{
  "id": "skin-cancer",
  "title": "Skin cancer",
  "lang": "en",
  "source_lang": "en",
  "summary": "Skin cancer is the most common type of cancer, arising from the skin's keratinocytes or melanocytes. Its main forms are basal cell carcinoma, squamous cell carcinoma, and melanoma.",
  "category": "health",
  "subcategory": "diseases",
  "type": "concept",
  "aliases": [
    "cutaneous cancer",
    "cutaneous carcinoma",
    "skin neoplasm"
  ],
  "generated_at": "2026-10-15",
  "model": "pro/claude-haiku-5-5",
  "url": "https://aiwiki.page/en/skin-cancer/",
  "translations": {
    "zh-Hans": {
      "url": "https://aiwiki.page/zh/skin-cancer/",
      "json": "https://aiwiki.page/zh/skin-cancer.json"
    }
  },
  "sections": [
    {
      "heading": "",
      "text": "Skin cancer is a group of malignant tumours that arise from the cells of the skin, most often the epidermis. The major forms are basal cell carcinoma and cutaneous squamous cell carcinoma, which together are called keratinocyte or non-melanoma skin cancers, and melanoma, which develops from melanocytes. The first two are far more common and usually localised and curable, while melanoma is rarer but accounts for most skin cancer deaths because it invades nearby tissue and spreads to distant organs. Ultraviolet (UV) radiation from the sun and from artificial sources such as tanning devices is the principal environmental cause, which makes the disease one of the most preventable cancers and a central concern of public-health policy.\n\nThis entry explains the biology behind these tumours, beginning with the structure of the skin and the cell types from which each cancer arises. It then describes each major type and the rarer cancers that also occur in the skin, followed by the causes and risk factors, including UV damage to DNA, genetic susceptibility and immune suppression, and the molecular changes that drive tumour growth. The later sections cover clinical diagnosis and staging, prevention and screening, the main treatments from surgery to targeted and immune-based therapies, the global epidemiology and trends, the historical discovery of the causes, and current research and unresolved questions."
    },
    {
      "heading": "Definition and classification",
      "text": "Skin cancer is a malignant growth of cells in the skin. Like other cancers, it arises when mutations accumulate in a cell and disrupt the controls on its division. Pathologists first sort skin tumours by how far they have extended. A carcinoma in situ is non-invasive: its malignant cells remain within the epidermis, the outer layer of the skin, and do not form independent nests of cells in the dermis beneath it. Invasive tumours break through this boundary and grow into the dermis or deeper tissue. The distinction determines how a lesion is staged and how much risk it carries, and it is applied to melanoma and keratinocyte cancers alike.\n\nMelanoma and non-melanoma skin cancers\n\nClinically, the main division separates melanoma from non-melanoma skin cancer (NMSC). Melanoma arises from melanocytes, the pigment-producing cells of the epidermis. NMSC is a heterogeneous group, most of which are keratinocyte carcinomas, tumours of keratinocytes. These include basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC). Rarer NMSCs include Merkel cell carcinoma, sebaceous carcinoma and cutaneous lymphomas.\n\nThe cell of origin determines the type because each cell population has its own location, growth pattern and capacity for spread. Basal cells, squamous cells and melanocytes sit at different depths and behave differently once transformed. The origin of BCC is not fully settled. Its cells resemble basal keratinocytes, but the outer root sheath of the hair follicle has also been proposed as its source, which is consistent with BCC occurring mostly on hair-bearing skin.\n\nTerminology in clinical practice and registries\n\nIn clinical records, BCC, SCC and melanoma are the three main diagnoses, and the names of these tumours carry the same meaning across most dermatology and pathology work. Registry data are less uniform. Many European cancer registries do not record BCC and SCC separately, so they report NMSC as a single category. Under the International Classification of Diseases, melanoma has its own code, C43, while other skin cancers are grouped under C44 and distinguished by histology. Surveillance case definitions also differ. Some combine BCC, SCC, Merkel cell carcinoma and in situ carcinoma under one heading while handling melanoma separately. Comparisons between countries or studies therefore depend on which categories are included, and a count labelled \"skin cancer\" may or may not contain melanoma.\n\nRelative frequency and behaviour\n\nBCC is the most frequent type. In one population-based Swiss registry for 1976–1992, 63% of cases were BCC, 25% were SCC, 9% were melanoma and 3% were other histological types. Within NMSC, BCC accounts for roughly three-quarters or more of cases and SCC for about a quarter, although the exact ratio varies by population. A U.S. estimate cited by a skin cancer foundation puts annual diagnoses at about 3.6 million BCCs and 1.8 million SCCs.\n\nMelanoma is much less common, but it is the most dangerous. In the same Swiss registry, age-standardised mortality in men in 1991–1992 was 2.6 per 100,000 for melanoma and 0.7 per 100,000 for all other skin cancers combined. Melanoma is therefore classified by its behaviour rather than its case numbers. It is more likely than the keratinocyte cancers to grow deeply and metastasise if untreated, and it accounts for a disproportionate share of skin cancer deaths. The same U.S. estimate projected about 112,000 invasive and 122,680 in situ melanomas for 2026, with roughly 8,510 deaths, illustrating that the in situ and invasive categories must be reported separately when comparing burden."
    },
    {
      "heading": "Structure of the skin and cells of origin",
      "text": "Layers of the skin\n\nHuman skin has three principal layers, from the surface inward: the epidermis, the dermis and the hypodermis. The epidermis is a stratified squamous epithelium that contains no blood vessels, so it depends on the dermis for nutrients, which diffuse across the dermoepidermal junction. The dermis is a thick connective-tissue layer built largely from collagen and fibroblasts, and it houses blood and lymph vessels, hair follicles, sweat glands and nerves. The hypodermis is mainly fatty and loose connective tissue that stores energy and provides thermal protection. Most skin cancers begin in the epidermis, because both of the cell types that give rise to the common forms, keratinocytes and melanocytes, reside there. A smaller group of tumours, such as some sarcomas and lymphomas, arises in the dermis or deeper tissue and is covered in later sections.\n\nKeratinocytes and their renewal\n\nKeratinocytes make up the large majority of epidermal cells. Keratinocytes comprise about 90% of the epidermis and are responsible for its structure and barrier functions. Only the cells of the deepest layer, the stratum basale, divide. This basal layer is composed of a single row of cuboidal to columnar keratinocytes that are mitotically active, ensuring continuous regeneration of the epidermis. These basal cells are anchored to the basement membrane by hemidesmosomes, which separate the epidermis from the dermis.\n\nAs daughter cells move upward, they differentiate. Cells of the stratum spinosum, the \"prickle cell layer\", are linked by desmosomes and contain cytokeratin filaments, and the flattened cells of the upper layers give squamous cell carcinoma its name. At the final stage of differentiation the keratinocytes loose their nucleus and organelles and become dead. The resulting corneocytes form the stratum corneum, which is shed continuously. Estimates of renewal time vary with body site and method. It usually takes about 14 days for the basal cells to be keratinized into corneocytes, and about another 14 days for the corneocytes to be desquamated as grime. Thus the epidermis constantly repeat turnover in total of a 4- to 6-week cycle. Other measurements give somewhat longer whole-epidermis figures, and turnover slows with age.\n\nMelanocytes and melanin\n\nMelanocytes are scattered among the basal keratinocytes. Melanocytes are derived from embryonic neural crest, and they are not part of the keratinocyte lineage. Their main product is melanin, which is synthesised and stored inside melanosomes. Melanocytes extend dendrites between keratinocytes and transfer melanosomes into them, so that a single melanocyte can provide melanin for approximately 30 keratinocytes.\n\nMelanin protects deeper tissue mainly by absorbing ultraviolet energy. Instead of becoming very reactive when hit by UV light, melanin releases the extra energy as heat; it reacts less than 1 out of every 1000 times it becomes excited. This allows melanin to protect more sensitive molecules, like DNA, from UV exposure. Melanin granules therefore reduce how much UV radiation reaches the nuclei of keratinocytes. The protection is not uniform, however. Pheomelanin generates more reactive oxygen species and cyclobutane pyrimidine dimers under UV than eumelanin does, and melanocytes themselves handle reactive melanin intermediates that can damage DNA. Tanning is also an early defence: one study reported that the response begins before a visible tan develops.\n\nWhy location shapes growth and invasion\n\nThe position of each cell population helps explain how its tumours behave. Keratinocyte tumours arise within a densely packed, continuously renewing epithelium that is tightly bound to the basement membrane, so they typically grow in a contiguous mass and extend downward through the basement membrane into the dermis. Basal-layer tumours therefore tend to remain locally confined before deeper invasion occurs.\n\nMelanocytes, by contrast, are dispersed singly among basal keratinocytes and are not bound together by desmosomes in the same way. A melanocytic tumour can therefore spread horizontally within the epidermis before it invades downward, a pattern that later sections describe as the basis of melanoma staging. Once any tumour reaches the dermis, the vessels and lymphatics there provide routes for spread, which explains why depth of invasion is central to prognosis for both groups."
