Predictors of non-sentinel lymph node metastasis in breast cancer patients with positive sentinel lymph node (Pilot study)

ORIGINAL ARTICLE

Predictors of non-sentinel lymph node metastasis in breast

cancer patients with positive sentinel lymph node

(Pilot study)

q

Hany Eldweny

, Khaled Alkhaldy

, Noha Alsaleh

, Majda Abdulsamad

,

Ahmed Abbas

*

_{, Ahmad Hamad}

_{, Sherif Mounib}

_{, Tarek Essam}

_,

Pawel Kukawski

, Jean-Yves Bobin

, Medhat Oteifa

, Henney Amanguono

,

Fawaz Abulhoda

, Sharjeel Usmani

, Amany Elbasmy

a

Department of Surgical Oncology, Kuwait Cancer Control Center, Kuwait

b

Department of Pathology, Kuwait Cancer Control Center, Kuwait

c

Department of Nuclear Medicine, Kuwait Cancer Control Center, Kuwait

d

Department of Biostatistics and Cancer Epidemiology, Kuwait Cancer Control Center, Kuwait Received 15 May 2011; accepted 29 November 2011

Available online 23 January 2012

KEYWORDS Breast cancer; Sentinel lymph node; Lymphoscintigraphy

Abstract Background:Sentinel Lymph Node Biopsy (SLNB) procedure was found to be an accu-rate method of staging the axilla in patients with early stage breast cancer. The standard of care for breast cancer patients with positive SLN metastasis includes complete Axillary Lymph Node Dissection (ALND). However, in 40–70% of patients, the SLN is the only involved axillary node. Factors predicting non SLN metastasis should be identified in order to define subgroups of patients with positive SLN in whom the axilla may be staged by SLNB alone.

Objectives:To identify the factors predicting metastatic involvement of the non-SLNs in breast cancer patients having SLN metastasis.

q

Presented at the 2nd International Breast Cancer Conference, Kuwait, March 2009.

* Corresponding author.

E-mail address:ahmednci@gmail.com(A. Abbas).

1110-0362 ª 2011 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V.

Peer review under responsibility of Cairo University. doi:10.1016/j.jnci.2011.12.004

Production and hosting by Elsevier

Cairo University

Journal of the Egyptian National Cancer Institute

www.sciencedirect.com

Patients and Methods:Data were collected and analyzed from 80 patients with early stage invasive breast cancer (T1, T2, N0, M0) who underwent SLNB at the Surgical Oncology Department, Kuwait Cancer Control Center (KCCC) between November 2004 and February 2009. SLNB was performed using a combined technique (radioactive colloid, and blue dye) in the majority of cases. In some cases, only one technique was used. Complete ALND was performed in the case of failure of SLN identification and in patients with positive SLN. Multiple variables (patient, tumor, and SLN characteristics) were tested as possible predictors of nonsentinel lymph node metastasis. Results:The mean age of patients at diagnosis was 46.6 years. The median tumor size was 2 cm. The SLN identification rate was 96.2% (77 out of 80 patients). The SLN was positive in 24 patients (31%), and half of these showed evidence of capsular invasion. The median number of SLNs removed was two. The median number of positive SLNs was one. The incidence of non-SLN metas-tasis associated with positive SLN was 50% (12 out of 24 patients). Lymphovascular invasion was found to be the only factor associated with non-SLN metastases. In addition, two trends were observed, though they did not reach the statistical significance: the first is that the majority of patients having capsular invasion of the SLN (8 out of 12 patients, 67%) had positive non-SLN metastasis, and the second is that the patients having more than one SLN metastasis were more likely to have non-SLN metastasis (4 out of 5, 80%).

Conclusion:In the current pilot study, only the lymphovascular invasion in the area of the primary tumor was found to be significantly related to the nonsentinel lymph node metastasis. There was a tendency toward higher incidence of nonsentinel lymph node metastasis associated with the number of positive SLN and capsular invasion of SLN, though this did not reach the statistical significance. This could be attributed to the small number of patients recruited. Further evaluation of the pre-dictors of nonsentinel lymph node metastasis on a larger number of patients is required. The val-idation of these predictors in prospective studies may enable approximately half of early stage breast cancer patients with positive SLN to be staged with SLNB alone while avoiding the morbid-ity of unnecessary ALND.

ª 2011 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V.

Introduction

Surgical intervention in the diagnosis and treatment of breast cancer has undergone an extensive transformation from radi-cal mastectomy to lumpectomy, lymph node dissection, and irradiation in appropriately selected patients. The trend toward conservative surgical intervention without compromis-ing cure is also becompromis-ing applied to the evaluation of the axillary lymph nodes[1].

