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10.1245/ASO.2005.06.013
Annals of Surgical Oncology 12:440-448 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Sentinel Lymph Node Tumor Load: An Independent Predictor of Additional Lymph Node Involvement and Survival in Melanoma

Ronald J. C. L. M. Vuylsteke, MD1, Paul J. Borgstein, MD, PhD1, Paul A. M. van Leeuwen, MD, PhD1, Hester A. Gietema, MD1, Barbara G. Molenkamp, MD1, Markwin G. Statius Muller, MD, PhD1, Paul J. van Diest, MD, PhD2, Joost R. M. van der Sijp, MD, PhD1 and Sybren Meijer, MD, PhD1

1 Department of Surgical Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
2 Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: Paul A. M. van Leeuwen, MD, PhD; E-mail: pam.vleeuwen{at}vumc.nl


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Even though 60% to 80% of melanoma patients with a positive sentinel lymph node (SLN) have no positive additional lymph nodes (ALNs), all these patients are subjected to an ALN dissection (ALND) with its associated morbidity. The aim of this study was to predict the absence of ALN metastases in patients with a positive SLN by using features of the primary melanoma and SLN tumor load.

Methods: Of 71 SLN-positive patients, 52 had metastasis limited to the SLN (group 1), and 19 had ≥1 positive ALN after ALND (group 2). The tumor load of the SLN was assessed by measuring the total surface area by computerized morphometry. Breslow thickness, ulceration and lymphatic invasion of the primary tumor, and total SLN metastatic area were tested as covariates predicting the absence of positive ALNs.

Results: The mean SLN metastatic area was 1.18 mm2 (group 1) and 3.39 mm2 (group 2) (P = .003) and was the only significant and independent factor after multivariate analysis (P = .02). None of the patients with both a Breslow thickness <2.5 mm and an SLN metastatic area <.3 mm2 had a positive ALN.

Conclusions: SLN metastatic area can be used to predict the absence of positive ALNs in melanoma patients. In this study, patients with a Breslow thickness <2.5 mm and an SLN tumor load <.3 mm2 seemed to have no positive ALN and had excellent survival. We hypothesize that this subgroup might not benefit from ALND. Prospective larger trials, using this model and randomizing between ALND and no ALND, should confirm this hypothesis.

Key Words: Sentinel lymph node • Melanoma • Additional lymph node • Metastatic area


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sentinel lymph node (SLN) biopsy has become the standard procedure in our hospital for patients with a primary cutaneous melanoma and no clinically detectable regional lymph node metastases. It has been shown to be a reliable method with low false-negative rates.1–4 SLN biopsy offers a reliable procedure to predict lymphatic tumor spread. Biopsy of the SLN will allow lymph node metastasis (clinically occult or microscopic metastasis) to be identified at a very early stage of development and will spare approximately 80% of patients who have a negative SLN a superfluous elective lymph node dissection.2,5–7 Because only a few lymph nodes have to be screened by the pathologist, this can be done with more attention, thus resulting in a higher sensitivity for finding metastatic cells.8

The concept of the SLN procedure is based on the theory of an orderly progression of the metastatic process within the lymphatic system.9 The SLN has a barrier function for disseminating tumor cells and an effective filtering capacity.10 When the SLN is tumor negative, there should conceptually be no second-echelon metastasis, and an additional lymph node dissection (ALND) can be omitted.7,11 When metastatic tumor cells are detected in the SLN, there is a fair chance that there are further second-echelon metastases, and an ALND follows as a rule to achieve local control.

However, only 20% to 33% of patients who have undergone an ALND after a positive SLN have additional tumor-involved lymph nodes in the dissected draining lymph node basin.5,6,12,13 The current accurate methods for detecting small groups of metastatic cells in the SLN upstage many patients who have no tumor spread beyond the SLN and might not need an ALND. A method to predict the absence of tumor spread beyond the SLN would spare this group of patients unnecessary ALND and its associated morbidity.

