetres; No. ¼ number; QAS ¼ quality assessment score;RF ¼ radiofrequency; SD ¼ standard deviation; SR ¼ specimen radiography; USA ¼ United States of America.

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Table 2Summary measures of success, second operation rate and time.

Article no. IMA method Final pathology margin status Procedure classifiedas success

Second operation required Average differencein operation time

1 Intraoperative DSM Study 21.8% positiveControl 47.6% positive

Yes (p ¼ 0.012) Study 14.6%; Control 17.1%(p ¼ 0.641)

�2 min

2 Ultrasound Study 13.3% positive Yes Study 4% Not reported3 RF spectroscopy probe Not reported Yes (p < 0.0001) Study 14.1%; Control 29.9% Not reported4 Frozen section Not reported Yes Study 19.3%; Control 55.3%

(p ¼ 0.0961)þ27 min

5 Frozen section Study 6% positiveControl 10% positive

Yes Study 11%; Control 25%(p < 0.001)

þ30 min

6 RF spectroscopy probe Not reported Yes Study 18%; Historical 38.8% Not reported7 Ultrasound 24.4% positive Yes 4.44% Not reported8 Imprint cytology Not reported Yes (p < 0.001) Not reported þ20e25 min9 Ultrasound Not reported Yes Not reported Not reported10 Touch smear cytology 12.5% positive Yes Not reported Not reported11 Optical coherence tomography 45% positive Yes Not reported Not reported12 Ultrasound Study 33.3% positive

Control 39.0% positiveYes however p > 0.5 Study 20.8%; Control 30.5%

(p ¼ 0.184)Not reported

13 Frozen section 16% positive Yes 16% þ25 min14 Frozen section Study 12.5% positive

Control 20.0% positiveYes (p ¼ 0.002) Study 12.5%; Control 37.1%

(p ¼ 0.002)Not reported

15 RF spectroscopy probe Study 40% positiveControl 59% positive

Yes (p ¼ 0.044) Study 12.6%; Control 18.6%(p ¼ 0.098)

Not reported

16 Gamma camera & probe Centred 39% positive Not reported Not reported þ5 min17 Gamma probe 21.1% positive No (p ¼ 0.23) Not reported Not reported18 RF spectroscopy probe 38.6% positive Yes Not reported þ7.37 min19 Frozen section 11.3% positive Yes 11.4% Not reported20 Gross tissue inspection & SR Invasive 17% positive

DCIS 28.1% positiveYes 8.7% Not reported

21 Intraoperative DSM 28.2% positive Yes Not reported �19 min22 Macroscopic margin assessment 9.1% positive Yes 7.3% Not reported23 2-view specimen mammography 11.8% positive Yes 5% þ15 min24 Gross tissue inspection & SR 24% positive Yes (p < 0.0001) 22% (p ¼ 0.029) Not reported25 Ultrasound Study 11% positive

Control 45% positiveYes (p ¼ 0.007) Not reported �1 min

26 Imprint cytology 10.9% positive Yes Not reported þ20 min27 Ultrasound Study 3.5% positive

Control 29% positiveYes (p < 0.05) 13.7% �15 min

No. ¼ Number; DCIS ¼ ductal carcinoma in situ.

Table 3Summary measures of sensitivity, specificity, positive predictive value, negative predictive value and accuracy.

