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Keywords:

  • histology;
  • melanoma;
  • prognosis;
  • sentinel lymph node

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

BACKGROUND:

In melanoma, different classification systems have been proposed that predict overall survival (OS) and recurrence-free survival (RFS) based on findings in the sentinel lymph node (SLN). The authors of this report compared the RFS and OS of 697 melanoma patients as predicted by various classification systems.

METHODS:

The Rotterdam system (based on the greatest dimension of the largest tumor cell deposit), the Augsburg S-classification (based on tumor penetrative depth [TPD]), and the Hannover system (based on a combination of tumor load, TPD, and invasion of the capsule) were studied in 697 consecutive melanoma patients who underwent SLN biopsy at the authors' center.

RESULTS:

In univariate analyses, the Rotterdam and Hannover systems (but not the S-classification) identified 1 group of SLN-positive patients that had OS and RFS similar to the OS and RFS of SLN-negative patients. The intermediate groups from all classification systems did not differ significantly with regard to RFS and/or OS from the adjacent groups. In multivariate analysis using a Cox model, the greatest dimension of the largest tumor cell deposit (cutoff point, <0.1 mm vs ≥0.1 mm), the TPD (cutoff point, ≤2 mm vs >2 mm), and capsular involvement represented independent parameters for RFS; and TPD and capsular involvement also were independent parameters for OS. On the basis of these 3 parameters, a new scoring system for risk assessment in patients with melanoma is proposed that can distinguish 3 separate groups of patients that differed significantly in OS and RFS.

CONCLUSIONS:

Different parameters of independent prognostic significance were identified in SLNs from patients with melanoma. Combining these parameters, the prognosis of patients with melanoma was predicted more precisely by the new scoring system than by currently published classification systems. Cancer 2010. © 2010 American Cancer Society.

Sentinel lymph node (SLN) biopsy has been an established procedure in melanoma since the early 1990s.1 The status of the SLN is the most important predictor of survival, as indicated in many studies,2-8 and, thus, is included in the current American Joint Committee on Cancer (AJCC) staging system for melanoma.9 In the current AJCC classification, number of positive SLNs is used as a parameter for SLN involvement; ie, 1 positive SLN is classified N1a, and 2 or 3 positive SLNs are classified as N2a.9

However, the histopathologic pattern of SLN involvement is heterogeneous, ranging from single, isolated melanoma cells to the complete replacement of lymph node tissue by melanoma cells. To predict the prognosis of patients more precisely, different parameters and risk-assessment systems of SLN involvement have been developed in recent years. These SLN parameters reflect mainly the amount and pattern of melanoma involvement, such as the depth and invasion of melanoma cells within the lymph node parenchyma (tumor penetrative depth [TPD]),10 the expansion of melanoma cells into the lymph node capsule (capsular involvement),6 and the greatest dimension (diameter) of the largest tumor cell deposit (tumor burden). van Akkooi et al published a risk-assessment system (called the Rotterdam system) based on the greatest dimension of the tumor cell deposit. Three different groups were defined with increasing deposit size and decreasing survival rates.11, 12 Patients who had metastases in an SLN that measured <0.1 mm had significantly better overall survival (OS) at 5 years than patients who had micrometastases that measured from 0.1 mm to 1.0 mm or >1.0 mm. Starz et al developed the so-called new S-classification based on the TPD.10 Patients who had a TPD <0.3 mm (S-I) reportedly had a significantly better prognosis than patients who had a TPD between 0.3 mm and 1 mm (S-II) and patients who had a TPD >1 mm (S-III). Finally, we established the Hannover system to differentiate between patients who have a favorable prognosis and patients who have a poor prognosis by combining 3 parameters of tumor load (<30 cells vs ≥30 cells), TPD (≤2 mm vs >2 mm), and capsular invasion (absent vs present).6 Each parameter was assigned 1 point, and, the more points a patient had, the worse their prognosis.

