- Email: [email protected]
Solitary positive sentinel lymph node accompanied by negative sentinel lymph node(s) is predictive of a negative completion axillary lymph node dissection
The American Journal of Surgery 194 (2007) 856 – 859
Presentation
Solitary positive sentinel lymph node accompanied by negative sentinel lymph node(s) is predictive of a negative completion axillary lymph node dissection Weesam Alkhatib, M.D.a,*, Carol Connor, M.D.a, Fan Fang, M.D., Ph.D.b a
Department of Surgery, University of Kansas Medical Center, 4960 Murphy Administration Building, Mail Stop 2005, 3901 Rainbow Blvd, Kansas City, KS 66160, USA b Department of Pathology, University of Kansas Medical Center, 2017 Wahl Hall West, Mail Stop 3045, 3901 Rainbow Blvd, Kansas City, KS 66160, USA Manuscript received June 13, 2007; revised manuscript August 13, 2007 Presented at the 59th Annual Meeting of the Southwestern Surgical Congress, Rancho Mirage, CA, March 25–29, 2007
Abstract Background: Many patients with a positive sentinel lymph node (SLN) have a negative axillary lymph node dissection (ALND). We hypothesized that a solitary positive SLN associated with at least 1 negative SLN is predictive of a negative completion ALND. Omission of ALND may be possible in these patients. Methods: A retrospective review of 392 consecutive patients who underwent SLNB was performed. The 78 (20%) SLN-positive patients were divided into 4 groups: group 1: solitary positive SLN associated with at least 1 negative SLN; group 2: more than 1 positive SLN with at least 1 negative SLN; group 3: solitary positive SLN with no additional SLNs; and group 4: more than 1 positive SLN and all SLNs positive. Results: Excluding extracapsular extension, only 3% of group 1 patients had a positive ALND. Positive ALND was found in 15% of group 2, 29% of group 3, and 77% of group 4. Conclusions: A solitary positive SLN accompanied by additional negative SLN(s) is predictive of a negative completion ALND. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Sentinel lymph nodes; Axillary lymph node; Breast cancer; Extracapsular invasion
Sentinel lymph node biopsy (SLNB) is based on the premise that the first lymph node(s) draining the breast can be identified and that lymphatic metastases will follow this lymph node distribution [1]. This premise has been validated clinically, and SLNB is now the accepted initial axillary staging procedure in patients with invasive breast cancer. The 2001 Philadelphia Consensus Conference on sentinel node in breast cancer recommended that axillary lymph node dissection (ALND) should be reserved for patients with a positive SLNB [2]. The completion ALND documents the complete number of positive nodes, which allows accurate staging. In addition, it prevents an axillary recurrence that may occur if non-SLNs are left behind. Data are now accumulating on axillary lymph node dissections performed in patients with a positive SLN. In approximately 57% of patients, the SLN is the only positive ALN [3]. * Corresponding author. Tel.: ⫹1-913-568-7137; fax: ⫹1-913-588-7540. E-mail address: [email protected]
Although nomograms have been developed to determine which SLN-positive patients are at risk of positive non-SLN [4], it remains unclear whether a subset of patients can be identified who do not require a completion ALND. We hypothesized that ALN metastases most likely would occur in a stepwise progression via the identified SLN and would not skip any additional negative SLN(s). Therefore, the presence of a negative SLN beyond a positive one should predict the absence of further axillary disease. We reviewed our experience with SLNB to determine if this hypothesis is valid, and whether it may be used to avoid ALND in this subset of patients. Because tumor size is known to influence the risk of axillary lymph node metastases, this variable was included in the analysis to determine if a significant difference in tumor size existed between the groups. Methods We performed a retrospective review of 392 breast cancer patients who underwent SLNB by one surgeon between
0002-9610/07/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.08.029
W. Alkhatib et al. / The American Journal of Surgery 194 (2007) 856 – 859
