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Originally published as JCO Early Release 10.1200/JCO.2005.03.3225 on March 27 2006 © 2006 American Society of Clinical Oncology. Micrometastases in Sentinel Lymph Node in a Multicentric Study: Predictive Factors of Nonsentinel Lymph Node Involvement—Groupe Des Chirurgiens De La Federation Des Centres De Lutte Contre Le Cancer
From the Institut Paolio Calmettes, Marseille; Institut Curie, Paris; Centre Leon Berard, Lyon; Centre Rene Gauducheau, Nantes Saint-Herblain; Centre Oscard Lambret, Lille; Centre Val D'Aurelle, Montpellier; Centre Jean Perrin, Clermont-Ferrand, France Address reprint requests to Gilles Houvenaeghel, Institut Paoli Calmettes, 232 Blvd Sainte Marguerite, 13011 Marseille, Cedex 9, France; e-mail: houvenag{at}marseille.fnclcc.fr
PURPOSE: To determine the rate of nonsentinel lymph node (NSN) involvement at axillary lymph node dissection (ALND) and predictive factors of this involvement following detection of micrometastasis in sentinel nodes (SN). METHODS: We analyzed 700 observations of SN micrometastases with additional ALND with the characteristics of the patients, tumors, and SN.
RESULTS: Involvement of SN was diagnosed 388 times by serial sections (55.4%) with standard hemoxylin and eosin staining (HES) and 312 times solely on immunohistochemical analysis (IHC; 44.6%). The accurate size of the micrometastases was indicated in 488 cases: 301 larger than 0.2 mm (61.7%) and 187 CONCLUSION: This study confirms the value of serial sections and the vital role played by IHC in screening for small micrometastases. Omission of additional ALND may be envisaged with minimal risk for pT1a and pT1b tumors, and pT1a-b-c tumors corresponding to tubular, colloidal, or medullar cancers.
Since the initial publications1,2 concerning the use of the sentinel node (SN) procedure in early-stage breast carcinoma, the development of this technique has been considerable. Following the first phase feasibility studies, the technical procedures and indications have gradually been stipulated, including a learning period.3 At the same time, the benefits in terms of morbidity have been compared with axillary lymph node dissection (ALND).4 The histopathologic analysis methods have been improved in order to ensure a more precise staging and to reduce the false-negative rate.5 Similarly, the WHO definitions of different types of metastases have been revised in three categories: isolated cells or submicrometastases (< 0.2 mm), micrometastases (  0.2 but < 2 mm), and macrometastases ( 2 mm). Some debate continues as to SN micrometastasis prognostic value, particularly as the potential role of immunohistochemistry in their demonstration is also a matter of debate. The purpose of this study was to determine: (1) the rate of nonsentinel lymph node (NSN) involvement at ALND in the case of SN micrometastasis, (2) predictive factors of NSN involvement at ALND, and (3) the existence of a subpopulation of patients in whom ALND can be omitted.
Between January 1998 and December 2003, we carried out a retrospective study of 16 centers of patients presenting with micrometastasis in SN, who had undergone an additional Berg I and II ALND by consensus. The analytic data concerned: (1) patient characteristics (age, hormonal status); (2) clinical characteristics of the tumor (TNM stage, localization); (3) identification procedures for SN (injection site of the isotope and dye, staining or not of the SN, number and localization of SN). The histopathologic data studied were: (1) breast tumor (histologic type, size, Scarff Bloom Richardson grade, lymphovascular invasion [LVI], hormonal receptors); (2) SN (intraoperative biopsy, analytic methods for SN, including number of sections, spacing between sections, performance of immunohistochemical analysis [IHC], number of sections analyzed by IHC, and size of micrometastases); (3) number of lymph nodes (LN) analyzed after ALND (by standard analysis without serial sections or IHC) and number of metastatic NSN.
Descriptive statistics are reported as frequencies and percentages, or means and standard deviations. Distributions of categoric variables were compared using standard
A total of 700 cases were studied. The mean patient age was 56 years (median, 55 years; range, 25 to 86). The characteristics of the tumors are given in Table 1. The mean histopathologic tumor size was 19 mm (median, 15 mm; range, 1 to 170 mm). The results of SN identification and the sites of injection are given in Table 2 and Table 3.