Theoretically, risk-assessment systems need to fulfill 2 criteria: 1) maximizing the variability of outcomes among the different groups of patients and 2) minimizing the variability of outcomes among 1 group of patients.13 To date, unique risk-assessment systems have been analyzed in unique populations, but the discriminative power of different risk-assessment systems for predicting prognosis in patients with melanoma has not been compared. The objective of the current study was to compare the prognostic value of different histopathologic and clinical parameters as well as risk-assessment systems by applying them to the same group of patients.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

We studied a population of 697 consecutive patients who had primary cutaneous melanoma (Breslow tumor thickness ≥1 mm) diagnosed in our department between April 2000 and December 2006. Primary melanomas were excised with a 2-cm safety margin. At the time of diagnosis, patients were without clinical or radiologic evidence of metastasis (initial staging was performed by chest x-ray, abdominal ultrasound, assessment of peripheral lymph nodes, and measuring S-100 tumor marker levels in serum). All patients underwent SLN biopsy as described previously.14 In 217 patients (31%), melanoma cells in the SLN were detected by hematoxylin and eosin (H&E) staining or immunohistochemistry (see below) and were considered micrometastases. Thus, micrometastases were defined as melanoma cells in the SLN identified by histopathology or immunohistochemistry that could not be detected by clinical or radiologic investigation.

One hundred seventy-five patients underwent completion lymph node dissection (CLND) after a positive SLN biopsy, and the CLND specimen was positive in 27 of 175 patients (15.4%). Eight patients refused to undergo CLND, 12 patients did not undergo CLND for medical reasons that prohibited a major procedure under general anesthesia, and CLND was not recommended in 22 patients because of low tumor burden. Follow-up investigations were performed according to the recommendations of the German Dermatologic Society15 and included a clinical examination every 3 months and a chest x-ray and ultrasound studies of lymph nodes and the abdomen every 6 months. The mean follow-up was 49.5 months, and the median follow-up was 47.8 months (range, 0.1-110.1 months). One hundred forty-three patients (21%) had recurrent melanoma, and 95 patients (14%) died of causes related to melanoma.

Histopathologic and Immunohistochemical Staining: Workup of SLN

Lymph nodes were fixed in formaldehyde, embedded in paraffin, and processed as described previously14 according to the recommendation of Cochran et al.16 Depending on the size of the lymph node, between 1 and 8 sections were cut, because it has been demonstrated that the examination of multiple sections increases sensitivity for detecting micrometastases.

Each section was processed cut-face down for routine paraffin embedding using automated devices (Pathcenter and Histocenter 640CX51; Shandon, Astmoor, United Kingdom), and sections were cut for H&E staining and immunohistochemistry following the recommendation of Cochran et al.16 For all patients, the same immunohistochemical procedures were used. Highly sensitive immunohistochemistry for HMB45 (clone HMB45; 1:60 dilution; DakoCytomation, Hamburg, Germany) and Melan A (clone A103; dilution 1:300; DakoCytomation) was performed with an automated immunostainer (Horizon; DakoCytomation) using an indirect streptavidin-biotin method following the standardized methylation-sensitive amplified polymorphism protocol provided by the manufacturer. Pretreatment for antigen retrieval was performed by gentle cooking overnight at 70°C in Target Retrieval Solution (DakoCytomation) for Melan A and by proteinase K for HMB45. Negative controls were performed using isotype-matched, irrelevant antibodies of the same species. Newfuchsin was used as chromogen, because its bright-red color allows easy discrimination from brown melanin pigment in melanocytic cells and macrophages and from other endogenous pigments like siderin.

Histopathologic Parameters Assessed in the SLN

Melanoma cells were detected in 1 SLN in 166 of 217 patients (76.5%) and in more than 1 SLN in 51 of 217 patients (23.5%). In the latter patients, the lymph node with the highest tumor burden was used for further analysis.

Parameters that we assessed in the SLNs can be grouped in 4 categories: First, tumor burden (ie, the amount of melanoma cells) was assessed in different ways: 1) the size of the largest tumor cell deposit was estimated semiquantitatively by counting the number of cells in direct contact with one another (isolated cells, small deposits of <30 cells, large deposits of ≥30 cells); 2) the greatest dimension of the largest tumor cell deposit was measured with an ocular micrometer and grouped into 4 categories (a greatest dimension <0.1 mm, 0.1-1.0 mm, >1.0 mm, and ≤0.2 mm) according to van Akkooi et al and Scheri et al11, 17; or 3) the number of positive SLNs (1 vs ≥1). Second, the peripheral expansion of tumor cells was assessed (ie, the presence of tumor cells within the capsule of the SLN denoted capsular involvement). Third, the central expansion of tumor cells was assessed (ie, the depth of invasion was measured according to Starz et al with the ocular micrometer as the maximal distance between the inner layer of the lymph node capsule or trabecule and melanoma cells in the lymph node parenchyma10). The term “tumor penetrative depth” (TPD) was used to designate this distance according to the proposal of Scolyer and coworkers.7

