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{{Infobox medical condition (new)
| name = Melanoma
| synonyms = Malignant melanoma
| image = Melanoma.jpg
| caption = A melanoma of approximately 2.5 [[centimeters|cm]] by 1.5 cm
| pronounce = {{IPAc-en|audio=melanoma-pronunciation.ogg|ˌ|m|ɛ|l|ə|ˈ|n|oʊ|m|ə}}
| field = [[Oncology]] and [[dermatology]]
| symptoms = [[nevus|Mole]] that is increasing in size, has irregular edges, change in color, itchiness, or [[Ulcer (dermatology)|skin breakdown]].<ref name=NCI2015/>
| complications =
| onset =
| duration =
| causes = [[Ultraviolet light]] (Sun, [[tanning lamp|tanning devices]])<ref name=WCR2014/>
| risks = Family history, many moles, [[immunosuppression|poor immune function]]<ref name=NCI2015/>
| diagnosis = [[Tissue biopsy]]<ref name=NCI2015/>
| differential = [[Seborrheic keratosis]], [[lentigo]], [[blue nevus]], [[dermatofibroma]]<ref>{{cite journal|last1=Goldstein|first1=BG|last2=Goldstein|first2=AO|title=Diagnosis and management of malignant melanoma.|journal=American Family Physician|date=1 April 2001|volume=63|issue=7|pages=1359–68, 1374|pmid=11310650}}</ref>
| prevention = [[Sunscreen]], avoiding UV light<ref name=WCR2014/>
| treatment = Surgery<ref name=NCI2015/>
| medication =
| prognosis = [[Five-year survival rates]] in USA 98% (localized), 17% (disseminated)<ref name=SEER2015/>
| frequency = 3.1 million (2015)<!-- prevalence --><ref name=GBD2015Pre>{{cite journal|last1=GBD 2015 Disease and Injury Incidence and Prevalence|first1=Collaborators.|title=Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015.|journal=Lancet|date=8 October 2016|volume=388|issue=10053|pages=1545–1602|pmid=27733282|doi=10.1016/S0140-6736(16)31678-6|pmc=5055577}}</ref>
| deaths = 59,800 (2015)<ref name=GBD2015De>{{cite journal|last1=GBD 2015 Mortality and Causes of Death|first1=Collaborators.|title=Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015.|journal=Lancet|date=8 October 2016|volume=388|issue=10053|pages=1459–1544|pmid=27733281|doi=10.1016/s0140-6736(16)31012-1}}</ref>
}}
<!-- Definition and symptoms -->
'''Melanoma''', also known as '''malignant melanoma''', is a type of [[cancer]] that develops from the pigment-containing cells known as [[melanocyte]]s.<ref name=NCI2015>{{cite web|title=Melanoma Treatment–for health professionals (PDQ®)|url=http://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq|website=National Cancer Institute|accessdate=30 June 2015|date=June 26, 2015|deadurl=no|archiveurl=https://web.archive.org/web/20150704213842/http://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq|archivedate=4 July 2015|df=}}</ref> Melanomas typically occur in the skin, but may rarely occur in the mouth, [[intestines]], or [[uveal melanoma|eye]].<ref name=NCI2015/><ref name=WCR2014/> In women, they most commonly occur on the legs, while in men they are most common on the back.<ref name=WCR2014/> Sometimes they develop from a [[nevus|mole]] with concerning changes including an increase in size, irregular edges, change in color, itchiness, or [[Ulcer (dermatology)|skin breakdown]].<ref name=NCI2015/>

<!-- Cause and diagnosis -->
The primary cause of melanoma is [[ultraviolet light]] (UV) exposure in those with low levels of [[human skin color|skin pigment]].<ref name=WCR2014/><ref>{{cite journal |vauthors=Kanavy HE, Gerstenblith MR |title=Ultraviolet radiation and melanoma |journal=Semin Cutan Med Surg |volume=30 |issue=4 |pages=222–8 |date=December 2011 |pmid=22123420 |doi=10.1016/j.sder.2011.08.003 |url=http://linkinghub.elsevier.com/retrieve/pii/S1085-5629(11)00130-1}}</ref> The UV light may be from either the sun or from other sources, such as [[tanning lamp|tanning devices]].<ref name=WCR2014/> About 25% develop from moles.<ref name=WCR2014/> Those with many moles, a history of affected family members, and who have [[immunosuppression|poor immune function]] are at greater risk.<ref name=NCI2015/> A number of rare genetic defects such as [[xeroderma pigmentosum]] also increase risk.<ref name=Az2014/> Diagnosis is by [[biopsy]] of any concerning skin lesion.<ref name=NCI2015/>

