LETTER TO THE EDITOR Is the Effectiveness of Sentinel Lymph Node Intraoperative Examination Proven? To the Editor: e read with interest the article by Taffurelli et al,1 “Effectiveness of Sentinel Lymph Node Intraoperative Examination in 753 Women With Breast Cancer: Are We Overtreating Patients?” Although the authors have to be commended for their attempt to justify a less aggressive but equally effective surgical treatment, several concerns are raised when considering the limitations of the results of this study, retrospective in its nature. We also have concerns regarding the analysis of the results and the conclusions. The generalizability of these results is questionable. Although large, the database and the results seem a heterogeneous sum of several different histotypes of breast cancer (we assume that they have included infiltrating ductal carcinomas, infiltrating lobular carcinomas, and ductal carcinoma in situ with high Van Nuys prognostic index score, but this has not been specified in the methods). This means including in the analysis of the results several different varieties of breast cancer, including lesions of any stage up to T2, any grade, any biological features, and patients of any age. Furthermore, the number of sentinel lymph nodes (SLNs) detected, the number of positive SLNs, and the occurrence of extranodal extent have not been reported, nor have these been considered in the interpretation of the results. The authors did not specify the histological subtypes. Clearly, lobular histology would make the value of frozen section (FS) analysis much more questionable. Furthermore, it would be extremely important to analyze the number of patients with metastatic non-SLN according to the other parameters well known to contribute to it, such as the number of SLNs identified (P < 0.001), the number of positive SLNs (P < 0.001), SLN metastasis size (P < 0.001), extranodal extension (P < 0.001), tumor size (P = 0.001), lymphovascular invasion (P = 0.019), and histology (P = 0.034).2 None of these factors have been analyzed with regard to their distribution within
W
Disclosure: All authors have seen and approved this version of the manuscript. The authors declare no conflicts of interest. C 2013 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/13/25904-e0069 DOI: 10.1097/SLA.0000000000000472
the patient population, and a stratification of SLN biopsy results according to the histotype of the primary lesion, staging and size, biological characteristics, and patient age is missing. The interpretation of the results of SLN biopsy in this series, in terms of the occurrence of metastases in SLNs, subsequent need of axillary lymph node dissection, and the incidence of non-SLN mets, is therefore questionable. How can recommendations be made regarding the significance of micrometastases in SLNs and eventually the benefit of subsequent axillary lymph node dissection when micrometastases are found in a patient with a high-grade ductal carcinoma in situ versus a patient presenting with infiltrating lobular carcinoma or versus another patient with infiltrating ductal carcinoma? How can a less aggressive surgical treatment option be recommended in a young patient with T2 invasive ductal carcinoma, G3, than in an older patient presenting with a T1 invasive lobular carcinoma, G1/2? Regarding the macrometastases, it would be interesting and of great benefit to compare the group identified by FS analysis with the group identified on the basis of permanent sections relative to the rate of positive non-SLNs, as it would be important to specify how many positive non-SLNs were there. When describing the 8 patients with positive non-SLN micromets, the authors do not specify any of the demographic and histological parameters in this group, for example, lobular histology or a neoadjuvant chemotherapy treatment. Neither the number nor the extent of non-SLN involvement in these patients is described. Furthermore, the overall and Mic (micrometastasis)-ITC (isolated tumor cell)– specific sensitivity rate in this series is significantly lower than that reported in the literature (roughly 20% less)3 and this performance further affects the reliability of these results. In a landmark article of a very wellconducted and precise randomized controlled trial of Veronesi et al,4 after a careful report of characteristics of the patients, side effects, and unfavorable events and deaths, the calculated overall accuracy of the sentinel node status was 96.9% and sensitivity 91.2%, far above the results of the present study. One significant difference between the 2 series is the different numbers of sections (4–6) obtained from each lymph node for intraoperative examination. This difference raises the obvious concern that with FS analysis and 4 to 6 slides, metastatic involvement of SLNs might be underdetected, possibly leading to downstaging of the intraoperative SLN biopsy status and maybe even missing non-SLN mets? A mean follow-up of 32 months in this study is extremely short to draw meaningful
Annals of Surgery r Volume 259, Number 4, April 2014