Staining of the SN was seen in 88.8% of the reported case subjects (435 subjects of 490); in 89.9% (286 of 318) following peritumoral injection and in 84.8% (117 of 138) following periareolar injection (not significant), respectively.
Histopathologic Study Involvement of SN was diagnosed in 388 case subjects by serial sections (55.4%) with standard hematoxylin and eosin staining (HES). An additional IHC study was performed in 512 case subjects (73.1%) and involvement of the SN was diagnosed in 312 patients (44.6%) on IHC analysis only, irrespective of the tumor size (P = .57; Table 2). The exact size of the micrometastases was specified in 254 patients and was approximated in 488 patients as being greater or less than 0.2 mm overall (Table 2). Detection of submicrometastases varied according to the type of analysis performed on the SN (Table 4). The significant detection factors for submicrometastases by logistic regression analysis were spacing between sections and IHC analysis (P < .000).
Factors Affecting Involvement of NSN Additional ALND accompanying SN biopsies allowed analysis of a mean of 11 LN (median, 10; range, 4 to 37). The mean number of LN examined, including SN, was 13 (median, 12; range, 5 to 39). Ninety-four patients presented metastatic involvement of NSN (13.4%; 94 of 700), with only one involved LN in 66% of the patients (62 of 94), two LNs in 18.1% of patients (17 of 94), three LN in 5.3% of patients (5 of 94), and more than three LN in 10.6% of patients (10 of 94). This NSN involvement increased significantly with T stage (P = .0006), the tumor size (P < .000), tumor grade, the presence of LVI, and in cases of mixed carcinomas, or if micrometastases in the SN were solely identified by HES staining. However, it is important to note that no difference was seen in the rates of NSN involvement between submicrometastases and micrometastases (Table 5).
With multivariate analysis, the significant predictive factors were as follows: pT stage  versus more than 20 mm (P < .0001; OR, 2.54; 95% CI, 1.607 to 4.014), micrometastases detected by HES versus IHC alone (P = .027; OR, 1.734; 95% CI, 1.084 to 2.773), and presence or absence of LVI (P = .021; OR, 1.706; 95% CI, 1.082 to 2.690). The rate of NSN involvement according to these factors is given in Table 6. For tumors pT 20 mm, the only significant factor in multivariate analysis was size ( or > 10 mm; P = .0074; OR, 3.066; 95% CI, 1.350 to 6.964). For tumors smaller than 5 mm, detection of micrometastases by IHC was associated with an absence of involvement of the NSN. A risk of NSN involvement of more than 40% was seen for tumors measuring more than 21 mm with LVI, in which micrometastases were revealed by HES.
The number of NSN involved differed significantly according to the histopathologic tumor size (P = .048); involvement was consistently localized to a single NSN for tumors 10 mm (Table 7).
Only one case among the 46 tumors (2%) corresponding to tubular, colloidal, or medullar cancer presented NSN involvement with an SN micrometastasis of more than 0.2 mm detected by HES (tumor of 25 mm, grade 2, with no LVI), and no NSN metastasis was seen in the 34 cases of these tumors 20 mm.
The detection of micrometastases correlates with the histopathologic technique used and predictive factors such as the tumor size. In the literature, the detection rates of micrometastases ranged between 6.6% and 27.4% when the SN technique is performed, with a mean of 15.1% (905 of 5,982 patients), representing 18.3% to 58.9% of all the SN metastases, with a mean of 44.2% (905 of 2,048 patients).6-17 IHC increases the SN involvement rate from 9% to 47% when compared with HES staining only.18,19 The detection rate of micrometastases by IHC alone was 44.6% in our study, and between 10% and 67.4%, with a mean of 45.7% (321 of 702 patients), in the literature.5,7,8,10,13,16,20-24 Screening using polymerase chain reaction analytic techniques significantly increases these rates by up to 66%.25 However, these techniques are not recommended in clinical practice. Thus, the practical attitude facing the detection of a micrometastases is a question of current interest since this situation is not rare.