<!-- Prevention, treatment and prognosis -->
Using [[sunscreen]] and avoiding UV light may prevent melanoma.<ref name=WCR2014/> Treatment is typically removal by surgery.<ref name=NCI2015/> In those with slightly larger cancers, nearby [[lymph nodes]] may be tested for spread.<ref name=NCI2015/> Most people are cured if spread has not occurred.<ref name=NCI2015/> For those in whom melanoma has spread, [[Cancer immunotherapy|immunotherapy]], [[biologic therapy]], [[radiation therapy]], or [[chemotherapy]] may improve survival.<ref name=NCI2015/><ref name=Syn2017>{{Cite journal|last=Syn|first=Nicholas L|last2=Teng|first2=Michele W L|last3=Mok|first3=Tony S K|last4=Soo|first4=Ross A|title=De-novo and acquired resistance to immune checkpoint targeting|url=http://linkinghub.elsevier.com/retrieve/pii/S1470204517306071|journal=The Lancet Oncology |volume=18|issue=12|pages=e731–41 |pmid=29208439 |doi=10.1016/s1470-2045(17)30607-1}}</ref> With treatment the [[five-year survival rates]] in the United States is 98% among those with localized disease and 17% among those in whom spread has occurred.<ref name=SEER2015>{{cite web|title=SEER Stat Fact Sheets: Melanoma of the Skin|url=http://seer.cancer.gov/statfacts/html/melan.html|website=NCI|deadurl=no|archiveurl=https://web.archive.org/web/20140706134347/http://seer.cancer.gov/statfacts/html/melan.html|archivedate=2014-07-06|df=}}</ref> The likelihood that it will come back or spread depends how [[Breslow's depth|thick the melanoma]] is, how fast the cells are dividing, and whether or not the overlying skin has broken down.<ref name=WCR2014/>

<!-- Epidemiology -->
Melanoma is the most dangerous type of skin cancer.<ref name=WCR2014/> Globally, in 2012, it newly occurred in 232,000 people.<ref name=WCR2014/> In 2015 there were 3.1 million with active disease which resulted in 59,800 deaths.<ref name=GBD2015Pre/><ref name=GBD2015De/> Australia and New Zealand have the highest rates of melanoma in the world.<ref name=WCR2014/> There are also high rates in Northern Europe and North America, while it is less common in Asia, Africa, and [[Latin America]].<ref name=WCR2014/> Melanoma is more common in men than women.<ref name=Az2014/> Melanoma has become more common since the 1960s in areas which are mostly populated with [[white people]].<ref name=WCR2014>{{cite book|title=World Cancer Report 2014.|date=2014|publisher=World Health Organization|isbn=9283204298|pages=Chapter 5.14|url=https://www.iarc.fr/en/publications/pdfs-online/wcr/2003/WorldCancerReport.pdf|deadurl=no|archiveurl=https://web.archive.org/web/20140530232406/http://www.iarc.fr/en/publications/pdfs-online/wcr/2003/WorldCancerReport.pdf|archivedate=2014-05-30|df=}}</ref><ref name=Az2014>{{cite journal|last1=Azoury|first1=SC|last2=Lange|first2=JR|title=Epidemiology, risk factors, prevention, and early detection of melanoma.|journal=The Surgical clinics of North America|date=October 2014|volume=94|issue=5|pages=945–62, vii|pmid=25245960|doi=10.1016/j.suc.2014.07.013}}</ref>

