Melanoma#Staging

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 "ABCDEEFG":{{cite web|url=https://www.cdc.gov/cancer/skin/basic_info/symptoms.htm|title=CDC - What Are the Symptoms of Skin Cancer?|date=26 June 2018|website=www.cdc.gov|language=en-us|access-date=1 February 2019|archive-date=7 December 2018|archive-url=https://web.archive.org/web/20181207125444/https://www.cdc.gov/cancer/skin/basic_info/symptoms.htm|url-status=live}}{{cite journal | vauthors = Daniel Jensen J, Elewski BE | title = The ABCDEF Rule: Combining the "ABCDE Rule" and the "Ugly Duckling Sign" in an Effort to Improve Patient Self-Screening Examinations | journal = The Journal of Clinical and Aesthetic Dermatology | volume = 8 | issue = 2 | pages = 15 | date = February 2015 | pmid = 25741397 | pmc = 4345927 }}

• Asymmetry
• Borders (irregular with edges and corners)
• Colour (variegated)
• Diameter (greater than {{convert|6|mm|2|abbr=on|lk=out}}, about the size of a pencil eraser)
• Evolving over time

This classification does not apply to nodular melanoma, which has its own classifications:{{cite web|url=https://www.molemap.co.nz/knowledge-centre/efg-nodular-melanomas|title=The EFG of Nodular Melanomas {{!}} MoleMap New Zealand|website=The EFG of Nodular Melanomas {{!}} MoleMap New Zealand|language=en-US|access-date=1 February 2019|archive-date=2 February 2019|archive-url=https://web.archive.org/web/20190202041434/https://www.molemap.co.nz/knowledge-centre/efg-nodular-melanomas|url-status=live}}

• 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.{{source?|date=May 2025}} Brain metastases are particularly common in patients with metastatic melanoma.{{cite journal | vauthors = Fiddler IJ | title = Melanoma Metastasis | journal = Cancer Control | volume = 2 | issue = 5 | pages = 398–404 | date = October 1995 | pmid = 10862180 | doi = 10.1177/107327489500200503 | doi-access = free }} It can also spread to the liver, bones, abdomen, or distant lymph nodes.{{citation needed|date=June 2022}}

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).{{cite book | vauthors = Goydos JS, Shoen SL | title = Melanoma | chapter = Acral Lentiginous Melanoma | series = Cancer Treatment and Research | volume = 167 | pages = 321–9 | date = 2016 | pmid = 26601870 | doi = 10.1007/978-3-319-22539-5_14 | isbn = 978-3-319-22538-8 }} People with dysplastic nevus syndrome, also known as familial atypical multiple mole melanoma, are at increased risk for the development of melanoma.{{cite journal | vauthors = Perkins A, Duffy RL | title = Atypical moles: diagnosis and management | journal = American Family Physician | volume = 91 | issue = 11 | pages = 762–767 | date = June 2015 | pmid = 26034853 }}

Having more than 50 moles indicates an increased risk of melanoma. A weakened immune system makes cancer development easier due to the body's weakened ability to fight cancer cells.{{cite news|url=http://www.mayoclinic.org/diseases-conditions/melanoma/basics/risk-factors/con-20026009|title=Melanoma Risk factors |work=Mayo Clinic|access-date=10 April 2017 |url-status=live|archive-url=https://web.archive.org/web/20170410133759/http://www.mayoclinic.org/diseases-conditions/melanoma/basics/risk-factors/con-20026009|archive-date=10 April 2017}}

UV radiation exposure from tanning beds increases the risk of melanoma.{{cite journal | vauthors = Boniol M, Autier P, Boyle P, Gandini S | title = Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis | journal = BMJ | volume = 345 | pages = e4757 | date = July 2012 | pmid = 22833605 | pmc = 3404185 | doi = 10.1136/bmj.e4757 }} 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.{{cite journal | vauthors = El Ghissassi F, Baan R, Straif K, Grosse Y, Secretan B, Bouvard V, Benbrahim-Tallaa L, Guha N, Freeman C, Galichet L, Cogliano V | title = A review of human carcinogens--part D: radiation | journal = The Lancet. Oncology | volume = 10 | issue = 8 | pages = 751–752 | date = August 2009 | pmid = 19655431 | doi = 10.1016/S1470-2045(09)70213-X | collaboration = WHO International Agency for Research on Cancer Monograph Working Group | doi-access = free }}

Those who work in airplanes also appear to have an increased risk, believed to be due to greater exposure to UV.{{cite journal | vauthors = Sanlorenzo M, Wehner MR, Linos E, Kornak J, Kainz W, Posch C, Vujic I, Johnston K, Gho D, Monico G, McGrath JT, Osella-Abate S, Quaglino P, Cleaver JE, Ortiz-Urda S | title = The risk of melanoma in airline pilots and cabin crew: a meta-analysis | journal = JAMA Dermatology | volume = 151 | issue = 1 | pages = 51–58 | date = January 2015 | pmid = 25188246 | pmc = 4482339 | doi = 10.1001/jamadermatol.2014.1077 }}

UVB light, emanating from the sun at wavelengths between 315 and 280 nm, is absorbed directly by DNA in skin cells, which 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 strand of DNA. UVA light presents at wavelengths longer than UVB (between 400 and 315 nm); and it can also be absorbed directly by DNA in skin cells, but at lower efficiencies{{mdash}}about 1/100 to 1/1000 of UVB.{{cite journal | vauthors = Rünger TM, Farahvash B, Hatvani Z, Rees A | title = Comparison of DNA damage responses following equimutagenic doses of UVA and UVB: a less effective cell cycle arrest with UVA may render UVA-induced pyrimidine dimers more mutagenic than UVB-induced ones | journal = Photochemical & Photobiological Sciences | volume = 11 | issue = 1 | pages = 207–215 | date = January 2012 | pmid = 22005748 | doi = 10.1039/c1pp05232b | s2cid = 25209863 | doi-access = free | bibcode = 2012PhPhS..11..207R }}

Exposure to radiation (UVA and UVB) is a major contributor to developing melanoma.{{cite journal | vauthors = Wang SQ, Setlow R, Berwick M, Polsky D, Marghoob AA, Kopf AW, Bart RS | title = Ultraviolet A and melanoma: a review | journal = Journal of the American Academy of Dermatology | volume = 44 | issue = 5 | pages = 837–846 | date = May 2001 | pmid = 11312434 | doi = 10.1067/mjd.2001.114594 | s2cid = 7655216 }} Occasional extreme sun exposure that results in "sunburn" on areas of the human body is causally related to melanoma;{{cite journal | vauthors = Oliveria SA, Saraiya M, Geller AC, Heneghan MK, Jorgensen C | title = Sun exposure and risk of melanoma | journal = Archives of Disease in Childhood | volume = 91 | issue = 2 | pages = 131–138 | date = February 2006 | pmid = 16326797 | pmc = 2082713 | doi = 10.1136/adc.2005.086918 }} and such areas of only intermittent exposure apparently explains why melanoma is more common on the back in men and on the legs in women. 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.{{cite journal | vauthors = Lee JA, Strickland D | title = Malignant melanoma: social status and outdoor work | journal = British Journal of Cancer | volume = 41 | issue = 5 | pages = 757–763 | date = May 1980 | pmid = 7426301 | pmc = 2010319 | doi = 10.1038/bjc.1980.138 }}{{cite journal | vauthors = Pion IA, Rigel DS, Garfinkel L, Silverman MK, Kopf AW | title = Occupation and the risk of malignant melanoma | journal = Cancer | volume = 75 | issue = 2 Suppl | pages = 637–644 | date = January 1995 | pmid = 7804988 | doi = 10.1002/1097-0142(19950115)75:2+<637::aid-cncr2820751404>3.0.co;2-# | s2cid = 196354681 }} Other factors are mutations in (or total loss of) tumor suppressor genes. Using sunbeds with their deeply penetrating UVA rays has been linked to the development of skin cancers, including melanoma.{{Cite web|url=https://www.who.int/mediacentre/news/notes/2005/np07/en/|archive-url=https://web.archive.org/web/20090616124844/http://www.who.int/mediacentre/news/notes/2005/np07/en/|url-status=dead|title=WHO | The World Health Organization recommends that no person under 18 should use a sunbed|archive-date=16 June 2009|website=WHO}}

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 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.{{cite journal | vauthors = Khlat M, Vail A, Parkin M, Green A | title = Mortality from melanoma in migrants to Australia: variation by age at arrival and duration of stay | journal = American Journal of Epidemiology | volume = 135 | issue = 10 | pages = 1103–1113 | date = May 1992 | pmid = 1632422 | doi = 10.1093/oxfordjournals.aje.a116210 }}

Incurring multiple severe sunburns increases the likelihood that future sunburns develop into melanoma due to cumulative damage. UV-high sunlight and tanning beds are the main sources of UV radiation that increase the risk for melanoma{{Cite web |date=1 September 2022 |title=Can we get skin cancer from tanning beds? |url=https://www.curadermbcc.eu/blog/skin-cancer-from-tanning-beds/ |access-date=3 September 2022 |website=CuradermBCC |language=en-US |archive-date=3 September 2022 |archive-url=https://web.archive.org/web/20220903131033/https://www.curadermbcc.eu/blog/skin-cancer-from-tanning-beds/ |url-status=live }} and living close to the equator increases exposure to UV radiation.

A number of rare mutations, which often run in families, greatly increase melanoma susceptibility.{{cite journal | vauthors = Soura E, Eliades PJ, Shannon K, Stratigos AJ, Tsao H | title = Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome | journal = Journal of the American Academy of Dermatology | volume = 74 | issue = 3 | pages = 395–407; quiz 408–410 | date = March 2016 | pmid = 26892650 | pmc = 4761105 | doi = 10.1016/j.jaad.2015.08.038 }} 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.{{Cite journal |last=Primiero |first=Clare A. |last2=Yanes |first2=Tatiane |last3=Finnane |first3=Anna |last4=Soyer |first4=H. Peter |last5=McInerney-Leo |first5=Aideen M. |date=2021 |title=A Systematic Review on the Impact of Genetic Testing for Familial Melanoma I: Primary and Secondary Preventative Behaviours |url=https://pubmed.ncbi.nlm.nih.gov/33588421 |journal=Dermatology |volume=237 |issue=5 |pages=806–815 |doi=10.1159/000513919 |issn=1421-9832 |pmid=33588421}}

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).{{citation needed|date=June 2022}}

Familial melanoma is genetically heterogeneous,{{cite journal | vauthors = Greene MH | title = The genetics of hereditary melanoma and nevi. 1998 update | journal = Cancer | volume = 86 | issue = 11 Suppl | pages = 2464–2477 | date = December 1999 | pmid = 10630172 | doi = 10.1002/(SICI)1097-0142(19991201)86:11+<2464::AID-CNCR3>3.0.CO;2-F | s2cid = 32817426 | doi-access = free }} 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).{{cite journal | vauthors = Halachmi S, Gilchrest BA | title = Update on genetic events in the pathogenesis of melanoma | journal = Current Opinion in Oncology | volume = 13 | issue = 2 | pages = 129–136 | date = March 2001 | pmid = 11224711 | doi = 10.1097/00001622-200103000-00008 | s2cid = 29876528 }} 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.{{cite web | url = https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=1029 | title = CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) | publisher = U.S. National Library of Medicine | access-date = 4 September 2017 | archive-date = 17 November 2004 | archive-url = https://web.archive.org/web/20041117054925/http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene | url-status = live }} 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.{{cite journal | vauthors = Soura E, Eliades PJ, Shannon K, Stratigos AJ, Tsao H | title = Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome | journal = Journal of the American Academy of Dermatology | volume = 74 | issue = 3 | pages = 395–407; quiz 408–10 | date = March 2016 | pmid = 26892650 | pmc = 4761105 | doi = 10.1016/j.jaad.2015.08.038 }}

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.{{Citation needed|date=November 2018}} Mutation of the MDM2 SNP309 gene is associated with increased risks for younger women.{{cite journal | vauthors = Firoz EF, Warycha M, Zakrzewski J, Pollens D, Wang G, Shapiro R, Berman R, Pavlick A, Manga P, Ostrer H, Celebi JT, Kamino H, Darvishian F, Rolnitzky L, Goldberg JD, Osman I, Polsky D | title = Association of MDM2 SNP309, age of onset, and gender in cutaneous melanoma | journal = Clinical Cancer Research | volume = 15 | issue = 7 | pages = 2573–2580 | date = April 2009 | pmid = 19318491 | pmc = 3881546 | doi = 10.1158/1078-0432.CCR-08-2678 }}

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.{{cite journal | vauthors = Bliss JM, Ford D, Swerdlow AJ, Armstrong BK, Cristofolini M, Elwood JM, Green A, Holly EA, Mack T, MacKie RM | title = Risk of cutaneous melanoma associated with pigmentation characteristics and freckling: systematic overview of 10 case-control studies. The International Melanoma Analysis Group (IMAGE) | journal = International Journal of Cancer | volume = 62 | issue = 4 | pages = 367–376 | date = August 1995 | pmid = 7635560 | doi = 10.1002/ijc.2910620402 | s2cid = 9539601 }}

A family history of melanoma greatly increases a person's risk, because mutations in several genes have been found in melanoma-prone families.{{cite journal | vauthors = Miller AJ, Mihm MC | title = Melanoma | journal = The New England Journal of Medicine | volume = 355 | issue = 1 | pages = 51–65 | date = July 2006 | pmid = 16822996 | doi = 10.1056/NEJMra052166 }} People with a history of one melanoma are at increased risk of developing a second primary tumor.{{cite journal | vauthors = Rhodes AR, Weinstock MA, Fitzpatrick TB, Mihm MC, Sober AJ | title = Risk factors for cutaneous melanoma. A practical method of recognizing predisposed individuals | journal = JAMA | volume = 258 | issue = 21 | pages = 3146–3154 | date = December 1987 | pmid = 3312689 | doi = 10.1001/jama.258.21.3146 }}

Fair skin is the result of having less melanin in the skin, which means less protection from UV radiation exists.

File:Diagram showing where melanoma is most likely to develop CRUK 383.svg

File:Metastatic Melanoma Cells Nci-vol-9872-300.jpgs (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.{{cite journal | vauthors = Ciarletta P, Foret L, Ben Amar M | title = The radial growth phase of malignant melanoma: multi-phase modelling, numerical simulations and linear stability analysis | journal = Journal of the Royal Society, Interface | volume = 8 | issue = 56 | pages = 345–368 | date = March 2011 | pmid = 20656740 | pmc = 3030817 | doi = 10.1098/rsif.2010.0285 }} 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.{{Cite web |title=Melanoma |url=https://dermatology.ca/public-patients/diseases-conditions/skin-cancer/melanoma/ |access-date=2025-04-17 |website=Canadian Dermatology Association |language=en-US}}

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.{{Citation needed|date=July 2023}} The Breslow's depth of the lesion is usually less than {{convert|1|mm|2|abbr=on|lk=out}}, 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 {{convert|1|mm|2|abbr=on|lk=out}}, and the tumor involves the deeper parts of the dermis.

