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Home , Carcinoma in situ, Invasion (cancer), Metastasis, Sentinel lymph node

The American Journal of (2017) 213, 171-180

Review Is sentinel node indicated in patients with a diagnosis of ductal ? A systematic literature review and meta-analysis

Hiba El Hage Chehade, M.D., M.R.C.S.*, Hannah Headon, M.B.B.S., B.Sc., Umar Wazir, M.B.B.S., M.R.C.S., M.Sc., Houssam Abtar, M.D., Abdul Kasem, M.D., F.R.C.S., Kefah Mokbel, M.S., F.R.C.S.

The London Institute, Princess Grace Hospital, 42-52 Nottingham Place, London W1U 5NY, UK

KEYWORDS: Abstract Sentinel BACKGROUND: Recent discussion has suggested that some cases of ductal (DCIS) biopsy; with high risk of invasive may require sentinel (SLNB). Ductal carcinoma in METHODS: Systematic literature review identified 48 studies (9,803 DCIS patients who underwent situ; SLNB). Separate analyses for patients diagnosed preoperatively by core sampling and patients diagnosed Breast postoperatively by specimen were conducted to determine the percentage of patients with axillary nodal involvement. Patient factors were analyzed for associations with risk of nodal involvement. RESULTS: The mean percentage of positive SLNBs was higher in the preoperative group (5.95% vs 3.02%; P 5 .0201). Meta-regression analysis showed a direct association with tumor size (P 5 .0333) and grade (P 5 .00839) but not median age nor tumor upstage rate. CONCLUSIONS: The SLNB should be routinely considered in patients with large (.2 cm) high- grade DCIS after a careful multidisciplinary discussion. In the context of breast conserving surgery, the SLNB is not routinely indicated for low- and intermediate-grade DCIS, high-grade DCIS smaller than 2 cm, or pure DCIS diagnosed by definitive surgical excision. Crown Copyright Ó 2016 Published by Elsevier Inc. All rights reserved.

Ductal carcinoma in situ (DCIS) is the predominant At present, the treatment of DCIS comprises wide local noninvasive breast neoplasia in the United Kingdom, excision or to achieve local control of the dis- comprising 83% of all in situ breast diagnosed.1 ease. In patients treated with breast conserving surgery, radiotherapy may be considered to reduce the risk of local recurrence. This review was funded by grants from the Hope Foun- In breast cancer, the status of the regional lymph nodes has dation (London, UK). been found to be the most important prognostic factor and The authors declare no conflicts of interest. predictor of survival and therefore has important implica- * Corresponding author. Tel.: 144 207 908 2101; fax: 144 207 908 tions for future treatment decisions.2 As DCIS is noninvasive 2275. E-mail address: [email protected] by definition, this implies that there should be no spread to the Manuscript received February 24, 2016; revised manuscript April 19, . Subsequently, omission of axillary 2016 dissection is now the standard of treatment since previous

0002-9610/$ - see front matter Crown Copyright Ó 2016 Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2016.04.019 172 The American Journal of Surgery, Vol 213, No 1, January 2017