February 2000 and August 2006. Identification of the sentinel node(s) was performed using the combined technique of radioisotope and blue dye. Intraoperative frozen section of the SLNs was performed, and an immediate ALND was performed if a positive SLN was identified. Intraoperative frozen section results on both negative and positive SLNs were verified by permanent hematoxylin-eosin and AE1/ AE3 immunostain. The SLN-positive patients were divided into 4 groups: group 1 (38 patients): solitary positive SLN with additional SLN(s) that were all negative; group 2 (13 patients): more than 1 positive SLN with at least 1 negative SLN; group 3 (14 patients): solitary positive SLN with no additional SLNs; and group 4 (13 patients): more than 1 positive SLN and all SLNs positive. Statistical analysis was performed between groups 1 to 4 to determine the significance of our findings. The mean tumor size with statistical analysis also was documented and compared between groups 1 through 4. Results Of these 392 patients, 78 (20%) had at least 1 positive SLN leading to completion ALND. The average age of the SLN-positive patients was 53.6 years old with an average tumor size of 2.4 cm. In group 1, 38 patients had a solitary positive SLN with at least 1 negative SLN (Table 1). Of these patients, 5% (2 of 38) had a positive completion ALND. One of the 2 patients in group 1 with a positive non-SLN had evidence of extracapsular extension in the positive SLN. If extracapsular extension was excluded, only 3% (1 of 37) had a positive ALND. Group 2 is defined as patients with more than 1 positive SLN associated with a negative SLN. Within this group, 15% (2 of 13) had a positive ALND (Table 1). If a solitary positive SLN was found without an associated SLN (group 3), 29% (4 of 14) had a positive ALND. If more than 1 SLN was identified, and all SLN were positive (group 4), 77% (10 of 13) had a positive ALND (Table 1). We used a chi-squared test to analyze the significance of our findings within each group (Table 1). Group 1 had a chi-squared value of 5.9, group 2 of 11.8, group 3 of 23.5, and group 4 of 58.8. By using this mode, we determined our data to be highly statistically significant with a Fisher exact test P value of less than .00001. The mean tumor size of groups 1, 2, and 3 were 2.1, 2.3, and 1.6 cm, respectively. In group 4, the mean tumor size Table 1 Percentage of patients with (⫹) ALND after (⫹) SLNB Group
(⫹) SLNB (⫹) ALND % of patients Chi-squared with (⫹) test column ALND percentages
1 2 3 4 Total no. of patients with (⫹) SLN
38 13 14 13 78
2 2 4 10
5 15 29 77
5.9 11.8 23.5 58.8 P ⬍ .00001
857
Table 2 Analysis of variance statistical analysis of tumor size Group
Tumor size, cm
Least squared mean
Error
P value comparison with group 4
1 2 3 4
2.1 2.3 1.6 3.5
.31 .57 .49 .49
⬍.0001 .0002 .0021 ⬍.0001
.024 .13 .0085
was 3.5 cm. Statistical analysis of tumor sizes using oneway analysis of variance was conducted (Table 2). The overall model was significant with F ⫽ 2.78 and a P value of .05. Because the overall model was significant, post hoc analysis was conducted using the least squared means procedure in SAS (SAS Institute, Inc, Cary, NC). Table 2 shows that group 4 patients (average, 3.5 cm) had a larger tumor size than each of the other groups, but it was only significant when compared with groups 1 and 2 (P values of .024 and .0085, respectively). There was no significant difference in tumor size between groups 1, 2, and 3. Comments The sentinel node concept is based on the principle that the afferent lymphatics draining the primary tumor course first to the SLN(s), followed by the regional lymphatic basin. About 57% of patients with positive axillary lymph nodes only have a single positive SLN [5]. Based on this concept of lymphatic drainage, additional SLNs would be the most likely axillary nodes to harbor additional metastatic disease. If this concept can be validated clinically, it may allow identification of a subset of patients who do not require a completion ALND. There have been numerous attempts to determine which patients with a positive SLN are unlikely to have a positive completion ALND. One such attempt, the Memorial Sloan Kettering Breast Cancer Nomogram, is available online and individual patient data can be entered, yielding a percentage prediction of non-SLN positivity for that patient [4]. The nomogram contains 9 variables and has been found to be a fairly accurate predictor for the likelihood of non-SLN metastasis for various populations [6,7]. However, many of these variables (size of the tumor, presence of lymphovascular invasion, and multifocality) may be unclear