==Signs and symptoms==
Early signs of melanoma are changes to the shape or color of existing [[Mole (skin marking)|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]], [[Ulcer (dermatology)|ulcerate]] or bleed.<ref>{{cite web|url=http://www.melanomawarningsigns.com/|title=MelanomaWarningSigns.com|publisher=|deadurl=yes|archiveurl=https://web.archive.org/web/20150801214405/http://melanomawarningsigns.com/|archivedate=2015-08-01|df=}}</ref> Early signs of melanoma are summarized by the mnemonic "ABCDE":
*'''A'''symmetry
* '''B'''orders (irregular with edges and corners)
*'''C'''olor (variegated)
*'''D'''iameter (greater than {{convert|6|mm|2|abbr=on|lk=out}}, about the size of a pencil eraser)
*'''E'''volving over time
These classifications do not, however, apply to the most dangerous form of melanoma, nodular melanoma, which has its own classifications:

*'''E'''levated above the skin surface
*'''F'''irm to the touch
*'''G'''rowing
Metastatic melanoma may cause nonspecific [[paraneoplastic syndrome|paraneoplastic symptoms]], including loss of appetite, [[nausea]], vomiting and fatigue. [[Metastasis]] of early melanoma is possible, but relatively rare: less than a fifth of melanomas diagnosed early become metastatic. [[brain metastasis|Brain metastases]] are particularly common in patients with metastatic melanoma.<ref>{{cite journal |author=Fiddler IJ |title=Melanoma metastasis |journal=Cancer Control |volume=2 |issue=5 |pages=398–404 |date=October 1995 |pmid=10862180}}</ref> It can also spread to the liver, bones, abdomen or distant lymph nodes.

==Cause==
Melanomas are usually caused by DNA damage resulting from exposure to ultraviolet light from the sun. Genetics also plays a role.

Having more than fifty moles indicates an increased risk melanoma might arise. A weakened immune system makes it easier for cancer to arise due to the body’s weakened ability to fight cancer cells.<ref name=Mayo2016>{{Cite news|url=http://www.mayoclinic.org/diseases-conditions/melanoma/basics/risk-factors/con-20026009|title=Melanoma Risk factors – Mayo Clinic|work=Mayo Clinic|access-date=2017-04-10 |deadurl=no|archiveurl=https://web.archive.org/web/20170410133759/http://www.mayoclinic.org/diseases-conditions/melanoma/basics/risk-factors/con-20026009|archivedate=2017-04-10|df=}}</ref>

===UV radiation===
The ultraviolet radiation from tanning beds increases the risk of melanoma.<ref name="pmid22833605">{{cite journal|last=Boniol|first=M|author2=Autier, P|author3= Boyle, P|author4= Gandini, S|title=Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis.|journal=BMJ (Clinical research ed.)|date=Jul 24, 2012|volume=345|pages=e4757|pmid=22833605|pmc=3404185|doi=10.1136/bmj.e4757}}</ref> 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.<ref>{{Cite journal |author=WHO International Agency for Research on Cancer Monograph Working Group |title=A Review of Human Carcinogens—Part D:Radiation |journal=[[The Lancet Oncology]]|date = August 2009| volume=10| issue=8| pages=751–2| doi=10.1016/S1470-2045(09)70213-X| pmid=19655431}}</ref>

Those who work in airplanes also appear to have an increased risk, believed to be due to greater exposure to UV.<ref>{{cite journal|last1=Sanlorenzo|first1=Martina|last2=Wehner|first2=Mackenzie R.|last3=Linos|first3=Eleni|last4=Kornak|first4=John|last5=Kainz|first5=Wolfgang|last6=Posch|first6=Christian|last7=Vujic|first7=Igor|last8=Johnston|first8=Katia|last9=Gho|first9=Deborah|last10=Monico|first10=Gabriela|last11=McGrath|first11=James T.|last12=Osella-Abate|first12=Simona|last13=Quaglino|first13=Pietro|last14=Cleaver|first14=James E.|last15=Ortiz-Urda|first15=Susana|title=The Risk of Melanoma in Airline Pilots and Cabin Crew|journal=JAMA Dermatology|date=January 2015|doi=10.1001/jamadermatol.2014.1077 |pmid=25188246 |pmc=4482339 |volume=151 |issue=1 |pages=51–8}}</ref>