For statistical analyses, chi-square tests and Kaplan-Meier tests were performed with the software SPSS (version 13.0; SPSS Inc; Chicago, Ill). For multivariate analyses, a Cox model was used and included parameters that were significant in univariate analyses and were described in 1 of the established risk-assessment systems (Rotterdam system, S-classification, Hannover system) or parameters that were established in previous studies (TPD >2 mm [Scolyer et al7]; isolated, immunohistochemically positive cells [Satzger et al18]; a greatest dimension ≤0.2 mm of the largest tumor cell deposit [Scheri et al17]; and the number of positive SLNs [Gershenwald et al19]). The following histopathologic parameters of the SLN were analyzed in different combinations: capsular involvement, TPD (with cutoff points of 0.3 mm, 1 mm, and 2 mm), tumor load (with cutoff points of <30 cells vs ≥30 cells), the number of positive SLNs (1 vs ≥1), and the greatest dimension of the largest tumor cell deposit (with cutoff points of 0.1 mm, 0.2 mm. and 1 mm). P values and confidence intervals were calculated. P values <.05 were considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

Characterization of Patients

Six hundred ninety-seven consecutive patients with primary melanoma (Breslow thickness ≥1 mm) were reviewed who underwent SLN biopsy in our department between April 2000 and December 2006. The SLN was positive in 217 of 697 patients (31.1%).

In univariate analyses, we compared patients who had micrometastases in SLNs with patients who had histopathologically and immunohistochemically negative SLNs. Patient characteristics with regard to clinic, primary melanoma, and the number of positive SLNs are listed in Table 1. The mean follow-up was 49.5 months (median, 47.8 months; range, 0.1-110.1 months).

Table 1. Characterization of 697 Patients With Melanoma Patients Who Underwent Sentinel Lymph Node Evaluation
CharacteristicNo. of Patients (%)P
Negative SLNPositive SLN
  1. SLN, sentinel lymph node; NA, not available.

No. of patients480 (68.9)217 (31.1) 
Age, y  .128
 Median6262 
 Mean5957 
 Range19-9018-91 
Sex  .008
 Women241 (50.2)96 (44.2) 
 Men239 (49.8)121 (55.8) 
Breslow thickness, mm  <.001
 Median1.702.50 
 Mean2.253.35 
 Range1-181-17 
 1-2321 (66.9)84 (38.7)<.001
 >2-4109 (22.7)72 (33.2) 
 >450 (10.4)61 (28.1) 
Clark level  <.001
 III224 (46.7)60 (27.6) 
 IV210 (43.8)113 (52.1) 
 V46 (9.6)44 (20.3) 
Ulceration  <.001
 No387 (80.6)134 (61.8) 
 Yes93 (19.4)80 (36.9) 
Regression  .007
 No387 (80.6)187 (86.2) 
 Yes93 (19.4)30 (13.8) 
Location  .003
 Head61 (12.7)14 (6.4) 
 Trunk162 (33.8)90 (41.5) 
 Extremities257 (53.5)113 (52.1) 
No. of SLNs  .001
 Median13 
 Mean1.61.9 
 Range1-51-6 
No. of positive SLNs  NA
 1166 (76.5) 
 243 (19.8) 
 37 (3.2) 
 41 (0.5) 
Recurrence  <.001
 No417 (86.9)137 (63.1) 
 Yes63 (13.1)80 (36.9) 
Initial recurrence  <.001
 Locoregional cutaneous20/63 (31.7)29/80 (36.2) 
 Regional lymph nodes17/63 (27)13/80 (16.3) 
 Distant metastases26/63 (41.3)38/80 (47.5) 
Total distant metastases  <.001
 No436 (90.8)154 (71) 
 Yes44 (9.2)63 (29) 
Death  <.001
 No409 (85.2)152 (70) 
 Yes, melanoma41 (8.5)54 (24.9) 
 Yes, other30 (6.3)11 (5.1) 

There was a predominance men among the patients who had positive SLNs (55.8%) compared with the patients who had negative SLNs (49.8%). The mean ages of the 2 groups did not differ significantly. Primary melanomas with positive SLNs, as expected, were significantly thicker, had higher Clark levels, and were ulcerated more often. The primary disease sites were head and neck (12.7% for SLN-negative patients and 6.4% for patients with micrometastases), trunk (33.8% for SLN-negative patients and 41.5% for patients with micrometastases), and extremities (53.5% for SLN-negative patients and 52.1% for patients with micrometastases).

