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Sentinel lymph node biopsy in patients with microinvasive breast cancer: A systematic review and meta-analysis
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ScienceDirect EJSO 40 (2014) 5e11
www.ejso.com
Review
Sentinel lymph node biopsy in patients with microinvasive breast cancer: A systematic review and meta-analysis H. Gojon a, D. Fawunmi b, A. Valachis c,d,* b
a Department of Oncology, Karolinska Solna, 171 76 Stockholm, Sweden Department of Internal Medicine, M€alarsjukhuset, 63188 Eskilstuna, Sweden c Department of Oncology, M€alarsjukhuset, 63188 Eskilstuna, Sweden d University of Uppsala, 751 85 Uppsala, Sweden
Accepted 28 October 2013 Available online 5 November 2013
Abstract Background: The aim of this meta-analysis is to evaluate the role of sentinel lymph node biopsy (SLNB) in patients with microinvasive breast cancer. Methods: We searched MEDLINE and ISI Web of Science to identify studies including patients with microinvasive breast cancer who underwent SLNB and reported the rate of sentinel-node positivity. We performed proportion meta-analysis using either fixed or randomeffects model based on the between-study heterogeneity. Findings: A total of 24 studies including 968 patients met the eligibility criteria. The summary estimate for the sentinel-node (SN) positivity rate was 3.2% (95% Confidence Interval (CI): 2.1%e4.6%), 4.0% (95% CI 2.7%e5.5%), and 2.9% (95% CI: 1.6%e4.6%) for macrometastasis, micrometastasis and isolated tumor cells (ITC) respectively. Significant between-study heterogeneity was observed only in the metaanalysis of ITC positivity rate. Interpretation: The amount of positive sentinel node in patients with proven microinvasive breast cancer is relatively low. As a result, the indications for SLNB in these patients should be probably individualized. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Microinvasive; Sentinel node biopsy; Breast cancer; Meta-analysis
Introduction Microinvasive breast cancer comprises a subset of T1 breast cancer in which the focus of invasion is no larger than 1 mm in size.1 These foci of invasive cells are usually observed in the background of ductal carcinoma in situ (DCIS).2,3 By definition, DCIS is preinvasive and does not have the potential to spread to regional lymph nodes. In the presentinel lymph node biopsy (SLNB) era, axillary dissection in patients with DCIS was not recommended due to the high morbidity of the procedure and the questionable * Corresponding author. Department of Oncology, M€alarsjukhuset, 63188 Eskilstuna, Sweden. Tel.: þ46 16 103790; fax: þ46 16 104035. E-mail addresses: [email protected], [email protected] (A. Valachis). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.10.020
clinical benefit.4 In this new era of SLNB, where the method has become the standard of care in the staging of breast cancer due to the considerably lower morbidity than axillary dissection,5,6 SLNB can be recommended in patients with DCIS in the preoperative biopsy in certain circumstances. For instance, SLNB can be recommended when a mastectomy is indicated, as axillary staging by SLNB is essentially impossible if an invasive tumor is found with examination of surgical specimens.7 SLNB is also recommended if microinvasion is found on final pathology.7 However, the evidence for this recommendation is considered insufficient because the studies that underlies the recommendation are mostly retrospective with small sample size.8e31 The purpose of this meta-analysis is to gather all available evidence and evaluate the role of SLNB in patients with microinvasive breast cancer.
