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The prognostic significance of sentinel node tumour burden in melanoma patients: An international, multicenter study of 1539 sentinel node-positive melanoma patients
European Journal of Cancer, 1, 50, pages 111 - 120
Sentinel node (SN) biopsy (SNB) and completion lymph node dissection (CLND) when SN-positive have become standard of care in most cancer centres for melanoma. Various SN tumour burden parameters are assessed to determine the heterogeneity of SN-positivity. The aim of the present study was to validate the prognostic significance of various SN tumour burden micromorphometric features and classification schemes in a large cohort of SN-positive melanoma patients.
In 1539 SN-positive patients treated between 1993 and 2008 at 11 melanoma treatment centres in Europe and Australia, indices of SN tumour burden (intranodal location, tumour penetrative depth (TPD) and maximum size of SN tumour deposits) were evaluated.
Non-subcapsular location, increasing TPD and increasing maximum size were all predictive factors for non-SN (NSN) status and were independently associated with poorer melanoma-specific survival (MSS). Patients with subcapsular micrometastases <0.1 mm in maximum dimension had the lowest frequency of NSN metastasis (5.5%). Despite differences in SN biopsy protocols and clinicopathologic features of the patient cohorts (between centres), most SN parameters remained predictive in individual centre populations. Maximum SN tumour size > 1 mm was the most reliable and consistent parameter independently associated with higher non-SN-positivity, poorer disease-free survival (DFS) and poorer MSS.
In this large retrospective, multicenter cohort study, several parameters of SN tumour burden including intranodal location, TPD and maximum size provided prognostic information, but their prognostic significance varied considerably between the different centres. This could be due to sample size limitations or to differences in SN detection, removal and examination techniques.
Keywords: Melanoma, Sentinel node biopsy, Pathology and survival.
Twenty years ago, sentinel node (SN) biopsy (SNB) was introduced as a staging technique for patients with early-stage melanoma  and . Since then, SN status has been shown to be the strongest independent prognostic factor in patients with clinically localised primary cutaneous melanoma , , , and .
First introduced in the 6th edition (2001) of the American Joint Commission on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) staging system for cutaneous melanoma, sentinel lymph node tumour burden is now established as an N1–2a staging criterion in the tumour-node-metastasis (TNM) staging system , , and . However, specific sub-groups of SN-positive patients have vastly differing survival rates, ranging from approximately 30% to over 90% , , , , , and . Patient characteristics, primary tumour and SN parameters and models for risk stratification of SN-positive patients have been assessed in numerous studies with respect to prediction of non-SN (NSN) status and survival , , , , , , , , , , and . Ideally, the parameters utilised for prognostic stratification must be easy and quick to assess and reproducible  and . The best validated prognostic SN tumour burden parameters to date are: tumour penetrative depth beneath the SN capsule, maximum size of SN tumour deposits and intranodal location of SN tumour , , , , , , , , , , , , , , and .
In recent years, the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group (MG) and Melanoma Institute Australia (MIA) have each gathered large independent datasets of SN-positive patients, assessed micromorphometric parameters of tumour in SNs and demonstrated the prognostic importance of these factors , , and . The aim of the current study was to combine the large European and Australian patient cohorts, and evaluate the prognostic significance of SN tumour burden parameters and classification schemes overall. A secondary aim was to assess and compare the predictive power of these parameters in individual melanoma treatment centres.
2. Patients and methods
Patients diagnosed between 1993 and 2008 with primary melanoma and a positive SN, at eleven melanoma treatment centres (10 EORTC MG centres in six different countries and one centre, MIA, Sydney, Australia) were studied. Patient demographics, information on previous medical history and follow-up data were collected by each centre. SN tumour burden was measured and classified by at least two of the following morphometric parameters: intranodal location (9/11 centres)  , maximum size of the largest discrete SN tumour deposit (11/11 centres)  and ) and tumour penetrative depth (7/11 centres; , , and ). The RDC (Rotterdam–Dewar Combined) classification was derived from the Rotterdam classification and the modified Dewar classification (9/11 centres)  .