The host elicits an immunological reaction against the tumor during the VGP,{{cite journal |title=ASCO Annual Meeting Proceedings Part I. Abstract: Protective effect of a brisk tumor infiltrating lymphocyte infiltrate in melanoma: An EORTC melanoma group study |journal=Journal of Clinical Oncology |volume=25 |issue=18S |page=8519 |year=2007 |doi=10.1200/jco.2007.25.18_suppl.8519 |url=http://www.asco.org/ascov2/Meetings/Abstracts?vmview=abst_detail_view&confID=47&abstractID=34439 |url-status=live |archive-url=https://web.archive.org/web/20110725021007/http://www.asco.org/ascov2/Meetings/Abstracts?vmview=abst_detail_view&confID=47&abstractID=34439 |archive-date=25 July 2011 | vauthors = Spatz A, Gimotty PA, Cook MG, van den Oord JJ, Desai N, Eggermont AM, Keilholz U, Ruiter DJ, Mihm MC |url-access=subscription }} 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.{{cite journal | vauthors = Davies MA, Samuels Y | title = Analysis of the genome to personalize therapy for melanoma | journal = Oncogene | volume = 29 | issue = 41 | pages = 5545–5555 | date = October 2010 | pmid = 20697348 | pmc = 3169242 | doi = 10.1038/onc.2010.323 }}

A cause common to most cancers is damage to DNA.{{cite book | vauthors = Barrett JC |chapter=Mutagenesis and Carcinogenesis|chapter-url= https://archive.org/details/originsofhumanca00brug/ |title=Origins of Human Cancer |publisher=Cold Spring Harbor Press |year=1991 |isbn=0-87969-404-1 | veditors = Brugge J, Curran T, Harlow E, McCormick F |editor-link1 =Joan Brugge |editor-link2=Tom Curran (medical researcher) |editor-link3=Ed Harlow |chapter-url-access=registration |via=Internet Archive |url-access=registration |url=https://archive.org/details/originsofhumanca00brug }} UVA light mainly causes thymine dimers.{{cite journal | vauthors = Sage E, Girard PM, Francesconi S | title = Unravelling UVA-induced mutagenesis | journal = Photochemical & Photobiological Sciences | volume = 11 | issue = 1 | pages = 74–80 | date = January 2012 | pmid = 21901217 | doi = 10.1039/c1pp05219e | s2cid = 45189513 | doi-access = free | bibcode = 2012PhPhS..11...74S }} 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, cyclobutane pyrimidine dimer (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.{{cite journal | vauthors = Budden T, Bowden NA | title = The role of altered nucleotide excision repair and UVB-induced DNA damage in melanomagenesis | journal = International Journal of Molecular Sciences | volume = 14 | issue = 1 | pages = 1132–1151 | date = January 2013 | pmid = 23303275 | pmc = 3565312 | doi = 10.3390/ijms14011132 | doi-access = free }} 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.{{cite journal | vauthors = Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie K, Baldwin J, Wargo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner SN, Lander ES, Getz G, Chin L, Garraway LA | title = Melanoma genome sequencing reveals frequent PREX2 mutations | journal = Nature | volume = 485 | issue = 7399 | pages = 502–506 | date = May 2012 | pmid = 22622578 | pmc = 3367798 | doi = 10.1038/nature11071 | bibcode = 2012Natur.485..502B }} On average, about 80,000 mutated bases (mostly C>T transitions) and about 100 structural rearrangements were found per melanoma genome. This is much higher than the roughly 70 mutations across generations (parent to child).{{cite journal | vauthors = Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ | title = Analysis of genetic inheritance in a family quartet by whole-genome sequencing | journal = Science | volume = 328 | issue = 5978 | pages = 636–639 | date = April 2010 | pmid = 20220176 | pmc = 3037280 | doi = 10.1126/science.1186802 | bibcode = 2010Sci...328..636R }}{{cite journal | vauthors = Campbell CD, Chong JX, Malig M, Ko A, Dumont BL, Han L, Vives L, O'Roak BJ, Sudmant PH, Shendure J, Abney M, Ober C, Eichler EE | title = Estimating the human mutation rate using autozygosity in a founder population | journal = Nature Genetics | volume = 44 | issue = 11 | pages = 1277–1281 | date = November 2012 | pmid = 23001126 | pmc = 3483378 | doi = 10.1038/ng.2418 }} Among the 25 melanomas, about 6,000 protein-coding genes had missense, nonsense, or splice site mutations. The transcriptomes of over 100 melanomas has also been sequenced and analyzed. Almost 70% of all human protein-coding genes are expressed in melanoma. Most of these genes are also expressed in other normal and cancer tissues, with some 200 genes showing a more specific expression pattern in melanoma compared to other forms of cancer. Examples of melanoma specific genes are tyrosinase, MLANA, and PMEL.{{cite web|url=https://www.proteinatlas.org/humanpathology/melanoma|title=The human pathology proteome in melanoma – The Human Protein Atlas|website=www.proteinatlas.org|access-date=2 October 2017|archive-date=2 October 2017|archive-url=https://web.archive.org/web/20171002215621/https://www.proteinatlas.org/humanpathology/melanoma|url-status=live}}{{cite journal | vauthors = Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, Benfeitas R, Arif M, Liu Z, Edfors F, Sanli K, von Feilitzen K, Oksvold P, Lundberg E, Hober S, Nilsson P, Mattsson J, Schwenk JM, Brunnström H, Glimelius B, Sjöblom T, Edqvist PH, Djureinovic D, Micke P, Lindskog C, Mardinoglu A, Ponten F | title = A pathology atlas of the human cancer transcriptome | journal = Science | volume = 357 | issue = 6352 | pages = eaan2507 | date = August 2017 | pmid = 28818916 | doi = 10.1126/science.aan2507 | s2cid = 206659235 | doi-access = free }}

UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. This strong mutagenic factor makes cutaneous melanoma the tumor type with the highest number of mutations.{{cite journal | vauthors = Ellrott K, Bailey MH, Saksena G, Covington KR, Kandoth C, Stewart C, Hess J, Ma S, Chiotti KE, McLellan M, Sofia HJ, Hutter C, Getz G, Wheeler D, Ding L | title = Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines | journal = Cell Systems | volume = 6 | issue = 3 | pages = 271–281.e7 | date = March 2018 | pmid = 29596782 | pmc = 6075717 | doi = 10.1016/j.cels.2018.03.002 }} When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of activating transcription factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells;{{cite journal | vauthors = Leslie MC, Bar-Eli M | title = Regulation of gene expression in melanoma: new approaches for treatment | journal = Journal of Cellular Biochemistry | volume = 94 | issue = 1 | pages = 25–38 | date = January 2005 | pmid = 15523674 | doi = 10.1002/jcb.20296 | s2cid = 23515325 }}{{cite journal | vauthors = Bhoumik A, Singha N, O'Connell MJ, Ronai ZA | title = Regulation of TIP60 by ATF2 modulates ATM activation | journal = The Journal of Biological Chemistry | volume = 283 | issue = 25 | pages = 17605–17614 | date = June 2008 | pmid = 18397884 | pmc = 2427333 | doi = 10.1074/jbc.M802030200 | doi-access = free }}{{cite journal | vauthors = Bhoumik A, Jones N, Ronai Z | title = Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 12 | pages = 4222–4227 | date = March 2004 | pmid = 15010535 | pmc = 384722 | doi = 10.1073/pnas.0400195101 | doi-access = free | bibcode = 2004PNAS..101.4222B }} studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer progression.{{cite journal | vauthors = Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V | title = The role of ATF-2 in oncogenesis | journal = BioEssays | volume = 30 | issue = 4 | pages = 314–327 | date = April 2008 | pmid = 18348191 | doi = 10.1002/bies.20734 | s2cid = 678541 }}{{cite journal | vauthors = Huang Y, Minigh J, Miles S, Niles RM | title = Retinoic acid decreases ATF-2 phosphorylation and sensitizes melanoma cells to taxol-mediated growth inhibition | journal = Journal of Molecular Signaling | volume = 3 | pages = 3 | date = February 2008 | pmid = 18269766 | pmc = 2265711 | doi = 10.1186/1750-2187-3-3 | doi-access = free }}

Cancer stem cells may also be involved.{{cite journal | vauthors = Parmiani G | title = Melanoma Cancer Stem Cells: Markers and Functions | journal = Cancers | volume = 8 | issue = 3 | pages = 34 | date = March 2016 | pmid = 26978405 | pmc = 4810118 | doi = 10.3390/cancers8030034 | doi-access = free }}

Large-scale studies, such as The Cancer Genome Atlas, have characterized recurrent somatic alterations likely driving initiation and development of cutaneous melanoma. The Cancer Genome Atlas study has established four subtypes: BRAF mutant, RAS mutant, NF1 mutant, and triple wild-type.{{cite journal | title = Genomic Classification of Cutaneous Melanoma | journal = Cell | volume = 161 | issue = 7 | pages = 1681–1696 | date = June 2015 | pmid = 26091043 | pmc = 4580370 | doi = 10.1016/j.cell.2015.05.044 | collaboration = Cancer Genome Atlas Network | vauthors = Akbani R, Akdemir KC, Aksoy BA, Albert M, Ally A, Amin SB, Arachchi H, Arora A, Auman JT, Ayala B, Baboud J, Balasundaram M, Balu S, Barnabas N, Bartlett J, Bartlett P, Bastian BC, Baylin SB, Behera M, Belyaev D, Benz C, Bernard B, Beroukhim R, Bir N, Black AD, Bodenheimer T, Boice L, Boland GM, Bono R, Bootwalla MS }}

The most frequent mutation occurs in the 600th codon of BRAF (50% of cases). BRAF is normally involved in cell growth, and this specific mutation renders the protein constitutively active and independent of normal physiological regulation, thus fostering tumor growth.{{cite journal | vauthors = Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, Palmieri G, Testori A, Marincola FM, Mozzillo N | title = The role of BRAF V600 mutation in melanoma | journal = Journal of Translational Medicine | volume = 10 | issue = 1 | pages = 85 | date = July 2012 | pmid = 22554099 | pmc = 3391993 | doi = 10.1186/1479-5876-10-85 | doi-access = free }} RAS genes (NRAS, HRAS and KRAS) are also recurrently mutated (30% of TCGA cases) and mutations in the 61st or 12th codons trigger oncogenic activity. Loss-of-function mutations often affect tumor suppressor genes such as NF1, TP53 and CDKN2A. Other oncogenic alterations include fusions involving various kinases such as BRAF,{{cite journal | vauthors = Botton T, Talevich E, Mishra VK, Zhang T, Shain AH, Berquet C, Gagnon A, Judson RL, Ballotti R, Ribas A, Herlyn M, Rocchi S, Brown KM, Hayward NK, Yeh I, Bastian BC | title = Genetic Heterogeneity of BRAF Fusion Kinases in Melanoma Affects Drug Responses | journal = Cell Reports | volume = 29 | issue = 3 | pages = 573–588.e7 | date = October 2019 | pmid = 31618628 | pmc = 6939448 | doi = 10.1016/j.celrep.2019.09.009 }} RAF1,{{cite journal | vauthors = McEvoy CR, Xu H, Smith K, Etemadmoghadam D, San Leong H, Choong DY, Byrne DJ, Iravani A, Beck S, Mileshkin L, Tothill RW, Bowtell DD, Bates BM, Nastevski V, Browning J, Bell AH, Khoo C, Desai J, Fellowes AP, Fox SB, Prall OW | title = Profound MEK inhibitor response in a cutaneous melanoma harboring a GOLGA4-RAF1 fusion | journal = The Journal of Clinical Investigation | volume = 129 | issue = 5 | pages = 1940–1945 | date = May 2019 | pmid = 30835257 | pmc = 6486352 | doi = 10.1172/JCI123089 }} ALK, RET, ROS1, NTRK1.,{{cite journal | vauthors = Wiesner T, He J, Yelensky R, Esteve-Puig R, Botton T, Yeh I, Lipson D, Otto G, Brennan K, Murali R, Garrido M, Miller VA, Ross JS, Berger MF, Sparatta A, Palmedo G, Cerroni L, Busam KJ, Kutzner H, Cronin MT, Stephens PJ, Bastian BC | title = Kinase fusions are frequent in Spitz tumours and spitzoid melanomas | journal = Nature Communications | volume = 5 | issue = 1 | pages = 3116 | date = May 2014 | pmid = 24445538 | pmc = 4084638 | doi = 10.1038/ncomms4116 | bibcode = 2014NatCo...5.3116W }} NTRK3{{cite journal | vauthors = Yeh I, Tee MK, Botton T, Shain AH, Sparatta AJ, Gagnon A, Vemula SS, Garrido MC, Nakamaru K, Isoyama T, McCalmont TH, LeBoit PE, Bastian BC | title = NTRK3 kinase fusions in Spitz tumours | journal = The Journal of Pathology | volume = 240 | issue = 3 | pages = 282–290 | date = November 2016 | pmid = 27477320 | pmc = 5071153 | doi = 10.1002/path.4775 }} and MET{{cite journal | vauthors = Yeh I, Botton T, Talevich E, Shain AH, Sparatta AJ, de la Fouchardiere A, Mully TW, North JP, Garrido MC, Gagnon A, Vemula SS, McCalmont TH, LeBoit PE, Bastian BC | title = Activating MET kinase rearrangements in melanoma and Spitz tumours | journal = Nature Communications | volume = 6 | issue = 1 | pages = 7174 | date = May 2015 | pmid = 26013381 | pmc = 4446791 | doi = 10.1038/ncomms8174 | doi-access = free | bibcode = 2015NatCo...6.7174Y }} BRAF, RAS, and NF1 mutations and kinase fusions are remarkably mutually exclusive, as they occur in different subsets of patients. Assessment of mutation status can, therefore, improve patient stratification and inform targeted therapy with specific inhibitors.{{citation needed|date=September 2022}}

In some cases (3–7%) mutated versions of BRAF and NRAS undergo copy-number amplification.

The research done by Sarna's team proved that heavily pigmented melanoma cells have Young's modulus about 4.93, when in non-pigmented ones it was only 0.98.{{cite journal | vauthors = Sarna M, Krzykawska-Serda M, Jakubowska M, Zadlo A, Urbanska K | title = Melanin presence inhibits melanoma cell spread in mice in a unique mechanical fashion | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 9280 | date = June 2019 | pmid = 31243305 | pmc = 6594928 | doi = 10.1038/s41598-019-45643-9 | bibcode = 2019NatSR...9.9280S }} In another experiment they found that elasticity of melanoma cells is important for its metastasis and growth: non-pigmented tumors were bigger than pigmented and it was much easier for them to spread. They showed that there are both pigmented and non-pigmented cells in melanoma tumors, so that they can both be drug-resistant and metastatic.

