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10.1245/s10434-006-9267-6
Annals of Surgical Oncology 14:1604-1611 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Natural History of Melanoma in 773 Patients with Tumor-Negative Sentinel Lymph Nodes

Theresa G. Zogakis, MD, Richard Essner, MD, He-jing Wang, MD, Leland J. Foshag, MD and Donald L. Morton, MD

Roy E. Coats Research Laboratories, John Wayne Cancer Institute at Saint John’s Health Center, 2200 Santa Monica Blvd., Santa Monica, California

Correspondence: Address correspondence and reprint requests to: Richard Essner, MD, E-mail: essnerr{at}jwci.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: A tumor-negative sentinel lymph node (SLN) does not preclude recurrence of melanoma. We hypothesized that certain patient-related and tumor factors are predictive of a worse outcome in these patients.

Methods: Disease-free survival (DFS), overall survival (OS), and recurrence patterns were retrospectively analyzed in 773 patients who underwent lymphatic mapping and SLN biopsy for primary cutaneous melanoma at our institution between 1995 and 2002, and who had tumor-negative SLNs by standard pathological analysis. Patient sex, age, tumor site and thickness, ulceration status, Clark level, and histology were evaluated for their influence on outcome by univariate and multivariate Cox regression analysis and classification and regression tree analysis.

Results: DFS and OS at 5 years were 88% and 93%, respectively. Sixty-nine (8.9%) of 773 patients developed recurrence. Three-year OS was lower in patients with distant recurrence (17.1%) than in those with local/regional recurrence (55.5%). By multivariate analysis, primary tumor thickness (P < .0001), site on head/neck versus trunk (P = .0093) versus extremity (P = .0042), and ulceration status (P = .0024) were independently significant for DFS; primary tumor thickness (P = .0106) and ulceration status (P = .0001) also were independently significant for OS. Classification and regression tree analysis demonstrated DFS was shortest in patients who had ulcerated tumors >2 mm.

Conclusions: Melanoma will recur in approximately 9% of patients with tumor-negative SLNs. Patients with thick, ulcerated melanomas on the head or neck have the highest risk for recurrence. This group should be followed closely for recurrence and considered for adjuvant therapy.

Key Words: Melanoma • Sentinel node • Recurrence • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Since its introduction in 1990,1 lymphatic mapping (LM) and sentinel node biopsy (SNB) has become widely accepted as a minimally invasive technique for staging the regional lymph node basin in patients with melanoma. LM/SNB is based on the concept that tumor cells from a primary melanoma will spread initially to at least one node, the sentinel lymph node (SLN), in the regional nodal basin.2 This SLN can be identified, surgically removed, and evaluated for the presence of occult metastases. LM/SNB eliminates the need for a complete lymphadenectomy to stage melanoma. Because the LM/SNB specimen is so much smaller than the standard lymphadenectomy specimen, it can be examined by meticulous histopathologic techniques that are more likely to detect micrometastatic disease.3

The tumor status of the SLN is one of the most important prognostic indicators in patients with melanoma. The three-year disease-free survival (DFS) rates for patients with tumor-negative and tumor-positive SLNs are 88.5% and 55.8%, respectively.4 Because patients with tumor-positive SLNs have a shorter DFS, they are more likely to receive closer follow-up and be considered for adjuvant therapy. However, certain patients with tumor-negative SLNs may also be at high risk for recurrence and poor outcome. We hypothesized that patient-related and tumor- related factors as well as recurrence patterns would be predictive of outcome in tumor-negative SLN patients. Identifying these factors should allow us to improve risk stratification and thereby better direct therapy and follow-up.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We reviewed a prospectively acquired melanoma database to identify patients with American Joint Committee on Cancer (AJCC) stage I or II cutaneous melanoma5 who underwent successful LM/SNB at our institution from January 1995 to December 2002 and for whom clinical, pathological, and follow-up data were available. A joint institutional review board for Saint John’s Health Center and the John Wayne Cancer Institute approved this study. Eligible patients had a single primary cutaneous melanoma and no prior diagnosis of malignancy (except non-melanomatous skin cancer). They were not eligible for the prospective randomized Multicenter Selective Lymphadenectomy Trial,6 or they refused randomization in that trial. All patients underwent LM/SNB in conjunction with complete excision of the primary melanoma (negative surgical margins) no more than 3 months after a diagnosis of melanoma.

