melanoma melanoma melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). in women, they most commonly occur on the legs, while in men, they most commonly occur on the back. about 25% of melanomas develop from moles. changes in a mole that can indicate melanoma include an increase in size, irregular edges, change in color, itchiness, or skin breakdown. not to be confused with multiple myeloma. melanomaother namesmalignant melanomaa melanoma of approximately 2.5 cm (1 in) by 1.5 cm (0.6 in)pronunciation/ˌmɛləˈnoʊmə/ (listen) specialtyoncology and dermatologysymptomsmole that is increasing in size, has irregular edges, change in color, itchiness, or skin breakdown.causesultraviolet light (sun, tanning devices)risk factorsfamily history, many moles, poor immune functiondiagnostic methodtissue biopsydifferential diagnosisseborrheic keratosis, lentigo, blue nevus, dermatofibromapreventionsunscreen, avoiding uv lighttreatmentsurgeryprognosisfive-year survival rates in us 99% (localized), 25% (disseminated)frequency3.1 million (2015)deaths59,800 (2015) the primary cause of melanoma is ultraviolet light (uv) exposure in those with low levels of the skin pigment melanin. the uv light may be from the sun or other sources, such as tanning devices. those with many moles, a history of affected family members, and poor immune function are at greater risk. a number of rare genetic conditions, such as xeroderma pigmentosum, also increase the risk. diagnosis is by biopsy and analysis of any skin lesion that has signs of being potentially cancerous. using sunscreen and avoiding uv light may prevent melanoma. treatment is typically removal by surgery. in those with slightly larger cancers, nearby lymph nodes may be tested for spread (metastasis). most people are cured if spread has not occurred. for those in whom melanoma has spread, immunotherapy, biologic therapy, radiation therapy, or chemotherapy may improve survival. with treatment, the five-year survival rates in the united states are 99% among those with localized disease, 65% when the disease has spread to lymph nodes, and 25% among those with distant spread. the likelihood that melanoma will reoccur or spread depends on its thickness, how fast the cells are dividing, and whether or not the overlying skin has broken down. melanoma is the most dangerous type of skin cancer. globally, in 2012, it newly occurred in 232,000 people. in 2015, 3.1 million people had active disease, which resulted in 59,800 deaths. australia and new zealand have the highest rates of melanoma in the world. high rates also occur in northern europe and north america, while it is less common in asia, africa, and latin america. in the united states, melanoma occurs about 1.6 times more often in men than women. melanoma has become more common since the 1960s in areas mostly populated by people of european descent. signs and symptoms early signs of melanoma are changes to the shape or color of existing moles or, in the case of nodular melanoma, the appearance of a new lump anywhere on the skin. at later stages, the mole may itch, ulcerate, or bleed. early signs of melanoma are summarized by the mnemonic "abcdef": asymmetry borders (irregular with edges and corners) colour (variegated) diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser) evolving over time this classification does not apply to nodular melanoma, which has its own classifications: elevated above the skin surface firm to the touch growing metastatic melanoma may cause nonspecific paraneoplastic symptoms, including loss of appetite, nausea, vomiting, and fatigue. metastasis (spread) of early melanoma is possible, but relatively rare; less than a fifth of melanomas diagnosed early become metastatic. brain metastases are particularly common in patients with metastatic melanoma. it can also spread to the liver, bones, abdomen, or distant lymph nodes. cause melanomas are usually caused by dna damage resulting from exposure to uv light from the sun. genetics also play a role. melanoma can also occur in skin areas with little sun exposure (i.e. mouth, soles of feet, palms of hands, genital areas). people with dysplastic nevus syndrome, also known as familial atypical multiple mole melanoma, are at increased risk for the development of melanoma. having more than 50 moles indicates an increased risk in melanoma might arise. a weakened immune system makes cancer development easier due to the body's weakened ability to fight cancer cells. uv radiation uv radiation exposure from tanning beds increases the risk of melanoma. the international agency for research on cancer finds that tanning beds are "carcinogenic to humans" and that people who begin using tanning devices before the age of thirty years are 75% more likely to develop melanoma. those who work in airplanes also appear to have an increased risk, believed to be due to greater exposure to uv. uvb light (wavelengths between 315 and 280 nm) from the sun is absorbed by skin cell dna and results in a type of direct dna damage called cyclobutane pyrimidine dimers. thymine, cytosine, or cytosine-thymine dimers are formed by the joining of two adjacent pyrimidine bases within a dna strand. somewhat similarly to uvb, uva light (longer wavelengths between 400 and 315 nm) from the sun or from tanning beds can also be directly absorbed by skin dna (at about 1/100 to 1/1000 of the efficiency of uvb). exposure to radiation (uva and uvb) is one of the major contributors to the development of melanoma. occasional extreme sun exposure (resulting in "sunburn") is causally related to melanoma. melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). the risk appears to be strongly influenced by socioeconomic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers. other factors are mutations in or total loss of tumor suppressor genes. use of sunbeds (with deeply penetrating uva rays) has been linked to the development of skin cancers, including melanoma. possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. melanoma rates tend to be highest in countries settled by migrants from northern europe which have a large amount of direct, intense sunlight to which the skin