Article no. IMA method Sensitivity Specificity Positive predictivevalue

Negative predictivevalue

Accuracy

1 Intraoperative DSM Not reported Not reported Not reported Not reported Not reported2 Ultrasound 80% 86.6% 23.3% 95.1% 99.6%3 RF spectroscopy probe Not reported Not reported Not reported Not reported Not reported4 Frozen section 91.1% 100% 100% 97.9% 98.3%5 Frozen section Not reported Not reported Not reported Not reported 94%6 RF spectroscopy probe Not reported Not reported Not reported Not reported 73%7 Ultrasound 25% 95% 27% 95% Not reported8 Imprint cytology 85% 100% Not reported Not reported 89.7%9 Ultrasound 100% 74% Not reported Not reported Not reported10 Touch smear cytology 70% 97.1% 77.78% 95.77% 93.8%11 Optical coherence tomography 100% 82% 82% 100% 90%12 Ultrasound Not reported Not reported Not reported Not reported Not reported13 Frozen section Not reported Not reported Not reported Not reported Not reported14 Frozen section 80% 87.5% 86.5% 81.4% 83.8%15 RF spectroscopy probe Not reported Not reported Not reported Not reported Not reported16 Gamma camera & probe Not reported Not reported Not reported Not reported 60%17 Gamma probe Not reported Not reported Not reported Not reported Not reported18 RF spectroscopy probe 71% 68% Not reported Not reported Not reported19 Frozen section 73.08% 99.59% 91.94% 98.32% 98.02%20 Gross tissue inspection & SR 91.7% 77.8% Not reported Not reported 87.4%21 Intraoperative DSM 36% 71% 50%% 84%% Not reported22 Macroscopic margin assessment 73% 88% Not reported Not reported Not reported23 2-view specimen mammography 54.55% 87.8% 37.5% 93.51% Not reported24 Gross tissue inspection & SR Not reported Not reported Not reported Not reported Not reported25 Ultrasound Not reported Not reported Not reported Not reported Not reported26 Imprint cytology 80% 85% 40% 97% 85%27 Ultrasound Not reported Not reported Not reported Not reported Not reported

DSM ¼ digital specimen mammography; IMA ¼ intraoperative margin assessment; No. ¼ number; RF ¼ radiofrequency; SR ¼ specimen radiography.

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second operation rate was evident for IDSM [8] or ultrasound [19].Only six studies reported the time variations when an IMA methodwas introduced. IDSM decreased the operation time by 2 minwhencompared to SSM [8]. The gamma camera and probe increasedoperation time on average by 5 min. Frozen section increasedoperating time ranging from 20 to 30 min, consistent with thefinding of a prospective experimental study [11].

Taking into account level of concordance, second operation rateand operation time, IDSM [8] appeared to perform best with asecond operation rate of 14.6% compared to 17.1% in the controlgroup (no significant difference), a decrease of 2 min on average inoperation time and a significant level of concordance (p ¼ 0.012).Ultrasound [19] also performed well, with a second operation rateof 20.8% compared to 30.5% in the control group (no significantdifference), with no information reported on operation time.

Overall, accuracy of IMA was well reported. Ultrasound [9] re-ported the highest level of accuracy (99.6%), followed by frozensection (98.02% [26] and 94% [12]) and optical coherence tomog-raphy [18] (90%). Imprint cytology [15] had a sensitivity of 85% andspecificity of 100%. The other imprint cytology study [33] reported asensitivity and specificity of 80% and 85% respectively. Opticalcoherence tomography [18] reported a sensitivity of 100% andspecificity of 82%, but average operation time was unavailable. Thesensitivity and specificity of ultrasound [9,16] were also good ac-cording to two studies, yet the additional surgical time to apply theultrasound to the specimen and in the cavity was not reported.

Discussion

Breast cancer was the most commonly diagnosed cancer amongfemales in Australia in 2012, and the second leading cause of cancerdeath [35]. During 2006e2010 the 5 year survival rate for breastcancer was 89% [36]. Local recurrence following breast conservingtherapy (BCT) for DCIS has been reported as 3.9e10.5% and invasivebreast cancer 5e22% [2,37e40], with positive or close marginsbeing a risk factor [4,39,41]. As approximately 25% of patientsrequire a second operation to ensure clear margins, a methodcapable of accurately assessing intraoperative margins wouldpotentially reduce the number of second operations as well as therecurrence rate.

Intraoperative pathological assessment

In general, the intraoperative pathological methods performedwell according to our systematic review. Accuracy rates for frozensection were reported between 83.8 and 98.3%, touch smear andimprint cytology between 85% and 93.8%, and gross tissue inspec-tion combined with specimen radiology was 87.4%, all with largesample sizes [11,12,15,17,21,26,27,33]. The sensitivity and specificityrates in the frozen section studies reported here are generallyconsistent with those reported in the literature [21,42,43]. Also, theimprint cytology sensitivity and specificity rates reported here aresimilar to those in the literature [43e45].

Although the sensitivity, specificity and accuracy of pathologicalIMA methods are high, these methods add significant time to theoperation, often between 20 and 30min on average. This extra timeincurred has a number of adverse implications including additionalcosts, reduction in number of cases treated per day, additional timeunder anaesthetic and loss of productivity time for theatre staffwhilst waiting for results to be returned. Moreover, touch smearand imprint cytology methods only assess the direct surgicalmargin and cannot assess beneath the surface so therefore do notidentify where there may be residual disease up to 5 mm under thesurface.