Table 1 Characteristics of studies included in the preoperative sample Positive results Upstage Number of Median rate Study Design cases age Total (%) ITC (%) Micrometastases (%) Macrometastases (%) (%) Francis et al, 20155 Retrospective 1,234 54 132 (10.7) 66 (5.4) 36 (2.9) 30 (2.4) NR Tunon-de-Lara et al, Prospective 196 54.3 27 (14.1) 8 (4.1) 8 (4.1) 11 (5.6) NR 201539 Nowikiewicz et al, Retrospective 111 55 4 (3.6) NR NR NR NR 201528 Ruvalcaba-Limon Retrospective 50 51.6 5 (10) 0 (0) 3 (6) 2 (4) NR et al, 201435 Walters et al, 201543 Retrospective 84 57.7 1 (1.2) 0 (0) 1 (1.2) 0 (0) 17.2 Banys et al, 20149 Retrospective 316 55 3 (.9) 1 (.3) NR NR 0 Namm et al, 201527 Retrospective 52 54.8 3 (6) 0 (0) 2 (3.8) 1 (1.9) 32 Osako et al, 201430 Retrospective 336 NR 23 (6.8) 0 (0) 6 (1.8) 17 (5) 33.6 Ozkan-Gurdal et al, Prospective 33 51 1 (3.3) NR NR NR 0 201431 Guillot et al, 201418 Prospective 109 51 11 (9) 8 (7.3) 2 (1.8) 1 (.9) NR Rajan et al, 201338 Retrospective 25 56.9 0 (0) 0 (0) 0 (0) 0 (0) NR Chin-Lenn et al, Retrospective 306 57 3 (2.1) NR NR NR 17 201410 Zapardiel et al, Retrospective 84 NR 6 (6.9) NR NR NR NR 201344 Ballehaninna et al, Retrospective 267 57 13 (4.8) 4 (1.5) 6 (2.2) 3 (1.1) 15.4 20138 Fancellu et al, Prospective 140 56 2 (1.4) NR NR NR 1.4 201217 Park et al, 201332 Prospective 238 48.5 10 (4.2) NR NR NR 42.6 Ansari et al, 20127 Retrospective 61 NR 3 (4.9) 1 (1.6) 0 (0) 2 (3.3) NR Osako et al, 201229 Prospective 623 50 13 (2.1) NR NR NR NR Meretoja et al, Prospective 280 58 21 (7.5) 16 (5.7) 3 (1.1) 2 (.7) NR 201225 Chvalny et al, 201111 Retrospective 44 NR 4 (9) NR NR NR NR Usmani et al, 201141 Prospective 23 48 1 (4) NR NR NR 30 Miyake et al, 201126 Prospective 103 49 2 (5.4) NR NR NR 35.9 Han et al, 201119 Retrospective 131 55 18 (13.7) NR NR NR 36.6 Prendeville et al, Retrospective 181 NR 7 (4) 6 (3.3) 0 (0) 1 (.6) 30 201534 Matsen et al, 201424 Retrospective 414 54 32 (7.7) 0 (0) 26 (6.3) 6 (1.4) NR Kotani et al, 201623 Retrospective 161 NR 1 (.62) NR NR NR 20 Son et al, 201137 Retrospective 48 50.6 1 (2.08) NR NR NR NR Collado et al, 201012 Prospective 65 NR 11 (16.9) NR NR NR 33.8 D’Eredita et al, Prospective 52 56 1 (1.9) 0 (0) 1 (1.9) 0 (0) NR 200914 Hung et al, 201020 Retrospective 103 54 12 (11.6) 3 (2.9) 5 (4.9) 4 (3.9) 29.9 Doyle et al, 200916 Retrospective 145 NR 11 (7.6) 4 (2.8) 3 (2.1) 4 (2.8) 37.9 Polom et al, 200933 Retrospective 183 57 10 (5.5) NR NR NR 4 Tunon-de-Lara et al, Prospective 161 56 6 (3.73) 0 (0) 4 (2.5) 2 (1.2) 30 200840 Intra et al, 200821 Prospective 854 NR 16 (1.9) 4 (.47) 7 (.8) 5 (.6) NR Dominguez et al, Retrospective 179 48 20 (11.3) 18 (10.1) 2 (1.1) 0 (0) 11.2 2008 15 Cserni et al, 200213 Prospective 10 NR 1 (10) 0 (0) 1 (10) 0 (0) NR Veronesi et al, Prospective 508 NR 9 (1.8) 0 (0) 5 (1.0) 4 (.8) NR 200542 Katz et al, 200622 Retrospective 110 55 8 (7.34) 0 (0) 8 (7.3) 0 (0) NR Sakr et al, 200636 Prospective 39 54 4 (10) 0 (0) 4 (10.3) 0 (0) 25.7 This table outlines the studies included in the preoperative sample (n 5 39). ITC 5 isolated tumor cells; NR 5 not reported. H. El Hage Chehade et al. SLNB in DCIS patients 173