when the positive SLN is identified by frozen section. This limits the usefulness of the nomogram for surgeons deciding intraoperatively whether to proceed with an ALND. If this nomogram had been used to determine the need for ALND in our group 1 subset of patients, an ALND would have been recommended in 5% of the patients. The nomogram supports our hypothesis that group 1 patients, excluding those with extracapsular invasion, have a low axillary lymph node metastatic rate. Our data revealed that 5% (2 of 38) of group 1 patients with a solitary positive SLN and additional negative SLN(s) had a positive completion ALND. However, 1 of those patients had extracapsular extension in the SLN. Extracapsular extension is a known predictor of additional positive ALNs. One study that evaluated patients with extracapsular extension of the SLN found that 26% (18 of 70) had positive
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W. Alkhatib et al. / The American Journal of Surgery 194 (2007) 856 – 859
axillary metastasis on completion ALND. This suggests that these patients were more likely to have non–sentinel node involvement and should undergo ALND [7]. If we exclude our patient with extracapsular invasion, only 3% (1 of 37) had a positive ALND. Based on these preliminary results, 97% of patients with a solitary negative SLN and additional negative SLN will have a negative completion ALND. A false-negative rate of 5% or less (risk of a positive completion ALND) currently is accepted for the SLNB procedure. An ALND is no longer considered necessary when this level of risk is present. Therefore, it would be appropriate to consider omission of completion ALND if a similar subset of SLNB-positive patients could be identified. Previous studies attempting to identify patients with a higher risk of non–sentinel node metastasis based on SLN characteristics found that only the number of sentinel node metastasis (1 vs ⬎1) was a significant predictor of non– sentinel node metastasis [7,8]. Although our study also showed an increased risk of a positive completion ALND as the number of positive SLNs increased, the presence of a single positive SLN was only predictive of a negative completion ALND if it was associated with at least 1 additional negative SLN. If a solitary SLN (without extracapsular extension) was accompanied by at least 1 negative SLN (group 1), there was a 3% risk of a positive non-SLN. In patients with a solitary SLN with no associated negative SLNs, there was a 29% risk of a positive non-SLN. We found these results to be highly statistically significant, which suggests a true difference existing between each group. Therefore, patients with more than 1 positive SLN and an associated negative SLN (group 2), a solitary SLN with no additional SLN (group 3), or more than 1 positive SLN without additional SLN (group 4) have a significant risk of additional positive non-SLNs (15%, 29%, and 77%, respectively) and should undergo a completion ALND. Group 4, patients with the largest average tumor size, was the only group with a significantly larger tumor size than the other 3 groups, and had more positive axillary lymph nodes than the other 3 groups. This suggests that patients with larger tumors are more likely to have more than 1 positive SLN and more likely to need a completion ALND. This was supported by a publication from the University of Louisville suggesting that the size of the tumor is proportional to the number of positive sentinel and completion ALNs [9]. However, within our first 3 groups of patients there was no significant difference in tumor size even though the risk of a positive completion ALND varied from 5% to 29%. Therefore, tumor size alone is not sufficient to identify a subset of patients with a positive SLNB and a low risk of completion ALND. In our study, the combination of a solitary SLN and at least 1 negative SLN was the only predictor of a low risk of non-SLN metastases. The primary limit of this study is the relatively small sample size. Recommendations regarding completion ALND are therefore limited pending further evaluation of this hypothesis. However, these preliminary results warrant further investigation. The addition of similar data from other institutions would add validity to these findings. If our hypothesis is confirmed, it may be possible to selectively omit completion ALND in a significant number of patients with early stage breast cancer.