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Materials and methods Search strategy We conducted a comprehensive systematic electronic search through MEDLINE and ISI Web of Knowledge, without year or language restriction, by using the following searching algorithm: (microinvasive OR occult) AND (breast OR mammary) AND (cancer OR carcinoma OR tumor OR malign*) AND (sentinel OR sentinel node biopsy OR SLNB). The last search was updated on April 2013. We also conducted secondary referencing by manually reviewing reference lists of potentially eligible articles. Additionally, the reference lists of selected review articles were reviewed to ensure that other relevant publications were included. In studies with multiple publications from the same patient sample, only data from the most recent publication were included in the systematic review and in metaanalysis. Study selection Studies were included in our systematic review and meta-analysis if they fulfilled the following criteria: published research articles including patients with microinvasive breast cancer who underwent SLNB and reported the rate of sentinel-node positivity. We excluded case reports, studies that reported axillary node positivity rate after performing axillary dissection but not SLNB, and studies that did not report adequate data on micorinvasive breast cancer. Data extraction One investigator (AV) selected articles that potentially met our inclusion criteria on the basis of their titles and abstracts. Full articles were then retrieved for a more detailed assessment. For the eligible studies, two reviewers (HG, AV) abstracted the data independently on a predefined form. Differences between reviewers were resolved by discussion. The following data were collected from each study: first author’s last name, year of publication, country of the population, type of study (retrospective/prospective), definition of microinvasive breast cancer, SLNB technique used, number of patients, median age, ER status, PgR status, tumor grade, number of patients with involved sentinel lymph nodes (SLN) (macrometastasis/micrometastasis/isolated tumor cells (ITC)), number of patients who underwent axillary dissection after SLNB and involved lymph nodes after axillary dissection. Outcome measures The primary outcome of the meta-analysis was the calculation of overall pooled proportion (%) of SLN
positivity for macrometastasis (defined as the presence of tumor deposit in SLN measuring >2 mm in greatest dimension32). Secondary outcomes were the overall pooled proportion of SLN positivity for micrometastasis and for ITC. We defined as micrometastasis the presence of a tumor deposit greater than 0.2 mm and 2 mm in the SLN and as ITC the presence of a tumor deposit 0.2 mm.32 We also reported the proportion of non-SLN positivity after axillary dissection in patients with SLN positive disease. Data synthesis and analysis We calculated the pooled proportion for each outcome along with the corresponding 95% confidence intervals (CI). Continuity correction was applied to studies with zero counts (no positive SLNs) and these were given an arbitrary small count of 0.5 to avoid computational problems. We assessed the presence of statistical heterogeneity among the studies by using the Q statistics and the magnitude of heterogeneity by using the I2 statistic. We considered a p-value <0.10 or an I2 value of greater than 50% as indicative of substantial heterogeneity. When substantial heterogeneity was not observed, the pooled proportion was calculated based on the fixed-effects model using the inverse-variance method. When substantial heterogeneity was observed, the pooled proportion was calculated based on the random-effects model using the DerSimonian and Laird method. We calculated the pooled proportion for SLN positivity that allowed for comparison in different subgroups, including the type of study design (retrospective, retrospective from prospective database, prospective), the SLNB technique used (blue dye, radiolabeled colloid, both), the number of patients analyzed in the eligible studies (30 patients, >30 patients), and the presence or absence of adequate definition of microinvasion. The statistical analyses were performed using StatsDirect statistical software version 2.7.9 (StatsDirect, Sale, Cheshire, UK). Results Eligible studies A total of 225 abstracts were identified with the search criteria; of these, 42 full-text articles were reviewed as potentially eligible and 24 met the inclusion criteria (Fig. 1). Fifteen studies9,12,13,15e17,19,20,23e26,28,29,31 were retrospective, 78,10,11,18,21,22,27 were retrospective with retrieval of data from a prospectively collected database while two14,30 was prospective. The number of patients with microinvasive breast cancer included in the eligible studies ranged between 7 and 112 patients, with a total of 968 patients. The characteristics of eligible studies are shown in Table 1.
H. Gojon et al. / EJSO 40 (2014) 5e11
7
225 potentially relevant studies identified and screened for retrieval from electronic search
185 studies excluded on basis of title or abstract
42 studies retrieved in full text 18 studies excluded based on exclusion criteria: 9 lack of separate data on sentinel node biopsy 6 duplicate publication 2 reviews 1 Not adequate data on
24 studies included in the systematic review: 18 included in the meta-analysis of macrometastasis 18 studies included in the meta-analysis of micrometastasis 22 studies included in the meta-analysis
Figure 1. Flow diagram of study selection for inclusion in this review and meta-analysis.
SLN positivity rate (macrometastasis) Eighteen studies8e23,29,31 including 756 patients presented data on the SLN-positivity rate for macrometastasis. The summary estimate for the SLN-positivity rate was 3.2% (95% CI: 2.1%e4.6%) (Fig. 2). No between-study heterogeneity was observed. No significant differences in the pooled rate were observed among the different subgroups (Table 2). SLN positivity rate (micrometastasis e ITC) The summary estimate for the SLN-positivity rate was 4.0% (95% CI 2.7%e5.5%) and 2.9% (95% CI: 1.6%e 4.6%) for micrometastasis (18 studies8e23,29,31; 756 patients) and ITC (22 studies8e27,29,31; 884 patients) respectively. No between-study heterogeneity was observed in the meta-analysis of micrometastasis. However, significant between-study heterogeneity was observed in the metaanalysis of ITC positivity rate. The only statistically significant difference among the subgroups was the higher rate of ITC observed in studies with an adequate definition of microinvasin compared to studies without definition (Table 2).