2.2. Lymphatic mapping, sentinel node biopsy and completion lymph node dissection
At all centres, SNB was offered to patients with Breslow thickness ⩾ 1 mm or to patients with thinner tumours with adverse prognostic features such as ulceration, a high mitotic rate or Clark level IV or V invasion. SNB was performed using the triple technique identifying SNs with a combination of lymphoscintigraphy, pre-operative injection of blue dye at the primary melanoma site and intraoperative use of a gamma probe. Full details have been reported previously , , , , and . However, there were some differences in the procedures for identifying and removing SNs at the different centres. These included differences in the radiocolloids used for pre-operative lymphoscintigraphy, the timing and planes of view utilised for lymphoscintigraphy, the type and volume of blue dye used, the type and sensitivity of the hand-held gamma probe and the criteria utilised for defining a SN, as well as the experience of the nuclear medicine physicians, radiologists and surgical oncologists performing these procedures. Excised SNs were fixed in buffered formalin and sent for pathologic examination. Subsequently, SN tumour burden was determined by histopathologic review of available tissue sections. Completion lymph node dissection (CLND) was performed in 1381 of 1539 (90%) SN-positive patients. Reasons for not performing CLND were eligibility for the EORTC 1208 (Minitub) study (Clinicaltrials.gov identifier NCT01942603), the presence of micrometastases <0.1 mm in maximum dimension since an excellent survival is to be expected, enrolment in the observation arm of the second Multicenter Selective Lymphadenectomy Trial (MSLT-II) ( Clinicaltrials.gov identifier NCT00297895 ), patient refusal of further treatment or when surgical and anaesthetic risks associated with CLND were considered too great due to patient co-morbidities.
2.3. Pathology processing and analysis
There were also differences in the pathology processing and analysis of retrieved SNs between the eleven different centres. Generally, SNs from most of the ten EORTC MG centres were processed and assessed according to the basic principles of the EORTC MG SN pathology protocol as described by Cook et al.  and , whilst the SNs at MIA were processed according to a different protocol  and . A more detailed description of the differences between these protocols is provided in the Supplementary methods .
Between 1993 and 2008, 1539 patients diagnosed with primary melanoma were found to have a positive SN. Clinicopathologic characteristics of all SN-positive patients are summarised in Table 1 . The numbers of patients from each centre were: MIA (n = 350), Warsaw (n = 245), Guildford (n = 214), Amsterdam – NKI (n = 116), Rotterdam (n = 115), Padova (n = 109), Amsterdam – VUMC (n = 107), Berlin (n = 86), Milan (n = 73), Villejuif (n = 68) and Groningen (n = 56) ( Table S1 ). Mean age was 52.3 (standard deviation (SD) ± 15.3) years. Median Breslow thickness was 2.95 mm (interquartile range (IQR) 1.80–4.50 mm). Ulceration was present in 46% of the melanomas. Median maximum SN tumour size was 0.90 mm (IQR 0.30–2.50 mm) ( Tables 1 and S1). Mean and median follow-up times were 42 and 32 (IQR 20–58) months, respectively. In 1381 (90%) patients, CLND was performed.
|Mean ± SD||52.3 ± 15.3|
|Head & neck||211||14|
|Breslow thickness (mm)|
|Mean ± SD||3.74 ± 0.10|
|Median (IQR)||2.95 (1.80–4.50)|
|Number of removed SNs|
|Number of positive SNs|
|Intranodal location (Dewar classification)|
|Tumour penetrative depth (mm)|
|Median (IQR)||0.80 (0.30–1.95)|
|Tumour penetrative depth (mm)|
|Maximum size (mm)|
|Median (IQR)||0.90 (0.30–2.50)|
|Rotterdam classification (mm)|
|Maximum size (mm)|
|Maximum size (mm)|
|<0.1 mm subcapsular||69||5|
|<0.1 mm non-subcapsular||55||4|
|0.1–1.0 mm subcapsular||160||11|
|0.1–1.0 mm non-subcapsular||435||31|
Abbreviations: SSM = superficial spreading melanoma; NM = nodular melanoma; IQR = interquartile range, SD = standard deviation; CLND = completion lymph node dissection; RDC = Rotterdam–Dewar Combined.
