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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

Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusions

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.

1. Introduction

Twenty years ago, sentinel node (SN) biopsy (SNB) was introduced as a staging technique for patients with early-stage melanoma [1] and [2]. Since then, SN status has been shown to be the strongest independent prognostic factor in patients with clinically localised primary cutaneous melanoma [3], [4], [5], and [6].

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 [7], [8], and [9]. However, specific sub-groups of SN-positive patients have vastly differing survival rates, ranging from approximately 30% to over 90% [3], [10], [11], [12], [13], and [14]. 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 [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], and [21]. Ideally, the parameters utilised for prognostic stratification must be easy and quick to assess and reproducible [22] and [23]. 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 [6], [11], [13], [15], [16], [17], [18], [21], [24], [25], [26], [27], [28], [29], and [30].

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 [6], [15], and [27]. 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

2.1. Patients

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) [16] , maximum size of the largest discrete SN tumour deposit (11/11 centres) [13] and [30]) and tumour penetrative depth (7/11 centres; [11], [18], and [29]). The RDC (Rotterdam–Dewar Combined) classification was derived from the Rotterdam classification and the modified Dewar classification (9/11 centres) [6] .

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 [14], [31], [32], [33], and [34]. 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. [14] and [35], whilst the SNs at MIA were processed according to a different protocol [36] and [37]. A more detailed description of the differences between these protocols is provided in the Supplementary methods .

3. Results

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.

Table 1 Clinicopathologic factors for all sentinel node positive patients (n = 1539).

Characteristic n %
Gender
Female 702 46
Male 837 54
 
Age (years)
Mean ± SD 52.3 ± 15.3
⩽50 693 45
>50 846 55
 
Location
Extremity 779 51
Trunk 533 35
Head & neck 211 14
Other 14 1
Missing 2  
 
Melanoma subtype
SSM 572 48
NM 536 45
Other 89 7
Missing 342  
 
Breslow thickness (mm)
Mean ± SD 3.74 ± 0.10
Median (IQR) 2.95 (1.80–4.50)
T1 90 6
T2 394 26
T3 616 40
T4 435 28
Missing 4  
 
Clark level
I–II 37 3
III 350 24
IV 921 62
V 172 12
Missing 59  
 
Ulceration
Absent 781 54
Present 655 46
Missing 103  
 
Number of removed SNs
1 468 36
2 426 33
3 411 32
Missing 234  
 
Number of positive SNs
1 1030 79
2 228 17
⩾3 53 4
Missing 230  
 
Intranodal location (Dewar classification)
Subcapsular 248 18
Non-subcapsular 1155 82
Missing 136  
 
Tumour penetrative depth (mm)
Median (IQR) 0.80 (0.30–1.95)
S-classification
SI 246 30
SII 227 28
SIII 344 42
Missing 722  
 
Tumour penetrative depth (mm)
⩽0.5 333 41
>0.5 484 59
Missing 722  
 
Maximum size (mm)
Median (IQR) 0.90 (0.30–2.50)
 
Rotterdam classification (mm)
<0.1 146 10
0.1–1.0 665 43
>1.0 728 47
 
Maximum size (mm)
⩽2 1094 71
>2 445 29
 
Maximum size (mm)
⩽1    
>1    
 
RDC classification
<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
>1.0 mm 684 49
Missing 136  
 
CLND performed
No 158 10
Yes 1381 90
 
NSN status
Negative 1098 80
Positive 283 21
 
Time SNB
1993–2002 714 46
2003–2008 825 54

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 ).

Table 2 Factors predictive of non-sentinel node status.

Characteristic Total NSN-positive p-Value lowast
  n n %  
Age
⩽50 637 118 18.5  
>50 744 165 22.2 NS
 
Breslow thickness
T1 80 10 12.5 Ref.
T2 348 61 17.5 NS
T3 549 94 17.1 NS
T4 400 117 29.3 0.003
 
Ulceration
Absent 686 122 17.8 Ref.
Present 600 144 24.0 0.006
 
Dewar classification
Subcapsular 217 19 8.8 Ref.
Non-subcapsular 1040 229 22.0 <0.001
 
S-classification
SI 202 23 11.4 Ref.
SII 195 35 17.9 NS
SIII 309 76 24.6 <0.001
 
Tumour penetrative depth (mm)
⩽0.5 274 30 10.9 Ref.
>0.5 432 104 24.1 <0.001
 
Rotterdam classification (mm)
<0.1 117 14 12.0 Ref.
0.1–1.0 589 93 15.8 NS
>1.0 675 176 26.1 0.001
 
Maximum size (mm)
⩽1 706 107 15.1 Ref.
>1 675 176 26.1 <0.001
 
Maximum size (mm)
⩽2 964 150 15.6 Ref.
>2 417 133 31.9 <0.001
 
RDC classification
<0.1 mm subcapsular 55 3 5.5 Ref.
<0.1 mm non-subcapsular 43 9 20.9 0.030
0.1–1.0 mm subcapsular 146 16 11.0 NS
0.1–1.0 mm non-subcapsular 379 55 14.5 NS
>1.0 mm 634 165 26.0 0.003

lowast 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 ).