In all cases, preoperative lymphoscintigraphy was performed to map the nodal drainage basin and each SLN.6 Approximately 1 to 4 hours before operative incision, .5 to 1 mCi of filtered 99mTc-labeled sulfur colloid was injected intradermally around the primary melanoma. A scintillation camera and a handheld gamma probe (Neoprobe 2000; Neoprobe, Dublin, OH) were then used to identify the draining lymphatic basin and each SLN within the basin. The nuclear medicine physician marked the skin over each SLN site for reference by the surgeon during intraoperative mapping.

Surgeons operating on the patients in this study were highly trained in LM/SNB and used a standardized approach.6 After the induction of anesthesia in the operating room, the surgeon performed an intradermal injection of .5 to 1 mL of isosulfan blue dye (Lymphazurin 1%; Tyco, Norwalk, CT) in the area of the primary melanoma. The handheld gamma probe was then used to identify each radioactive node and measure its radioactivity (counts per second recorded in triplicate) before (in vivo) and after (ex vivo) excision. These radioactive nodes were removed as SLNs until the counts within the basin approached measured background levels. Background counts were obtained from three neutral body sites (10 to 20 cm from the primary injection site and lymph node basin). Lymph nodes that were stained blue and/or radioactive above background levels were collected as SLNs and sent to the pathology department for assessment. After all SLNs had been removed, the primary tumor was widely excised.

Pathologists well trained in SLN histopathological evaluation examined all SLN specimens by a standardized technique.7 Each SLN was sectioned at 2-mm intervals, fixed in 10% buffered formalin, and embedded in paraffin. Paraffin-embedded nodal tissue was further sectioned at two levels separated by 200 µm. Sections were stained with hematoxylin and eosin and antibodies to HMB-45 and S-100 (immunohistochemistry).7 If no tumor cells were seen by both hematoxylin and eosin staining and immunohistochemistry, then the SLN was considered tumor negative.

After LM/SNB, all patients were routinely seen at the John Wayne Cancer Institute by their surgeon. On average, each patient underwent physical examination every 3 to 4 months for the first 3 years and every 6 months after that to the end of the fifth year. After the fifth year, examinations were annual. Chest radiographs and laboratory tests of complete blood count, lactate dehydrogenase level, and liver function were repeated at each clinic visit. Other radiographic studies such as computed tomography, magnetic resonance imaging, or positron emission tomography scanning were performed as indicated by symptoms and findings of clinical examination.

Sites and dates of recurrences were entered into the database for all patients. Recurrences were identified as local (within a 2-cm radius of the primary tumor site), in transit (in the tumor-draining dermal lymphatics >2 cm from the primary tumor site), nodal (within the drainage basin), or distant. The date of last follow-up and disease status at the time of last follow-up were also recorded for each patient.

Statistical Analysis
Overall survival (OS) from the time of LM/SNB was estimated by the Kaplan-Meier8 method, and the survival curve was constructed. Patient sex and age, and primary tumor thickness, histology, location, and ulceration were evaluated for their influence on OS by univariate analysis by the Cox model.9 Relative risk ratios and 95% confidence intervals were estimated. Multivariate analysis to examine the association of patient- and tumor-related characteristics with OS was performed by Cox proportional hazard regression model.9 For variable selection, a stepwise method was used. Similar analyses were performed for DFS defined as the time from LM/SNB to first recurrence or the date of last follow-up.

Classification and regression tree (CART) analysis10 was applied to establish prognostic groups for DFS. Survival functions for the prognostic groups were determined by the Kaplan-Meier method,8 and intergroup differences in DFS were determined by log rank analysis. Differences in patient- and tumor-related characteristics for tumor-negative SLN patients who did or did not develop recurrence not were evaluated by {chi}2 or Wilcoxon rank sum tests.

The survival function from the time of local/intransit, nodal, or distant recurrence was determined by the Kaplan-Meier method,8 and the survival curve for each site of recurrence was constructed. Patients with simultaneous first recurrences at more than one site were categorized by their most distant site of first recurrence; for example, a patient with simultaneous in-transit and distant first recurrences was considered to have a distant recurrence.