LN micrometastases are defined by size, which must be smaller than 2 mm. Submicrometastases measuring less than 0.2 mm correspond to clumps of cells or isolated cells pN0(i+).26 However the reproducibility of diagnosing micrometastasis
Practical Value of Micrometastasis Diagnosis The primary objective of this study was to determine the incidence of the NSN involvement in case of SN micrometastasis. Screening was performed to determine subgroups of patients with a low risk of NSN involvement, in whom additional ALND could be avoided. A number of studies have provided convergent proof of highly significant reduction in morbidity when axillary surgery was only limited to the SN removal.4,27 Nevertheless, concern about the therapeutic implication of additional axillary procedures depends on the level of risk, acceptable or unacceptable, of missing metastatic NSN or conversely performing numerous unnecessary ALND. The rate of NSN involvement ranges in the different series from 0% to 57%, with a maximum patient population of 110.30 The rate that we report (13.4%) is lower than the pooled proportion of 20.2% (95% CI, 15.5% to 24.9%) in the meta-analysis by Cserni et al.30 Significant predictive factors of NSN involvement were histopathologic tumor size, micrometastases detected by IHC alone, and absence of LVI, similar to the predictive factors previously determined for SN macrometastases.5,9,10,20,33 Tumor size is a criterion already reported in several studies (Table 8). 5,7,11,13,17,21,29-31,34 In contrast with the many authors who reported on smaller series, we did not find the size of micrometastases to be a significant factor (Table 9), 7,12,13,35-39 which certain authors used as an argument (micrometastases < 1 mm or 0.2 mm), together with a tumor size smaller than 10 mm, against ALND.6,11,21,24,29,40 This is a notion of key importance because the majority of histopathology protocols do not attempt to identify metastases smaller than 0.2 mm. In our study, we showed that submicrometastases detected by HES have a predictive value equivalent to that of micrometastases and could be missed other than with serial sectioning. Although IHC has a lower predictive value, this technique is not negligible for tumors measuring larger than 10 mm. The European recommendations19 stipulate screening only for micrometastases (> 0.2 mm), and IHC is not recommended. However in our study, 43.4% (76 of 175) of micrometastases detected by IHC alone were larger than 0.2 mm. The presence of LVI has also been shown to be significantly predictive of NSN involvement in case of SN macro- or micrometastases in the studies by Weiser et al9 (41% v 26% without LVI; P = .021), Turner et al5 (65% v 37%; P = .01), and Nos et al10 (34% v 20%; P = .015).
We identified two subgroups of patients for whom additional treatment of the axilla could be avoided: pT1a (n = 26) and pT1b tumors (n = 142), with risk of NSN involvement 5% (8 of 168) and no risk of involvement of more than one NSN. This subgroup represents 24% of our cases; and 34 tubular, colloidal, or medullary carcinomas, with no NSN involvement (one pT1a, 14 pT1b, 19 pT1c), representing 4.9% of our cases. The prognostic value of SN micrometastases continues to be debated,18,19,41 because one or more published studies present divergent results. However, the larger studies appear to show a worse prognosis in the presence of micrometastases in comparison with the absence of LN involvement.42-46 So far, the recommended therapeutic approach in patients with SN micrometastasis is to perform an additional ALND. Although the prognostic value of these micrometastases is still being debated, as well as their therapeutic role to indicate an adjuvant treatment, their detection is of practical value to indicate ALND. The absence of screening for micrometastases by serial sectioning could result in an increase of the false-negative (FN) SN procedures up to 2%. Thus, macrometastases to a single NSN would be missed in 8.8% of the patients, and 4.6% of the patients with two or more macrometastatic NSN would be missed and understaged. The detection of micrometastases by IHC, which was questioned,19 also seems to us to be of interest because 9.9% of these micrometastases were associated with the presence of at least one macrometastasis in a NSN: 63.5% with a single node affected, 23.8% with two NSN affected, and 12.7% with three or more NSN affected. This rate of NSN involvement following the diagnosis of SN involvement by IHC alone ranged from 0% to 25% (Table 10), 5,7,8,10,12,13,16,20-24,33,39,47-50 with a rate of 9.4% (95% CI, 6.2 to 12.6) reported in the meta-analysis by Cserni et al.30 These cases of NSN involvement associated with SN micrometastases may be suspected, at least in part, every time that the isotopic detection and preoperative lymphoscintigraphy reveal a late binding or a low intensity of the SN.51 The palpation of the axilla via the incision of the SN biopsy should be performed routinely so as to detect massively involved LN that have been excluded of the lymphatic mapping.