Table 2 Characteristics of studies included in the postoperative sample Positive results Number of Median Micrometastases Macrometastases Study Design cases age Total (%) ITC (%) (%) (%) Zetterlund et al, Retrospective 753 60 11 (1.5) 6 (.8) 3 (.4) 2 (.3) 201452 Tada et al, 201050 Retrospective 225 51.2 1 (.39) 0 (0) 0 (0) 1 (.4) Sakr et al, 200849 Retrospective 110 NR 7 (6) 4 (3.6) 0 (0) 3 (2.7) Takacs et al, Retrospective 48 55.8 0 (0) 0 (0) 0 (0) 0 (0) 200951 Kelly et al, 200346 Retrospective 41 55.4 1 (2.44) NR NR NR Intra et al, 200345 Prospective 223 50.1 7 (3.14) 0 (0) 5 (2.2) 2 (.9) Zavagno et al, Prospective 102 59.4 1 (.98) 0 (0) 1 (.98) 0 (0) 200553 Mabry et al, 200648 Prospective 171 50 10 (5.8) 10 (5.8) 0 (0) 0 (0) Leidenius et al, Retrospective 71 56 5 (7) 3 (4.2) 1 (1.4) 1 (1.4) 200647 This table outlines the studies include in the postoperative sample (n 5 9). ITC 5 isolated tumor cells; NR 5 not reported. reports have established that this practice had no adverse and add to previous reviews such as that by Francis et al5 by effect on overall survival or disease recurrence in those including the latest research and examining any factors that with pure in situ disease.3 Despite this, recent studies have may predispose toward a greater risk of having a positive suggested that some DCIS cases do in fact harbor an invasive SLNB result. From this, we hope to be able to identify a sub- component, meaning that leaving the lymph nodes intact may set of patients with a diagnosis of DCIS who would benefit increase the risk of local recurrence.4 from undergoing an SLNB as part of their management plan. It has been proposed that select patients diagnosed with DCIS determined to be at high risk of harboring an invasive Methods component should undergo biopsy (SLNB). If positive, a complete axillary dissection may be Literature search considered, weighing the risk of recurrence disease and the morbidities of the procedure. A literature search of electronic databases including This study aims to evaluate whether the use of SLNB is PubMed and Ovid was conducted including entries up until appropriate in DCIS and investigate whether there are any March 2016 with no upper limit. The following search factors contributing toward a higher risk of invasive disease terms were used: sentinel lymph node biopsy AND ductal

Table 3 Statistical tests for heterogeneity Preoperative sample Postoperative sample Effect size and 2-tailed Effect size and 2-tailed 95% interval t test 95% interval t test Number Point Lower Upper P Number Point Lower Upper P Model of studies estimate limit limit Z-value value Model of studies estimate limit limit Z-value value Fixed 39 .073 .067 .08 251.847 0 Fixed 9 .033 .025 .045 221.759 0 Random 39 .053 .042 .067 222.25 0 Random 9 .03 .017 .053 211.488 0 Heterogeneity Heterogeneity Q-value df (Q) P value I squared Q-value df (Q) P value I squared 196.462 38 0 80.658 23.432 8 .003 65.859 Tau squared Standard error Variance Tau Tau squared Standard error Variance Tau .424 .189 .036 .651 .454 .392 .154 .673 This table outlines the statistical tests carried out for heterogeneity. Significant heterogeneity was observed with an I2 of 80.7% in preoperative sample and 65.7% in the postoperative sample. 174 The American Journal of Surgery, Vol 213, No 1, January 2017