Worst-case scenario: SLN-positivity rate for macrometastasis Six additional studies25e30 (212 patients) with data on SLN-positivity rate have not been included in the primary meta-analysis because they did not present separate data on positivity for macro- or micrometastasis. If we assumed that all the positive SLNs observed in these studies were macrometastases, the SLN-positivity rate for macrometastasis was 4.3% (95% CI: 3.1%e5.6%) (24 studies; 968 patients). Therefore, on a worst-case scenario, the risk for macrometastasis in SLNB in patients with microinvasive breast cancer is 5.6%. Non-SLN positivity rate in sentinel node positive disease Fifteen studies included data on non-SLN positivity in SLN positive disease. In total, 47 patients underwent axillary dissection following diagnosis of SLN macrometastasis. The summary non-SLN positivity rate was 29.7% (95% CI: 19.1% e 41.2%).
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Table 1 Characteristics of eligible studies. Author
No of patients with microinvasive breast cancer
Type of study
Gray8 Sakr9 Intra10 Katz11 Ross12 Takacs13 Wong14 Yi15 Zavagno16 Zavotsky17 Pimiento18 Cserni19 Meretoja20 Klauber-DeMore21 Lyons22 Le Bou€edec23 Tunon-de-Lara24 Camp25 Cox26 Wilkie27 Fortunato28 Cserni29 Collado30 Guth31
77 54 41 21 9 8 24 91 43 14 87 31 34 29 112 41 45 17 15 51 77 20 7 20
Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective
SLNB technique
from prospective database from prospective database from prospective database
from prospective database
from prospective database from prospective database
from prospective database
Blue dye and Tc-99m Blue dye and Tc-99m Tc-99m sulfur colloid Blue dye and Tc-99m NR Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Tc-99m sulfur colloid Blue dye Blue dye and Tc-99m NR Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Tc-99m sulfur colloid Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m
Definition of microinvasion sulfur colloid sulfur colloid sulfur colloid sulfur colloid sulfur colloid sulfur colloid
sulfur colloid sulfur sulfur sulfur sulfur sulfur
colloid colloid colloid colloid colloid
sulfur sulfur sulfur sulfur sulfur sulfur
colloid colloid colloid colloid colloid colloid
NR NR NR NR <0.1 NR NR NR NR NR <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 NR <0.1 <0.1 NR <0.1 <0.1
cm
cm cm cm cm cm cm cm cm cm cm cm cm
Abbreviations: No, number; SLN, Sentinel Lymph Node Biopsy; NR, Not Reported; Tc, Technetium.
Discussion This meta-analysis of nearly 1000 patients with microinvasive breast cancer who underwent SLNB showed that the SLN-positivity rate for macrometastasis in those patients was low (3.2%). Even in the worst-case scenario, based on the 95% confidence interval, the positivity rate remained acceptably low, namely 5.6%. Similar low positivity rates were observed for micrometastases or ITC. Microinvasive breast cancer is mainly observed after postoperative pathologic analysis in the setting of DCIS. The postsurgical discovery of unexpected microinvasive foci usually leads to additional axillary surgery with SLNB. However, this common clinical practice is based on scarce evidence. Indeed, the latest guidelines from the American Society of Clinical Oncology, which published on 2005, recommended the use of SLNB in case of microinvasion but the authors recognized that the evidence for this recommendation is insufficient.7 Our meta-analysis does not justify this recommendation considering the low rates of SLN-positivity. Our meta-analysis adds to the growing body of evidence against the use of SLNB in patients with microinvasive breast cancer. Apart from the low risk for SLN-positivity observed in our meta-analysis, several studies have reported excellent prognosis in those patients irrespective of the lymph node involvement.18,20,33e36 The risk of distant metastasis in these studies ranges from 0% to 2% with a
median follow-up up to 4 years in most of the available studies. Therefore, even if we identify patients with lymph node involvement, an improvement to this already excellent prognosis by adjuvant therapy will be highly unlikely. In addition, clinical36 and pathologic37 studies have shown that the natural history of microinvasive breast cancer closely resembles that of DCIS; therefore the treatment strategy between the two entities should not be different. Our meta-analysis revealed low rates of SLN-positivity for micrometastasis and ITC as well. Considering the questionable prognostic value of micrometastasis or ITC in SLN,38,39 the lack of clinical benefit with additional axillary surgery in patients with SLN micrometastases,40 and the low rates of SLN-positivity that was found in our meta-analysis, it seems fully justified to omit the SLNB in patients with such an extremely low tumor burden such as those with microinvasion. One could argue that the non-SLN positivity rate was considerably high in our meta-analysis. However, this rate should always be evaluated in the context of the SLNpositivity rate. The patients with microinvasive breast cancer and SLN positive disease (3.2% according to our metaanalysis) have a 29.7% risk for metastasis in non-SLN. Thus, the patients with microinvasive breast cancer before axillary surgery have a risk of 0.95% for metastasis in non-SLN. This risk is not high enough to justify a SLNB to all the patients with microinvasive breast cancer. However, this observation raises the question whether there are
H. Gojon et al. / EJSO 40 (2014) 5e11
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Figure 2. Pooled estimate of sentinel lymph node positivity rate for macrometastasis.
subgroups of patients with microinvasive cancer and a higher risk for lymph node involvement that could derive benefit from SLNB. While several studies28,41,42 have identified risk factors for lymph node involvement, including
comedo type necrosis, the number of ductals involved by DCIS, lymphatic invasion, positive estrogen receptor status, tumor grade III, and young age, other studies have failed to link the risk of node involvement to any clinicopathologic
Table 2 Pooled sentinel lymph node positivity rates: Subgroup analysis.
