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Annals of Surgical Oncology 8:116-122 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Significance of Plasma Cytokine Levels in Melanoma Patients With Histologically Negative Sentinel Lymph Nodes

Geoffrey A. Porter, MD, Joseph Abdalla, MS, Meisheng Lu, MD, MSc, Shannon Smith, Diane Montgomery, Elizabeth Grimm, PhD, Merrick I. Ross, MD, Paul F. Mansfield, MD, Jeffrey E. Gershenwald, MD and Jeffrey E. Lee, MD

From the Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.

Correspondence: Address correspondence and reprint requests to: Dr. Jeffrey E. Lee, Dept. of Surgical Oncology–Box 106, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; Fax: 713-745-4426; E-mail: jelee{at}notes.deacc.tmc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Introduction: Although sentinel lymph node (SLN) status is the most powerful predictor of prognosis in patients with clinically localized melanoma, a proportion of melanoma patients with histologically negative SLNs will still recur. It is hypothesized that tumor response may be altered or mediated by specific cytokines. We therefore investigated whether levels of IL-4, IL-6, IL-10, TNF-{alpha}, or IFN-{gamma} would predict disease recurrence in melanoma patients with histologically negative SLNs.

Methods: This prospective cohort study involved 218 patients with clinically localized melanoma who underwent a histologically negative SLN biopsy. Preoperative plasma cytokine levels were determined by enzyme-linked immunosorbent assay on these patients, as well as on 90 healthy controls. Kaplan-Meier life tables were constructed, and Cox proportional hazards analyses were performed to assess predictors of disease-free survival (DFS).

Results: At a median follow-up of 43 months, 33 of 218 patients (15%) had suffered disease recurrence. Melanoma patients had significant elevations of IL-4, IL-6, and IL-10 compared to healthy controls; levels of IFN-{gamma} were less elevated in melanoma patients compared to controls. Despite this, melanoma patients with detectable IFN-{gamma} levels were at significantly higher risk for recurrence compared to patients with undetectable levels (5-year DFS 70% vs. 86%, P = .03). On multivariate analysis including standard melanoma prognostic factors, only tumor thickness (P = .004) and the presence of detectable IFN-{gamma} levels (P = .05) were significant independent prognostic factors for disease-free survival.

Conclusions: Among melanoma patients with clinically localized disease who have undergone a histologically negative SLN biopsy, presence of a detectable plasma level of IFN-{gamma} is an independent predictor of disease recurrence. Elevated levels of IFN-{gamma} may identify a group of early-stage melanoma patients who are more likely to have recurrence of disease and who may benefit from adjuvant therapies, including immunotherapies.

Key Words: Cytokine • Melanoma • Sentinel lymph node


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Over the past decade, intraoperative lymphatic mapping (IOLM) and sentinel lymph node (SLN) biopsy have been shown to be a reliable method of assessing the status of the regional lymph node basin in patients presenting with primary melanoma.1–5 In patients presenting with primary melanoma and clinically negative lymph nodes, the histologic status of the SLN is the strongest predictor of disease recurrence and survival.5 However, there exists a subpopulation of melanoma patients who develop recurrences even though they have histologically negative sentinel lymph nodes.5 Identification of predictors of recurrence in this otherwise low-risk population may help identify mechanisms responsible for melanoma progression, identify a population of melanoma patients at higher risk for disease recurrence who may benefit from adjuvant therapies, and suggest potential novel therapeutic approaches for high-risk melanoma patients.

Cytokines are proteins and glycoproteins secreted by a variety of cell types. Interleukin 4 (IL-4), IL-6, and IL-10 are classically considered to be products of type 2 helper T cells, which participate in humoral immune responses. IFN-{gamma} is commonly produced by type 1 helper T cells, which participate in cellular immune responses. TNF-{alpha} is produced by a variety of cell types, including macrophages, in response to endotoxin, inflammation, or tissue injury. These cytokines are involved in the growth, differentiation, and functional activities of a wide variety of cellular components; the classic categories noted earlier may or may not reflect the role these molecules play in cancer initiation or progression.