S-Plus computer software was used for CART analysis; SAS software was used for all other analyses (SAS Institute, Cary, NC). A two-sided significance level of .05 was used for all tests.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Between January 1995 and December 2002, a total of 915 patients underwent LM/SNB for primary cutaneous melanoma and met the criteria for our review. Of the 915 patients, 773 (84.5%) had tumor-negative SLNs. These patients had a mean age of 54 years (range, 8–91 years) and a mean primary tumor thickness of 1.56 mm (range, .15–14.0 mm). Most melanomas were nonulcerated (83%) and had superficial spreading (63%), predominately located on the trunk (40%) and extremities (40%).

The average number of SLNs collected per patient was 2.3 (range, 1–8). Most SLNs were collected from the axillary (50%) or inguinal basins (22%); only 5.8% of all patients had SLNs collected from more than one lymphatic basin.

Of 773 patients with tumor-negative SLNs, 69 (8.9%) developed recurrence, and 40 (5.2%) died of melanoma over a median follow-up of 36.7 months (range, .1–106 months).11 The 1-year, 3-year, and 5-year DFS rates for the 773 patients were 98%, 91%, and 88%, respectively (Fig. 1Go). Corresponding rates of OS were 99.7%, 96%, and 92.7%, respectively (Fig. 2Go).


Figure 1
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  		FIG. 1. Disease-free survival curve for 773 patients with tumor-negative sentinel lymph nodes (SLN).

 

Figure 2
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  		FIG. 2. Overall survival curve for 773 patients with tumor-negative sentinel lymph nodes (SLN).

 
Because 1 patient had simultaneous local and distant recurrence and 3 patients had simultaneous intransit and nodal recurrence, there were 73 sites of first recurrence among the 69 patients.11 Of the 73 sites, 9 (1.2%) were local, 14 (1.8%) were in transit, 13 (1.7%) were nodal, and 37 (4.8%) were distant. All nodal first recurrences were in the dissected SLN basin. Three-year survival rates from the time of first recurrence for patients with local/in-transit, nodal, or distant recurrence were 48.7%, 63.5%, and 17.1%, respectively. By log rank analysis, differences in survival between patients with local/in-transit and nodal versus distant first recurrence were statistically significant (Fig. 3Go). However, the time to the development of local/in-transit (median, 23 months; range, 2.5–91.8 months) versus nodal (median, 17.6 months; range, 1.1–46.3 months) versus distant (median, 25.9 months; range, 1.4–88.8 months) recurrence was not statistically different.


Figure 3
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  		FIG. 3. Kaplan-Meier estimates of survival after local/in-transit, nodal or distant first recurrences in patients with tumor-negative sentinal lymph nodes. Reprinted with permission from Zogakis et al.11

 
By {chi}2 analysis or Wilcoxon rank sum test, we found that patients who developed recurrence were more likely to be older than 60 years and have thicker and/or ulcerated primary tumors of the nonsuperficial spreading type, located on the head or neck (Tables 1Go and 2Go). This finding was in agreement with the results of the univariate analysis, which identified patient age and primary tumor site, thickness, Clark level, ulceration, and histology as statistically significant (P < .05) prognostic factors for DFS (Table 3Go). Because CART analysis demonstrated a statistically significant difference for DFS when primary tumor thickness was >2 mm versus ≤2 mm, this cutoff point was used in the multivariate analysis as well. By multivariate analysis (Cox model), primary tumor thickness >2 mm, head/neck location, and ulceration statistically significantly shortened DFS (Table 4Go). When primary tumor thickness was >2 mm, the risk of recurrence increased approximately fourfold (P < .0001). According to CART analysis, tumor thickness was the most important prognostic factor for DFS (Fig. 4Go). Three-year DFS rate was 94.8% ± 1.1% (32 of 613 patients) in patients with primary tumors ≤2 mm versus 77.3% ± 3.7% (37 of 152 patients) in patients with primary tumors >2 mm (P < .0001). When the primary tumor was no more than 2 mm thick, its location on the head/neck (P = .002) and its Clark level above III (P = .0102) statistically significantly decreased DFS (Fig. 4Go). When the primary tumor was >2 mm in thickness, the presence of ulceration tended to decrease DFS (P = .0571). Patients with ulcerated melanomas >2 mm thick had the shortest DFS (P < .0001) (Fig. 5Go).


