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Prognostic Value of Extracapsular Extension of Axillary Lymph Node Metastases in T1 to T3 Breast Cancer

¹ Department of General Surgery and Surgical Oncology, Surgical Oncology Unit, University of Siena, Policlinico Le Scotte, V. le Bracci, 53100 Siena, Italy
² General Surgery Unit, University of Siena, Policlinico Le Scotte, V. le Bracci, 53100 Siena, Italy

Correspondence: Address correspondence and reprint requests to: Alessandro Neri, MD; E-mail: neria{at}unisi.it.

	ABSTRACT

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Background: The importance of extracapsular extension (ECE) of axillary metastases as a risk factor for either local or distant recurrence and poorer survival in breast cancer has been suggested, but its prognostic value has not been uniformly confirmed.

Methods: From a prospective database including 1142 breast cancer patients operated on at the Department of General Surgery and Surgical Oncology of the University of Siena, we selected 376 cases with pT1 to pT3 node-positive breast cancer. The prognostic significance of ECE of axillary metastases was evaluated with respect to disease-free survival, overall survival, and the patterns of disease recurrence. Such prognostic significance was then compared with that of other clinical and pathologic factors.

Results: With a median follow-up of 103 months, factors with independent prognostic value for disease-free survival by multivariate analysis included absence of estrogen receptors (P < .0005), pN category (P < .01), presence of lymphovascular invasion (LVI; P < .005), and ECE (P < .0001). An independent negative prognostic effect on overall survival was observed for absence of estrogen and progesterone receptors (P < .05), pN category (P < .05), and presence of LVI (P < .005) and ECE (P < .0001). The presence of ECE was significantly related to an increased risk of regional (13.4% vs. 6.6%; P = .037) and distant (43% vs. 16.2%; P < .001) recurrences.

Conclusions: ECE demonstrated a stronger statistical significance in predicting prognosis than the pN category and was also related to an increased risk of distant recurrences. We suggest that the decision on adjuvant therapy should consider the presence of ECE of axillary metastases and peritumoral LVI as indicators of high biological aggressiveness.

Key Words: Breast neoplasm • Axilla • Lymphatic metastases • Prognosis • Multivariate analysis • Prospective studies

	INTRODUCTION

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Metastatic involvement of axillary lymph nodes is the most important prognostic factor for invasive breast cancers. A direct negative correlation between the number of involved nodes and survival has been demonstrated.¹ In the new edition of the American Joint Committee on Cancer (AJCC) staging system for breast carcinoma, the prognostic value of the number of metastatic lymph nodes has been recognized by classifying the parameter pN as N1a, N2a, and N3a when 1 to 3, 4 to 9, and 10 axillary nodes are involved, respectively.² This modification of the staging system reflects a common clinical practice, because the choice of adjuvant postoperative therapies is usually based on the number of metastatic nodes found at the time of operation; it also corrects the older classification, which considered this pathologic parameter only as a subcategory of stage pN1.³ However, the new staging system does not consider the presence of extracapsular extension (ECE) of axillary nodal metastasis as a prognostic indicator.

The importance of ECE as a risk factor for either local or distant recurrence and poorer survival had been suggested by some studies^4,5 and confirmed by more recent series.^6,7 However, ECE was associated with other indicators of extension of axillary metastases (number of involved nodes and size of nodal metastases) and had greater significance in patients with fewer axillary metastatic nodes.

This prognostic value has not been uniformly confirmed in other studies aimed at finding a correlation between the presence of ECE and the risk of local and regional relapse, overall survival (OS), and identification of patients for whom postoperative radiotherapy should be considered. Indeed, only Leonard et al.⁸ showed the presence of ECE as a prognostic factor for DFS and OS. Conversely, other authors^9–13 have reported ECE to be a limited and dependent prognostic indicator, explaining that the poorer patient success rate and the higher incidence of relapses are due to the statistically significant association between ECE and a high number of metastatic axillary nodes. However, it is uniformly accepted that the incidence of axillary relapses in the presence of ECE is low and that postoperative radiotherapy on the axilla is not necessary, provided that a level 2 axillary dissection is correctly performed.^8–13

In this study, we have evaluated the effect of ECE on the risk of relapse and global survival in patients affected by invasive breast cancer with positive axillary lymph nodes and the prognostic significance of ECE in relation to other pathologic and clinical factors—particularly, the number of metastatic nodes.