3.3. Survival

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 ).

Table 3 Univariate analyses for melanoma-specific survival of all sentinel node positive patients.

Characteristic Univariate analysis
  HR 95% CI p-Value
Gender
Female 1    
Male 1.30 1.07–1.57 0.009
 
Age (years)
Continuous 1.02 1.01–1.02 <0.001
⩽50 1    
>50 1.36 1.12–1.65 0.002
 
Location
Extremity 1    
Trunk 0.99 0.80–1.22 NS
Head & neck 0.99 0.74–1.32 NS
 
Melanoma subtype
SSM 1    
NM 1.59 1.27–2.00 <0.001
Other 1.87 1.27–2.75 0.002
 
Breslow thickness (mm)
Continuous 1.08 1.06–1.09 <0.001
T1 1    
T2 1.71 0.88–3.31 NS
T3 2.67 1.41–5.07 0.003
T4 5.09 2.69–9.63 <0.001
 
Clark level
I–III 1    
IV 1.47 1.15–1.89 0.002
V 2.27 1.64–3.15 <0.001
 
Ulceration
Absent 1    
Present 2.49 2.03–3.05 <0.001
 
Dewar classification
Subcapsular 1    
Non-subcapsular 1.75 1.31–2.35 <0.001
 
Tumour penetrative depth (mm)
Continuous 1.19 1.13–1.26 <0.001
⩽0.5 1    
>0.5 1.77 1.34–2.35 <0.001
 
S-classification
SI 1   0.016
SII 1.58 1.09–2.28
SIII 1.93 1.38–2.70 <0.001
 
Maximum size (mm)
Continuous 1.10 1.08–1.12 <0.001
⩽1 1    
>1 1.96 1.61–2.37 <0.001
⩽2 1    
>2 2.17 1.79–2.64 <0.001
 
Rotterdam classification (mm)
<0.1 1    
0.1–1.0 1.99 1.21–3.28 0.007
>1.0 3.55 2.17–5.80 <0.001
 
RDC classification
<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
>1.0 mm 3.43 1.69–6.93 0.001
 
NSN status
Negative 1    
Positive 2.03 1.63–2.52 <0.001
 
CLND performed
No 1    
Yes 0.87 0.62–1.20 NS
 
Year of SNB
1993–2002 1    
2003–2008 0.89 0.72–1.10 NS

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 ).

Table 4 Four different stepwise multivariate Cox’s hazard regression models for melanoma-specific survival for all sentinel node positive patients.

Multivariate Model lowast (n) Significant Variable for SN tumour burden Melanoma-specific survival
      HR 95% CI p-Value
#1   Dewar classification      
(n = 1159) Breslow a Subcapsular 1    
Age a Non-subcapsular 1.49 1.07–2.08 0.018
NSN status        
Ulceration        
 
#2   S-classification      
(n = 679) Breslow a SI 1    
Age a SII 1.49 0.99–2.26 NS
NSN status SIII 1.63 1.12–2.38 0.011
Ulceration        
 
#3   Rotterdam classification      
(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
Ulceration        
 
#4   RDC classification      
(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
Ulceration >1.0 mm 2.37 1.05–5.37 0.038

lowast 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.

4. Discussion

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 [38] and [39].

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 [6] and [21]. 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 [6] . 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 [6] 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 [10] . 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.

gr1

Fig. 1 Melanoma-specific survival curves for all SN-positive patients.

In all centres, SNs were detected by pre-operative lymphoscintigraphy and identified at the time of surgery with blue dye and a gamma probe [31], [32], [40], and [41]. 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 [42], [43], and [44]. 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 [14], [33], [35], [37], [45], [46], and [47]. 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 [14] . 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.

gr2

Fig. 2 Box plot showing the median and 95 percentile of (blue) the Breslow thickness and (green) the maximum sentinel node tumour size per centre.

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

None declared.

Acknowledgements

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.

Appendix A. Supplementary data

 

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Supplementary data 1

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Supplementary Tables

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Footnotes

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

lowast Corresponding author: Address: Institut de Cancérologie Gustave Roussy, 94800 Villejuif, Paris-Sud, France. Tel.: +33 1 42114016; fax: +33 1 42115252.

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.