Study design Prospective Retrospective from prospective database Retrospective SLNB technique Blue dye Radiolabeled colloid Both Patients analyzed 30 patients >30 patients Definition of microinvasion <0.1 cm Not defined
Macrometastasis
Micrometastasis
Isolated tumor cells
Included studies
Included studies
Included studies
Pooled rate (95% CI)
Pooled rate (95% CI)
Pooled rate (95% CI)
1 6
NC 3.4 (1.8e5.5)
1 6
NC 4.3 (2.4e6.6)
1 7
11
2.7 (1.3e4.5)
11
4.0 (2.3e6.2)
14
2.7 (1.0e5.2)
1 2 13
NC 6.9 (2.5e13.2) 2.9 (1.7e4.3)
1 2 13
NC 4.5 (1.2e9.8) 4.0 (2.7e5.6)
1 3 16
NC 1.3 (0.3e4.3) 3.2 (1.6e5.3)
8 10
4.4 (1.7e8.2) 2.9 (1.8e4.4)
8 10
3.3 (1.1e6.7) 4.2 (2.8e5.9)
10 12
3.5 (1.4e6.6) 2.6 (1.1e4.8)
8 10
3.3 (1.7e5.4) 3.1 (1.6e5.0)
8 11
4.5 (2.6e6.8) 3.6 (2.0e5.6)
10 11
4.7 (3.0e6.7) 1.3 (0.4e2.6)a
Abbreviations: CI, Confidence Interval; SLNB, Sentinel Lymph Node Biopsy; NC, Not Calculated. a p-value <0.05.
NC 3.9 (2.3e6)
10
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factor.10,11,31 However, the small number of patients as well as the lack of multivariable analysis to identify risk factors in some studies10,11,28,31 limit the validity of the results. Further studies on this direction are necessary. There are several limitations in our meta-analysis that deserve attention. First, the nature of the majority of studies was retrospective and as a result prone to biases. Furthermore, eligible studies have been performed in different times (from 1999 to 2012) and some differences in the sentinel node technique among studies should be expected since there has been an improvement of the technique over the years. However, a subgroup analysis based on the SLNB technique could not reveal any significant difference in SLN-positivity rates. In addition, several studies did not define the microinvasion. The lack of standardized definition has historically been a limitation in the literature of microinvasive breast cancer. However, when positivity rates only from studies with adequate definition of microinvasion were pooled, the results on SLN-positivity for macrometastasis were similar with those from studies without adequate definition. Finally, in some cases, multiple reports were published over time and considerable effort was expended in an attempt to identify and utilize the most suitable report. It is possible, however, that some nonduplicated patients might have been included. In conclusion, the amount of positive SLN in patients with proven microinvasive breast cancer is relatively low. As a result, the indications for SLNB in these patients should be probably individualized. Future research should be focused to investigate whether there are subgroups of patients with higher risk for lymph node involvement that might derive benefit from SLNB and maybe additional adjuvant therapy. Funding source This study has been funded by the Centre for Clinical Research S€ ormland, Uppsala University. Conflict of interest statement The authors have no conflict of interest to declare.
