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10.1245/s10434-006-9241-3
Annals of Surgical Oncology 14:906-912 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Histological Features of Melanoma Sentinel Lymph Node Metastases Associated with Status of the Completion Lymphadenectomy and Rate of Subsequent Relapse

Anand Govindarajan, MD1, Danny M. Ghazarian, MD, PhD2, David R. McCready, MD1,3 and Wey L. Leong, MD, MSc1,3

1 Division of General Surgery, University of Toronto, Toronto, ON, Canada
2 Department of Pathology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
3 Department of Surgical Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, 610 University Avenue, Suite 3-130, M5G 2M9, Toronto, ON, Canada

Correspondence: Address correspondence and reprint requests to: Wey L. Leong, MD, MSc; E-mail: Wey.Leong{at}uhn.on.ca


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: The current recommendation for patients with cutaneous melanoma and a positive sentinel lymph node (SLN) biopsy is a completion lymph node dissection (CLND). This study sought to define a population of SLN-positive patients, based on their histological pattern of SLN metastases, who may not require CLND.

Methods: All patients with SLN-positive cutaneous melanoma who underwent CLND between March 1999 and December 2004 at a single academic institution were enrolled. Metastatic deposits in the SLN were categorized by their histological zone of involvement (subcapsular, parenchymal and/or sinusoidal). Logistic regression was used to examine the effect of SLN zone, size of nodal metastases, and other histological factors on CLND positivity. Kaplan-Meier and Cox models were used to study disease recurrence.

Results: A total of 127 patients were included, and 15.8% had positive non-sentinel nodes. In adjusted analyses, the size of the largest tumor deposit in the SLN was the only factor associated with CLND status. No patients with a tumor deposit ≤0.20 mm had a positive CLND. Although a specific zone of tumor involvement was not predictive of CLND status, involvement of all three zones was independently associated with increased recurrence. Size of the largest tumor deposit was also associated with recurrence, with no recurrences in patients with nodal deposits ≤0.20 mm.

Conclusion: Histologic features of tumor metastases in positive SLN may be useful in defining a population of patients who may be spared CLND and a group at high risk of recurrence.

Key Words: Melanoma • Sentinel lymph node • Metastasis • Histopathology


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Cutaneous melanoma is the eighth most common cancer in North America and is the deadliest form of skin cancer.1 The most important prognostic factor in cutaneous melanoma is the spread of tumor to the regional lymph nodes.2–6 The emergence of sentinel lymph node (SLN) biopsy techniques in 19927 has reduced the morbidity associated with determining the nodal status by allowing patients with negative SLN to safely avoid a complete lymphadenectomy and its attendant morbidity. As a result, SLN biopsy is currently the nodal staging procedure of choice in patients with clinically non-metastatic melanoma of tumor stage T1b or greater, with only SLN-positive patients proceeding to a completion lymphadenectomy (CLND) for clearance of any remaining nodal disease.8,9 However, only 20%9–13 of SLN-positive patients will have further tumor involvement of non-sentinel nodes; thus, the remaining 80% of patients with no further nodal involvement will receive no oncologic benefit from a completion lymphadenectomy. Therefore, a number of studies have examined ways to "ultrastage" patients with positive SLN in order to identify a subgroup who may not require a CLND.9,10,12–25 Previous studies have described the histological pattern of the metastatic deposits in the SLN,22,26 the present study examines the relationship between the pattern and size of nodal metastases with the status of the CLND and disease recurrence.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Study Design and Population
A retrospective cohort study design was used and all patients with primary cutaneous melanoma who had a positive SLN biopsy and subsequent completion lymphadenectomy between March 1999 and December 2004 at a single academic institution (Princess Margaret Hospital, University of Toronto, Toronto, Canada) were included. The indications for SLN biopsies were melanoma with a depth ≥1 mm, Clark’s level IV or the presence of ulceration.