    },
    {
      "heading": "Basal cell carcinoma",
      "text": "Clinical appearance and sites\n\nBasal cell carcinoma (BCC) is the most frequently diagnosed skin cancer, and it is common enough that close to one in five Americans may be affected in a lifetime. Most lesions develop on sun-exposed skin, and most BCCs occur in sun-exposed areas, commonly on the face.\n\nThe classic nodular lesion usually begins as a shiny papule that enlarges gradually. Over months or years, a shiny, pearly border with prominent engorged vessels (telangiectases) on the surface and a central dell (ie, central depression) or ulcer may form. The centre can flatten and crust before it breaks down, which is why an ulcer that fails to heal is a recognised warning sign. Nodular BCC is the most common type and usually presents on the head (eyelids, cheeks, forehead).\n\nOther presentations are less obvious. The superficial subtype appears as a thin, pink plaque, papule, or macule with a pink, pearly border that is most commonly seen on the chest, back, or extremities. Pigmented variants can look like dark lesions, and the morpheaform form is firm, depressed, and smooth, and often resembles scars or localized patches of scleroderma. Because of this, a new scar without a history of injury is a reason for examination.\n\nGrowth, local invasion and metastasis\n\nBCC grows slowly and is confined to the epidermis in its early stage. As it enlarges, it spreads locally and destroys tissue. BCC infiltrate tissues in a three dimensional fashion. Perivascular and perineural invasion is associated with aggressive tumours. Deeper extension can reach cartilage, bone and the meninges. In one reported case, a recurrent scalp tumour invaded parietal bone, dura mater, and sigmoid sinus even though imaging had not shown bony destruction beforehand.\n\nMetastasis is uncommon. Reported rates vary widely, from 0.0028% to 0.5%, and when spread does occur it tends to follow lymphatic and hematogenous spread, most commonly to regional lymph nodes, followed by the lung and bone. Spread is most likely in the excessively large, ulcerated, locally destructive, and recurrent basal cell carcinoma. Deaths are rare and usually result from damage to vital structures, not from distant disease. Rarely, patients die because the carcinoma invades or impinges on underlying vital structures or orifices (eg, eyes, ears, mouth, bone, dura mater).\n\nRecurrence and histological subtypes\n\nRecurrence at the original site is a central clinical problem. Marginal recurrence is usually visible within 6 to 12 months. The risk is highest in the central face: the risk of recurrence is greatest on and around the eyelids, nose and mouth. Difficulty in defining margins and the wish to limit surgical deformity both contribute to this pattern.\n\nThe principal histological subtypes are nodular, superficial and morpheaform, although others are recognised. Other variants include micronodular, infiltrative and basosquamous BCC which are aggressive with high local recurrence. The infiltrative and morpheaform forms together account for 10% of basal cell carcinomas. The morpheaform type is considered the most dangerous because its boundaries are hard to see clinically, so it can extend further than it appears. Therefore this type of BCC has the poorest prognosis since it can subclinically destroy surrounding tissue.\n\nHereditary syndromes and the Hedgehog pathway\n\nBasal cell nevus syndrome, also called Gorlin–Goltz syndrome, is an inherited condition. It is a rare, inherited autosomal dominant disorder primarily caused by mutations in the PTCH1 gene, which regulates the Hedgehog signaling pathway. Affected people may develop multiple basal cell carcinomas of the skin, which may develop in those <20 years. Jaw cysts (odontogenic keratocysts) and skeletal anomalies are also typical features, and the syndrome carries additional tumour risks such as medulloblastoma.\n\nPTCH1 is a tumour suppressor. Its product forms part of the Hedgehog pathway, which governs cell growth and development. Hedgehog (Hh) signaling pathway, which also appears somatically mutated in more than 85% of sporadic BCCs. This explains why hedgehog pathway inhibitors such as vismodegib and sonidegib can control tumours in both inherited and sporadic disease, a point treated more fully in the sections on treatment and molecular pathogenesis. In Gorlin syndrome, recurrences of basal cell carcinomas (BCCs) are common in patients with Gorlin–Goltz syndrome due to the genetic basis of the disease."
    },
    {
      "heading": "Cutaneous squamous cell carcinoma",
      "text": "Cutaneous squamous cell carcinoma (cSCC) develops from the keratinocytes of the epidermis. In terms of frequency it ranks second among keratinocyte cancers, where it accounts for roughly 30% of all keratinocyte cancers. Its distribution follows cumulative sunlight exposure: the sun-exposed head and neck is the most frequent site of disease. Clinically, lesions may appear as firm nodules, scaly or crusted patches, or ulcers that do not heal. Tumours on the ear and lip are treated with particular caution, because the ear and vermilion lip are both named among the features that place a lesion in a higher-risk category.\n\nMost cSCCs are preceded by actinic keratosis (AK), a rough, sun-induced lesion of the epidermis. The atypical cells in actinic keratosis and in squamous cell carcinoma look morphologically identical, and molecular studies have found shared changes such as mutations in the tumour suppressor gene TP53. Estimates of how often an individual AK becomes invasive vary widely. One large cohort reported a progression risk of 0.60% at 1 year and 2.57% at 4 years, while a review placed the annual risk of an individual lesion between 0 and 0.53%. Because lesions tend to occur in clusters across chronically damaged skin, the cumulative risk for a patient is higher than the risk for any single lesion, and the same patient may develop several new AKs over time. Progression is usually described as passing through an in situ stage (squamous cell carcinoma in situ, or Bowen's disease) before invasion through the basement membrane, although not every AK follows this path, and some regress.\n\nUnlike basal cell carcinoma, which rarely spreads, cSCC has a real capacity to metastasise. Perineural invasion is one of the clearest markers of this difference. Its reported risks are 35% for lymph node metastasis and 15% for distant metastasis, compared with 15% and 3.3% for SCC without perineural invasion. Immune suppression is another major factor. Tumours in people with chronic immunosuppression often show other adverse features at the same time, such as large size and poor differentiation. Oral retinoids have been used in organ transplant recipients with numerous AKs, where they reduce the risk of SCC development. Chronic wounds, burn scars and long-standing ulcers are also recognised as settings in which cSCC can arise and behave more aggressively, although the evidence for this is less systematic than for immune suppression.\n\nPrognosis is assessed using high-risk features. The AJCC eighth edition lists tumour diameter >2 cm, depth of tumour >6 mm, perineural invasion of nerves ≥0.1 mm or nerves situated deep to the dermis, poorly differentiated histology, and location on the ear or lip. The depth threshold has changed over time: the 2011 modified system used depth greater than 2 mm and Clark level as criteria. Perineural invasion, while uncommon, carries a particularly heavy weight in assessment. Its depth also matters: in one retrospective series, the mean histopathologic depth to PNI was 2.7 mm, and depth varied by site, being shallowest in the head and deepest on the trunk. Some authorities include deep invasion (involvement beyond the subcutaneous fat or > 6 mm) and minor bone erosion as further markers. Grading systems such as the Brigham and Women's Hospital classification combine these factors to assign a tumour category.\n\nSources differ on the precise definition of high-risk status, and this affects clinical decisions. One review notes that there is poor concordance in current guidelines on which patient and tumor characteristics constitute high-risk features, with discrepancies between the AJCC and the National Comprehensive Cancer Network. Reported frequencies of perineural invasion also vary: one source gives only accounting for 1–2% of cSCC cases, whereas the AJCC-based estimate cited above puts it at approximately 2.5% to 5% of primary SCCs. Such differences reflect the use of different cohorts and definitions, and they mean that the same lesion may be classed differently depending on the staging system applied."
    },
    {
      "heading": "Melanoma",
      "text": "Melanoma arises from melanocytes, the pigment-producing cells that sit mainly in the basal layer of the epidermis and supply melanin to neighbouring keratinocytes. Because the malignant cell is a melanocyte rather than a keratinocyte, melanoma differs from basal and squamous cell carcinoma in its growth pattern, its capacity to spread and its response to treatment. Its clinical significance rests less on case numbers, which are a small fraction of all skin cancers, than on its behaviour: it is the form most likely to spread and kill.\n\nMain subtypes\n\nCutaneous melanoma is traditionally divided into four main subtypes: superficial spreading, nodular, lentigo maligna and acral lentiginous. The scheme descends from a histogenetic classification proposed by the American pathologist Wallace Clark in 1967, which grouped tumours chiefly by the appearance of their in situ component. In the United States, superficial spreading melanoma accounts for roughly 70–75% of cases, nodular melanoma for about 10–15%, lentigo maligna for around 5% and acral lentiginous melanoma for 2–3%. Superficial spreading melanoma usually occurs on intermittently sun-exposed skin, often in younger adults, and typically appears as a flat or slightly raised patch with irregular borders and mixed colours. Nodular melanoma is the most aggressive form: it lacks a recognisable prodromal radial phase, grows quickly, is often elevated and firm, and is more common in men and on the trunk, head and neck. Lentigo maligna develops from a pre-existing lentigo on chronically sun-damaged skin of older people, and is generally slow growing. Acral lentiginous melanoma arises on palms, soles and under the nails, and it is not related to sun exposure. Several rarer variants, including desmoplastic, nevoid, spitzoid and mucosal melanomas, are recognised separately, and each carries its own mutation profile. Histological subtype is not part of formal staging, but it correlates with behaviour and guides surgery and adjuvant therapy.\n\nGrowth phases and tumour thickness\n\nMelanomas are conceptually divided into a radial growth phase and a vertical growth phase. In the radial phase, the lesion spreads laterally within the epidermis, either in situ or as minimal invasion into the upper dermis, and it is considered non-tumorigenic: it does not form nodules that can metastasise, and prognosis is excellent. The vertical growth phase begins when tumour cells form a dermal nest or mass and invade deeper into the dermis, gaining the capacity to metastasise. An older series from the early 2000s noted that most melanomas diagnosed at that time had already progressed to vertical growth. The duration of the radial phase varies widely; some lesions metastasise within a month of invasion, while others take more than five years.\n\nThe most important prognostic measure is the Breslow thickness, the distance in millimetres from the granular layer of the epidermis to the deepest tumour cell, which is not measured for in situ lesions. Mitotic rate, the presence of tumour-infiltrating lymphocytes, ulceration and anatomic site are also used. In one Western Canadian series, five-year survival was around 98% for lesions thinner than 0.76 mm, but it fell to about 66% at 3–5 mm. Vertical growth and mitotic activity are also strong predictors of sentinel lymph node positivity in thin melanomas, which is why they are included in pathology reports. Nodular melanomas can be thick at diagnosis even when visible changes are modest, and a study of superficial spreading melanomas with a vertical phase found that thicker tumours had higher mitotic rates and faster growth.\n\nClinical warning signs and the ABCDE criteria\n\nThe first sign of melanoma is often a change in an existing mole or the appearance of a new pigmented spot. In later stages a lesion may itch, ulcerate or bleed. The ABCDE mnemonic summarises the features to look for: asymmetry, irregular or blurred borders, colour variegation (several shades of brown, black, tan, red, blue or white), diameter greater than about 6 mm, and evolution, meaning any change in size, shape, colour or height. Clinicians also use the \"ugly duckling\" sign, in which a lesion looks unlike the other moles on the same person. The ABCDE criteria, however, do not fit every case. Nodular melanomas may be symmetrical and uniformly coloured, and amelanotic, subungual and scalp lesions are easily missed, so a firm, growing or bleeding lesion should be assessed regardless of its appearance.\n\nMetastatic pathways and mortality\n\nMelanoma spreads through both the lymphatic and the blood circulation. Lymphatic spread usually goes first to regional lymph nodes, which is the most common site of early metastasis; in one study, tumour cells had invaded lymphatic vessels in 70% of melanomas that later metastasised, compared with 12% of those that did not. Haematogenous spread carries tumour cells to distant organs, most often the lungs, liver, brain and bone. Brain metastases are particularly common in advanced disease, and metastatic melanoma can cause nonspecific systemic symptoms such as fatigue and weight loss. Early melanoma metastasises less often; fewer than one in five melanomas diagnosed early become metastatic. Melanoma accounts for only about 1% of skin cancer diagnoses, yet it is responsible for the majority of skin-cancer deaths, because basal and squamous cell carcinomas rarely spread, whereas metastatic melanoma has historically resisted conventional chemotherapy. This resistance is the main reason the development of immunotherapy and targeted therapy has changed outcomes for advanced disease, as discussed in the sections on diagnosis and treatment."