Elevated levels of various cytokines, including some of those just listed, have been implicated in advanced stage or recurrence of certain solid tumors.6 Specifically, elevated levels of IL-6 have been linked to resistance to IL-2 therapy and poor prognosis in patients with stage IV melanoma.7 Additionally, elevated levels of IL-10 have been associated with advanced stage (III and IV) melanoma.8

Both IL-6 and IL-10 have been reported to be present commonly in melanoma tumors. IFN-{gamma} and TNF-{alpha} are less commonly present, and IL-4 has been detected only following autologous vaccination.9–15 The source of elevated circulating levels of IL-6 or IL-10 detected in advanced stage melanoma patients may, therefore, be the result of production by the metastatic melanoma tumor cells themselves or, alternatively, by tumor-associated lymphocytes.16

IL-4 and IFN-{gamma} are among the cytokines that have been identified as potent modulators of melanoma immune responses. IL-4, for example, promotes the proliferation of melanoma-specific cytotoxic T lymphocytes.17 IFN-{gamma}, on the other hand, can upregulate HLA class II expression on lymphocytes in melanoma patients,18 as well as on the melanoma tumor cells themselves.19–21 IFN-{gamma} also has been reported to suppress the growth of melanoma cell lines.22,23 Despite these in vitro activities, neither IL-424 nor IFN-{gamma}25 has proven effective in the treatment of patients with advanced-stage melanoma.

Taken together, these data suggest that any role for these cytokines in the melanoma patient is likely to be complex; the available in vitro evidence does not adequately explain the clinical associations noted. Previous research regarding the role of these cytokines in melanoma has involved the study of either specific melanoma cell lines; fresh, frozen, or preserved melanoma tumors; or patients with advanced disease. Melanoma patients at relatively low risk for disease recurrence have not been studied specifically.

We hypothesized that elevated levels of certain cytokines might help explain the uncommon recurrences observed in melanoma patients who, by standard objective criteria, appear to be at low risk for disease recurrence. The objective of this study was to determine whether elevated levels of specific cytokines (IL-4, IL-6, IL-10, IFN-{gamma}, or TNF-{alpha}) were independently associated with recurrence in melanoma patients who underwent a histologically negative SLN biopsy. Any such associations identified could be helpful as prognostic markers and could provide direction in investigation of immune mechanisms responsible for recurrence in melanoma patients.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
A prospective database was created containing information from melanoma patients who underwent IOLM and SLN biopsy at the University of Texas M. D. Anderson Cancer Center. As is standard practice at the institution, patients who were offered this procedure generally had (1) tumor thickness of at least 1.0 mm or, if < 1.0 mm, at least Clark level IV evidence of tumor ulceration or regression; (2) no evidence of metastatic melanoma in regional lymph nodes by clinical examination (clinical TNM stage I or II); and (3) no evidence of distant metastases by physical examination, chest radiograph, and lactic dehydrogenase level. The primary outcome in this study was disease recurrence.

SLN Mapping Technique
To establish lymphatic drainage patterns, all patients with primary tumors located in anatomic areas with ambiguous lymphatic drainage underwent preoperative lymphoscintigraphy using intradermal 99mTc human serum albumin (1 mCi; Mediphysics, Inc, Arlington Heights, IL) or 99mTc sulfur colloid (1 mCi; Hirsch Industries, Inc, Richmond, VA) within 1 month of the planned IOLM and SLN biopsy.

IOLM and SLN biopsy was performed as previously described.5 Briefly, following the intradermal administration of 1 to 3 ml of isosulfan blue (Lymphazurin 1%; Hirsch Industries, Inc, Richmond, VA), IOLM and SLN biopsy was performed on all nodal basins that had been identified by preoperative lymphoscintigraphy. More recently (November 1994–December 1997), patients undergoing SLN biopsy were injected intradermally with 0.5–1.0 mCi 99mTc sulfur colloid (1 mCi; Hirsch Industries, Inc, Richmond, VA) 1 to 4 hours preoperatively; IOLM was guided by a hand-held gamma probe in addition to isosulfan blue injection. An SLN was defined as a lymph node in a regional basin that localized blue dye or concentrated radiotracer uptake. Sentinel lymph nodes were excised and analyzed by routine hematoxylin and eosin staining of bivalved specimens; immunohistochemical staining using antisera to S-100 or HMB-45 was used to clarify equivocal findings. More recently, serial sectioning was performed on all initially negative SLNs. All patients underwent wide local excision of the primary melanoma with margins appropriate for tumor thickness.

Cytokine Levels
Plasma cytokine levels of IL-4, IL-6, IL-10, IFN-{gamma}, and TNF-{alpha} were determined using an immunosorbent assay (Cytoscreen, Biosource International, Inc, Camarillo, CA). All measurements were performed according to the procedures recommended by the manufacturer. Sensitivities were set as follows: IL-4, 7.8 pg/ml; IL-6, 15.6 pg/ml; IL-10, 15.6 pg/ml; TNF-{alpha}, 15.6 pg/ml; and IFN-{gamma}, 15.6 pg/ml. Plasma samples were obtained from melanoma patients before wide local excision and SLN biopsy; plasma samples also were obtained from 90 healthy volunteers. Samples were stored frozen at -80°C before analysis, and plasma cytokine levels were batch-processed from thawed samples. Patient and control samples were coded and tested concurrently. The results of cytokine testing were analyzed and recorded in a blinded fashion, independent of clinical data acquisition and subsequent analysis.