Lymph Node Biopsy and Pathological Assessment
Sentinel node biopsies were performed using peritumoral injections of unfiltered 20–40 MBq 99Tc-sulfur colloid with or without injection of blue dye. Nodes were considered sentinel if they were blue or if they registered more than 10% of the hottest node on a gamma probe. The technique has been previously described in full by McCready et al.27 The sentinel nodes were processed by the method detailed by Cochran et al.28 They were stained with hematoxylin and eosin (H&E) as well as the immunohistochemical stains S-100 and HMB-45. All nodes were analyzed and reported prospectively by a single dermatopathologist for consistency. Measurements of tumor foci within the SLN were made using a Leica optical micrometer. All CLND specimens were analyzed in a routine manner, with lymph nodes bisected or trisected (based on size) and stained with H&E. Immunohistochemical stains were used for confirmatory testing when necessary.

Data Collection
Variables related to patient demographics, tumor factors, and sentinel node factors were recorded. The sentinel node was divided into three histological zones as described previously26—subcapsular, parenchymal and sinusoidal—and metastatic deposits in the SLN were described by their histological zone of involvement. The subcapsular zone consisted of the entire subcapsular area of the SLN including the subcapsular sinus. The parenchymal zone referred to tumor foci within the parenchyma of the SLN including areas of the cortex that were not in contact with the capsule. The sinusoidal region comprised the medullary sinuses. Involved zones were analyzed in two ways. First, the number of zones involved (1, 2, or 3) was used as the primary predictor variable. Secondly, each zone was treated as a categorical variable, with the involvement of each zone being a dichotomous variable for each patient. The size of the largest tumor focus in the SLN (defined as the maximal diameter of the tumor focus on cross-sectional slices) and the number of tumor foci were also measured. The primary outcome measure was the finding of positive non-sentinel nodes at completion lymphadenectomy. Time to recurrence was analyzed as a secondary outcome. The study was approved by the institutional Research Ethics Board.

Statistics
Descriptive and summary statistics were calculated for all variables. Univariate analysis of factors associated with the primary outcome (status of the completion lymphadenectomy) was analyzed using the t test or Wilcoxon rank sum test for continuous variables and the chi-square or Fisher’s exact test for categorical data. Variables were then entered into a multivariable logistic regression model to control for potential confounders, yielding odds ratios and 95% confidence intervals. The secondary outcome (disease recurrence) was analyzed using Kaplan-Meier methods for univariate analysis, with curves compared using the log-rank test. Cox proportional hazard models were used to control for confounding variables. Hazard ratios and 95% confidence intervals were generated. Time-to-event analysis was used for the secondary outcome as the patients received variable lengths of follow-up. Covariates for multivariable modeling were selected based on clinico-pathologic considerations and results of univariate testing. All variables in multivariable models were checked for multicollinearity prior to inclusion. A significance level of P < 0.05 was used and all tests were two-sided. Statistical analysis was performed using SAS v9.1 (SAS Institute, Inc. Cary, NC, USA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
A total of 127 patients met the study criteria. Patient, tumor and SLN characteristics are listed in Table 1Go. The median follow-up was 31.2 months (interquartile range 13.6–46.0). The majority of tumor deposits in the SLN were in the subcapsular zone, the parenchymal zone or both. A median of 2 SLNs were removed for each patient (range 1–11), and a median of 1 sentinel node per patient was positive (range 1–3).


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  		TABLE 1. Patient, tumor and sentinel lymph node (SLN) characteristics of study population
 
Lymph Node Basin Status
A mean of 18.5 lymph nodes (median: 16.0, inter-quartile range: 12–24) were retrieved during the completion lymphadenectomy. The proportion of patients with at least one positive non-sentinel node on CLND was 15.8%. In univariate (Table 1Go) and multivariable analysis (not shown), the specific histological zone of tumor involvement within the SLN was not a significant predictor of the status of the CLND, using both the number of zones involved and the pattern of zones involved as the predictor variable. Furthermore, there were no specific zones of tumor involvement that were consistently associated with a negative CLND. For example, of the 33 patients with isolated involvement of the subcapsular zone, 5 had positive non-sentinel nodes, and 3 of these patients developed a recurrence.

