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Biomarkers play an important role in the diagnosis and prognostic classification of various cancers and can be useful in monitoring the patient's clinical course of disease and response to therapy. Generally, biomarkers are proteins and their expressions are associated with malignant disease. In the majority of cases, the marker molecules are expressed by the tumour cells themselves or by the tumour microenvironment cells. Thus, most biomarkers can primarily be found in malignant tissues, but after active secretion or passive release at tumour destruction, they become detectable in body fluids such as blood. Besides morphological and histopathological biomarkers (anatomic site, type of the primary tumour, tumour size, invasion depth, vascular invasion and ulceration), an increasing variety of serological markers have been identified, providing the possibility of a more detailed diagnostic and prognostic subgrouping of tumour entities, up to and even changing existing classification systems. The goal of this review is to provide an overview of old and more recent serological biomarkers in malignant melanoma. We will first focus on confirmed and nonconfirmed serum tumour markers, followed by proteomic profiling, an innovative approach to identify new and better serological biomarkers in melanoma, and ending with the predictive factors for treatments in this pathology.