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  		TABLE 1. Clinical characteristics of 773 patients with melanoma-negative sentinel nodes
 

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  		TABLE 2. Pathological characteristics of primary melanomas in 773 patients with tumor-negative sentinel nodes
 

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  		TABLE 3. Univariate analysis of clinical and pathological factors for disease-free survival in patients with tumor-negative sentinel nodes
 

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  		TABLE 4. Multivariate analysis (Cox model) of prognostic factors for disease-free survival in patients with tumor-negative sentinel nodes
 

Figure 4
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  		FIG. 4. Classification and regression tree (CART) analysis for recurrence.

 

Figure 5
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  		FIG. 5. Kaplan-Meier estimates of disease-free survival for prognostic groups identified by classification and regression tree (CART) analysis.

 
Univariate analysis identified patient age and primary tumor site, thickness, Clark level, ulceration, and histology as significant (P < .05) prognostic factors for OS (Table 5Go). When these factors were included in a multivariate analysis (Cox model), ulceration and primary tumor thickness remained significant for OS (Table 6Go). By use of the cutoff of 2 mm, primary tumor thickness was the most statistically significant prognostic factor for OS. Patients with melanomas >2 mm had an approximately sixfold higher risk of melanoma-related death.


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  		TABLE 5. Univariate analysis of clinical and pathological factors for overall survival in patients with tumor-negative sentinel nodes
 

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  		TABLE 6. Multivariate analysis (Cox model) of prognostic factors for overall survival in patients with tumor-negative sentinel nodes
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The histological status of the SLN is a valuable prognostic factor for recurrence and survival. A multi-institutional study of patients with melanoma undergoing LM/SNB showed the histological status of the SLN to be more important than any other clinical or pathologic prognostic factor;4 3-year DFS rates were 88.5% and 55.8% for patients with tumor-negative and tumor-positive SLNs, respectively (P < .0001). The tumor status of the SLN can also be used to identify patients who may benefit from additional therapy such as complete lymph node dissection or adjuvant therapy, and who may be enrolled onto certain clinical trials.

The SLN is a sensitive indicator of the tumor status of all nodes in the regional lymphatic drainage basin. In their original report, Morton et al.2 performed complete lymph node dissections after tumor-negative LM/SNB to determine the presence of metastases in non-SLNs. Only two of 3079 non-SLNs contained micrometastasis, a false-negative rate for LM/SNB of <1%. However, a more clinically relevant way to determine the staging accuracy of LM/SNB is to monitor the rate of same-basin recurrence among patients with tumor-negative SLNs. Of the 773 patients in our study, only 8.9% developed recurrence, and only 1.7% developed recurrence in the SLN basin. This low rate of same-basin nodal recurrence in patients with tumor-negative SLNs validates the accuracy of LM/SNB to determine the presence of regional nodal disease.

Many groups have reported on nonnodal factors that influence survival and recurrence in patients with clinically localized melanoma. Tumor thickness, Clark level, age, sex, location of the primary lesion, and the presence of primary tumor ulceration have all been identified as important prognostic indicators.12–19 Other studies have reported on factors that influence patient DFS or OS when the SLN is tumor negative.20–22 Our study differs from these because we identified clinical or pathological factors that affect OS and DFS in a large number (773) of tumor-negative SLN patients who underwent uniform LM/SNB and histopathological SLN evaluation. This standardized approach allowed for accurate SLN identification and histopathological analysis and reduced the possibility of false-negative SLN diagnosis.

In our study, primary tumor thickness was the most important prognostic factor for OS and DFS in tumor-negative SLN patients. This finding is not unexpected. In 1970, Breslow23 first introduced a method of measuring the depth of melanoma invasion in millimeters as a reproducible assessment that correlated well with patient survival. Since that time, several studies have confirmed tumor thickness to be one of the most important factors that affects survival.12–19 We used the primary tumor (T) stages defined by the current AJCC staging system5,12 to categorize the thickness of the primary melanoma. Tumor thickness was initially analyzed by multivariate analysis as a continuous variable and found to greatly influence both OS and DFS. However, we wanted to define a cutoff point that physicians could use to better identify high-risk patients. CART analysis showed that patients with primary tumors >2 mm (T3 and T4) had a 4.3-fold higher risk for recurrence and a 6.3-fold higher risk for shortened survival compared with those with thinner primary tumors (T1 and T2).