[[Ultraviolet|Ultraviolet UVB light]] (wavelengths between 315 – 280&nbsp;nm) from the sun is absorbed by skin cell DNA and results in a type of [[direct DNA damage]] called [[Pyrimidine dimers|cyclobutane pyrimidine dimers (CPDs)]]. [[Thymine]]-thymine, [[cytosine]]-cytosine or cytosine-thymine [[Protein dimer|dimer]]s are formed by the joining of two adjacent [[pyrimidine]] bases within a DNA strand. Somewhat similarly to [[UVB]], [[Ultraviolet|UVA light]] (longer wavelengths between 400 – 315&nbsp;nm) from the sun or from tanning beds can also be directly absorbed by skin DNA (at about 100 to 1000 fold lower efficiency than UVB is absorbed).<ref name="pmid22005748">{{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=Photochem. Photobiol. Sci. |volume=11 |issue=1 |pages=207–15 |date=January 2012 |pmid=22005748 |doi=10.1039/c1pp05232b }}</ref>

Studies suggest that exposure to [[ultraviolet]] radiation (UVA<ref name="uva">{{Cite journal|vauthors=Wang S, Setlow R, Berwick M, Polsky D, Marghoob A, Kopf A, Bart R | title = Ultraviolet A and melanoma: a review | journal = J Am Acad Dermatol | volume = 44 | issue = 5 | pages = 837–46 | year = 2001 | pmid = 11312434 | doi = 10.1067/mjd.2001.114594}}</ref> and UVB) is one of the major contributors to the development of melanoma. Occasional extreme sun exposure (resulting in "[[sunburn]]") is causally related to melanoma.<ref>{{Cite journal|vauthors=Oliveria S, Saraiya M, Geller A, Heneghan M, Jorgensen C | title = Sun exposure and risk of melanoma | journal = Arch Dis Child | volume = 91 | issue = 2 | pages = 131–8 | year = 2006 | pmid = 16326797 | doi = 10.1136/adc.2005.086918 | pmc = 2082713}}</ref> Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers.<ref>{{Cite journal|vauthors=Lee J, Strickland D | title = Malignant melanoma: social status and outdoor work | journal = Br J Cancer | volume = 41 | issue = 5 | pages = 757–63 | year = 1980 | pmid = 7426301 | pmc = 2010319| doi = 10.1038/bjc.1980.138}}</ref><ref>{{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=637–44 |date=January 1995 |pmid=7804988 |doi= 10.1002/1097-0142(19950115)75:2}}</ref> Other factors are [[mutation]]s in or total loss of [[tumor suppressor gene]]s. Use of [[sunbed]]s (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.<ref>[http://www.who.int/mediacentre/news/notes/2005/np07/en/ The World Health Organization recommends that no person under 18 should use a sunbed] {{webarchive|url=https://web.archive.org/web/20090616124844/http://www.who.int/mediacentre/news/notes/2005/np07/en/ |date=2009-06-16 }}</ref>

Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of [[skin pigmentation]]. Melanoma rates tend to be highest in countries settled by migrants from [[northern Europe]] that have a large amount of direct, intense sunlight that the skin of the settlers is not adapted to, most notably [[Australia]]. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia.<ref>{{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 = Am J Epidemiol | volume = 135 | issue = 10 | pages = 1103–13 | year = 1992 | pmid = 1632422}}</ref>

Having multiple severe sunburns increases the likelihood that future sunburns develop into melanoma due to cumulative damage.<ref name=Mayo2016/> The sun and tanning beds are the main sources of UV radiation that increase the risk for melanoma and living close to the equator increases exposure to UV radiation.<ref name=Mayo2016/>

===Genetics===
A number of rare mutations, which often run in families, greatly increase melanoma susceptibility. Several [[genes]] increase risks. Some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene called [[melanocortin 1 receptor|MC1R]] that causes red hair, have a relatively lower elevated risk. [[Genetic testing]] can be used to search for the mutations.

One class of mutations affects the gene [[P16 (gene)|CDKN2A]]. An alternative [[reading frame]] mutation in this gene leads to the destabilization of [[p53]], a [[transcription factor]] involved in [[apoptosis]] and in fifty percent of human cancers. Another mutation in the same gene results in a nonfunctional inhibitor of [[CDK4]], a [[cyclin]]-dependent [[kinase]] that promotes [[cell division]]. Mutations that cause the skin condition [[xeroderma pigmentosum]] (XP) also increase melanoma susceptibility. Scattered throughout the genome, these mutations reduce a cell's ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant (the chances of a carrier to express the phenotype is high).