File:Melanoma vs normal mole ABCD rule NCI Visuals Online.jpg

File:Pie chart of incidence and malignancy of pigmented skin lesions.png of pigmented skin lesions, by relative rates upon biopsy and malignancy potential, including "melanoma" at right]]

Looking at or visually inspecting the area in question is the most common method of suspecting a melanoma.{{cite journal |vauthors=Wurm EM, Soyer HP |title=Scanning for melanoma |date=October 2010 |journal=Australian Prescriber |volume=33 |pages=150–55 |doi=10.18773/austprescr.2010.070 |doi-access=free }} Moles that are irregular in color or shape are typically treated as candidates. To detect melanomas (and increase survival rates), it is recommended to learn to recognize them (see "ABCDE" mnemonic), to regularly examine moles for changes (shape, size, color, itching or bleeding) and to consult a qualified physician when a candidate appears.{{cite web |title=Prevention: ABCD's of Melanoma |publisher=American Melanoma Foundation |url=http://www.melanomafoundation.org/prevention/abcd.htm |url-status=dead |archive-url=https://web.archive.org/web/20030423111111/http://melanomafoundation.org/prevention/abcd.htm |archive-date=23 April 2003 }}{{cite journal | vauthors = Friedman RJ, Rigel DS, Kopf AW | title = Early detection of malignant melanoma: the role of physician examination and self-examination of the skin | journal = CA | volume = 35 | issue = 3 | pages = 130–151 | year = 1985 | pmid = 3921200 | doi = 10.3322/canjclin.35.3.130 | s2cid = 20787489 | doi-access = free }} In-person inspection of suspicious skin lesions is more accurate than visual inspection of images of suspicious skin lesions.{{cite journal | vauthors = Dinnes J, Deeks JJ, Grainge MJ, Chuchu N, Ferrante di Ruffano L, Matin RN, Thomson DR, Wong KY, Aldridge RB, Abbott R, Fawzy M, Bayliss SE, Takwoingi Y, Davenport C, Godfrey K, Walter FM, Williams HC | title = Visual inspection for diagnosing cutaneous melanoma in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 12 | pages = CD013194 | date = December 2018 | pmid = 30521684 | pmc = 6492463 | doi = 10.1002/14651858.CD013194 }}

When used by trained specialists, dermoscopy is more helpful to identify malignant lesions than use of the naked eye alone.{{cite journal | vauthors = Dinnes J, Deeks JJ, Chuchu N, Ferrante di Ruffano L, Matin RN, Thomson DR, Wong KY, Aldridge RB, Abbott R, Fawzy M, Bayliss SE, Grainge MJ, Takwoingi Y, Davenport C, Godfrey K, Walter FM, Williams HC | title = Dermoscopy, with and without visual inspection, for diagnosing melanoma in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2018 | issue = 12 | pages = CD011902 | date = December 2018 | pmid = 30521682 | pmc = 6517096 | doi = 10.1002/14651858.CD011902.pub2 }} Reflectance confocal microscopy may have better sensitivity and specificity than dermoscopy in diagnosing cutaneous melanoma but more studies are needed to confirm this result.{{cite journal | vauthors = Dinnes J, Deeks JJ, Saleh D, Chuchu N, Bayliss SE, Patel L, Davenport C, Takwoingi Y, Godfrey K, Matin RN, Patalay R, Williams HC | title = Reflectance confocal microscopy for diagnosing cutaneous melanoma in adults | journal = The Cochrane Database of Systematic Reviews | volume = 12 | issue = 12 | pages = CD013190 | date = December 2018 | pmid = 30521681 | pmc = 6492459 | doi = 10.1002/14651858.CD013190 | collaboration = Cochrane Skin Group }}

However, many melanomas present as lesions smaller than 6 mm in diameter, and all melanomas are malignant when they first appear as a small dot. Physicians typically examine all moles, including those less than 6 mm in diameter. Seborrheic keratosis may meet some or all of the ABCD criteria, and can lead to false alarms. Doctors can generally distinguish seborrheic keratosis from melanoma upon examination or with dermatoscopy.{{Cite journal |last=Gniadecki |first=Robert |last2=Mourad |first2=Ahmed |date=June 2019 |title=Differentiating malignant melanoma from other lesions using dermoscopy |url=https://pubmed.ncbi.nlm.nih.gov/31189629 |journal=Canadian Family Physician |volume=65 |issue=6 |pages=412–414 |issn=1715-5258 |pmc=6738388 |pmid=31189629}}

Some advocate replacing "enlarging" with "evolving": moles that change and evolve are a concern. Alternatively, some practitioners prefer "elevation". Elevation can help identify a melanoma, but lack of elevation does not mean that the lesion is not a melanoma. Most melanomas in the US are detected before they become elevated. By the time elevation is visible, they may have progressed to the more dangerous invasive stage.{{Citation needed|date=September 2022}}

File:Malignant melanoma (1) at thigh Case 01.jpg|Melanoma in skin biopsy with H&E stain – this case may represent superficial spreading melanoma.

File:Lymph node with almost complete replacement by metastatic melanoma.jpg|Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is a focal deposition of melanin.

File:Dermatoscope1.JPG|A dermatoscope

File:Malignant Melanoma, right posterior thigh.png|Melanoma, right posterior thigh

File:Melanoma in situ, vertex scalp.jpg|Melanoma in situ, vertex scalp marked for biopsy

File:Malignant Melanoma in situ evolving Right clavicle.jpg|Melanoma in situ, evolving, right clavicle marked for biopsy

File:Malignant Melanoma, vertex scalp.jpg|Melanoma, vertex scalp marked for biopsy

File:Malignant Melanoma right medial thigh.jpg|Melanoma, right medial thigh marked for biopsy

File:Malignant Melanoma Right Posterior Shoulder.jpg|Melanoma, right posterior shoulder circled for biopsy

File:Malignant Melanoma Left Forearm.jpg|Melanoma, left forearm marked for biopsy

File:Malignant Melanoma Left Forearm post excision.jpg|Melanoma left forearm post excision with purse-string closure

File:Melanoma in situ Right Forehead.jpg|Melanoma in situ, right forehead marked for biopsy

File:Melanoma in situ Right Forehead dermatoscope.jpg|Melanoma in situ, dermatoscope image, right forehead marked for biopsy

File:Malignant Melanoma right temple medial adjacent sebaceous hyperplasia right temple lateral.jpg|Melanoma in situ, evolving, a medial right temple with adjacent sebaceous hyperplasia, lateral

File:Malignant Melanoma in situ Left Anterior Shoulder.jpg|Melanoma in situ, left anterior shoulder marked for biopsy

File:Malignant Melanoma in situ Right Anterior Shoulder.jpg|Melanoma in situ, right anterior shoulder marked for biopsy

File:Malignant Melanoma in situ Left Upper Inner Arm.jpg|Melanoma in situ, left upper inner arm

File:Malignant Melanoma in situ Left Forearm.jpg|Melanoma in situ marked for biopsy, left forearm

File:Malignant Melanoma right upper medial back.jpg|Melanoma in situ, right upper medial back, marked for biopsy

File:Malignant Melanoma Mid Frontal Scalp.jpg|Melanoma, mid frontal scalp

File:Malignant Melanoma Left Mid Back.jpg|Melanoma, left mid-back marked for biopsy

File:Malignant Melanoma Left Mid Back Dermatoscope.jpg|Melanoma, left mid-back marked for biopsy, through dermatoscope

File:Gross pathology of melanoma metastasis.jpg|Gross pathology of melanoma metastasis, which is pigment-forming in a vast majority of cases, giving it a dark appearance

File:Histopathology of a metastatic melanoma to a lymph node.jpg|Histopathology of a metastatic melanoma to a lymph node, H&E stain, showing poorly differentiated cells

File:Histopathology of a metastatic melanoma to a lymph node, Melan-A stain.jpg|Metastatic melanoma on immunohistochemistry for Melan-A, which helps in diagnosing uncertain cases

File:Immunohistochemistry stain for SOX10 in a metastatic melanoma to a lymph node.jpg|Metastatic melanoma on immunohistochemistry for SOX10, another helpful stain in uncertain cases

One method is the "ugly duckling sign".{{cite journal | vauthors = Mascaro JM, Mascaro JM | title = The dermatologist's position concerning nevi: a vision ranging from "the ugly duckling" to "little red riding hood" | journal = Archives of Dermatology | volume = 134 | issue = 11 | pages = 1484–1485 | date = November 1998 | pmid = 9828892 | doi = 10.1001/archderm.134.11.1484 | doi-broken-date = 2 December 2024 }}

Correlation of common lesion characteristics is made. Lesions that deviate from the common characteristics are labeled an "ugly duckling", and a further professional exam is required. The "Little Red Riding Hood" sign suggests that individuals with fair skin and light-colored hair might have difficult-to-diagnose amelanotic melanomas. Extra care is required when examining such individuals, as they might have multiple melanomas and severely dysplastic nevi. A dermatoscope must be used to detect "ugly ducklings", as many melanomas in these individuals resemble nonmelanomas or are considered to be "wolves in sheep's clothing".{{cite web|url=http://dermnetnz.org/doctors/dermoscopy-course/introduction.html|title=Introduction to Dermoscopy|publisher=DermNet New Zealand|url-status=live|archive-url=https://web.archive.org/web/20090507183545/http://dermnetnz.org/doctors/dermoscopy-course/introduction.html|archive-date=7 May 2009}}

These fair-skinned individuals often have lightly pigmented or amelanotic melanomas that do not present easy-to-observe color changes and variations. Their borders are often indistinct, complicating visual identification without a dermatoscope.

Amelanotic melanomas and melanomas arising in fair-skinned individuals are very difficult to detect, as they fail to show many of the characteristics in the ABCD rule, break the "ugly duckling" sign, and are hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines.

Following a visual examination and a dermatoscopic exam, or in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining severity. Elliptical excisional biopsies may remove the tumor, followed by histological analysis and Breslow scoring. Incisional biopsies such as punch biopsies are usually contraindicated in suspected melanomas, because of the possibility of sampling error{{cite journal | vauthors = Montgomery BD, Sadler GM | title = Punch biopsy of pigmented lesions is potentially hazardous | journal = Canadian Family Physician | volume = 55 | issue = 1 | pages = 24; autor reply 24 | date = January 2009 | pmid = 19155361 | pmc = 2628830 }} or local implantation causing misestimation of tumour thickness.{{cite journal | vauthors = Luk PP, Vilain R, Crainic O, McCarthy SW, Thompson JF, Scolyer RA | title = Punch biopsy of melanoma causing tumour cell implantation: another peril of utilising partial biopsies for melanocytic tumours | journal = The Australasian Journal of Dermatology | volume = 56 | issue = 3 | pages = 227–231 | date = August 2015 | pmid = 25827527 | doi = 10.1111/ajd.12333 | s2cid = 2510803 }}{{cite journal | vauthors = Lin SW, Kaye V, Goldfarb N, Rawal A, Warshaw E | title = Melanoma tumor seeding after punch biopsy | journal = Dermatologic Surgery | volume = 38 | issue = 7 Pt 1 | pages = 1083–1085 | date = July 2012 | pmid = 22471244 | doi = 10.1111/j.1524-4725.2012.02384.x | s2cid = 3431248 }} However, fears that such biopsies may increase the risk of metastatic disease seem unfounded.{{cite journal | vauthors = Martin RC, Scoggins CR, Ross MI, Reintgen DS, Noyes RD, Edwards MJ, McMasters KM | title = Is incisional biopsy of melanoma harmful? | journal = American Journal of Surgery | volume = 190 | issue = 6 | pages = 913–917 | date = December 2005 | pmid = 16307945 | doi = 10.1016/j.amjsurg.2005.08.020 }}{{cite journal | vauthors = Yamashita Y, Hashimoto I, Abe Y, Seike T, Okawa K, Senzaki Y, Murao K, Kubo Y, Nakanishi H | title = Effect of biopsy technique on the survival rate of malignant melanoma patients | journal = Archives of Plastic Surgery | volume = 41 | issue = 2 | pages = 122–125 | date = March 2014 | pmid = 24665419 | pmc = 3961608 | doi = 10.5999/aps.2014.41.2.122 }}

Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up for high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (with any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes. The diagnosis method should be used in conjunction with (and not as a replacement for) dermoscopic imaging, with a combination of both methods appearing to give extremely high rates of detection.

Melanoma is a type of neuroectodermal neoplasm.{{cite journal | vauthors = Mills SE | title = Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas | journal = Modern Pathology | volume = 15 | issue = 3 | pages = 264–278 | date = March 2002 | pmid = 11904342 | doi = 10.1038/modpathol.3880522 | s2cid = 34498802 | doi-access = free }} There are four main types of melanoma:{{cite book | chapter = Melanoma | chapter-url = https://books.google.com/books?id=wGclDwAAQBAJ&pg=PA805 | archive-url = https://web.archive.org/web/20200804005558/https://books.google.se/books?id=wGclDwAAQBAJ&pg=PA805 | archive-date=4 August 2020 | page = 805 | vauthors = Ferri F | title=Ferri's clinical advisor 2019 : 5 books in 1 | publisher=Elsevier | location=Philadelphia, PA | year=2019 | isbn=978-0-323-52957-0 | oclc=1040695302 }}

Other histopathologic types are:

File:Anal Melanoma.JPG

• Mucosal melanoma; When melanoma occurs on mucous membranes.
• Desmoplastic melanoma
• Melanoma with small nevus-like cells
• Melanoma with features of a Spitz nevus
• Uveal melanoma
• Vaginal melanoma
• Polypoid melanoma, a subclass of nodular melanoma.

A melanoma in situ has not invaded beyond the basement membrane, whereas an invasive melanoma has spread beyond it.

Some histopathological types of melanoma are inherently invasive, including nodular melanoma and lentigo maligna melanoma, where the in situ counterpart to lentigo maligna melanoma is lentigo maligna.{{cite journal | vauthors = McKenna JK, Florell SR, Goldman GD, Bowen GM | title = Lentigo maligna/lentigo maligna melanoma: current state of diagnosis and treatment | journal = Dermatologic Surgery | volume = 32 | issue = 4 | pages = 493–504 | date = April 2006 | pmid = 16681656 | doi = 10.1111/j.1524-4725.2006.32102.x | s2cid = 8312676 }} Lentigo maligna is sometimes classified as a very early melanoma,{{cite web|url=https://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/melanoma/precancerous-conditions/?region=on|website=Canadian Cancer Society|title=Precancerous conditions of the skin|access-date=26 February 2020|archive-date=3 August 2020|archive-url=https://web.archive.org/web/20200803223354/https://www.cancer.ca/en/cancer-information/cancer-type/skin-melanoma/melanoma/precancerous-conditions/?region=on|url-status=live}} and sometimes a precursor to melanoma.{{cite journal| vauthors = Fleming C |s2cid=71464540|title=How to manage patients with lentigo maligna|journal=Melanoma Research|volume=20|year=2010|pages=e26|issn=0960-8931|doi=10.1097/01.cmr.0000382797.99333.66}}

Superficial spreading melanomas and acral lentiginous melanomas can be either in situ or invasive,{{cite web|url=http://www.pathologyoutlines.com/topic/skintumormelanocyticmelanomainsitu.html|title=Skin melanocytic tumor - Melanoma - Melanoma in situ|website=pathology Outlines| vauthors = Hale CS |access-date=26 February 2020|archive-date=26 February 2020|archive-url=https://web.archive.org/web/20200226115931/http://www.pathologyoutlines.com/topic/skintumormelanocyticmelanomainsitu.html|url-status=dead}} Topic Completed: 1 May 2013. Revised: 23 May 2019 but acral lentiginous melanomas are almost always invasive.{{cite journal | vauthors = Park HS, Cho KH | title = Acral lentiginous melanoma in situ: a diagnostic and management challenge | journal = Cancers | volume = 2 | issue = 2 | pages = 642–652 | date = April 2010 | pmid = 24281086 | pmc = 3835096 | doi = 10.3390/cancers2020642 | doi-access = free }}

Further context on cancer staging is available at TNM.