The most effective injection site to obtain the highest identification rates and the lowest FN rates remains controversial. We demonstrated no difference in rates of metastatic NSN according to the injection sites. The FN rate of the SN technique is considered greater for tumors localized in the upper-outer or in the lower-inner quadrant. We found no influence of tumor location on the rates of NSN involvement. The reliability of the different SN intraoperative analysis methods could not be evaluated in our study. The advantages and disadvantages of the different methods are known and their results are comparable.19 However, the detection of micrometastases by intraoperative analysis remains somewhat haphazard and unreliable. Because the detection of micrometastases has a therapeutic impact, at least to indicate further ALND, the analytic methods used must identify SN involvement in metastases smaller than 2 mm. The number of sections, at least six or more to complete the LN exhaustion, and the spacing between sections, are key parameters in the detection. Spacing of 150 to 300 microns allows detection of micrometastases measuring even smaller than 0.2 mm. Wider spacing carries the risk of nondetection of a high percentage of hidden metastases smaller than 0.2 mm. Because the size of micrometastases does not appear to be significantly correlated with the involvement of the NSN, their detection remains important in practical terms.
Treatment of the Axilla in Case of SN Micrometastasis The efficiency of axilla irradiation in the absence of ALND has been demonstrated over a long period.52 Given the fact that additional treatment of the axilla in the presence of SN micrometastasis is indicated most frequently after definitive histopathologic examination, further axilla irradiation could be proposed as an alternative to additional ALND and left to the patient's choice. However, to date, there are few data concerning the morbidity related to the irradiation of the axilla following SN procedure. Irradiation of the breast following breast-conserving treatment remains a standard procedure. It has been shown that because of tangential fields, the area concerned by breast irradiation included the lower part of the axilla, corresponding to the most common site of LN involvement. The delivered dose in this area is likely to control a residual LN involvement, if not massive. The rate of axillary relapse following ALND ranges from 0% to 2.1%, with a median follow-up of 40 to 180 months.18,23,53-59 These relapses are seen in two thirds of the cases within the first 2 years of follow-up.27,52,54-60 An axillary relapse in the absence of ALND following a negative SN biopsy is seen in 0% to 1.4% of the cases, with a median follow-up of 14 to 46 months,27,61-68 and in 0.12% (3 of 2,340) with a median follow-up of 31 months in the study reported by Naik et al.28 The rate of axillary relapse, though very low, was nevertheless significantly higher when ALND was not carried out after the discovery of a positive SN (1.4% [3 of 210] v 0.18% [7 of 3,798]; P = .013).28 Axillary relapse is thus rare; this relapse rate was 18.6% in the NSABP-B04 study in the absence of ALND following mastectomy, though the rate of LN involvement was 40% in the group undergoing ALND.
Risk of Undertreatment in Case of SN Micrometastasis In conclusion, the detection of micrometastases, irrespective of size, is currently a key element in clinical practice to indicate ALND because of the risk of NSN involvement. Omission of additional ALND may be envisaged with minimal risk for pT1a and pT1b tumors, as well as pT1a-b-c tumors corresponding to tubular, colloidal, or medullar cancers, particularly because the lower part of the axilla can be included in the mammary irradiation field. This study emphasizes the value of screening for micrometastases by IHC, because no relationship has been found between the size of the micrometastases and the involvement of the NSN.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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ABSTRACT
INTRODUCTION
2 tests. A multiple linear regression model was used to identify factors associated with NSN involvement. All significant variables in the univariate analyses were included in the first model. We then used a selection procedure based on the adjusted R2. The best model identified was the model with the largest adjusted R2, whether or not the variables included were significant. Odds ratios (OR) are presented with their 95% CI. All statistical tests were two-sided at the 5% level of significance and analyses were performed using SAS Version 8.2 (SAS/STAT User's Guide, Version 6, 1990; SAS Institute, Cary, NC). 