    },
    {
      "heading": "Rare and other skin cancers",
      "text": "Skin cancers outside the common basal cell carcinoma, squamous cell carcinoma and melanoma categories are individually uncommon. Several of them, however, follow very different biological courses, and they are often mistaken for benign conditions at first presentation.\n\nMerkel cell carcinoma\n\nMerkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin, named for its ultrastructural resemblance to Merkel cells, a mechanoreceptor population in the epidermis. Its annual incidence in the United States was about 0.7 per 100,000 in 2013, but cases rose by 95% between 2000 and 2013, faster than melanoma. Tumours typically occur in older adults with fair skin on sun-exposed sites, appearing as a firm, rapidly growing, usually painless pink-red or violaceous nodule. Two main causal routes are recognised. In virus-positive tumours, HIV-independent integration of Merkel cell polyomavirus into the host genome has been found in up to 80% of cases, whereas virus-negative tumours carry a heavy load of UV-induced mutations. Immunosuppression, including that from HIV infection, organ transplantation or haematological malignancy, is associated with a substantially higher incidence. The cell of origin remains debated. The disease recurs in about 40% of patients, often at distant sites, and immune checkpoint inhibitors have produced durable benefit in roughly half of those with advanced disease.\n\nCutaneous lymphomas\n\nCutaneous lymphomas are lymphomas that present in the skin rather than being derived from keratinocytes or melanocytes. The most frequent form is cutaneous T-cell lymphoma (CTCL), a malignancy of T lymphocytes that usually develops over years. Early lesions are persistent, itchy, scaly patches or thickened plaques that look like eczema or psoriasis and respond poorly to conventional topical treatment. Diagnosis can therefore be delayed for years, and multiple biopsies with histopathological and immunophenotypic analysis are often needed to distinguish it from inflammatory dermatoses. Because the cell of origin is a lymphocyte, management follows lymphoma staging and systemic or skin-directed lymphoma therapies rather than the wide surgical excision used for carcinomas.\n\nDermatofibrosarcoma protuberans\n\nDermatofibrosarcoma protuberans (DFSP) is a slow-growing malignant tumour of the dermis and subcutaneous fat. More than 90% of cases carry a characteristic rearrangement, t(17;22), involving chromosomes 17 and 22, typically forming a supernumerary ring chromosome. It most often arises on the trunk as a firm, skin-coloured or violaceous nodule and rarely metastasises. Because it resembles benign lumps and grows slowly, it is frequently misdiagnosed in primary care before a biopsy is taken. Histological confirmation with CD34 positivity is required, and complete excision with clear margins is the main treatment, since incomplete removal carries a high risk of local recurrence.\n\nAngiosarcoma\n\nCutaneous angiosarcoma arises from endothelial cells lining blood or lymphatic vessels and is among the most aggressive tumours of the skin. Three clinical variants are recognised: tumours of the scalp and face in older people, tumours arising in chronically lymphoedematous limbs (Stewart–Treves syndrome, first described in 1948 after axillary lymph node clearance for breast cancer), and tumours occurring after radiotherapy. Early lesions appear as bruise-like erythematous or violaceous nodules, patches or plaques, which may be taken for benign vascular lesions; one reported case was initially diagnosed as a Masson's tumour. Dense lymphocytic infiltrates can make the histology resemble lymphoma. The tumour is highly invasive, with a high rate of local recurrence and distant spread, which is why prognosis is generally poor when diagnosis is late.\n\nKaposi sarcoma\n\nKaposi sarcoma (KS) is an angioproliferative tumour, first described by Moritz Kaposi in 1872 as a slow-growing \"classic\" form seen mainly in older men of Mediterranean or Jewish ancestry. The discovery of human herpesvirus 8 (HHV-8, also known as KSHV) identified the causative agent, although the virus is necessary but not sufficient for disease. The HIV epidemic produced a far more aggressive form, and KS remains most common in people with advanced HIV, particularly in sub-Saharan Africa where HHV-8 is endemic. Other forms include an endemic African type and a form that arises in patients receiving immunosuppressive drugs after transplantation. The HIV Tat protein, immune dysfunction and inflammatory cytokines are thought to amplify the oncogenic effects of HHV-8. Whether the lesions are true neoplasms or reactive angioproliferations is still debated. Diagnosis rests on histopathology of cutaneous or nodal tissue, and treatment combines antiretroviral therapy with chemotherapy in more advanced disease.\n\nDiagnostic delay and its consequences\n\nAcross these tumours, the initial appearance often resembles eczema, benign nodules or vascular lesions, so biopsy is frequently delayed. For angiosarcoma and DFSP, delayed recognition matters because early surgical removal is closely linked to local control and survival. For CTCL, a late diagnosis means that treatment begins later and staging is often incomplete. For MCC and KS, delayed recognition can mean that the underlying immune status or viral infection is not addressed alongside the tumour. Persistent, enlarging or non-healing lesions that fail to respond to routine treatment are therefore the usual triggers for referral and biopsy."
    },
    {
      "heading": "Causes and ultraviolet radiation",
      "text": "Ultraviolet radiation and DNA damage\n\nUltraviolet (UV) radiation is the main environmental cause of skin cancer. Sunlight reaching the ground includes UVB and UVA bands, and the two damage DNA in different ways. UVB, at roughly 280–320 nm, is absorbed directly by DNA. Its energy joins neighbouring pyrimidine bases, mainly thymine pairs, into cyclobutane pyrimidine dimers (CPDs) and, less often, pyrimidine (6–4) pyrimidone photoproducts. Cells normally remove these lesions through nucleotide excision repair. A lesion that escapes repair and is still present when the cell copies its DNA can produce a mutation at the damaged site. The cytosine within a CPD can deaminate to uracil, and the replication machinery then places an adenine opposite it, so the result is a C-to-T change, or a tandem CC-to-TT change. These base changes are the classic UVB signature, and they are recorded as mutational signatures in tumour genome sequencing.\n\nThese signatures are common in melanoma. Analyses of cancer genomes indicate that 70% or more of cutaneous melanomas carry a UVB-linked pattern. Other melanoma mutations, including T>A, T>C and C>A substitutions in non-dipyrimidine contexts, do not match the classic pattern, which has led researchers to look for other sources of damage.\n\nThe contested role of UVA\n\nUVA (about 320–400 nm) makes up roughly 90% of the solar energy reaching the surface, yet its contribution to skin cancer has been debated for decades. UVA forms CPDs much less efficiently than UVB, but a larger share of those UVA-induced CPDs sit at TT sequences. UVA also generates oxidised bases such as 8-oxoguanine, which cause a different, less common class of mutation. Experiments on engineered human skin found that UVA-induced mutations cluster in the basal layer of the epidermis, whereas UVB-induced mutations are distributed differently. Because UVA can produce the same C-to-T pattern as UVB in some experimental systems, the mutation signature alone does not settle which wavelength caused a given tumour. The current view is that both bands contribute, with UVB dominant for the classic signature and UVA implicated in some non-classic melanoma mutations through indirect damage.\n\nCumulative exposure, intermittent sunburn and cancer type\n\nThe relation between UV dose and risk depends on the cancer type. Squamous cell carcinoma is most strongly linked to chronic, cumulative UVB exposure over many years, and it often develops from actinic keratoses on photoaged skin. Basal cell carcinoma responds to both lifetime dose and episodes of intense exposure, and childhood and adolescent sun exposure appears especially important. Melanoma is most closely linked to intense, intermittent exposure that causes blistering sunburn, rather than steady exposure. In a Florida case-control study, a history of blistering sunburn was associated with roughly twofold odds of both basal cell carcinoma and squamous cell carcinoma. Sun-exposure patterns also differ by occupation: outdoor workers and people living at high UV index levels have continuous exposure, whereas indoor workers who spend weekends or holidays outdoors experience intermittent exposure.\n\nIndoor tanning\n\nIndoor tanning devices emit UV radiation, and the International Agency for Research on Cancer (IARC) classified them as Group 1, carcinogenic to humans, in 2009. The classification rested on a review of case-control studies and a meta-analysis of 19 studies that assessed sunbed exposure and melanoma. An earlier IARC meta-analysis reported a relative risk of about 1.15 for ever-use of tanning beds, and a risk of about 1.75 for first use before age 35. Later pooled analyses found a smaller overall association of about 1.25 for ever-use, with the largest increases among people who started young. The evidence for melanoma is generally rated sufficient, while the evidence for squamous cell carcinoma is considered limited. Some cohort studies have also reported associations with basal cell carcinoma.\n\nYoung people, regions and occupations\n\nIndoor tanning is most common among young adults, and use declines with age. Because early exposure carries the greatest risk, youth access has become a focus of legislation and public health policy. In one study, teenage girls posing as 15-year-olds without parental consent obtained sessions at 81% of tanning facilities they visited in Minnesota and Massachusetts, despite state laws prohibiting this. Outdoor exposure patterns vary sharply by region, with the highest continuous exposure in areas with high UV index values, and by occupation, with outdoor labourers at greatest risk of squamous cell carcinoma. These differences shape both the regional epidemiological pattern of skin cancer and the design of prevention messages."