In SLN-negative patients, 63 of 480 (13.1%) developed recurrent disease, and 41 of 480 (8.5%) died from melanoma-related causes; whereas, in the patients who had micrometastases, 80 of 217 (36.9%) developed recurrent disease, and 54 of 217 (24.9%) died of melanoma-related causes. In SLN-positive patients who did not undergo CLND, 10 of 42 (23.8%) developed recurrent disease compared with 70 of 105 (40%) SLN-positive patients who underwent CLND.

Univariate Analyses of Histopathologic SLN Parameters and Prognosis

In univariate analyses, several SLN parameters were correlated with recurrence-free survival (RFS) and OS. Different cutoff points were applied, as suggested in the literature and mentioned above (see Materials and Methods). Increasing tumor burden was associated with a poorer prognosis, as assessed by a semiquantitative evaluation of the number of melanoma cells in the largest cluster (<30 cells vs ≥30 cells), in terms of both OS (P < .001) and RFS (P < .001). In SLN-positive patients, a greatest dimension of the largest cluster <0.1 mm versus 0.1 mm to 1 mm versus >1.0 mm (according to the Rotterdam system) was associated significantly with survival rates in terms of both OS (P < .001) and RFS (P < .001) compared with survival rates in SLN-negative patients. The number of positive SLNs achieved significance for RFS (P = .002) but not for OS (P = .136). With regard to the peripheral expansion of tumor cells into the SLN, capsular involvement was correlated with poorer RFS (P < .001) and OS (P < .001). The central expansion of tumor cells measured as TPD was correlated significantly with OS and RFS with cutoff points of ≤2 mm versus >2 mm (P < .001 and P < .001, respectively) and, as measured according to the Augsburg S-classification, with cutoff points of <0.3 mm versus 0.3 mm to 1.0 mm versus >1.0 mm (P = .006 and P < .001, respectively). Finally the Hannover system was able to discriminate between groups of patients (0 points vs 1 point vs 2 points vs 3 points) that had significant differences in OS (P < .001) and RFS (P < .001).

Kaplan-Meier Analyses

Rotterdam system

In Kaplan-Meier analyses, the Rotterdam criteria for tumor burden were highly significant predictors of RFS (P < .001) and OS (P < .001) in SLN-positive patients compared with SLN-negative patients (Fig. 1a,b). The separation of Kaplan-Meier curves for OS (Rotterdam criteria: 0.1-1 mm vs >1 mm) did not achieve significance (P = .103) (Table 2). Patients who had micrometastases <0.1 mm (greatest dimension of the largest tumor cell deposit) had favorable survival rates, similar to those for SLN-negative patients, in terms of both OS (P = .400) and RFS (P = .183).

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Figure 1. The Kaplan-Meier was used to analyze overall survival (OS) and recurrence-free survival (RFS) according to (a,b) the Rotterdam system, (c,d) the Augsburg S-classification, (e,f) the Hannover system, and (g,h) the Hannover-II system. SLN indicates sentinel lymph node.

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Table 2. Comparison of the Discriminative Power of Different Risk-Assessment Systems (the Rotterdam System, the Augsburg S-Classification, the Hannover System, and the Hannover-II System) With P Values Calculated for Separate Groups
Scoring SystemParameters/and CutoffsNo. of PatientsP
OSRFS
SLN-Negative vs Group 1Group 1 vs Group 2Group 2 vs Group 3Group 3 vs Group 4SLN-Negative vs Group 1Group 1 vs Group 2Group 2 vs Group 3Group 3 vs Group 4
  1. OS indicates overall survival; RFS, recurrence-free survival; SLN, sentinel lymph node; NA, not applicable.

