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doi   10.1700/1146.12633
Tumori 2012;98(4):413-420




Sentinel node biopsy in early breast cancer: lessons learned from more than 1000 cases at a single institution
Alessandro Fancellu1, Pierina Cottu1, Claudio F Feo1, Daniele Bertulu1, Giuliana Giuliani1, Silvia Mulas1, Valeria Sanna2, Silvia Mura3, Giuseppe Madeddu4, and Angela Spanu4
1Clinical Surgery Unit, University of Sassari; 2Oncology Unit, ASL 1, Sassari; 3Oncology Unit,
and
4Nuclear Medicine Unit, University of Sassari, Sassari, Italy

Key words: sentinel node, early breast cancer, axillary lymph node dissection, survival.

This research was not funded. The authors have no disclosures to make or conflicts of interest to report.

Correspondence to: Dr Alessandro Fancellu, UO Clinica Chirurgica, University of Sassari, V.le San Pietro 43, 07100 Sassari, Italy.
Tel +39-079-228432;
fax +39-079-228394;
email afancel@uniss.it

Received November 16, 2011;
accepted March 23, 2012.

abstract

Aims. The aims of this paper are to report the development of sentinel node biopsy (SNB) in breast cancer at a single institution and to discuss the relevant issues on SNB still to be elucidated.
Patients and methods. From 1998 to 2010, 1021 SNBs with frozen section examination were carried out in patients with breast cancer. In the early period (1998-2002) SNB was always combined with axillary lymph node dissection (ALND). From 2002 onwards, only patients with a positive SNB result underwent ALND (late period). The characteristics of patients with infiltrating carcinoma (IC) and ductal carcinoma in situ (DCIS) and the histological status of the sentinel nodes were examined. The survival outcomes of node-negative patients were compared between patients submitted to SNB and ALND (ALND group) during the early period and patients who underwent only SNB during the late period (SNB group).
Results. The sentinel node was identified intraoperatively in 98.3% of cases. During the early period the overall accuracy of SNB was 97.0%. During the late period, 700 patients with IC and 140 with DCIS underwent SNB. In the IC group, 149 patients (21.3%) had sentinel node macrometastases and 36 (5.1%) micrometastases; of that subgroup, 21 underwent ALND and no other metastatic lymph nodes were found, and 15 underwent SNB only. Axillary recurrences were observed in 4 patients (0.77%) with negative SNB; none of these were among the patients with micrometastatic SNB. Two patients (1.4%) with DCIS had a positive SNB. In node-negative patients the 5-year overall survival was 96.7% in the ALND group and 96.5% in the SNB group ( P = 0.63). The 5-year disease-free survival was 93.8% and 93.2% in the ALND and SNB groups, respectively (P = 0.77).
Conclusions. Overall and disease-free survival in patients with a negative SNB result and no further axillary surgery were equal to those in patients with negative ALND. Intraoperative assessment of the sentinel node in expert hands has a low false-negative rate and allows immediate ALND in patients with sentinel node metastases, avoiding the need for a second operation. ALND for sentinel node micrometastases may be safely omitted in most patients with early stage breast cancer.
Introduction
Axillary lymph node dissection (ALND) has for years been considered an essential part of breast cancer treatment. However, the common finding of histologically negative lymph nodes in 65-70% of ALND specimens, together with the understanding that lymph node status is important essentially as a staging procedure, has led to an attempt to develop a less invasive method of axillary staging. In the late 1990s the sentinel node biopsy (SNB) technique, first used in patients with cutaneous melanoma, was applied to patients with early stage breast cancer1-3.
Since then it has been widely applied and there is a substantial literature to demonstrate that SNB is a reliable method for ascertaining the status of the axillary lymph nodes. Therefore, SNB is nowadays accepted as the standard of care for axillary staging in early stage breast cancer4-6. In current practice, SNB permits to limit ALND to patients with metastatic sentinel nodes, thus sparing the majority of women with breast cancer unnecessary ALND. Compared with ALND, SNB has the advantages of reduced postoperative pain, faster recovery, and a lower risk of lymphedema and complications linked to potential damage to the nervous and vascular structures of the axilla4,7-9.
The SNB concept has radically changed the approach to breast cancer and has opened new scenarios in surgical and adjuvant treatments. We have performed SNB in breast cancer patients since 1998. The present study, based on 1021 consecutive cases, addresses the development of this method and analyzes the operative and survival outcomes. Relevant issues on SNB that are still to be elucidated are also discussed.
Patients and methods
A prospective evaluation of SNB in breast cancer was initiated at our institute towards the end of 1998. All members of the surgical team have experience in breast cancer surgery. The main steps in the development of SNB at our institute are summarized in Figure 1. Initially, the selection criteria for SNB were unifocal infiltrating carcinoma (IC) with a maximum diameter of 3 cm, clinically negative axillary lymph nodes and no previous breast surgery. From September 1998 to August 2002 SNB was always combined with standard ALND. For this first part of our experience, we analyzed the feasibility of SNB and its accuracy in axillary staging. Since September 2002, we have performed ALND only in patients with SNB positive for metastases. In accordance with the evolving standards of SNB practice, from 2005 we have started to broaden the indications to include patients with both multifocal and multicentric carcinoma, those previously submitted to surgical biopsy of the tumor, and those harboring tumors larger than 3 cm.