Sentinel Lymph Node Biopsy (SLNB), introduced by Krag et al.[2]and Giuliano et al.[3]in the early 1990s, represents a new standard of care for axillary node staging in patients with early-stage, clinically node-negative breast cancer. SLN is the first lymph node in a nodal basin to drain the primary tumor

[3]. In theory, if the Sentinel Lymph Node (SLN) does not con-tain metastatic cancer, the remainder of the nodal basin will be negative for metastasis. Therefore, the morbidity of nodal dis-section can be avoided in patients with negative SLN[4]. In breast cancer, multiple studies have shown that the SLN is accurate in predicting the absence of nodal metastasis[5–7]. If histopathologic examination shows that the SLN is free of metastasis, the other nodes in the same axilla are highly unli-kely (1–2%) to contain tumor cells and the patient is unliunli-kely to benefit from ALND[8]. The false negative rate of SLNB, which is the proportion of patients with negative SLNs but with subsequently proven axillary metastases, has varied be-tween 0% and 20% of all node positive patients[9].

If a positive SLN is found, it is currently recommended to continue with ALND[10]. However, in 40–70% of patients the SLN is the only involved axillary node[1,11–13], implying that

these patients are undergoing unnecessary ALND, with no ther-apeutic benefit or further staging information provided[14].

Factors predicting nonSentinel Lymph Node (non-SLN) metastasis should be identified in order to define the subgroup of patients with positive SLN in whom the axilla may be staged by SLN biopsy alone[15].

The aim of the current study is to identify the factors predicting metastatic involvement of the non-SLNs in breast cancer patients having SLN metastasis.

Patients and methods

The data of the patients having early stage invasive breast can-cer (T1, T2, N0 and M0) who underwent SLN biopsy at the Surgical Oncology Department of the Kuwait Cancer Control Center (KCCC) between November 2004 and February 2009 were collected and analyzed.

Inclusion criteria

Early stage invasive breast cancer with clinically negative axil-lary lymph nodes. (T1/T2, N0 and M0), histologic or cytologic diagnosis of the primary tumor obtained, successful SLNB in which at least one SLN is identified, metastatic disease is iden-tified in the SLN and complete ALND was performed . Definitions

A node was considered to be a SLN if it was identified by 1 or more of the following three criteria[1]: (1) the node was blue; Open access under CC BY-NC-ND license.

(2) the node had a blue stained afferent lymphatic vessel(s) leading to it; (3) the node had an in vivo radioactivity at least three times the background count.

The non-SLNs were defined as all the non-stained and/or the non-radioactive lymph nodes removed either during the SLNB procedure (i.e., palpable nodes) or during the ALND

[16].

SLNB technique

SLNB was performed using one of the following techniques, which were previously described: preoperative lymphoscintig-raphy with radioactive nanocolloid alone [5], blue dye tech-nique alone [3], or combined technique using radioactive colloid and blue dye[17].

Preoperative lymphoscintigraphy

Lymphoscintigraphy was performed in the day of surgery and we adopted the technique previously reported by Veronesi et al. [18]. Technetium-99 (1 mCi) labeled nanocolloid was divided in four aliquots of 0.4 ml in tuberculin syringes. These were injected intradermally in the area of the skin overlying the tumor. Patients were imaged using dual head gamma camera. Dynamic images (128· 128 matrix) of 1 min per hour for 30 min were obtained in anterior projection followed by static anterior and lateral images of the breast and axilla. Gamma finder probe was used to localize the SLN on the skin in the camera room, preoperatively in the theater, and after surgical excision of the SLN.

Surgical technique

Surgery was performed 2–3 h after lymphoscintigraphy. After induction of general anesthesia, 2–3 ml of patent blue dye was injected in different locations, according to the operating sur-geon: (1) Peritumoral; (2) Periareolar; or (3) in the area of the skin overlying the tumor. In the latter two locations, the dye was injected either intradermally or subcutaneously. If an exci-sion biopsy had been previously performed, the dye was injected at the periphery of the wall of the biopsy cavity. The breast was then massaged for 5–10 min. A hand held gamma probe was used to identify the areas of increased radioactivity in the axilla and skin markings were drawn over these areas. A small transverse axillary incision was then made at the axillary hair line and the axillary fascia divided. Blue stained lymphatic channel was followed to the blue stained lymph nodes which were then dissected. The gamma probe was used to identify the radioactive (hot) nodes. All blue stained and/or radioactive nodes were removed and labeled ‘‘Sentinel lymph node (s)’’. All SLNs underwent frozen section examination. Negative nodes were further subjected to routine H and E stained permanent sections. Complete ALND was performed in the case of failure of SLN identification and in patients with posi-tive SLN. ALND was performed as a second procedure if the SLN was negative on the frozen section but proved to contain metastatic disease on paraffin section. After removal of the SLN(s), attention was directed to the primary tumor and either wide local excision or mastectomy was performed.