Rotterdam system (based on greatest dimension of deposit)        
 Group 1<0.1 mm85.400.016.016NA.183.001.103NA
 Group 20.1-1.0 mm77        
 Group 3>1.0 mm55        
Augsburg S-classification (based on tumor penetrative depth), mm        
 Group 1<0.3 mm65.261.161.073NA.019.513.003NA
 Group 20.3-1.0 mm67        
 Group 3>1.0 mm85        
Hannover system (based on tumor penetrative depth, >30 cells, capsular involvement)        
 Group 10 Points77.520.252.068.001.119.077.189<.001
 Group 21 Points61        
 Group 32 Points53        
 Group 43 Points26        
Hannover-II system (based on tumor penetrative depth, greatest dimension of deposit <0.1 mm, and capsular involvement)        
 Group 1<0.1 mm85.400.012<.001NA.183.001<.001NA
 Group 2≥0.1 mm and 0 or 1 points105        
 Group 3≥0.1 mm and 2 points27        
S-classification

The central expansion of tumor cells measured as TPD was correlated significantly with OS (P = .006) and RFS (P < .001) with different cutoff points according to the new S-classification (Fig. 1c,d). Patients who had a TPD <0.3 mm had a significantly poorer RFS than patients who had negative SLNs (P = .019), but the OS was similar (P = .261). Kaplan-Meier curves for adjacent groups of SLN-positive patients (TPD <0.3 mm vs 0.3-1 mm and TPD 0.3-1 mm vs >1 mm, respectively) did not diverge significantly in terms of OS or RFS (Table 2).

Hannover system

The Hannover classification with a combination of different parameters (tumor load, TPD, and capsular invasion) could achieve significance in Kaplan-Meier analyses for RFS (P < .001) or OS (P < .001) (Fig. 1e,f). Separate Kaplan-Meier curves (Hannover system: 1 point vs 2 points and 2 points vs 3 points) did not diverge significantly for OS or RFS (Table 2). Patients who had micrometastases in an SLN but no additional positive parameter (tumor load ≥30 cells, TPD >2 mm, capsular invasion) had favorable survival rates, similar to the rates for SLN-negative patients, in terms of both OS (P = .520) and RFS (P = .119).

Multivariate Correlation of Histopathologic Parameters of the SLN and Prognosis

To determine independent prognostic parameters of the SLN, we performed a backwards, stepwise Cox multivariate analysis that included all parameters and all cutoff points that were included in 1 of the published risk-assessment systems (Rotterdam system, S-classification, Hannover system) or that have been established in previous studies (isolated, immunohistochemically positive cells vs cell clusters [Satzger et al18]; a greatest dimension of the largest tumor cell deposit ≤0.2 mm vs >0.2 mm [Scheri et al17]; and the number of positive SLN [Gershenwald et al19]). These analyses revealed 3 parameters that had independent prognostic significance: ie, capsular involvement (present vs absent), TPD with a cutoff point at 2 mm (≤2 mm vs >2 mm), and the greatest dimension of the largest tumor cell deposit with cutoff point at 0.1 mm (<0.1 mm vs ≥0.1 mm) (Table 3).

Table 3. The Prognostic Significance of Histopathologic Parameters in Sentinel Lymph Nodes Analyzed by Backwards, Stepwise Cox Multivariate Analysis
Parameter/CutoffOSRFS
PHR95%CIPHR95%CI
  1. OS indicates overall survival; HR, hazard ratio; CI, confidence interval; IPC, isolated immunohistochemically positive cells; TPD, tumor penetrative depth.

Greatest dimension of deposit, mm      
 <0.1 vs ≥0.1.0510.4410.194-1.003.0060.4000.208-0.772
 <0.2 vs ≥0.2.9111.0590.389-2.883.5430.7520.300-1.885
 <1 vs ≥1.9951.0030.427-2.351.4771.2610.666-2.386
IPC: Yes vs no.9070.9060.175-4.703.3881.6930.513-5.588
No. of positive lymph nodes: 1 vs ≥1.6311.1700.615-2.226.1520.7020.432-1.139
Tumor load: <30 cells vs ≥30 cells.9370.9520.279-3.243.2221.6710.733-3.810
TPD, mm      
 ≤0.3 vs >0.3.2600.6020.248-1.457.4500.7730.397-1.506
 ≤1 vs >1.4161,3640.645-2.883.8840.9510.487-1.859
 ≤2 vs >2.0340.4980.261-0.949.0010.4010.234-0.685
Capsular involvement: Yes vs no.0020.3600.188-0.691.0340.5940.367-0.960