3.1. Differences between centres
Significant differences in primary tumour and SN characteristics were observed between centres ( Table S1 and Fig. 2 ). Median Breslow thickness was 3.00 mm for the European cohort and 2.43 mm for the Australian cohort (p = 0.001), and ulceration was more common in the European than the Australian cohort (45% versus 35%, p ⩽ 0.001). The median maximum SN tumour sizes for the European and Australian cohorts were not significantly different (0.95 and 0.80 mm, respectively, p = 0.126).
3.2. NSN status
Details of NSN status were available for 1381 patients who had a CLND. Breslow thickness, ulceration, Clark level of invasion, number of SNs removed and all micromorphometric parameters were significant predictors of NSN status (p < 0.05) ( Table 2 ). Of the SN tumour burden parameters, the RDC classification sub-group with subcapsular micrometastases <0.1 mm in maximum dimension had the lowest NSN-positivity rate (5.5%). ( Table 2 ).
Univariate binary logistic regression was used to calculate the significance of individual strata for each classification system in predicting NSN status; only the p-values are reported here.
Abbreviations: NSN = non-sentinel node. NS = not significant. Ref = reference category. RDC = Rotterdam–Dewar Combined.
As continuous variables measured in millimetres, maximum SN metastasis size (odds ratio (OR) = 1.11, 95% confidence interval (CI): 1.07–1.15, p < 0.001) and tumour penetrative depth (OR = 1.26, 95% CI: 1.15–1.38, p < 0.001) were significant predictors of NSN status in the overall cohort ( Table S2 ). The categorisation of maximum size (⩽1 versus >1 mm and ⩽2 versus >2 mm), tumour penetrative depth (TPD) (⩽0.5 versus >0.5 mm) and intranodal location (subcapsular versus non-subcapsular) resulted in a statistically significant stratification of risk for NSN-positivity ( Table 2 ). When comparing the eleven melanoma centres, there was variation in the prediction of NSN-positivity by the proposed classification systems ( Table S3 ). Classifications of maximum SN tumour size using a 1 or 2 mm cut-off significantly stratified risk for NSN-positivity in 5/11 and 6/11 centres, respectively. The Rotterdam system, RDC system, TPD, S-classification and intranodal location significantly stratified risk for NSN-positivity in only 2/11, 1/9, 2/7, 2/7 and 2/9 centres, respectively ( Table S3 ).
In univariate analysis of the overall cohort, factors significantly associated with melanoma-specific survival (MSS) were: patient sex, age, melanoma subtype, Breslow thickness, Clark level, ulceration, Dewar classification, TPD, S-classification, maximum size, Rotterdam classification, RDC classification (only in the sub-groups of patients with tumour deposits >1.0 mm in maximum dimension and in patients with deposits >0.1–1.0 mm in maximum dimension and non-subcapsular) and NSN status ( Table 3 ).
|Head & neck||0.99||0.74–1.32||NS|
|Breslow thickness (mm)|
|Tumour penetrative depth (mm)|
|Maximum size (mm)|
|Rotterdam classification (mm)|
|<0.1 mm subcapsular||1|
|<0.1 mm non-subcapsular||1.17||0.43–3.24||NS|
|0.1–1.0 mm subcapsular||1.80||0.84–3.86||NS|
|0.1–1.0 mm non-subcapsular||2.05||1.00–4.2||0.050|
|Year of SNB|
Abbreviations: HR = hazard ratio; CI = confidence interval; SE = standard error; SSM = superficial spreading melanoma; NM = nodular melanoma; SN = sentinel node; NSN = non-sentinel node; NS = not significant; CLND = completion lymph node dissection; RDC = Rotterdam–Dewar Combined.
