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© 2001 American Society for Clinical Oncology Serum S-100B Protein as a Prognostic Marker in Malignant Cutaneous MelanomaFrom the Departments of Oncology, Clinical Chemistry, and Cancer Epidemiology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden. Address reprint requests to Eva Djureen Mårtenson, Radiumhemmet, Karolinska Hospital, S-171 76 Stockholm, Sweden; email: evadj{at}rah.ks.se
PURPOSE: To evaluate whether S-100B protein in serum is an independent prognostic marker in malignant melanoma. MATERIALS AND METHODS: S-100B protein in serum was analyzed in 1,007 consecutive patients with histologically verified cutaneous malignant melanoma. At the time of blood sampling, 876 patients were in clinical stage I, 35 were in stage II, and 96 were in stage III. The serum concentrations of S-100B protein were measured by a luminescence immunoassay (LIA). RESULTS: The mean serum concentration of S-100B protein was significantly related to clinical stage, with the lowest level in stage I and the highest in stage III. In a multivariate analysis, S-100B protein levels in serum showed the strongest prognostic impact of the factors analyzed with respect to disease-specific survival in clinical stages II to III, followed by clinical stage. Serum S-100B protein was not a significant independent prognostic factor in clinical stage I, where tumor thickness showed the strongest relation to melanoma-specific survival, followed by ulceration and satellites. CONCLUSION: This investigation contains the largest material of patients so far analyzed with the new LIA assay of S-100B protein in serum and confirms that S-100B protein in serum is correlated with clinical stage and is an independent prognostic marker in clinical stages II and III.
THE INCIDENCE OF malignant melanoma has steadily increased in white populations worldwide during the last decades. In the Swedish National Cancer Registry, 1,607 new cases were registered during 1998 compared with 238 cases registered in 1960, corresponding to a seven-fold increase.1 The estimate of prognosis for patients with malignant melanoma in clinical practice today relies mainly on histopathologic examination of excised tumors.2 For patients with local disease, tumor thickness shows the best correlation to prognosis.3,4 For patients with regional lymph node metastases, the number of involved lymph nodes is the strongest prognostic factor.5 However, these prognostic factors fail to accurately predict the outcome of many patients. Thus a large part of the variation in prognosis is still unexplained in melanoma patients. Today, efforts are made to develop efficient adjuvant therapies for patients with high-risk malignant melanoma.6 This increases the need for reliable methods to select patients with high risk of relapse as well as for techniques to monitor the effect of therapy and to detect early relapse. Serum analyses of tumor markers are used in the clinical management of several malignancies, for example, cancer of the prostate (prostate-specific antigen)7 and colorectal cancer (carcinoembryonic antigen).8 Several factors known to be connected to melanoma disease have been studied to find a reliable tumor marker for malignant melanoma. Serum levels of neuron-specific enolase9,10 and lipid-bound sialic acid (LASA-P)11 have been shown to be elevated in a number of patients with disseminated melanoma. Among the melanin-related metabolites, 5-S-cysteinyl-dopa levels in serum or urine have the strongest correlation with the overall survival rate.12,13 However, at present, the sensitivity and diagnostic accuracy of these factors are too low to give them any role as useful tumor markers for malignant melanoma. Contradictory results have been published regarding detection of circulating melanoma cells in peripheral blood as reflected by the presence of tyrosinase mRNA analyzed by reverse transcriptase polymerase chain reaction. After the first report published by Smith et al in 1991,14 further encouraging results were published by some investigators, showing a high sensitivity of the method. Thus Brossart et al15 reported 100% sensitivity and Mellado et al16 94% sensitivity for detection of distant metastases. However, several reports from other groups have shown a considerably lower sensitivity with this method17-20; for instance, Kunter et al17 reported only 19% sensitivity for detection of metastatic melanoma. Considering the results so far presented, tyrosinase transcripts detected by reverse transcriptase polymerase chain reaction cannot be considered a reliable tumor marker for patients with malignant melanoma. S-100B protein is a 21-kd thermo-labile acidic dimeric protein consisting of two beta subunits, which was originally isolated from the CNS.21 The biologic function of S-100B protein is to a large extent unknown. It affects the assembly and disassembly of microtubules and it also interacts in a calcium-dependent manner with the p53 tumor suppressor gene. It has been shown that this interaction in vitro inhibits p53 phosphorylation by protein kinase C.22 When assayed by monoclonal antibodies in immunohistochemistry of tumor biopsies, S-100 protein is today a well-established marker of malignant melanoma.23,24 In recent years, reports have been published showing that the serum level of S-100B protein, analyzed by an immunoradiometric assay (IRMA; Sangtec Medical, Bromma, Sweden), is correlated with clinical stage in patients with cutaneous melanoma.25-29 The mean level of S-100B protein in serum increases with clinical stage, with the highest values in disseminated disease. Serum levels of S-100B protein have been compared with other known prognostic parameters to investigate whether they add prognostic information.30,31 In a report by Abraha et al,28 there was a significant correlation between the level of S-100B protein in serum and the Breslow thickness of the tumor. A combination of these two values improved the sensitivity and specificity of predicting secondary spread. Miliotes et al31 selected