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H. Gojon et al. / EJSO 40 (2014) 5e11 25. Camp R, Feezor R, Kasraeian A, et al. Sentinel lymph node biopsy for ductal carcinoma in situ: an evolving approach at the University of Florida. Breast J 2005;11:394–7. 26. Cox CE, Nguyen K, Gray RJ, et al. Importance of lymphatic mapping in ductal carcinoma in situ (DCIS): why map DCIS? Am Surg 2001; 67:513–9. 27. Wilkie C, White L, Dupont E, Cantor A, Cox CE. An update of sentinel lymph node mapping in patients with ductal carcinoma in situ. Am J Surg 2005;190:563–6. 28. Fortunato L, Santoni M, Drago S, et al. Rome Breast Cancer Study Group. Sentinel lymph node biopsy in women with pT1a or “microinvasive” breast cancer. Breast 2008;17:395–400. 29. Cserni G, Boross G, Maraz R, et al. Sentinel lymph node biopsy for in situ carcinoma of the breast. Experience at the Bacs-Kiskun County Hospital and review of the literature. Magy Seb 2006;59:164–72. 30. Collado MV, Ruiz-Tovar J, Garcıa-Villanueva A, et al. Sentinel lymph node biopsy in selected cases of ductal carcinoma in situ. Clin Transl Oncol 2010;12:499–502. 31. Guth AA, Mercado C, Roses DF, Darvishian F, Singh B, Cangiarella JF. Microinvasive breast cancer and the role of sentinel node biopsy: an institutional experience and review of the literature. Breast J 2008;14:335–9. 32. Greene FL, Page DL, Fleming ID, et al, editorss. Greene FL in AJCC cancer staging manual, Breast cancer. 6th ed. New York, NY: Springer-Verlag; 2002, p. 221–40. 33. Murphy CD, Jones JL, Javid SH, et al. Do sentinel node micrometastases predict recurrence risk in ductal carcinoma in situ and ductal carcinoma in situ with microinvasion? Am J Surg 2008;196:566–8. 34. Broekhuizen LN, Wijsman JH, Peterse JL, Rutgers EJ. The incidence and significance of micrometastases in lymph nodes of patients with
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Review
Sentinel lymph node biopsy in patients with microinvasive breast cancer: A systematic review and meta-analysis H. Gojon a, D. Fawunmi b, A. Valachis c,d,* b
a Department of Oncology, Karolinska Solna, 171 76 Stockholm, Sweden Department of Internal Medicine, M€alarsjukhuset, 63188 Eskilstuna, Sweden c Department of Oncology, M€alarsjukhuset, 63188 Eskilstuna, Sweden d University of Uppsala, 751 85 Uppsala, Sweden
Accepted 28 October 2013 Available online 5 November 2013
Abstract Background: The aim of this meta-analysis is to evaluate the role of sentinel lymph node biopsy (SLNB) in patients with microinvasive breast cancer. Methods: We searched MEDLINE and ISI Web of Science to identify studies including patients with microinvasive breast cancer who underwent SLNB and reported the rate of sentinel-node positivity. We performed proportion meta-analysis using either fixed or randomeffects model based on the between-study heterogeneity. Findings: A total of 24 studies including 968 patients met the eligibility criteria. The summary estimate for the sentinel-node (SN) positivity rate was 3.2% (95% Confidence Interval (CI): 2.1%e4.6%), 4.0% (95% CI 2.7%e5.5%), and 2.9% (95% CI: 1.6%e4.6%) for macrometastasis, micrometastasis and isolated tumor cells (ITC) respectively. Significant between-study heterogeneity was observed only in the metaanalysis of ITC positivity rate. Interpretation: The amount of positive sentinel node in patients with proven microinvasive breast cancer is relatively low. As a result, the indications for SLNB in these patients should be probably individualized. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Microinvasive; Sentinel node biopsy; Breast cancer; Meta-analysis
Introduction Microinvasive breast cancer comprises a subset of T1 breast cancer in which the focus of invasion is no larger than 1 mm in size.1 These foci of invasive cells are usually observed in the background of ductal carcinoma in situ (DCIS).2,3 By definition, DCIS is preinvasive and does not have the potential to spread to regional lymph nodes. In the presentinel lymph node biopsy (SLNB) era, axillary dissection in patients with DCIS was not recommended due to the high morbidity of the procedure and the questionable * Corresponding author. Department of Oncology, M€alarsjukhuset, 63188 Eskilstuna, Sweden. Tel.: þ46 16 103790; fax: þ46 16 104035. E-mail addresses: [email protected], [email protected] (A. Valachis). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.10.020
clinical benefit.4 In this new era of SLNB, where the method has become the standard of care in the staging of breast cancer due to the considerably lower morbidity than axillary dissection,5,6 SLNB can be recommended in patients with DCIS in the preoperative biopsy in certain circumstances. For instance, SLNB can be recommended when a mastectomy is indicated, as axillary staging by SLNB is essentially impossible if an invasive tumor is found with examination of surgical specimens.7 SLNB is also recommended if microinvasion is found on final pathology.7 However, the evidence for this recommendation is considered insufficient because the studies that underlies the recommendation are mostly retrospective with small sample size.8e31 The purpose of this meta-analysis is to gather all available evidence and evaluate the role of SLNB in patients with microinvasive breast cancer.