    },
    {
      "heading": "Risk factors and susceptibility",
      "text": "Skin phenotype and response to sunlight\n\nThe strongest individual predictor of skin cancer is how the skin reacts to sunlight. The Fitzpatrick skin phototype scale classifies people by how readily their skin burns and how well it tans. People in the lowest categories, who burn easily and tan poorly, have the highest melanoma rates. Pale skin, light or red hair, light eyes and freckling tend to occur together in this group, reflecting low levels of dark eumelanin and a limited capacity to add pigment after UV exposure. Fair-skinned populations in Europe, North America, Australia and New Zealand therefore record the highest incidence worldwide. Darker-skinned people are diagnosed less often, but this lower risk does not translate into protection from acral and mucosal melanomas, which are not driven by UV exposure to the same degree.\n\nSunburn history is an independent factor. Blistering or peeling burns, particularly before the age of 20, carry a markedly higher melanoma risk, and childhood exposure appears to matter more than adult exposure. Migration studies in Australia suggest that adults who move there tend to keep the risk profile of their country of birth, which points to early-life exposure and phenotype rather than the environment alone.\n\nGenetic susceptibility\n\nMost melanomas arise in people without a known inherited predisposition, but germline variation contributes substantially to risk. The MC1R gene regulates the type of melanin a melanocyte produces. Variants linked to red hair, fair skin, freckling and sun sensitivity raise melanoma risk even when other visible features are absent; three common variants (R151C, R160W and D294H) account for much of this association. Their effect is partly independent of pigmentation.\n\nGermline mutations in CDKN2A, which encodes the cell-cycle regulator p16INK4a, are the principal high-penetrance cause of familial melanoma, while mutations in CDK4 are rarer. MC1R variants modify the risk conferred by CDKN2A mutations. In one study of 815 carriers, a single common MC1R variant roughly doubled melanoma risk, and two or more variants increased it nearly sixfold. In melanoma-prone pedigrees, carrying an MC1R variant alongside a CDKN2A mutation was associated with earlier onset of disease. Family history of melanoma is itself a strong factor; in a case-control study of Italian patients, CDKN2A-positive individuals with an affected relative showed a very large increase in risk, and a previous melanoma places a person at high risk of further primary melanomas.\n\nNaevi, atypical moles and age\n\nA high number of melanocytic naevi is among the strongest known risk factors for melanoma, and the naevus count is itself partly genetically determined. Large congenital naevi also raise risk. Atypical (dysplastic) naevi, which show irregular borders, variegated colour and disordered melanocytic architecture, are more common in fair-skinned people and in those with high cumulative sun exposure. Most melanomas arise on previously normal skin, although a substantial minority (often cited as 20–30%) develop from existing moles. The probability that any single atypical naevus becomes a melanoma is low, but people with many of them have a much higher overall risk. Familial atypical multiple mole melanoma (FAMMM) syndrome describes the combination of many atypical naevi with a family history of melanoma.\n\nAge is a risk factor for all major skin cancers. Keratinocyte cancers are concentrated in older adults because damage accumulates over decades, whereas melanoma is also diagnosed in younger adults. Actinic keratosis, a precursor of squamous cell carcinoma, is associated with other melanoma risk factors in some clinical series.\n\nOccupational and cumulative sun exposure\n\nCumulative exposure is measured not only by holidays and leisure but by work. Outdoor occupations such as farming, construction, fishing and lifeguarding carry high daytime UV doses over many years. In the Italian case-control study mentioned above, occupational sun exposure increased melanoma risk several-fold in both CDKN2A-negative and CDKN2A-positive individuals, a result that reflected local occupational patterns. Indoor tanning, which is discussed in the section on causes, is a separate and additional exposure.\n\nImmune suppression\n\nLong-term immunosuppression impairs the immune system's ability to detect and eliminate precancerous cells, and it is the best-documented host factor for keratinocyte cancers. Solid organ transplant recipients are the most studied group. Estimates of their excess risk vary by study and by tumour type: one review puts keratinocyte cancer risk at 10 to 65 times that of the general population, while another reports a 65- to 250-fold increase for cutaneous squamous cell carcinoma. These tumours tend to be more aggressive, recur more often and metastasise more readily than in the general population. Reduced inflammation around these tumours can also cause their depth and invasion to be underestimated clinically.\n\nThe choice of immunosuppressive drug matters. Some observational data indicate that mycophenolate-based regimens are associated with lower squamous cell carcinoma risk than azathioprine-based regimens, but with a higher risk of basal cell carcinoma. The effect of immunosuppression also interacts with UV exposure and latitude, and male sex, older age and the type of transplanted organ (as a proxy for immunosuppressive intensity) are established additional factors. Immune suppression from HIV infection and other chronic treatments raises keratinocyte cancer risk in a similar way, and it also contributes to melanoma risk."
    },
    {
      "heading": "Molecular pathogenesis",
      "text": "Growth-signalling and tumour-suppressor genes\n\nSkin cancers accumulate mutations in a limited set of genes that control proliferation, cell death and DNA maintenance. In cutaneous melanoma, the two most frequent driver oncogenes are BRAF and NRAS, which encode components of the MAPK growth-signalling cascade. Activating lesions in these two genes rarely coexist in the same tumour, so each usually marks a separate molecular route to disease cite 3-12. Among the remaining drivers, NF1, a negative regulator of RAS signalling, is hit in roughly a tenth to a seventh of cases, which places it behind BRAF, NRAS and TP53 in frequency cite 8-2. TP53 encodes the p53 transcription factor, which acts as a brake on the cell cycle and can trigger apoptosis when DNA damage is severe. When TP53 is inactivated, damaged cells can pass checkpoints that would normally stop them, which allows mutations to accumulate.\n\nThe DNA damage response and nucleotide excision repair\n\nUltraviolet light generates bulky lesions, mainly cyclobutane pyrimidine dimers and 6–4 photoproducts, that distort the double helix. A normal cell responds by pausing the cell cycle, recruiting repair machinery and, if the damage cannot be fixed, eliminating itself. The main repair route for these lesions is nucleotide excision repair (NER). It operates in two sub-pathways: global genome repair, which scans the whole genome, and transcription-coupled repair, which works preferentially on the transcribed strand of active genes cite 16-9. Because the two sub-pathways act on different regions, a defect in one does not necessarily abolish the other.\n\nThe clearest evidence that defective NER raises risk comes from xeroderma pigmentosum (XP), a rare inherited disorder. Its patients have a markedly increased risk of UV-induced cancers, with estimates of up to about 10,000-fold for non-melanoma skin cancers and about 2,000-fold for melanoma cite 18-7. Cells from these patients cannot efficiently repair the major UV photoproducts cite 17-4. The clinical severity differs between complementation groups. XP-C, which lacks global genome repair while transcription-coupled repair remains intact, is among the most tumour-prone groups cite 17-5. Loss of the translesion polymerase η (XP-V) adds a separate mechanism, because it impairs error-free bypass of the lesions that remain after NER has acted cite 18-4. Genome sequencing of XP tumours shows that the efficiency of NER shapes where mutations accumulate across the genome, not only how many arise cite 18-9.\n\nImmune evasion, inflammation and the stroma\n\nMelanoma cells lose immunogenicity as they evolve, and some acquire the ability to suppress anti-tumour T cells within their surroundings cite 24-3. The tumour microenvironment contains tumour-associated macrophages, regulatory T cells, myeloid-derived suppressor cells and cancer-associated fibroblasts. Together these cells secrete immunosuppressive cytokines such as IL-10, TGF-β and VEGF, which favour growth and dampen immune attack cite 28-1. Cancer-associated fibroblasts can additionally block the activation of natural killer cells cite 29-11. Dendritic cells in melanoma are often arrested at an immature stage, so they cannot properly present tumour antigens to the adaptive immune system cite 21-8.\n\nTumours are commonly grouped by immune architecture. Immune-inflamed tumours contain many T cells, but these are often exhausted by chronic antigen exposure, while immune-excluded tumours hold T cells in the surrounding stroma without letting them reach the tumour cells, and immune-desert tumours have few T cells at all cite 21-6,21-7. This distinction matters because the density and distribution of cytotoxic T cells in the stroma has been associated with responsiveness to immunotherapy cite 21-2. Inflammation itself is double-edged: chronic inflammation within the tumour can both supply pro-tumour signals and sustain an immune response that the tumour has learned to neutralise.\n\nGenomic differences by sun exposure and subtype\n\nMelanomas arising on chronically sun-damaged skin differ genetically from those on intermittently exposed skin. NRAS codon 61 mutations were found in about 29% of primary tumours from chronically exposed sites, compared with about 21% from intermittently exposed sites. BRAF mutations showed the opposite pattern, appearing in about 21% of tumours on chronically exposed sites and about 48% on intermittently exposed ones cite 7-1,7-2,7-3. Earlier work reported that BRAF mutations were significantly more common in melanomas arising on skin without chronic sun damage, whereas RAS mutations were confined to BRAF-wild-type tumours. Chronically sun-damaged melanomas more often showed increased copies of the CCND1 gene, while melanomas from less-exposed skin more often lost chromosome 10 cite 9-1,9-2. Patients with NRAS-mutant tumours tend to be older, to have had UV exposure, and to present with thicker primary tumours and higher mitotic rates cite 8-1.\n\nGenomic classification also varies by subtype. Superficial spreading melanoma on low-damage skin typically carries BRAF V600E mutations, whereas lentigo maligna and nodular melanomas on high-damage skin more often carry non-V600E BRAF, NF1, NRAS or KIT alterations. Desmoplastic melanoma is characterised by NF1 and MAPK pathway changes cite 5-7. Experimental work in mice has found that a single UVB exposure produced roughly twice as many single-nucleotide variants in Braf-mutant as in Nras-mutant melanomas, which suggests that the genotype modifies UV sensitivity cite 2-4. However, other analyses report UV-type mutation signatures in a similar proportion of NRAS- and BRAF-mutant human melanomas cite 1-2, so the relationship between genotype, UV exposure and mutational burden remains incompletely resolved."