Because of multicollinearity between SN tumour burden parameters, four different multivariate models were used. Each multivariate model contained the following variables: Breslow thickness, age, NSN status, ulceration and one of the four SN tumour burden parameters. Other significant prognostic factors at univariate analyses, i.e. sex, melanoma subtype and Clark level, were not included due to insignificance in the multivariate model. Significant prognostic factors for poorer MSS in the multivariate models included the presence of non-subcapsular metastases, TPD > 1 mm and maximum SN tumour size > 1 mm ( Table 4 ). The SII sub-group of the S-classification and the 0.1–1 mm sub-group of the Rotterdam classification did not vary significantly from the reference groups (SI and <0.1 mm, respectively). ( Table 4 ).
|Multivariate Model (n)||Significant||Variable for SN tumour burden||Melanoma-specific survival|
|(n = 1159)||Breslow a||Subcapsular||1|
|(n = 679)||Breslow a||SI||1|
|(n = 1278)||Breslow a||<0.1 mm||1|
|Age a||0.1–1.0 mm||1.75||0.99–3.11||NS|
|NSN status||>1.0 mm||2.56||1.45–4.50||0.001|
|(n = 1159)||Breslow a||<0.1 mm subcapsular||1|
|Age a||<0.1 mm non-subcapsular||1.26||0.41–3.91||NS|
|NSN status||0.1–1.0 mm subcapsular||1.54||0.64–3.69||NS|
|0.1–1.0 mm non-subcapsular||1.85||0.81–4.25||NS|
Four different multivariate analyses were performed due to multicollinearity between the four classifications for sentinel node tumour burden, i.e. modified Dewar classification, S-classification, Rotterdam classification and RDC classification.
a The variables age and Breslow are continuous variables.
Abbreviations: HR = hazard ratio; CI = confidence interval; NSN = non-sentinel node; RDC = Rotterdam–Dewar Combined.
A comparison of the eleven melanoma centres revealed variation in the accuracy of survival prediction using the various classification systems ( Tables S4 and S5 ). The two classifications of maximum SN tumour size (⩽1 versus >1 mm and ⩽2 versus >2 mm) were the most consistently significant, distinguishing prognostic sub-groups for MSS in 6/11 and 5/11 centres and prognostic sub-groups for disease-free survival (DFS) in 7/11 and 8/11 centres. TPD and the S-classification were more frequently predictive of DFS than MSS. Non-subcapsular tumour location was significantly associated with DFS and MSS in only one of nine centres.
Micromorphometric parameters of SN tumour burden (TPD, intranodal tumour location and maximum tumour size) were all predictive factors for NSN status ( Table 2 ), DFS ( Table S5 ) and MSS ( Table 3 ) in this large cohort of SN-positive patients treated at eleven different centres. The SN classification systems assessed in the study significantly differentiated MSS outcomes for each sub-group on univariate analysis ( Table 3 ). However, when adjusting for known prognostic factors in multivariate MSS analysis, at least one cut-off for each system (S-classification, RDC and Rotterdam classifications) failed to significantly differentiate outcome ( Table 4 ). Similarly, not all cut-offs significantly stratified risk of NSN-positivity or univariate DFS outcomes ( Table 2 and S5). After adjustment for other clinico-pathologic factors, increasing age, increasing Breslow thickness, presence of ulceration and NSN status, non-subcapsular location (Dewar classification), high TPD (SIII of S-classification) and increasing maximum size of tumour (>1 or >2 mm or the Rotterdam comparison of >1 mm with <0.1 mm) were independently associated with poorer MSS ( Table 4 ). Patients within the RDC classification sub-group having micrometastases <0.1 mm in maximum dimension in a subcapsular location had the lowest NSN-positivity rate (5.5%) ( Table S2 ).