	PATIENTS AND METHODS

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From January 1985 to December 1999, 1142 patients affected by invasive breast cancer underwent surgery at the Department of Surgery and Oncology of the University of Siena, Italy. Clinical and pathologic data regarding these patients were prospectively recorded in a computerized database. From this database, we selected

1. Patients submitted to radical or partial mastectomy plus axillary dissection and pT1 to pT3 breast cancers with nodal involvement in the absence of distant metastases. We excluded cases with only axillary micrometastases, defined as metastases <2 mm.
   
2. Patients with a complete follow-up by December 31, 2002. Follow-up information was collected directly from our outpatient clinic after a standardized program of clinical and instrumental examinations. We excluded 21 patients from the study because of incomplete follow-up.
   

Finally, 376 patients with a mean age of 59 years (range, 25–84 years) represented the study population. A radical modified mastectomy, without removal of the pectoralis major muscle, was performed in 272 cases (72.3%), and a partial mastectomy was performed in 104 cases (27.7%). Until 1993, tumor size >2 cm and the presence of clinically palpable axillary lymph nodes, as well as cancers located in central quadrants, were considered contraindications to a partial mastectomy. All patients submitted to partial mastectomy received radiotherapy on the residual breast, with a boost to the tumor bed; no patient received axillary or chest wall irradiation. An adjuvant medical treatment was administered in 372 cases (98.9%); 249 women received chemotherapy. In 123 cases, a hormonal treatment was used as a single therapy and in 64 cases as a treatment after chemotherapy.

In addition to the presence of ECE of axillary metastases, we considered age, menopausal status, histological type of cancer, microscopic size of the tumor measured at the greatest diameter of the invasive component, grade of tumor according to the ScarJ-Bloom-Richardson classification, number of examined and involved axillary lymph nodes, presence of peritumoral lymphovascular invasion (LVI), and hormone-receptor status (assessed by immunohistochemistry) as prognostic variables.

Patients were grouped according to age as younger than 40 years, 41 to 60 years, and 61 years or older. Tumor size was evaluated by grouping tumors as <1 cm (pT1a and pT1b), 1 to 1.9 cm (pT1c), 2 to 4.9 cm (pT2), and 5 cm (pT3). The pN parameter was categorized according to the new AJCC staging system as pN1a, pN2a, and pN3a according to the number of metastatic axillary lymph nodes.²

Recurrences of disease were classified as local (breast or chest wall), regional (axillary, supraclavicular, or internal mammary lymph nodes), or distant. Concomitant local and regional recurrences were considered regional, whereas concomitant local, regional, and distant recurrences were considered distant.

Disease-free survival (DFS) and OS were calculated from the date of surgery. Median follow-up for patients who had survived as of December 2002 was 103 months (range, 36–215 months). We evaluated the prognostic significance of ECE of axillary metastases with respect to DFS, OS, and the patterns of disease recurrence. We then compared such prognostic significance with that of the other clinical and pathologic factors considered.

Menopausal status was unknown in 2 cases (.5%), and tumor grade was not evaluated in 11 patients (2.9%); these data were coded as missing values for the purposes of statistical analysis. The two groups of ECE-positive and ECE-negative patients were compared by the ² test for categorical variables and by Student’s t-test of means for continuous variables. Actuarial DFS and OS were calculated with the Kaplan-Meier method.

The prognostic value of the clinicopathologic factors considered in this study was evaluated by univariate analysis and the ² test; a P value <.05 was considered statistically significant. To evaluate independent prognostic significance and relative risk, multivariate analysis was performed by Cox logistic regression and included any variable that achieved a significant difference on univariate analysis. Statistical analysis was performed with SPSS, version 8.0 (SPSS Inc., Chicago, IL).

	RESULTS

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In the 376 patients who represent the study population, a median number of 15 axillary lymph nodes was examined (mean, 15.86; range, 6–49); the median number of involved lymph nodes was 3 (mean, 5.41; range, 1–36). ECE was present in 179 women (47.6%) with a mean age of 60 years; the group of ECE-negative patients included 197 women (52.4%) with a mean age of 58 years (P = .091). The characteristics of the two groups are listed in Table 1.

ECE-positive patients had a significantly higher mean number of examined and involved lymph nodes, with a higher incidence of pN2a (40.2% vs. 22.3% in ECE-negative patients) and pN3a (29.6% vs. 3.6% in ECE-negative patients) stages. The mean number of examined lymph nodes in ECE-negative patients was 14.95 (median, 14), which was lower than in ECE-positive cases, yet consistent with a level 2 axillary dissection.