    },
    {
      "heading": "Diagnosis, staging and pathology",
      "text": "Clinical examination and dermoscopy\n\nMost skin cancers are first suspected on visual inspection, and the examiner judges a lesion's size, outline, colour, surface and any change over time. Pigmented lesions are usually screened with the ABCDE criteria described in the melanoma section. Dermoscopy extends this inspection. A handheld dermatoscope magnifies the lesion and uses polarised or fluid-coupled illumination to reveal colour and structural patterns that the naked eye cannot resolve. Because pigment lying deeper in the dermis looks different under the instrument, the colour distribution offers a rough indication of how deep a melanocytic lesion extends. The benefit depends on formal training, so primary care clinicians often refer suspicious lesions to dermatologists for specialist assessment.\n\nBiopsy techniques\n\nHistological examination is the only route to a definitive diagnosis. The choice of technique is shaped by the suspected tumour and by what the pathologist needs to measure:\n\n- Shave biopsy removes a thin superficial layer with a blade, is suited to raised lesions, and usually needs no sutures.\n- Saucerisation (deep scoop shave) is used for flat or pigmented lesions and can sample deeper tissue than a simple shave.\n- Punch biopsy uses a circular cutter, typically 2 to 6 mm in diameter, to take a cylindrical full-thickness sample that reaches the subcutaneous fat. It is useful when the dermis or fat must be examined.\n- Excisional biopsy, performed as an ellipse or with a small punch, removes the whole lesion with a surrounding margin. It is preferred for small suspected melanomas because the intact specimen allows accurate measurement of tumour thickness.\n\nPartial sampling carries a risk of underestimating depth. In one series of 332 melanoma patients, most diagnostic biopsy margins were positive, and the T stage changed in about 8% of patients, with punch biopsies over-represented among those changes. Guidance on biopsying suspected melanoma nonetheless remains debated, and the choice between techniques is weighed against the lesion's site and cosmetic considerations.\n\nHistopathological criteria\n\nPathologists examine vertically sectioned, haematoxylin-and-eosin-stained tissue to separate the main entities. In melanoma, the key measurements are the Breslow thickness (the vertical distance from the top of the granular layer, or from the base of any ulcer, to the deepest invasive cell), the presence of ulceration, the mitotic rate, the Clark level, regression and lymphovascular invasion. Basal cell carcinoma is recognised by basaloid nests with peripheral palisading and stromal retraction; its nodular, superficial and infiltrative (morpheaform) subtypes differ in the arrangement of these nests within the dermis. Squamous cell carcinoma shows atypical keratinocytes with keratinisation, intercellular bridges or keratin pearls, and is graded by differentiation. Keratinocyte lesions confined to the full thickness of the epidermis are classified as in situ disease.\n\nTNM and AJCC staging\n\nMelanoma is staged with the TNM system of the American Joint Committee on Cancer (AJCC), currently the 8th edition, in force from 2018. The T category depends mainly on Breslow thickness, with thresholds at 1.0, 2.0 and 4.0 mm, and on ulceration. Tumours under 0.8 mm without ulceration are T1a; those of 0.8 to 1.0 mm, or thinner tumours with ulceration, are T1b. Mitotic rate was dropped as a T1 criterion but remains prognostic. The N category records the number and detection mode of regional nodal metastases, along with in-transit, satellite and microsatellite lesions, and microsatellites upstage node-negative disease. The M category covers distant metastasis, and the combined stage groups range from 0 (in situ) to IV.\n\nKeratinocyte cancers are handled differently. The AJCC has a dedicated TNM system for cutaneous squamous cell carcinoma, introduced in 2010, in which the T category is set by tumour diameter, invasion of cranial bone and high-risk features: location on the ear or lip, thickness above 2 mm or Clark level IV or deeper, poor differentiation and perineural invasion. This system is intended for head and neck tumours, and other sites are often assessed with alternatives such as the Brigham and Women's Hospital scheme. Experts disagree on which features define high risk: the AJCC places most lesions in the low-risk group, while the NCCN guidelines place most in the high-risk group. Basal cell carcinoma is usually not assigned a formal TNM stage, and its management rests on size, site, subtype and histological margins.\n\nPrognosis, sentinel lymph node biopsy and treatment choice\n\nBreslow thickness is the principal determinant of melanoma prognosis, and ulceration adds further information. Sentinel lymph node biopsy (SLNB) is the standard way to test regional nodes. It is indicated for melanomas of at least 1 mm without evidence of metastasis, and for 0.8 to 1.0 mm lesions when risk features such as ulceration, high mitotic activity, younger age or lymphovascular invasion are present. Nodal metastasis is reported in roughly 5 to 10% of early tumours, compared with 35 to 50% for those thicker than 4 mm. A positive sentinel node moves the patient into the nodal stage category and changes the treatment discussion. Over time, SLNB has shifted the role of nodal surgery from routine completion lymph node dissection toward identifying patients who may benefit from adjuvant systemic therapy.\n\nFor keratinocyte cancers, high-risk features guide decisions on imaging, SLNB, postoperative radiotherapy and intensified follow-up, although consensus surveys show that many specialists do not rely on stage alone to choose treatment beyond surgery."
    },
    {
      "heading": "Prevention, screening and sun protection",
      "text": "Primary prevention and community trials\n\nPrimary prevention aims to stop skin cancers forming by limiting exposure to ultraviolet radiation. The main measures are seeking shade, especially around midday, wearing protective clothing such as broad-brimmed hats and tightly woven fabrics, and applying sunscreen. Evidence on sunscreen comes mainly from the Nambour trial in Queensland, Australia. In 1992, 1,621 randomly selected adults were assigned to daily or discretionary use of a sunscreen of SPF 15 or higher on the head, neck, arms and hands, with or without beta-carotene supplements. Daily use reduced new squamous cell carcinomas, with reported reductions ranging from roughly 40 to 60 per cent depending on the follow-up period and the analysis. Basal cell carcinoma showed no clear benefit. Sunscreen also lowered the rate of actinic keratoses during the first two years. Long-term follow-up found a lower melanoma risk in the daily-use group, but the difference did not reach statistical significance. Outdoor time did not differ between groups, which argues against people compensating by spending more time in the sun.\n\nAdherence was the trial's weak point. About 56 per cent of the intervention group reported applying sunscreen on at least five days a week, and the amount applied was about half the recommended quantity. Similarly, a later high-risk trial found that only half of participants had used sunscreen in the week before baseline. Community prevention therefore depends on sustained behaviour change rather than on a single message, and the protective effect of sunscreen is limited when people apply too little.\n\nThe UV Index\n\nThe UV Index was developed by the World Health Organization together with the World Meteorological Organization and the United Nations Environment Programme. It expresses the expected peak level of sunburn-producing ultraviolet radiation for a given location and day, on an open-ended scale that is conventionally shown from 0 to 11 or more. Values are colour-coded, and each band is linked to recommended protective measures, ranging from minimal precautions at low values to shade, clothing, hats and sunscreen at high and extreme values. Public forecasts publish the index alongside weather reports, which allows public health messages to be targeted to the day's conditions. Its limitations are that it refers to a clear-sky estimate, does not capture the greater exposure from reflective surfaces such as snow, sand and water, and does not describe the heat or infrared component of sunlight.\n\nSkin self-examination and clinician screening\n\nSelf-examination encourages people to check their skin regularly for new or changing lesions, often using the ABCDE criteria. Clinician screening involves a visual skin examination during routine care. The United States Preventive Services Task Force concluded in 2023 that the evidence is insufficient to assess the balance of benefits and harms of clinician visual skin examination in asymptomatic adolescents and adults. It found inadequate evidence that such screening reduces morbidity or mortality, and inadequate evidence of its harms. The task force specifically called for research in populations with diverse skin tones. The statement does not apply to people with a personal or family history of skin cancer or to those with symptoms.\n\nThe debate centres on whether earlier detection of melanoma saves lives. Supporters point to the fact that lesions are visible, that examinations are non-invasive, and that melanoma thickness at diagnosis predicts survival. Critics note that the trials needed to show a mortality benefit have not been conducted, and that screening can lead to over-diagnosis and unnecessary excisions. Some countries have nonetheless introduced organised skin checks; Germany, for example, has offered a statutory skin examination to adults aged 35 and over since 2008. Whether such programmes reduce deaths remains unresolved.\n\nChemoprevention and high-risk groups\n\nNicotinamide, a form of vitamin B3, is the most studied oral chemopreventive agent. In the ONTRAC phase 3 trial in high-risk immunocompetent patients, 500 mg twice daily for 12 months reduced new non-melanoma skin cancers by 23 per cent compared with placebo, with a 30 per cent lower rate of squamous cell carcinoma and a non-significant 20 per cent lower rate of basal cell carcinoma. The benefit did not persist after treatment stopped. A later trial in organ-transplant recipients who had at least two keratinocyte cancers in the previous five years, the ONTRANS study, found no difference, with 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group. Observational data from a veterans' cohort have since reported lower skin cancer rates among users, but such studies cannot establish causation, and expert opinion on routine use remains divided.\n\nOrgan-transplant recipients carry a markedly higher risk of keratinocyte cancers and skin cancer-related death because immunosuppressive drugs weaken immune surveillance of UV-damaged cells. Prevention in this group combines intensive sun protection, regular dermatological review, prompt treatment of precancerous lesions, and, in some cases, adjustment of immunosuppressive regimens. Because transplant-specific prevention trials are small or negative, management is largely guided by risk stratification and clinical judgement rather than by proven chemopreventive regimens."