To determine whether SNB had an impact on outcome for patients with negative axillary lymph nodes, we compared the survival of lymph-node-negative patients who underwent SNB and ALND (ALND group) with that of SNB-negative patients who had undergone no further axillary surgery (SNB group). Differences in mean and medians between the 2 groups were compared using the Mann-Whitney U test. Categorical variables were analyzed using the chi-square test. Kaplan-Meier curves of overall survival (OS) and disease-free survival (DFS) were then obtained for each group. In addition, statistical analyses were performed that compared the 2 groups by means of the log-rank test. P values <0.05 were considered statistically significant.
Lymphoscintigraphy
The technique for lymphoscintigraphy and SBN has been described elsewhere10,11. Briefly, the day before surgery 37 MBq technetium-labeled colloid (until 2002: sulfur colloid, Lymphoscint, Amersham-Sorin, Italy; 2003-2010: albumin colloid, Nanocoll, GE Healthcare, Italy) was subdermally injected overlying the tumor. The cutaneous projection of non-palpable tumors was obtained using ultrasonography or mammography. In multicentric tumors the radiotracer was injected subdermally in the periareolar area. Lymposcintigraphy was performed the same day to visualize the lymphatic flow pathways. A consecutive series of planar images of 300 seconds each were acquired immediately after injection for 1 hour followed by late (2 hour) images. A 57Co-penmark was used during acquisition to mark the skin projection of the sentinel node. The sentinel node site seen at lymphoscintigraphy and marked on the skin was preoperatively confirmed by a handheld gamma detector probe (Navigator Gamma Guidance System, United States Surgical Cooperation, Norwalk, CT, USA).
Surgery and radioguided SNB
All operations were carried out with the patient under general anesthesia 18-24 hours after radiotracer injection. In breast-conserving surgery, we performed only 1 arcuate skin incision for the quadrantectomy and the SNB in the case of tumors located in the upper or lower-outer quadrants. This incision could be slightly extended to the axilla when ALND was required. Two different skin incisions were needed for tumors located in the lower-inner quadrant. Using a gamma detector probe, the sentinel node(s) were identified and removed. The sentinel node was defined as the lymph node with a hot spot of radioactivity. After sentinel node removal, the axillary basin was rechecked by the probe to count the residual radioactivity; a count inferior to 10% of the hottest sentinel node was considered as background activity. The sentinel node was sent for frozen section examination. If the SNB was positive for metastases, classical ALND with removal of the 3 levels of Berg was performed.
Pathological examination of the sentinel node
Intraoperative frozen section assessment of the sentinel lymph node was carried out in each case. The sentinel node was bisected and half of it was used for frozen examination. At least eight 3-6-μm-thick serial sections were examined. The other half of the lymph node and the remaining frozen tissue were fixed and embedded in paraffin for permanent hematoxylin and eosin examination. If this traditional stain was doubtful, the sections were stained for cytokeratins. Micrometastases were defined as metastatic lesions larger than 0.2 mm and no larger than 2.0 mm in diameter, whereas lesions smaller than 0.2 mm were defined as isolated tumor cells12.
Results
The application of SNB at our institute evolved gradually over the years. SNB was carried out in 1012 of 1820 patients operated on for breast cancer between September 1998 and August 2010. In 9 patients with bilateral carcinoma a bilateral SNB was carried out, thus accounting for a total of 1021 SNB procedures. Six patients were male. The mean age of the patients was 56 years (SD±11.32) (range, 26-89). Eight hundred and six patients had IC and 175 had DCIS (Table 1).
Sentinel node identification
The sentinel node was identified intraoperatively in 996 (97.5%) of the 1021 cases. Lymphoscintigraphy failed to identify the sentinel node in 25 patients. However, in 9 of these the intraoperative search with the probe was able to correctly identify the sentinel node, so it was correctly identified intraoperatively in 98.3% of cases. The number of sentinel nodes identified and removed at surgery was 1 in 614 (60.1%) cases, 2 in 313 (30.7%) cases, 3 in 84 (8.2%) cases, and 4 in 10 cases (1%) (Table 1).



