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Increased sampling will lead to an increase in detection, but is it clinically relevant?
European Journal of Cancer (2012) 48, 2486– 2487
Available at www.sciencedirect.com
journal homepage: www.ejconline.com
Letter to the Editor
Increased sampling will lead to an increase in detection, but is it clinically relevant? Rikke Riber-Hansen a,⇑, Nina Hastrup b, Ole Clemmensen c, Mette Ramsing a, Stephen Jacques Hamilton-Dutoit a, Torben Steiniche d a
Institute of Pathology, Aarhus University Hospital, Noerrebrogade 44, DK-8000 Aarhus C, Denmark Department of Pathology, Rigshospitalet, Frederik V’s Vej 11, DK-2100 Copenhagen O, Denmark c Department of Clinical Pathology, Odense University Hospital, Winsloewparken 15, DK-5000 Odense C, Denmark d Department of Pathology, Vejle Hospital, Kabbeltoft 25, DK-7100 Vejle, Denmark b
In response: We are grateful that Dr. van Akkooi and colleagues have taken time to comment on our recent study on melanoma metastases in sentinel lymph nodes (SLNs),1 and that this gives us an opportunity to discuss their concerns about apparent confusions in our paper, particularly regarding the number of sections recommended in the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group (MG) histological protocol. The correspondents believe there is a misunderstanding in our use of steps and levels, claiming a step to be the distance between two levels. They are naturally free to choose to apply these terms in that way. However, there is clearly no semantic obligation to do so. By analogy with a ladder or staircase, a step can refer both to a vertical distance and to a horizontal level. We have used step, step-section and level synonymously. A more important point is their claim that there is a contradiction in our paper regarding the number of sections we used in our comparisons with the EORTC protocol. Here there may be room for confusion. However, while we may not have explained the root of this problem clearly, the confusion springs primarily from ⇑ Corresponding author: Tel.: +45 78 46 74 78; fax: +45 78 46 74 99.
E-mail address: [email protected] (R. Riber-Hansen). 0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.03.024
variations in the recommended EORTC protocols themselves. The aim of our study was, as described, to investigate the SLN protocol-dependent bias for patient inclusion in actual treatment trials, such as the EORTC 18071 trial of adjuvant anti-CTLA-4 monoclonal antibody (Ipilimumab). It is true that the EORTC MG originally recommended a protocol of six levels, 50 lm apart.2 However, the protocol described for the EORTC 18071 trial (Version 1.1, 18 February, 2008; Appendix J, p. 147–148) uses only five levels, 50 lm apart (Fig. 1). Following the introduction of the EORTC 18071 trial, it is this most recent EORTC protocol variant that has been adopted as the national protocol in Denmark, and that we have used for comparison in our work. In practice, we added a sixth 50 lm level in our study (in order to be able to continue thereafter with levels at 250 lm intervals according to our ‘extensive protocol’). However, this sixth level was not included in our analysis as part of the EORTC MG protocol. In fact, had we included this level in the EORTC analysis, only minor changes would have resulted. Thus, one of the eight patients with metastases missed by the five-level protocol would have been detected by a six-level protocol. The size of this parenchymal metastasis was 0.09 mm in the sixth level, while subsequent step-sectioning showed a size of 0.28 mm, again shifting one patient from possible MINITUB trial inclusion to completion
R. Riber-Hansen et al. / European Journal of Cancer 48 (2012) 2486–2487
2487
that they actually prove the value of this procedure in patients with small metastases, in effect converting them to a course of disease comparable with SLN negative patients. Without reliable evidence we cannot know. Finally, the claim that increased sampling will never reduce the detected tumour load is a truth with modification. While it is true that adding levels will never convert a SLN positive patient to be SLN negative, the same does not always apply when estimating metastasis size. It is correct that examining a different region of the SLN than originally studied will only ever maintain or increase an estimate of metastasis size. However, if complete step-sectioning and stereologically based volume estimates are used,7 adding levels in-between the original levels will increase precision and may in fact result in a lower metastasis volume estimate than originally achieved. In contrast, the metastasis diameter measurement will only ever increase or stay the same. This is one reason why we continue to strive for optimal size estimates, based on combined stereology and digital image analysis, to be applied in all areas of pathology. We believe this to be the path to pathology protocols that are not only evidence based, but also both practical and cost-effective. For now, we continue to recommend a protocol of complete step-sectioning for melanoma SLNs – i.e. five or six levels at defined distances evenly spaced throughout the lymph node. Conflict of interest statement Fig. 1. EORTC 18071 trail sentinel lymph node histological protocol.