File:Diagram showing the T stages of melanoma CRUK 373.svg

Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.{{cite journal | vauthors = Weight RM, Viator JA, Dale PS, Caldwell CW, Lisle AE | title = Photoacoustic detection of metastatic melanoma cells in the human circulatory system | journal = Optics Letters | volume = 31 | issue = 20 | pages = 2998–3000 | date = October 2006 | pmid = 17001379 | doi = 10.1364/OL.31.002998 | bibcode = 2006OptL...31.2998W }} However, there is lack of evidence in the accuracy of staging of people with melanoma with various imaging methods.{{cite journal | vauthors = Dinnes J, Ferrante di Ruffano L, Takwoingi Y, Cheung ST, Nathan P, Matin RN, Chuchu N, Chan SA, Durack A, Bayliss SE, Gulati A, Patel L, Davenport C, Godfrey K, Subesinghe M, Traill Z, Deeks JJ, Williams HC | title = Ultrasound, CT, MRI, or PET-CT for staging and re-staging of adults with cutaneous melanoma | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 7 | pages = CD012806 | date = July 2019 | pmid = 31260100 | pmc = 6601698 | doi = 10.1002/14651858.CD012806.pub2 | collaboration = Cochrane Skin Group }}

Melanoma stages according to AJCC, 8th edition:{{cite journal | vauthors = Gershenwald JE, Scolyer RA, Hess KR, Sondak VK, Long GV, Ross MI, Lazar AJ, Faries MB, Kirkwood JM, McArthur GA, Haydu LE, Eggermont AM, Flaherty KT, Balch CM, Thompson JF | title = Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual | journal = CA | volume = 67 | issue = 6 | pages = 472–492 | date = November 2017 | pmid = 29028110 | pmc = 5978683 | doi = 10.3322/caac.21409 }}, citing
Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer International Publishing; 2017:563‐585).

• TX: Primary tumor thickness cannot be assessed (such as a diagnosis by curettage)
• T0: No evidence of primary tumor (such as unknown primary or completely regressed melanoma)

Stage 1 and 2 require an N (lymph node) class of:

:*N0 – No regional metastases.

Stage 1, 2 and 3 require an M (metastasis status) of:

• M0: No evidence of distant metastasis

Older systems include "Clark level" and "Breslow's depth", quantifying microscopic depth of tumor invasion.

File:Malignes Melanom.jpg

Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates the metastatic spread of the disease to the liver.

It is common for patients diagnosed with melanoma to have chest X-rays and an LDH test, and in some cases CT, MRI, and/or PET scans. Although controversial, sentinel lymph node biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph nodes. A diagnosis of melanoma is supported by the presence of the S-100 protein marker.

HMB-45 is a monoclonal antibody that reacts against an antigen present in melanocytic tumors such as melanomas. It is used in anatomic pathology as a marker for such tumors. The antibody was generated to an extract of melanoma. It reacts positively against melanocytic tumors but not other tumors, thus demonstrating specificity and sensitivity. The antibody also reacts positively against junctional nevus cells but not intradermal nevi, and against fetal melanocytes but not normal adult melanocytes.

HMB-45 is nonreactive with almost all non-melanoma human malignancies, with the exception of rare tumors showing evidence of melanogenesis (e.g., pigmented schwannoma, clear cell sarcoma) or tumors associated with tuberous sclerosis complex (angiomyolipoma and lymphangiomyoma).

There is no evidence to support or refute adult population screening for melanoma.{{cite journal | vauthors = Johansson M, Brodersen J, Gøtzsche PC, Jørgensen KJ | title = Screening for reducing morbidity and mortality in malignant melanoma | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 6 | pages = CD012352 | date = June 2019 | pmid = 31157404 | pmc = 6545529 | doi = 10.1002/14651858.CD012352.pub2 | collaboration = Cochrane Skin Group }}

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),{{cite journal | vauthors = Autier P | title = Cutaneous malignant melanoma: facts about sunbeds and sunscreen | journal = Expert Review of Anticancer Therapy | volume = 5 | issue = 5 | pages = 821–833 | date = October 2005 | pmid = 16221052 | doi = 10.1586/14737140.5.5.821 | s2cid = 6091309 }} following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection.

Using artificial light for tanning was once believed to help prevent skin cancers, but it can actually lead to an increased incidence of melanomas.{{cite journal | vauthors = Clough-Gorr KM, Titus-Ernstoff L, Perry AE, Spencer SK, Ernstoff MS | title = Exposure to sunlamps, tanning beds, and melanoma risk | journal = Cancer Causes & Control | volume = 19 | issue = 7 | pages = 659–669 | date = September 2008 | pmid = 18273687 | pmc = 6367654 | doi = 10.1007/s10552-008-9129-6 }}

UV nail lamps, which are used in nail salons to dry nail polish, are another common and widespread source of UV radiation that could be avoided.{{cite journal | vauthors = Shihab N, Lim HW | title = Potential cutaneous carcinogenic risk of exposure to UV nail lamp: A review | journal = Photodermatology, Photoimmunology & Photomedicine | volume = 34 | issue = 6 | pages = 362–365 | date = November 2018 | pmid = 29882991 | doi = 10.1111/phpp.12398 | s2cid = 46958616 | doi-access = free }}{{cite journal | vauthors = O'Sullivan NA, Tait CP | title = Tanning bed and nail lamp use and the risk of cutaneous malignancy: a review of the literature | journal = The Australasian Journal of Dermatology | volume = 55 | issue = 2 | pages = 99–106 | date = May 2014 | pmid = 24592921 | doi = 10.1111/ajd.12145 | s2cid = 206984768 }} Although the risk of developing skin cancer through UV nail lamp use is low, it is still recommended to wear fingerless gloves and/or apply SPF 30 or greater sunscreen to the hands before using a UV nail lamp.

The body uses UV light to generate vitamin D so there is a need to balance getting enough sunlight to maintain healthy vitamin D levels and reducing the risk of melanoma; it takes around a half-hour of sunlight for the body to generate its vitamin D for the day and this is about the same amount of time it takes for fair-skinned people to get a sunburn. Exposure to sunlight can be intermittent instead of all at one time.{{cite journal | vauthors = Greinert R, de Vries E, Erdmann F, Espina C, Auvinen A, Kesminiene A, Schüz J | title = European Code against Cancer 4th Edition: Ultraviolet radiation and cancer | journal = Cancer Epidemiology | volume = 39 | issue = Suppl 1 | pages = S75–S83 | date = December 2015 | pmid = 26096748 | doi = 10.1016/j.canep.2014.12.014 | hdl-access = free | doi-access = free | hdl = 1765/86460 }}

Sunscreen appears to be effective in preventing melanoma.{{cite journal | vauthors = Kanavy HE, Gerstenblith MR | title = Ultraviolet radiation and melanoma | journal = Seminars in Cutaneous Medicine and Surgery | volume = 30 | issue = 4 | pages = 222–228 | date = December 2011 | pmid = 22123420 | doi = 10.1016/j.sder.2011.08.003 | doi-broken-date = 1 November 2024 }} In the past, use of sunscreens with a sun protection factor (SPF) rating of 50 or higher on exposed areas were recommended; as older sunscreens more effectively blocked UVA with higher SPF.{{Cite web|url=http://www.cancer.org/docroot/cri/content/cri_2_4_2x_can_melanoma_be_prevented_50.asp|archive-url=https://web.archive.org/web/20060627025413/http://www.cancer.org/docroot/cri/content/cri_2_4_2x_can_melanoma_be_prevented_50.asp|url-status=dead|title=Can Melanoma Be Prevented?|archive-date=27 June 2006}} Currently, newer sunscreen ingredients (avobenzone, zinc oxide, and titanium dioxide) effectively block both UVA and UVB even at lower SPFs. Sunscreen also protects against squamous cell carcinoma, another skin cancer.{{cite journal | vauthors = Burnett ME, Wang SQ | title = Current sunscreen controversies: a critical review | journal = Photodermatology, Photoimmunology & Photomedicine | volume = 27 | issue = 2 | pages = 58–67 | date = April 2011 | pmid = 21392107 | doi = 10.1111/j.1600-0781.2011.00557.x | doi-access = | s2cid = 29173997 }}

Concerns have been raised that sunscreen might create a false sense of security against sun damage.{{cite journal | vauthors = Planta MB | title = Sunscreen and melanoma: is our prevention message correct? | journal = Journal of the American Board of Family Medicine | volume = 24 | issue = 6 | pages = 735–739 | date = 1 November 2011 | pmid = 22086817 | doi = 10.3122/jabfm.2011.06.100178 | s2cid = 1477485 | doi-access = free }}

A 2005 review found tentative evidence that statin and fibrate medication may decrease the risk of melanoma.{{cite journal | vauthors = Dellavalle RP, Drake A, Graber M, Heilig LF, Hester EJ, Johnson KR, McNealy K, Schilling L | title = Statins and fibrates for preventing melanoma | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD003697 | date = October 2005 | volume = 2014 | pmid = 16235336 | doi = 10.1002/14651858.CD003697.pub2 | url = http://www.cochrane.org/CD003697/SKIN_currently-there-is-no-clear-evidence-that-cholesterol-drugs-reduce-melanoma-risk. | access-date = 3 July 2018 | url-status = live | archive-url = https://web.archive.org/web/20180704034655/http://www.cochrane.org/CD003697/SKIN_currently-there-is-no-clear-evidence-that-cholesterol-drugs-reduce-melanoma-risk. | archive-date = 4 July 2018 | url-access = subscription | pmc = 11102950 }} A 2006 review however did not support any benefit.{{cite journal | vauthors = Freeman SR, Drake AL, Heilig LF, Graber M, McNealy K, Schilling LM, Dellavalle RP | title = Statins, fibrates, and melanoma risk: a systematic review and meta-analysis | journal = Journal of the National Cancer Institute | volume = 98 | issue = 21 | pages = 1538–1546 | date = November 2006 | pmid = 17077356 | doi = 10.1093/jnci/djj412 | doi-access = free }}

File:Malignant melanoma on chest.jpg

Confirmation of the clinical diagnosis is done with a skin biopsy. This is usually followed up with a wider excision of the scar or tumor. Depending on the stage, a sentinel lymph node biopsy may be performed. Controversy exists around trial evidence for sentinel lymph node biopsy;{{cite web|url=http://www.malignant-melanoma.org/sentinel-node-biopsy/sentinel-node-biopsy-false-positivity/ |title=The Sentinel Node Biopsy Procedure in Melanoma does not offer a survival advantage |publisher=Malignant Melanoma |date=8 January 2008 |access-date=13 August 2012 |url-status=dead |archive-url=https://web.archive.org/web/20120711150413/http://www.malignant-melanoma.org/sentinel-node-biopsy/sentinel-node-biopsy-false-positivity/ |archive-date=11 July 2012 }} with unclear evidence of benefit as of 2015.{{cite journal | vauthors = Kyrgidis A, Tzellos T, Mocellin S, Apalla Z, Lallas A, Pilati P, Stratigos A | title = Sentinel lymph node biopsy followed by lymph node dissection for localised primary cutaneous melanoma | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 5 | pages = CD010307 | date = May 2015 | pmid = 25978975 | pmc = 6461196 | doi = 10.1002/14651858.CD010307.pub2 }} Treatment of advanced melanoma is performed from a multidisciplinary approach.

Excisional biopsies may remove the tumor, but further surgery is often necessary to reduce the risk of recurrence. Complete surgical excision with adequate surgical margins and assessment for the presence of detectable metastatic disease along with short- and long-term followup is standard. Often this is done by a wide local excision (WLE) with {{convert|1-2|cm|1|abbr=on}} margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually {{convert|0.2-0.5|cm|1|abbr=on}}. Many surgeons consider {{convert|0.5|cm|1|abbr=on}} the standard of care for standard excision of melanoma-in-situ,{{cite journal | vauthors = Clark GS, Pappas-Politis EC, Cherpelis BS, Messina JL, Möller MG, Cruse CW, Glass LF | title = Surgical management of melanoma in situ on chronically sun-damaged skin | journal = Cancer Control | volume = 15 | issue = 3 | pages = 216–224 | date = July 2008 | pmid = 18596673 | doi = 10.1177/107327480801500304 | doi-access = free }} but {{convert|0.2|cm|1|abbr=on}} margin might be acceptable for margin controlled surgery (Mohs surgery, or the double-bladed technique with margin control). The wide excision aims to reduce the rate of tumor recurrence at the site of the original lesion. This is a common pattern of treatment failure in melanoma. Considerable research has aimed to elucidate appropriate margins for excision with a general trend toward less aggressive treatment during the last decades.{{cite journal | vauthors = Balch CM, Urist MM, Karakousis CP, Smith TJ, Temple WJ, Drzewiecki K, Jewell WR, Bartolucci AA, Mihm MC, Barnhill R | title = Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial | journal = Annals of Surgery | volume = 218 | issue = 3 | pages = 262–7; discussion 267–9 | date = September 1993 | pmid = 8373269 | pmc = 1242959 | doi = 10.1097/00000658-199309000-00005 }} A 2009 meta-analysis of randomized controlled trials found a small difference in survival rates favoring wide excision of primary cutaneous melanomas, but these results were not statistically significant.{{cite journal | vauthors = Sladden MJ, Balch C, Barzilai DA, Berg D, Freiman A, Handiside T, Hollis S, Lens MB, Thompson JF | title = Surgical excision margins for primary cutaneous melanoma | journal = The Cochrane Database of Systematic Reviews | volume = 129 | issue = 4 | pages = CD004835 | date = October 2009 | pmid = 19821334 | doi = 10.1002/14651858.CD004835.pub2 }}

Mohs surgery has been reported with cure rate as low as 77%{{cite book| vauthors = Mohs FE, Mikhail GR |title=Mohs micrographic surgery|url={{google books |plainurl=y |id=8j9sAAAAMAAJ}}|date=January 1991|publisher=W.B. Saunders|isbn=978-0-7216-3415-9|pages=13–14|url-status=live|archive-url=https://web.archive.org/web/20160107215207/https://books.google.com/books?id=8j9sAAAAMAAJ|archive-date=7 January 2016}} and as high as 98.0% for melanoma-in-situ.{{cite journal | vauthors = Bene NI, Healy C, Coldiron BM | title = Mohs micrographic surgery is accurate 95.1% of the time for melanoma in situ: a prospective study of 167 cases | journal = Dermatologic Surgery | volume = 34 | issue = 5 | pages = 660–664 | date = May 2008 | pmid = 18261099 | doi = 10.1111/j.1524-4725.2007.34124.x | quote = Cure rate as high as 98% for small melanoma in situ, and as high as 95% noted for lentigo maligna variant of melanona in situ has been reported with Mohs surgery. | s2cid = 23386371 }} CCPDMA and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this "intra-epithelial" type of melanoma.

