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10.1245/ASO.2006.02.020
Annals of Surgical Oncology 13:465-474 (2006)
© 2006 Society of Surgical Oncology
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Original Article

The Prognostic Effect of the Number of Histologically Examined Axillary Lymph Nodes in Breast Cancer: Stage Migration or Age Association?

Michael Schaapveld, PhD1, Elisabeth G. E. de Vries, MD, PhD2, Winette T. A. van der Graaf, MD, PhD2, Renée Otter, MD, PhD1, Jakob de Vries, MD, PhD3 and Pax H. B. Willemse, MD, PhD2

1 Comprehensive Cancer Center North-Netherlands, P.O. Box 330, 9700 AH Groningen, The Netherlands
2 Department of Medical Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
3 Department of Surgical Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands

Correspondence: Address correspondence and reprint requests to: Michael Schaapveld, PhD; E-mail: m.schaapveld{at}ikn.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The number of pathologically examined axillary nodes has been associated with breast cancer survival, and examination of ≥10 nodes has been advocated for reliable axillary staging. The considerable variation observed in axillary staging prompted this population-based study, which evaluated the prognostic effect of a variable number of pathologically examined nodes.

Methods: In total, 5314 consecutive breast cancer patients who underwent mastectomy or breast-conserving surgery and axillary dissection between 1994 and 1999 were included. The prognostic effect of the examined number of nodes was assessed with crude and relative survival analysis.

Results: A median number of 12 (range, 1–43) nodes were histologically examined, and 59% of the patients had no nodal tumor involvement. The number of examined nodes decreased with age (P < .001) and increased with tumor size (P < .001). Stratified for the number of tumor-positive nodes, overall survival seemed to be worse for patients with <10 compared with patients with ≥10 examined nodes (P < .001), whereas the relative survival did not differ. After adjusting for age, tumor size, number of positive nodes, and detection by screening in a multivariate analysis, the number of examined nodes was not associated with relative survival.

Conclusions: This study shows that the association between the number of pathologically examined axillary nodes and overall survival in node-negative and node-positive patients results from stage migration. The absence of an association between the number of examined nodes and relative survival further indicates that the association between the number of examined nodes and crude survival is confounded by age.

Key Words: Breast cancer • Axillary staging • Crude survival • Relative survival • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS
 RESULTS
 DISCUSSION
 REFERENCES
 
The axillary lymph node status is the most important prognostic indicator for primary breast cancer. Although adjuvant systemic treatment is no longer solely based on the nodal status, the presence of axillary metastases is still a major indication. In addition, with more adjuvant treatment options, a trend to select adjuvant therapy depending on risk factors, such as the number of positive nodes, has evolved.1,2 An axillary lymph node dissection is first and foremost a staging procedure. However, because 10% to 35% of the clinically node-negative patients with a primary tumor ≤2 cm have positive lymph nodes at axillary dissection,3,4 a standard axillary clearing means overtreatment of the axilla, especially for patients with small tumors. The introduction of the sentinel node biopsy in recent years has fueled the discussion about the need for axillary dissection in breast cancer staging.5–10 Prospective data comparing long-term locoregional control and survival after sentinel node biopsy or standard axillary dissection are still lacking. However, in current practice, a standard axillary dissection is already limited to patients with tumor-positive sentinel nodes or larger tumors.

There is no convincing evidence that the number of examined nodes influences patients’ prognosis, but the number of examined nodes does add more precision to the axillary nodal status and, as such, may have prognostic relevance. Many studies have reported a strong association between the extent of axillary dissection and the number of positive nodes2,3,11–14 and an association with survival, both in node-negative and node-positive patients.14–22 Using the Surveillance, Epidemiology, and End Results (SEER) data, Krag and Single21 also found that the number of removed nodes was associated with the crude survival of patients with zero or one to three positive nodes. Although the study included an impressive number of patients, it remains questionable whether crude survival is a valid end point for studying the association between axillary surgery and prognosis. Using the same SEER database, Polednak22 showed that in node-negative patients, examination of fewer nodes was associated not only with an increased risk of death due to breast cancer, but also with an increased risk of death from other causes. This could raise questions about the reliability of the cause-of-death coding in the SEER database, but an alternative explanation for this finding is an inverse association between age and the number of examined nodes.4,12,13 Whether this association represents a biological effect or less extensive axillary surgery in elderly patients is unclear. Strikingly, according to SEER data, older women are less likely to have axillary dissection than younger women.23

Age may be associated with the number of examined nodes and clearly is associated with survival. Therefore, the relevance of an association between crude survival and the number of examined nodes becomes questionable, especially in heterogenous patient populations. The use of relative survival allows indirect correction for non–breast cancer–related deaths. To our knowledge, relative survival has not been used before to study the prognostic effect of the number of examined nodes.