There was considerable heterogeneity between centres with regard to primary tumour characteristics and SN tumour burden features. The differences between centres are clear. Median Breslow thickness and ulceration rate ranged from 2.1 mm and 25.5% in the Amsterdam – VUMC centre (n = 107) to 4.00 mm and 67.7% in the Warsaw centre (n = 245) ( Table S1 ). Patients from the Amsterdam – NCI centre (n = 116) had no patients with <0.1 mm SN metastases, whilst 27% of the Berlin cohort had <0.1 mm SN metastases. The percentage of SN-positive patients with subcapsular metastases ranged from 4% in the Warsaw cohort to 38% in the Berlin cohort. The median maximum SN tumour size for the total group of patients was 0.90 mm, with a range of 0.50–1.70 mm. Moreover, no clear correlation between the thickness of the primary lesion and the SN tumour burden at each centre was apparent ( Fig. 2 ). These large variations may not only reflect differences in clinical presentation and management of melanoma patients in the different centres, but also differences in the methodologies used to identify, remove and examine SNs, and possibly the use of pre-operative SN ultrasound screening in some centres  and .
SN tumour burden parameters were not of prognostic and predictive value in each individual centre ( Tables S2–S5 ). In the combined cohort of SN-positive patients (n = 1539), all four SN tumour burden classification systems were independently prognostic in univariate analysis for MSS ( Table 3 , Fig. 1 ), which is in line with previous studies of these parameters  and . In those studies, patients with minimal SN tumour burden, i.e. <0.1 mm metastases in a subcapsular location, had an excellent estimated 5-year MSS of approximately 90%, which is equivalent to that of SN-negative patients  . However, in the combined cohort of the present study, patients with micrometastases <0.1 mm had an 83% 5-year MSS, whilst patients with subcapsular metastases (of any size) had a 5-year MSS of 72% ( Fig. 1 ). This suggests that the excellent 5-year MSS estimate reported in the earlier studies  may have been influenced by lead-time bias. However, follow-up has not been extended compared to the earlier study. The only difference between earlier results and results of this study is the addition of data from two centres. It is nevertheless important to bear in mind that for patients with SN micrometastases <0.1 mm in maximum dimension, 5-year survival figures may be misleading because if recurrence does occur, it is likely to be much later than recurrence in patients with larger SN metastases. This was demonstrated clearly in the AJCC Melanoma Database analysis, which highlighted the very great differences in prognosis and time to recurrence for patients with nodal micrometastases and those with nodal macrometastases  . When the data were analysed by centre, there were substantial differences in the prognosis for patients with minimal SN tumour burden (<0.1 mm), with the MSS ranging from 54% to 100% in different centres.
In all centres, SNs were detected by pre-operative lymphoscintigraphy and identified at the time of surgery with blue dye and a gamma probe , , , and . However, as detailed in the Methods section, there were some important differences in how SNs were identified in different centres. These differences may have influenced the results of this study because it is well documented that variations in any part of the SNB technique (including in nuclear medicine, surgery and pathology) can affect the accuracy of SNB , , and . There were also differences between protocols utilised for SN pathology assessment at MIA and most of the European melanoma centres. The main difference was the larger number of sections cut from each half of the SN in European centres. Furthermore, the EORTC protocol was altered slightly during the period of this study (as detailed in the Supplementary methods ). Potentially these differences could be important because examination of extra sections of SNs can increase the SN-positivity rate , , , , , , and . The number of sections pathologically examined and the distance between the sections may also affect the reported size, location and TPD of melanoma metastases in a SN and therefore its sub-classification according to the various proposed classification schemes. In view of this it might be predicted that an increase in the SN-positivity rate might be associated with an increase in the detection rate of minimal SN tumour burden cases  . Interestingly, the percentage of patients with minimal SN tumour burden (<0.1 mm) in our study differed significantly between individual European centres (where a greater number of sections were cut, allegedly according to the same protocol) ( Table S1 , Fig. 2 ) but was not significantly different in the Australian cohort compared to the European cohort overall.
In conclusion, primary tumour and SN tumour burden parameters assessed in this large retrospective multicenter study have been shown to provide valuable prognostic information in SN-positive patients. A maximum SN tumour size > 1 mm separated the cohort into two groups of similar size, and was the most consistent independent predictor of NSN-positivity and poorer DFS and MSS in individual centres, and in the combined cohort. The study has provided valuable insights into the prognostic value of SN tumour burden assessment in patients with melanoma. However, prospective studies with long term follow-up are clearly required to establish a classification system for SN tumour burden that consistently and accurately stratifies patients into meaningful prognostic groups with respect to NSN-positivity and survival outcomes, and is not unduly affected by minor variations in SN identification and examination protocols.