Early period of SNB (September 1998-August 2002)
During the early period of our study (September 1998 - August 2002), we performed SNB in 181 patients with infiltrating breast carcinoma. All of them underwent SNB and ALND regardless of the histological status of the sentinel node. The results are summarized in Table 2. In 126 (69.6%) patients the sentinel node was negative for metastases and in 55 (30.4%) it was positive. The sensitivity of SNB was 91.6%, specificity 100%, positive predictive value 100%, negative predictive value 96.0%, and overall accuracy 97.0%. Five patients (2.8%) with negative pathological examination of the sentinel node were found to have metastases in the remnant axillary lymph nodes. This amounts to a false-negative rate of 8.3%.



Late period of SNB (September 2002-August 2010)
SNB in patients with infiltrating carcinoma. The characteristics of the patients with IC operated on between July 2002 and August 2010 are summarized in Table 3. Tumor size was ≤1 cm in 222 cases, between 1 and 2 cm in 340, and greater than 2 cm in 138. The percentages of histologically positive SNB were 9.5%, 25.6% and 55.0%, respectively. Five hundred and seventy patients had ductal IC, 102 patients lobular IC, and 28 patients had other tumor histologies. The sentinel node was negative in 515 cases (73.6%), positive for macrometastases in 149 (21.3%), and positive for micrometastases in 36 (5.1%). In 40 patients (4.5%) we found a discordance between frozen section and final pathology of the sentinel lymph node. The sentinel nodes harboring isolated tumor cells were considered as negative. The sentinel node was the only metastatic lymph node in 83 patients (44%) with histologically positive SNB, 84% of whom presenting micrometastases and 5% isolated tumor cells in the sentinel node.
Of the 36 patients with micrometastases in the sentinel node, 21 were submitted to ALND and 15 underwent no further surgical treatment in the axilla. In this subgroup, no other metastatic lymph nodes were found in the patients submitted to ALND. To date, none of the 15 patients who underwent SNB only developed axillary relapses.




Axillary recurrence after negative SNB. Our follow-up policy for patients submitted to only SNB consisted of clinical examination and ultrasonography of the axilla every 6 months. After a median follow-up of 37 months, 4 patients with negative SNB experienced axillary recurrence (0.77%). All 4 of them then underwent standard ALND. Primary breast surgery had consisted of breast-conserving surgery in 2 patients and mastectomy in the other 2. None of the patients submitted to quadrantectomy had cancer recurrence in the breast at the time of axillary recurrence.
SNB in patients with DCIS. One hundred and forty patients with DCIS underwent SNB. Between 2002 and 2005 SNB was performed in all patients with DCIS. From 2005 SNB was done only in selected cases, i.e., when mastectomy was required, when a palpable mass was present, and when, based on the mammogram, foci of microinvasion were likely. DCIS had been diagnosed by vacuum-assisted core biopsy in 104 patients and by surgical biopsy in 36. Overall, 2 patients (1.4%) had a positive SNB. Both patients had extensive DCIS preoperatively diagnosed by vacuum-assisted biopsy and underwent mastectomy with immediate reconstruction. The final mastectomy specimen revealed foci of microinvasion and invasive adenocarcinoma in both cases.
Survival
One hundred and twenty-nine node-negative patients submitted to both SNB and ALND between September 1998 and August 2002 (ALND group) were compared with 163 node-negative patients submitted to SNB only between September 2002 and December 2005 (SNB group). The demographic and histopathological features were largely comparable in the 2 groups (Table 4), the only exceptions being a Mib-1 labeling index ≤10% and ductal histology, which were higher in the SNB group (P <0.05). Local and adjuvant treatments did not differ between the 2 groups. In the ALND group, the mean number of removed lymph nodes was 14 (range, 10-36). In the SNB group, the mean number of removed sentinel nodes was 1.43 (range, 1-3).
The median follow-up was 109 months (range, 9-125) for the ALND group and 55 months (range, 11-90) for the SNB group. The 5-year OS was 96.7% in the ALND group and 96.5% in the SNB group (P = 0.63) (Figure 2). The 5-year DFS was 93.8% and 93.2% in the ALND and SNB groups, respectively (P = 0.77) (Figure 3).






