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A Comparison of Outcomes for the Patients with Pathologically Node-negative Breast Cancer and Who Were Treated Either with Sentinel Lymph Node Biopsy Only or with Conventional Axillary Lymph Node Dissection

for SLNB.(8-11) A false negative result after performing Purpose: False negative results obtained with the use of a sentinel lymph node biopsy (SLNB) can result in down staging of tumors, whereas the use of a more elaborated pathological examination of sentinel lymph nodes might lead to upstaging of tumors. The purpose of this study was to compare results after performing only an SLNB as compared with performing conventional axillary lymph node dissection (ALND) without an SLNB in pathologically node negative (pN0) breast cancer patients. Methods: From April 2004 to June 2007, SLNBs were performed for patients with primary breast cancer who had no clinical evidence of a lymph node metastasis. A total of 272 patients were treated with only an SLNB. During the same period, 278 patients were confirmed as pN0 after conventional ALND without an SLNB. A prospectively collected database and medical records of these patients were reviewed. Results: For patients that had undergone only an SLNB, there was no local or regional recurrence. A distant metastasis developed in four patients (1.5%). In patients that had undergone ALND without an SLNB, a recurrence was found in 13 patients (4.7%). Patients that had undergone only an SLNB showed significantly better diseasefree survival as compared to patients that had undergone ALND without an SLNB (p=0.032). Conclusion: pN0 patients treated with only an SLNB showed a significantly better outcome as compared to patients treated with conventional ALND without an SLNB. These results suggest that performing an SLNB might result in the upstaging of a subset of patients who would have been understaged by the use of conventional ALND.


INTRODUCTION
Evaluating for the possible presence of axillary lymph node metastasis is critical to predict the prognosis and to determine the treatment strategy for those patients suffering with breast cancer.(1) The use of axillary lymph node dissection (ALND), which has long been performed to assess the axillary stage, can cause acute or chronic arm edema and long-term morbidities such as a limitation of shoulder motion, paresthesia of the arm, loss of sensation or pain. (2)(3)(4) About ten years ago, the use of a sentinel lymph node biopsy (SLNB) was introduced into the field of breast cancer treatment and this has rapidly became one of the standard methods for axillary staging in many institutions. (5)(6)(7)(8) However, several questions have been raised about the use of only SLNB for axillary staging. A false negative rate of 2-10% has continuously been reported for SLNB. (8)(9)(10)(11) A false negative result after performing Purpose: False negative results obtained with the use of a sentinel lymph node biopsy (SLNB) can result in down staging of tumors, whereas the use of a more elaborated pathological examination of sentinel lymph nodes might lead to upstaging of tumors. The purpose of this study was to compare results after performing only an SLNB as compared with performing conventional axillary lymph node dissection (ALND) without an SLNB in pathologically node negative (pN0) breast cancer patients. Methods: From April 2004 to June 2007, SLNBs were performed for patients with primary breast cancer who had no clinical evidence of a lymph node metastasis. A total of 272 patients were treated with only an SLNB. During the same period, 278 patients were confirmed as pN0 after conventional ALND without an SLNB. A prospectively collected database and medical records of these patients were reviewed. Results: For patients that had under-gone only an SLNB, there was no local or regional recurrence. A distant metastasis developed in four patients (1.5%). In patients that had undergone ALND without an SLNB, a recurrence was found in 13 patients (4.7%). Patients that had undergone only an SLNB showed significantly better diseasefree survival as compared to patients that had undergone ALND without an SLNB (p =0.032). Conclusion: pN0 patients treated with only an SLNB showed a significantly better outcome as compared to patients treated with conventional ALND without an SLNB. These results suggest that performing an SLNB might result in the upstaging of a subset of patients who would have been understaged by the use of conventional ALND. SLNB might result in the down-staging of a tumor and so deprive the patient of a chance for proper management, such as chemotherapy. On the other hand, there is also the possibility of up-staging of a tumor due to a more elaborated examination of the sentinel lymph nodes (SLNs) with using multiple node sections and immunohistochemical methods. (12)(13)(14) There currently are insufficient answers about what would happen with the sum of these opposite effects of SLNB, that is, down-staging versus up-staging.
We have proposed that if down-staging of a tumor after performing SLNB was more common, then the prognosis of the pathologically node negative (pN0) patients treated with only SLNB would be worse than that for the patients who were treated with conventional ALND. In contrast, if up staging of a tumor that' s due to the more elaborated examination of the SLNs were more common than a finding of a false negative result, then the patients who undergo SLNB only would show a better prognosis than that of the patients who undergo ALND without SLNB.
At our institution, performing SLNB only has been done since April 2004 (and after the learning curve period) to treat those patients with negative SLNs on the serial frozen sections. In this study, we compared the outcomes of pN0 patients who were treated either with SLNB only or with conventional ALND without SLNB during the same time period.