The size of the largest tumor deposit in the SLN was a significant predictor of the status of the CLND in univariate and multivariable analyses. There were no instances of positive non-sentinel nodes when the largest tumor deposit in the SLN was ≤0.20 mm (Table 2Go). After adjusting for confounding variables, the odds ratio (OR) of a positive CLND was 1.08 (95% CI: 1.01–1.17) for every 0.5mm increase in the size of the tumor focus in the SLN.


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  		TABLE 2. Association of positive completion lymph node dissection with tumor deposit size and ratio of positive SLNs
 
Recurrence
During the follow-up period, the recurrence rate was 30.7% in this population of SLN-positive patients. In unadjusted analysis, the zone of tumor involvement within the SLN was significantly associated with recurrence. Specifically, involvement of all 3 zones (subcapsular, parenchymal and sinusoidal) was significantly associated with increased recurrence (Fig. 1Go, median time to recurrence: 10.9 versus 59.1 months where one or two zones were involved). Involvement of the subcapsular zone was associated with a larger increase in risk of recurrence [hazard ratio (HR): 5.2, 95% CI: 1.2–21.7] than involvement of the other zones (HR for parenchymal zone: 2.1, 95% CI: 0.99–4.4; HR for sinusoidal zone: 1.9, 95% CI: 0.7–5.0). The following factors were also associated with increased recurrence: CLND positivity, increased size of the largest tumor focus in the SLN, increased depth of the primary tumor, and the presence of ulceration of the primary tumor. There were no recurrences when the size of the largest tumor focus in the SLN was smaller than 0.20 mm. After adjusting for confounders, involvement of all three zones remained an independent predictor of increased recurrence (Table 3Go), whereas involvement of specific zones did not remain significantly associated with recurrence. Of the six patients that had all three zones involved, five (83%) developed a systemic recurrence. Depth of the primary tumor and the presence of ulceration remained associated with an increase in recurrence.


Figure 1
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  		FIG. 1. Association of time to melanoma recurrence with number of zones involved by tumor. Patients with three zones involved have significantly increased recurrence compared to patients with one or two zones involved.

 

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  		TABLE 3. Multivariable analysis of recurrence with number of involved zones as primary predictor
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
The poor prognostic significance of positive nodal status in cutaneous melanoma has been shown in previous studies.2–6 However, recent meta-analyses and systematic reviews have shown limited therapeutic benefit with a routine practice of elective lymph node dissection, likely due to the fact that the majority of patients do not harbor node-positive disease.29–31 SLN status has been shown to correlate with status of the entire lymph node basin, and indeed may be a better staging tool than elective lymph node dissection.7,32–37 Thus, it is currently used as the procedure of choice for nodal staging. The negative predictive value of a SLN is high as there is an orderly progression of melanoma metastasis first to the SLN before progressing to the remaining lymph nodes.38 However, only 15–20% of patients with positive SLN will have additional non-sentinel nodes positive in the CLND,9–12 but in most centers, all patients with a positive SLN will be offered a CLND, a procedure that is associated with higher cost and morbidity. As a result, several studies have examined ways to ultrastage the SLN to determine if there is a subset of SLN-positive patients who do not require CLND and have a better prognosis.9,10,12–25 The results of these studies are somewhat variable and have not resulted in a consistent set of predictors of CLND status.

Some studies have suggested that the histological location of the tumor deposits in the SLN and the tumor burden within the SLNs may be important predictors of CLND status.14–16,19,22–25 Starz et al. suggested that there was a progression of tumor through the SLN starting in the pericapsular area of the afferent lymphatic, and progressing through the parenchyma into the deepest layers of the SLN where the medullary sinuses lie and the efferent lymphatics arise.25 They also showed that the depth of the tumor deposit in the SLN correlated with the risk of spread to non-sentinel nodes and long-term patient outcomes. Although others have confirmed these find-ings,19,23,24 depth alone could not reliably identify a group of patients who uniformly had a negative CLND and thus could have been spared the procedure. In a retrospective study of 146 patients in the United Kingdom, Dewar et al. suggested that CLND may be safely avoided in patients with isolated metastases to the subcapsular zone because they did not observe any positive non-sentinel nodes in this group.22 In our study, however, 5 out of 33 (15.2%) patients with isolated subcapsular metastases had positive nodes on CLND, 3 of whom developed a subsequent recurrence. The reasons for the conflicting results in the two studies are not clear, but may be due to sampling bias secondary to relatively small sample sizes, or due to differences in assessing the CLND specimen. In addition, although a tumor focus can be localized within a SLN by an experienced pathologist, categorizing it into zones is dependent on the precise histologic definitions used at the institution. The reproducibility of this categorization outside of single-centre series’ has not been established, and therefore, we cannot exclude the possibility that there were subtle differences between the two studies in classifying the microanatomic locations of the tumor foci in the SLN. Based on our result, we do not recommend using isolated subcapsular zone involvement as a factor to avoid CLND.