    },
    {
      "heading": "Treatment",
      "text": "Surgical excision and Mohs micrographic surgery\n\nSurgical removal is the main treatment for most keratinocyte cancers and for localised melanoma. In standard excision, the tumour is removed with a rim of normal skin, and the width of that rim (the margin) depends on tumour type, size and site. For small, well-demarcated, low-risk basal cell carcinomas, a safety margin of 3 mm gives satisfactory results. Larger or high-risk lesions call for wider margins, with one review suggesting a 4-6 mm margin to achieve clear margins. Narrow margins taken for cosmetic reasons carry a real cost: a pathology report indicating \"margins free of residual tumor\" is often inaccurate, and there are recurrence rates of up to 38%.\n\nMohs micrographic surgery addresses this problem by examining the margins during the operation. The tumour is excised and immediately examined under a microscope, and if the margins are insufficient, more tissue is removed until they are clear. Five-year cure rates reported for Mohs versus standard excision are 99% versus 90% for primary basal cell carcinoma, 94% versus 83% for recurrent basal cell carcinoma, 97% versus 92% for primary cutaneous squamous cell carcinoma, and 90% versus 77% for recurrent squamous cell carcinoma. Mohs is generally preferred for high-risk lesions, such as those that are large, sit in sensitive areas of the head and neck, or show aggressive growth patterns. Cure rates for squamous cell carcinoma are not as high as Mohs surgery for basal cell carcinoma. Melanoma is usually managed by wide local excision, with margins set by tumour thickness, rather than by Mohs.\n\nRadiotherapy\n\nRadiotherapy is used mainly for keratinocyte cancers that cannot be removed surgically without functional or cosmetic harm, for tumours with incomplete excision, and for palliation of advanced disease. Trials have also combined radiation with hedgehog-pathway inhibitors such as vismodegib in advanced head and neck basal cell carcinoma.\n\nTopical and field treatments\n\nTopical agents and photodynamic therapy are used mainly for actinic keratosis and superficial lesions. Fluorouracil works by blocking methylation of deoxyuridylic acid via inhibition of thymidylate synthetase, and imiquimod is an immune response modifier. In one randomised comparison, fluorouracil produced the best cumulative success rate, at 75%, compared with 54% for imiquimod and 38% for methyl aminolevulinate with photodynamic therapy. Photodynamic therapy relies on a photosensitiser: topical application of aminolevulinic acid or one of its derivatives is followed by light activation, which produces singlet oxygen species, resulting in cell death. Its main drawbacks are pain, burning, pruritus, erythema, crusting, and inflammation. Combining photodynamic therapy with imiquimod has improved complete clearance compared with monotherapy in a meta-analysis of trials.\n\nSystemic therapy for advanced melanoma\n\nSystemic therapy has changed the outlook for advanced melanoma. Ipilimumab, pembrolizumab and nivolumab have been shown to improve survival in patients with advanced melanoma. For first-line treatment of metastatic or unresectable disease, guidelines recommend single-agent anti-PD-1 therapy (pembrolizumab or nivolumab) or combination anti-PD-1 and anti-CTLA-4 therapy with nivolumab and ipilimumab. Checkpoint inhibitors produce fewer responses than targeted drugs, but these responses can be durable. Immune-related toxicity needs monitoring; for example, a heightened uveitis risk has been reported with checkpoint therapy and BRAF/MEK therapy, which calls for ocular monitoring.\n\nTargeted therapy applies to tumours with a BRAF V600 mutation, which is present in about 40-50% of patients with cutaneous melanoma. Combinations of BRAF and MEK inhibitors, including dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib, are used in these patients. Their responses are fast but often short-lived, and resistance to BRAF/MEK inhibition and comparatively low response rates to immune checkpoint inhibitors remain clinical challenges. Adding a checkpoint inhibitor to BRAF/MEK therapy has been studied in randomised trials; triple therapy has shown improvements in progression-free survival and durability of response compared to BRAF/MEK inhibition alone, although the best place for it in the treatment sequence is still debated. For resected stage III disease, adjuvant options include checkpoint inhibitors or dabrafenib/trametinib.\n\nAdvanced keratinocyte cancers\n\nFor locally advanced or metastatic basal cell carcinoma that cannot be treated with surgery or radiotherapy, hedgehog-pathway inhibitors such as vismodegib and sonidegib are used. For metastatic or locally advanced squamous cell carcinoma in patients who are not candidates for curative surgery or radiotherapy, the anti-PD-1 antibody cemiplimab is approved.\n\nOutcomes, recurrence and follow-up\n\nRecurrence after excision is the main concern for basal and squamous cell carcinomas, and follow-up consists largely of clinical skin examination, since these tumours seldom metastasise. For melanoma, outcomes depend on stage at treatment. In the CheckMate 067 trial, about half of patients receiving nivolumab with ipilimumab were alive at five years, a substantial change from the pre-immunotherapy era. Follow-up for melanoma includes skin and nodal examination and imaging, with most recurrences occurring within the first few years. Long-term safety data for newer agents are still accumulating."
    },
    {
      "heading": "Epidemiology and global burden",
      "text": "Global figures\n\nGlobal estimates depend on the year, the registry base and whether keratinocyte cancers are included, so the figures below differ between sources. The WHO's annual estimate places non-melanoma cases at roughly 2 to 3 million and melanoma at about 132,000. Both groups have become more common over recent decades, although the WHO notes that trends for non-melanoma cancers are hard to establish because registration has been unreliable. A GLOBOCAN fact sheet lists about 337,969 melanoma cases and 58,398 melanoma deaths, a substantially higher count that reflects a different estimation method. Another secondary source attributes a figure of more than 65,000 melanoma deaths a year to the WHO. Despite being far less frequent, melanoma accounts for most skin cancer deaths. Deaths from basal cell and squamous cell carcinoma are rare by comparison, and U.S. estimates for deaths from these two cancers range from about 2,000 to 8,000 people each year, mostly from squamous cell skin cancer.\n\nNational patterns\n\nIn the United States, the National Cancer Institute's SEER program projected 112,000 new melanoma cases and 8,510 deaths in 2026, with a five-year relative survival of 94.7% for 2016–2022. Keratinocyte cancers are counted less precisely. US cancer registries record melanoma but not basal or squamous cell carcinoma, so the commonly cited figures of about 3.6 million basal cell carcinoma cases and 1.8 million squamous cell carcinoma cases each year are estimates rather than registry totals.\n\nLifetime risk varies sharply by race and ethnicity. The American Cancer Society currently gives about 3% (1 in 33) for White people, 0.1% (1 in 1,000) for Black people, and 0.5% (1 in 200) for Hispanic people. Earlier ACS estimates were different, giving 1 in 38 for whites, and 1 in 167 for Hispanics, which shows how sensitive these numbers are to the underlying data. Melanoma incidence is highest in populations with lighter skin, and the incidence of melanoma among non-Hispanic White individuals is almost 30 times higher than that among non-Hispanic Black or Asian/Pacific Islander individuals.\n\nAustralia has the highest recorded incidence in the world. Among white populations, incidence rises as latitude falls, and in Australia the annual rates are 10 and over 20 times the rates in Europe for women and men respectively.\n\nTrends over recent decades\n\nRates have risen for several decades. In Australia, Canada and the United States, the prevalence of non-melanoma skin cancers increased by a factor of more than two between the 1960s and the 1980s. Melanoma incidence has risen since the early 1970s, an average 4 per cent every year in the United States. The increase is steepest in young adults; incidence among women under 30 has soared by 50% since 1980, according to a US advocacy organisation.\n\nPart of the rise in counts reflects better detection. Current US projections expect 122,680 cases to be noninvasive (in situ) and 112,000 to be invasive, and the number of invasive cases has grown quickly in recent years. Mortality has not risen at the same pace. In the SEER data, the age-adjusted US death rate was 2.13 per 100,000 in 2017 and 1.98 in 2023. Whether earlier diagnosis of thin or in situ lesions adds to overdiagnosis, rather than preventing deaths, remains a matter of debate.\n\nDisparities by race, ethnicity and skin tone\n\nMelanoma is less frequent in people with darker skin, but outcomes are worse. Skin cancers on darker skin are often diagnosed in their later stages, when it's more difficult to treat. In one American series, 22% of melanoma cases in African American patients were diagnosed after spread to nearby lymph nodes, and 14% after spread to distant organs. Lesions in these patients often arise on the palms, soles, nail beds and genital areas, sites that are less routinely examined, which can lead to delayed or missed diagnoses. A Mayo Clinic analysis of 492,597 patients reported that Black men in particular were more often diagnosed with extremity melanoma and at later stages than White patients.\n\nSurvival gaps are substantial. For 2013–2019, one analysis reported a five-year survival rate of 94% among White individuals but only 71% among Black individuals. In Wayne County, Michigan, Black patients were about three times more likely than their White counterparts to die within five years of their diagnosis, and the higher mortality rates were most likely due to later-stage diagnosis. The role of stage is supported by adjusted analyses. In one SEER study, the cause-specific mortality for Black patients was lower than for White patients after adjustment for stage, but when examining all-cause mortality, this difference disappeared. In another analysis of the Wayne County data, no increased risk of death due to melanoma was observed following adjustment of data for the stage, age, and sex, which indicates that differences in stage at diagnosis account for much of the gap. Socioeconomic context also matters: in a single-centre study, higher neighbourhood disadvantage was significantly associated with advanced-stage melanoma at presentation, independent of individual demographic and socioeconomic factors."