Conclusions This report of one surgeon’s experience with SLNB and completion ALND suggests that patients with a solitary positive SLN and at least 1 negative SLN may not require completion ALND. Patients with extracapsular extension, a positive SLN without associated negative SLN(s), or more than 1 positive SLN require completion ALND. References [1] Giuliano AE. Mapping a pathway for axillary staging: a personal perspective on the current status of sentinel lymph node dissection for breast cancer. Arch Surg 1999;34:195–9. [2] Giuliano A, Schwartz G. Summary of the proceedings of the Philadelphia Consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast. Semin Breast Dis 2002;5:2542–51. [3] Giuliano A, Haigh PI, Brennan MB, et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2000;18:2553–9. [4] Memorial Sloan Kettering SLN Nomogram. Available at: www. mskcc.org/mskcc/html/15938.cfm. [5] Turner RR, Ollila DW, Krasne DL, Giuliano AE. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 1997;226:150 –158. [6] Smidt ML, Kuster DM, Van der Wilt Jan, et al. Can the Memorial Sloan-Kettering Cancer Center nomogram predict the likelihood of nonsentinel lymph node metastases in breast cancer patients in The Netherlands? Ann Surg Oncol 2005;12:1066 –72. [7] Goyal A, Douglas-Jones A, Newcombe RG, et al, ALMANAC Trialist Group. Predictors of non-sentinel node metastasis in breast cancer patients. Eur J Cancer 2004;40:1731–7. [8] Soni NK, Carmalt HL, Gillett DJ, et al. Evaluation of a breast cancer nomogram for prediction of non-sentinel lymph node positivity. Eur J Surg Oncol 2005;31:958 – 64. [9] Stitzenberg KB, Meyer AA, Stern SL, et al. Extracapsular extension of the sentinel lymph node metastasis: a predictor of nonsentinel node tumor burden. Ann Surg 2003;237:607–13.
Discussion Scott Petersen, M.D. (Phoenix, AZ): I congratulate Dr. Alkhatib and his colleagues on a nice presentation and a well-written article. They have reviewed a single series of 78 patients who underwent completion axillary lymph node dissections after finding a positive sentinel lymph node. The technique of sentinel lymph node biopsy is well described in the text, and 1 surgeon, Dr. Conner, performed the sentinel node biopsies in all the patients. Their data confirm what other authors have identified, namely that increasing primary tumor size is associated with a higher incidence of positive sentinel lymph nodes. In addition, in patients with multiple resected sentinel nodes, the number of positive nodes correlates with an increased rate of positive completion axillary lymph node dissections. The authors suggest, and their data bear this out, that if multiple sentinel nodes are identified and only a single node is positive, a completion axillary lymph node dissection is unlikely (only 3% in their series) to uncover any further metastatic disease. They also suggest that these patients may not need a completion axillary dissection at all. They have amply discussed the limitations of their study in the article including its retrospective nature and the small number of patients. If they follow their own recommendations in the future, almost 50% (48.7%) of their patients would be spared an unnecessary axillary dissection and its attendant morbidity.
W. Alkhatib et al. / The American Journal of Surgery 194 (2007) 856 – 859
I have several questions for the authors. First, the literature shows a definite “learning curve” with the technique of sentinel lymph node biopsy. Were there differences in the number of sentinel nodes identified during the course of the study? For example, were more nodes identified in the latter years of the review? Second, are you that confident in the interpretation of your frozen section results and what would you recommend at postoperative day 2 when the permanent section of the lymph nodes reveals micrometastasis or extracapsular invasion in an additional sentinel node? Three, were any lymph node dissections performed in patients in whom the sentinel lymph node(s) were negative? If yes, what was the incidence of metastatic disease in those patients? If no, did any of those patients subsequently present with axillary recurrences? Finally, what was your morbidity associated with the 78 patients in the series who underwent axillary lymph node dissections? I enjoyed the presentation, and as a trauma surgeon who infrequently performs an axillary dissection unless a bullet wound or a stab wound is involved, I learned something from reading the article and listening to the presentation. I thank the program committee for inviting me to discuss this important article.
859
Carol Conner, M.D. (Kansas City, KS): The average number of sentinel lymph nodes was not included in this analysis, but the primary surgeon in this study was no longer in the learning phase of the procedure. Therefore, we would not expect a significant change in this variable over time. As our study and others have shown, extracapsular invasion is associated with a significant risk of positive nonsentinel nodes. In our practice, this remains an indication for a completion axillary lymph node dissection. If a patient has a small favorable tumor with a solitary micrometastases and additional negative sentinel lymph nodes, the risks/benefits of observation versus completion axillary lymph node dissection are discussed with the patient. Elimination of a completion axillary lymph node dissection in this subset of patients remains controversial. A completion axillary lymph node dissection was not performed if the sentinel lymph nodes were negative. However, a trial of 30 sentinel lymph node biopsies with completion axillary lymph node dissection was performed by this surgeon before initiating routine sentinel lymph node biopsy. There were no false-negatives in this series of 30 patients. In this author’s series of patients who had sentinel lymph node biopsy without axillary lymph node dissection, there has been no axillary recurrence.