Figure 1 Forest plot for the meta-analysis for the preoperative sample. A random-effects model for meta-analysis was adopted for the preoperative sample. This forest plot was generated which shows a pooled estimate of 5.3%. carcinoma in situ; DCIS AND sentinel lymph node biopsy; an SLNB as part of their management. Studies had to report sentinel node mapping and DCIS and sentinel lymph node the number of patients who had positive SLNBs. mapping and . The ‘‘related Exclusion criteria included studies which did not report articles’’ command was used to broaden the search, and the number of positive SLNBs, did not specify that patients the bibliographies of appropriate articles were studied to had been diagnosed with DCIS, or did not specify whether identify any further records. this was a preoperative diagnosis on the basis of triple Abstracts of the results were analyzed, and records which assessment and/or core samples, or a postoperative diag- seemed to fit inclusion criteria had the full manuscript nosis after analysis of the surgical specimen. Letters, accessed. These records were fully read, and all those which commentaries, and reviews were also excluded. fit the inclusion criteria were included in analysis. Inclusion and exclusion criteria Analysis

Inclusion criteria comprised studies performed on The meta-analysis of the studies included was performed female patients with a diagnosis of DCIS who underwent as advised by the Cochrane Library.6 H. El Hage Chehade et al. SLNB in DCIS patients 175

Figure 2 Forest plot for the meta-analysis in the postoperative sample. A random-effects model for the meta-analysis was adopted for the postoperative sample. This forest plot was generated showing a pooled estimate of 3.5%.

Some studies assessed the SLNB-positive rate in defin- positive SLNBs between preoperative and postoperative itive DCIS, ie, those with a postoperative diagnosis of diagnoses. To carry out the meta-analysis, we separated DCIS, whereas others reported this as a function of those the included studies depending on whether the diagnosis with a preoperative diagnosis of DCIS. We, therefore, of DCIS was given preoperatively or postoperatively and performed separate analyses in these groups as the then conducted 2 separate meta-analyses. Pooled estimates frequency of a positive SLNB may differ between the 2. were calculated with 95% confidence intervals. Cochran’s Data on the number of patients, the SLNB technique, the Q test was used to test the null hypothesis, and heteroge- number of patients with positive SLNBs, the median age, neity was calculated using an I2 index. For both groups, a and the biopsy method were collected, tabulated, and funnel plot was created to look for publication bias, and subsequently analyzed. both the Begg and Mazumdar Rank Correlation test and An analysis of variance analysis was conducted to look Egger’s test of the intercept were performed to support for any significant difference in the mean percentage of this. Duval and Tweedie’s trim and fill method was used

Figure 3 A funnel plot from the preoperative sample. A funnel plot was generated for the preoperative sample to look for evidence of publication bias. As not all the points are within the prescribed margins, there is evidence of publication bias in this sample. 176 The American Journal of Surgery, Vol 213, No 1, January 2017