In the North Netherlands, large interhospital variation in the number of examined nodes has been observed previously.13 This study was initiated to assess the effect of the number of pathologically examined axillary lymph nodes on the crude and relative survival of breast cancer.


   PATIENTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS
RESULTS
 DISCUSSION
 REFERENCES
 
All women with a diagnosis of histologically proven invasive breast carcinoma surgically treated between January 1994 and January 1999 in the Comprehensive Cancer Center North (CCCN) region and who had had an axillary dissection yielding at least one lymph node were eligible for entry. For patients with synchronous bilateral breast cancer, defined as a contralateral breast cancer within 3 months of the index cancer, the most advanced tumor was designated as the first tumor irrespective of the actual date of diagnosis. Patients with a previous invasive cancer other than nonmelanoma skin cancer and patients with distant metastases were excluded. The patients were selected through the CCCN regional population-based cancer registry, which covers a population of approximately 2.1 million in the North Netherlands. One university medical center, 16 community hospitals, 4 radiotherapy facilities, and 7 pathology laboratories serve the CCCN region. In The Netherlands, a breast-screening program has been ongoing since 1990 in which all women between the ages of 50 and 69 years (from 1999 onward, 50–75 years) are invited for biennial mammography screening. The screening program was fully implemented in the CCCN area in 1997.

Data Collection by the Regional Cancer Registry
Pathologisch Anatomisch Landelÿh Geautomatiseerd Archief (PALGA), a Dutch nationwide network and registry of histopathology and cytopathology, regularly submits reports of all diagnosed malignancies to the cancer registry. The national hospital discharge databank, which receives discharge diagnoses of admitted patients from all hospitals, completes case ascertainment. The cancer registry has no access to death certificates. After notification, trained registry personnel collect data on diagnosis, staging, and treatment from the medical records, including pathology and surgery reports, in the hospitals. Vital status is established either through information derived from the patient’s medical record or through linkage of cancer registry data with population registries of the municipalities in the registry area (last in 2003; in The Netherlands, the municipal population registries contain information on the vital status of their inhabitants). For a subset of elderly patients and patients with a relatively poor prognosis (stage III breast cancer), vital status was checked through their general practitioners, because patients could have moved to municipalities outside the registry areas and died there. All patients were staged according to the tumor-node-metastasis system.24,25 Staging was based on pathologic information, and clinical information was used if pathology data were missing.

Guidelines for Staging and Treatment
The prevailing treatment guidelines during the study period are briefly outlined below. The guidelines required a description of the number of nodes examined, the number of positive nodes, and the presence of extranodal extension in the pathologist’s report to the surgeon on the axillary lymph node dissection specimen. Initially, the guideline did not detail the examination of a minimal number of axillary nodes. Since 1996 the examination of at least 6 and since 1998 the examination of at least 10 nodes was required. Generally, the routinely formalin-fixed axillary dissection specimen was examined by sharp or blunt manual dissection. Manual dissection of the unfixed axillary fat, chemical clearing, and radiological examination of the remaining fatty tissue were not routinely used. Harvested nodes were histologically examined by using routine hematoxylin and eosin staining; immunohistochemical staining was not applied on a routine basis. Until 1998, premenopausal node-positive patients were to receive adjuvant chemotherapy, and postmenopausal node-positive patients typically received 2 years of tamoxifen. Since 1998, the indications for adjuvant therapy have been extended to include node-negative patients with less favorable tumor characteristics (intermediate or poorly differentiated tumors ≥2 cm). Locoregional radiotherapy on parasternal, axillary, and infraclavicular and supraclavicular nodes was indicated in case of more than three positive axillary nodes, extranodal growth, lymphangioinvasion, or a positive apical node. Irradiation of the parasternal nodes was indicated for node-positive patients with a medially located tumor. The sentinel node biopsy was introduced in the CCCN region at the end of 1998. In this study, all patients who underwent a sentinel node biopsy did so as part of a learning curve of the surgeon and consequently underwent axillary lymph node dissection irrespective of the outcome of the sentinel node biopsy.

