ORIGINAL ARTICLE Prognostic Significance and Diagnostic Value of Protein S-100 and Tyrosinase in Patients With Malignant Melanoma Raquel Andre ´s, MD, Jose I. Mayordomo, Carmen Visus, Dolores Isla, Javier Godino, Pilar Escudero, Alberto Saenz, Eugenia Ortega, Rodrigo Lastra, Julio Lambea, Elena Aguirre, Luis Elosegui, Ivan Marcos, Manuel Ruiz-Echarri, Esther Millastre, Berta Sa ´ez-Gutierrez, Laura Asin, Maria J. Vidal, Ana Ferrer, Armando Giner, Luis Larrad, Francisco J. Carapeto, and Alejandro Tres Objectives: The utility of many molecules as tumor markers in melanoma has been investigated with different results. The aims of this study was to compare the value of tyrosinase mRNA by reverse transcription polymerase chain reaction (RT-PCR) in peripheral blood and of serum S-100 protein in patients with melanoma at different stages of disease. Methods: We have studied 90 peripheral blood samples correspond- ing to 90 patients that had been diagnosed with melanoma. The clinical staging at the time of blood sampling was performed according to the American Join Committee on Cancer guidelines. S-100 protein in serum was measured by enzyme-linked immu- nosorbent assay (normal range: 0 – 0.150 g) and the presence of tyrosinase mRNA was assessed by RT-PCR. Results: Median progression-free survival was 281 days for tyrosi- nase positive patients and it has not been reached for tyrosinase negative patients (P = 0.03). Median progression free survival was 213 days for patients with elevated serum S-100 and it has not been reached for patients with normal level of serum S-100 (P  0.001). Median overall survival (OS) was 396 days for tyrosinase positive patients and it has not been reached for negative patients (P = 0.0096). Median OS was 282 days for patients with elevated serum S-100 and it has not been reached for patients with normal level of serum S-100 (P  0.001). In a multivariate analysis, both markers have significant prognostic value for time to progression and for survival ( 2 test). Conclusions: RT-PCR for tyrosinase mRNA and S-100 are signif- icant prognostic factors for progression-free survival and OS in melanoma. S-100 has higher sensitivity and specificity than tyrosi- nase. Key Words: S-100 protein, tyrosinase, RT-PCR, melanoma (Am J Clin Oncol 2008;31: 335–339) T he prognosis of melanoma patients has steadily improved due to early detection campaigns in the last decades. However, 20%–25% of melanoma patients will develop lo- cal, regional, and/or distant metastasis and the majority will eventually die. 1 Depending on the characteristics of the pri- mary tumor, a broad variety of clinical and radiologic proce- dures is recommended for the detection of metastases in patients with melanoma. Laboratory test are routinely used in melanoma patients by most physicians, 2 but none of these are considered as standard tumor markers in this particular disease. The identification of circulating tumor cells in the peripheral blood of patients with malignant melanoma by detection of melanoma associated protein transcripts using the reverse transcription polymerase chain reaction (RT- PCR) technique has been introduced as a noninvasive and sensitive technique for early detection of tumor progression and metastatic disease. 3 Tyrosinase, an enzyme that is in- volved in the melanin biosynthesis pathway, 4 is the most frequently used marker to detect the presence of circulating melanoma cells; however, its usefulness as a marker is highly debated. 5–11 An alternative approach for detection of meta- static disease is the analysis of S-100 protein in the serum of melanoma patients. An immunoradiometric assay and, more recently, a luminoimmunometric assay (LIA) were developed for determination of the serum concentration of the -subunit of the S-100 protein. An elevation of this protein has been observed in patients with malignant melanoma, and a positive correlation with disease progression has been demonstrated. 12–16 The aim of this prospective study was to compare the value of detection of tyrosinase mRNA by RT-PCR in pe- ripheral blood and of serum S-100 protein in patients with melanoma at different stages of disease. PATIENTS AND METHODS Patients From June 2000 to October 2001, peripheral blood samples were obtained from 90 patients with histologically proven melanoma attending the melanoma clinic of the Uni- versity Hospital of Zaragoza. From the Servicio de Oncologı ´a Me ´dica, Hospital Clı ´nico Universitario Lozano Blesa, Av. San Juan Bosco, 15 50009 Zaragoza, Spain. Reprints: Raquel Andre ´s, MD, Servicio de Oncologı ´a Me ´dica, Hospital Clı ´nico Universitario Lozano Blesa, Av. San Juan Bosco, 15 50009 Zaragoza, Spain. E-mail: andresraquel@hotmail.com. Copyright © 2008 by Lippincott Williams & Wilkins ISSN: 0277-3732/08/3104-0335 DOI: 10.1097/COC.0b013e318162f11e American Journal of Clinical Oncology • Volume 31, Number 4, August 2008 335