Conflict of interest statement
We thank the participating EORTC MG centres and MIA, and their surgical, dermatology and pathology departments for providing data for this study. We also thank Stefan Suciu, Barry Powell, Christy Walker, Sandro Pasquali, Zbigniew Nowecki, Wanda Michej, Angana Mitra, Julia Newton-Bishop, Iris van der Ploeg, Mari van Hout, Francesco Cataldo, Cristina Montesco and Alan Spatz for their contributions to this paper.
-  D.L. Morton, L. Wanek, J.A. Nizze, et al. Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Analysis of prognostic factors in 1134 patients from the John Wayne Cancer Clinic. Ann Surg. 1991;214(4):491-499 discussion 499–501
-  D.L. Morton, D.R. Wen, J.H. Wong, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127(4):392-399 Crossref
-  D.L. Morton, J.F. Thompson, A.J. Cochran, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13):1307-1317 Crossref
-  J.F. Thompson, W.H. McCarthy, C.M. Bosch, et al. Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res. 1995;5(4):255-260 Crossref
-  A. Doubrovsky, J.H. De Wilt, R.A. Scolyer, et al. Sentinel node biopsy provides more accurate staging than elective lymph node dissection in patients with cutaneous melanoma. Ann Surg Oncol. 2004;11(9):829-836 Crossref
-  A.P. van der Ploeg, A.C. van Akkooi, P. Rutkowski, 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):2206-2214 Crossref
-  C.M. Balch, A.C. Buzaid, S.J. Soong, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. 2001;19(16):3635-3648
-  C.M. Balch, J.E. Gershenwald, S.J. Soong, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-6206 Crossref
-  J.E. Gershenwald, S.J. Soong, C.M. Balch. 2010 TNM staging system for cutaneous melanoma…and beyond. Ann Surg Oncol. 2010;17(6):1475-1477 Crossref
-  C.M. Balch, J.E. Gershenwald, S.J. Soong, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28(14):2452-2459 Crossref
-  H. Starz, K. Siedlecki, B.R. Balda. Sentinel lymphonodectomy and s-classification: a successful strategy for better prediction and improvement of outcome of melanoma. Ann Surg Oncol. 2004;11(3 Suppl.):162S-168S
-  M. Wiener, K.M. Acland, H.M. Shaw, et al. Sentinel node positive melanoma patients: prediction and prognostic significance of nonsentinel node metastases and development of a survival tree model. Ann Surg Oncol. 2010;17(8):1995-2005 Crossref
-  A.C.J. van Akkooi, Z. Nowecki, C. Voit, G. Schaefer-Hesterberg, W. Michej, J.H.W. de Wilt, et al. Minimal sentinel node (SN) tumor burden according to the Rotterdam criteria is the most important prognostic factor for survival in melanoma patients. A multicenter study in 388 SN positive patients. Ann Surg. 2008;248(6)
-  A.P. van der Ploeg, A.C. van Akkooi, P.I. Schmitz, et al. EORTC Melanoma Group sentinel node protocol identifies high rate of submicrometastases according to Rotterdam Criteria. Eur J Cancer. 2010;46(13):2414-2421 Crossref
-  R. Murali, C. Desilva, J.F. Thompson, R.A. Scolyer. Non-Sentinel Node Risk Score (N-SNORE): a scoring system for accurately stratifying risk of non-sentinel node positivity in patients with cutaneous melanoma with positive sentinel lymph nodes. J Clin Oncol. 2010;28(29):4441-4449 Crossref
-  D.J. Dewar, B. Newell, M.A. Green, et al. The microanatomic location of metastatic melanoma in sentinel lymph nodes predicts nonsentinel lymph node involvement. J Clin Oncol. 2004;22(16):3345-3349 Crossref
-  J.E. Gershenwald, R.H. Andtbacka, V.G. Prieto, et al. Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol. 2008;26(26):4296-4303 Crossref