Pathological examination of the sentinel and non-sentinel lymph nodes

SLNs were bi-valved and intraoperative frozen section (F.S.) examination was performed. Step sections at two levels were taken; each section was 4 lm thick. Negative and inconclusive cases were deferred for paraffin embedded permanent section evaluation. The intraoperative frozen section report of posi-tive, negaposi-tive, or inconclusive was submitted to the operating surgical team. Additional information of micro (<2 mm) or macro (P2 mm) metastases were given for the positive cases. The average time utilized for F.S. examination was 12 min. Negative and inconclusive SLNs were fixed using 10% forma-lin and routinely processed. Serial step-sections at three levels at 75 lm intervals were taken; each section was 3 lm thick. The sections were stained routinely with Hemtoxylin and Eosin (H and E) and slides were examined for metastases. Immunohistochemical stains (IHC) were performed for suspi-cious cases using monoclonal antibody for cytokeratin AE1/3. Otherwise, IHC was not routinely done.

Patients with positive SLN on intraoperative or permanent section pathologic evaluation underwent synchronous or com-pletion of ALND respectively. The lymph nodes were rou-tinely processed and a single section, 3 lm thick, was taken from each node. Slides were examined by two pathologists before a report is issued.

Analysis

Multiple variables were tested as possible predictors of non-SLN metastasis. These included patient characteristics: tumor location and method of breast cancer diagnosis (clinically or mammographically detected), tumor characteristics: size, his-tology, grade, estrogen and progesterone receptor and Her 2-neu status, and lymphovascular invasion, and SLN character-istics: number of positive SLNs, size of metastasis in the SLN (micrometastasis from 0.2 to 2 mm, and macrometastasis P2 mm), and presence of capsular invasion.

Statistical analysis was performed using SPSS statistical software in addition to Chi2and Fisher’s exact tests whenever appropriate. A P value 6 0.05 was considered statistically significant.

Results

The current study included 80 female patients having early stage invasive breast cancer (T1, T2, N0 and M0) who under-went SLNB procedure.Table 1shows the clinicopathological data of the patients.

The mean age at diagnosis was 46.6 years. Forty patients (50%) had left breast cancer, 39 (48%) had right breast cancer, and one patient had bilateral disease. The tumor was located in the upper outer quadrant in the majority of cases (47 patients, 59%). Seventy two (91%) of patients presented clinically with a breast lump and the remainder had mammographically de-tected lesions. Seventy patients (87.5%) underwent wide local excision of the primary tumor, and 10 patients (12.5%) under-went mastectomy.

Fifty eight patients (72.5%) had Infiltrating Duct Carci-noma (IDC); mostly grade II (55%), 8 patients (10%) had Infiltrating Lobular Carcinoma (ILC), 6 (7.5%) medullary carcinoma, 5 (6%) Ductal Carcinoma In Situ (DCIS) with microinvasion, and 3 (4%) mucinous carcinoma. The median tumor size was 2 cm.

Twenty five patients (31%) showed evidence of lymphovas-cular invasion in the area of the primary tumor. Estrogen and progesterone receptors were positive in 64 patients (80%); Her 2-neu was overexpressed in 6 patients (8%).

The SLNB was performed using a combined technique in 63 patients (79%), blue dye only in 14 (17%) or radiocolloid only in 3 patients (4%). The SLN identification rate was 96.2% (77 out of 80 patients). The SLN was positive in 24 pa-tients (31%), and half of these showed evidence of capsular invasion. Eighteen positive SLN (75%) were diagnosed by fro-zen section and 6 (25%) were negative on frofro-zen section but found to harbor metastatic disease on paraffin section. The median number of SLNs removed was 2, and the median num-ber of positive SLNs was one. Four patients (17%) had micro-metastasis, while 20 (83%) had macrometastasis in the SLN.