patients with primary melanoma without known metastases who had data on tumor markers recorded during their follow-up. In the multivariate analysis, tumor thickness and serum levels of S-100B protein turned out to be independent prognostic factors with respect to time to relapse, whereas serum levels of S-100B protein and tumor ulceration had independent prognostic power in relation to survival, using a cutoff value of 0.05 µg/L. However, because Miliotes et al used the IRMA S-100B protein assay, which normally has a detection limit of approximately 0.2 µg/L, absolute values below that level are probably uncertain. Buer et al30 studied patients with disseminated malignant melanoma. In their study, elevated serum S-100B protein was a prognostic factor for overall survival in patients with metastatic disease. However, in the multivariate analysis, lactate dehydrogenase and the presence of liver metastases turned out to be the strongest independent prognostic factors. The level of S-100B protein in serum correlated significantly with increasing levels of lactate dehydrogenase but added no independent prognostic information. It is difficult to compare these results with those of other reports of serum S-100B protein analyses because an extremely high cutoff value of 3.0 µg/L was chosen, which is considerably greater than those used by other research groups. There are also reports comparing serum levels of S-100B protein with other potential tumor markers for melanoma. Serum S-100B protein has been shown to have a higher sensitivity and specificity than serum neuron-specific enolase10,25,32 in patients with disseminated malignant melanoma. It is also better correlated with survival than serum levels of LASA-P31 and serum levels of the melanin metabolites 5-S-cysteinyldopa and 6-hydroxy-5-methoxyindole-2-carboxylic acid.13 S-100B protein serum levels have furthermore been reported to be correlated with progression and regression of disease in patients receiving antitumoral treatment.25,27,33 In the two first studies,25,27 very few patients were included, but the report presented recently by Hauschild et al33 is based on a larger number of patients and shows a correlation between response to treatment and reduction in the level of S-100B protein in serum. These results indicate that S-100B protein in serum might be used to follow response to treatment in patients with metastatic disease, although further studies must be performed to confirm it. The aim of our study was to investigate whether a single analysis of S-100B protein in serum with a new luminescence immunoassay (Sangtec S100B LIA; Sangtec Medical) is an independent prognostic factor in patients with malignant melanoma in different clinical stages.
Patients Between August 1990 and March 1995, venous blood samples were obtained from 1,007 consecutive patients (506 male and 501 female patients) with malignant cutaneous melanoma attending the Department of Oncology, Radiumhemmet, Karolinska Hospital for scheduled follow-up visits. The mean age of the patients was 55.1 years (range, 16 to 95 years). In all patients, the diagnosis of primary invasive cutaneous melanoma had been verified by histology. Patient data were recorded in the Regional Cancer Registry of the Stockholm-Gotland counties, from which information on patient characteristics was obtained. The investigation was approved by the local ethics committee. The three-stage system for classification of malignant melanoma was used.34 At the time of blood sampling, 876 patients were in clinical stage I (primary melanoma with or without satellites within 5 cm), 35 were in clinical stage II (regional lymph node metastases and/or in transit metastases), and 96 were in clinical stage III (distant metastases). For clinical stage I, the date of diagnosis was defined as the date when the patients had their primary melanoma removed. The majority of patients then underwent a wide resection at the Department of Plastic Surgery before they were referred to the Department of Oncology, Radiumhemmet, for their first follow-up visit. The interval from diagnosis to the first visit at our clinic was usually around 2 months. From most patients the blood sample for S-100B analysis was obtained at their first or second visit at our clinic. For the present study, we allowed a maximum interval of 180 days from the diagnosis of the primary melanoma to the day on which a blood sample was taken for analysis of S-100B protein. The minimum length of the interval from the date of diagnosis to the date of blood sampling was 1 day and the median interval was 77 days. For patients in clinical stage II and III, the time of diagnosis of metastatic disease was defined as the date when the first metastasis was diagnosed. For clinical stage II and III, the minimum interval between diagnosis of metastatic disease and blood sampling was 0 days for both stages, the maximum interval was 1,646 days for clinical stage II and 2,550 days for clinical stage III, with median values of 67 and 47 days, respectively. The staging information for clinical stage II was based on clinical nodal stage confirmed by pathologic analysis of fine-needle or surgical biopsies, because neither sentinel node biopsy nor elective lymph node dissection were routinely performed. The baseline date for measuring survival of patients in all clinical stages was defined as the date at which the blood sample was obtained. Median follow-up time from blood sampling was 1,638 days for all patients, 1,706 days for patients in clinical stage I, 524 days for clinical stage II, and 179 days for clinical stage III. In addition to analysis of S-100B protein levels, blood samples were also used for measurements of other biochemical serum parameters, such as albumin, C-reactive protein, and orosomucoid (the main component in LASA-P), which were analyzed by standard methods routinely used at the Department of Clinical Chemistry, Karolinska Hospital. S-100B protein levels in serum were also measured in 412 healthy adult subjects to establish a reference interval.