Variable Definitions and Statistics
Survival was calculated from the date of diagnosis until the date of death, the date of the most recent linkage with the municipal population registries, or the date of last contact (the date of the last hospital visit or of the last contact with the general practitioner), whichever came first. The overall survival probability was estimated with the Kaplan-Meier method, and the distributions of crude survival were compared by using the log-rank test. The expected survival (ES) probability was calculated by using age- and period-matched mortality rates based on Dutch female life expectancy tables.26 The ES was estimated with the Ederer II method.27 The cumulative relative survival, the ratio of the overall survival and the ES, was analyzed by using Stata (version 8.0) and a relative survival function written by Paul Dickman (http://www.pauldickman.com/teaching/tampere2004).

The relative survival can be considered as an estimator of the excess risk of death or of the excess mortality ratio (EMR). The excess mortality rate was calculated by subtracting the expected number of deaths, as estimated from the ES probability, from the observed number of deaths and dividing this figure by the accumulated person-years. The EMR is derived from the ratio of the excess mortality rates. EMRs were estimated in a generalized linear model with a Poisson error structure based on collapsed relative survival data by using exact survival times.28 In this model, the effect of the number of examined nodes was studied while adjusting for the effect of various covariables on the excess mortality. The model assumes that the relative excess risks are constant within follow-up intervals. Follow-up time was stratified in annual intervals, except for the follow-up years 7, 8, and 9, which were grouped together because the numbers at risk became too small. Variables included in the model were the age at diagnosis, the tumor size (using the tumor-node-metastasis categories T1, T2, T3/T4, and T unknown), the mode of tumor detection (screen detected or other), the number of examined nodes (categorized as 0–5, 6–10, 11–15, 16–20, and 21+), and the number of positive nodes (categorized as none, 1–3, 4–6, and 7+). To assess the assumption of proportional hazards, interactions with follow-up time were included in the model. Model fit was evaluated with the model-based Pearson {chi}2 goodness-of-fit test statistic.29 All reported P values are two sided; the statistical significance level was set at P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS
 RESULTS
DISCUSSION
 REFERENCES
 
Table 1Go shows patient and tumor characteristics. A total of 5314 patients were eligible for analysis; 59.0% were node negative, 25.1% had 1 to 3 positive axillary nodes, and 15.9% had ≥4 positive axillary nodes. A median number of 12 nodes (range, 1–43) was examined: 4.6% of the patients had <6 nodes examined. The number of examined nodes increased slightly over the 5-year study period (P < .001) and increased with larger tumor size (P < .001). It decreased with older age (P < .001). The proportions of patients with <10 nodes examined were 22.1%, 26.4%, 32.5%, 32.8%, and 35.8% for patients aged <50, 50 to 59, 60 to 69, 70 to 79, and ≥80 years, respectively. The proportion of node-positive patients increased with a larger number of examined nodes, from 28.6% when <6 to 52.6% when >20 nodes were examined (P < .001). Only a few node-negative patients (8.1%) and nearly all node-positive patients (95.1%) received adjuvant systemic therapy.


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  		TABLE 1. Selected patient and tumor characteristics according to the number of positive nodes
 
The median follow-up was 5.6 years, during which 1161 patients (21.8%) died. Table 2Go shows the 5-year overall and relative survival proportions for patients with <10 and patients with ≥10 examined nodes for all patients combined and stratified according to the number of positive nodes (zero, 1–3, or >3 positive nodes). Whether <10 or ≥10 nodes were examined, the 5-year overall survival estimates for all patients combined were remarkably similar (81.5% vs. 81.7%; not significant). However, if the patients were stratified according to the number of positive nodes, patients with 1 to 3 positive nodes and <10 examined lymph nodes did seem to experience shorter overall survival (P = .008; Fig. 1Go) than patients with 1 to 3 positive nodes and ≥10 examined nodes. Although no overall survival difference was seen among node-negative patients or patients with >3 positive nodes, when the overall survival of all patients was analyzed, adjusted for the number of positive nodes, patients with <10 examined nodes had worse survival than patients with ≥10 examined nodes (P = .0009).


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  		TABLE 2. Five-year overall survival (OS) and relative survival (RS) according to the number of nodes examined, stratified for the number of positive nodes
 

Figure 1
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  		FIG. 1. Relative survival of 5314 breast cancer patients according to the number of examined and the number of positive lymph nodes.

 
The differences in the 5-year relative survival proportions between patients with <10 and ≥10 examined nodes were considerably smaller than the differences in crude survival (Table 2Go). Again, the relative 5-year survival estimates for all patients combined were similar for patients with <10 or ≥10 examined nodes (90.2% vs. 88.5%, respectively). However, in contrast with the results of the crude survival analysis, even after adjustment for the number of positive nodes, the relative survival did not differ between patients with <10 or ≥10 examined nodes.