Familial melanoma is genetically heterogeneous,<ref>{{Cite journal| author = Greene MH. | title = The genetics of hereditary melanoma and nevi | journal = Cancer | volume = 86 | issue = 11 | pages = 2464–77 | year = 1998 | pmid = 10630172 | doi = 10.1002/(SICI)1097-0142(19991201)86:11 }}</ref> 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).<ref>{{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 | year = 2001 | pmid = 11224711 | doi = 10.1097/00001622-200103000-00008}}</ref> The multiple [[Tumor suppressor gene|tumor suppressor]] 1 (CDKN2A/MTS1) gene encodes p16INK4a – a low-[[molecular weight]] protein inhibitor of [[cyclin-dependent kinase|cyclin-dependent protein kinases]] (CDKs) – which has been localised to the p21 region of [[Chromosome 9 (human)|human chromosome 9]].<ref>[https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=1029 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)] {{webarchive|url=https://web.archive.org/web/20041117054925/http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene |date=2004-11-17 }} from Entrez Gene</ref>

Other mutations confer lower risk, but are more common in the population. People with mutations in the [[MC1R]] gene, for example, 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; in fact, all red-haired people have a mutated copy. Mutation of the [[MDM2]] SNP309 gene is associated with increased risks for younger women.<ref name="pmid19318491">{{cite journal |last1=Firoz for Cancer Research |first1=EF |last2=Warycha |first2=M |last3=Zakrzewski |first3=J |last4=Pollens |first4=D |last5=Wang |first5=G |last6=Shapiro |first6=R |last7=Berman|first7=R |last8=Pavlick |first8=A |last9=Manga |first9=P |last10=Ostrer |first10=H. |last11=Celebi |first11=J. T. |last12=Kamino |first12=H. |last13=Darvishian |first13=F. |last14=Rolnitzky |first14=L. |last15=Goldberg |first15=J. D. |last16=Osman |first16=I. |last17=Polsky |first17=D. |title=Association of MDM2 SNP309, Age of Onset, and Gender in Cutaneous Melanoma. |journal=Clinical Cancer Research |volume=15 |issue=7 |pages=2573–80|year=2009 |pmid=19318491 |doi=10.1158/1078-0432.CCR-08-2678}}</ref>

Fair- and red-haired people, persons with multiple atypical [[nevi]] or [[dysplastic nevus|dysplastic nevi]] and persons born with giant [[congenital melanocytic nevi]] are at increased risk.<ref name="IMAGE">{{Cite journal|vauthors=Bliss J, Ford D, Swerdlow A, Armstrong B, Cristofolini M, Elwood J, Green A, Holly E, Mack T, MacKie R | 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 = Int J Cancer | volume = 62 | issue = 4 | pages = 367–76 | year = 1995 | pmid = 7635560 | doi = 10.1002/ijc.2910620402}}</ref>

A family history of melanoma greatly increases a person's risk because mutations in several genes have been found in melanoma-prone families.<ref>{{Cite journal|vauthors=Miller A, Mihm M | title = Melanoma | journal = N Engl J Med | volume = 355 | issue = 1 | pages = 51–65 | year = 2006 | pmid = 16822996 | doi = 10.1056/NEJMra052166}}</ref> People with a history of one melanoma are at increased risk of developing a second primary tumor.<ref>{{Cite journal|vauthors=Rhodes A, Weinstock M, Fitzpatrick T, Mihm M, Sober A | title = Risk factors for cutaneous melanoma. A practical method of recognizing predisposed individuals | journal = JAMA | volume = 258 | issue = 21 | pages = 3146–54 | year = 1987 | pmid = 3312689 | doi = 10.1001/jama.258.21.3146}}</ref>

Fair skin is the result of having less melanin in the skin, which means there is less protection from UV radiation.<ref name=Mayo2016/> A family history could indicate a genetic predisposition to melanoma.<ref name=Mayo2016/>

==Pathophysiology==
[[File:Diagram showing where melanoma is most likely to develop CRUK 383.svg|thumb|right|Where melanoma is most likely to develop]]
[[File:Metastatic Melanoma Cells Nci-vol-9872-300.jpg|thumb|Molecular basis for melanoma cell motility: actin-rich [[podosome]]s (yellow), along with [[cell nucleus|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 (skin)|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&nbsp;mm thick. Because the cancer cells have not yet reached the blood vessels deeper in the skin, it is very unlikely that this early-stage melanoma will spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely removed with surgery.

