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The clinical relevance of positive sentinel nodes only versus positive nonsentinel lymph nodes in breast cancer patients
The American Journal of Surgery 186 (2003) 333–336
Scientific paper
The clinical relevance of positive sentinel nodes only versus positive nonsentinel lymph nodes in breast cancer patients Charles Cox, M.D.a,*, Elisabeth L. DuPont, M.D.a, Ben Furman, M.D.a, Nicholas Stowella, John Clarka, Mark Eberta, Nils M. Diaz, M.D.a, Alan Cantor, Ph.D.b a
Department of Surgery, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, 12902 Magnolia Dr., Suite 3157, Tampa, FL 33612, USA b Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA Manuscript received June 3, 2003; revised manuscript June 21, 2003 Presented at the Fourth Annual Meeting of the American Society of Breast Surgeons, Atlanta, Georgia, April 30 –May 4, 2003
Abstract Background: The purpose of this study was to determine the difference in clinical outcomes for patients with histologically positive sentinel lymph nodes (SLN⫹) compared with patients with histologically positive nonsentinel second echelon lymph nodes (NSLN⫹). Methods: Eight hundred thirteen node positive patients from a prospectively accrued database of 3,200 patients who underwent sentinel node mapping were evaluated. In all, 506 of the 813 patients (62%) were SLN⫹ only and 307 of the 813 patients (38%) were SLN⫹ plus at least one NSLN⫹. Patients’ overall survival and disease-free survival were obtained and statistical analyses performed comparing the two groups. Results: As the number of NSLN⫹ increased, there was a significant difference in disease-free survival (P ⫽ 0.001) and overall survival (P ⫽ 0.003) between those patients who had 0 to 4 NSLN⫹ and those who had 5 or more NSLN⫹. The SLN⫹ only patients did not show significant differences with respect to survival, based on the number of SLN⫹ (overall survival, disease-free survival; P ⫽ 0.742) Conclusions: The survival (overall survival, disease-free survival) for patients with 3 or more SLN⫹ was not statistically different than for patients with 1 or 2 SLN⫹ (P ⫽ 0.742). However, an alteration of biologic behavior was observed when multiple NSLN⫹ contain metastatic breast cancer. Involvement of 5 or more NSLN⫹ portends a significantly (P ⫽ 0.001) worse prognosis, regardless of the number of SLN⫹. © 2003 Excerpta Medica, Inc. All rights reserved. Keywords: Sentinel lymph nodes; Nonsentinel lymph nodes; Outcome; Prognosis; Breast cancer; Recurrence; Lymphatic mapping
The staging and diagnosis of breast cancer has been changed owing to the increased use of lymphatic mapping and the relevance of the sentinel lymph node. The current standard of care for patients being surgically treated for breast cancer by either lumpectomy or mastectomy includes lymphatic mapping employing a blue dye, radiocolloid or a combination of both. Lymph nodes that are the primary or first nodes in the pathway to the regional basin are sentinel lymph nodes (SLN) and exhibit either a blue stain or a sufficiently high radioactive count. These lymph nodes are then pathologically analyzed using immunohistochemistry or standard histological stain* Corresponding author. Tel.: ⫹1-813-972-8480; fax: ⫹1-813-9797287. E-mail address: [email protected]
ing (hematoxylin and eosin). Turner et al [1,2] have demonstrated the validity of the sentinel node theory by confirming with exhaustive nodal analysis that a negative sentinel node is highly predictive of the remaining axillary nodes being negative. Other studies report that there have been no axillary recurrences in patients who had negative pathological findings of the SLNs [3,4]. When the SLN is positive other nodes in the basin may be involved in as many as 40% of the patients [5,6]. Studies have demonstrated downregulation of various immunologic functions of SLNs [7]. The question then arises, is there some biologic difference for those patients in whom the SLNs are the only positive nodes as compared with those who have second echelon nodes involved? The recent implementation of lymphatic mapping techniques, along with its incremental improvement in detection of nodal disease has raised
0002-9610/03/$ – see front matter © 2003 Excerpta Medica, Inc. All rights reserved. doi:10.1016/S0002-9610(03)00266-6
334
B. Furman et al. / The American Journal of Surgery 186 (2003) 333–336
Fig. 1. Overall survival for all patients with positive sentinel lymph nodes depending on the number of positive sentinel lymph nodes.