Although it was mentioned that patients with tumor-positive SLNs could be divided into several subgroups, most studies published so far have not found any factor to be significant in predicting the chance for positive additional lymph nodes (ALNs) in patients with positive SLNs.12,14–16 Combinations of Breslow thickness of the primary tumor, volume of tumor involvement in the SLN, and reduced density of interdigitating dendritic cells in the SLN (as an index of nodal immune downregulation) have been mentioned as powerful predictors of non-SLN tumor status and clinical outcome.13,17–20

The aim of this study was to analyze the SLN metastatic area in combination with primary tumor parameters as predictors of metastatic involvement of ALNs. With these variables, a simple model is created to predict the absence of lymphatic tumor spread beyond the SLN(s). Eventually, this might obviate an ALND for a subset of SLN-positive patients.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
From August 1993 to September 2001, a total of 454 consecutive patients with a clinical stage I or II cutaneous melanoma, as defined by the American Joint Committee on Cancer, underwent SLN biopsy in a prospective study.21 All patients were treated according to the same protocol; no alterations where introduced during the study. Breslow thickness, Clark level of invasion, presence of lymphatic invasion, and ulceration of the primary melanoma were determined or were reevaluated if a patient was referred from another hospital. SLNs were successfully detected and removed in 447 patients (98%) from a total of 531 regional lymph node basins. The SLN was not found in three patients. In four patients the SLN was left in situ to avoid potential morbidity associated with the intervention: three patients had their SLN situated in the parotid gland, and in one patient the SLN was situated deep in the axilla.

The group consisted of 245 women and 209 men with a median age of 49 years (range, 6–84 years). The mean Breslow thickness was 1.79 mm (median, 1.37 mm; range, .50–9.00 mm). From this group, the patients with a positive SLN were selected and finally divided into a group without ALN involvement (group 1) and a group with involvement of ALN (group 2).

Triple Technique
To determine lymphatic drainage patterns, all patients underwent dynamic and static lymphoscintigraphy (LS) before surgery. 99mTc-labeled colloidal albumin (Nanocoll; Sorin Biomedica, Saluggia, Italy) with a particle size of 30 to 80 nm was used as tracer and was given through two to four intradermal injections with 10 MBq in .15 mL per injection as described by van der Veen et al.22 These injections were given just adjacent to the scar of the excision biopsy. Immediately after the injections, dynamic LS was started: 20 images of 60 seconds each. Static LS (300 seconds per image) was made 2 to 18 hours after the injection to check whether initial accumulations had retained the tracer. A handheld gamma-detection probe (C-trak [Care Wise Medical Products, Morgan Hill, CA] or CTC-4 [Radiation Monitoring Devices, Watertown, MA]) with settings of 120 keV (lower threshold) and 160 keV (upper threshold) was used to verify the side of the SLNs. All sites were marked on the skin with indelible ink. Surgery was performed 2 to 24 hours after injection of the tracer.

Shortly before the operation, .15 to .5 mL of Patent Blue V (Laboratoire Guerbet, Aulnay-sous-Bois, France) was injected intradermally next to the initial side of the melanoma. A sterile-packed gamma probe was used to localize the site of the incision. The blue dye and gamma probe helped in localizing the SLN(s) during meticulous dissection. These nodes were subsequently excised. A lymph node was considered an SLN during surgery when it stained blue, had an in situ radioactivity count of at least 3 times that of the background, or had an ex vivo radioactivity count of at least 10 times greater than that of the background. To establish that all hot nodes had been removed, residual activity in the basin was checked with the gamma probe after removal of the SLN(s). Residual lymph nodes were excised if they contained radioactivity >10% of the SLN. Cautious palpation of the lymph node basin was performed to detect enlarged or pathologic non-SLNs. When indicated, a wide local excision of the primary scar was performed after the SLN procedure.