ALND was performed in 27 patients, 24 patients having positive SLN and 3 patients in whom the SLN could not be identified. The non-SLNs were positive in 12 out of 27 patients (44%). If we excluded the 3 patients in whom ALND was per-formed due to failure of identification of the SLN (and in whom also the ALND revealed negative non-SLNs), the inci-dence of non-SLN metastasis associated with positive SLN will be 50% (12 out of 24 patients).

The median number of non-SLNs removed by ALND was 20. The number of positive non-SLNs ranged from 1 (in 66% of patients) to 7.

Lymphovascular invasion was found to be the only factor associated significantly with non-SLN metastases. All of the 12 patients with non-SLN metastasis had lymphovascular invasion in the area of the primary tumor. On the other hand, 15 patients had negative non-SLNs, and nine of them had no lymphovascular invasion. This association was found to be of high statistical significance (P 0.001).

Other clinicopathological variables were not found to be predictors of statistical significance. However, two trends were observed: the first is that the majority of patients having capsular invasion of the SLN (8 out of 12 patients, 67%) had non-SLN metastasis, and the second is that the patients having more than one SLN metastasis were more likely to have non-SLN metastasis (4 out of 5, 80%) (Table 2).

Table 1 The clinicopathological data of the patients with breast cancer.

Patients data (n = 80) No. (%)

Age (years) Mean Range 46.6 ± 9.4 26–68 Clinical presentation Breast lump Mammographically detected 72 (91%) 8 (9%) Side Right breast Left breast Bilateral 39 (48%) 40 (50%) 1 (2%) Operation

Wide local excision Mastectomy 70 (87.5%) 10 (12.5%) Tumor characteristics Site UOQ UIQ LIQ LOQ Central 47 (59%) 12 (15%) 10 (12%) 8 (10%) 3 (4%) Size (cm) Mean Range 2.2 ± 1.2 0.8–11 Histology IDC ILC Medullary

DCIS with microinvasion Mucinous 58 (72.5%) 8 (10%) 6 (7.5%) 5 (6%) 3 (4%) Grade (n = 63) I II III 15 (24%) 35 (55%) 13 (21%) Lymphovascular invasion Positive Negative 25 (31%) 55 (69%) ER/PR status Positive Negative Not available 64 (80%) 15 (18.8%) 1 (1.2%)

Her 2-neu status Positive Negative Indeterminate Not available 6 (8%) 65 (81%) 5 (6%) 4 (5%) SLN characteristics No. of SLNs removed Mean Range 2.7 ± 1.8 1–8 Size of largest SLN (cm) Mean Range 1.7 ± 0.7 0.6–3.5 No. of positive SLNs Mean Range 1.5 ± 0.9 1–6 Table 1 Continued.

Patients data (n = 80) No. (%)

Capsular invasion of positive SLN (n = 24) Positive Negative 12 (50%) 12 (50%) Size of metastasis (n = 24) 0.2 mm P 2 mm 4 (17%) 20 (83%) UOQ: upper outer quadrant. UIQ: upper inner quadrent. LIQ: lower inner quadrent.

LOQ: lower outer quadrent. IDC: invasive duct carcinoma. ILC: invasive lobular carcinoma.

Discussion

Several investigators have examined the histopathological variables of the primary tumor and the SLN metastasis that can influence the risk of additional disease in the non-SLNs (Table 3). This present extensive research was needed to an-swer important questions – do all patients with positive SLNs require ALND?, and if not, what is the selected subgroup of SLN-positive patients in whom completion of ALND may not be necessary?

The rationale for initiating these studies was based on two important observations; the first one is that in 40–70% of early breast cancer patients the SLN is the only involved axillary lymph node [1,16,29], which means that approximately half of patients having positive SLN are undergoing ALND unnec-essarily. The second observation was the low incidence of regional failure in patients with SLN metastasis who did not undergo ALND, either because of the associated serious comorbidity that precluded ALND or because the patient re-fused the procedure. In a study by Naik et al.[30], at a median follow up of 31 months, the axillary recurrence was infrequent both in SLN-positive patients who had completion ALND and those who did not, 0.35% and 1.4% respectively. They com-mented that this small difference, while statistically significant, may lack clinical significance. Moreover, at a median follow up of 28–32 months, Guenther et al. [31], Fant et al. [32], and Jeruss et al.[33]found no axillary recurrences among SLN-po-sitive patients who did not undergo ALND, and suggested that patients with SLN metastasis are ideal candidates for trials evaluating the necessity of ALND. Similarly, in a study by Takei et al.[10], the relapse-free survival of patients with posi-tive SLN treated with SLNB alone was almost identical to that of patients with negative SLN treated with SLNB alone. These results suggest that there is a subset of low risk, SLN-positive patients in whom ALND might not be needed[30].