Figure 4 A funnel plot from the postoperative sample. A funnel plot was generated for the postoperative sample to look for evidence of publication bias. Again, there is some evidence of publication bias. to look for differences between observed and adjusted Results pooled rates. In addition, a meta-regression analysis was carried out to Forty-eight articles were identified and analyzed identify factors associated with a higher risk of having a yielding a total of 9,803 patients. This included both positive SLNB result. Statistical significance was consid- retrospective and prospective studies. ered at P , .05. The primary endpoint was the percentage of DCIS patients with positive SLNBs. Studies were divided based on the time of diagnosis of DCIS (ie, preoperative vs postoperative diagnosis). Characteristics of the included Table 4 Statistical tests for publication bias studies are shown in Tables 1 and 2. The incidence of Test SLNB positivity was significantly higher in the preopera- Test result Preoperative tive diagnosis group (n 5 39 studies),5,7–44 with a mean Classic fail-safe N 581 of 5.95% (range 5 0% to 16.9%) vs a mean of 3.02% N (per study) (range 5 0% to 7%) in the postoperative diagnosis group Begg and Tau 2.217 (n 5 9 studies)45–53 (P 5 .0201). Further analysis showed Mazumdar rank z-value for tau 1.948 that axillary nodal harbored isolated tumor cells correlation test P value (1 tailed) .026 (ITCs), micrometastasis, and macrometastasis in 24.4% P value (2 tailed) .051 (median 12.5%), 48.5% (median 43.8%), and 23.1% (me- 2 Egger’s Test of Intercept 2.139 dian 22.7%), respectively in the preoperative diagnosis 2 the intercept 95% CI lower limit 3.288 studies, vs 33.95% (median 27.3%), 27.3 (median 10%), (2 tailed) and 26.2% (median 19.1%) in the postoperative diagnosis 95% CI upper limit 2.990 (2 tailed) group. However, not all studies reported the incidence of P value (1 tailed) .000 ITCs; therefore, this should be interpreted with caution. P value (2 tailed) .001 In the meta-analysis, significant heterogeneity was 2 Duval and Observed pooled effect .053 observed between the studies with an I statistic of 80.7% Tweedie’s Trim Adjusted pooled effect .073 and 65.7% in the preoperative and postoperative groups, and Fill Studies trimmed 11.000 respectively (Table 3). Thus, a random-effects model was Missing values To right of adopted, and pooled estimate of positive SLNB of 5.3% mean and 3.0% were reported in the preoperative and postopera- This table outlines the statistical tests carried out to assess for tive diagnosis, respectively (Figs. 1 and 2). A funnel plot evidence of publication bias in the preoperative sample. The results are was subsequently created which showed evidence of publi- suggestive of publication bias, resulting in an adjusted pooled cation bias in both groups (Figs. 3 and 4) supported by estimate of 7.3%. Begg and Mazumdar rank correlation test and Egger’s H. El Hage Chehade et al. SLNB in DCIS patients 177