When the tumor cells start to move in a different direction — vertically up into the epidermis and into the [[papillary dermis]] — cell behaviour changes dramatically.<ref name=Hershkovitz10/>

The next step in the evolution is the invasive radial growth phase, which is a confusing term; however, it explains the process of the radial growth, in which individual cells start to acquire invasive potential. From this point on the melanoma is capable of spreading. 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 the 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,<ref>{{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 |url=http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=34439 |deadurl=no |archiveurl=https://web.archive.org/web/20110725021007/http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=34439 |archivedate=2011-07-25 |df= }}</ref> which is judged by the presence and activity of the [[tumor infiltrating lymphocyte]]s (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.<ref name="pmid20697348">{{Cite journal | last = Davies | first = M A |author2=Samuels, Y | title = Analysis of the genome to personalize therapy for melanoma | journal = Oncogene | volume = 29 | issue = 41 | pages = 5545–55 | year = 2010 | pmid = 20697348 |doi = 10.1038/onc.2010.323 | pmc = 3169242 }}</ref>

In general, cancers are caused by damage to [[DNA]].<ref>{{cite book |vauthors=Bernstein C, Prasad AR, Nfonsam V, Bernstein H |chapter=DNA Damage, DNA Repair and Cancer |chapterurl=http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer |editor=Clark Chen |title=New Research Directions in DNA Repair |publisher=InTech |year=2013 |isbn=978-953-51-1114-6 }}</ref> UVA light mainly causes thymine-thymine dimers.<ref name="pmid21901217">{{cite journal |vauthors=Sage E, Girard PM, Francesconi S |title=Unravelling UVA-induced mutagenesis |journal=Photochem. Photobiol. Sci. |volume=11 |issue=1 |pages=74–80 |date=January 2012 |pmid=21901217 |doi=10.1039/c1pp05219e }}</ref> 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 1/10th, 1/10th and 1/3rd the frequencies of UVA-induced thymine-thymine dimers, respectively.

If unrepaired, CPD photoproducts can lead to mutations by inaccurate [[translesion synthesis]] during DNA replication or repair. The most frequent mutations due to inaccurate synthesis past CPDs are cytosine to thymine (C>T) or CC>TT [[Transition (genetics)|transition mutations]]. These are commonly referred to as UV fingerprint [[mutation]]s, as they are the most specific mutation caused by UV, being frequently found in sun-exposed skin but rarely found in internal organs.<ref name="pmid23303275">{{cite journal |vauthors=Budden T, Bowden NA |title=The Role of Altered Nucleotide Excision Repair and UVB-Induced DNA Damage in Melanomagenesis |journal=Int J Mol Sci |volume=14 |issue=1 |pages=1132–51 |year=2013 |pmid=23303275 |pmc=3565312 |doi=10.3390/ijms14011132 }}</ref> Errors in DNA repair of UV photoproducts, or inaccurate synthesis past these photoproducts, can also lead to deletions, insertions and [[chromosomal translocation]]s.

The entire genomes of 25 melanomas were sequenced.<ref name="pmid22622578">{{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=502–6 |date=May 2012 |pmid=22622578 |pmc=3367798 |doi=10.1038/nature11071 }}</ref> On average, about 80,000 mutated bases (mostly C>T transitions) and about 100 structural rearragements were found per melanoma genome. This is much higher than the approximately 70 mutations across generations (parent to child).<ref>{{cite journal |vauthors=Roach JC, Glusman G, Smit AF, etal |title=Analysis of genetic inheritance in a family quartet by whole-genome sequencing |journal=Science |volume=328 |issue=5978 |pages=636–9 |date=April 2010 |pmid=20220176 |pmc=3037280 |doi=10.1126/science.1186802 }}</ref><ref>{{cite journal |vauthors=Campbell CD, Chong JX, Malig M, etal |title=Estimating the human mutation rate using autozygosity in a founder population |journal=Nat. Genet. |volume=44 |issue=11 |pages=1277–81 |date=November 2012 |pmid=23001126 |pmc=3483378 |doi=10.1038/ng.2418 }}</ref> Among the 25 melanomas, about 6,000 protein-coding genes had [[Missense mutation|missense]], [[Nonsense mutation|nonsense]] or [[splice site mutation]]s. 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 (gene)|PMEL]].<ref name="proteinatlas.org">{{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=2017-10-02}}</ref><ref name="Uhlen eaan2507">{{Cite journal|last=Uhlen|first=Mathias|last2=Zhang|first2=Cheng|last3=Lee|first3=Sunjae|last4=Sjöstedt|first4=Evelina|last5=Fagerberg|first5=Linn|last6=Bidkhori|first6=Gholamreza|last7=Benfeitas|first7=Rui|last8=Arif|first8=Muhammad|last9=Liu|first9=Zhengtao|date=2017-08-18|title=A pathology atlas of the human cancer transcriptome |url=http://science.sciencemag.org/content/357/6352/eaan2507|journal=Science |volume=357|issue=6352|pages=eaan2507|doi=10.1126/science.aan2507 |pmid=28818916}}</ref>