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Materials and methods Search strategy We conducted a comprehensive systematic electronic search through MEDLINE and ISI Web of Knowledge, without year or language restriction, by using the following searching algorithm: (microinvasive OR occult) AND (breast OR mammary) AND (cancer OR carcinoma OR tumor OR malign*) AND (sentinel OR sentinel node biopsy OR SLNB). The last search was updated on April 2013. We also conducted secondary referencing by manually reviewing reference lists of potentially eligible articles. Additionally, the reference lists of selected review articles were reviewed to ensure that other relevant publications were included. In studies with multiple publications from the same patient sample, only data from the most recent publication were included in the systematic review and in metaanalysis. Study selection Studies were included in our systematic review and meta-analysis if they fulfilled the following criteria: published research articles including patients with microinvasive breast cancer who underwent SLNB and reported the rate of sentinel-node positivity. We excluded case reports, studies that reported axillary node positivity rate after performing axillary dissection but not SLNB, and studies that did not report adequate data on micorinvasive breast cancer. Data extraction One investigator (AV) selected articles that potentially met our inclusion criteria on the basis of their titles and abstracts. Full articles were then retrieved for a more detailed assessment. For the eligible studies, two reviewers (HG, AV) abstracted the data independently on a predefined form. Differences between reviewers were resolved by discussion. The following data were collected from each study: first author’s last name, year of publication, country of the population, type of study (retrospective/prospective), definition of microinvasive breast cancer, SLNB technique used, number of patients, median age, ER status, PgR status, tumor grade, number of patients with involved sentinel lymph nodes (SLN) (macrometastasis/micrometastasis/isolated tumor cells (ITC)), number of patients who underwent axillary dissection after SLNB and involved lymph nodes after axillary dissection. Outcome measures The primary outcome of the meta-analysis was the calculation of overall pooled proportion (%) of SLN
positivity for macrometastasis (defined as the presence of tumor deposit in SLN measuring >2 mm in greatest dimension32). Secondary outcomes were the overall pooled proportion of SLN positivity for micrometastasis and for ITC. We defined as micrometastasis the presence of a tumor deposit greater than 0.2 mm and 2 mm in the SLN and as ITC the presence of a tumor deposit 0.2 mm.32 We also reported the proportion of non-SLN positivity after axillary dissection in patients with SLN positive disease. Data synthesis and analysis We calculated the pooled proportion for each outcome along with the corresponding 95% confidence intervals (CI). Continuity correction was applied to studies with zero counts (no positive SLNs) and these were given an arbitrary small count of 0.5 to avoid computational problems. We assessed the presence of statistical heterogeneity among the studies by using the Q statistics and the magnitude of heterogeneity by using the I2 statistic. We considered a p-value <0.10 or an I2 value of greater than 50% as indicative of substantial heterogeneity. When substantial heterogeneity was not observed, the pooled proportion was calculated based on the fixed-effects model using the inverse-variance method. When substantial heterogeneity was observed, the pooled proportion was calculated based on the random-effects model using the DerSimonian and Laird method. We calculated the pooled proportion for SLN positivity that allowed for comparison in different subgroups, including the type of study design (retrospective, retrospective from prospective database, prospective), the SLNB technique used (blue dye, radiolabeled colloid, both), the number of patients analyzed in the eligible studies (30 patients, >30 patients), and the presence or absence of adequate definition of microinvasion. The statistical analyses were performed using StatsDirect statistical software version 2.7.9 (StatsDirect, Sale, Cheshire, UK). Results Eligible studies A total of 225 abstracts were identified with the search criteria; of these, 42 full-text articles were reviewed as potentially eligible and 24 met the inclusion criteria (Fig. 1). Fifteen studies9,12,13,15e17,19,20,23e26,28,29,31 were retrospective, 78,10,11,18,21,22,27 were retrospective with retrieval of data from a prospectively collected database while two14,30 was prospective. The number of patients with microinvasive breast cancer included in the eligible studies ranged between 7 and 112 patients, with a total of 968 patients. The characteristics of eligible studies are shown in Table 1.
H. Gojon et al. / EJSO 40 (2014) 5e11
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225 potentially relevant studies identified and screened for retrieval from electronic search
185 studies excluded on basis of title or abstract
42 studies retrieved in full text 18 studies excluded based on exclusion criteria: 9 lack of separate data on sentinel node biopsy 6 duplicate publication 2 reviews 1 Not adequate data on
24 studies included in the systematic review: 18 included in the meta-analysis of macrometastasis 18 studies included in the meta-analysis of micrometastasis 22 studies included in the meta-analysis
Figure 1. Flow diagram of study selection for inclusion in this review and meta-analysis.