Statistical Analysis
Univariate analyses included the {chi}2 test to compare categorical variables. If a 2 x 2 table contained a cell count of < 5, Fisher’s exact test was used. Continuous data were compared between two groups by the Student’s t-test where the data appeared normally distributed, or the Mann-Whitney U-test if the data appeared skewed. Kaplan-Meier survival curves were constructed using melanoma recurrences as end points, and the log-rank test was used to test for statistical significance between Kaplan-Meier curves. To control confounding and interaction, multivariate analysis was performed using Cox proportional hazards regression. The appropriateness of the proportional hazards assumption was assessed using log (-log) plots. In addition, time-dependent covariates of each included variable were assessed in all Cox models. In no situation was a time-dependent covariate found to be statistically significant. The model for disease-free survival was created using a forward selection approach, examining all variables tested on univariate analysis, with entry into the model set at a conservative P < .10. All two-way interaction terms were tested for inclusion in the regression models. Two-tailed tests were used wherever the data so allowed, and statistical significance was set a priori at P < .05. All analyses were performed using SPSS for Windows 6.1 (SPSS Inc., Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study and Patient Characteristics
Cytokine levels were determined in a total of 218 patients who underwent IOLM and SLN biopsy and were found to have a histologically negative SLN. Clinical and pathologic characteristics of these patients are summarized in Table 1. The median follow-up in the study cohort was 43 months.


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  		TABLE 1. Clinical and pathologic characteristics of the study cohort (n = 218)
 
A total of 33 patients (15%) suffered melanoma recurrence. Twenty-two patients (67%) had recurrences in the form of distant metastases; nine patients (27%) had regional recurrence; and two patients (6%) had local recurrences. Seventeen of the 33 recurrences (52%) occurred within 2 years of the negative SLN biopsy.

Cytokine Levels
The distribution of the IL-4, IL-6, IL-10, IFN-{gamma}, and TNF-{alpha} levels among the study patients and normal controls is shown in Table 2. Undetectable levels of cytokines were found in most of the patients and controls. Serum IL-4, IL-6, and IL-10 levels were, on average, significantly higher in the melanoma patient population compared to the control population. There was a trend—although not statistically significant—toward higher TNF-{alpha} levels in melanoma patients. Conversely, IFN-{gamma} levels were more often detectable and higher in the control population compared with melanoma patients.


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  		TABLE 2. Distribution of cytokine levels among controls (n = 90) and SLN-negative melanoma patients (n = 218)
 
The distribution of patient characteristics and specific known prognostic factors in melanoma patients according to the presence of detectable cytokine levels is displayed in Table 3. No significant differences in these factors were identified based on presence of detectable cytokine levels.


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  		TABLE 3. Distribution of patient characteristics according to presence of detectable cytokine levels (n = 218)
 
Cytokine Levels and Recurrence
A summary of the univariate analysis of disease-free survival is shown in Table 4. Increasing tumor thickness, presence of tumor ulceration, and detectable levels of IFN-{gamma} all were associated with a reduced length of disease-free survival. A trend toward reduced disease-free survival duration also was noted in patients with detectable levels of TNF-{alpha} (P = .09). Kaplan Meier-curves of disease-free survival according to the presence of detectable IFN-{gamma} and TNF-{alpha} levels are illustrated in Figures 1 and 2, respectively. No significant associations were identified between the presence of detectable IL-4, IL6, or IL-10 levels and disease-free survival duration.


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  		TABLE 4. Univariate and multivariate analysis of prognostic factors for disease-free survival (n = 218)
 


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  		FIG. 1. Kaplan-Meier survival curves for disease-free survival according to the presence of detectable serum IFN-{gamma} levels.

 


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  		FIG. 2. Kaplan-Meier survival curves for disease-free survival according to the presence of detectable serum TNF-{alpha} levels.

 
The multivariate analysis of disease-free survival duration is summarized in Table 4. Using this approach, tumor thickness (P = .004) and presence of detectable IFN-{gamma} (P = .05) were independent prognostic factors for recurrence. The presence of tumor ulceration was included in the model based on the selection criteria used in the regression approach.