    },
    {
      "heading": "Historical understanding of causes and treatment",
      "text": "The earliest clear link between a skin cancer and an external cause came from occupational medicine. In 1775 the London surgeon Percivall Pott reported scrotal cancer in men who had worked as chimney sweeps. Pott observed a high rate of scrotal cancer in men who worked as chimney sweeps in London. He found coal soot in the skin sores of these men and concluded that routine exposure to soot put them at high risk for this cancer. The lesion, a squamous cell carcinoma, appeared after a long latency. After a latent period of 20-25 years, a large number of these boys developed cancer of the skin of the scrotum, known at the time as \"sootwart.\" Pott's report is often cited as the first identification of an occupational carcinogen, and it helped shift public opinion toward restricting child labour in chimney sweeping.\n\nIn the nineteenth century, sunlight emerged as a second suspected cause. Clinicians noticed that cancers clustered on sun-exposed skin of farmers, sailors and other outdoor workers, and that skin cancers were more common on the face and hands than on covered areas. In 1870 the Viennese dermatologist Moriz Kaposi described xeroderma pigmentosum, a rare inherited condition in which sun-exposed skin develops cancers at very young ages, which later provided a model for the role of UV-induced DNA damage. Melanoma was classified separately from keratinocyte cancers during the twentieth century. Diagnostic systems such as Clark levels (1969) and Breslow thickness (1970) turned melanoma's depth of invasion into a measurable prognostic variable, which remains central to pathological staging.\n\nSurgical treatment also changed in this period. Trained as a general surgeon at the University of Wisconsin, Frederic E. Mohs developed the Mohs micrographic surgery (MMS) technique in 1938 to remove skin cancer lesions while still a medical student. The method arose from accidental observations in animal studies: injected 20% zinc chloride solution inadvertently caused tissue necrosis in tumor and normal tissue. Further, he found that microscopic examination of this necrotic tissue showed well-preserved tumor and cell histology. This fixed-tissue method, called chemosurgery, was slow; it could take days to complete, and it gradually gave way to fresh tissue technique. The introduction of the fresh-tissue technique in 1953 avoided zinc chloride fixation and worked particularly well on eyelid tumors. The principle of excising tumours under microscopic control, with tissue mapped and examined at each stage, underpins modern practice, which reduces the normal treatment time to one visit and allows for immediate reconstruction of the wound.\n\nFrom the 2000s, two developments reshaped understanding of causes and treatment. Genome sequencing showed that melanomas carry a distinctive pattern of mutations. Early work on protein kinase genes found a strong accumulation of C to T transition mutations in human melanoma, and a whole-genome study of a melanoma cell line followed in 2010. One of the most well-known UVB mutation signatures consists of tandem CC to TT mutations, and this double-base substitution mutation was strongly elevated in this melanoma genome. Subsequent work traced the most common signature to the most frequent damage type, the cis-syn cyclobutane pyrimidine dimer (CPD), which arises after absorption of photons by DNA bases, while later studies identified additional melanoma mutation classes that do not fit this pattern, linking some of them to UVA exposure and other photoproducts. These findings connected epidemiology with molecular evidence and the DNA repair biology of sunlight exposure.\n\nTreatment was transformed at the same time. Metastatic melanoma had historically responded poorly to chemotherapy and radiation-therapy. In 2011 the United States approved ipilimumab, a monoclonal-antibody that blocks the CTLA-4 checkpoint and became the first immune checkpoint inhibitor approved for the disease, and vemurafenib, a BRAF inhibitor for tumours carrying the BRAF V600E mutation. Subsequent approvals of PD-1 inhibitors and combined BRAF and MEK inhibition extended survival for many patients with advanced disease. Recognition of biomarkers such as BRAF status and immune-related response patterns, validated through clinical trials, now guides the choice between these therapies."
    },
    {
      "heading": "Public health policy and sun-safety campaigns",
      "text": "Australia and the SunSmart model\n\nAustralia's programme is the most extensively evaluated example of a national-scale sun-safety strategy. Its origins lie in a 1981 television campaign, in which the Anti-Cancer Council of Victoria (now Cancer Council Victoria) approached broadcaster Philip Adams to design a message at a time when melanoma rates were rising. The resulting \"Slip! Slop! Slap!\" advertisement, featuring a cartoon seagull, was produced by a small creative team and became a lasting part of Australian health communication. The broader programme is usually dated separately: later in 1988, it was rolled into a new multi-faceted skin cancer prevention program, called \"SunSmart\". Reference works therefore differ on whether 1981 or 1988 marks the start, and the two dates describe the advertising phase and the institutional programme respectively.\n\nThe SunSmart approach combined public education with structural change. Its widespread implementation of policies for hat wearing and shade provision in child care centres, primary schools, and workplaces is central to its design, and sun-protective items were treated as a tax deductible expense for outdoor workers. The programme's evaluators attributed its durability to the vital integration of research and evaluation, on one hand, and a strong basis of consistency and continuity, on the other. Cost-effectiveness modelling estimated that more than 103,000 skin cancers (9,000 melanomas and 94,000 NMSC) were prevented in Victoria from 1988 to 2003. Survey data show a more uneven picture: sun protection and sunburn show substantial general improvement over time, but have stalled in recent years. A later analysis linked a fall in melanoma incidence among people under 40 with the programme's introduction, although this is an association rather than a proven causal effect.\n\nRegulation of indoor tanning\n\nIndoor tanning has been regulated more rapidly than most other exposure routes. The International Agency for Research on Cancer (IARC) classified indoor tanning devices as carcinogenic to humans, and this classification provided the basis for many subsequent laws. The number of countries with nationwide indoor tanning legislation restricting youth 18 years or younger increased from 2 countries in 2003 to 11 countries in 2011. By 2019, three countries had an outright ban (Australia, Brazil, Iran), while many others had age limits. Brazil's ban of 2011 and Australia's 2015 prohibition of commercial tanning salons were early examples of total bans. In the United States, federal action has focused on labelling. The Food and Drug Administration required that makers of sunlamps and related devices must include a prominent label, known as a \"black box\" warning, on their devices, stating they should not be used by people under 18. In 2015 the agency also proposed a statutory ban on use by under-18s, which brings it in line with recommendations made by the International Agency for Research on Cancer.\n\nAge restrictions depend heavily on enforcement at the level of individual businesses. In the United States, 42 states and districts regulate the use of tanning facilities, but 20 states and 1 territory prohibit minors from the use of tanning facilities. In a review of such laws, two studies showed that compliance with age-related bans by tanning businesses is fairly high (i.e., 70–77 %), which leaves a notable share of minors able to access devices where rules exist.\n\nWorkplace sun protection\n\nOutdoor work is one of the main sources of occupational UV exposure, and the requirements placed on employers vary widely. In Victoria, in 1987, Cancer Council Victoria began to work with unions, employers and labour organisations to develop guidelines on workers' UV radiation exposure. These guidelines fed into national documents and subsequently into occupational health and safety legislation. In the United States, the position is less direct. While OSHA regulations recognize sun exposure as a work hazard, the federal agency has largely left the specifics up to the state OSHAs to administer. Federal rules require protective equipment where employees are overexposed, but there must be an employee overexposure established to the sun's radiation in order for 29 CFR 1910.132(a) to apply. Several states have therefore set out shade and water requirements more explicitly.\n\nIn Singapore, the approach is framed within heat-stress regulation. Under the national framework, employers are required to provide shaded rest areas for workers exposed to heat stress and UV radiation. Authorities report that since introducing the heat stress framework, MOM has been conducting checks on outdoor work sites to ensure compliance, and has taken enforcement action against 213 non-compliant employers to date. Legal obligations do not always translate into practice: a German study found that despite legal obligations, half of a sample of German apprentices from different outdoor professions are not provided with sun-protective measures from their employer.\n\nHealth systems and early detection\n\nHealth-system roles in sun-safety policy include both prevention and early detection. In Victoria, the SunSmart programme has, with funding from VicHealth and the Victorian Government, delivered iconic skin cancer prevention and early detection programs to all Victorians, including workplaces, schools, early childhood centres and healthcare workers. More broadly, the stage at which a skin cancer is found depends on how readily people can have suspicious lesions examined, which in turn depends on referral pathways, the availability of dermatologists and primary-care training. Where access is limited, diagnosis tends to occur later, and the associated treatment becomes more extensive. Evaluations of such programmes therefore need to consider both behaviour change and the capacity of clinical services to respond to increased demand for examination."