conclusions with regard to axillary recurrence and survival and to suggest a less aggressive policy. In addition, the median follow-up time of this long range (1–60 months) has not been provided. All other series from the literature suggesting such conclusions have longer followup, of at least 60 months.5 Furthermore, this series has not reported data regarding overall mortality, distant disease-free survival, or breast recurrence-free survival. The discussion regarding the number of positive non-SLNs in the Mi-ITC group is misleading and confusing. The rate of positive non-SLNs cannot be mixed up with the rate of axillary recurrence. It is not “perhaps” scientifically incorrect, it is completely incorrect. Positive non-SLNs and axillary recurrence after SLN biopsy are absolutely not identical. Many positive axillary nodes will never become symptomatic, especially not over a short follow-up period and while receiving adjuvant medical and radiation therapy. The reported rate of false-negative SLNs at FS analysis is relatively high. Seventy cases were found to have false-negative micrometastatic SLNs and 16 with falsenegative macrometastatic. Similarly, some of the SLNs diagnosed as micrometastatic or isolated tumor cell on FS analysis would have probably been upstaged to macrometastatic after final pathological examination, and recommendations based on the diagnosis of micrometastases on FS analysis become largely nonreliable and hazardous. Discordance between intraoperative FS analysis and definitive histology of SLNs is common, and in a series of 879 consecutive patients with breast cancer, a complementary axillary lymph node dissection was performed in 108 of the 151 patients with a discordant FS analysis. Additional tumorpositive axillary lymph nodes were found in 17 patients (16%), leading to “upstaging” in 7 patients (6%). Subsequent nonsurgical treatment was adjusted in 4 patients (4%).6 Finally, in Table 4, note that the accuracy is the proportion of true results (both true positives and true negatives) in the population: Accuracy = (Number of true positives + Number of true negatives) / (Number of true positives + False positives + False negatives + True negatives) whereas the sensitivity of a test is the proportion of people with a disease who test positive for it. Sensitivity = (Number of true positives) (Number of true positives www.annalsofsurgery.com | e69
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 259, Number 4, April 2014
Letter to the Editor
+ Number of false negatives) = Probability of a positive test given that the patient is ill In the table, sensitivity and accuracy, it seems, have been used synonymously and the numbers shown are for sensitivity. Salomone Di Saverio, MD, PhD Eleonora Giorgini, MD Department of Surgery Maggiore Hospital Bologna Local Health District Bologna, Italy Eli Avisar, MD, FACS Division of Surgical Oncology DeWitt Daughtry Family
e70 | www.annalsofsurgery.com
Department of Surgery University of Miami–Miller School of Medicine Miami, FL [email protected]
REFERENCES 1. Taffurelli M, Montroni I, Santini D, et al. Effectiveness of sentinel lymph node intraoperative examination in 753 women with breast cancer: are we overtreating patients? Ann Surg. 2012;255:976– 980. 2. Mittendorf EA, Hunt KK, Boughey JC, et al. Incorporation of sentinel lymph node metastasis size into a nomogram predicting nonsentinel lymph node involvement in breast cancer patients with a positive sentinel lymph node. Ann Surg. 2012;255:109–115. 3. Liu LC, Lang JE, Lu Y, et al. Intraoperative frozen section analysis of sentinel lymph nodes in
breast cancer patients: a meta-analysis and singleinstitution experience [published online ahead of print September 3, 2010]. Cancer. 2011;117:250– 258. doi:10.1002/cncr.25606. 4. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349:546–553. 5. Pernas S, Gil M, Ben´ıtez A, et al. Avoiding axillary treatment in sentinel lymph node micrometastases of breast cancer: a prospective analysis of axillary or distant recurrence. Ann Surg Oncol. 2010;17:772– 777. 6. Geertsema D, Gobardhan PD, Madsen EV, et al. Discordance of intraoperative frozen section analysis with definitive histology of sentinel lymph nodes in breast cancer surgery: complementary axillary lymph node dissection is irrelevant for subsequent systemic therapy. Ann Surg Oncol. 2010;17: 2690–2695.
C 2013 Lippincott Williams & Wilkins
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
W
Disclosure: All authors have seen and approved this version of the manuscript. The authors declare no conflicts of interest. C 2013 by Lippincott Williams & Wilkins Copyright ISSN: 0003-4932/13/25904-e0069 DOI: 10.1097/SLA.0000000000000472
the patient population, and a stratification of SLN biopsy results according to the histotype of the primary lesion, staging and size, biological characteristics, and patient age is missing. The interpretation of the results of SLN biopsy in this series, in terms of the occurrence of metastases in SLNs, subsequent need of axillary lymph node dissection, and the incidence of non-SLN mets, is therefore questionable. How can recommendations be made regarding the significance of micrometastases in SLNs and eventually the benefit of subsequent axillary lymph node dissection when micrometastases are found in a patient with a high-grade ductal carcinoma in situ versus a patient presenting with infiltrating lobular carcinoma or versus another patient with infiltrating ductal carcinoma? How can a less aggressive surgical treatment option be recommended in a young patient with T2 invasive ductal carcinoma, G3, than in an older patient presenting with a T1 invasive lobular carcinoma, G1/2? Regarding the macrometastases, it would be interesting and of great benefit to compare the group identified by FS analysis with the group identified on the basis of permanent sections relative to the rate of positive non-SLNs, as it would be important to specify how many positive non-SLNs were there. When describing the 8 patients with positive non-SLN micromets, the authors do not specify any of the demographic and histological parameters in this group, for example, lobular histology or a neoadjuvant chemotherapy treatment. Neither the number nor the