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Although the vast majority of melanomas have a known primary site, approximately 3.2% of all melanomas present in distant sites with no known primary site. Melanoma of unknown primary most often presents in lymph nodes, followed by subcutaneous sites, and finally visceral organs. Various hypotheses regarding the origin of melanoma of unknown primary have been proposed, including spontaneous regression of the primary tumor, and the presence of ectopic melanocytes within lymph nodes and visceral organs. Melanoma of unknown primary is less well studied in comparison with melanoma of known primary, but its clinical, molecular, and genetic characteristics have been recently clarified. Specifically, melanoma of unknown primary occurs more often in men in the fourth and fifth decades of life, and shares a similar genetic and molecular signature as cutaneous melanomas arising on skin that is intermittently exposed to the sun, including the back and upper legs. In addition, the prognosis of these patients has also been clarified, and patients with melanoma of unknown primary have improved survival compared to stage-matched patients with melanoma of known primary. This chapter reviews recent advances in the understanding of melanoma of unknown primary, highlighting its genetic and molecular characteristics, epidemiology, prognosis, and treatment, as well as its relationship with melanoma of known primary site.
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