many questions regarding predicted outcomes. Research comparing the long-term survival of patients with respect to the number of positive lymph nodes, either sentinel or nonsentinel, may reflect new survival trends based on these new data. This “Will Rogers effect” inevitably will be seen in the measured outcomes of breast cancer care for all stages of the disease. Van der wal et al [8] describe that 10-year survival decreases for patients who have a lymph node ratio (LNR) of invaded/ removed lymph nodes of more than 0.2 compared with those who have a LNR less than 0.2. These data imply that increased involvement of the axilla by metastatic tumor portends a much poorer prognosis and is used to justify a more thorough removal of axillary nodes. However, one may now ask the question whether clinical outcome is changed based on the number of positive sentinel (SLN⫹) or nonsentinel (NSLN⫹) nodes?
Methods More than 3,200 patients have undergone lymphatic mapping using the combination technique at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, from 1997 to 2002. Under the provisions of an Institutional Review Board approved protocol to review the de-identified HIPPA compliant breast cancer data from the Moffitt breast cancer database and the Moffitt tumor registry, 813 patients (25.4%) were assessed and found to have metastatic involvement of at least one sentinel lymph node. In all, 506 of 813 patients (62%) had positive SLNs only while 307 of 813 (38%) had both positive SLN and NSLN.
Recurrence data were collected for all patients along with vital status information and the date of the last follow-up. These data were collected to assess overall survival and disease-free survival for patients depending on lymph node status. The two sets of patients were broken down into subsets, which separated patients on the basis of the exact number of SLN⫹ or NSLN⫹.
Results The SLN⫹ only group was compared with the SLN⫹, NSLN⫹ group to see if there was a difference in survival depending on the type of lymph nodes involved. There was no statistical difference in survival between these two groups. The number of positive SLNs in the SLN⫹ only group ranged from 1 to 9. This set was broken down into three subsets. The first subset included those patients with only 1 SLN⫹; the second with only 2 SLN⫹; and the third subset included those with 3 or more SLN⫹. A KaplanMeier graph shows that overall survival does not differ significantly as the number of SLN⫹ increases (P ⫽ 0.742; Fig. 1). Multiple analyses were performed to test the difference, if any, between the different subsets based on the numbers of SLN⫹ versus NSLN⫹ (ie, 1SLN⫹ 1NSLN⫹ versus 2SLN⫹; 2SLN⫹ 2NSLN⫹ versus 4 SLN⫹, and so forth). A Kaplan-Meier graph shows that there appears to be a threshold number of NSLN⫹ where patient prognosis worsens. There is a significant difference in the 5-year disease free survival of patients who have 0-4 NSLN⫹ (91% ⫾ 3%)
B. Furman et al. / The American Journal of Surgery 186 (2003) 333–336
335
Fig. 2. Disease-free survival for the 0 to 4 postitive nonsentinel lymph nodes (NSLN⫹) group and for the 5 or more NSLN⫹ group.
and those who have 5 or more NSLN⫹ (68% ⫾ 8%; P ⫽ 0.001; Fig. 2). These findings were also confirmed for the 5-year overall survival (91 ⫾ 3% versus 70 ⫾ 9%; P ⫽ 0.003; Fig. 3). The average number of SLN⫹ for the 0-4 NSLN⫹ (n ⫽ 725) group was 1.58 ⫾ 0.77 and the average number of SLN⫹ for the 5 or more NSLN⫹ group (n ⫽ 88) was 1.66 ⫾ 0.88. The difference in SLN⫹ in these two groups was not significant (P ⫽ 0.27).