The presence of primary tumor ulceration also negatively impacted survival and was associated with a twofold higher risk for recurrence in tumor-negative SLN patients. Ulceration of a primary melanoma correlates with increased mitotic rate and increased metastatic potential.24 Because of its prognostic significance independent of other pathological factors, the current AJCC staging system has integrated ulceration as a "b" designation in the T category.

The concept that the location of the primary tumor influences outcome was reported before the use of LM/SNB to stage the regional nodal basin. Wong et al.25 observed a decreased 5-year survival in patients with stage II melanoma arising in the upper back, back of the arms, neck, and scalp compared with other sites. Urist et al.26 found that patients with melanomas located on the head and neck had a decreased survival rate compared with those with melanoma on the extremities, independent of tumor thickness.

To our knowledge, our study is the first to demonstrate that head and neck location of a primary melanoma greatly influences the rate of recurrence in patients with tumor-negative SLNs, independent of other clinical or pathological factors. Many other studies of recurrence patterns and outcome in patients with tumor-negative SLNs have not included patients with head and neck primary tumors, did not report the anatomical distribution of the primary tumors, had a small proportion of head and neck primary tumors, or did not evaluate prognostic factors on the basis of lymph node status.20–22

Some centers do not routinely perform LM/SNB in patients with head or neck primary tumors because of the technical aspects of the procedure. Typically, melanomas of the head and neck drain to multiple basins within the neck;27–30 this requires exploration of multiple sites and the identification of more than one SLN, making the technique more cumbersome and unappealing to some surgeons. However, we have found that LM/SNB is a highly accurate and minimally invasive technique for identifying patients whose head and neck melanomas have metastasized to regional nodes,31 and we advocate its routine use for this group of patients.

The fact that primary tumors of the head and neck are associated with a shorter DFS does not necessarily mean that SLN identification or analysis is inaccurate. In our study, only 2 of 24 patients who developed recurrence after treatment of head/neck melanoma did so within the nodal basin. Histopathological review of all SLNs from patients who developed recurrence did not demonstrate an increased number of false-negative results for head and neck primary tumors compared with primary tumors at other sites (data not shown). We believe that primary melanomas of the head or neck may have a more aggressive biology. Further analysis of these patients may provide better insight into the biology of their disease.

A tumor-negative SLN is associated with a good prognosis in most patients with melanoma, but our results indicate that a small subset (8.9%) of tumor-negative SLN patients will develop recurrence. Because our median follow-up time was relatively short (3 years), the incidence of recurrence in this study may be underestimated. Nevertheless, by investigating patterns of recurrence over this time period, we found that the most likely site of recurrence was distant (4.8%), imparting the worst outcome compared with other sites of recurrence.11 Patients with thick, ulcerated melanomas located on the head and neck are at highest risk for recurrence. Because of this risk, these patients require close follow-up with scheduled physical examinations, and they should be offered adjuvant therapy and considered for clinical trials.


   ACKNOWLEDGMENTS
 
Presented in part at the annual meeting of the Surgical Society of Oncology, Atlanta, GA, March 3–6, 2005. Supported by grant CA29605 from the National Cancer Institute and by funding from the Amyx Foundation Inc. (Boise, ID), Mrs. Alice Johnson McKinney, the Wayne and Gladys Valley Foundation (Oakland, CA), Nancy and Carroll O’Connor (Los Angeles, CA), the George Hoag Family Foundation (Los Angeles, CA [R.E.]), and the Saban Family Foundation (Los Angeles, CA [R.E.]). We thank Gwen Berry for her editorial assistance.

Received for publication March 4, 2005. Accepted for publication September 7, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Morton DL, Cagle LA, Wong J, et al. (1990) Intraoperative lymphatic mapping and selective lymphadenectomy: technical details of a new procedure for clinical stage I melanoma. Presented at the Annual Meeting of the Society of Surgical Oncology, Washington, DC.
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