-  R.A. Scolyer, L.X. Li, S.W. McCarthy, et al. Micromorphometric features of positive sentinel lymph nodes predict involvement of nonsentinel nodes in patients with melanoma. Am J Clin Pathol. 2004;122(4):532-539
-  J.H. Lee, R. Essner, H. Torisu-Itakura, et al. Factors predictive of tumor-positive nonsentinel lymph nodes after tumor-positive sentinel lymph node dissection for melanoma. J Clin Oncol. 2004;22(18):3677-3684 Crossref
-  A. Meier, I. Satzger, B. Volker, et al. Comparison of classification systems in melanoma sentinel lymph nodes–an analysis of 697 patients from a single center. Cancer. 2010;116(13):3178-3188
-  I.M.C. van der Ploeg, B.B.R. Kroon, N. Antonini, et al. Comparison of three micromorphometric pathology classifications of melanoma metastases in the sentinel node. Ann Surg. 2009;250:301-304 Crossref
-  R. Murali, A.J. Cochran, M.G. Cook, et al. Interobserver reproducibility of histologic parameters of melanoma deposits in sentinel lymph nodes: implications for management of patients with melanoma. Cancer. 2009;115(21):5026-5037 Crossref
-  A.C. van Akkooi, A. Spatz, A.M. Eggermont, et al. Expert opinion in melanoma: the sentinel node; EORTC Melanoma Group recommendations on practical methodology of the measurement of the microanatomic location of metastases and metastatic tumour burden. Eur J Cancer. 2009;45(16):2736-2742 Crossref
-  I. Satzger, B. Volker, A. Meier, et al. Criteria in sentinel lymph nodes of melanoma patients that predict involvement of nonsentinel lymph nodes. Ann Surg Oncol. 2008;15(6):1723-1732 Crossref
-  I.M.C. van der Ploeg, B.B.R. Kroon, N. Antonini, et al. Is completion lymph node dissection needed in case of minimal melanoma metastasis in the sentinel node?. Ann Surg. 2009;249(6):1003-1007 Crossref
-  R. Murali, C. DeSilva, S.W. McCarthy, et al. Sentinel lymph nodes containing very small (<0.1 mm) deposits of metastatic melanoma cannot be safely regarded as tumor-negative. Ann Surg Oncol. 2012;19(4):1089-1099 Crossref
-  R. Murali, C. Desilva, J.F. Thompson, R.A. Scolyer. Factors predicting recurrence and survival in sentinel lymph node-positive melanoma patients. Ann Surg. 2011;253(6):1155-1164 Crossref
-  I. Satzger, B. Volker, M. Al Ghazal, et al. Prognostic significance of histopathological parameters in sentinel nodes of melanoma patients. Histopathology. 2007;50(6):764-772 Crossref
-  H. Starz, B.R. Balda, K.U. Kramer, et al. A micromorphometry-based concept for routine classification of sentinel lymph node metastases and its clinical relevance for patients with melanoma. Cancer. 2001;91(11):2110-2121 Crossref
-  A.C. van Akkooi, J.H. de Wilt, C. Verhoef, 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):1578-1585 Crossref
-  J.J. Albertini, C.W. Cruse, D. Rapaport, et al. Intraoperative radio-lympho-scintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg. 1996;223(2):217-224 Crossref
-  J.C. Alex, D.L. Weaver, J.T. Fairbank, et al. Gamma-probe-guided lymph node localization in malignant melanoma. Surg Oncol. 1993;2(5):303-308 Crossref
-  A.C. van Akkooi, J.H. de Wilt, C. Verhoef, et al. High positive sentinel node identification rate by EORTC melanoma group protocol. Prognostic indicators of metastatic patterns after sentinel node biopsy in melanoma. Eur J Cancer. 2006;42(3):372-380 Crossref
-  J.F. Thompson, J.R. Stretch, R.F. Uren, et al. Sentinel node biopsy for melanoma: where have we been and where are we going?. Ann Surg Oncol. 2004;11(3 Suppl.):147S-151S
