Predictors of non-sentinel lymph node metastasis in breast cancer patients

https://doi.org/10.1016/j.ejca.2004.04.006Get rights and content

Abstract

In many patients, the sentinel lymph node (SLN) is the sole site of regional nodal metastasis. This subgroup of patients would not be expected to benefit from completion axillary lymph node dissection (CALND). This study evaluated the factors that may determine the likelihood of additional positive nodes in the axilla in the presence of sentinel node metastasis. A total of 618 breast cancer patients underwent SLN biopsy based on lymphoscintigraphy, intraoperative gamma probe detection, and blue dye mapping using 99mTc-nanocolloid and Patent Blue V injected peritumourally. This was followed by standard axillary node clearance at the same operation. Of the 201 patients with a positive SLN, 105 (52%) patients had no further positive nodes in the axilla, 96 (48%) patients had additional metastasis in non-sentinel lymph nodes (NSLN) upon CALND. In patients with a positive SLN, increasing tumour size and tumour grade significantly increased the frequency of additional positive nodes on univariate analysis. The number of SLNs removed and the number of negative SLNs were significant negative predictors. Increasing tumour burden in the sentinel nodes (determined by the number of positive SLNs) was significantly associated with increasing likelihood of positive NSLNs. Multivariate analysis revealed that the rest of the axilla is more likely to be positive if there are more positive than negative SLNs removed and more likely to be negative otherwise. A group of cases from one centre (Cardiff) were subjected to further detailed analysis. Tumour burden in the positive SLN was assessed by measuring the size of metastasis, percentage replacement of the SLN by tumour and by documenting extracapsular extension (ECE) around the SLN. Of the 64 patients with a positive SLN, 34 (53%) patients had no further positive nodes in the axilla, 30 patients (47%) had additional metastasis in NSLNs upon CALND. Increasing tumour burden in the SLN was associated with additional positive nodes in the axilla. Multivariate analysis revealed that size of the SLN metastasis is the most important predictor of involvement of only the SLN. Overall, in patients with a positive SLN, the difference in the number of positive and negative SLNs removed and size of the metastasis in the SLN, all predicted the frequency of additional positive nodes.

Introduction

Axillary lymph node metastasis in patients with early breast cancer is the single most important prognostic factor for recurrence and survival, and forms the basis for important therapeutic decisions. Axillary dissection involves considerable use of resources, and increases the risk of acute and late morbidity that may adversely affect the patient's quality of life [1], [2], [3], [4], [5].

Sentinel lymph node (SLN) biopsy is rapidly emerging as a new `standard of care' in breast cancer. It has the potential to identify those patients most likely to be helped by axillary dissection, namely those with positive nodes. Conversely, node-negative patients are spared the morbidity resulting from an unnecessary extensive operation. Numerous studies have documented SLN biopsy to be highly predictive of axillary node status, with a false-negative rate of less than 5% [6], [7]. Completion axillary lymph node dissection (CALND) is recommended for patients who have SLN metastasis. However, the need for routine CALND in these patients has been questioned [8], [9].

In approximately 50%–65% of patients, the SLN is the sole site of regional node metastasis and these patients would not be expected to benefit from CALND [8], [9], [10], [11], [12]. As a result, identifying specific characteristics of the tumour and SLN that can reliably predict which patients with SLN metastasis have a low likelihood of non-sentinel lymph node (NSLN) involvement and may not benefit from CALND is an important goal.

This analysis sought to identify a subgroup of patients with a positive SLN who do not need to be exposed to the morbidity and cost associated with CALND.

Section snippets

Patients and methods

The Axillary Lymphatic Mapping Against Nodal Axillary Clearance (ALMANAC) trial [13] is a multicentre randomised trial in the United Kingdom comparing sentinel node biopsy with standard axillary treatment in the management of patients with early breast cancer. The trial consists of two phases. In phase 1, a validation phase, all surgeons performed SLN biopsy in 40 patients with invasive breast cancer followed by the axillary procedure, sampling or clearance, which would be the standard

Analysis of detailed histopathological factors

Because of the multi-institutional nature of the present study, analysis of detailed histopathological factors (presence of tumour lymphovascular invasion, size of metastasis in the SLN, percentage replacement of the SLN by tumour, presence of extracapsular extension around the SLN) was restricted to one centre only (Cardiff). H&E stained sections of all SLNs containing tumour were retrieved from the pathology archive and viewed by a consultant histopathologist. The sizes of the lymph node and

Statistical analysis

The relationship between positivity of NSLNs and the predictive factors listed in Table 1, Table 2 was assessed using the χ2 test for binary and unordered categorical variables. For predictive factors on a continuous or ordinal scale, the Mann–Whitney test was applied to the uncategorised data. Factors at or close to the nominal α=0.05 level in univariate analyses were entered into a stepwise logistic regression.

Results

The overall SLN identification rate was 593/618 (96%), of which 17 (3%) were false-negatives. Analyses are based on the 201 patients who had at least one positive SLN and proceeded to axillary clearance. The median age was 54 years (range 26–80 years). Four were male. Clinicopathological characteristics are shown in Table 1. The mean number of SLNs removed per patient was 2.2 (range 1–9), of which 1.4 (range 1–6) were positive. 105 (52%) patients had no further positive nodes in the axilla, 96

Analysis of Cardiff patients

Further analyses are based on the 64 Cardiff patients who had at least one positive SLN and proceeded to axillary clearance. All were female and their median age was 54 years (range 35–89 years). Clinicopathological characteristics are shown in Table 2. Detailed pathology data is unknown for 5 patients as their slides could not be retrieved from the pathology archive. 30 (47%) patients had positive NSLNs. The mean size of SLN metastasis was 6.2 mm (standard deviation (SD)6.0). The proportion

Discussion

SLN biopsy is evolving as the preferred technique for axillary staging in breast cancer. What has not confidently been determined is the benefit of further axillary lymph node dissection if the SLN is positive, although this is being evaluated in ongoing studies. Although axillary nodal status is frequently considered in making adjuvant therapy decisions, the role of axillary lymph node dissection as a therapeutic procedure remains controversial. The increased use of adjuvant systemic and

Acknowledgements

The validation phase of the ALMANAC trial was funded by the Medical Research Council, UK.

ALMANAC Writing Committee: Mr. U. Chetty, Professor P. Ell, Professor L. Fallowfield, Mr. M. Kissin, Professor R. Mansel, Dr. R. Newcombe and Mr. M. Sibbering.

ALMANAC Trialists Group: Professor R. Mansel (Principal Investigator), Mr. T.I. Abdullah, Miss E. Anderson, Mr. L. Barr, Professor N. Bundred, Mr. M. Chare, Mr. U. Chetty, Mr. S. Courtney, Mr. D. Crawford, Mr. R. Cummins, Mr. C. Davies, Mr. M. Dixon,

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