Melanomas that spread usually do so to the lymph nodes in the area of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications, but no overall survival benefit. Recently, the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumor.{{cite web|url=http://www.malignant-melanoma.org/surgery/lymph-node-dissection-surgery/ |title=The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) |url-status=dead |archive-url=https://web.archive.org/web/20090106181514/http://www.malignant-melanoma.org/surgery/lymph-node-dissection-surgery/ |archive-date=6 January 2009 }}

Biopsy of sentinel lymph nodes is a widely used procedure when treating cutaneous melanoma.{{cite journal | vauthors = Crowson AN, Haskell H | title = The role of sentinel lymph-node biopsy in the management of cutaneous melanoma | journal = Giornale Italiano di Dermatologia e Venereologia | volume = 148 | issue = 5 | pages = 493–499 | date = October 2013 | pmid = 24005142 }}{{cite journal | vauthors = Ross MI, Gershenwald JE | title = Sentinel lymph node biopsy for melanoma: a critical update for dermatologists after two decades of experience | journal = Clinics in Dermatology | volume = 31 | issue = 3 | pages = 298–310 | date = May–Jun 2013 | pmid = 23608449 | doi = 10.1016/j.clindermatol.2012.08.004 }}

Neither sentinel lymph node biopsy nor other diagnostic tests should be performed to evaluate early, thin melanoma, including melanoma in situ, T1a melanoma or T1b melanoma ≤ 0.5mm.{{Citation |author1=American Academy of Dermatology |author1-link=American Academy of Dermatology |date=February 2013 |title=Five Things Physicians and Patients Should Question |publisher=American Academy of Dermatology |work=Choosing Wisely: an initiative of the ABIM Foundation |url=http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-dermatology/ |access-date=5 December 2013 |url-status=dead |archive-url=https://web.archive.org/web/20131201171621/http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-dermatology/ |archive-date=1 December 2013 }}, which cites:

• {{cite journal | vauthors = Bichakjian CK, Halpern AC, Johnson TM, Foote Hood A, Grichnik JM, Swetter SM, Tsao H, Barbosa VH, Chuang TY, Duvic M, Ho VC, Sober AJ, Beutner KR, Bhushan R, Smith Begolka W | title = Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology | journal = Journal of the American Academy of Dermatology | volume = 65 | issue = 5 | pages = 1032–1047 | date = November 2011 | pmid = 21868127 | doi = 10.1016/j.jaad.2011.04.031 | hdl-access = free | collaboration = American Academy of Dermatology | doi-access = free | hdl = 20.500.12749/1682 }}
• {{cite book|title=AJCC cancer staging manual|year=2010|publisher=Springer |isbn=978-0-387-88440-0|author=American Joint Committee on Cancer|edition=7th | veditors = Edge SB }}
• {{Citation |author=National Comprehensive Cancer Network |year=2012 |title=National Comprehensive Cancer Network clinical practice guidelines in oncology (NCCN Guidelines): melanoma |publisher=National Comprehensive Cancer Network |location=Fort Washington, Pennsylvania |url=https://subscriptions.nccn.org/gl_login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf |access-date=5 December 2013 |url-status=dead |archive-url=https://web.archive.org/web/20131228154542/https://subscriptions.nccn.org/gl_login.aspx?ReturnURL=http%3A%2F%2Fwww.nccn.org%2Fprofessionals%2Fphysician_gls%2FPDF%2Fmelanoma.pdf |archive-date=28 December 2013 }}{{closed access}} People with these conditions are unlikely to have the cancer spread to their lymph nodes or anywhere else and have a 5-year survival rate of 97%. Because of these considerations, sentinel lymph node biopsy is considered unnecessary health care for them. Furthermore, baseline blood tests and radiographic studies should not be performed only based on identifying this kind of melanoma, as there are more accurate tests for detecting cancer and these tests have high false-positive rates. To potentially correct false positives, gene expression profiling may be used as auxiliary testing for ambiguous and small lesions.

Sentinel lymph node biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs.{{Citation needed|date=May 2013}} A process called lymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site to localize the sentinel node(s). Further precision is provided using a blue tracer dye, and surgery is performed to biopsy the node(s). Routine hematoxylin and eosin (H&E) and immunoperoxidase staining will be adequate to rule out node involvement. Polymerase chain reaction (PCR) tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative sentinel lymph node actually had a small number of positive cells in their nodes. Alternatively, a fine-needle aspiration biopsy may be performed and is often used to test masses.

If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. If the disease is completely resected, the patient will be considered for adjuvant therapy.

Excisional skin biopsy is the management of choice. Here, the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue.{{cite journal | vauthors = Swanson NA, Lee KK, Gorman A, Lee HN | title = Biopsy techniques. Diagnosis of melanoma | journal = Dermatologic Clinics | volume = 20 | issue = 4 | pages = 677–680 | date = October 2002 | pmid = 12380054 | doi = 10.1016/S0733-8635(02)00025-6 }} To avoid disruption of the local lymphatic drainage, the preferred surgical margin for the initial biopsy should be narrow (1 mm). The biopsy should include the epidermal, dermal, and subcutaneous layers of the skin. This enables the histopathologist to determine the thickness of the melanoma by microscopic examination. This is described by Breslow's thickness (measured in millimeters). However, for large lesions, such as suspected lentigo maligna, or for lesions in surgically difficult areas (face, toes, fingers, eyelids), a small punch biopsy in representative areas will give adequate information and will not disrupt the final staging or depth determination. In no circumstances should the initial biopsy include the final surgical margin (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. A large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram-directed lymphnode dissection. A small punch biopsy can be used at any time where for logistical and personal reasons a patient refuses more invasive excisional biopsy. Small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring.

Adjuvant treatment after surgery may reduce the risk of recurrence after surgery, especially in high-risk melanomas. Routines vary in different countries, but today (2024) the most common adjuvant treatment is immune checkpoint inhibitor treatment for up to a year post-surgery.{{cite journal | vauthors = Thomas D, Bello DM | title = Adjuvant immunotherapy for melanoma | journal = Journal of Surgical Oncology | volume = 123 | issue = 3 | pages = 789–797 | date = March 2021 | pmid = 33595889 | doi = 10.1002/jso.26329 | s2cid = 231943836 }}

In the early 2000s, a relatively common strategy was to treat patients with high risk of recurrence with up to a year of high-dose interferon treatment, which has severe side effects, but may improve the patient's prognosis slightly.{{cite journal | vauthors = Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH | title = Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684 | journal = Journal of Clinical Oncology | volume = 14 | issue = 1 | pages = 7–17 | date = January 1996 | pmid = 8558223 | doi = 10.1200/JCO.1996.14.1.7 | s2cid = 24020903 }} A 2013 meta-analysis suggested that the addition of interferon alpha increased disease-free and overall survival for people with AJCC TNM stage II-III cutaneous melanoma.{{cite journal | vauthors = Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V | title = Interferon alpha for the adjuvant treatment of cutaneous melanoma | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 6 | pages = CD008955 | date = June 2013 | pmid = 23775773 | pmc = 10773707 | doi = 10.1002/14651858.CD008955.pub2 | url = http://www.cochrane.org/CD008955/SKIN_interferon-treatment-melanoma-patients-after-surgical-removal-their-tumour | access-date = 11 June 2018 | url-status = live | archive-url = https://web.archive.org/web/20180612144237/http://www.cochrane.org/CD008955/SKIN_interferon-treatment-melanoma-patients-after-surgical-removal-their-tumour | archive-date = 12 June 2018 }} A 2011 meta-analysis showed that interferon could lengthen the time before a melanoma comes back but increased survival by only 3% at 5 years. The unpleasant side effects also greatly decrease quality of life.{{cite journal |vauthors=Wheatley K, Ives N, Eggermont A, Kirkwood J, Cascinelli N, Markovic SN, Hancock B, Lee S, Suciu S |year= 2007 |title= Interferon-α as an adjuvant therapy for melanoma: an individual patient meta-analysis of randomised trials |journal= J Clin Oncol |volume= 25 |issue= 18 Suppl |page= 8526 |doi=10.1200/jco.2007.25.18_suppl.8526 }} In the European Union, interferon is usually not used outside the scope of clinical trials.{{cite journal | vauthors = Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, Blum RH | title = High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190 | journal = Journal of Clinical Oncology | volume = 18 | issue = 12 | pages = 2444–2458 | date = June 2000 | pmid = 10856105 | doi = 10.1200/JCO.2000.18.12.2444 }}{{cite journal | vauthors = Kirkwood JM, Ibrahim JG, Sondak VK, Ernstoff MS, Ross M | title = Interferon alfa-2a for melanoma metastases | journal = Lancet | volume = 359 | issue = 9310 | pages = 978–979 | date = March 2002 | pmid = 11918944 | doi = 10.1016/S0140-6736(02)08001-7 | s2cid = 33866115 }}

Chemotherapy drugs such as dacarbazine have been the backbone of metastatic melanoma treatment since FDA approval in 1975; however, its efficacy in terms of survival has never been proven in an RCT. Since the approval of immune checkpoint inhibitors, dacarbazine and its oral counterpart temozolomide constitute potential treatment options in later lines of therapy.{{Cite journal | vauthors=Ryden V, El-Naggar AI, Koliadi A, Ladjevardi CO, Digkas E, Valachis A, Ullenhag GJ | date=2023-12-29 |title=The role of dacarbazine and temozolomide therapy after treatment with immune checkpoint inhibitors in malignant melanoma patients: A case series and meta-analysis |journal=Pigment Cell & Melanoma Research | volume=37 | issue=3 | pages=352–362 |language=en |doi=10.1111/pcmr.13156 |issn=1755-1471|pmid=38158376|doi-access=free }}

Multiple drugs are available to patients to decrease the size of the tumor. By lessening the size of the tumor, some symptoms can be relieved; however, this does not necessarily lead to remission. Some of these drugs are dacarbazine, temozolomide, and fotemustine. Combinations of drugs are also used and, in some cases, present higher remission rates. These medication combinations can have harmful side effects. To maintain quality of life, patients require assistive treatments and observation. Although combinations of drugs increase remission rates, the survival rate does not show an increase.{{cite journal | vauthors = Garbe C, Terheyden P, Keilholz U, Kölbl O, Hauschild A | title = Treatment of melanoma | journal = Deutsches Ärzteblatt International | volume = 105 | issue = 49 | pages = 845–851 | date = December 2008 | pmid = 19561811 | pmc = 2689638 | doi = 10.3238/arztebl.2008.0845 }}

In people with locally advanced cutaneous malignancies and sarcoma, isolated limb infusion (ILI) has been found to be a minimally invasive and well-tolerated procedure for delivering regional chemotherapy.{{cite journal | vauthors = O'Donoghue C, Perez MC, Mullinax JE, Hardman D, Sileno S, Naqvi SM, Kim Y, Gonzalez RJ, Zager JS | title = Isolated Limb Infusion: A Single-Center Experience with Over 200 Infusions | journal = Annals of Surgical Oncology | volume = 24 | issue = 13 | pages = 3842–3849 | date = December 2017 | pmid = 29019175 | pmc = 7771340 | doi = 10.1245/s10434-017-6107-9 | s2cid = 28907006 }}{{cite journal | vauthors = Giles MH, Coventry BJ | title = Isolated limb infusion chemotherapy for melanoma: an overview of early experience at the Adelaide Melanoma Unit | journal = Cancer Management and Research | volume = 5 | pages = 243–249 | date = August 2013 | pmid = 23990731 | pmc = 3753062 | doi = 10.2147/cmar.s45746 | doi-access = free }}

Melanoma cells have mutations that allow them to survive and grow indefinitely in the body.{{cite journal | vauthors = Pasquali S, Hadjinicolaou AV, Chiarion Sileni V, Rossi CR, Mocellin S | title = Systemic treatments for metastatic cutaneous melanoma | journal = The Cochrane Database of Systematic Reviews | volume = 2 | issue = 2 | pages = CD011123 | date = February 2018 | pmid = 29405038 | pmc = 6491081 | doi = 10.1002/14651858.CD011123.pub2 }} Small-molecule targeted therapies work by blocking the genes involved in pathways for tumor proliferation and survival. The main treatments are BRAF, C-Kit and NRAS inhibitors.{{cite journal | vauthors = Berger M, Richtig G, Kashofer K, Aigelsreiter A, Richtig E | title = The window of opportunities for targeted therapy in BRAFwt/NRASwt/KITwt melanoma: biology and clinical implications of fusion proteins and other mutations | journal = Giornale Italiano di Dermatologia e Venereologia | volume = 153 | issue = 3 | pages = 349–360 | date = June 2018 | pmid = 29600692 | doi = 10.23736/S0392-0488.18.05970-9 }} These inhibitors work to inhibit the downstream pathways involved in cell proliferation and tumour development due to specific gene mutations.{{cite journal | vauthors = Broussard L, Howland A, Ryu S, Song K, Norris D, Armstrong CA, Song PI | title = Melanoma Cell Death Mechanisms | journal = Chonnam Medical Journal | volume = 54 | issue = 3 | pages = 135–142 | date = September 2018 | pmid = 30288368 | pmc = 6165917 | doi = 10.4068/cmj.2018.54.3.135 }} People can be treated with small-molecule targeted inhibitors if they are positive for the specific mutation. BRAF inhibitors, such as vemurafenib and dabrafenib and a MEK inhibitor trametinib are the most effective, approved treatments for BRAF positive melanoma.{{cite journal | vauthors = Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, He Y, Burrall B, Duong C, Kloxin AM, Sultani H, Wilken R, Martinez SR, Patel F | title = Metastatic melanoma - a review of current and future treatment options | journal = Acta Dermato-Venereologica | volume = 95 | issue = 5 | pages = 516–524 | date = May 2015 | pmid = 25520039 | doi = 10.2340/00015555-2035 | doi-access = free | url = https://digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=4849&context=open_access_pubs }} Melanoma tumors can develop resistance during therapy which can make therapy no longer effective, but combining the use of BRAF and MEK inhibitors may create a fast and lasting melanoma therapy response.{{cite journal | vauthors = Kuske M, Westphal D, Wehner R, Schmitz M, Beissert S, Praetorius C, Meier F | title = Immunomodulatory effects of BRAF and MEK inhibitors: Implications for Melanoma therapy | journal = Pharmacological Research | volume = 136 | pages = 151–159 | date = October 2018 | pmid = 30145328 | doi = 10.1016/j.phrs.2018.08.019 | s2cid = 207369519 | doi-access = free }}

A number of treatments improve survival over traditional chemotherapy. Biochemotherapy (chemotherapy with cytokines IL-2 and IFN-α) combined with BRAF inhibitors improved survival for people with BRAF positive melanoma. Biochemotherapy alone did not improve overall survival and had higher toxicity than chemotherapy. Combining multiple chemotherapy agents (polychemotherapy) did not improve survival over monochemotherapy. Targeted therapies result in relatively short progression-free survival (PFS) times. The therapy combination of dabrafenib and trametinib has a 3-year PFS of 23%, and 5-year PFS of 13%.

