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Early detection of malignant melanoma remains the key factor in lowering mortality from this cancer. Recognizing the importance of this issue 25 years ago, our group at New York University published in CA: A Cancer Journal for Clinicians the mnemonic "ABCD" to facilitate the early diagnosis of melanoma. Studies have demonstrated the usefulness of this paradigm in enhancing early melanoma diagnosis as a part of clinical examinations, mass screenings, and public education programs. Approaches to melanoma diagnosis have dynamically evolved during the ensuing quarter century. In the 1990s, dermoscopy enabled the recognition of new subsurface features to differentiate between malignant and benign pigmented lesions. During the last decade, new computer-based technologies have improved diagnostic sensitivity and specificity and may result in optimizing lesion selection for biopsy and pathology review. Despite all of the advances in melanoma diagnosis, timely recognition, detection, and rapid treatment of melanoma remain critical. Although pathologic examination remains the gold standard for diagnosis, this cancer has the potential to be diagnosed through noninvasive approaches because of its cutaneous location. From the development of the ABCDs through current attempts that use complex computer algorithms and genetic markers, a clinician's ability to detect melanoma in its earliest form has been augmented. However, a "good clinical eye" is still fundamental to selecting the lesions for evaluation among the sea of those that are prevalent. As current approaches are refined and new techniques are developed, the improved ability to diagnose this cancer will hopefully enhance reaching the goal of reducing melanoma mortality. CA Cancer J Clin 2010;60:301-316.

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