In Table 3Go, the overall and excess mortality for patients with <10 and ≥10 examined nodes are compared by age at diagnosis in an attempt to clarify the subtle differences in outcome when overall or relative survival is analyzed. Whereas for patients aged <50 years, the overall and excess mortality rates were very similar as a result of the decrease in life expectancy with older age, the gap between the overall and excess mortality rates widened increasingly. Whereas patients aged <50 years experienced a 14.3-fold excess number of deaths (228 deaths observed vs. 16 expected), patients aged ≥70 years experienced only 1.3 times the number of deaths expected (483 deaths observed vs. 383 expected). Although the estimates for the overall mortality ratio and the EMR were remarkably similar, adjusted for age and the number of positive nodes, the EMR did not differ between patients with <10 or ≥10 examined nodes.


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  		TABLE 3. Overall mortality ratios and excess mortality ratios according to the number of nodes examined, stratified for age at diagnosis and the number of positive nodes
 
In a multivariate analysis, the EMR increased strongly with an increase in the number of positive lymph nodes and decreased with older age; this implies that the youngest patients experienced higher excess mortality due to breast cancer and that mortality increased with larger tumor size (Table 4Go). Somewhat surprisingly, patients with screen-detected disease had a 50% lower EMR than those with non–screen-detected disease. The tumor size did differ between patients with screen-detected and non–screen-detected tumors, and it proved that this was not fully adjusted for in our analysis. Among patients with a T1 tumor, the screen-detected tumors were smaller: 33.8% were ≤1 cm (T1a or T1b), compared with 20.5% of the non–screen-detected tumors (P < .001). Tumor size did not differ for patients with a T2 tumor (P = .169). Inclusion of a variable for tumor size, subdividing T1 tumors into T1a/T1b and T1c tumors, did, however, not alter the estimate for the effect of screening (EMR, .52; 95% confidence interval [CI], .37–.72). Adjusted for patient age, tumor size, number of positive lymph nodes, and method of detection, the number of examined nodes was not found to be associated with excess mortality.


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  		TABLE 4. Estimated excess mortality ratios (EMR) and 95% confidence intervals (CIs)
 
We also estimated a model for patients with no or fewer than three positive nodes, because a prognostic effect due to increased staging accuracy was expected to be most pronounced in these patient groups (Table 4Go, model 2). The results did not differ much from the model that included patients with four or more positive nodes, although the protective effect of screening was stronger. The goodness-of-fit tests showed no evidence for a lack of fit for either model (model 1: {chi}2 = 791.19; df = 759; P = .203; model 2: {chi}2 = 408.86; df = 403; P = .409; both models fitted without the number of examined nodes).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS
 RESULTS
 DISCUSSION
REFERENCES
 
This population-based study, which included a large number of unselected patients with a nearly complete follow-up for vital status, showed that the variation in the number of pathologically examined lymph nodes was not associated with excess mortality when we adjusted for the prognostic effect of the number of positive nodes, tumor size, age, and method of detection. The relatively large interhospital variation in the number of examined nodes in our region provided a quasi-natural experiment to explore the prognostic significance of the number of examined nodes with a sufficient range in the number of examined nodes. Overall survival was found to be associated only with the number of examined nodes, when adjusted for the number of positive nodes. However, the association between patient age and the number of examined nodes and, thus, underlying differences in ES at least partly explained this finding.

In several studies, including ours, a larger number of examined axillary nodes was associated with an increase in the number of positive nodes and with improved accuracy of the pathologic nodal status.4,11–14 Many studies have reported a positive association between the number of examined lymph nodes and overall survival, both in node-negative and node-positive patients.14–22 The association between examining more lymph nodes and improved overall survival probably largely reflects stage migration. The improved staging accuracy will result in a better prognosis in all patient strata, as defined by the number of positive nodes, but will not affect the prognosis of the patient population as a whole.30 In our study, the overall and relative 5-year survival rates were 81.5% and 90.2% for patients with <10 compared with 81.7% and 88.5% for patients with ≥10 nodes, respectively.

To have a real effect on patient prognosis, the number of examined nodes must be directly related to the risk of locoregional or distant recurrence. A meta-analysis of six randomized trials comparing the survival of patients with and without axillary dissection found a small survival benefit for patients who underwent axillary dissection (5.4%; 95% CI, 2.7%–8.0%).31 However, five of the trials were performed before 1975, and it is clear that the results of this meta-analysis cannot be translated into an era in which systemic adjuvant treatment is widely used.