Lifileucel (Amtagvi) is a tumor-derived autologous T cell immunotherapy that was approved for medical use in the United States in February 2024.{{cite press release | title=FDA Approves First Cellular Therapy to Treat Patients with Unresectable or Metastatic Melanoma | website=U.S. Food and Drug Administration | date=16 February 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma | archive-url=https://web.archive.org/web/20240216230351/https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma | url-status=dead | archive-date=16 February 2024 | access-date=18 February 2024}}{{cite press release | title=Iovance's Amtagvi (lifileucel) Receives U.S. FDA Accelerated Approval for Advanced Melanoma | publisher=Iovance Biotherapeutics Inc | via=GlobeNewswire | date=16 February 2024 | url=https://www.globenewswire.com/news-release/2024/02/16/2830923/0/en/Iovance-s-AMTAGVI-lifileucel-Receives-U-S-FDA-Accelerated-Approval-for-Advanced-Melanoma.html | access-date=18 February 2024}}

Immunotherapy is aimed at stimulating the person's immune system against the tumor, by enhancing the body's own ability to recognize and kill cancer cells.{{cite journal | vauthors = Sanlorenzo M, Vujic I, Posch C, Dajee A, Yen A, Kim S, Ashworth M, Rosenblum MD, Algazi A, Osella-Abate S, Quaglino P, Daud A, Ortiz-Urda S | title = Melanoma immunotherapy | journal = Cancer Biology & Therapy | volume = 15 | issue = 6 | pages = 665–674 | date = June 2014 | pmid = 24651672 | pmc = 4049781 | doi = 10.4161/cbt.28555 }} The current approach to treating melanoma with immunotherapy includes three broad categories of treatments including cytokines, immune check point inhibitors, and adoptive cell transfer. These treatment options are most often used in people with metastatic melanoma and significantly improves overall survival. However, these treatments are often costly. For example, one immune check point inhibitor treatment, pembrolizumab, costs US$10,000 to $12,000 for a single dose administered every 3 weeks.{{cite journal | vauthors = Dranitsaris G, Zhu X, Adunlin G, Vincent MD | title = Cost effectiveness vs. affordability in the age of immuno-oncology cancer drugs | journal = Expert Review of Pharmacoeconomics & Outcomes Research | volume = 18 | issue = 4 | pages = 351–357 | date = August 2018 | pmid = 29681201 | doi = 10.1080/14737167.2018.1467270 | s2cid = 5079628 }}

Cytokine therapies used for melanoma include IFN-a and IL-2.{{cite journal | vauthors = West HJ | title = JAMA Oncology Patient Page. Immune Checkpoint Inhibitors | journal = JAMA Oncology | volume = 1 | issue = 1 | pages = 115 | date = April 2015 | pmid = 26182315 | doi = 10.1001/jamaoncol.2015.0137 | doi-access = }} IL-2 (Proleukin) was the first new therapy approved (1990 EU, 1992 US) for the treatment of metastatic melanoma in 20 years.{{Cite web |title=Interleukin-2 (IL2) for Metastatic Melanoma |url=https://www.curemelanoma.org/patient-eng/melanoma-treatment/immunotherapy/interleukin-2-il-2-proleukin/ |access-date=5 October 2022 |website=Melanoma Research Alliance |language=en-US}} IL-2 may offer the possibility of a complete and long-lasting remission in this disease in a small percentage of people with melanoma.{{cite journal | vauthors = Buzaid AC | title = Management of metastatic cutaneous melanoma | journal = Oncology | volume = 18 | issue = 11 | pages = 1443–50; discussion 1457–9 | date = October 2004 | pmid = 15609471 }} Intralesional IL-2 for in-transit metastases has a high complete response rate ranging from 40 to 100%. Similarly, IFN-a has shown only modest survival benefits and high toxicity, limiting its use as a stand-alone therapy.

Immune check point inhibitors include anti-CTLA-4 monoclonal antibodies (ipilimumab and tremelimumab), toll-like receptor (TLR) agonists, CD40 agonists, anti-PD-1 (pembrolizumab, pidilizumab, and nivolumab) and PD-L1 antibodies. Evidence suggests that anti-PD-1 antibodies are more effective than anti-CTLA4 antibodies with less systemic toxicity. The five-year progression-free survival for immunotherapy with pembrolizumab is 21%. A therapeutic approach that includes the combination of different therapies improves overall survival and progression-free survival compared to treatment with the separate immunotherapy drugs alone.

Ongoing research is looking at treatment by adoptive cell transfer.{{cite journal | vauthors = Rosenberg SA, Restifo NP | title = Adoptive cell transfer as personalized immunotherapy for human cancer | journal = Science | volume = 348 | issue = 6230 | pages = 62–68 | date = April 2015 | pmid = 25838374 | pmc = 6295668 | doi = 10.1126/science.aaa4967 | bibcode = 2015Sci...348...62R }} Adoptive cell transfer refers to the application of pre-stimulated, modified T cells or dendritic cells and is presently used to minimize complications from graft-versus-host disease.{{cite journal | vauthors = Zang YW, Gu XD, Xiang JB, Chen ZY | title = Clinical application of adoptive T cell therapy in solid tumors | journal = Medical Science Monitor | volume = 20 | pages = 953–959 | date = June 2014 | pmid = 24912947 | pmc = 4063985 | doi = 10.12659/msm.890496 }}

The combination nivolumab/relatlimab (Opdualag) was approved for medical use in the United States in March 2022.{{cite press release | title=U.S. Food and Drug Administration Approves First LAG-3-Blocking Antibody Combination, Opdualag (nivolumab and relatlimab-rmbw), as Treatment for Patients with Unresectable or Metastatic Melanoma | publisher=Bristol Myers Squibb | via=Business Wire | date=18 March 2022 | url=https://www.businesswire.com/news/home/20220304005561/en/U.S.-Food-and-Drug-Administration-Approves-First-LAG-3-Blocking-Antibody-Combination-Opdualag%E2%84%A2-nivolumab-and-relatlimab-rmbw-as-Treatment-for-Patients-with-Unresectable-or-Metastatic-Melanoma | access-date=19 March 2022 | archive-date=19 March 2022 | archive-url=https://web.archive.org/web/20220319212135/https://www.businesswire.com/news/home/20220304005561/en/U.S.-Food-and-Drug-Administration-Approves-First-LAG-3-Blocking-Antibody-Combination-Opdualag%E2%84%A2-nivolumab-and-relatlimab-rmbw-as-Treatment-for-Patients-with-Unresectable-or-Metastatic-Melanoma | url-status=live }}

Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceedingly high (up to 50%). This is due to the ill-defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation of the standard "bread-loafing" technique of fixed tissue histology – result in a high "false negative" error rate, and frequent recurrences. Margin control (peripheral margins) is necessary to eliminate the false negative errors. If bread loafing is used, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control. A meta-analysis of the literature in 2014 found no randomized controlled trials of surgical interventions to treat lentigo maligna or melanoma in-situ, even though surgery is the most widely used treatment.{{cite journal | vauthors = Tzellos T, Kyrgidis A, Mocellin S, Chan AW, Pilati P, Apalla Z | title = Interventions for melanoma in situ, including lentigo maligna | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 12 | pages = CD010308 | date = December 2014 | pmid = 25526608 | doi = 10.1002/14651858.CD010308.pub2 | pmc = 11005944 }}

Mohs surgery has been done with cure rate reported to be as low as 77%, and as high as 95% by another author. The "double scalpel" peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods.{{cite journal | vauthors = Johnson TM, Headington JT, Baker SR, Lowe L | title = Usefulness of the staged excision for lentigo maligna and lentigo maligna melanoma: the "square" procedure | journal = Journal of the American Academy of Dermatology | volume = 37 | issue = 5 Pt 1 | pages = 758–764 | date = November 1997 | pmid = 9366823 | doi = 10.1016/S0190-9622(97)70114-2 }}

Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. Some derma-surgeons are combining the two methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months. While some studies have suggested the adjuvant use of topical tazarotene, the current evidence is insufficient to recommend it and suggests that it increases topical inflammation, leading to lower patient compliance.

Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with un-resectable distant metastases. Kilovoltage x-ray beams are often used for these treatments and have the property of the maximum radiation dose occurring close to the skin surface.{{cite journal | vauthors = Hill R, Healy B, Holloway L, Kuncic Z, Thwaites D, Baldock C | title = Advances in kilovoltage x-ray beam dosimetry | journal = Physics in Medicine and Biology | volume = 59 | issue = 6 | pages = R183–R231 | date = March 2014 | pmid = 24584183 | doi = 10.1088/0031-9155/59/6/r183 | s2cid = 18082594 | bibcode = 2014PMB....59R.183H }} It may reduce the rate of local recurrence but does not prolong survival.{{cite journal | vauthors = Bastiaannet E, Beukema JC, Hoekstra HJ | title = Radiation therapy following lymph node dissection in melanoma patients: treatment, outcome and complications | journal = Cancer Treatment Reviews | volume = 31 | issue = 1 | pages = 18–26 | date = February 2005 | pmid = 15707701 | doi = 10.1016/j.ctrv.2004.09.005 }} Radioimmunotherapy of metastatic melanoma is currently under investigation.

Radiotherapy has a role in the palliation of metastatic melanoma.{{cite book | vauthors = Ford MB, Mitchell MF, Boyer KL, Ford MB, Judkins AF, Levin B | chapter = Cancer Epidemiology | title = Primary Care Oncology | date = 1999 | pages = 1–27 }}

File:Diagram showing the most common places for melanoma to spread to CRUK 312.svg

File:5YearSurvival2008to14.jpg

Factors that affect prognosis include:

• tumor thickness in millimeters (Breslow's depth),
• depth related to skin structures (Clark level),
• type of melanoma,
• presence of ulceration,
• presence of lymphatic/perineural invasion,
• presence of tumor-infiltrating lymphocytes (if present, prognosis is better),
• location of lesion,
• presence of satellite lesions, and
• presence of regional or distant metastasis.{{cite journal | vauthors = Homsi J, Kashani-Sabet M, Messina JL, Daud A | title = Cutaneous melanoma: prognostic factors | journal = Cancer Control | volume = 12 | issue = 4 | pages = 223–229 | date = October 2005 | pmid = 16258493 | doi = 10.1177/107327480501200403 | doi-access = free }}

Certain types of melanoma have worse prognoses but this is explained by their thickness. Less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.

When melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. Extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic have a more favorable prognosis than macrometastases. In some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely employed test known as the polymerase chain reaction (PCR), the prognosis is better. Macro-metastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extracapsular extension, the prognosis is worse still. In addition to these variables, expression levels and copy number variations of a number of relevant genes may be used to support assessment of melanoma prognosis.{{cite journal | vauthors = van Kempen LC, Redpath M, Robert C, Spatz A | title = Molecular pathology of cutaneous melanoma | journal = Melanoma Management | volume = 1 | issue = 2 | pages = 151–164 | date = November 2014 | pmid = 30190820 | pmc = 6094595 | doi = 10.2217/mmt.14.23 }}{{cite journal | vauthors = Brunner G, Reitz M, Heinecke A, Lippold A, Berking C, Suter L, Atzpodien J | title = A nine-gene signature predicting clinical outcome in cutaneous melanoma | journal = Journal of Cancer Research and Clinical Oncology | volume = 139 | issue = 2 | pages = 249–258 | date = February 2013 | pmid = 23052696 | doi = 10.1007/s00432-012-1322-z | s2cid = 20257709 }}

Stage IV melanoma, in which it has metastasized, is the most deadly skin malignancy: five-year survival is 22.5%.{{cite journal|doi=10.1146/annurev-cancerbio-030419-033533|doi-access=free|title=Nongenetic Mechanisms of Drug Resistance in Melanoma|year=2020| vauthors = Rebecca VW, Herlyn M |journal=Annual Review of Cancer Biology|volume=4|pages=315–330}} When there is distant metastasis, the cancer is generally considered incurable. The five-year survival rate is less than 10%.{{cite journal | vauthors = Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, Fleming ID, Gershenwald JE, Houghton A, Kirkwood JM, McMasters KM, Mihm MF, Morton DL, Reintgen DS, Ross MI, Sober A, Thompson JA, Thompson JF | title = Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma | journal = Journal of Clinical Oncology | volume = 19 | issue = 16 | pages = 3635–3648 | date = August 2001 | pmid = 11504745 | doi = 10.1200/JCO.2001.19.16.3635 | url = http://www.jco.org/cgi/content/full/19/16/3635 | url-status = dead | access-date = 31 July 2006 | citeseerx = 10.1.1.475.6560 | archive-url = https://web.archive.org/web/20060305151011/http://www.jco.org/cgi/content/full/19/16/3635 | archive-date = 5 March 2006 }} The median survival is 6–12 months. Treatment is palliative, focusing on life extension and quality of life. In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis. Survival is better with metastasis in which the location of the primary tumor is unknown.{{cite journal | vauthors = Bae JM, Choi YY, Kim DS, Lee JH, Jang HS, Lee JH, Kim H, Oh BH, Roh MR, Nam KA, Chung KY | title = Metastatic melanomas of unknown primary show better prognosis than those of known primary: a systematic review and meta-analysis of observational studies | journal = Journal of the American Academy of Dermatology | volume = 72 | issue = 1 | pages = 59–70 | date = January 2015 | pmid = 25440435 | doi = 10.1016/j.jaad.2014.09.029 }}

There is not enough definitive evidence to adequately stage, and thus give a prognosis for, ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g., rectal melanoma), although these tend to metastasize more easily. Even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a pathology report might indicate.

About 200 genes are prognostic in melanoma, with both unfavorable genes where high expression is correlated to poor survival and favorable genes where high expression is associated with longer survival times. Examples of unfavorable genes are MCM6 and TIMELESS; an example of a favorable gene is WIPI1.