Proposal for an Improved Risk-Assessment System

We developed a new risk-assessment system that differentiates significantly between all groups of patients but is as convenient as possible. This system was based on the parameters that were associated significantly and independently with prognosis (Table 3): ie, the greatest dimension of the largest tumor cell deposit (cutoff point, <0.1 mm/≥0.1 mm), TPD (≤2 mm/>2 mm), and capsular involvement (absent/present). It appears to be sufficient to consider patients with deposits <0.1 mm as a single group. This group has a prognosis similar to that of SLN-negative patients, and additional parameters (TPD and capsular involvement) do not add prognostic information for these patients. If we focus on the 85 patients who had micrometastases in the SLN and a greatest dimension of the largest tumor cell deposit <0.1 mm, in 15 of those patients, an additional parameter (TPD >2 mm or capsular involvement) was detected. We compared the RFS and OS rates of patients who had micrometastases measuring <0.1 mm with the survival rates of patients who had micrometastases <0.1 mm and 1 additional parameter from the Hannover classification (TPD or capsular involvement), and neither group differed significantly (P = .412 and P = .137, respectively). Therefore, patients who had a greatest dimension of the largest tumor cell deposit <0.1 mm were considered as a single group (Hannover-II, Group 1). Patients who had micrometastases ≥0.1 mm and, at most, 1 additional point were classified into Hannover-II, Group 2. Patients who had micrometastases ≥0.1 mm and 2 additional points were classified into Hannover-II, Group 3 (Table 4). In the Hannover-II classification, all separate groups (Group 1 vs Group 2 and Group 2 vs Group 3) diverged significantly in terms of OS and RFS (Fig. 1g,h; Table 2). Patients with a negative SLN and patients with micrometastases <0.1 mm (OS, P = .542; RFS, P = .507) had similar survival rates, and all other separated groups of patients diverged significantly.

Table 4. An Improved Hannover Scoring System (Hannover-II) for Patients With Melanoma That Relies on a Histopathologic Evaluation of a Sentinel Lymph Node Based on 3 Criteria: Greatest Dimension of the Largest Deposit, Tumor Penetrative Depth, and Involvement of the Capsule
GroupCriterion 1Criterion 2Remark
  1. SLN indicates sentinel lymph node; TPD, tumor penetrative depth.

1Largest deposit <0.1 mm Prognosis similar to patients with negative SLN
2Largest deposit ≥0.1 mmMaximum of 1 additional parameterIntermediate prognosis
3Largest deposit ≥0.1 mmBoth TPD >2 mm and involvement of capsulePoor prognosis

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES

We compared histopathologic parameters and risk-assessment systems that predict prognosis in our group of 697 melanoma patients with known clinical course. SLNs were obtained in our center and analyzed by the same standardized histopathologic workup and evaluation.6

All risk-assessment systems were able to separate groups of patients with excellent and poor prognoses. However, the discriminative power of the various systems differed considerably.

In the current study, we confirmed the prognostic relevance of a greatest dimension of 0.1 mm for the largest tumor cell deposit, as described previously by van Akkooi et al.11, 12 Patients who had deposits <0.1 mm had a prognosis similar to that of SLN-negative patients. This is remarkable considering the differences between the study by van Akkooi et al and our study with regard to primary tumor parameters and SLN involvement. Whereas van Akkooi et al indicated a median Breslow thickness of 4 mm and 40 of their 388 patients (10%) had deposits <0.1 mm in an SLN, in our patients, the median Breslow thickness was 2.5 mm, and a greater proportion of patients had micrometastases <0.1 mm (85 of 217 patients; 39%). Thus, the tumors in our patients were in an earlier stage of development. Furthermore, the cutoff point of 0.1 mm is consistent with our previous finding that SLN-positive patients who have a very low tumor burden (isolated, immunohistochemically positive cells in the SLN) have a prognosis similar to that of SLN-negative patients.18 The 0.1-mm cutoff point (according to the Rotterdam criteria11, 12) was superior to the 0.2-mm cutoff proposed by Scheri et al and Govindarajan et al,17, 20 which also agrees with our previous finding that patients who have isolated, immunohistochemically positive cells have a better prognosis than patients who have cell clusters that measure up to 0.2 mm in greatest dimention.21

Our Kaplan-Meier analyses of separated groups revealed significant differences between almost all groups according to the Rotterdam system. Only the comparison of patients in Rotterdam Group 2 (0.1-1 mm) versus patients in Rotterdam Group 3 (>1 mm) did not achieve statistical significance for OS; ie, the comparative power of the Rotterdam system was high but, in a comparison between adjacent groups of patients with higher tumor burden, it was suboptimal, and the cutoff point at 1 mm seems to be dispensable, because it does not add independent prognostic information.