Presentation
Solitary positive sentinel lymph node accompanied by negative sentinel lymph node(s) is predictive of a negative completion axillary lymph node dissection Weesam Alkhatib, M.D.a,*, Carol Connor, M.D.a, Fan Fang, M.D., Ph.D.b a
Department of Surgery, University of Kansas Medical Center, 4960 Murphy Administration Building, Mail Stop 2005, 3901 Rainbow Blvd, Kansas City, KS 66160, USA b Department of Pathology, University of Kansas Medical Center, 2017 Wahl Hall West, Mail Stop 3045, 3901 Rainbow Blvd, Kansas City, KS 66160, USA Manuscript received June 13, 2007; revised manuscript August 13, 2007 Presented at the 59th Annual Meeting of the Southwestern Surgical Congress, Rancho Mirage, CA, March 25–29, 2007
Abstract Background: Many patients with a positive sentinel lymph node (SLN) have a negative axillary lymph node dissection (ALND). We hypothesized that a solitary positive SLN associated with at least 1 negative SLN is predictive of a negative completion ALND. Omission of ALND may be possible in these patients. Methods: A retrospective review of 392 consecutive patients who underwent SLNB was performed. The 78 (20%) SLN-positive patients were divided into 4 groups: group 1: solitary positive SLN associated with at least 1 negative SLN; group 2: more than 1 positive SLN with at least 1 negative SLN; group 3: solitary positive SLN with no additional SLNs; and group 4: more than 1 positive SLN and all SLNs positive. Results: Excluding extracapsular extension, only 3% of group 1 patients had a positive ALND. Positive ALND was found in 15% of group 2, 29% of group 3, and 77% of group 4. Conclusions: A solitary positive SLN accompanied by additional negative SLN(s) is predictive of a negative completion ALND. © 2007 Excerpta Medica Inc. All rights reserved. Keywords: Sentinel lymph nodes; Axillary lymph node; Breast cancer; Extracapsular invasion
Sentinel lymph node biopsy (SLNB) is based on the premise that the first lymph node(s) draining the breast can be identified and that lymphatic metastases will follow this lymph node distribution [1]. This premise has been validated clinically, and SLNB is now the accepted initial axillary staging procedure in patients with invasive breast cancer. The 2001 Philadelphia Consensus Conference on sentinel node in breast cancer recommended that axillary lymph node dissection (ALND) should be reserved for patients with a positive SLNB [2]. The completion ALND documents the complete number of positive nodes, which allows accurate staging. In addition, it prevents an axillary recurrence that may occur if non-SLNs are left behind. Data are now accumulating on axillary lymph node dissections performed in patients with a positive SLN. In approximately 57% of patients, the SLN is the only positive ALN [3]. * Corresponding author. Tel.: ⫹1-913-568-7137; fax: ⫹1-913-588-7540. E-mail address: [email protected]
Although nomograms have been developed to determine which SLN-positive patients are at risk of positive non-SLN [4], it remains unclear whether a subset of patients can be identified who do not require a completion ALND. We hypothesized that ALN metastases most likely would occur in a stepwise progression via the identified SLN and would not skip any additional negative SLN(s). Therefore, the presence of a negative SLN beyond a positive one should predict the absence of further axillary disease. We reviewed our experience with SLNB to determine if this hypothesis is valid, and whether it may be used to avoid ALND in this subset of patients. Because tumor size is known to influence the risk of axillary lymph node metastases, this variable was included in the analysis to determine if a significant difference in tumor size existed between the groups. Methods We performed a retrospective review of 392 breast cancer patients who underwent SLNB by one surgeon between
0002-9610/07/$ – see front matter © 2007 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2007.08.029
W. Alkhatib et al. / The American Journal of Surgery 194 (2007) 856 – 859