Although the histological zones of tumor involvement in the SLN were not associated with the status of the CLND, they were associated with recurrence. Patients with extensive SLN involvement, defined as a SLN in which all three zones (subcapsular, parenchymal and sinusoidal) were involved with tumor had a 13-fold increased risk of recurrence compared to patients whose SLN only had one or two zones involved, despite controlling for primary tumor depth and ulceration. As this factor was not associated with CLND status but was an independent predictor of recurrence, it could reflect the presence of an aggressive tumor that may have already spread beyond the nodal basin. This hypothesis is supported by the observation that all patients in this group who developed a recurrence, developed systemic recurrences. However, it must be recognized that, in this study, only six patients had all three SLN zones involved.

The size of the largest tumor deposit in the SLN was predictive of CLND positivity in both univariable and multivariable analysis. This is consistent with other studies that have found that the burden of tumor within the SLN is a significant predictor of CLND status.12,19–21,39 To enhance the clinical applicability of this continuous measure, we divided these patients into three categories. As there is no classification system for the size of nodal metastasis in melanoma, we tested the classification for breast cancer, in which experience with SLNs is most abundant, and categorized the size of the largest tumor deposit in the SLN as ≤0.20, 0.20–2.0 or ≥2.0 mm. Under this classification, we found that no patients in the ≤0.20 mm category [the equivalent of isolated tumor cells in breast cancer, stage pN0(i+)] had positive non-sentinel nodes on CLND and that there was a significant gradient of increasing CLND positivity across the three categories. Furthermore, no patients in the ≤0.20 mm category had a recurrence during the follow-up period. Our findings, although based on a small sample size, do suggest that this subgroup of patients may be spared CLND and its attendant morbidity. However, it will need to be tested prospectively on larger sample sizes with longer follow-up before it can be widely applied.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
The SLN biopsy is the current standard nodal staging procedure for patients with melanoma9 and has been shown to correlate with CLND status and long-term prognosis. However, the majority of patients with SLN-metastases does not have involvement of non-sentinel nodes and thus may not derive any therapeutic benefit from a CLND. In this study, we examined the histology of the metastatic foci within the SLN to identify factors that may predict the status of the CLND and disease recurrence. We found that patients with increased tumor burden in the SLNs, as quantified by the size of the largest tumor focus, had an increased likelihood of positive non-sentinel nodes on CLND. More importantly, we were able to define a subgroup of patients with minimal disease in the SLN (focus size ≤ 0.20 mm) who may be spared a CLND as there were no instances of positive non-sentinel nodes and no recurrences in this group. In contrast to a prior study,22 we did not find that the histological zone of tumor involvement (subcapsular, parenchymal, or sinusoidal) was significantly associated with CLND status, but did find that the number of zones involved was an independent predictor of recurrence. This suggests that involvement of all three zones with metastases is a marker of extensive nodal involvement that may indicate spread beyond the nodal basin and thus an increased risk of recurrence. The factors identified in this study (size of largest tumor deposit and histological zone of involvement) may be used to define a subgroup of patients who do not require CLND, as well as a group of patients who have a high risk of recurrence despite adequate nodal clearance. Further prospective studies are warranted to determine the reproducibility of classifying tumor deposits by their histologic zone, and to determine the generalizability of these findings to other centres and patient populations.

Received for publication August 18, 2006. Accepted for publication August 19, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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