The S-100B Protein Assay
Statistical Analysis
The serum concentrations of S-100B protein in the healthy reference group were less than 0.23 µg/L for all 412 individuals. The geometric mean value was 0.02 µg/L and 95% of the individuals had values  0.10 µg/L. No sex-related differences were observed. In patients with cutaneous melanoma, the mean serum concentration of S-100B protein was significantly related to clinical stage, with the lowest value in clinical stage I and the highest in stage III (Table 1). One hundred seven (12%) of 876 patients in clinical stage I had S-100B protein levels greater than the reference limit (> 0.10 µg/L), 18 (51%) of 35 patients in clinical stage II had such levels, and 76 (79%) of 96 patients in clinical stage III had such levels.
In the univariate analyses, several factors were significantly correlated with melanoma-specific survival, both in clinical stage I and in stages II to III ( Tables 2 and 3). There were significant differences in disease-specific survival for patients with S-100B values greater than and less than the reference limit of 0.10 µg/L, both when analyzed in the whole group of patients and in the subset of patients with metastatic disease (clinical stages II to III) (Figs 1 and 2). In the whole patient population, 91% of the individuals with values less than 0.10 µg/L were alive after 5 years, compared with 51% of the individuals with values greater than 0.10 µg/L (Fig 1). Of patients in clinical stages II and III, 30% with values less than 0.10 µ/L and 6% with values greater than 0.10 µ/L, respectively, were alive after 5 years (Fig 2).
Patients in clinical stage III were divided into three groups: 12 patients in whom the metastases had been resected and thus were clinically tumor-free at the time of blood sampling, 19 patients with only subcutaneous and/or lymph node metastases, and 61 patients with disseminated metastases to one or more of the following organs: visceral organs, brain, and/or bone. The groups were compared with one-way analysis of variance with F test. Patients without remaining overt metastases had significantly lower levels of S-100B protein in serum compared with the other two groups with a manifest tumor burden. There was, however, no significant difference between the two groups with metastases present ( Fig 3).
In clinical stage I, 193 patients had primary tumors lacking vertical growth phase, and among these patients, no deaths were recorded. Therefore, only patients with tumors with vertical growth phase were selected for the multivariate analysis. For the multivariate analysis in clinical stage I, altogether 626 patients were available. Among these, 24 patients were excluded because of missing data. Another six patients were excluded because they had died of other causes than melanoma before the first event was recorded in the whole group of patients (ie, before any patients had died from melanoma). Thus 596 patients in clinical stage I were included in the analysis. In clinical stages II to III, no patients were excluded; all 131 cases were included in the analysis. The following factors were significantly correlated with melanoma survival in clinical stage I in the multivariate analysis: tumor thickness (P < .001; relative hazard [RH] = 1.3 per 1-mm increment), with the highest impact, followed by ulceration (P = .001; RH = 2.8 when present) and satellites (P = .018; RH = 5.8 when present) ( Table 4). Thus serum S-100B protein was not a significant independent prognostic factor in patients in clinical stage I with respect to disease-specific survival.
In contrast, in clinical stages II and III, the S-100B protein level in serum was the strongest independent prognostic factor for melanoma survival (P < .001; RH = 2.1 per 1-unit increment in the 10-logarithm), followed by clinical stage (stage II v III P = .006; RH = 1.9 for stage III) ( Table 5).
In patients with regional lymph node metastases, the number of involved lymph nodes is known to be a prognostic factor.5 We therefore subdivided our patients in clinical stage II with metastases to regional lymph nodes in two groups according to whether one (11 patients) or several (18 patients) lymph nodes were engaged. The survival of patients did not differ significantly between these groups (P = .10; data not shown), and there was also no significant difference in S-100B protein serum levels between the groups (P = .70; data not shown).
