Molecular Pathology of Cutaneous Melanoma and Nonmelanoma Skin Cancer

Abstract

Recent data indicate that the dramatic rise in incidence of skin cancers recorded in the last decades is still in progress. According to the National Cancer Institute, more than one million cases of cutaneous malignancies were diagnosed in the USA in 2009, with these estimates likely to be exceedingly conservative. Analogous trends have been observed worldwide, posing a considerable socioeconomic burden especially in Western countries; these numbers are all the more striking as incidence rates for the majority of other cancers are either steady or decreasing. Although nonmelanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), accounts for up to 90 % of all skin cancer cases, also cutaneous melanoma (CM) incidence is constantly on the rise; importantly, prognosis of advanced melanoma is still dismal, with 5-year survival rates for patients with metastatic disease below 10 %. Meanwhile, substantial scientific advances have been made in pathology, genetics, and basic research of skin cancer, dramatically altering the approach in diagnosing and treating both CM and NMSC. Novel insights have been gained regarding inherited determinants of predisposition to skin neoplasms, mechanisms of ultraviolet light (UV)-induced oncogenesis, and molecular pathways regulating cutaneous cancer onset and progression; sizeable progress has been made also in understanding the pathogenesis of less common cutaneous malignancies, including adnexal neoplasms, Merkel cell carcinoma (MCC), and dermatofibrosarcoma protuberans (DFSP). The once prevailing concept that cancer simply stems from the unregulated proliferation of a monoclonal and homogenous cell population is being replaced by a more complex notion, viewing tumors as heterogeneous collections of multiple subpopulations with different genetic background, molecular features, and responsiveness to external stimuli. Accordingly, established diagnostic classifications and prognostic schemes are being revisited in light of recent molecular discoveries, new therapeutic agents are being developed targeting key drivers in skin cancer pathogenesis, and molecular diagnostics are becoming integral part of patients’ management. The recent introduction of next generation genomics techniques and their rapid diffusion are destined to further revolutionize this field. We propose an extensive overview of the molecular pathways involved in UV-induced oncogenesis as well as pathogenesis of CM; further, we offer a comprehensive synopsis of the molecular pathology of NMSC (including BCC as well as SCC and related precursors), selected adnexal neoplasms, MCC, and DFSP.