UV radiation causes [[DNA damage|damage]] to the [[DNA]] of cells, typically [[thymine]] dimerization, which when unrepaired can create [[mutation]]s in the cell's [[gene]]s. When the cell [[cell division|divides]], these mutations are propagated to new generations of cells. If the mutations occur in [[protooncogene]]s or [[tumor suppressor gene]]s, 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;<ref>{{cite journal |vauthors=Leslie MC, Bar-Eli M |title=Regulation of gene expression in melanoma: new approaches for treatment |journal=J. Cell. Biochem. |volume=94 |issue=1 |pages=25–38 |date=January 2005 |pmid=15523674 |doi=10.1002/jcb.20296}}</ref><ref>{{cite journal |vauthors=Bhoumik A, Singha N, O'Connell MJ, Ronai ZA |title=Regulation of TIP60 by ATF2 modulates ATM activation |journal=J. Biol. Chem. |volume=283 |issue=25 |pages=17605–14 |date=June 2008 |pmid=18397884 |pmc=2427333 |doi=10.1074/jbc.M802030200}}</ref><ref>{{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=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=12 |pages=4222–7 |date=March 2004 |pmid=15010535 |pmc=384722 |doi=10.1073/pnas.0400195101}}</ref> studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer progression.<ref>{{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=314–27 |date=April 2008 |pmid=18348191 |doi=10.1002/bies.20734 }}</ref><ref>{{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=J Mol Signal |volume=3 |page=3 |year=2008 |pmid=18269766 |pmc=2265711 |doi=10.1186/1750-2187-3-3}}</ref>

[[Cancer stem cells]] may also be involved.<ref>{{cite journal|last1=Parmiani|first1=G|title=Melanoma Cancer Stem Cells: Markers and Functions.|journal=Cancers|date=11 March 2016|volume=8|issue=3|pmid=26978405|doi=10.3390/cancers8030034|pmc=4810118|page=34}}</ref>

==Diagnosis==
[[File:Melanoma vs normal mole ABCD rule NCI Visuals Online.jpg|thumb|ABCD rule illustration: On the left side from top to bottom: melanomas showing (A) Asymmetry, (B) a border that is uneven, ragged, or notched, (C) coloring of different shades of brown, black, or tan and (D) diameter that had changed in size. The normal moles on the right side do not have abnormal characteristics (no asymmetry, even border, even color, no change in diameter).]]
[[File:Dermatoscope1.JPG|thumb|A [[dermatoscope]]]]
[[File:Malignant melanoma (1) at thigh Case 01.jpg|thumb|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|thumb|Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is focal deposition of melanin.]]
Visual inspection is the most common diagnostic technique.<ref name="ap01">{{cite journal |vauthors=Wurm EM, Soyer HP |title=Scanning for melanoma |date=October 2010 |journal=Australian Prescriber |issue=33 |pages=150–5 |url=http://www.australianprescriber.com/magazine/33/5/150/5 |deadurl=no |archiveurl=https://web.archive.org/web/20101019035021/http://australianprescriber.com/magazine/33/5/150/5 |archivedate=2010-10-19 |df= }}</ref> 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 above), to regularly examine [[Melanocytic nevus|moles]] for changes (shape, size, color, itching or bleeding) and to consult a qualified physician when a candidate appears.<ref>{{cite web |title=Prevention: ABCD's of Melanoma |publisher=American Melanoma Foundation |url=http://www.melanomafoundation.org/prevention/abcd.htm |deadurl=no |archiveurl=https://web.archive.org/web/20030423111111/http://melanomafoundation.org/prevention/abcd.htm |archivedate=2003-04-23 |df= }}</ref><ref>{{Cite journal | vauthors = Friedman R, Rigel D, Kopf A | title = Early detection of malignant melanoma: the role of physician examination and self-examination of the skin | journal = CA Cancer J Clin | volume = 35 | issue = 3 | pages = 130–51 | year = 1985 | pmid = 3921200 | url = http://onlinelibrary.wiley.com/doi/10.3322/canjclin.35.3.130/abstract | doi = 10.3322/canjclin.35.3.130 | deadurl = no | archiveurl = https://web.archive.org/web/20140521231912/http://onlinelibrary.wiley.com/doi/10.3322/canjclin.35.3.130/abstract | archivedate = 2014-05-21 | df = }}</ref>