Comments The results of our study show that once a patient reaches a certain threshold of positive NSLN⫹ their prognosis is significantly poorer, regardless of the number of SLN⫹. Moreover, there is no statistically significant difference in the survival of patients with 1, 2, or 3 or more SLN⫹ (Fig. 1).
Fig. 3. Overall survival for the 0 to 4 postitive nonsentinel lymph nodes (NSLN⫹) group and for the 5 or more NSLN⫹ group.
336
B. Furman et al. / The American Journal of Surgery 186 (2003) 333–336
From a clinical perspective there is an improved prognosis if a patient has a higher ratio of SLN⫹ compared with NSLN⫹. The increase in incidence of recurrence in patients with NSLN⫹ may be due to the fact that the primary breast cancer has passed the first echelon (the sentinel nodes), and is now involving a second echelon node (the nonsentinel nodes), which in turn suggests that the cancer is more likely to spread systemically to other organs. Furthermore, an alteration of biologic behavior with respect to immune activity may be occurring that allows the nonsentinel nodes to become hospitable for metastatic disease.[7] The role of the nonsentinel nodes in the prognosis of patients with breast cancer is important. Total numbers of positive nodes need to be evaluated and more intense treatment options may be necessary for patients with 5 or more NSLN⫹. It appears that the status of the nonsentinel nodes may be more predictive of a worse outcome than the status of the sentinel lymph nodes. It is felt that the metastatic involvement of the second echelon nodes portends a higher risk of distant tumor metastasis in that patient, as well as a poorer overall survival outcome. Perhaps an even more powerful statement can be made from these analyses regarding sentinel node status. That is, that regardless of the number of positive sentinel nodes that exist there appears to be little if any alteration in long-term survival (overall survival or disease-free survival). If indeed this observation withstands the scrutiny of long-term multiinstitutional trials it would represent a significant paradigm shift in the way chemotherapeutic trials are conducted worldwide. Indeed, studies of 4 to 9 positive node disease would have to be stratified as to whether the positive nodes were sentinel or nonsentinel. Patients in those studies
with 4 to 9 positive sentinel nodes may be the only longterm survivors independent of the chemotherapy they have received based solely upon their improved prognostic category. Accurate staging based upon sentinel node status may set a new paradigm for adjuvant therapy in breast cancer care. References [1] Canavese G, Gipponi M, Catturich A, et al. Sentinel lymph node mapping in early-stage breast cancer: technical issues and results with vital blue dye mapping and radioguided surgery. J Surg Oncol 2000; 74:61– 8. [2] Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999;91:368 –73. [3] Shivers S, Cox C, Leight G, et al. Final results of the Department of Defense multicenter breast lymphatic mapping trial. Ann Surg Oncol 2002;9:248 –55. [4] Hansen NM, Grube BJ, Giuliano AE. The time has come to change the algorithm for the surgical management of early breast cancer. Arch Surg 2002;137:1131–5. [5] Abdessalam SF, Zervos EE, Prasad M, et al. Predictors of positive axillary lymph nodes after sentinel lymph node biopsy in breast cancer. Am J Surg 2001;182:316 –20. [6] Weaver DL, Krag DN, Ashikaga T, et al. Pathologic analysis of sentinel and nonsentinel lymph nodes in breast carcinoma: a multicenter study. Cancer 2000;88:1099 –107. [7] Cochran AJ, Morton DL, Stern S, et al. Sentinel lymph nodes show profound downregualtion of antigen-presenting cells of the paracortex: implications for tumorbiology and treatment. Mod Pathol 2001;14: 604 – 8. [8] Van der Wal BC, Butzelaar RM, van der Meij S, et al. Axillary lymph node ratio and total number of removed lymph nodes: predictors of survival in stage I and II breast cancer. Eur J Surg Oncol 2002;28: 481–9.