SLN positivity rate (macrometastasis) Eighteen studies8e23,29,31 including 756 patients presented data on the SLN-positivity rate for macrometastasis. The summary estimate for the SLN-positivity rate was 3.2% (95% CI: 2.1%e4.6%) (Fig. 2). No between-study heterogeneity was observed. No significant differences in the pooled rate were observed among the different subgroups (Table 2). SLN positivity rate (micrometastasis e ITC) The summary estimate for the SLN-positivity rate was 4.0% (95% CI 2.7%e5.5%) and 2.9% (95% CI: 1.6%e 4.6%) for micrometastasis (18 studies8e23,29,31; 756 patients) and ITC (22 studies8e27,29,31; 884 patients) respectively. No between-study heterogeneity was observed in the meta-analysis of micrometastasis. However, significant between-study heterogeneity was observed in the metaanalysis of ITC positivity rate. The only statistically significant difference among the subgroups was the higher rate of ITC observed in studies with an adequate definition of microinvasin compared to studies without definition (Table 2).
Worst-case scenario: SLN-positivity rate for macrometastasis Six additional studies25e30 (212 patients) with data on SLN-positivity rate have not been included in the primary meta-analysis because they did not present separate data on positivity for macro- or micrometastasis. If we assumed that all the positive SLNs observed in these studies were macrometastases, the SLN-positivity rate for macrometastasis was 4.3% (95% CI: 3.1%e5.6%) (24 studies; 968 patients). Therefore, on a worst-case scenario, the risk for macrometastasis in SLNB in patients with microinvasive breast cancer is 5.6%. Non-SLN positivity rate in sentinel node positive disease Fifteen studies included data on non-SLN positivity in SLN positive disease. In total, 47 patients underwent axillary dissection following diagnosis of SLN macrometastasis. The summary non-SLN positivity rate was 29.7% (95% CI: 19.1% e 41.2%).
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Table 1 Characteristics of eligible studies. Author
No of patients with microinvasive breast cancer
Type of study
Gray8 Sakr9 Intra10 Katz11 Ross12 Takacs13 Wong14 Yi15 Zavagno16 Zavotsky17 Pimiento18 Cserni19 Meretoja20 Klauber-DeMore21 Lyons22 Le Bou€edec23 Tunon-de-Lara24 Camp25 Cox26 Wilkie27 Fortunato28 Cserni29 Collado30 Guth31
77 54 41 21 9 8 24 91 43 14 87 31 34 29 112 41 45 17 15 51 77 20 7 20
Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Retrospective Prospective Retrospective
SLNB technique
from prospective database from prospective database from prospective database
from prospective database
from prospective database from prospective database
from prospective database
Blue dye and Tc-99m Blue dye and Tc-99m Tc-99m sulfur colloid Blue dye and Tc-99m NR Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Tc-99m sulfur colloid Blue dye Blue dye and Tc-99m NR Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Tc-99m sulfur colloid Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m Blue dye and Tc-99m
Definition of microinvasion sulfur colloid sulfur colloid sulfur colloid sulfur colloid sulfur colloid sulfur colloid
sulfur colloid sulfur sulfur sulfur sulfur sulfur
colloid colloid colloid colloid colloid
sulfur sulfur sulfur sulfur sulfur sulfur
colloid colloid colloid colloid colloid colloid
NR NR NR NR <0.1 NR NR NR NR NR <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 NR <0.1 <0.1 NR <0.1 <0.1
cm
cm cm cm cm cm cm cm cm cm cm cm cm
Abbreviations: No, number; SLN, Sentinel Lymph Node Biopsy; NR, Not Reported; Tc, Technetium.
Discussion This meta-analysis of nearly 1000 patients with microinvasive breast cancer who underwent SLNB showed that the SLN-positivity rate for macrometastasis in those patients was low (3.2%). Even in the worst-case scenario, based on the 95% confidence interval, the positivity rate remained acceptably low, namely 5.6%. Similar low positivity rates were observed for micrometastases or ITC. Microinvasive breast cancer is mainly observed after postoperative pathologic analysis in the setting of DCIS. The postsurgical discovery of unexpected microinvasive foci usually leads to additional axillary surgery with SLNB. However, this common clinical practice is based on scarce evidence. Indeed, the latest guidelines from the American Society of Clinical Oncology, which published on 2005, recommended the use of SLNB in case of microinvasion but the authors recognized that the evidence for this recommendation is insufficient.7 Our meta-analysis does not justify this recommendation considering the low rates of SLN-positivity. Our meta-analysis adds to the growing body of evidence against the use of SLNB in patients with microinvasive breast cancer. Apart from the low risk for SLN-positivity observed in our meta-analysis, several studies have reported excellent prognosis in those patients irrespective of the lymph node involvement.18,20,33e36 The risk of distant metastasis in these studies ranges from 0% to 2% with a
median follow-up up to 4 years in most of the available studies. Therefore, even if we identify patients with lymph node involvement, an improvement to this already excellent prognosis by adjuvant therapy will be highly unlikely. In addition, clinical36 and pathologic37 studies have shown that the natural history of microinvasive breast cancer closely resembles that of DCIS; therefore the treatment strategy between the two entities should not be different. Our meta-analysis revealed low rates of SLN-positivity for micrometastasis and ITC as well. Considering the questionable prognostic value of micrometastasis or ITC in SLN,38,39 the lack of clinical benefit with additional axillary surgery in patients with SLN micrometastases,40 and the low rates of SLN-positivity that was found in our meta-analysis, it seems fully justified to omit the SLNB in patients with such an extremely low tumor burden such as those with microinvasion. One could argue that the non-SLN positivity rate was considerably high in our meta-analysis. However, this rate should always be evaluated in the context of the SLNpositivity rate. The patients with microinvasive breast cancer and SLN positive disease (3.2% according to our metaanalysis) have a 29.7% risk for metastasis in non-SLN. Thus, the patients with microinvasive breast cancer before axillary surgery have a risk of 0.95% for metastasis in non-SLN. This risk is not high enough to justify a SLNB to all the patients with microinvasive breast cancer. However, this observation raises the question whether there are
H. Gojon et al. / EJSO 40 (2014) 5e11
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Figure 2. Pooled estimate of sentinel lymph node positivity rate for macrometastasis.