Advocates of ALND after positive SLN have stated that the clinical and prognostic significance of a precise count of tumor-involved nodes justifies the morbidity and cost of the procedure, since the disease severity is directly related to the number of positive nodes [34,35]. They also argued that axillary dissection provides locoregional control and, there-fore, the potential for improved overall survival [36]. Oppo-nents argued that patients with SLN metastasis will receive systemic therapy, regardless of any additional nodal metasta-sis, and therefore any residual disease does not influence

choice of therapy and may itself be eradicated by the systemic therapy. The current pattern of adjuvant therapy have re-duced greatly the necessity for quantifying axillary disease, and it is likely that breast radiation therapy (with opposing tangents treating low axillary nodes), chemotherapy, and hor-monal therapy will be effective in treating regional disease

[14]. Opponents also argued that a therapeutic benefit of ALND has never been proven conclusively, nor the effect of locoregional failure on overall survival[31].

These debates have provoked the initiation of three large randomized phase III studies: the American College Of Sur-geons Oncology Group trial (ACOSOG Z0011) compares overall survival, disease free survival, locoregional control, and morbidity of ALND Vs no ALND after positive SLN

[37]; the After Mapping of the Axilla: Radiotherapy Or Surgery (AMAROS) trial compares the efficacy of axillary radiotherapy with ALND in preventing axillary recurrence in patients with positive SLNs[38]; and the International Breast Cancer Study Group trial (IBCSG 23-01) randomizes patients to ALND Vs no ALND after SLN micrometastasis to deter-mine the prognostic significance of SLN micrometastasis[39]. Among the clinicopathologic variables that would be useful for predicting which early breast cancer patients are at higher risk for additional non-SLN metastasis, size of the primary tu-mor, size of the SLN metastasis and lymphovascular invasion in the area of primary tumor were the most commonly ana-lyzed (Table 3).

In the current study, Lymphovascular invasion was found to be the only factor associated significantly with non-SLN metastases. Our results are comparable to those reported by Travagli et al.[17]who studied the same clinicopathological variables, though in a double number of patients, and found that lymphatic invasion was the only factor that correlated with metastasis to non-SLN.

In addition, in the current study, there was a tendency to-ward higher incidence of non-SLN metastasis associated with the increased number of positive SLNs and with capsular inva-sion of SLN (though these did not reach the statistical signif-icance, which could be attributed to the small number of patients recruited). These two variables were also identified by other authors (Table 2). Capsular invasion of the SLN is a poor prognostic feature that usually occurs at the vascular root of the lymph node hilum, with involvement of efferent lymphatic vessels. Thus it represents tumor cells in-transit to other sites [40]. Alkhatib et al. [41] found that a solitary

Table 2 Pathological variables predicting NSLN metastasis in breast cancer patients with positive SLN.

Pathological variable NSLN +ve NSLN ve Pvalue

Frequency % Frequency %

Lymphovascular invasion

+ve 12 100 6 40.0 0.001

ve 0 0 9 60.0

Capsular invasion of +ve SLN

+ve 8 66.7 4 40.0 0.391

ve 4 33.3 6 60.0

Number of positive SLNs

1 8 47.1 4 80.0 0.323

positive SLN (without extracapsular extension) accompanied by at least one negative SLN is associated with 3% risk of a positive non-SLN.

The other two predictors of non-SLN metastasis that were reported by most of the literature are the size of the primary tumor and the size of lymph node metastasis. However, some studies, including the current one, did not reach to the same conclusion (Table 2). Noteworthy is the prognostic significance and the clinical implications of SLN micrometastasis which is still a matter of debate and extensive research. While some studies have concluded that patients with or without microme-tastasis had no significant prognostic differences[42,43], other studies have shown that patients with micrometastasis have higher recurrence rate and lower overall survival than patients without lymph node metastasis[44,45]. Reynolds et al.[4], and Chu et al.[11], found that the increasing size of the primary tu-mor and increasing size of lymph node metastasis were associ-ated with non-SLN involvement. On the other hand, one of the most commonly utilized nomograms for predicting non-SLN metastasis; the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram;[14]did not include the size of lymph node metastasis as a predictive parameter. The authors of this nomogram found difficulty in assessing the size of lymph node metastasis because of the difference in the pattern of distribu-tion of malignant cells within the node, some nodes may have scattered single cells or multiple small clusters of cells, the size of which cannot be measured. They commented that the vol-ume of lymph node metastasis is a more accurate estimate, but, according to their view, this is time consuming and some-what impractical.