During follow-up, we recorded 166 occurrences of disease relapse, with a mean DFS of 61% at year 5 and of 51% at year 10. One hundred sixteen women died of disease with an OS of 80.1% at year 5 and of 63.9% at year 10).

Menopausal status, tumor grade, and histological type did not prove to be statistically significant prognostic factors for DFS and OS on univariate analysis. Differences in actuarial DFS and OS according to the clinicopathologic factors that achieved statistical significance on univariate analysis are listed in Table 2. The results of multivariate analysis for DFS and OS are listed in Tables 3 and 4.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Overall survival (OS) by extracapsular extension (ECE) (Kaplan-Meier).

View larger version (13K): [in this window] [in a new window]   FIG. 2. Overall survival by lymphovascular invasion (LVI) status (Kaplan-Meier).

We recorded two axillary relapses (1.1%) in ECE-positive patients. One was an isolated recurrence, and the other was associated with distant relapse. Three axillary recurrences (1.5%) were found in ECE-negative patients, two of which were associated with a regional recurrence.

	DISCUSSION

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In our study, we found ECE of axillary metastases in 47.6% of the cases. This is an intermediate percentage between the values reported in the literature, which range from 32.3% to 58.7%.^8–11,13 The significantly higher percentage of modified radical mastectomies performed in the ECE-positive patients can be explained by the larger size and the wider axillary metastatic extension of this group of tumors.

In the ECE-positive patients, we observed a mean of 16.96 axillary lymph nodes examined, which is greater than in the ECE-negative patients examined; however, the mean number of 14.95 nodes examined in ECE-negative patients satisfies the criteria for a level 2 axillary dissection. ECE significantly correlated with LVI, more metastatic axillary lymph nodes (8.13 vs. 2.93), and a higher incidence of cases with 4 or more involved nodes (69.8% vs. 25.9%). The correlation between ECE and larger tumor size was of marginal value, whereas the correlation with hormone receptor–negative tumors was significant. These data are in line with previously reported results indicating that ECE consistently correlated with other prognostically negative factors—primarily with a higher number of metastatic lymph nodes.^8–13

However, these data question the real prognostic and, consequently, therapeutic importance of ECE in node-positive breast cancers. Our finding of a very low incidence of axillary relapses after a level 2 axillary dissection, with similar values in ECE-positive (1.1%) and ECE-negative (1.5%) cases, is in agreement with all of the data reported in recent studies^8–13 and does not confirm the previously proposed indication to perform adjuvant axillary irradiation in the presence of ECE.¹⁴

The prognostic importance of ECE was first stressed by Fisher et al.,⁴ who reported a significant correlation with an increased risk of short-term relapse, and then by Mambo and Gallagher,⁵ who demonstrated a poorer 5-year survival in women with 3 or fewer involved lymph nodes in the presence of ECE. More recently, Clayton and Hopkins⁷ published the results of a study performed on a large series of 399 invasive breast cancers with metastatic axillary nodes and reported that ECE had a statistically significant effect on long-term survival in women with 6 or fewer involved lymph nodes.

These data have not been confirmed by further studies on the correlations between patterns of recurrence and the presence of ECE in node-positive breast cancers. Only Leonard et al.⁸ found a significant correlation between ECE and poorer 5- and 10-year survival. This correlation was also confirmed after correction for other prognostic factors, despite a lower statistical significance than the number of involved lymph nodes.

Other studies have demonstrated the prognostic role of ECE, but its value was limited to univariate analysis and was not confirmed after correction for other prognostic factors—mainly the number of involved lymph nodes. Donegan et al.⁹ demonstrated a correlation between ECE and 5-year survival only in women with three or fewer metastatic nodes, without independent value and without correlation with the patterns of relapse; similar results were reported by others.^10,13 In these studies, however, a variable percentage of the patients received different types of adjuvant radiotherapy on the regional lymph nodes, and this may have influenced the effect of ECE on the prognosis.

In a series of 254 women who underwent mastectomy without any postoperative radiation, Fisher et al.¹¹ reported a significant prognostic effect of ECE on OS and on the risk of local relapse which was not maintained after correction for the number of involved lymph nodes. In this study, ECE correlated with a doubled risk of local and regional relapse, and the author recommended adjuvant postoperative radiotherapy to the axilla, chest wall, and supraclavicular region in all ECE-positive patients. Mignano et al.¹² described a larger series of 487 patients without radiotherapy and reported a particularly low incidence of ECE (10.26%); on univariate analysis, they confirmed a significant prognostic value of ECE for survival only.