Patients
From April 2004 to June 2007, the patients who had a primary invasive breast cancer smaller than 5 cm and pN0 stage disease and who were treated with SLNB only or with conventional ALND at Korea Cancer Center Hospital were considered for the study. The patients who received SLNB followed by ALND and the patients who were treated with neoadjuvant chemotherapy prior to surgery were excluded from the study. The patients with lymph node metastases larger than 0.2 mm (micrometastases) were classified as N1mic and they were excluded from this study.
The sixth edition of the AJCC Cancer Staging Manual was used for staging. (15) The prospectively collected database and medical records of the patients were reviewed for the following clinical and pathological variables: the age at the initial diagnosis, the pathological tumor size, the hormonal receptor status, the expression of c-erb-B2 and the method of treatment. On immunohistochemistry, strong nuclear staining for estrogen receptor or progesterone receptor in more than 10% of tumor nuclei was regarded as positive. Strong and complete cell membrane staining for c-erb-B2 was interpreted as 3+.
The patients were divided into two groups. The SLNB only group was defined as those patients with negative SLNs and they did not undergo further ALND. A total of 272 patients were included in this group. The ALND without SLNB group was defined as the patients who were treated by conventional level I and II ALND without SLNB.
Among these patients, the patients who had less than ten harvested lymph nodes were excluded from this study to avoid the effect of misclassification due to a small number of harvested lymph nodes. (16)(17)(18) A total of 278 patients were included in the ALND without SLNB group.

Surgical treatment for the axillary lymph nodes
As both SLNB and ALND have been considered as standard procedures for axillary staging, the patients were treated with SLNB or ALND without SLNB at the discretion of the individual breast surgeons and the patients. For the ALND without SLNB, conventional level I and II axillary lymph node dissection was performed without SLNB.

Histopathological evaluation of the lymph nodes
The harvested SLNs were submitted to the pathology department for immediate frozen section diagnosis. For the intraoperative evaluation, SLNs with diameters ≤5 mm were bisected, whereas the nodes that measured >5

Statistical analysis
The probabilities of disease free survival were calculat-

RESULTS
The demographic and pathological characteristics

Treatment characteristics
The proportion of patients who were treated with a lumpectomy was higher in the SLNB only group. Radio-SLNB vs ALND in pN0 Patients 267 therapy was performed more often in the SLNB only group, but none of the patients had received radiotherapy for an axillary lymph node ( Table 2). The incidence of administering chemotherapy and hormonal therapy were well balanced between the patients of both groups.

Recurrence
During the mean follow-up period of 27.4 months, a recurrence developed in 17 patients (3.1%). In the SLNB only group, there was no local or regional recurrence.
Distant metastasis was found in four patients (1.5%). In the ALND without SLNB group, there were 13 cases (4.7 %) of disease recurrence, one case of regional recurrence and 12 cases of systemic relapse. The disease-free survival of the SLNB only group was significantly better than that for the ALND without SLNB group (p=0.032) ( Figure   1). Age at diagnosis, T stage, hormonal receptor status, c-erb-B2 status and radiation therapy does not have any significant relation with disease recurrence (Table 3).

DISCUSSION
Although the use of SLNB has become the standard approach for axillary staging in many medical centers, some critical questions still remain unanswered. (20)(21)(22)(23)(24) The biggest concern with utilizing SLNB is its false-negative rate, which is about 2-10% as reported in most studies. In this study, we compared the disease-free survival of pN0 patients and we found that the prognosis of the pN0 patients who were treated with SLNB only was significantly better than that of the patients who were treated with ALND without SLNB. This is not a randomized study, This study has some limitation because it was retrospective surgery. First, mastectomy was more frequently performed in the ALND group. However, It is already well known that the survival is not different between the mastectomy and breast conserving therapy. All patient received lumpectomy in this study were treated by radiation therapy. Therefore, we considered this difference between two groups would not affect the result of this study. Second, the mass size of the SLNB only group had tendency to be smaller than that of the ALND group. Even though the difference was little, it could have influence on this result as selection bias.

CONCLUSION
In the present study we found that the prognosis of the pN0 patients treated with SLNB only was significantly better than the prognosis of the patients treated with ALND without SLNB. This finding strongly suggests that the use of SLNB leads to up-staging of tumors, and the effect of this up-staging might surpass the possible negative impact on the prognosis of patients that is due to a false-negative result after SLNB. However, because it is only a short-term follow-up results, a long term follow-up results are needed to make a definitive conclusion.