SERUM S100: A NEW TUMOR MARKER IN METASTATIC MALIGNANT MELANOMA1
Birgit Stoffel-Wagner, Hua Bei Guo, Thomas Bierwirth, Jörg Mezger,
Departments of Clinical Biochemistry, Dermatology and Internal Medicine,
Institut für Klinische Biochemie - Universität Bonn
Sigmund-Freud-Str. 25 - 53105 Bonn - Germany
Tel.: 0228 2876513 - Fax.: 0228 2875028
1. The complete study will be published in one of the next issues of the European Journal of Cancer (Guo HB, Stoffel-Wagner B, Bierwirth T, Mezger J, Klingmüller D. Clinical significance of serum S100 in metastatic malignant melanoma. Eur J Cancer, 1995, in press.)
The incidence of melanoma has increased dramatically in the past decades [1, 2]. As melanoma can metastasize to any organ, follow-up after surgery is difficult. Therefore, a major challenge facing clinical biochemical research is to detect specific and reliable serum markers that are of value in diagnosing and monitoring progression of the disease.
S100 is an acidic calcium-binding protein with a molecular weight of 21 000 found in the nervous system of vertebrates .In immunohistochemistry the use of S100 is well established for the diagnosis of malignant melanoma. Recent studies have shown that S100 is excreted from melanoma cells . Lately, it was demonstrated that neuron-specific enolase (NSE) is a useful prognostic factor for metastatic malignant melanoma [3,4].
The aims of this study were to analyse the clinical significance of serum S100 at the time of diagnosis of malignant melanoma, to evaluate the use of serum S100 in the follow-up of patients treated for malignant melanoma and to compare serum levels of S100 with NSE in patients with malignant melanoma.
Serum samples were taken from 126 patients with malignant melanoma. Staging was performed according to the criteria of the American Joint Committee on Cancer (AJCC) based on the tumor-node-metastasis (TNM) system: stage I (T1/T2, N0, M0), stage II (T3/T4, N0, M0), stage III (any T, N1/2, M0) and stage IV (any T, any N, M1) . 80 patients had a stage I or II disease, 23 patients a stage III disease and 23 patients had a stage IV disease. The reference groups consisted of 25 healthy persons, 45 patients with benign skin lesions. Serum S100 was measured by an immunoradiometric assay (Byk-Sangtec Diagnostics, Dietzenbach, Germany). The detection limit of the S100-IRMA was 0.15 µg/l. Serum NSE was determined using a commercially available radioimmunassay (Pharmacia, Uppsala, Sweden). The detection limit was 2 µg/l. Values exceeding 12.5 µg/l were considered as elevated.
In the reference groups consisting of 45 patients with benign skin lesions and 25 healthy persons, serum S100 concentrations were < 0.15 µg/l in all cases. S100 was detectable only in one of 80 patients without metastases (stage I/II). Values exceeding 0.15 µg/l were found in 2 of the 23 patients with stage III (sensitivity: 8.7%) and 17 of the 23 patients with stage IV (sensitivity: 73.9%). The overall sensitivity for metastatic malignant melanoma stage III/IV was 41.3% (19/46). In the reference groups NSE concentrations were below the cut-off value in all cases. In 7 of 80 patients without metastases (stage I/II) serum NSE was elevated (sensitivity: 8.75%). Increased serum concentrations of NSE (>12.5µg/l) were found in 3 of 23 patients with stage III (sensitivity: 13.0%) and in 8 of 23 patients with stage IV (sensitivity: 34.8%). The overall sensitivity for metastatic malignant melanoma (stage III/IV) was 23.9% (11/46). The sensitivity of S100 for metastatic malignant melanoma stage IV was significantly higher than that of NSE (p<0.05).
Serum S100 and NSE concentrations were serially measured in 23 patients with malignant melanoma stage III/IV in the course of treatment. Two representative follow-ups are shown in Fig. 1 and 2.
In some patients, serum S100 showed a gradual rise accompanying the progression of the disease under treatment. For example, in a 57-year-old man, liver, spleen, and bone metastases were already present at the time of diagnosis (Fig. 1). Serum S100 and NSE were slightly elevated. With progression of liver and spleen metastases, serum S100 and NSE levels began to increase. For example, a representative liver metastasis increased from a diameter of 3 cm to a diameter of 6 cm. When bone and CT scan indicated even further progression, a chemoperfusion of the liver witha-interferon and interleukin-2 was performed. Serum NSE levels remained between 117.3 and 97.7 µg/l, but S100 persistently rose from 7.4 to 98.4 µg/l corresponding to an enlargement of the liver metastasis to 8 cm and to the clinical deterioration until death.
In other patients a decline of serum S100 concentrations was observed corresponding to response to therapy, whereas serum S100 increased again, when radiological diagnostics showed later on progression of the disease. For example, in a 44-year-old woman with stage IV, the first measurement showed elevated serum S100 and NSE concentrations (Fig. 2). Metastases in the right lower lobe of the lung and visceral metastases were demonstrated by CT scan. During immunotherapy witha-interferon and interleukin-2, stable disease was achieved, and serum S100 remained slightly elevated. Afterwards S100 and NSE levels increased again and a thoracal and abdominal CT indicated progression of lung and visceral metastases. Now, in both, the left and the right lobe of the lung metastases were found. Despite two courses of cytostatic therapy and further immunotherapy, CT scan demonstrated progressive lung metastases and MRI scan showed intraspinal metastases in the level of the 8th and 9th thoracic vertebra. The changes of serum NSE correlated with serum S100 throughout the whole course of the disease.
The data presented here confirm serum S100 to have a interesting sensitivity (41.3%) for advanced disease (stage III/IV). 17 of 20 patients with initially detectable serum S100 had distant metastases, whereas elevated serum S100 concentrations were detected in only 2 patients with involvement of lymph nodes (stage III). In only one of 80 patients without metastases (stage I/II), serum S100 exceeded 0.15 µg/l. The low incidence of elevated serum S100 levels in patients without metastases indicates clearly that serum S100 is not useful for screening or for early diagnosis of the disease.
Serum S100 was serially determined in patients with metastases (stage III/IV). To our knowledge, this study is the first to follow-up on the development of serum S100 in patients with metastatic melanoma. Serum S100 concentrations reflected the course of the disease during therapy. A persistent rise in serum S100 indicated progression of the disease, whereas decline in serum S100 indicated response to therapy. Reflecting the fact that no complete remission was achieved, S100 remained detectable in all patients.
In conclusion, the current study supports the clinical significance of serum S100 in metastatic malignant melanoma. Serum S100 showed a higher sensitivity than serum NSE and correlated with the clinical stage of the tumor. Serial measurements of S100 were helpful to monitor the treatment.
The authors would like to thank Mrs. I. Horn for her excellent technical assistance and help with the preparation of this manuscript.
1. Hoffmann SJ, Yohn JJ, Norris DA, Smith CM, Robinson WA. Cutaneous malignant melanoma. Curr Probl Dermatol, 1993, 5, 7-41.