Pathologic Examination
After the SLN procedure, harvested SLN(s) were fixed in neutral buffered formaldehyde, lamellated according to size, and completely embedded in paraffin. SLNs smaller than .5 cm were processed and paraffin-embedded intact. Those between .5 and 1.0 cm were halved, and SLNs larger than 1.0 cm were lamellated into pieces approximately .5 cm in size. One initial 4-µm-thick hematoxylin and eosin (H&E)-stained section was made per block. When negative, four additional step ribbons were cut at 250-µm intervals. Of each ribbon, one section was stained with H&E, and two were used for S-100 and HMB-45 immunohistochemistry as described previously.8

The SLN metastatic area was determined by using an interactive video morphometry system (Q-prodit; Leica, Cambridge, UK). In every SLN found to contain metastatic tumor cells, the configuration of the metastatic cells, the number of foci, and their distribution within the lymph node were examined. The SLN section containing the largest visible amount of metastatic tumor cells was selected. The surface areas of the individual tumor deposits in this single section were measured, and the SLN metastatic area was calculated by summing up these areas. In case of two positive SLNs, the one with the largest tumor load was used. The SLN metastatic areas were measured by two independent observers, of which one observer measured the areas twice with an interval of approximately 8 weeks. The intraobserver and interobserver reproducibility was good, with Spearman’s correlation coefficients of .99 and .98, respectively.

At a later date, an additional regional lymphadenectomy was performed when the SLN(s) contained metastatic tumor cells, if the patient agreed. From the dissected draining lymph node basin, all lymph nodes were recovered. The lymph nodes were lamellated and embedded as described previously. From each block, one section was cut and stained with H&E.

Patients with a negative SLN were followed up only. Follow-up comprised regular outpatient physical examination at 3- to 6-month intervals. Relevant diagnostic investigations occurred only when indicated. The median follow-up was 64 months (range, 3–124 months).

Statistical Analysis
Statistical analysis was performed with SPSS for Windows 98 (SPSS Inc., Chicago, IL). Categorical variables were analyzed by using the {chi}2 test. Non-parametric data were analyzed by using the Mann-Whitney U-test. Pearson’s correlation analysis was performed for Breslow thickness and area of metastasis in the SLN. All relevant variables that were associated with the presence of positive ALNs by univariate regression analysis were included in a multivariate logistic regression analysis: Breslow thickness, SLN metastatic area, and presence of ulceration and lymphatic invasion in the primary tumor. Analysis of disease-free (DFS) and overall survival (OS) was performed by the Kaplan-Meier approach, and differences between curves were analyzed with the log-rank test. Multivariate survival analysis was performed with Cox regression. P values <.05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
SLN Identification
Eighty patients (18%) had a tumor-positive SLN. The SLN of one patient was located in the parotid gland. Fine-needle aspiration biopsy showed the SLN to contain metastatic cells. She was not subjected to a complete triple-technique SLN procedure but underwent an ALND after this fine-needle biopsy. Of the remaining 79 patients, ultimately 71 were subjects of the study.

The mean Breslow thickness of the primary tumor was 2.86 mm (median, 2.30 mm; range, .69–9.00 mm). The remaining patient and tumor characteristics are listed in Table 1Go. One hundred forty-three SLNs were detected in 93 regional lymph node basins (1.5 SLNs per basin). Sixty-seven patients had 1 tumor-draining basin, 11 patients had 2, and 1 patient had 4. The mean number of SLNs per patient was 1.8.


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  		TABLE 1. Characteristics of the patients with removed positive sentinel lymph nodes
 
A total of 872 (median, 11.5 per patient) ALNs were removed by ALND in 74 patients, and 5 patients refused to undergo ALND for personal reasons. These five patients are all alive after a median follow-up of 59 months. Of these 74 patients, the SLNs of 55 (74%) patients were the only lymph nodes to contain melanoma, whereas 19 (26%) patients had non-SLNs involved: 10 (53%) patients had 1 non-SLN involved, 4 (21%) had 2 non-SLNs involved, and 5 (26%) patients had ≥3 non-SLNs involved.