Discussion
SNB has been steadily gaining popularity since the initial experiences in the late 1990s and is nowadays considered the standard of care for axillary staging in patients with early-stage breast cancer5. Indeed, a large amount of data has shown that SNB is a safe and feasible alternative to classical ALND for axillary staging purposes. The indications for this technique have rapidly expanded, so that at the present time it is simpler to ask which patients are to be excluded from SNB than which are to be included.
Tumor size is no longer important as an inclusion criterion, and in line with the recent trends we now perform SNB for breast tumors up to 5 cm, when preoperative chemotherapy is not required13,14. Conceptually, there is no reason for patients with large tumors to be excluded from SNB, although the likelihood of finding a positive sentinel node is higher as the tumor size increases.
Multifocality and multicentricity are no longer considered to be contraindications as the present view is that there is only 1 sentinel node for the whole breast. A recent review showed that the success rates and false-negative rates of SNB in multifocal/multicentric cancers are similar to those for small unifocal cancers15. However, the authors warn that the rates of sentinel node positivity and non-sentinel node positivity are higher. Since 2005 we have been performing SNB also in patients with multicentric or multifocal tumors by injecting the radiotracer in the periareolar area. The sentinel node was correctly identified in all patients.
Previous surgical excision of the tumor is also no longer considered a contraindication. Whereas it was previously thought that in such cases the interruption of the lymphatic vessels would alter the lymphatic drainage to the axilla and thus render the SNB inaccurate, it has since been shown that the sentinel node may be effectively identified in this situation16. We were able to confirm this in the patients of our study who were first submitted to surgical tumor excision and then to SNB. Besides, it should be noted that this situation rarely occurs, as the preoperative diagnosis of breast malignancy is currently obtained from core biopsies using stereotactic or ultrasound imaging guidance.
In the early period of our study (September 1998-August 2002), SNB was always combined with classical ALND regardless of the histological status of the sentinel node. During this period, the false-negative rate was 8.3%; this finding was in line with the literature data of that moment2. In September 2002 we started to carry out ALND only in patients with positive SNB. The aforementioned early period of SNB may be considered our learning curve, which has actually been a long-lasting phase. There are 2 main reasons for this; first, we wanted to rigorously evaluate the accuracy of the technique we were carrying out, and second, during the early 2000s substantial evidence began to emerge that patients with negative SNB could be spared ALND. Obviously, a training program in which a group of patients are submitted to ALND regardless of the sentinel node status can no longer be proposed for ethical reasons. There is, however, a learning curve for SNB, in which a sentinel node identification rate of >90% should be obtained. We strongly recommend that SNB be performed in centers with a multidisciplinary team with expertise in the diagnosis and treatment of breast cancer.
SNB in patients with DCIS has been a matter of debate for years, as DCIS by itself is not able to metastatize to axillary lymph nodes. Initially, we used to perform SNB in every patient with DCIS preoperatively diagnosed either by surgical biopsy or vacuum-assisted stereotactic biopsy. Only 2 patients had a positive SNB. Both patients underwent mastectomy and final histological examination revealed foci of microinvasion and invasive adenocarcinoma. At present, SNB is not advisable in every patient with pure DCIS 17. SNB should be carried out only in patients undergoing mastectomy or whenever a significant risk of microinvasion is found at final histology17-19.
From the first case onwards, we carried out intraoperative frozen sections for sentinel node assessment. Whether or not to perform intraoperative sentinel node examination is still a matter of debate20. One argument in its favor is that it allows immediate ALND in patients with a positive sentinel node, thus avoiding a second operation. This accounts for about 25% of patients undergoing SNB. On the other hand, the frozen section result may be discordant with the paraffin section histology, thus necessitating reoperation when a SNB negative on frozen section becomes positive after paraffin section examination. When the patients of the present study were divided into an early period (1998-2002) and a late period (2002-2010), there was a significant difference with respect to the disagreement between frozen section and definitive histology on a paraffin-embedded specimen. At present the results are discordant in less than of 5% of patients. The relatively low discordance rate between frozen section and final histology observed in our series is likely a reflection of both multidisciplinary expertise in SNB and pathologists’ skills in conducting and interpreting the results of sentinel node frozen sections. In many European and US breast units, intraoperative assessment of the sentinel node is not performed and preoperative SNB under local anesthesia is preferred 20,21. We believe that both methods are valid. The key figure in the intraoperative SNB examination policy is the pathologist: if the discordance rate between frozen and paraffin sections is low, then intraoperative assessment of SNB is an acceptable policy with some important advantages over preoperative SNB.