    },
    {
      "heading": "Climate change and changing UV exposure",
      "text": "Ozone depletion and climate change act on UV exposure through different routes, and their regional effects are not uniform. Stratospheric ozone filters most of the most harmful UV before it reaches the surface. Chlorofluorocarbons (CFCs) and related gases thinned that layer, and the Montreal Protocol, which entered into force in 1989, has since cut global use of the most damaging ozone-depleting substances by some 98%. Because these compounds persist for decades, the hole grew in the years following ratification. Recovery is projected to bring mid-latitude and polar ozone back to 1980 levels by the mid-21st century, although delayed recovery prolongs UV exposure even in temperate regions. Modelling by the US Environmental Protection Agency suggests that the Protocol's full implementation will prevent a very large number of skin cancers among people born between 1890 and 2100, and that people born in 2040 or later would face no excess risk from ozone depletion if compliance continues. Whether ozone depletion has itself driven rising incidence is contested: in Australia, for example, the Cancer Council notes that the UVB increase from ozone loss may have contributed to the increasing skin cancer incidence rates ... since the 1970s, but other factors, such as sun-seeking behaviour during the second half of the 20th century and an ageing population are also important.\n\nClimate change does not produce UV radiation directly, but it modifies the conditions that determine how much reaches the ground. While climate change does not directly generate UV radiation, it exacerbates exposure through indirect mechanisms. Changes in clouds and aerosols matter here: in the northern mid-latitudes, reductions in cloud cover and aerosols have led to an increase in ultraviolet radiation in recent decades. Overall, one 2025 study in Nature found that from 1979 to 2010, UV radiation increased about 3% across the globe, with the greatest increases in midlatitude areas such as the northern United States and Canada. Future trends remain uncertain. The ozone assessment panel of the Montreal Protocol has observed that, outside the polar regions, future UV changes will likely be dominated by changes in factors other than ozone, including changes in climate and air pollution. Regional UV also depends on latitude, altitude, cloud cover and haze, so no definite UV dose can be attributed to a particular region.\n\nThe clearest signal of climate-linked risk comes from northern regions that historically had low UV exposure. Regions like Scandinavia and northern Canada, historically protected by low traditional sun exposure profiles such as shorter summers and lower UV indices, now report rising cases. One longitudinal study in Scandinavia reported a > 4% annual increase in melanoma incidence over the past two decades, correlating with prolonged summer seasons and more frequent heatwaves. Warmer summers also bring people outdoors. Climate change could also be increasing the time spent outdoors in regions that used to have fewer warm-weather days. National data are not uniform, however: incidence has increased in some countries (e.g., United Kingdom, Sweden, Canada, Norway, France, and Lithuania), but declined or stabilised in others (e.g., Hungary, Australia, and Denmark).\n\nBehaviour and migration shape exposure as much as the physical environment does. Migration can move people with lighter skin into brighter climates: the higher incidences are in many cases for many persons with light skin living in brighter areas than their ancestors in northern Europe. Leisure and cultural norms are equally important. In northern US states, for instance, dermatologists describe a summer culture in which every summer you get sunburned, and intermittent high-dose exposure is linked to melanoma more strongly than steady, chronic exposure. The climate–UV relationship also complicates prevention. Heat may increase the damage from UV: Australian researchers found that when cells experience heat stress, they produce proteins that inhibit the \"self-destruct\" signal, enabling more damaged cells to survive. Reviewers describe these interacting effects as several paradoxes involving human behavior, ozone layer recovery, and socioeconomic factors, which means that a decline in ozone-related UV can be offset by warmer climates, longer outdoor seasons and more sunbathing. For this reason, public-health reviews emphasise sun safety education, early detection programs, and international climate policies together rather than relying on any single measure."
    },
    {
      "heading": "Research directions and open questions",
      "text": "Artificial intelligence for image-based detection\n\nMachine-learning systems that classify clinical photographs and dermoscopic images of pigmented lesions are among the most intensively studied tools in the field. Retrospective studies have reported accuracy on par with, or above, that of experienced dermatologists, but prospective clinical trials in authentic clinical settings have lagged behind that enthusiasm. A Swedish study addressed this gap by running a prospective trial across 36 primary care centres. In a separate prospective study, an open-source algorithm was tested on 603 biopsied lesions from 435 participants, and dermatologists revised their estimated melanoma probabilities after seeing the algorithm's scores, which allowed the tool's real-world influence on decisions to be measured AI studies of this kind estimated the probability of melanoma and indicated management choices before and after real-time exposure to algorithm scores. Another comparison found that the algorithm and specialists identified melanoma with similar accuracy, and more than half of the melanoma diagnoses were either in situ or less than 1 mm deep, which points to a possible role in detecting early lesions.\n\nValidation remains the central problem. A review of the literature observed that many reported performance figures come from internal validation settings and may not fully reflect performance across different populations, institutions, imaging devices, skin tones, lesion sub-types, and clinical workflows. A pooled analysis of published studies found an overall AUROC of 0.88, but diagnostic performance fell to 0.82 in darker skin tones compared with 0.89 in lighter skin, and to 0.81 in smartphone settings, indicating persistent equity gaps in training data. Consumer applications have expanded faster than their evidence base: of 39 skin cancer applications assessed, none were evaluated for diagnostic accuracy. Prospective work on triage tools for generalist clinicians in underserved regions is more recent. One validation reported that, when clinicians used the tool, their performance improved significantly, reaching a sensitivity of 0.804 and specificity of 0.924.\n\nBiomarkers for prognosis and immunotherapy response\n\nAnti-CTLA-4 and anti-PD-1 antibodies are now standard treatments for metastatic melanoma, yet up to 70% of melanoma patients show resistance to this treatment. Even the most studied tissue markers are imperfect. PD-L1 immunohistochemical expression, DNA mismatch repair deficiency, and tumour mutation burden are the most studied predictive tissue biomarkers, although these are weak predictors of ICI response. Newer candidates are being tested in existing patient cohorts. In one such analysis, CD27 expression reached AUC values of 0.763 (PRJEB23709, n = 91) and 0.659 (GSE91061, n = 51), and in one cohort it identified good responders with a sensitivity of 69.8%, outperforming PD-L1, which showed a sensitivity of only 27.9%. Such results require prospective confirmation before any clinical use.\n\nResistance is also mechanistically complex. This low response rate is caused by innate as well as acquired resistance, and responders may later relapse. Immunosuppressive cells, including myeloid-derived suppressor cells and regulatory T cells, are implicated in blunting the response of effector T and B cells immunotherapy. Circulating tumour DNA is under study as a dynamic marker, since declining levels indicate effective therapy and rising levels signal potential progression or resistance. The gut microbiota has also been proposed as a modifier of efficacy, through metabolites such as short-chain fatty acids.\n\nEvidence gaps in prevention\n\nPublic education is a central open question. Reviews argue that awareness campaigns should cover not only the ABCDE rule and the ugly duckling sign but also mnemonics that highlight acral, amelanotic and nodular melanoma, forms that the standard criteria may miss. One review concluded that population-level education that reaches patients often missed by current screening may reduce melanoma mortality more effectively and affordably than improving screening technology or increasing screening frequency. Evidence on which messages change sun-protection behaviour among young people, and among high-risk groups such as people with many moles or transplant recipients, is limited and largely non-comparative, so the most effective approach for each audience is still unsettled.\n\nScreening and early-stage disease\n\nThe benefit of population screening is contested. The Cochrane review found that general adult population screening for malignant melanoma is not supported or refuted by evidence from well-designed trials up to May 2018. The most detailed natural experiment is Germany's programme, introduced in 2008: after comparison with nine neighbouring countries without such programmes, researchers found an average annual mortality reduction of 1.8%, compared with 2.2% in control countries, with no statistically significant difference between the groups. Low participation may have limited the programme's effect, a possibility the authors noted alongside opportunistic screening in comparator countries and evolving use of effective systemic therapies. The overdiagnosis argument rests on the observation that incidence of mostly localised melanoma has risen without a matching fall in mortality, and critics warn of excess morbidity from unnecessary biopsies along with higher healthcare costs and patient distress. Proponents, by contrast, note that skin cancer screening has the potential to reduce melanoma mortality by detecting tumors at an earlier stage. Modelling is now being used to compare risk-tailored strategies; an Australian microsimulation model is designed to assess their cost-effectiveness.\n\nFor early-stage disease, the key uncertainty is which patients need more intensive management. Stage 1 disease accounts for most newly diagnosed melanomas each year, with 5-year survival rates of 99%, and there are no studies showing that gene expression profile tests can identify the small fraction who need more. Whether such patients benefit from gene expression testing, sentinel node biopsy or closer surveillance therefore remains open.\n\nLong-term outcomes of new therapies\n\nCombination immunotherapy and targeted regimens have been in routine use for only a limited number of years, so the durability of responses, the risk of late toxicity and the safe duration of treatment are not yet fully characterised. Long-term follow-up of patients who achieve prolonged remission will be needed to determine whether these therapies change overall survival at the population level."
    }
  ],
  "links": [
    "cancer",
    "public-health",
    "mutation",
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    "cancer-immunotherapy",
    "biopsy",
    "hiv-aids",
    "organ-transplantation",
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  ],
  "license": "https://creativecommons.org/licenses/by/4.0/"
}