February 2000 and August 2006. Identification of the sentinel node(s) was performed using the combined technique of radioisotope and blue dye. Intraoperative frozen section of the SLNs was performed, and an immediate ALND was performed if a positive SLN was identified. Intraoperative frozen section results on both negative and positive SLNs were verified by permanent hematoxylin-eosin and AE1/ AE3 immunostain. The SLN-positive patients were divided into 4 groups: group 1 (38 patients): solitary positive SLN with additional SLN(s) that were all negative; group 2 (13 patients): more than 1 positive SLN with at least 1 negative SLN; group 3 (14 patients): solitary positive SLN with no additional SLNs; and group 4 (13 patients): more than 1 positive SLN and all SLNs positive. Statistical analysis was performed between groups 1 to 4 to determine the significance of our findings. The mean tumor size with statistical analysis also was documented and compared between groups 1 through 4. Results Of these 392 patients, 78 (20%) had at least 1 positive SLN leading to completion ALND. The average age of the SLN-positive patients was 53.6 years old with an average tumor size of 2.4 cm. In group 1, 38 patients had a solitary positive SLN with at least 1 negative SLN (Table 1). Of these patients, 5% (2 of 38) had a positive completion ALND. One of the 2 patients in group 1 with a positive non-SLN had evidence of extracapsular extension in the positive SLN. If extracapsular extension was excluded, only 3% (1 of 37) had a positive ALND. Group 2 is defined as patients with more than 1 positive SLN associated with a negative SLN. Within this group, 15% (2 of 13) had a positive ALND (Table 1). If a solitary positive SLN was found without an associated SLN (group 3), 29% (4 of 14) had a positive ALND. If more than 1 SLN was identified, and all SLN were positive (group 4), 77% (10 of 13) had a positive ALND (Table 1). We used a chi-squared test to analyze the significance of our findings within each group (Table 1). Group 1 had a chi-squared value of 5.9, group 2 of 11.8, group 3 of 23.5, and group 4 of 58.8. By using this mode, we determined our data to be highly statistically significant with a Fisher exact test P value of less than .00001. The mean tumor size of groups 1, 2, and 3 were 2.1, 2.3, and 1.6 cm, respectively. In group 4, the mean tumor size Table 1 Percentage of patients with (⫹) ALND after (⫹) SLNB Group
(⫹) SLNB (⫹) ALND % of patients Chi-squared with (⫹) test column ALND percentages
1 2 3 4 Total no. of patients with (⫹) SLN
38 13 14 13 78
2 2 4 10
5 15 29 77
5.9 11.8 23.5 58.8 P ⬍ .00001
857
Table 2 Analysis of variance statistical analysis of tumor size Group
Tumor size, cm
Least squared mean
Error
P value comparison with group 4
1 2 3 4
2.1 2.3 1.6 3.5
.31 .57 .49 .49
⬍.0001 .0002 .0021 ⬍.0001
.024 .13 .0085
was 3.5 cm. Statistical analysis of tumor sizes using oneway analysis of variance was conducted (Table 2). The overall model was significant with F ⫽ 2.78 and a P value of .05. Because the overall model was significant, post hoc analysis was conducted using the least squared means procedure in SAS (SAS Institute, Inc, Cary, NC). Table 2 shows that group 4 patients (average, 3.5 cm) had a larger tumor size than each of the other groups, but it was only significant when compared with groups 1 and 2 (P values of .024 and .0085, respectively). There was no significant difference in tumor size between groups 1, 2, and 3. Comments The sentinel node concept is based on the principle that the afferent lymphatics draining the primary tumor course first to the SLN(s), followed by the regional lymphatic basin. About 57% of patients with positive axillary lymph nodes only have a single positive SLN [5]. Based on this concept of lymphatic drainage, additional SLNs would be the most likely axillary nodes to harbor additional metastatic disease. If this concept can be validated clinically, it may allow identification of a subset of patients who do not require a completion ALND. There have been numerous attempts to determine which patients with a positive SLN are unlikely to have a positive completion ALND. One such attempt, the Memorial Sloan Kettering Breast Cancer Nomogram, is available online and individual patient data can be entered, yielding a percentage prediction of non-SLN positivity for that patient [4]. The nomogram contains 9 variables and has been found to be a fairly accurate predictor for the likelihood of non-SLN metastasis for various populations [6,7]. However, many of these variables (size of the tumor, presence of lymphovascular invasion, and multifocality) may be unclear when the positive SLN is identified