Due to intensified research in recent years the understanding of the molecular mechanisms involved in the development of melanoma has dramatically improved. The identification of morphological surrogates and prognostic parameters in tumors with such genetic alteration seems therefore crucial when differentiating and classifying this heterogeneous tumor entity in more detail and thus facilitates the stratification of prognosis as well as therapy. This review summarizes the current understanding of carcinogenesis and PF-04449913 gives a detailed overview of known morphologic and potentially future genetic prognostic parameters in malignant melanoma. 1 Introduction Despite all preventive and therapeutical efforts melanoma is still the most aggressive and deadliest skin cancer especially in PF-04449913 persons of fair complexion. To a certain extent primary prevention campaigns already achieved an earlier diagnosis of thinner tumors with a better prognosis . Incidence rates are nonetheless increasing worldwide mainly due to unreasonable sun exposure habits especially in young adults . Once diagnosed prognosis and therapy is stratified so far by several clinicopathological risk factors such as tumor thickness sentinel lymph node status ulceration and the recently added mitotic rate . In view of an often unpredictable rather heterogeneous biological behavior mainly in >4?mm thick (Stage IIC) or locally advanced melanoma (Stage III) the AJCC classification remains of limited clinical relevance in particular for these high risk patients . Moreover we currently do not have reliable tissue biomarkers that mark the disease of the individual patient for progression or complete remission . At the same time an enormous amount of basic research within the last decade has dramatically changed the molecular understanding of melanoma. Proof of several specific genomic key mutations such that BRAF could not only be causally linked to disease progression  but PF-04449913 also gave rise to new highly effective therapies targeted specifically at those mutated molecules . While the multistep carcinogenesis of melanoma is still too little understood in its complexity in order to foresee when how and what kind of mutation develops in PF-04449913 an invasive or metastatic tumor genome-wide genetic analysis of primary or metastatic tumors will undoubtedly change future classifications and subsequent treatment algorithms. But are standard clinical prognostic parameters such as age location and metastasis already outdated? Could dermatopathology the current cost-efficient diagnostic gold standard consequently be redundant? PF-04449913 Will we possibly be able to correlate certain histomorphologic features to specific genetic aberrations and their consecutive pathological or compensatory molecular cascades in order to recognize treat or even prevent the systemic metastasic impact of this tumor in our patients? These important questions arise and may contribute to a better classification of melanoma patients. With the focus on their metastatic potential our review summarizes the current knowledge of genetic as well as molecular features of malignant melanoma and examines their possible correlation. Moreover we discuss the clinical implications as well as current therapies that may target these new hallmarks of melanoma. 2 Epidemiology of Malignant Melanoma A growing body of evidence has already addressed melanoma as an “umbrella term” for several biological distinct subtypes as a result of multiple causative genetic aberrations impaired pathways or epigenetic changes. Epidemiology in contrast strongly indicates that UV-induced DNA damage is the primary cause of melanoma development  even though certain regions in which melanoma subtypes occur such as mucosal or acral tumours are not typically exposed to ultraviolet light. Numerous studies about phenotypic risks such as age gender and skin type favour sun exposure as the major cause for thinner tumors of less Mouse monoclonal to Influenza A virus Nucleoprotein incidence in young patients (<35 years) on minimally exposed sites and thicker tumours in elderly patients and UV-exposed locations such as the head and neck [9 10 Searching for the underlying causes of initiation and progression in these melanomas it was demonstrated that cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (PP) photoproducts are the most abundant DNA lesions in those UV-exposed tumors . A well-determined repair system of minimal necessary factors such as XPA RPA XPC and so forth is however sufficient to.