An increased neutrophil-to-lymphocyte ratio is associated with worse outcomes.{{cite journal | vauthors = Zhan H, Ma JY, Jian QC | title = Prognostic significance of pretreatment neutrophil-to-lymphocyte ratio in melanoma patients: A meta-analysis | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 484 | pages = 136–140 | date = September 2018 | pmid = 29856976 | doi = 10.1016/j.cca.2018.05.055 | s2cid = 44155588 }}{{cite journal | vauthors = Wade RG, Robinson AV, Lo MC, Keeble C, Marples M, Dewar DJ, Moncrieff MD, Peach H | title = Baseline Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios as Biomarkers of Survival in Cutaneous Melanoma: A Multicenter Cohort Study | journal = Annals of Surgical Oncology | volume = 25 | issue = 11 | pages = 3341–3349 | date = October 2018 | pmid = 30066226 | pmc = 6132419 | doi = 10.1245/s10434-018-6660-x | doi-access = free }}{{cite journal | vauthors = Robinson AV, Keeble C, Lo MC, Thornton O, Peach H, Moncrieff MD, Dewar DJ, Wade RG | title = The neutrophil-lymphocyte ratio and locoregional melanoma: a multicentre cohort study | journal = Cancer Immunology, Immunotherapy | volume = 69 | issue = 4 | pages = 559–568 | date = April 2020 | pmid = 31974724 | pmc = 7113207 | doi = 10.1007/s00262-019-02478-7 | doi-access = free }}

File:Worldwide Melanoma of Skin Cancer Incidence - 2008 Globocan.svg new cases per year of melanoma of the skin per 100,000 inhabitants in 2008{{cite web|url=http://www-dep.iarc.fr/|title=CANCERMondial (GLOBOCAN)|year=2010|website=GLOBOCAN|access-date=12 August 2010|url-status=live|archive-url=https://web.archive.org/web/20120217163455/http://www-dep.iarc.fr/|archive-date=17 February 2012}}{{Div col|small=yes|colwidth=10em}}

{{legend|#b3b3b3|no data}}

{{legend|#ffff65|less than 1.75}}

{{legend|#fff200|1.76–3.50}}

{{legend|#ffdc00|3.51–5.25}}

{{legend|#ffc600|5.26–7.00}}

{{legend|#ffb000|7.01–8.75}}

{{legend|#ff9a00|8.76–10.50}}

{{legend|#ff8400|10.51–12.25}}

{{legend|#ff6e00|12.26–14.00}}

{{legend|#ff5800|14.01–15.75}}

{{legend|#ff4200|15.76–17.50}}

{{legend|#ff2c00|17.76–19.25}}

{{legend|#cb0000|more than 19.25}}

{{div col end}}]]

File:Melanoma and other skin cancers world map-Deaths per million persons-WHO2012.svg

Globally, in 2012, melanoma occurred in 232,000 people and resulted in 55,000 deaths. Australia and New Zealand have the highest rates of melanoma in the world. It has become more common in the last 20 years in areas that are mostly Caucasian.

The rate of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved.{{cite journal | vauthors = Berwick M, Wiggins C | title = The current epidemiology of cutaneous malignant melanoma | journal = Frontiers in Bioscience | volume = 11 | pages = 1244–1254 | date = May 2006 | pmid = 16368510 | doi = 10.2741/1877 | doi-access = free }}

Australia has a very high – and increasing – rate of melanoma. In 2012, deaths from melanoma occurred in 7.3–9.8 per 100,000 population. In Australia, melanoma is the third most common cancer in either sex; indeed, its incidence is higher than for lung cancer, although the latter accounts for more deaths. It is estimated that in 2012, more than 12,000 Australians were diagnosed with melanoma: given Australia's modest population, this is better expressed as 59.6 new cases per 100,000 population per year; >1 in 10 of all new cancer cases were melanomas.{{cite web|url=http://aihw.gov.au/cancer/cancer-in-australia-overview-2012/|title=Cancer in Australia: an overview 2012|publisher=AIHW|url-status=dead|archive-url=https://web.archive.org/web/20140602195619/http://aihw.gov.au/cancer/cancer-in-australia-overview-2012/|archive-date=2 June 2014|access-date=1 June 2014}} Melanoma incidence in Australia is matter of significance, for the following reasons:

• Australian melanoma incidence has increased by more than 30 per cent between 1991 and 2009.
• Australian melanoma age-standardized incidence rates were, as of 2008, at least 12 times higher than the world average.
• Australian melanoma incidence is, by some margin, the highest in the world.
• Overall age-standardized cancer incidence in Australia is the highest in the world, and this is attributable to melanoma alone. Age-standardized overall cancer incidence is similar to New Zealand, but there is a statistically significant difference between Australia and all other parts of the developed world including North America, Western Europe, and the Mediterranean.

{{Bar box|title=Melanoma rates by race and ethnicity in the US|titlebar=#DDD|left1=Race|right2=|width=240px|bars={{bar pixel|White|pink|25}}

{{bar pixel|American Indian|goldenrod|5}}

{{bar pixel|Mexican|tan|4}}

{{bar pixel|Asian|brown|1}}

{{bar pixel|Black|black|1|}}|caption=Melanomas diagnosed in the US per 100,000 people in 2018.U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on 2020 submission data (1999-2018): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; www.cdc.gov/cancer/dataviz, released in June 2021. Melanomas affect white people much more often than people in any other racial or ethnic classification.|float=right|barwidth=50px}}In the United States, about 9,000 people die from melanoma a year. In 2011, it affected 19.7 per 100,000, and resulted in death in 2.7 per 100,000.{{cite journal | vauthors = Guy GP, Thomas CC, Thompson T, Watson M, Massetti GM, Richardson LC | title = Vital signs: melanoma incidence and mortality trends and projections - United States, 1982-2030 | journal = MMWR. Morbidity and Mortality Weekly Report | volume = 64 | issue = 21 | pages = 591–596 | date = June 2015 | pmid = 26042651 | pmc = 4584771 | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6421a6.htm | url-status = live | archive-url = https://web.archive.org/web/20170531141344/https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6421a6.htm | archive-date = 31 May 2017 }}

In 2013:

• 71,943 people in the United States were diagnosed with melanomas of the skin, including 42,430 men and 29,513 women.
• 9,394 people in the United States died from melanomas of the skin, including 6,239 men and 3,155 women.{{cite web|url=https://www.cdc.gov/cancer/skin/statistics/|title=CDC – Skin Cancer Statistics|website=www.cdc.gov |access-date=10 April 2017|url-status=live|archive-url=https://web.archive.org/web/20170410214142/https://www.cdc.gov/cancer/skin/statistics/|archive-date=10 April 2017}}

The American Cancer Society's estimates for melanoma incidence in the United States for 2017 are:

• About 87,110 new melanomas will be diagnosed (about 52,170 in men and 34,940 in women).
• About 9,730 people are expected to die of melanoma (about 6,380 men and 3,350 women).

Melanoma is more than 20 times more common in whites than in African Americans. Overall, the lifetime risk of getting melanoma is about 2.5% (1 in 40) for whites, 0.1% (1 in 1,000) for African Americans, and 0.5% (1 in 200) for Mexicans.

The risk of melanoma increases as people age. The average age of people when the disease is diagnosed is 63.{{cite web|url=https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html|title=Key Statistics for Melanoma Skin Cancer|website=www.cancer.org|access-date=10 April 2017|url-status=live|archive-url=https://web.archive.org/web/20170410135926/https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html|archive-date=10 April 2017}}

Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However, one example lies in a 1960s examination of nine Peruvian mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones.{{cite journal | vauthors = Urteaga O, Pack GT | title = On the antiquity of melanoma | journal = Cancer | volume = 19 | issue = 5 | pages = 607–610 | date = May 1966 | pmid = 5326247 | doi = 10.1002/1097-0142(196605)19:5<607::AID-CNCR2820190502>3.0.CO;2-8 | doi-access = free }}

John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not knowing precisely what it was, he described it as a "cancerous fungous excrescence". The excised tumor was preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma.{{cite journal | vauthors = Bodenham DC | title = A study of 650 observed malignant melanomas in the South-West region | journal = Annals of the Royal College of Surgeons of England | volume = 43 | issue = 4 | pages = 218–239 | date = October 1968 | pmid = 5698493 | pmc = 2312310 }}

The French physician René Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculté de Médecine de Paris in 1804 and then published as a bulletin in 1806.{{cite journal | vauthors = Laennec RT |year= 1806 |title= Sur les melanoses |journal= Bulletin de la Faculté de Médecine de Paris |volume= 1 |pages= 24–26}}

The first English-language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820.{{cite journal | vauthors = Norris W | title = Case of Fungoid Disease | journal = Edinburgh Medical and Surgical Journal | volume = 16 | issue = 65 | pages = 562–565 | date = October 1820 | pmid = 30332089 | pmc = 5830209 }} In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and Therapeutical Remarks on That Disease). Norris was also a pioneer in suggesting a link between nevi and melanoma and the possibility of a relationship between melanoma and environmental exposures, by observing that most of his patients had pale complexions.Norris W. Eight cases of Melanosis with pathological and therapeutical remarks on that disease. London: Longman; 1857. He also described that melanomas could be amelanotic and later showed the metastatic nature of melanoma by observing that they can disseminate to other visceral organs.

The first formal acknowledgment of advanced melanoma as untreatable came from Samuel Cooper in 1840. He stated that the only chance for a cure depends upon the early removal of the disease (i.e., early excision of the malignant mole) ...'{{cite book| vauthors = Cooper S |title=The First Lines of the Theory and Practice of Surgery: Including the Principle Operations|url=https://books.google.com/books?id=hgE0AQAAMAAJ|year=1844|publisher=S.S. and W. Wood|access-date=14 December 2017|archive-date=4 August 2021|archive-url=https://web.archive.org/web/20210804234929/https://books.google.com/books?id=hgE0AQAAMAAJ|url-status=live}}

More than one and a half centuries later this situation remains largely unchanged.

The word melanoma came to English from 19th-century Neo-Latin{{Citation |author=Merriam-Webster |author-link=Merriam-Webster |title=Merriam-Webster's Collegiate Dictionary |publisher=Merriam-Webster |url=http://unabridged.merriam-webster.com/collegiate/ |access-date=20 July 2018 |archive-date=10 October 2020 |archive-url=https://web.archive.org/web/20201010163505/https://unabridged.merriam-webster.com/subscriber/login?redirect_to=%2Fcollegiate%2F |url-status=dead }} and uses combining forms derived from ancient Greek roots: melano- (denoting melanin) + -oma (denoting a tissue mass and especially a neoplasm), in turn from Greek μέλας melas, "dark",{{cite web | vauthors = Liddell HG, Scott R | url = https://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dme%2Flas | title = μέλας | archive-url = https://web.archive.org/web/20110605183904/http://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dme%2Flas | archive-date = 5 June 2011| work = A Greek-English Lexicon | publisher = Perseus }} and -ωμα oma, "process". The word melanoma has a long history of being used in a broader sense to refer to any melanocytic tumor, typically, but not always malignant,{{cite web |title=Dorland's Illustrated Medical Dictionary |publisher=Elsevier |url=http://dorlands.com/ |access-date=20 July 2018 |archive-date=11 January 2014 |archive-url=https://web.archive.org/web/20140111192614/http://dorlands.com/ |url-status=live }}{{cite web |title=The American Heritage Dictionary of the English Language |publisher=Houghton Mifflin Harcourt |url=https://ahdictionary.com/ |access-date=20 July 2018 |archive-date=25 September 2015 |archive-url=https://web.archive.org/web/20150925104737/https://ahdictionary.com/ |url-status=live }} but today the narrower sense referring only to malignant types has become so dominant that benign tumors are usually not called melanomas anymore and the word melanoma is now usually taken to mean malignant melanoma unless otherwise specified. Terms such as "benign melanocytic tumor" unequivocally label the benign types, and modern histopathologic tumor classifications used in medicine do not use the word for benign tumors.

Pharmacotherapy research for un-resectable or metastatic melanoma is ongoing.{{cite journal|title=Drugs in Clinical Development for Melanoma|journal=Pharmaceutical Medicine|date=23 December 2012|volume=26|issue=3|pages=171–83|doi=10.1007/BF03262391|url=http://adisonline.com/pharmaceuticalmedicine/Abstract/2012/26030/Drugs_in_Clinical_Development_for_Melanoma__.4.aspx|s2cid=13247048|access-date=12 June 2012|archive-date=1 January 2013|archive-url=https://archive.today/20130101232227/http://adisonline.com/pharmaceuticalmedicine/Abstract/2012/26030/Drugs_in_Clinical_Development_for_Melanoma__.4.aspx|url-status=dead|url-access=subscription}}

In clinical research, adoptive cell therapy and gene therapy, are being tested.{{cite journal | vauthors = Sotomayor MG, Yu H, Antonia S, Sotomayor EM, Pardoll DM | title = Advances in gene therapy for malignant melanoma | journal = Cancer Control | volume = 9 | issue = 1 | pages = 39–48 | year = 2002 | pmid = 11907465 | doi = 10.1177/107327480200900106 | doi-access = }}

Two kinds of experimental treatments developed at the National Cancer Institute (NCI), have been used in metastatic melanoma with tentative success.{{cite journal | vauthors = Hershkovitz L, Schachter J, Treves AJ, Besser MJ | title = Focus on adoptive T cell transfer trials in melanoma | journal = Clinical & Developmental Immunology | volume = 2010 | pages = 260267 | year = 2010 | pmid = 21234353 | pmc = 3018069 | doi = 10.1155/2010/260267 | doi-access = free }}

The first treatment involves adoptive cell therapy (ACT) using TILs immune cells (tumor-infiltrating lymphocytes) isolated from a person's own melanoma tumor. These cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily reduces normal T cells in the patient's body. TIL therapy following lymphodepletion can result in durable complete response in a variety of setups.{{cite journal | vauthors = Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA | title = Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens | journal = Journal of Clinical Oncology | volume = 26 | issue = 32 | pages = 5233–5239 | date = November 2008 | pmid = 18809613 | pmc = 2652090 | doi = 10.1200/JCO.2008.16.5449 }}{{cite journal | vauthors = Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, Levy D, Kubi A, Hovav E, Chermoshniuk N, Shalmon B, Hardan I, Catane R, Markel G, Apter S, Ben-Nun A, Kuchuk I, Shimoni A, Nagler A, Schachter J | title = Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients | journal = Clinical Cancer Research | volume = 16 | issue = 9 | pages = 2646–2655 | date = May 2010 | pmid = 20406835 | doi = 10.1158/1078-0432.CCR-10-0041 | url = https://aacr.figshare.com/articles/journal_contribution/Supplementary_Data_from_Clinical_Responses_in_a_Phase_II_Study_Using_Adoptive_Transfer_of_Short-term_Cultured_Tumor_Infiltration_Lymphocytes_in_Metastatic_Melanoma_Patients/22442211/1/files/39893097.pdf | access-date = 15 August 2011 | s2cid = 32568 | doi-access = free }}

The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.{{cite web|url=http://www.nih.gov/news/pr/aug2006/nci-31b.htm|title=New Method of Gene Therapy Alters Immune Cells for Treatment of Advanced Melanoma; Technique May Also Apply to Other Common Cancers|date=30 December 2015|url-status=live|archive-url=https://web.archive.org/web/20060928214625/http://www.nih.gov/news/pr/aug2006/nci-31b.htm|archive-date=28 September 2006}}