by frozen section. This limits the usefulness of the nomogram for surgeons deciding intraoperatively whether to proceed with an ALND. If this nomogram had been used to determine the need for ALND in our group 1 subset of patients, an ALND would have been recommended in 5% of the patients. The nomogram supports our hypothesis that group 1 patients, excluding those with extracapsular invasion, have a low axillary lymph node metastatic rate. Our data revealed that 5% (2 of 38) of group 1 patients with a solitary positive SLN and additional negative SLN(s) had a positive completion ALND. However, 1 of those patients had extracapsular extension in the SLN. Extracapsular extension is a known predictor of additional positive ALNs. One study that evaluated patients with extracapsular extension of the SLN found that 26% (18 of 70) had positive
858
W. Alkhatib et al. / The American Journal of Surgery 194 (2007) 856 – 859
axillary metastasis on completion ALND. This suggests that these patients were more likely to have non–sentinel node involvement and should undergo ALND [7]. If we exclude our patient with extracapsular invasion, only 3% (1 of 37) had a positive ALND. Based on these preliminary results, 97% of patients with a solitary negative SLN and additional negative SLN will have a negative completion ALND. A false-negative rate of 5% or less (risk of a positive completion ALND) currently is accepted for the SLNB procedure. An ALND is no longer considered necessary when this level of risk is present. Therefore, it would be appropriate to consider omission of completion ALND if a similar subset of SLNB-positive patients could be identified. Previous studies attempting to identify patients with a higher risk of non–sentinel node metastasis based on SLN characteristics found that only the number of sentinel node metastasis (1 vs ⬎1) was a significant predictor of non– sentinel node metastasis [7,8]. Although our study also showed an increased risk of a positive completion ALND as the number of positive SLNs increased, the presence of a single positive SLN was only predictive of a negative completion ALND if it was associated with at least 1 additional negative SLN. If a solitary SLN (without extracapsular extension) was accompanied by at least 1 negative SLN (group 1), there was a 3% risk of a positive non-SLN. In patients with a solitary SLN with no associated negative SLNs, there was a 29% risk of a positive non-SLN. We found these results to be highly statistically significant, which suggests a true difference existing between each group. Therefore, patients with more than 1 positive SLN and an associated negative SLN (group 2), a solitary SLN with no additional SLN (group 3), or more than 1 positive SLN without additional SLN (group 4) have a significant risk of additional positive non-SLNs (15%, 29%, and 77%, respectively) and should undergo a completion ALND. Group 4, patients with the largest average tumor size, was the only group with a significantly larger tumor size than the other 3 groups, and had more positive axillary lymph nodes than the other 3 groups. This suggests that patients with larger tumors are more likely to have more than 1 positive SLN and more likely to need a completion ALND. This was supported by a publication from the University of Louisville suggesting that the size of the tumor is proportional to the number of positive sentinel and completion ALNs [9]. However, within our first 3 groups of patients there was no significant difference in tumor size even though the risk of a positive completion ALND varied from 5% to 29%. Therefore, tumor size alone is not sufficient to identify a subset of patients with a positive SLNB and a low risk of completion ALND. In our study, the combination of a solitary SLN and at least 1 negative SLN was the only predictor of a low risk of non-SLN metastases. The primary limit of this study is the relatively small sample size. Recommendations regarding completion ALND are therefore limited pending further evaluation of this hypothesis. However, these preliminary results warrant further investigation. The addition of similar data from other institutions would add validity to these findings. If our hypothesis is confirmed, it may be possible to selectively omit completion ALND in a significant number of patients with early stage breast cancer.