Scientific paper
The clinical relevance of positive sentinel nodes only versus positive nonsentinel lymph nodes in breast cancer patients Charles Cox, M.D.a,*, Elisabeth L. DuPont, M.D.a, Ben Furman, M.D.a, Nicholas Stowella, John Clarka, Mark Eberta, Nils M. Diaz, M.D.a, Alan Cantor, Ph.D.b a
Department of Surgery, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, 12902 Magnolia Dr., Suite 3157, Tampa, FL 33612, USA b Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida, Tampa, FL, USA Manuscript received June 3, 2003; revised manuscript June 21, 2003 Presented at the Fourth Annual Meeting of the American Society of Breast Surgeons, Atlanta, Georgia, April 30 –May 4, 2003
Abstract Background: The purpose of this study was to determine the difference in clinical outcomes for patients with histologically positive sentinel lymph nodes (SLN⫹) compared with patients with histologically positive nonsentinel second echelon lymph nodes (NSLN⫹). Methods: Eight hundred thirteen node positive patients from a prospectively accrued database of 3,200 patients who underwent sentinel node mapping were evaluated. In all, 506 of the 813 patients (62%) were SLN⫹ only and 307 of the 813 patients (38%) were SLN⫹ plus at least one NSLN⫹. Patients’ overall survival and disease-free survival were obtained and statistical analyses performed comparing the two groups. Results: As the number of NSLN⫹ increased, there was a significant difference in disease-free survival (P ⫽ 0.001) and overall survival (P ⫽ 0.003) between those patients who had 0 to 4 NSLN⫹ and those who had 5 or more NSLN⫹. The SLN⫹ only patients did not show significant differences with respect to survival, based on the number of SLN⫹ (overall survival, disease-free survival; P ⫽ 0.742) Conclusions: The survival (overall survival, disease-free survival) for patients with 3 or more SLN⫹ was not statistically different than for patients with 1 or 2 SLN⫹ (P ⫽ 0.742). However, an alteration of biologic behavior was observed when multiple NSLN⫹ contain metastatic breast cancer. Involvement of 5 or more NSLN⫹ portends a significantly (P ⫽ 0.001) worse prognosis, regardless of the number of SLN⫹. © 2003 Excerpta Medica, Inc. All rights reserved. Keywords: Sentinel lymph nodes; Nonsentinel lymph nodes; Outcome; Prognosis; Breast cancer; Recurrence; Lymphatic mapping
The staging and diagnosis of breast cancer has been changed owing to the increased use of lymphatic mapping and the relevance of the sentinel lymph node. The current standard of care for patients being surgically treated for breast cancer by either lumpectomy or mastectomy includes lymphatic mapping employing a blue dye, radiocolloid or a combination of both. Lymph nodes that are the primary or first nodes in the pathway to the regional basin are sentinel lymph nodes (SLN) and exhibit either a blue stain or a sufficiently high radioactive count. These lymph nodes are then pathologically analyzed using immunohistochemistry or standard histological stain* Corresponding author. Tel.: ⫹1-813-972-8480; fax: ⫹1-813-9797287. E-mail address: [email protected]
ing (hematoxylin and eosin). Turner et al [1,2] have demonstrated the validity of the sentinel node theory by confirming with exhaustive nodal analysis that a negative sentinel node is highly predictive of the remaining axillary nodes being negative. Other studies report that there have been no axillary recurrences in patients who had negative pathological findings of the SLNs [3,4]. When the SLN is positive other nodes in the basin may be involved in as many as 40% of the patients [5,6]. Studies have demonstrated downregulation of various immunologic functions of SLNs [7]. The question then arises, is there some biologic difference for those patients in whom the SLNs are the only positive nodes as compared with those who have second echelon nodes involved? The recent implementation of lymphatic mapping techniques, along with its incremental improvement in detection of nodal disease has raised
0002-9610/03/$ – see front matter © 2003 Excerpta Medica, Inc. All rights reserved. doi:10.1016/S0002-9610(03)00266-6
334
B. Furman et al. / The American Journal of Surgery 186 (2003) 333–336
Fig. 1. Overall survival for all patients with positive sentinel lymph nodes depending on the number of positive sentinel lymph nodes.