Several nomograms have been developed by different insti-tutions to predict the probability of non-SLN metastasis. The first nomogram was developed by the MSKCC [14]and in-cludes tumor size, grade, number of positive and negative

SLNs, method of detection of the SLN, estrogen receptor sta-tus, lymphovascular invasion, and tumor multifocality. The Tenon hospital nomogram [29] included tumor size, size of SLN metastasis, and proportion of involved SLNs among all removed SLNs. The Cambridge University nomogram [46]

uses grade, Overall Metastatic tumor Size (OMS, the largest detected size of SLN metastasis), and the proportion of in-volved SLNs among all removed SLNs. The final nomogram, the Stanford University nomogram[47], uses tumor size, status of lymphovascular invasion, and the largest size of SLN metas-tasis. The predictive accuracy of these nomograms has been validated but the first one is the most widely used[15]. How-ever, it is limited by its complexity and inability to account for the size of nodal metastasis[29,47].

The number of patients recruited to the current study is small, which might have affected the results; however, this is a pilot study that included all early breast cancer patients who presented to a tertiary care referral center and who under-went SLNB. Patient accrual is continuing to aim at more re-fined elucidation of the results. Another potential weakness in the current study is the absence of the exact incidence of SLN micrometastasis, because IHC was not routinely per-formed. There might be undetected micrometastasis in some of the negative SLNs, which might have correlated with nega-tive non-SLNs. The reported occult metastasis detection rate is in the range of 9–33%[48]. However, IHC is currently not a part of the routine assessment of the SLN, but it is performed for suspicious findings on H and E stains[15,49,50].

In conclusion, in the current pilot study, 50% of patients with SLN metastasis had negative completion ALND and the lymphovascular invasion in the area of the primary tumor was found to be significantly related to the non-SLN metasta-sis. In addition, there was a tendency toward higher incidence of non-SLN metastasis associated with the capsular invasion

Table 3 Some of the studies reporting predictors of non-SLN metastasis in patients with positive SLNB, numbers represent the P values, NS: not significant.

Author No. of patients

with +ve SLN

% of non-SLN metastasis (with +ve SLN) (%)

Tumor size Lymphovascular invasion No. of +ve SLNs Size of SLN metastasis Capsular invasion of positive SLN Reynolds et al.[4] 60 46.5 0.0004 NS – 0.002 Chu et al.[11] 157 33.5 0.01 NS NS <0.0001 – Turner et al.[19] 194 45 0.03 0.03 NS 0.01 0.0001 Viale et al.[20] 109 22 NS – – 0.02 – Rahusen et al.[16] 93 49 NS NS 0.002 0.05 – Abdessalam et al.[21] 100 40 NS 0.004 NS 0.01 0.001 Kamath et al.[1] 101 59.4 0.005 – – 0.001 – Weiser et al.[22] 206 32 0.007 NS – 0.0002 – Wong et al.[23] 389 37 <0 .001 – <0 .001 – – Sachdev et al.[12] 55 60 0.0001 0.001 – 0.02 – Travagli et al.[17] 50 30 NS 0.01 NS NS –

Van Zee et al.[14] 702 – 0.0006 0.003 0.0001 – –

Nos et al.[24] 263 24 0.01 NS NS <0 .001 NS

Van Iterson et al.[25] 135 34 0.03 – 0.01 0.006 NS

Stitzenberg et al.[13] 74 46 NS – NS NS 0.01 Saidi et al.[26] 34 32 0.04 0.03 – NS 0.001 Fournier et al.[27] 42 36 NS NS – 0.03 – Fleming et al.[28] 54 48 NS NS – 0.02 0.01 Barranger et al.[29] 81 26.8 0.006 .006 0.04 0.01 Current study 24 50 NS 0.003 NS NS NS

and number of positive SLNs, though this did not reach the statistical significance, which could be attributed to the small number of patients recruited. Further evaluation of the predic-tors of nonsentinel lymph node metastasis on a larger number of patients is required. The validation of these predictors in prospective studies may enable approximately half of early stage breast cancer patients with positive SLN to be staged with SLNB alone while avoiding the morbidity of unnecessary ALND. Until the results of the large randomized studies com-paring overall survival, disease free survival, locoregional con-trol, and morbidity of ALND Vs no ALND after positive SLN are available, the current recommendation is to proceed with completion ALND in patients with SLN metastasis.

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