subgroups of patients with microinvasive cancer and a higher risk for lymph node involvement that could derive benefit from SLNB. While several studies28,41,42 have identified risk factors for lymph node involvement, including
comedo type necrosis, the number of ductals involved by DCIS, lymphatic invasion, positive estrogen receptor status, tumor grade III, and young age, other studies have failed to link the risk of node involvement to any clinicopathologic
Table 2 Pooled sentinel lymph node positivity rates: Subgroup analysis.
Study design Prospective Retrospective from prospective database Retrospective SLNB technique Blue dye Radiolabeled colloid Both Patients analyzed 30 patients >30 patients Definition of microinvasion <0.1 cm Not defined
Macrometastasis
Micrometastasis
Isolated tumor cells
Included studies
Included studies
Included studies
Pooled rate (95% CI)
Pooled rate (95% CI)
Pooled rate (95% CI)
1 6
NC 3.4 (1.8e5.5)
1 6
NC 4.3 (2.4e6.6)
1 7
11
2.7 (1.3e4.5)
11
4.0 (2.3e6.2)
14
2.7 (1.0e5.2)
1 2 13
NC 6.9 (2.5e13.2) 2.9 (1.7e4.3)
1 2 13
NC 4.5 (1.2e9.8) 4.0 (2.7e5.6)
1 3 16
NC 1.3 (0.3e4.3) 3.2 (1.6e5.3)
8 10
4.4 (1.7e8.2) 2.9 (1.8e4.4)
8 10
3.3 (1.1e6.7) 4.2 (2.8e5.9)
10 12
3.5 (1.4e6.6) 2.6 (1.1e4.8)
8 10
3.3 (1.7e5.4) 3.1 (1.6e5.0)
8 11
4.5 (2.6e6.8) 3.6 (2.0e5.6)
10 11
4.7 (3.0e6.7) 1.3 (0.4e2.6)a
Abbreviations: CI, Confidence Interval; SLNB, Sentinel Lymph Node Biopsy; NC, Not Calculated. a p-value <0.05.
NC 3.9 (2.3e6)
10
H. Gojon et al. / EJSO 40 (2014) 5e11
factor.10,11,31 However, the small number of patients as well as the lack of multivariable analysis to identify risk factors in some studies10,11,28,31 limit the validity of the results. Further studies on this direction are necessary. There are several limitations in our meta-analysis that deserve attention. First, the nature of the majority of studies was retrospective and as a result prone to biases. Furthermore, eligible studies have been performed in different times (from 1999 to 2012) and some differences in the sentinel node technique among studies should be expected since there has been an improvement of the technique over the years. However, a subgroup analysis based on the SLNB technique could not reveal any significant difference in SLN-positivity rates. In addition, several studies did not define the microinvasion. The lack of standardized definition has historically been a limitation in the literature of microinvasive breast cancer. However, when positivity rates only from studies with adequate definition of microinvasion were pooled, the results on SLN-positivity for macrometastasis were similar with those from studies without adequate definition. Finally, in some cases, multiple reports were published over time and considerable effort was expended in an attempt to identify and utilize the most suitable report. It is possible, however, that some nonduplicated patients might have been included. In conclusion, the amount of positive SLN in patients with proven microinvasive breast cancer is relatively low. As a result, the indications for SLNB in these patients should be probably individualized. Future research should be focused to investigate whether there are subgroups of patients with higher risk for lymph node involvement that might derive benefit from SLNB and maybe additional adjuvant therapy. Funding source This study has been funded by the Centre for Clinical Research S€ ormland, Uppsala University. Conflict of interest statement The authors have no conflict of interest to declare.
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