lymph node dissection. As for the change in metastasis diameter, two patients ineligible for the EORTC 18071 trial in the five-level version would have been eligible using the six-level version. In fact, the sixth level was the only level with a metastasis diameter above 1 mm for both these patients. However, this observation is largely irrelevant, given that the EORTC 18071 trial uses the five-level protocol. What then is the clinical importance of metastases detected only in the periphery of SLNs, and missed by EORTC protocols? The correspondents question the clinical relevance of detecting these tumours. However, seven of the eight patients with metastases in our study missed by the five-level EORTC MG protocol had metastases above the 0.1 mm threshold that is suggested by the EORTC MG as the level defining probable clinical relevance. We agree with Dr. van Akkooi and colleagues that pathology protocols should be evidence based. Indeed, the EORTC MG has published a number of studies that aimed to test the significance of metastases below the 0.1 mm limit.3–6 However, none of these studies have been randomised trials of treatment versus no treatment. All have been retrospective studies of patients treated with completion lymph node dissection, regardless of metastasis size. Thus, it could be argued
None declared. References 1. Riber-Hansen R, Hastrup N, Clemmensen O, et al. Treatment influencing down-staging in EORTC Melanoma Group sentinel node histological protocol compared with complete step-sectioning: a national multicentre study. Eur J Cancer 2012;48(3):347–52. 2. Cook MG, Green MA, Anderson B, et al. The development of optimal pathological assessment of sentinel lymph nodes for melanoma. J Pathol 2003;200(3):314–9. 3. van Akkooi A, de WJ, Verhoef C, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol 2006;17(10):1578–85. 4. van Akkooi AC, Nowecki ZI, Voit C, et al. Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. Ann Surg 2008;248(6):949–55. 5. van der Ploeg AP, van Akkooi AC, Schmitz PI, Koljenovic S, Verhoef C, Eggermont AM. EORTC Melanoma Group sentinel node protocol identifies high rate of submicrometastases according to Rotterdam Criteria. Eur J Cancer 2010;46(13):2414–21. 6. van der Ploeg AP, van Akkooi AC, Rutkowski P, et al. Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria. J Clin Oncol 2011;29(16):2206–14. 7. Riber-Hansen R, Nyengaard JR, Hamilton-Dutoit SJ, Steiniche T. Stage migration after minor changes in histologic estimation of tumor burden in sentinel lymph nodes: the protocol trap. Cancer 2009;115(10):2177–87.
Available at www.sciencedirect.com
journal homepage: www.ejconline.com
Letter to the Editor
Increased sampling will lead to an increase in detection, but is it clinically relevant? Rikke Riber-Hansen a,⇑, Nina Hastrup b, Ole Clemmensen c, Mette Ramsing a, Stephen Jacques Hamilton-Dutoit a, Torben Steiniche d a
Institute of Pathology, Aarhus University Hospital, Noerrebrogade 44, DK-8000 Aarhus C, Denmark Department of Pathology, Rigshospitalet, Frederik V’s Vej 11, DK-2100 Copenhagen O, Denmark c Department of Clinical Pathology, Odense University Hospital, Winsloewparken 15, DK-5000 Odense C, Denmark d Department of Pathology, Vejle Hospital, Kabbeltoft 25, DK-7100 Vejle, Denmark b
In response: We are grateful that Dr. van Akkooi and colleagues have taken time to comment on our recent study on melanoma metastases in sentinel lymph nodes (SLNs),1 and that this gives us an opportunity to discuss their concerns about apparent confusions in our paper, particularly regarding the number of sections recommended in the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group (MG) histological protocol. The correspondents believe there is a misunderstanding in our use of steps and levels, claiming a step to be the distance between two levels. They are naturally free to choose to apply these terms in that way. However, there is clearly no semantic obligation to do so. By analogy with a ladder or staircase, a step can refer both to a vertical distance and to a horizontal level. We have used step, step-section and level synonymously. A more important point is their claim that there is a contradiction in our paper regarding the number of sections we used in our comparisons with the EORTC protocol. Here there may be room for confusion. However, while we may not have explained the root of this problem clearly, the confusion springs primarily from ⇑ Corresponding author: Tel.: +45 78 46 74 78; fax: +45 78 46 74 99.