Most previous reports on serum levels of S-100B protein were based on an immunoradiometric assay of S-100B protein (IRMA; Sangtec) with a detection limit of 0.10 to 0.20 µg/L. The new S-100B protein analysis method we used in the present investigation is a luminometric immunoassay with a 10-fold lower functional detection limit of 0.02 µg/L. The only previously published report based on the new method is by Bonfrer et al,32 who analyzed sera from 251 patients with cutaneous malignant melanoma. They found a significant correlation between the level of S-100B in serum and clinical stage. In a stepwise Cox regression analysis, they showed serum S-100B protein to be a highly significant independent prognostic factor with respect to overall survival. The aim of our study was to investigate whether serum levels of S-100B protein analyzed by the new luminescence immunoassay is an independent prognostic factor in malignant melanoma in different clinical stages. This study includes the largest number of patients that has been analyzed with the new method. This material also includes the patients earlier reported in our study of serum S-100B protein based on the previous IRMA method.26 All samples from these patients have been reanalyzed with the luminescence immunoassay. In agreement with our previous study,26 the mean serum levels of S-100B protein were significantly related to clinical stage. However, with the immunoluminometric assay used in the present study, the mean serum levels obtained were slightly lower than those in the previous study, probably because of the increased sensitivity of the luminescence method. In the univariate regression analysis, the serum levels of S-100B protein were significantly related to clinical stage, which is in accordance with previous reports.25-29 Only a small proportion (12%) of patients in clinical stage I in our study had elevated S-100B protein levels (> 0.1 µg/L). This is in agreement with the results reported by Bonfrer et al,32 who found that only one of 179 patients in clinical stage I had a serum concentration of S-100B protein greater than the reference value. In our multivariate analysis, S-100B protein was not a significant independent prognostic factor in clinical stage I. In our previous smaller study using the S-100 IRMA assay, serum S-100B protein levels were shown to be an independent prognostic factor with respect to survival independent of clinical stage. In that study, however, S-100 serum values were treated as a categoric variable using a relatively high cutoff level of 0.6 µg/L, rather than as a continuos variable. Moreover, in the previous study, clinical data obtained from the Regional Cancer Registry contained some cases of misclassification of clinical stage, which have been corrected in the recent analysis. The present report, which includes the largest number of patients in clinical stage I hitherto published, clearly shows that serum levels of S-100B protein measured at a single occasion is not a significant independent prognostic factor with respect to disease-specific survival in patients with this disease stage. Whether S-100B protein will give any independent prognostic information in clinical stage I when serial blood samples are analyzed is currently being studied in ongoing investigations. For patients in clinical stages II and III, the serum level of S-100B protein was the strongest independent prognostic factor, followed by clinical stage. Thus the serum S-100B protein level was a stronger predictor of survival than the clinical stage itself. Our findings of a lack of correlation between the number of involved lymph nodes, S-100B protein levels, and prognosis may be due to the limited number of patients in clinical stage II in our material. Likewise, it is not excluded that the level of S-100B protein may be correlated with the number of involved lymph nodes when analyzed in a larger number of patients in clinical stage II. The correlation between increased serum S-100B protein and an adverse prognosis raises the question of whether S-100B protein in serum is mainly a measure of tumor burden or whether it also reflects the grade of malignancy of the disease. The findings that patients in clinical stage III who had had their tumors resected and were clinically tumor-free at the time of blood sampling showed significantly lower values of S-100B in serum compared with patients with overt metastases support the hypothesis that S-100B protein in serum mainly reflects the tumor burden (Fig 3). The similar levels of S-100B protein in patients with soft tissue or lymph node metastases compared to those with metastases in viscera, CNS, or bone also support this concept. Because S-100B protein was elevated in only a small proportion of patients in clinical stage I and failed to add independent prognostic information, it is likely that the present method to measure S-100B protein is too insensitive to detect minimal deposits of microscopic disease in this patient category. The serum level of S-100B protein is thus expected to increase with increasing tumor burden and would therefore be potentially useful as a marker for disease progression and regression. Accordingly, S-100B protein should decline in patients with disseminated melanoma when they are responding to treatment. This has been demonstrated by Guo et al,25 Henze et al,27 and Hauschild et al,33 who serially measured S-100B protein in serum in a number of patients with widespread metastatic melanoma undergoing systemic treatment. When patients responded to treatment, the elevated levels of S-100B protein in serum declined, whereas the levels increased in patients with progressive disease. Most patients in clinical stage II, ie, with regional lymph node metastases, undergo surgical resection of their metastases, and in a proportion of patients in clinical stage III, surgical resection of the metastatic tumors can also be performed, so that the patient becomes clinically tumor free. S-100B protein in serum might then be followed after surgical resection of the tumors to evaluate the effectiveness of the resection. In these situations, increasing levels of S-100B protein in serum might serve as an early signal of relapse and may possibly also be used to monitor the effect of adjuvant therapies. The level of S-100B protein in serum could also be of future value in selecting and following patients in clinical trials to estimate the patients’ tumor burden before and during the trial. However, sequential measurements of serum S-100B protein have so far only been reported with the old IRMA method,25,27,33 and only one of the studies included a large number of patients.33 Further studies therefore must be performed before analyses of S-100B protein in serum can be used routinely in clinical practice to supplement, or possibly to some extent replace, conventional methods for measuring progression and regression of the melanoma disease.