Area of Tumor Involvement in SLN
The slides of three patients were not available for measuring the area of metastasis in the SLN, so the characteristics of 71 patients were left for measuring the area of tumor involvement in the SLN and for statistical analysis.

Within the SLNs, the morphological distribution of metastatic tumor cells varied from tiny clusters of melanoma cells lying in the subcapsular sinus to extensive infiltration of the entire lymph node, replacing nearly all of the normal lymphoid tissue. The total surface area of the tumor foci within a lymph node seemed to correlate with their morphological distribution: very small deposits were always found in the subcapsular or marginal sinuses, whereas larger masses tended to involve the adjacent parenchyma or even extended beyond the outer nodal limits.

The 71 patients were divided into 2 subgroups: group 1 encompassed those in whom only the SLN(s) contained metastases (52 patients), whereas those with positive ALNs were assigned to group 2 (19 patients). The characteristics of the two groups are listed in Table 2Go.


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  		TABLE 2. Comparison of cutaneous melanoma patients (n = 71) with metastasis only in the SLN (group 1) and patients with additional positive regional lymph nodes (group 2)
 
In individual SLNs, the metastatic area ranged from .003 to 13.96 mm2, with a mean of 1.77 mm2. The mean SLN metastatic area was 1.18 mm2 for group 1 and 3.39 mm2 for group 2 (P = .003; Table 2Go). Actual values of the SLN metastatic area of each patient are shown in Fig. 1Go. There was a positive correlation between Breslow thickness and total metastatic surface area (correlation coefficient, .334; P = .004; Fig. 2Go).


Figure 1
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  		FIG. 1. Sentinel lymph node (SLN) metastatic area of cutaneous melanoma patients with only SLN involvement (group 1; 52 patients) compared with patients with positive additional lymph nodes (group 2; 19 patients). Horizontal bars represent the mean SLN metastatic area in both groups: 1.18 mm2 for group 1 and 3.39 mm2 for group 2 (P = .003).

 

Figure 2
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  		FIG. 2. Scatter plot of total sentinel lymph node (SLN) metastatic area and Breslow thickness for a group of cutaneous melanoma patients with (19 patients; circles) or without (52 patients; squares) additional lymph node metastases. No positive additional lymph nodes were found in patients with both an arbitrarily taken Breslow thickness of the primary tumor <2.5 mm and an SLN metastatic area <.3 mm2. Pearson’s correlation coefficient was .334 (P = .004).

 
In patients with an SLN metastatic area <.03 mm2 (10 patients), no positive ALNs were found. However, when only patients with a Breslow thickness <2.5 mm were considered, the threshold for the presence of positive ALNs increased to an area of .3 mm2. There was a significant correlation between SLN metastatic area and Breslow thickness (Pearson’s correlation coefficient, .334; P = .004; Fig. 2Go). In other words, no positive ALNs were found in patients with both an arbitrarily taken Breslow thickness of the primary tumor <2.5 mm and an SLN metastatic area <.3 mm2. In logistic regression, the SLN metastatic area was the only independent factor that was significant (P = .02) in predicting the presence of positive ALNs (Table 3Go).


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  		TABLE 3. Multivariate predictive value (logistic regression) of several factors for the presence of additional positive lymph nodes in SLN-positive cutaneous melanoma patients (n = 71)
 
Recurrent Disease
Recurrent disease was seen in 33 (46%) of the 71 patients during follow-up (Table 2Go). Twenty (38%) patients in group 1 had a recurrence, whereas 13 (68%) in group 2 had a recurrence (P = .03). Loco-regional cutaneous metastasis was the first recurrence to develop in 19 patients (11 in group 1 and 8 in group 2), whereas 14 patients (9 in group 1 and 5 in group 2) developed distant metastases as the first site of recurrence. None of the patients had a recurrence in the draining lymph node basin.