extent of non-SLN involvement in these patients is described. Furthermore, the overall and Mic (micrometastasis)-ITC (isolated tumor cell)– specific sensitivity rate in this series is significantly lower than that reported in the literature (roughly 20% less)3 and this performance further affects the reliability of these results. In a landmark article of a very wellconducted and precise randomized controlled trial of Veronesi et al,4 after a careful report of characteristics of the patients, side effects, and unfavorable events and deaths, the calculated overall accuracy of the sentinel node status was 96.9% and sensitivity 91.2%, far above the results of the present study. One significant difference between the 2 series is the different numbers of sections (4–6) obtained from each lymph node for intraoperative examination. This difference raises the obvious concern that with FS analysis and 4 to 6 slides, metastatic involvement of SLNs might be underdetected, possibly leading to downstaging of the intraoperative SLN biopsy status and maybe even missing non-SLN mets? A mean follow-up of 32 months in this study is extremely short to draw meaningful
Annals of Surgery r Volume 259, Number 4, April 2014
conclusions with regard to axillary recurrence and survival and to suggest a less aggressive policy. In addition, the median follow-up time of this long range (1–60 months) has not been provided. All other series from the literature suggesting such conclusions have longer followup, of at least 60 months.5 Furthermore, this series has not reported data regarding overall mortality, distant disease-free survival, or breast recurrence-free survival. The discussion regarding the number of positive non-SLNs in the Mi-ITC group is misleading and confusing. The rate of positive non-SLNs cannot be mixed up with the rate of axillary recurrence. It is not “perhaps” scientifically incorrect, it is completely incorrect. Positive non-SLNs and axillary recurrence after SLN biopsy are absolutely not identical. Many positive axillary nodes will never become symptomatic, especially not over a short follow-up period and while receiving adjuvant medical and radiation therapy. The reported rate of false-negative SLNs at FS analysis is relatively high. Seventy cases were found to have false-negative micrometastatic SLNs and 16 with falsenegative macrometastatic. Similarly, some of the SLNs diagnosed as micrometastatic or isolated tumor cell on FS analysis would have probably been upstaged to macrometastatic after final pathological examination, and recommendations based on the diagnosis of micrometastases on FS analysis become largely nonreliable and hazardous. Discordance between intraoperative FS analysis and definitive histology of SLNs is common, and in a series of 879 consecutive patients with breast cancer, a complementary axillary lymph node dissection was performed in 108 of the 151 patients with a discordant FS analysis. Additional tumorpositive axillary lymph nodes were found in 17 patients (16%), leading to “upstaging” in 7 patients (6%). Subsequent nonsurgical treatment was adjusted in 4 patients (4%).6 Finally, in Table 4, note that the accuracy is the proportion of true results (both true positives and true negatives) in the population: Accuracy = (Number of true positives + Number of true negatives) / (Number of true positives + False positives + False negatives + True negatives) whereas the sensitivity of a test is the proportion of people with a disease who test positive for it. Sensitivity = (Number of true positives) (Number of true positives www.annalsofsurgery.com | e69
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 259, Number 4, April 2014
Letter to the Editor
+ Number of false negatives) = Probability of a positive test given that the patient is ill In the table, sensitivity and accuracy, it seems, have been used synonymously and the numbers shown are for sensitivity. Salomone Di Saverio, MD, PhD Eleonora Giorgini, MD Department of Surgery Maggiore Hospital Bologna Local Health District Bologna, Italy Eli Avisar, MD, FACS Division of Surgical Oncology DeWitt Daughtry Family
e70 | www.annalsofsurgery.com
Department of Surgery University of Miami–Miller School of Medicine Miami, FL [email protected]
REFERENCES 1. Taffurelli M, Montroni I, Santini D, et al. Effectiveness of sentinel lymph node intraoperative examination in 753 women with breast cancer: are we overtreating patients? Ann Surg. 2012;255:976– 980. 2. Mittendorf EA, Hunt KK, Boughey JC, et al. Incorporation of sentinel lymph node metastasis size into a nomogram predicting nonsentinel lymph node involvement in breast cancer patients with a positive sentinel lymph node. Ann Surg. 2012;255:109–115. 3. Liu LC, Lang JE, Lu Y, et al. Intraoperative frozen section analysis of sentinel lymph nodes in
breast cancer patients: a meta-analysis and singleinstitution experience [published online ahead of print September 3, 2010]. Cancer. 2011;117:250– 258. doi:10.1002/cncr.25606. 4. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349:546–553. 5. Pernas S, Gil M, Ben´ıtez A, et al. Avoiding axillary treatment in sentinel lymph node micrometastases of breast cancer: a prospective analysis of axillary or distant recurrence. Ann Surg Oncol. 2010;17:772– 777. 6. Geertsema D, Gobardhan PD, Madsen EV, et al. Discordance of intraoperative frozen section analysis with definitive histology of sentinel lymph nodes in breast cancer surgery: complementary axillary lymph node dissection is irrelevant for subsequent systemic therapy. Ann Surg Oncol. 2010;17: 2690–2695.
C 2013 Lippincott Williams & Wilkins
Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