accounting for 15.7% of all neoplasia detected through the Table 5 Statistical tests for publication bias Nationa Health Service (NHS) Breast Screening Programme Test Test result Postoperative between 2003 and 2011.3 There are several points of conten- Classic fail-safe N 105 tion in the management of DCIS, one of which is the use of N (per study) SLNB. Begg and Tau 2.167 Although SLNB has become the standard treatment Mazumdar rank z-value for tau .626 option in clinically node negative invasive breast cancer, its P correlation test value (1 tailed) .266 routine use in the current management of DCIS is not P value (2 tailed) .532 warranted and would not be without its risks: the Axillary Egger’s Test of Intercept 21.191 Lymphatic Mapping Against Nodal Axillary Clearance the intercept 95% CI lower limit 24.266 (ALMANAC) trial demonstrated that 5% of patients un- (2 tailed) 54 95% CI upper limit 1.884 dergoing SLNB alone developed arm . (2 tailed) Furthermore, an increasing number of immediate hypersen- P value (1 tailed) .195 sitivity reactions have been reported after the use of Patent P value (2 tailed) .390 Blue V for breast cancer surgery with 1 multicenter trial Duval and Observed pooled effect .030 showing an incidence of .34% in 1,742 patients, 2 cases Tweedie’s Trim Adjusted pooled effect .037 of which required admission into the intensive care and Fill Studies trimmed 2.000 unit.55 A number of case studies also illustrated cases of Missing values To right of anaphylactic reactions.56–59 However, its use has now mean largely been replaced by methylene blue which is safer.60,61 This table outlines the statistical tests carried out to assess for Other potential complications include seromas, hematomas, evidence of publication bias in the postoperative sample. The results and arm .62,63 are suggestive of publication bias, resulting in an adjusted pooled estimate of 3.7%. Standard preoperative diagnostic techniques are known CI 5 confidence interval. to miss areas of small foci of invasive disease due to sampling and slicing.64 This is acknowledged by the most recent guidelines published by the American Society of test of the intercept. Subsequently, an adjusted estimate was Clinical which state that SLNB should be per- computed using Duval and Tweedie’s trim and fill method formed for DCIS in 2 circumstances: First, in patients un- which was calculated at 7.3% in the preoperative diagnosis dergoing mastectomy, as it would technically infeasible to studies and 3.7% in the postoperative diagnosis ones perform an SLNB in the aftermath. Second, as a second- (Tables 4 and 5). stage SLNB if an invasive component was found on the his- A meta-regression was also performed to determine the tological analysis of the tumor after breast conserving variables associated with SLNB positivity. Neither the surgery.65 However, it is unclear whether there is a role median age nor the upstage rate was associated with for a routine SLNB in DCIS patients undergoing breast 5 increased likelihood of positive SLNB (P .303 and conserving surgery. .1585, respectively). However, larger tumor size and higher This meta-analysis has demonstrated a significantly grade were significantly associated with SLNB positivity higher SLNB positivity in patients with preoperative 5 5 (P .03333 and P .00839, respectively; Table 6). diagnosis of DCIS than in those with postoperative diagnosis with a reported mean of 5.95% and 3.02%, Comments respectively (P 5 .0201). Especially if the cases with ITC are omitted, the final number of clinically relevant positive With the development and widespread introduction of nodes is too low to justify the routine use of SLNB in all high-quality digital mammography, DCIS is now considered cases of DCIS. However, identification of factors predictive the most rapidly growing subgroup of breast of a positive SLNB in the setting of DCIS would be of