DFS and OS
Patients were divided into three subgroups. Subgroup A comprised patients with a Breslow thickness <2.5 mm, an SLN tumor load <.3 mm2, and no positive ALNs (n = 21), subgroup B comprised all other patients without positive ALNs (Breslow thickness ≥2.5 mm, SLN metastatic area ≥.3 mm2, or both; n = 31), and subgroup C encompassed patients with positive ALNs (n = 19). Subgroup A had a significantly better DFS (P < .0001) and OS (P < .0001) compared with the rest of the patients (Figs. 3Go and 4Go, respectively). Five-year DFS was 87% ± 8.6% (± SEM) for group A, 52% ± 10.4% for group B, and 18% ± 10.9% for group C. Five-year OS was 94% ± 5.4%, 56% ± 10.7%, and 30% ± 12.1%, respectively.


Figure 3
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  		FIG. 3. Disease-free survival curves for cutaneous melanoma patients with a Breslow thickness <2.5 mm, a sentinel lymph node (SLN) metastatic area <.3 mm2, and no positive additional lymph nodes (ALNs) (group A); patients with a Breslow thickness ≥2.5 mm and/or an SLN metastatic area ≥.3 mm2 and no positive ALN (group B); and patients with a positive ALN (group C; P < .0001).

 

Figure 4
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  		FIG. 4. Overall survival curves for cutaneous melanoma patients with a Breslow thickness <2.5 mm, a sentinel lymph node (SLN) metastatic area <.3 mm2, and no positive additional lymph nodes (ALNs; group A); patients with a Breslow thickness ≥2.5 mm and/or an SLN metastatic area ≥.3 mm2 and no positive ALN (group B); and patients with a positive ALN (group C; P < .0001).

 
We performed a multivariate Cox regression analysis on all patients to determine the influence of several factors on DFS and OS (Table 4Go). The factors that were independently related to a poorer DFS included the presence of lymphatic invasion in the primary tumor (P = .02) and an SLN metastatic area ≥.3 mm2 (P = .007). An SLN metastatic area of ≥.3 mm2 was the only independent factor correlated with a worse OS (P = .01).


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  		TABLE 4. Multivariate Cox regression analysis of disease-free survival and overall survival for all SLN-positive cutaneous melanoma patients
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The SLN procedure has become common in cutaneous melanoma. Patients with a negative SLN are spared an ALND and are followed up during frequent visits at the outpatient department. The applied triple-technique procedure has been shown to be reliable, with a relatively low false-negative rate.1–4 If the SLN contains metastatic melanoma cells, an ALND follows at a later date. However, approximately two thirds of the patients with a positive SLN have metastases limited to the SLN.5,6,12,13 The significant associated morbidity of an ALND (paresthesias, wound infection, seroma formation, and lymphedema) without proven better long-term survival makes it worthwhile to try to develop a staging model to predict which group of patients with a positive SLN have ALN involvement and might benefit from an ALND and which group of patients might be saved from this additional operation. The development of immunohistochemistry with S-100, HMB-45, and Melan-A antibodies has made it possible to detect smaller (and, thereby, probably earlier) metastatic cells, but it upstages many patients who will not benefit from an ALND and necessitates the development of an additional staging system.

Varying degrees of nodal involvement in lymphatic spread have long been recognized, but the clinical significance of occult metastases, especially micrometastases (so far arbitrarily defined as metastases with a diameter <2 mm), continues to be a subject of debate. The clinical implications of micrometastases are not completely elucidated, and their biologic behavior is not yet clear.23,24 It is possible that there is a critical mass of cancer cells that confers prognostic implications.18,19,23