-  M.G. Cook, M.A. Green, B. Anderson, et al. The development of optimal pathological assessment of sentinel lymph nodes for melanoma. J Pathol. 2003;200(3):314-319 Crossref
-  R.A. Scolyer, R. Murali, S.W. McCarthy, J.F. Thompson. Pathologic examination of sentinel lymph nodes from melanoma patients. Semin Diagn Pathol. 2008;25(2):100-111 Crossref
-  R.A. Scolyer, R. Murali, I. Satzger, J.F. Thompson. The detection and significance of melanoma micrometastases in sentinel nodes. Surg Oncol. 2008;17(3):165-174 Crossref
-  A. Sanki, R.F. Uren, M. Moncrieff, et al. Targeted high-resolution ultrasound is not an effective substitute for sentinel lymph node biopsy in patients with primary cutaneous melanoma. J Clin Oncol. 2009;27(33):5614-5619 Crossref
-  C. Voit, A.C. Van Akkooi, G. Schafer-Hesterberg, et al. Ultrasound morphology criteria predict metastatic disease of the sentinel nodes in patients with melanoma. J Clin Oncol. 2010;28(5):847-852 Crossref
-  J.F. Thompson, R.F. Uren. Lymphatic mapping in management of patients with primary cutaneous melanoma. Lancet Oncol. 2005;6(11):877-885 Crossref
-  B.A. Kapteijn, O.E. Nieweg, S.H. Muller, et al. Validation of gamma probe detection of the sentinel node in melanoma. J Nucl Med. 1997;38(3):362-366
-  R.Z. Karim, R.A. Scolyer, W. Li, et al. False negative sentinel lymph node biopsies in melanoma may result from deficiencies in nuclear medicine, surgery, or pathology. Ann Surg. 2008;247(6):1003-1010 Crossref
-  R. Riber-Hansen, N. Hastrup, O. Clemmensen, 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):347-352 Crossref
-  R.A. Scolyer, J.F. Thompson, L.X. Li, et al. Failure to remove true sentinel nodes can cause failure of the sentinel node biopsy technique: evidence from antimony concentrations in false-negative sentinel nodes from melanoma patients. Ann Surg Oncol. 2004;11(3 Suppl.):174S-178S
-  H.N. Abrahamsen, S.J. Hamilton-Dutoit, J. Larsen, T. Steiniche. Sentinel lymph nodes in malignant melanoma: extended histopathologic evaluation improves diagnostic precision. Cancer. 2004;100(8):1683-1691 Crossref
-  K. Spanknebel, D.G. Coit, S.C. Bieligk, et al. Characterization of micrometastatic disease in melanoma sentinel lymph nodes by enhanced pathology: recommendations for standardizing pathologic analysis. Am J Surg Pathol. 2005;29(3):305-317 Crossref
-  H.A. Gietema, R.J. Vuylsteke, I.A. de Jonge, et al. Sentinel lymph node investigation in melanoma: detailed analysis of the yield from step sectioning and immunohistochemistry. J Clin Pathol. 2004;57(6):618-620 Crossref
a Erasmus University Medical Center, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
b Melanoma Institute Australia, Sydney, Australia
c Memorial Sloan Kettering Cancer Center, New York City, NY, USA
d Institut de Cancerologie Gustav Roussy, Villejuif, Paris-Sud, France
☆ Part of this work was presented at the 7th International Sentinel Node Society (ISNS) of November 2010 in Yokohama, Japan and at the 2011 European Multidisciplinary Cancer Congress of September 2011 in Stockholm, Sweden.
☆☆ Participating investigators (n = 9), all part of the EORTC Melanoma Group, who collected data and provided and cared for study patients:Piotr Rutkowski, MD, PhD, Martin Cook, MD, PhD, Omgo Nieweg, MD, PhD, Carlo R. Rossi, MD, PhD, Paul A.M. van Leeuwen, MD, PhD, Christiane Voit, MD, PhD, Alessandro Testori, MD, PhD, Caroline Robert, MD, PhD, Harald J. Hoekstra, MD, PhD.
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