of the settlers is not adapted, most notably australia. exposure during childhood is a more important risk factor than exposure in adulthood. this is seen in migration studies in australia. having multiple severe sunburns increases the likelihood that future sunburns develop into melanoma due to cumulative damage. the sun and tanning beds are the main sources of uv radiation that increase the risk for melanoma and living close to the equator increases exposure to uv radiation. genetics a number of rare mutations, which often run in families, greatly increase melanoma susceptibility. several genes increase risks. some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene called mc1r that causes red hair, have a relatively lower elevated risk. genetic testing can be used to search for the mutations. one class of mutations affects the gene cdkn2a. an alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in 50% of human cancers. another mutation in the same gene results in a nonfunctional inhibitor of cdk4, a cyclin-dependent kinase that promotes cell division. mutations that cause the skin condition xeroderma pigmentosum (xp) also increase melanoma susceptibility. scattered throughout the genome, these mutations reduce a cell's ability to repair dna. both cdkn2a and xp mutations are highly penetrant (the chances of a carrier to express the phenotype is high). familial melanoma is genetically heterogeneous, and loci for familial melanoma appear on the chromosome arms 1p, 9p and 12q. multiple genetic events have been related to melanoma's pathogenesis (disease development). the multiple tumor suppressor 1 (cdkn2a/mts1) gene encodes p16ink4a – a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (cdks) – which has been localised to the p21 region of human chromosome 9. fammm is typically characterized by having 50 or more combined moles in addition to a family history of melanoma. it is transmitted autosomal dominantly and mostly associated with the cdkn2a mutations. people who have cdkn2a mutation associated fammm have a 38 fold increased risk of pancreatic cancer. other mutations confer lower risk, but are more common in the population. people with mutations in the mc1r gene are two to four times more likely to develop melanoma than those with two wild-type (typical unaffected type) copies. mc1r mutations are very common, and all red-haired people have a mutated copy. mutation of the mdm2 snp309 gene is associated with increased risks for younger women. fair- and red-haired people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk. a family history of melanoma greatly increases a person's risk, because mutations in several genes have been found in melanoma-prone families. people with a history of one melanoma are at increased risk of developing a second primary tumor. fair skin is the result of having less melanin in the skin, which means less protection from uv radiation exists. a family history could indicate a genetic predisposition to melanoma. pathophysiology where melanoma is most likely to develop molecular basis for melanoma cell motility: actin-rich podosomes (yellow), along with cell nuclei (blue), actin (red), and an actin regulator (green). the earliest stage of melanoma starts when melanocytes begin out-of-control growth. melanocytes are found between the outer layer of the skin (the epidermis) and the next layer (the dermis). this early stage of the disease is called the radial growth phase, when the tumor is less than 1 mm thick, and spreads at the level of the basal epidermis. because the cancer cells have not yet reached the blood vessels deeper in the skin, it is very unlikely that this early-stage melanoma will spread to other parts of the body. if the melanoma is detected at this stage, then it can usually be completely removed with surgery. when the tumor cells start to move in a different direction – vertically up into the epidermis and into the papillary dermis – cell behaviour changes dramatically. the next step in the evolution is the invasive radial growth phase, in which individual cells start to acquire invasive potential. from this point on, melanoma is capable of spreading. the breslow's depth of the lesion is usually less than 1 mm (0.04 in), while the clark level is usually 2. the vertical growth phase (vgp) following is invasive melanoma. the tumor becomes able to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. the tumor thickness is usually more than 1 mm (0.04 in), and the tumor involves the deeper parts of the dermis. the host elicits an immunological reaction against the tumor during the vgp, which is judged by the presence and activity of the tumor infiltrating lymphocytes (tils). these cells sometimes completely destroy the primary tumor; this is called regression, which is the latest stage of development. in certain cases, the primary tumor is completely destroyed and only the metastatic tumor is discovered. about 40% of human melanomas contain activating mutations affecting the structure of the b-raf protein, resulting in constitutive signaling through the raf to map kinase pathway. an insult common to most cancers is damage to dna. uva light mainly causes thymine dimers. uva also produces reactive oxygen species and these inflict other dna damage, primarily single-strand breaks, oxidized pyrimidines and the oxidized purine 8-oxoguanine (a mutagenic dna change) at 1/10, 1/10, and 1/3rd the frequencies of uva-induced thymine dimers, respectively. if unrepaired, cpd photoproducts can lead to mutations by inaccurate translesion synthesis during dna replication or repair. the most frequent mutations due to inaccurate synthesis past cpds are cytosine to thymine (c>t) or cc>tt transition mutations. these are commonly referred to as uv fingerprint mutations, as they are the most specific mutation caused by uv, being frequently found in sun-exposed skin, but rarely found in internal organs. errors in dna repair of uv photoproducts, or inaccurate synthesis past these photoproducts, can also lead to deletions, insertions, and chromosomal translocations. the entire genomes of 25 melanomas were sequenced. on average, about 80,000 mutated bases