Supported by the Swedish Cancer Society, Stockholm, Sweden. We thank Anita Larsson, Rumjana Dijlai-Merzoug, and Birgitta Byström for their invaluable assistance.
S-100B protein analysis kits were provided by Sangtec Medical, Bromma, Sweden.
1. The National Board of Health and Welfare: Cancer incidence in Sweden 1998. Stockholm, Sweden, Nordstedts Tryckeri AB, 2000 2. Stadelmann WK, Rapaport DP, Soong S-J, et al: Prognostic clinicals and pathological features, in Balch C, Houghton AN, Sober AJ, et al (eds): Cutaneous Melanoma ( ed 3 ). St Louis, MO, Quality Medical Publishing, Inc, 1998, pp 12-35 3. Breslow A: Thickness, cross-sectional areas and depth of invasion on the prognosis of cutaneous melanoma. Ann Surg 172: 902-908, 1970[Medline] 4. Balch CM, Murad TM, Soong S-J, et al: A multifactorial analysis of melanoma: Prognostic histopathological features comparing Clark’s and Breslow’s staging methods. Ann Surg 188: 732-742, 1978[Medline]
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Gatter KC, Ralfkiaer E, Skinner J, et al: An immunocytochemical study of malignant melanoma and its differential diagnosis from other malignant tumours. J Clin Pathol 38: 1353-1357, 1985 25. Hua bei Guo , Stoffel-Wagner B, Bierwirth T, et al: Clinical significance of serum S-100 in metastatic malignant melanoma. Eur J Cancer 31A:1898-1902, 1995 26. von Schoultz E, Hansson L-O, Djureen E, et al: Prognostic value of serum analyses of S-100B protein in malignant melanoma. Melanoma Res 6: 133-137, 1996[Medline] 27. Henze G, Dummer R, Joller-Jemelka HI, et al: Serum S-100: A marker for disease monitoring in metastatic melanoma. Dermatology 194: 208-212, 1997[Medline] 28. Abraha HD, Fuller LC, Vivier AWPDU, et al: Serum S-100 protein: A potentially useful prognostic marker in cutaneous melanoma. Br J Dermatol 137: 381-385, 1997[Medline] 29. Hauschild A, Engel G, Brenner W, et al: S100B protein in serum is a significant prognostic factor in metastatic melanoma. Oncology 56: 338-344, 1999[Medline] 30. Buer J, Probst M, Franzke A, et al: Elevated serum levels of S-100 and survival in metastatic malignant melanoma. Br J Cancer 75: 1373-1376, 1997[Medline] 31. Miliotes G, Lyman GH, Cruse CW, et al: Evaluation of new putative tumor markers for melanoma. Ann Surg Oncol 3: 558-563, 1996[Medline] 32. Bonfrer JMG, Korse CM, Nieweg OE, et al: The luminescence immunoassay S-100: A sensitive test to measure circulating S-100B—Its prognostic value in malignant melanoma. Br J Cancer 77: 2210-2214, 1998[Medline] 33. Hauschild A, Engel G, Brenner W, et al: Predictive value of serum S100B for monitoring patients with metastatic melanoma during chemotherapy and/or immunotherapy. Br J Dermatol 140: 1065-1071, 1999[Medline] 34. Buzaid AC, Ross MI, Soong S-J: Classification and staging, in Balch C, Houghton AN, Sober AJ, et al (eds): Cutaneous Melanoma ( ed 3 ). St Louis, MO, Quality Medical Publishing, Inc, 1998, pp 37-47 35. Cox DR: Regression models and life-tables (with discussion). J Roy Stat Soc B 34: 187-220, 1972 36. Armitage P : Statistic methods in medical research. Oxford, United Kingdom, Blackwell Scientific Publications, 1985, pp 189-207 Submitted February 15, 2000; accepted September 26, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 = 234.9.