Conclusions This report of one surgeon’s experience with SLNB and completion ALND suggests that patients with a solitary positive SLN and at least 1 negative SLN may not require completion ALND. Patients with extracapsular extension, a positive SLN without associated negative SLN(s), or more than 1 positive SLN require completion ALND. References [1] Giuliano AE. Mapping a pathway for axillary staging: a personal perspective on the current status of sentinel lymph node dissection for breast cancer. Arch Surg 1999;34:195–9. [2] Giuliano A, Schwartz G. Summary of the proceedings of the Philadelphia Consensus conference on the role of sentinel lymph node biopsy in carcinoma of the breast. Semin Breast Dis 2002;5:2542–51. [3] Giuliano A, Haigh PI, Brennan MB, et al. Prospective observational study of sentinel lymphadenectomy without further axillary dissection in patients with sentinel node-negative breast cancer. J Clin Oncol 2000;18:2553–9. [4] Memorial Sloan Kettering SLN Nomogram. Available at: www. mskcc.org/mskcc/html/15938.cfm. [5] Turner RR, Ollila DW, Krasne DL, Giuliano AE. Histopathologic validation of the sentinel lymph node hypothesis for breast carcinoma. Ann Surg 1997;226:150 –158. [6] Smidt ML, Kuster DM, Van der Wilt Jan, et al. Can the Memorial Sloan-Kettering Cancer Center nomogram predict the likelihood of nonsentinel lymph node metastases in breast cancer patients in The Netherlands? Ann Surg Oncol 2005;12:1066 –72. [7] Goyal A, Douglas-Jones A, Newcombe RG, et al, ALMANAC Trialist Group. Predictors of non-sentinel node metastasis in breast cancer patients. Eur J Cancer 2004;40:1731–7. [8] Soni NK, Carmalt HL, Gillett DJ, et al. Evaluation of a breast cancer nomogram for prediction of non-sentinel lymph node positivity. Eur J Surg Oncol 2005;31:958 – 64. [9] Stitzenberg KB, Meyer AA, Stern SL, et al. Extracapsular extension of the sentinel lymph node metastasis: a predictor of nonsentinel node tumor burden. Ann Surg 2003;237:607–13.
Discussion Scott Petersen, M.D. (Phoenix, AZ): I congratulate Dr. Alkhatib and his colleagues on a nice presentation and a well-written article. They have reviewed a single series of 78 patients who underwent completion axillary lymph node dissections after finding a positive sentinel lymph node. The technique of sentinel lymph node biopsy is well described in the text, and 1 surgeon, Dr. Conner, performed the sentinel node biopsies in all the patients. Their data confirm what other authors have identified, namely that increasing primary tumor size is associated with a higher incidence of positive sentinel lymph nodes. In addition, in patients with multiple resected sentinel nodes, the number of positive nodes correlates with an increased rate of positive completion axillary lymph node dissections. The authors suggest, and their data bear this out, that if multiple sentinel nodes are identified and only a single node is positive, a completion axillary lymph node dissection is unlikely (only 3% in their series) to uncover any further metastatic disease. They also suggest that these patients may not need a completion axillary dissection at all. They have amply discussed the limitations of their study in the article including its retrospective nature and the small number of patients. If they follow their own recommendations in the future, almost 50% (48.7%) of their patients would be spared an unnecessary axillary dissection and its attendant morbidity.
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I have several questions for the authors. First, the literature shows a definite “learning curve” with the technique of sentinel lymph node biopsy. Were there differences in the number of sentinel nodes identified during the course of the study? For example, were more nodes identified in the latter years of the review? Second, are you that confident in the interpretation of your frozen section results and what would you recommend at postoperative day 2 when the permanent section of the lymph nodes reveals micrometastasis or extracapsular invasion in an additional sentinel node? Three, were any lymph node dissections performed in patients in whom the sentinel lymph node(s) were negative? If yes, what was the incidence of metastatic disease in those patients? If no, did any of those patients subsequently present with axillary recurrences? Finally, what was your morbidity associated with the 78 patients in the series who underwent axillary lymph node dissections? I enjoyed the presentation, and as a trauma surgeon who infrequently performs an axillary dissection unless a bullet wound or a stab wound is involved, I learned something from reading the article and listening to the presentation. I thank the program committee for inviting me to discuss this important article.
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Carol Conner, M.D. (Kansas City, KS): The average number of sentinel lymph nodes was not included in this analysis, but the primary surgeon in this study was no longer in the learning phase of the procedure. Therefore, we would not expect a significant change in this variable over time. As our study and others have shown, extracapsular invasion is associated with a significant risk of positive nonsentinel nodes. In our practice, this remains an indication for a completion axillary lymph node dissection. If a patient has a small favorable tumor with a solitary micrometastases and additional negative sentinel lymph nodes, the risks/benefits of observation versus completion axillary lymph node dissection are discussed with the patient. Elimination of a completion axillary lymph node dissection in this subset of patients remains controversial. A completion axillary lymph node dissection was not performed if the sentinel lymph nodes were negative. However, a trial of 30 sentinel lymph node biopsies with completion axillary lymph node dissection was performed by this surgeon before initiating routine sentinel lymph node biopsy. There were no false-negatives in this series of 30 patients. In this author’s series of patients who had sentinel lymph node biopsy without axillary lymph node dissection, there has been no axillary recurrence.