These studies indicate that the prognostic importance of ECE is substantially due to its correlation with high numbers of metastatic lymph nodes and that the decision about whether to administer an adjuvant therapy should be essentially based on this prognostic parameter. However, our study demonstrates a particularly important prognostic role of ECE in invasive breast cancers, in terms of both DFS (77.6% of ECE-negative vs. 42.4% of ECE-positive patients at 5 years and 66% of ECE-negative vs. 39.5% of ECE-positive patients at 10 years; P < .0001) and OS (84.6% of ECE-negative patients vs. 67.2% of ECE-positive patients at 5 years and 72% of ECE-negative patients vs. 45.9% of ECE-positive patients at 10 years; P < .0001). This prognostic value was confirmed to be independent by multivariate analysis, with a hazard ratio of 2.34 for DFS (P < .0001) and 2.97 for OS (P < .0001).

Peritumoral LVI had an independent prognostic value in our series. This is in accordance with the results published by Woo et al.¹⁵ regarding 1258 patients, in which LVI had a negative prognostic effect on long-term survival both in node-negative (80% vs. 89%; P < .0001) and node-positive (70% vs. 51%; P < .001) women.

The presence of hormone receptors in the tumor is an established positive prognostic factor for breast cancer,^15,16 even if this effect seems to be limited to the first years of follow-up^16,17 and is mainly related to the higher response rates to hormonal adjuvant therapy.¹⁸ Indeed, in our series, the independent positive prognostic value of estrogen receptors may have been at least partly related to the routine administration of hormonal adjuvant therapy, alone or after chemotherapy, in estrogen receptor–positive patients.

The prognostic significance of the presence of progesterone receptors found in our patients is confirmed by data recently reported in the literature.¹⁸ In our study, the number of involved axillary nodes was a strong indicator for DFS and OS, as reported in larger series,^1,19 which provided the basis for the recent modification of the tumor-node-metastasis staging system in breast cancer.²

However, according to our results, the presence of ECE demonstrated a stronger statistical significance than the pN category in predicting the prognosis; these findings contrast with data reported in the literature.^8–13 Since 1990, a larger percentage of patients in our series with more than three involved axillary lymph nodes received anthracycline-based adjuvant chemotherapy regimens. This may have influenced the effect of the pN category on survival, because patients with more metastatic nodes received more intense adjuvant treatments, and this may have prolonged the time to relapse in this part of the population, whose follow-up was shorter.²⁰

It is interesting to note that ECE and LVI modified the prognosis of the subgroups of patients split by the pN category. As reported in Tables 5 and 6, the 5- and 10-year DFS and OS were similar between pN1a LVI-positive patients and pN2a LVI-negative patients and between pN2a LVI-positive patients and pN3a LVI-negative patients. The same modification of prognosis can be observed in pN2a ECE-negative patients, who had better 5- and 10-year DFS and OS than pN1a ECE-positive patients.

On this basis, we suggest that the decision regarding whether to use adjuvant chemotherapy in breast cancer should be based not only on the number of metastatic axillary lymph nodes, which remains a cornerstone of the decision process, but also on other factors. These factors should include the hormone receptor status (as an indicator of responsiveness to hormone therapy) and ECE of axillary metastases and peritumoral LVI (as indicators of high biological aggressiveness), therefore mandating more aggressive regimens of chemotherapy.

In addition, recent clinical trials of postmastectomy radiotherapy have shown a substantial improvement in OS for node-positive women who receive radiotherapy,^21,22 and a recent meta-analysis showed a survival advantage for patients who underwent breast-conserving surgery followed by radiotherapy when compared with cases in which this technique was omitted.²³ ECE of axillary metastases, which in our study was related to an higher risk of regional recurrences and distant metastases, may be considered a selection criterion for adjuvant regional radiotherapy associated with systemic chemotherapy, either to reduce the number of local relapses or to improve survival. We also suggest that further studies be aimed at verifying possible correlations between these pathologic factors and other recent biological markers of tumor behavior, such as oncogenes or proliferative indexes.

Received for publication February 23, 2004. Accepted for publication October 21, 2004.

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