Because exploration of the cytokine data demonstrated that 5% to 14% of melanoma patients had markedly elevated cytokine levels (defined as more than 3 times the interquartile range), depending on the cytokine in question, duration of disease-free survival was reanalyzed treating the specific cytokine as a continuous variable. This showed increasing IL-4 levels to be significantly associated with disease recurrence on univariate analysis (P = .008). However, when IL-4 level was included in the multivariate model that included tumor thickness, ulceration, and presence of detectable IFN-{gamma} (Table 4), no significant independent prognostic association was identified (P = .21).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, patients with early stage melanoma and histologically negative SLNs had significantly higher levels of IL-4, IL-6 and IL-10 compared to non-cancer controls, and overall levels of IFN-{gamma} in the melanoma patients were relatively suppressed. In contrast, high IFN-{gamma} levels were independently associated with an increased risk of melanoma progression. This is the first study to identify the presence of altered cytokine levels in an early-stage melanoma patient population and to correlate those levels with risk of disease recurrence. Prior studies have identified elevated IL-67 and IL-108 levels in melanoma patients; however, these studies have focused on patients with advanced-stage disease.

Potential mechanisms that could be responsible for the presence of altered cytokine levels in these melanoma patients include: (1) production of cytokines by occult melanoma metastases; (2) production of cytokines by lymphocytes in response to the antigenic challenge of the tumor; or (3) genetic control of cytokine production linked to melanoma susceptibility. Direct evidence regarding these mechanisms will require additional investigations. However, although melanoma tumors commonly produce IL-6 or IL-10,9–15 the lack of association of either of these cytokines with melanoma recurrence in this study makes occult tumor as a source of the IL-6 or IL-10 elevations identified in this patient population less likely.

Production of cytokines by lymphocytes in response to the antigenic challenge of the melanoma tumor could help explain the apparently contradictory finding of suppressed IFN-{gamma} levels in the melanoma patients as a group, but increased levels in the melanoma patients who suffered disease recurrence. Suppressed IFN-{gamma} levels in the overall group, representing an early-stage, low-risk melanoma patient population, could be reflective of an effective immune response against the primary tumor. In contrast, high levels in the patients who developed recurrent disease could reflect the absence of an effective anti-melanoma immune response in these patients. IFN-{gamma} generally is considered to enhance antitumor immunity. However, IFN-{gamma} is not effective as monotherapy for melanoma patients with established metastatic disease; furthermore, in a phase III randomized trial of IFN-{gamma} as adjuvant therapy in high-risk melanoma patients, there was a trend toward a poorer disease-free and overall survival in the patients who received IFN-{gamma}.25 IFN-{gamma} has been shown to increase HLA class II expression both on lymphocytes from melanoma patients18 and on melanoma tumor cells.19–21 Elevated HLA class II antigen expression is found on both thicker primary melanoma tumors and melanoma metastases;26–28 increased HLA class II expression by tumor cells has complex immunologic effects, which can include the induction of immune tolerance.29,30 It is, therefore, plausible that increased HLA class II expression by melanoma tumors induced by high IFN-{gamma} levels could result in impaired immunorecognition of melanoma tumors and increased risk of disease progression. Measurement of IFN-{gamma} levels should be performed in a cohort of melanoma patients both before and after disease recurrence and at all stages of disease. HLA class II expression should be correlated with cytokine production in melanoma patients.

Finally, cytokine gene polymorphisms could help explain the associations between cytokine levels and melanoma incidence and progression identified in this study. Allelic variants of cytokine genes have been identified for IL-4, IL-6, IL-10, IFN-{gamma}, and TNF-{alpha}.31,32 In the cases of IL-10, IFN-{gamma}, and TNF-{alpha}, allelic variants include promoter region polymorphisms that have been associated with altered levels of cytokine production.31 Allelic variants of specific cytokine genes, including IFN-{gamma}, have been linked to an altered risk of transplant rejection31 or risk of development of autoimmune disease.33 Genetic polymorphisms in cytokine genes should be investigated in a cohort of melanoma patients and correlated with cytokine levels and risk of disease recurrence.

In summary, we described alterations in plasma cytokine levels associated with presence of early-stage melanoma, and identified elevated serum IFN-{gamma} levels as an independent prognostic factor in melanoma patients with histologically negative SLNs. Although these results are preliminary, they suggest that the presence of elevated IFN-{gamma} levels could identify a relatively high-risk subgroup within an otherwise low-risk melanoma patient population. Further investigation of this group of melanoma patients may identify a population of melanoma patients more likely to benefit from adjuvant therapies, and may result in identification of novel therapeutic approaches for high-risk melanoma patients, including novel approaches to immunotherapy.


   Footnotes
 
Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 17, 2000.

Received for publication June 22, 2000. Accepted for publication October 26, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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