Melanoma is a malignant tumour arising from melanocytes, the pigment-producing cells responsible for melanin production in the skin and certain other tissues. Most melanomas originate in the skin, but melanocytes are also present in sites such as the eye and mucosal surfaces, allowing melanoma to arise outside ordinary cutaneous locations. Cutaneous melanoma is characterised by malignant melanocyte proliferation and has a greater capacity for invasion and distant metastasis than most common non-melanoma Skin Cancer. Its biology is driven by combinations of genetic and epigenetic alterations that disrupt cellular proliferation, survival and differentiation. The disease ranges from thin, highly curable local tumours to advanced metastatic cancer requiring systemic therapy.
Major risk factors include ultraviolet exposure, intermittent intense sun exposure, sunburn, fair skin phenotype, numerous melanocytic naevi, atypical naevi, family history and certain inherited susceptibility variants. A history of melanoma substantially increases the risk of developing another melanoma. Some melanomas arise in people without the classic risk profile, demonstrating that absence of obvious risk factors does not exclude the disease. Genetic predisposition can involve alterations in pathways controlling cell growth and DNA damage responses. The relationship between ultraviolet exposure and melanoma is complex because exposure patterns, skin type, pigmentary phenotype and tumour biology interact rather than producing a simple dose-response relationship in every individual.
Melanoma can develop within a pre-existing naevus or arise as a new lesion. Clinical assessment often considers asymmetry, border irregularity, colour variation, diameter and evolution, with evolution being particularly important because change over time can indicate malignant transformation. Other warning features can include a lesion that differs noticeably from surrounding moles or develops bleeding, crusting or persistent inflammation. However, melanoma can be small, uniformly coloured or otherwise atypical, so visual rules are aids rather than diagnostic tests. Dermoscopy can improve assessment by revealing pigment networks, vascular patterns and structural features that may not be visible during unaided inspection.
Diagnosis requires histopathological examination of an appropriately sampled lesion. The pathology report can include Breslow thickness, ulceration, mitotic activity in some contexts, margin status and other microscopic characteristics. Breslow thickness measures the depth of tumour invasion and is a major determinant of primary tumour staging. Sentinel lymph-node biopsy may be considered for selected melanomas based largely on tumour thickness and other risk characteristics. Imaging is generally used according to stage and clinical circumstances rather than indiscriminately in every newly diagnosed thin melanoma. Accurate staging is essential because prognosis and treatment differ substantially between localised, regional and metastatic disease.
The molecular biology of Melanoma is heterogeneous. Activating alterations in the MAPK signalling pathway are common, with BRAF mutations occurring in a substantial proportion of cutaneous melanomas and providing a basis for targeted treatment in appropriate patients. Other tumours may contain alterations involving NRAS, NF1 or other pathways. Molecular testing is particularly relevant in advanced disease when targeted treatment is being considered. The presence of a mutation does not by itself determine prognosis or guarantee treatment response; it must be interpreted in relation to tumour type, stage and available clinical evidence. Molecular classification has transformed treatment options for subsets of patients with advanced disease.
Localised Melanoma is primarily managed surgically, with the objective of complete removal of the primary tumour and appropriate margins. Selected patients with higher-risk localised or regional disease may receive adjuvant systemic treatment designed to reduce the risk of recurrence. Advanced melanoma has undergone major therapeutic change through immune checkpoint inhibitors and molecularly targeted combinations for tumours with actionable mutations. Immunotherapy can produce durable responses in some patients, although responses are variable and immune-related adverse effects can affect multiple organs. Targeted therapy can produce rapid responses in appropriate molecularly defined tumours but can also be associated with acquired resistance.
Melanoma can spread through lymphatic and bloodstream routes to lymph nodes, skin or subcutaneous tissue, lungs, liver, brain and other organs. The biological ability to metastasise is influenced by tumour thickness, ulceration, molecular characteristics and host interactions. Brain metastases are clinically important in advanced disease and have become more treatable with modern systemic and local therapies. Recurrence can occur locally, regionally or at distant sites, and surveillance is therefore tailored to stage and risk. Melanoma arising in the eye or mucosal surfaces has distinct biology and treatment considerations and should not automatically be managed according to the pathways used for common cutaneous melanoma.
Prognosis is strongly stage-dependent, with thin localised tumours generally having substantially better outcomes than metastatic disease. Prevention includes reducing excessive ultraviolet exposure and avoiding artificial tanning, while awareness of changing lesions can facilitate earlier assessment. A common misconception is that melanoma only occurs in people with many moles or very fair skin; melanoma can occur in anyone with melanocytes. Another is that a lesion must be large or painful to be dangerous. Modern Melanoma care increasingly integrates pathology, molecular testing, surgery, immunotherapy and targeted therapy, making accurate classification essential. Despite major advances in metastatic treatment, treatment resistance and severe disease remain important clinical challenges.