many questions regarding predicted outcomes. Research comparing the long-term survival of patients with respect to the number of positive lymph nodes, either sentinel or nonsentinel, may reflect new survival trends based on these new data. This “Will Rogers effect” inevitably will be seen in the measured outcomes of breast cancer care for all stages of the disease. Van der wal et al [8] describe that 10-year survival decreases for patients who have a lymph node ratio (LNR) of invaded/ removed lymph nodes of more than 0.2 compared with those who have a LNR less than 0.2. These data imply that increased involvement of the axilla by metastatic tumor portends a much poorer prognosis and is used to justify a more thorough removal of axillary nodes. However, one may now ask the question whether clinical outcome is changed based on the number of positive sentinel (SLN⫹) or nonsentinel (NSLN⫹) nodes?
Methods More than 3,200 patients have undergone lymphatic mapping using the combination technique at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, from 1997 to 2002. Under the provisions of an Institutional Review Board approved protocol to review the de-identified HIPPA compliant breast cancer data from the Moffitt breast cancer database and the Moffitt tumor registry, 813 patients (25.4%) were assessed and found to have metastatic involvement of at least one sentinel lymph node. In all, 506 of 813 patients (62%) had positive SLNs only while 307 of 813 (38%) had both positive SLN and NSLN.
Recurrence data were collected for all patients along with vital status information and the date of the last follow-up. These data were collected to assess overall survival and disease-free survival for patients depending on lymph node status. The two sets of patients were broken down into subsets, which separated patients on the basis of the exact number of SLN⫹ or NSLN⫹.
Results The SLN⫹ only group was compared with the SLN⫹, NSLN⫹ group to see if there was a difference in survival depending on the type of lymph nodes involved. There was no statistical difference in survival between these two groups. The number of positive SLNs in the SLN⫹ only group ranged from 1 to 9. This set was broken down into three subsets. The first subset included those patients with only 1 SLN⫹; the second with only 2 SLN⫹; and the third subset included those with 3 or more SLN⫹. A KaplanMeier graph shows that overall survival does not differ significantly as the number of SLN⫹ increases (P ⫽ 0.742; Fig. 1). Multiple analyses were performed to test the difference, if any, between the different subsets based on the numbers of SLN⫹ versus NSLN⫹ (ie, 1SLN⫹ 1NSLN⫹ versus 2SLN⫹; 2SLN⫹ 2NSLN⫹ versus 4 SLN⫹, and so forth). A Kaplan-Meier graph shows that there appears to be a threshold number of NSLN⫹ where patient prognosis worsens. There is a significant difference in the 5-year disease free survival of patients who have 0-4 NSLN⫹ (91% ⫾ 3%)
B. Furman et al. / The American Journal of Surgery 186 (2003) 333–336
335
Fig. 2. Disease-free survival for the 0 to 4 postitive nonsentinel lymph nodes (NSLN⫹) group and for the 5 or more NSLN⫹ group.
and those who have 5 or more NSLN⫹ (68% ⫾ 8%; P ⫽ 0.001; Fig. 2). These findings were also confirmed for the 5-year overall survival (91 ⫾ 3% versus 70 ⫾ 9%; P ⫽ 0.003; Fig. 3). The average number of SLN⫹ for the 0-4 NSLN⫹ (n ⫽ 725) group was 1.58 ⫾ 0.77 and the average number of SLN⫹ for the 5 or more NSLN⫹ group (n ⫽ 88) was 1.66 ⫾ 0.88. The difference in SLN⫹ in these two groups was not significant (P ⫽ 0.27).