Extensive meta-analyses by the Early Breast Cancer Trialists’ Collaborative Group have shown that adjuvant chemotherapy and hormonal therapy will reduce the occurrence of distant metastases and prolong disease-free and overall survival in node-positive patients.32,33 If examination of fewer nodes would decrease the chance of finding a positive node, the subsequent omission of adjuvant treatment could result in an increased risk of locoregional or distant recurrence. Results from the National Surgical Adjuvant Breast and Bowel Project B-04 trial showed that even a small number of examined nodes predicted the nodal status with acceptable accuracy, although it underestimated the extent of nodal involvement.11 However, other retrospective studies did find a positive association between the number of examined nodes and the nodal status.4,13 Weir et al.20 reported increased regional relapse rates among node-negative patients with fewer examined nodes, and these patients tended to have a shorter observed survival, but only when the patients had not received systemic therapy. It remains unclear how many axillary nodes need to be examined to accurately reflect the pathologic nodal status. Although in this study node positivity was associated with the number of examined nodes and misclassification of the nodal status could have occurred, even for node-negative patients there was very little evidence that fewer examined nodes negatively affected overall or relative survival.

The number of examined nodes was not associated with differences in the relative survival of node-positive patients. Misclassification of the extent of nodal involvement in this patient group would not likely alter the planned adjuvant treatment. Actually, >95% of all node-positive patients received adjuvant systemic therapy. In a meta-analysis, Whelan et al.34 investigated the effect of locoregional radiotherapy on the survival of breast cancer patients and found a reduced risk of disease recurrence (odds ratio, .69; 95% CI, .58–.83) and a significant reduction of mortality (odds ratio, .83; 95% CI, .74–.94) in high-risk patients (stage II/III) treated with surgery and systemic therapy. In our study, locoregional radiotherapy was indicated only for patients with extensive lymph node involvement (i.e., more than three positive nodes). Misclassification of the extent of nodal involvement might have resulted in inappropriate omission of radiotherapy in some patients. However, even among patients with more than three positive nodes treated with a mastectomy, in our study population actually 21.3% did not receive radiotherapy: this could easily obscure any effect of omission of regional radiotherapy due to understaging of the axilla.

An alternative explanation would be that the differences in relative survival associated with the number of nodes examined were too small to detect in this study population. However, these differences are then likely very small. Most studies that have examined the prognostic relevance of the number of examined nodes actually included far fewer patients.17–20 Another explanation may be that the follow-up in our study was too short and that breast cancer deaths attributable to understaging of patients who were erroneously left untreated will become manifest only after longer follow-up.

Several studies that did find an association between the number of examined nodes and patient prognosis used overall survival as their main outcome parameter. Because age evidently will be inversely related to overall survival, this end point may be seriously biased if age is associated with the number of examined nodes, especially with respect to univariate comparisons. The evaluation of relative survival, as applied in our study, allows correction for non–breast cancer–related deaths while circumventing the problems associated with establishing the cause of death.

A striking finding in our study was the lower excess mortality for patients with screen-detected tumors, which remained after adjusting for tumor size, the number of positive nodes, and age. Better survival for patients with screen-detected disease has been reported previously.35–37 Although the possibility of residual confounding by tumor size remains, this does not likely explain the strength of the association. Screen-detected tumors may actually have a better prognosis than non–screen-detected tumors because of more favorable tumor characteristics. Screening may selectively detect occult tumors with a lower growth rate, a problem referred to as length-time bias. The lower excess mortality may be due to a lead-time effect: the virtual extension of survival through advancing the date of diagnosis. However, this only stresses the need to consider the method of detection when time trends in survival are evaluated.

The results of our study should not be interpreted as indicating that the extent of axillary dissection does not matter. In our study, for only a few patients did the dissection specimen comprise fewer than six nodes. Most patients had between 6 and 15 lymph nodes examined. This number seems to be sufficient to accurately predict the nodal status. The number of positive nodes, the strongest predictor of survival, was associated with the number of nodes examined. With more emphasis on patient-tailored medicine, the identification of patients at increased risk of breast cancer relapse, who should be treated more intensively, remains paramount. Therefore, an adequate axillary dissection should contain ideally at least 10 lymph nodes.

Received for publication February 22, 2005. Accepted for publication September 13, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS
 RESULTS
 DISCUSSION
 REFERENCES
 

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