Ultrasound

Among the other methods investigated, ultrasound was theonly IMA that returned notable results. At a �2 mm optimalmargin width a 99.6% accuracy rate was reported using a largesample size (223 patients), with only a 4% second operation rate[9]. The positive concordance between ultrasound and standardassessment was supported by the literature [14,16,19,32,34]. Thesensitivity of ultrasound ranged from 25 to 100% and specificityranged from 74 to 95%. A previous study reported a sensitivity of80% and a specificity of 90% [46], which is within the range ob-tained in our review. Ultrasound can be used to guide surgery inthe operating theatre. When applied by a trained operator, it canproduce results immediately, allowing the decision to take furthershavings with minimal impact on operating times. However, itshould be remarked that one study did report a poor sensitivity(25%) and a positive predictive value of 27%, when using ultra-sound on the excised specimen [14]. Furthermore whilst ultra-sound works well in dense soft tissue with no calcification, it doesnot perform well where there is multifocal cancer or calcification,which is often present with DCIS.

Radiofrequency spectroscopy

A radiofrequency (RF) spectroscopy probe offers an alternativeto ultrasound, by examining the electromagnetic signature of thetissue in the operating theatre. Four articles reported the use of anRF spectroscopy probe in breast surgery [10,13,22,25], with signif-icant level of concordance. Only two studies provided statisticalmeasures of performance under small sample settings. The accu-racy rate was reported as 86% when the optimal margin width was�2 mm [13] and sensitivity of 71% and specificity of 68% [25] werelower than those reported in the literature [47]. Although this de-vice does not greatly increase operating time and does provideimmediate feedback, its sensitivity and accuracy appeared to belower than pathological IMA methods, and second operation ratesdid not vary significantly from controls in prospective experimentalstudies. Large-sample studies are needed to ascertain whether thisdevice has an important role in IMA in breast surgery.

Digital specimen mammography

Two studies applied intraoperative digital specimen mammog-raphy [8,28], compared to standard specimen radiography ormammography, while another study used 2-view specimenmammography [30]. Despite its apparent concordance with stan-dard assessment, only one study reported a small second operationrate of 5% [30]. Moreover, poor sensitivities were evident [28,30],and data on accuracy were lacking. Use of this device tookapproximately the same time, or slightly longer, as a hand heldultrasound or RF spectroscopy probe, yet it could result in theexcision of more tissue than necessary. Further research with largersample sizes is required to confirm against standard assessment soas to identify the actual additional operation time incurred.

Optical coherence tomography

Only one study examined the use of optical coherence tomog-raphy in breast cancer surgery [18]. Although its reported summarymeasures such as accuracy rate, sensitivity and specificity appearedto be promising, additional operation time and second operationrate have not been investigated in the literature. Therefore, cautionis necessary beforemaking any recommendation concerning its usein breast surgery.

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Limitations

Themain limitation of this reviewwas the inability to report theimpact of IMA methods on subsequent breast cancer events, spe-cifically recurrence or invasion. Only four studies included infor-mation from longitudinal follow-up and therefore this informationwas not included in this review. The impact of calcifications ormultifocal cancers was not discussed in this review as this infor-mation was also not readily available in the articles reviewed.

Conclusion

This review systematically selected and analysed publishedliterature on IMA methods in BCT for breast cancer. Differentpathological IMA methods, specifically frozen section and touchsmear or imprint cytology, reported high accuracy rates but theycan add 20e30 min on operation time and thus are less appealing.Whilst two studies reporting the use of ultrasound showed highaccuracy rates, another performed poorly. Whilst ultrasound canreturn results in a short time period compared to pathologicalassessment methods, it does not perform well where there isassociated calcification or multifocal cancers. Further research,particularly using large samples, is required for application ofmammography, radiofrequency spectroscopy, and optical coher-ence tomography in IMA during BCT. The impact on intraoperativeassessment methods in multifocal cancers also needs to be furtherexplored.

Conflict of interest statement

No potential conflict of interest exists for listed authors.

Ethics approval

Ethics approval was not required for this systematic review.

Funding

There is no funding support associated with this review.

Acknowledgements

The authors acknowledge Dr. Nat Lenzo for his participation inthis review.

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