Comments The results of our study show that once a patient reaches a certain threshold of positive NSLN⫹ their prognosis is significantly poorer, regardless of the number of SLN⫹. Moreover, there is no statistically significant difference in the survival of patients with 1, 2, or 3 or more SLN⫹ (Fig. 1).
Fig. 3. Overall survival for the 0 to 4 postitive nonsentinel lymph nodes (NSLN⫹) group and for the 5 or more NSLN⫹ group.
336
B. Furman et al. / The American Journal of Surgery 186 (2003) 333–336
From a clinical perspective there is an improved prognosis if a patient has a higher ratio of SLN⫹ compared with NSLN⫹. The increase in incidence of recurrence in patients with NSLN⫹ may be due to the fact that the primary breast cancer has passed the first echelon (the sentinel nodes), and is now involving a second echelon node (the nonsentinel nodes), which in turn suggests that the cancer is more likely to spread systemically to other organs. Furthermore, an alteration of biologic behavior with respect to immune activity may be occurring that allows the nonsentinel nodes to become hospitable for metastatic disease.[7] The role of the nonsentinel nodes in the prognosis of patients with breast cancer is important. Total numbers of positive nodes need to be evaluated and more intense treatment options may be necessary for patients with 5 or more NSLN⫹. It appears that the status of the nonsentinel nodes may be more predictive of a worse outcome than the status of the sentinel lymph nodes. It is felt that the metastatic involvement of the second echelon nodes portends a higher risk of distant tumor metastasis in that patient, as well as a poorer overall survival outcome. Perhaps an even more powerful statement can be made from these analyses regarding sentinel node status. That is, that regardless of the number of positive sentinel nodes that exist there appears to be little if any alteration in long-term survival (overall survival or disease-free survival). If indeed this observation withstands the scrutiny of long-term multiinstitutional trials it would represent a significant paradigm shift in the way chemotherapeutic trials are conducted worldwide. Indeed, studies of 4 to 9 positive node disease would have to be stratified as to whether the positive nodes were sentinel or nonsentinel. Patients in those studies
with 4 to 9 positive sentinel nodes may be the only longterm survivors independent of the chemotherapy they have received based solely upon their improved prognostic category. Accurate staging based upon sentinel node status may set a new paradigm for adjuvant therapy in breast cancer care. References [1] Canavese G, Gipponi M, Catturich A, et al. Sentinel lymph node mapping in early-stage breast cancer: technical issues and results with vital blue dye mapping and radioguided surgery. J Surg Oncol 2000; 74:61– 8. [2] Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series. J Natl Cancer Inst 1999;91:368 –73. [3] Shivers S, Cox C, Leight G, et al. Final results of the Department of Defense multicenter breast lymphatic mapping trial. Ann Surg Oncol 2002;9:248 –55. [4] Hansen NM, Grube BJ, Giuliano AE. The time has come to change the algorithm for the surgical management of early breast cancer. Arch Surg 2002;137:1131–5. [5] Abdessalam SF, Zervos EE, Prasad M, et al. Predictors of positive axillary lymph nodes after sentinel lymph node biopsy in breast cancer. Am J Surg 2001;182:316 –20. [6] Weaver DL, Krag DN, Ashikaga T, et al. Pathologic analysis of sentinel and nonsentinel lymph nodes in breast carcinoma: a multicenter study. Cancer 2000;88:1099 –107. [7] Cochran AJ, Morton DL, Stern S, et al. Sentinel lymph nodes show profound downregualtion of antigen-presenting cells of the paracortex: implications for tumorbiology and treatment. Mod Pathol 2001;14: 604 – 8. [8] Van der Wal BC, Butzelaar RM, van der Meij S, et al. Axillary lymph node ratio and total number of removed lymph nodes: predictors of survival in stage I and II breast cancer. Eur J Surg Oncol 2002;28: 481–9.