An emerging issue in the SNB debate is whether or not ALND is needed in every patient with histologically positive SNB22. This arises from the evidence that the sentinel node is in 40-60% of cases the only metastatic lymph node of the axillary basin22,23. We observed this pattern in 44% of the patients with a positive sentinel node. Interestingly, 84% of them presented micrometastases and 5% isolated tumor cells in the sentinel node. SNB has led to a growing interest in the clinical significance of micrometastases in isolated tumor cells in axillary lymph nodes of breast cancer patients. The issue is still under debate, since some authors reported a detrimental effect of micrometastases on OS and DFS24, whereas others found similar survival outcomes between patients with negative and micrometastatic axillary lymph nodes25,26. An algorithm has been proposed to stratify patients with a positive SNB to undergo ALND or not27. However, this algorithm is not always reproducible in every center. Recent studies should answer this question. An interesting one was the ACOSOG Z00116, in which patients with clinical T1-2 N0 M0 breast cancer having a positive sentinel node were randomized to receive ALND or no further axillary treatment. The study was closed early because of a low accrual/event rate; nevertheless, it showed no trend toward a clinical benefit of ALND for patients with limited nodal disease6,16. Practical guidance for therapeutic conduct in patients with micrometastatic SNB is expected from the recently closed trial IBCSG 23-01, in which patients with breast cancer ≤5 cm and SNB micrometastases were randomized to undergo or not undergo ALND14. In our series, out of 36 patients with micrometastases in the sentinel node, 21 were submitted to ALND and 15 to no further surgical treatment in the axilla. In this subgroup, no other metastatic lymph nodes were found in the patients submitted to ALND. To date, none of the 15 patients who underwent only SNB developed axillary relapses. Our thought is that ALND should no longer be proposed for patients with micrometastases in the SNB; however, the results of the incoming trials will clarify this issue further.
The use of SNB in patients receiving primary chemotherapy is still under debate. At the beginning of the SNB era, preoperative chemotherapy was a contraindication because neoadjuvant treatment was usually reserved for patients with locally advanced breast cancer. However, as the indications for SNB broadened, studies were started on the application of SNB in these patients. Conceptually, if we accept the possibility that preoperative chemotherapy may understage the disease in both the breast and the axillary lymph nodes, we should also accept a method capable of sparing patients ALND if the lymph nodes are negative. At the moment, SNB is not the standard of care in patients undergoing preoperative chemotherapy, although evidence exists that SNB is feasible in this setting 28,29. We are currently running a protocol for the application of SNB after primary chemotherapy.
SNB appeals because of its capacity to spare most of the patients with early breast cancer the potential complications of unnecessary ALND. While these advantages are important, the introduction of a new technique in surgical oncology also requires proof that it does not compromise the survival after cancer. In our series, the OS and DFS of patients with negative SNB and no further axillary surgery did not differ significantly from those of patients with negative SNB who underwent ALND. According to the current literature, this important finding proves that omitting ALND in patients with negative SNB is safe in terms of oncological outcomes 30-32. In this regard, we wish to mention the recently published results of the NSABP B-32 study4. The survival outcomes of 1975 SNB-negative patients submitted to ALND were compared with those of 2011 patients who underwent SNB only. OS, DFS and regional control were statistically equivalent between groups. The conclusion was that when the SNB is negative, SNB alone without ALND is an appropriate, safe and effective therapy for breast cancer patients with clinically negative lymph nodes. Others have found better survival results in patients submitted only to SNB 33, likely due to the preservation of normal lymph nodes. The potential benefit of immunological surveillance by an intact axillary lymph node basin is a fascinating hypothesis that deserves further attention.
Conclusions
Sentinel node biopsy is nowadays accepted as the standard axillary staging method in early stage breast cancer and should be performed by multidisciplinary expert teams. The OS and DFS of patients with negative SNB and no further axillary surgery are equal to those of patients undergoing ALND. Intraoperative assessment of the sentinel node in expert hands has a low false-negative rate and allows immediate ALND in patients with sentinel node metastases, avoiding the need for a second operation. ALND for sentinel node micrometastases may be safely omitted in most patients with early stage breast cancer.
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