The new S-classification was developed by Starz et al and records the penetration depth of tumor cells in the lymph node.10 Patients with a TPD <0.3 mm (S-I) and a TPD between 0.3 mm and 1 mm (S-II) reportedly had a favorable prognosis, similar to SLN-negative patients. Survival rates for patients who had a TPD >1 mm (S-III) were significantly worse, although a statistical comparison of single groups was not performed.10 Our Kaplan-Meier analyses achieved similar results: Patients who had a TPD >1 mm had a significantly worse OS than patients who had a lower TPD (<0.3 mm and 0.3-1 mm). However, by comparing single groups, we were able to demonstrate that the survival rates for patients in adjacent groups, such as Group 2 versus Group 3 for OS and Group 1 versus Group 2 for RFS, did not diverge not significantly. Altogether, the discriminative power of the Rotterdam system appeared to exceed the discriminative power of the S-classification. One possible reason for these findings may be suboptimal cutoff points of the S-classification. Scolyer et al proposed a higher TPD limit of >2 mm to characterize patients with melanoma who had a poor prognosis.7 Consistent with Scolyer et al, in our previous study, we demonstrated that a cutoff point for TPD at >2 mm was superior to a TPD cutoff point at >1 mm.6 Again, in the multivariate analyses from the current study, a TPD >2 mm (but not a TPD >1 mm) was identified as an independent prognostic parameter. Therefore, a TPD >2 mm was integrated into the Hannover system, which combines the parameters TPD >2 mm, capsular involvement, and tumor burden >30 cells. The Hannover system is able to select SLN-positive patients who have an excellent prognosis, similar to the prognosis of SLN-negative patients. However, adjacent groups (such as Group 2 vs Group 3 for OS or Group 3 vs Group 4 for RFS) did not diverge significantly in the Hannover system. These findings may be related to the higher number of groups (in the Hannover system, there are 4 different groups compared with 3 groups in the Rotterdam system and S-classification). To enhance the discriminative power of the Hannover system and to consider the data from our multivariate analyses, we developed a new Hannover system (Hannover-II), which combines 3 parameters that had independent prognostic relevance in multivariate analyses (TPD >2 mm, capsular involvement, and a greatest dimension of the largest tumor cell deposit ≥0.1 mm). However, the determination of all parameters is required only for patients who have a maximal diameter deposit ≥0.1 mm. The additional parameters of TPD and capsular involvement had no impact on prognosis in patients who had micrometastases that measured <0.1 mm.

The Hannover-II system represents a unique risk-assessment system that has the ability to significantly separate all groups of patients, and particularly patients with higher tumor burden. Determining the other 2 parameters (TPD and capsular invasion) entailed little additional work. TPD can be measured very quickly, and capsular involvement can be detected easily during routine histopathology of the SLN. The combination of different independent parameters is leading to a considerable gain in knowledge, especially with regard to patients with higher tumor burden.

Several studies have demonstrated an impact on survival by the number of positive lymph nodes; therefore, that parameter is included in the current AJCC classification system.9, 19 However, Jakub et al reported that the number of positive SLNs did not affect survival when the metastatic disease was confined to the SLNs and did not spread to the non-SLNs.22 In line with these findings, the parameter number of positive SLNs (1 vs >1) could achieve significance only in RFS, and not in OS. in our univariate analyses.

In SLN-positive patients who did not undergo CLND, 10 of 42 patients (23.8%) developed recurrent disease, compared with 70 of 105 (40%) SLN-positive patients with CLND. The lower percentage of recurrences in the group of patients without CLND can be explained by the lower tumor burden of the respective SLNs. In 22 of 42 patients who did not undergo CLND, we did not recommended a CLND procedure because of the very low tumor burden (isolated, immunohistochemically positive cells).

The underlying study was calculated with a median follow-up of 47.8 months, similar to what was reported by Starz et al (median, 45.5 months) and longer than that reported by van Akkooi et al (median, 36 months).10, 12 Nevertheless, the possibility cannot be excluded that, over the long run, different findings can be achieved because of lead time bias. This phenomenon is based on the observation that smaller metastatic deposits will take longer for recurrence and the detection of possible metastatic disease.23 Future analyses with long-term follow-up should address this problem.

In conclusion, in this report, we present 3 statistically independent prognostic parameters that can be determined easily in a routine histopathologic examination of SLNs. The combination of these parameters was able to predict the prognosis for patients with melanoma most precisely. However, further studies in multi-institutional patient populations will be necessary to substantiate our findings.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONFLICT OF INTEREST DISCLOSURES
  7. REFERENCES