Table 6 Meta-regression Covariate Coefficient Standard error 95% lower 95% upper Z-value P value Tumor grade vs nodal involvement Intercept .00946 .00359 .00243 .01649 2.63608 .00839 High grade % 22.947 23.28096 23.28096 22.61303 217.29528 0 Tumor size vs nodal involvement Intercept .08947 .04204 .00707 .17187 2.12813 .03333 Tumor size 22.74722 .13064 23.00328 22.49116 221.0284 0 This table outlines the statistical test for meta-regression which was performed to investigate whether high tumor grade and tumor size was significantly associated with a higher risk of having a positive SLNB result. Significance was assumed when P , .05 (bold). 178 The American Journal of Surgery, Vol 213, No 1, January 2017 clinical utility. Our meta-analysis has established a signifi- defined as deposits less than .2 mm or less than 200 cells cant association between SLNB positivity and high tumor and have been reported with increasing frequency since grade and large tumor size but not with age at diagnosis the introduction of . It is not nor the upstage rate. currently considered an indication for further treatment Our finding of positive association between high tumor of the axilla.65,73 Micrometastases are defined as deposits grade and positive SLNB in DCIS patients is consistent with between .2 and 2 mm and have been found to be associ- findings in other studies where high-grade disease has been ated with a poorer prognosis than negative SLNB. Man- earmarked as an independent risk factor for clinically occult agement should be performed after multidisciplinary .66,67 Boler et al67 reported that patients with high- discussion to identify those patients who have a high grade disease were more likely to undergo SLNB although risk of harboring lymphatic spread since axillary lymph other studies failed to demonstrate a correlation between node dissection may be safely omitted.74 ITCs accounted the likelihood of SLN metastases and high tumor grade.22 for a large portion of our data and as the presence of ITCs Likewise, our finding of increased possibility of SLNB would not likely change treatment or disease outcomes, a positivity in larger tumors is similar to previous reports. Kondo better reporting of the proportion of cases with ITCs et al68 observed that tumors larger than 2 cm were significantly would have provide more clarity regarding the clinical associated with upstaging a previous DCIS tumor to invasive implications of a positive SLNB. disease. Furthermore, an audit from the UK NHS Breast Furthermore, the extent of the histological analysis (ie, Screening Programme has suggested that axillary surgery in the number of sections, the technique of specimen slicing, the setting of preoperatively diagnosed DCIS was associated and the use of IHC) of either the core biopsy or the with larger tumor size.3 Similarly, Chin-Lenn et al10 observed definitive histology is likely to be heterogeneous among the that in cases where DCIS was diagnosed preoperatively, hav- studies; nevertheless, the available data did not allow us to ing a larger tumor was associated with undergoing a SLNB. examine these potentially significant parameters. This is likely being done in conjunction with a mastectomy Similarly, clinical palpability of the tumor19,38 and re- performed in cases where extensive DCIS has made breast- ceptor status39,68 have been cited as predictors of axillary conserving surgery infeasible. involvement. However, the lack of data precluded their in- Our analysis did not find an association of positive SLNB clusion in this study. with clinically occult invasion. This is in contrast to several Finally, the current data did not permit the study of the studies included in our analysis.5,25,26 Indeed, it stands to association between the type of core biopsy (ie, standard reason that patients with large areas of high-grade DCIS core-needle biopsy [CNB] vs vacuum-assisted biopsy are more likely to harbor areas of clinically occult microin- [VAB]) and the incidence of sentinel lymph node metastasis. vasion, which should account for the increased rate of posi- However, the included studies failed to specify the pre- tive SLNB. Previous studies have found associations operative biopsy modality (ie, conventional CNB or VAB). between features of high-grade DCIS, such as opacity on This is a significant limitation since VAB has a greater mammogram and palpable tumors, and subsequent detection accuracy than CNB in identifying invasive disease.75 Kotani of invasion.18,42,43 Unfortunately, not all studies included in et al23 reported a positive SLNB rate of .6% in 199 DCIS pa- our meta-analysis reported on upstage rate after a preopera- tients who were diagnosed with preoperative stereotactic tive diagnosis of DCIS. Of those that did, the mean upstage VAB although 20% of these patients were upstaged on final rate reported was 23.2% (range 0% to 42.6%).5,9– pathology. Hence, they recommended avoiding SLNB in this 11,13,16,17,19,20,23,26,27,30,32,33,36,39,41,43 This equated to 714 subgroup of DCIS patients. In contrast, Meijnen et al76 of 3,246 cases (22%) in studies reporting upstage rate. Hope- emphasized the importance of SLNB in CNB-diagnosed fully, explicit reporting of the upstage rate in future studies DCIS patients as they have reported an upstage of 26.2% would resolve this anomaly. Alternatively, it is possible and SLNB positivity of 12.08%. Similarly, Omranipour that portion of the positive SLNBs may be due to other fac- et al77 suggested that SLNB should be indicated whenever tors, such as seeding core , or mechanical displace- the diagnosis of DCIS is based on CNB. ment, and therefore may not be of great clinical import.69,70 Moreover, questions arise regarding the optimal manage- Furthermore, we did not observe a significant correlation ment of patients with positive SLNB results who have a between age at diagnosis and the risk of SLNB positivity in preoperative diagnosis of DCIS: the significance of positive the present study. However, Yen et al71 reported that an age findings remains unclear. In our study, the most common of less than 55 years was an independent factor for finding was either ITCs or micrometastases. The American harboring invasive disease and suggested that younger Society of Clinical Oncology guidelines indicate that clini- patients with DCIS should be considered for SLNB. Like- cians should not recommend axillary lymph node dissection wise, Shah et al72 observed that women with DCIS older with early breast cancer patients who have 1 or 2 sentinel than 56 years were less likely to undergo SLNB. lymph node metastases and receive breast conserving therapy This study is not without limitations. Our meta-analysis and radiotherapy.64 Although SLNB would be inappropriate did not examine the type of the metastasis (ie, ITC vs in most cases of DCIS, the selected use of SLNB in the micrometastasis vs macrometastasis) due to the absence of case of extensive high-grade DCIS could be considered after this information in many of the included studies. ITCs are a thorough discussion within the multidisciplinary team. H. El Hage Chehade et al. SLNB in DCIS patients 179

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