The lymphatic spread of melanoma cells follows an orderly progression via the SLN to non-SLNs in the same draining lymph node basin. In the SLN, too, tumor cells are thought to follow an orderly progression, arriving in the subcapsular sinuses through an afferent capsular lymph vessel. Later, there is subcapsular outgrowth of malignant cells in the marginal sinuses and into the immediately adjacent cortical parenchyma. Finally, these cells extend to the deeper zones of the lymph node parenchyma, frequently follow the medullary sinuses to efferent lymphatic vessels, and may ultimately penetrate the capsule.17 At present there is no staging system that considers the volume of tumor found in the lymph nodes; they are simply considered to be positive or negative.21 The distribution of the melanoma cells in the SLN was, in combination with the Breslow thickness of the primary tumor, mentioned as a significant predictive factor for the chance of non-SLN involvement.17,20 This supports the use of a classification system of the metastatic spread in the SLN according to the size and distribution of the metastatic cells in the SLN, because a significant number of lymph node–positive patients have metastases limited to the SLN(s).

For breast carcinoma, it has been suggested that a combination of tumor size and the size of the metastasis in the SLN is predictive for the chance of non-SLN involvement.25,26 In a small melanoma study, Cochran et al.18 tried to improve the predictive accuracy with morphological techniques to determine the tumor load. Outcome was most accurately predicted to be favorable when fewer than four lymph nodes were involved and the total tumor diameter was <15% of the total nodal diameter.

By following a line of reasoning similar to that of Breslow when he devised his micrometer-based thickness measurement as a surrogate for primary tumor volume, we decided to assess the total surface area of tumor deposits in the SLN by morphometry as a measure for SLN tumor load. Because microscopic metastatic cells seldom appear as round foci but are often clustered along the subcapsular sinus, this method provides a more accurate assessment of tumor load than does tumor diameter.

In this study, the SLN metastatic area was the only independent predictor of positive ALNs. Irrespective of Breslow thickness, patients with an SLN metastatic area <.03 mm2 never had positive ALNs. Nevertheless, there was a significant correlation between Breslow thickness and SLN metastatic area. In patients with a Breslow thickness <2.5 mm, the SLN metastatic area threshold below which additional positive lymph nodes were never found was .3 mm2. These patients had an excellent 5-year DFS and OS (83% and 94%, respectively), comparable to those of patients with a negative SLN.27 Starz et al.17 used a comparable method to determine the tumor burden in the SLN. They used the S classification, which is based on the maximum depth of invasion of metastatic cells in the SLN; S0 represents no metastatic involvement of the SLN, and SIII represents a metastatic invasion of the SLN >1 mm. The predictive value of their S classification seems to be similar to the SLN metastatic area described in this study; it is a strong predictor of ALN involvement and survival.28 Cochran et al.20 described similar results regarding the relative area of tumor in the SLN.

In this study, the SLN metastatic area was independently related to a poorer DFS and was the only factor independently related to a worse OS. The fact that SLN metastatic area was the only factor significantly related to a worse OS might be explained by the fact that the median follow-up in this study was relatively short.

The ALNs in this study were examined with routine histological techniques (H&E). ALN involvement was present in 27% of these patients. These data seem comparable to the data of other studies that analyzed ALNs by using the same technique as for SLNs and found ALN involvement in 28% and 21% of patients, respectively.17,20 Whether analyzing the ALNs with the same technique as used for SLNs would increase the percentage of ALN involvement is not known.

In conclusion, the total SLN metastatic area may, in combination with the Breslow thickness of the primary tumor, be used to predict the absence of positive ALNs and survival. The combination of these factors makes it possible to formulate a staging model, so that superselective lymph node dissection becomes feasible. Such a microstaging system not only will avoid unnecessary morbidity, but also shows that patients with a positive SLN are a heterogeneous group. This study shows that patients with a Breslow thickness <2.5 mm and an SLN metastatic area <.3 mm2 might not benefit from an ALND. We hypothesize that an ALND might be omitted in these patients. Nevertheless, to answer these questions, a prospective trial in which SLN-positive patients are randomized between ALND and no ALND has to be performed.29,30


   ACKNOWLEDGMENTS
 
Supported by a grant from the Fritz Ahlqvist Foundation.

Received for publication June 8, 2004. Accepted for publication February 5, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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