A cancer vaccine showed modest benefit in late-stage testing in 2009 against melanoma.{{cite news |title=Immune System Taught To Fight Melanoma |date=30 May 2009 |publisher=CBSNews |url=https://www.cbsnews.com/news/immune-system-taught-to-fight-melanoma/ |url-status=live |archive-url=https://web.archive.org/web/20101029214646/http://www.cbsnews.com/stories/2009/05/30/health/main5050957.shtml |archive-date=29 October 2010 }}{{cite journal | vauthors = Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P | title = gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma | journal = The New England Journal of Medicine | volume = 364 | issue = 22 | pages = 2119–2127 | date = June 2011 | pmid = 21631324 | pmc = 3517182 | doi = 10.1056/NEJMoa1012863 }}

About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggested that B-Raf inhibitors including Plexxicon's vemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation.{{cite news |url=https://www.nytimes.com/2010/02/22/health/research/22trial.html |work=The New York Times |title=A Roller Coaster Chase for a Cure | vauthors = Harmon A |date=21 February 2010 |url-status=live |archive-url=https://web.archive.org/web/20170210085433/http://www.nytimes.com/2010/02/22/health/research/22trial.html |archive-date=10 February 2017 }} In June 2011, a large clinical trial confirmed the positive findings from those earlier trials.{{cite news|work=The New York Times| vauthors = Pollack A |date=5 June 2011|title=Drugs Show Promise Slowing Advanced Melanoma|url=https://www.nytimes.com/2011/06/06/health/research/06melanoma.html|url-status=live|archive-url=https://web.archive.org/web/20170131105246/http://www.nytimes.com/2011/06/06/health/research/06melanoma.html|archive-date=31 January 2017}}{{cite journal | vauthors = Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA | title = Improved survival with vemurafenib in melanoma with BRAF V600E mutation | journal = The New England Journal of Medicine | volume = 364 | issue = 26 | pages = 2507–2516 | date = June 2011 | pmid = 21639808 | pmc = 3549296 | doi = 10.1056/NEJMoa1103782 }}

In August 2011, Vemurafenib received FDA approval for the treatment of late-stage melanoma. In May 2013 the US FDA approved dabrafenib as a single agent treatment for patients with BRAF V600E mutation-positive advanced melanoma.{{cite news |url= https://www.reuters.com/article/us-glaxosmithkline-approvals-idUSBRE94S1A020130530 |title= GSK melanoma drugs add to tally of U.S. drug approvals |publisher= Reuters |date= 30 May 2013 |url-status= live |archive-url= https://web.archive.org/web/20150924181713/http://www.reuters.com/article/2013/05/30/us-glaxosmithkline-approvals-idUSBRE94S1A020130530 |archive-date= 24 September 2015 }}

Some researchers believe that combination therapies that simultaneously block multiple pathways may improve efficacy by making it more difficult for the tumor cells to mutate before being destroyed. In October 2012 a study reported that combining Dabrafenib with a MEK inhibitor trametinib led to even better outcomes. Compared to Dabrafenib alone, progression-free survival was increased to 41% from 9%, and the median progression-free survival increased to 9.4 months versus 5.8 months. Some side effects were, however, increased in the combined study.{{cite news|publisher=News Medical|date=1 October 2012|title=Combination of dabrafenib and trametinib delays development of treatment resistance in MM patients|url=http://www.news-medical.net/news/20121001/Combination-of-dabrafenib-and-trametinib-delays-development-of-treatment-resistance-in-MM-patients.aspx?page=2|url-status=live|archive-url=https://web.archive.org/web/20130514034005/http://www.news-medical.net/news/20121001/Combination-of-dabrafenib-and-trametinib-delays-development-of-treatment-resistance-in-MM-patients.aspx?page=2|archive-date=14 May 2013}}{{cite journal | vauthors = Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J | title = Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations | journal = The New England Journal of Medicine | volume = 367 | issue = 18 | pages = 1694–1703 | date = November 2012 | pmid = 23020132 | pmc = 3549295 | doi = 10.1056/NEJMoa1210093 }}

In January 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of people with BRAF V600E/K-mutant metastatic melanoma.{{cite news |url= http://www.onclive.com/web-exclusives/FDA-Approves-First-Ever-Combination-for-Metastatic-Melanoma |title= Dabrafenib/Trametinib Combination Approved for Advanced Melanoma |publisher= OncLive |date= 9 January 2014 |url-status= dead |archive-url= https://web.archive.org/web/20140125190539/http://www.onclive.com/web-exclusives/FDA-Approves-First-Ever-Combination-for-Metastatic-Melanoma |archive-date= 25 January 2014 |access-date= 4 February 2015 }} In June 2018, the FDA approved the combination of a BRAF inhibitor encorafenib and a MEK inhibitor binimetinib for the treatment of un-resectable or metastatic melanoma with a BRAF V600E or V600K mutation.{{cite journal | vauthors = Shirley M | title = Encorafenib and Binimetinib: First Global Approvals | journal = Drugs | volume = 78 | issue = 12 | pages = 1277–1284 | date = August 2018 | pmid = 30117021 | doi = 10.1007/s40265-018-0963-x | s2cid = 52020890 }}

Eventual resistance to BRAF and MEK inhibitors may be due to a cell surface protein known as EphA2 which is now being investigated.{{cite web |url=http://www.oncotherapynetwork.com/skin-cancer-melanoma-targets/counteracting-drug-resistance-melanoma |title=Counteracting Drug Resistance in Melanoma |year=2015 |url-status=live |archive-url=https://web.archive.org/web/20150204044952/http://www.oncotherapynetwork.com/skin-cancer-melanoma-targets/counteracting-drug-resistance-melanoma |archive-date=4 February 2015 }}

At the American Society of Clinical Oncology Conference in June 2010, the Bristol Myers Squibb pharmaceutical company reported the clinical findings of their drug ipilimumab. The study found an increase in median survival from 6.4 to 10 months in patients with advanced melanomas treated with the monoclonal ipilimumab, versus an experimental vaccine. It also found a one-year survival rate of 25% in the control group using the vaccine, 44% in the vaccine and ipilimumab group, and 46% in the group treated with ipilimumab alone.{{cite news |title= Bristol drug cuts death risk in advanced melanoma |url= https://www.reuters.com/article/idUSN0218461520100605 |work= Reuters |date= 5 June 2010 |url-status= live |archive-url= https://web.archive.org/web/20101109095301/http://www.reuters.com/article/idUSN0218461520100605 |archive-date= 9 November 2010 }} However, some have raised concerns about this study for its use of the unconventional control arm, rather than comparing the drug against a placebo or standard treatment.{{cite news |url=https://blogs.forbes.com/sciencebiz/2010/06/the-risk-for-bristol/ |title=The Risk For Bristol |work=Forbes |url-status=dead |archive-url=https://web.archive.org/web/20110315041905/http://blogs.forbes.com/sciencebiz/2010/06/06/the-risk-for-bristol/ |archive-date=15 March 2011}}{{cite web |url=http://www.news-medical.net/news/20100609/Phase-3-clinical-study-Ipilimumab-boosts-sustains-immune-system-responses-against-melanoma-tumors.aspx |title=Phase 3 clinical study: Ipilimumab boosts, sustains immune system responses against melanoma tumors |publisher=News-medical.net |date=9 June 2010 |access-date=13 August 2012 |url-status=live |archive-url=https://web.archive.org/web/20121019003945/http://www.news-medical.net/news/20100609/Phase-3-clinical-study-Ipilimumab-boosts-sustains-immune-system-responses-against-melanoma-tumors.aspx |archive-date=19 October 2012 }} The criticism was that although Ipilimumab performed better than the vaccine, the vaccine has not been tested before and may be causing toxicity, making the drug appear better by comparison.

Ipilimumab was approved by the FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery.{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm |title=FDA approves new treatment for a type of late-stage skin cancer | vauthors = Jefferson E |date=25 March 2011 |publisher=U.S. Food and Drug Administration (FDA) |access-date=25 March 2011 |url-status=dead |archive-url=https://web.archive.org/web/20110327063147/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm |archive-date=27 March 2011 }}{{cite news |url=https://www.nytimes.com/2011/03/26/business/26drug.html |title=Approval for Drug That Treats Melanoma | vauthors = Pollack A |date=25 March 2011 |work=The New York Times |access-date=27 March 2011 |url-status=live |archive-url= https://web.archive.org/web/20110401011816/http://www.nytimes.com/2011/03/26/business/26drug.html |archive-date=1 April 2011 }}{{cite web | work = Drugs.com | url = https://www.drugs.com/yervoy.html | title = Yervoy | archive-url = https://web.archive.org/web/20110809231412/http://www.drugs.com/yervoy.html | archive-date=9 August 2011}}

In June 2011, a clinical trial of ipilimumab plus dacarbazine combined this immune system booster with the standard chemotherapy drug that targets cell division. It showed an increase in median survival for these late stage patients to 11 months instead of the 9 months normally seen. Researchers were also hopeful of improving the five year survival rate, though serious adverse side-effects were seen in some patients. A course of treatment costs $120,000. The drug's brandname is Yervoy.{{cite journal | vauthors = Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD | title = Ipilimumab plus dacarbazine for previously untreated metastatic melanoma | journal = The New England Journal of Medicine | volume = 364 | issue = 26 | pages = 2517–2526 | date = June 2011 | pmid = 21639810 | doi = 10.1056/NEJMoa1104621 | doi-access = free }}

Advances in high resolution ultrasound scanning have enabled surveillance of metastatic burden to the sentinel lymph nodes.{{cite journal | vauthors = Voit C, Van Akkooi AC, Schäfer-Hesterberg G, Schoengen A, Kowalczyk K, Roewert JC, Sterry W, Eggermont AM | title = Ultrasound morphology criteria predict metastatic disease of the sentinel nodes in patients with melanoma | journal = Journal of Clinical Oncology | volume = 28 | issue = 5 | pages = 847–852 | date = February 2010 | pmid = 20065175 | doi = 10.1200/JCO.2009.25.7428 | doi-access = free }} The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) is evaluating ultrasound as an alternative to invasive surgical methods.{{cite web|url=http://www.malignant-melanoma.org/sunmel |title=malignant-melanoma.org |url-status=dead |archive-url=https://web.archive.org/web/20111014181613/http://www.malignant-melanoma.org/sunmel/ |archive-date=14 October 2011 }}

In some countries oncolytic virotherapy methods are studied and used to treat melanoma. Oncolytic virotherapy is a promising branch of virotherapy, where oncolytic viruses are used to treat diseases; viruses can increase metabolism, reduce anti-tumor immunity and disorganize vasculature.{{cite journal | vauthors = Forbes NE, Abdelbary H, Lupien M, Bell JC, Diallo JS | title = Exploiting tumor epigenetics to improve oncolytic virotherapy | journal = Frontiers in Genetics | volume = 4 | pages = 184 | date = September 2013 | pmid = 24062768 | pmc = 3778850 | doi = 10.3389/fgene.2013.00184 | doi-access = free }} Talimogene laherparepvec (T-VEC) (which is a herpes simplex virus type 1–derived oncolytic immunotherapy), was shown to be useful against metastatic melanoma in 2015 with an increased survival of 4.4 months.{{cite journal | vauthors = Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS | title = Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma | journal = Journal of Clinical Oncology | volume = 33 | issue = 25 | pages = 2780–2788 | date = September 2015 | pmid = 26014293 | doi = 10.1200/JCO.2014.58.3377 | s2cid = 23663167 | doi-access = free }}

Antiretrovirals have been tested in vitro against melanoma. The rationale behind this lies in their potential to inhibit human endogenous retroviruses, whose activity has been associated with the development of melanoma.{{cite journal | vauthors = Costa B, Vale N | title = Exploring HERV-K (HML-2) Influence in Cancer and Prospects for Therapeutic Interventions | journal = International Journal of Molecular Sciences | volume = 24 | issue = 19 | pages = 1615 | date = September 2023 | pmid = 37834078 | doi = 10.3390/ijms25031615 | doi-access = free | pmc = 10572383 }}{{cite journal | vauthors = Müller MD, Holst PJ, Nielsen KN | title = A Systematic Review of Expression and Immunogenicity of Human Endogenous Retroviral Proteins in Cancer and Discussion of Therapeutic Approaches | journal = International Journal of Molecular Sciences | volume = 23 | issue = 3 | pages = 1330 | date = January 2022 | pmid = 35163254 | pmc = 8836156 | doi = 10.3390/ijms23031330 | doi-access = free }}

Evidence from studies on melanoma cell lines indicates that antiretroviral drugs, including lamivudine, doravirine, and cabotegravir, can effectively downregulate the expression of human endogenous retroviruses (HERV-K). These drugs not only reduce cell growth and invasiveness but also enhance the potential of immune checkpoint therapies.{{cite journal | vauthors = Zanrè V, Bellinato F, Cardile A, Passarini C, Monticelli J, Di Bella S, Menegazzi M | title = Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines | journal = International Journal of Molecular Sciences | volume = 25 | issue = 3 | pages = 1615 | date = January 2024 | pmid = 38338893 | pmc = 10855363 | doi = 10.3390/ijms25031615 | doi-access = free }} Furthermore, they have shown promise in addressing resistance mechanisms that emerge following prolonged treatment with BRAF inhibitors like dabrafenib and AZ628. By restoring apoptosis, decreasing cell viability, and influencing tumor suppressor proteins, these antiretrovirals offer a compelling strategy to tackle therapeutic resistance in melanoma.{{cite journal | vauthors = Zanrè V, Bellinato F, Cardile A, Passarini C, Di Bella S, Menegazzi M | title = BRAF-Mutated Melanoma Cell Lines Develop Distinct Molecular Signatures After Prolonged Exposure to AZ628 or Dabrafenib: Potential Benefits of the Antiretroviral Treatments Cabotegravir or Doravirine on BRAF-Inhibitor-Resistant Cells | journal = International Journal of Molecular Sciences | volume = 25 | issue = 22 | pages = 11939 | date = November 2024 | pmid = 39596009 | pmc = 11593403 | doi = 10.3390/ijms252211939 | doi-access = free }} Further developments are awaited through animal model testing.

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{{Reflist}}

{{Wiktionary|melanoma}}

{{Commons category|Melanoma}}

{{Medical resources

| DiseasesDB = 7947

| ICD11 = {{ICD11|XH4846}}

| ICD10 = {{ICD10|C|43|9|c|43}}, {{ICD10|D03}}

| ICD9 = {{ICD9|172.9}}

| ICDO = {{ICDO|8720|3}}

| OMIM = 155600

| MedlinePlus = 000850

| eMedicineSubj = derm

| eMedicineTopic = 257

| eMedicine_mult = {{eMedicine2|med|1386}} {{eMedicine2|ent|27}} {{eMedicine2|plastic|456}}

| MeshID = D008545

}}

{{Diseases of the skin and appendages by morphology}}

{{Skin tumors, nevi and melanomas}}

{{Authority control}}

Category:Cancer

Category:Medical mnemonics

Category:Wikipedia medicine articles ready to translate