E-mail address: [email protected] (R. Riber-Hansen). 0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2012.03.024
variations in the recommended EORTC protocols themselves. The aim of our study was, as described, to investigate the SLN protocol-dependent bias for patient inclusion in actual treatment trials, such as the EORTC 18071 trial of adjuvant anti-CTLA-4 monoclonal antibody (Ipilimumab). It is true that the EORTC MG originally recommended a protocol of six levels, 50 lm apart.2 However, the protocol described for the EORTC 18071 trial (Version 1.1, 18 February, 2008; Appendix J, p. 147–148) uses only five levels, 50 lm apart (Fig. 1). Following the introduction of the EORTC 18071 trial, it is this most recent EORTC protocol variant that has been adopted as the national protocol in Denmark, and that we have used for comparison in our work. In practice, we added a sixth 50 lm level in our study (in order to be able to continue thereafter with levels at 250 lm intervals according to our ‘extensive protocol’). However, this sixth level was not included in our analysis as part of the EORTC MG protocol. In fact, had we included this level in the EORTC analysis, only minor changes would have resulted. Thus, one of the eight patients with metastases missed by the five-level protocol would have been detected by a six-level protocol. The size of this parenchymal metastasis was 0.09 mm in the sixth level, while subsequent step-sectioning showed a size of 0.28 mm, again shifting one patient from possible MINITUB trial inclusion to completion
R. Riber-Hansen et al. / European Journal of Cancer 48 (2012) 2486–2487
2487
that they actually prove the value of this procedure in patients with small metastases, in effect converting them to a course of disease comparable with SLN negative patients. Without reliable evidence we cannot know. Finally, the claim that increased sampling will never reduce the detected tumour load is a truth with modification. While it is true that adding levels will never convert a SLN positive patient to be SLN negative, the same does not always apply when estimating metastasis size. It is correct that examining a different region of the SLN than originally studied will only ever maintain or increase an estimate of metastasis size. However, if complete step-sectioning and stereologically based volume estimates are used,7 adding levels in-between the original levels will increase precision and may in fact result in a lower metastasis volume estimate than originally achieved. In contrast, the metastasis diameter measurement will only ever increase or stay the same. This is one reason why we continue to strive for optimal size estimates, based on combined stereology and digital image analysis, to be applied in all areas of pathology. We believe this to be the path to pathology protocols that are not only evidence based, but also both practical and cost-effective. For now, we continue to recommend a protocol of complete step-sectioning for melanoma SLNs – i.e. five or six levels at defined distances evenly spaced throughout the lymph node. Conflict of interest statement Fig. 1. EORTC 18071 trail sentinel lymph node histological protocol.
lymph node dissection. As for the change in metastasis diameter, two patients ineligible for the EORTC 18071 trial in the five-level version would have been eligible using the six-level version. In fact, the sixth level was the only level with a metastasis diameter above 1 mm for both these patients. However, this observation is largely irrelevant, given that the EORTC 18071 trial uses the five-level protocol. What then is the clinical importance of metastases detected only in the periphery of SLNs, and missed by EORTC protocols? The correspondents question the clinical relevance of detecting these tumours. However, seven of the eight patients with metastases in our study missed by the five-level EORTC MG protocol had metastases above the 0.1 mm threshold that is suggested by the EORTC MG as the level defining probable clinical relevance. We agree with Dr. van Akkooi and colleagues that pathology protocols should be evidence based. Indeed, the EORTC MG has published a number of studies that aimed to test the significance of metastases below the 0.1 mm limit.3–6 However, none of these studies have been randomised trials of treatment versus no treatment. All have been retrospective studies of patients treated with completion lymph node dissection, regardless of metastasis size. Thus, it could be argued
None declared. References 1. Riber-Hansen R, Hastrup N, Clemmensen O, et al. Treatment influencing down-staging in EORTC Melanoma Group sentinel node histological protocol compared with complete step-sectioning: a national multicentre study. Eur J Cancer 2012;48(3):347–52. 2. Cook MG, Green MA, Anderson B, et al. The development of optimal pathological assessment of sentinel lymph nodes for melanoma. J Pathol 2003;200(3):314–9. 3. van Akkooi A, de WJ, Verhoef C, et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol 2006;17(10):1578–85. 4. van Akkooi AC, Nowecki ZI, Voit C, et al. Sentinel node tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. Ann Surg 2008;248(6):949–55. 5. van der Ploeg AP, van Akkooi AC, Schmitz PI, Koljenovic S, Verhoef C, Eggermont AM. EORTC Melanoma Group sentinel node protocol identifies high rate of submicrometastases according to Rotterdam Criteria. Eur J Cancer 2010;46(13):2414–21. 6. van der Ploeg AP, van Akkooi AC, Rutkowski P, et al. Prognosis in patients with sentinel node-positive melanoma is accurately defined by the combined Rotterdam tumor load and Dewar topography criteria. J Clin Oncol 2011;29(16):2206–14. 7. Riber-Hansen R, Nyengaard JR, Hamilton-Dutoit SJ, Steiniche T. Stage migration after minor changes in histologic estimation of tumor burden in sentinel lymph nodes: the protocol trap. Cancer 2009;115(10):2177–87.