=== ABCDE ===
A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCDE":
* '''A'''symmetrical skin lesion.
* '''B'''order of the lesion is irregular.
* '''C'''olor: melanomas usually have multiple colors.
* '''D'''iameter: moles greater than 6&nbsp;mm are more likely to be melanomas than smaller moles.
* '''E'''nlarging: Enlarging or evolving

However, many melanomas present as lesions smaller than 6&nbsp;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&nbsp;mm in diameter. [[Seborrheic keratosis]] may meet some or all of the ABCD criteria, and can lead to [[false alarm]]s. Doctors can generally distinguish seborrheic keratosis from melanoma upon examination, or with [[dermatoscopy]].

Some advocate replacing enlarging with evolution. Certainly moles that change and evolve will be 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.

[[Nodular melanoma]]s do not fulfill these criteria, having their own mnemonic, "EFG":

* '''E'''levated: the lesion is raised above the surrounding skin.
* '''F'''irm: the nodule is solid to the touch.
* '''G'''rowing: the nodule is increasing in size.

=== Ugly duckling ===
A recent and novel method is the "ugly duckling sign".<ref name="pmid9828892">{{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=Arch Dermatol |volume=134 |issue=11 |pages=1484–5 |date=November 1998 |pmid=9828892 |doi=10.1001/archderm.134.11.1484}}
</ref> It is simple, easy to teach, and highly effective. Correlation of common lesion characteristics is made. Lesions that greatly deviate from the common characteristics are labeled an "Ugly Duckling", and a further professional exam is required. The "Little Red Riding Hood" sign<ref name="pmid9828892" /> 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 non-melanomas or are considered to be "wolves in sheep's clothing".<ref name="dermnetnz.org">{{cite web|url=http://dermnetnz.org/doctors/dermoscopy-course/introduction.html|title=Introduction to Dermoscopy|publisher=DermNet New Zealand|deadurl=no|archiveurl=https://web.archive.org/web/20090507183545/http://dermnetnz.org/doctors/dermoscopy-course/introduction.html|archivedate=2009-05-07|df=}}</ref> 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, [[Benign fibrous histiocytoma|dermatofibromas]], or [[Lentigo|lentigines]].

=== Biopsy ===
Following a visual examination and a dermatoscopic exam,<ref name="dermnetnz.org" /> 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 [[Skin biopsy#Punch biopsy|punch biopsies]] are usually contraindicated in suspected melanomas, because of the possibility of sampling error<ref name="pmid19155361">{{cite journal |vauthors=Montgomery BD, Sadler GM |title=Punch biopsy of pigmented lesions is potentially hazardous. |journal=Can Fam Physician |volume=55 |issue=1 |pages=24 |date=January 2009 |pmid=19155361 |pmc=2628830}}</ref> or local implantation causing misestimation of tumour thickness.<ref name="pmid25827527">{{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=Australas J Dermatol |volume=56 |issue=3 |pages=227–31 |date=August 2015 |pmid=25827527 |doi=10.1111/ajd.12333}}</ref><ref name="pmid22471244">{{cite journal |vauthors=Lin SW, Kaye V, Goldfarb N, Rawal A, Warshaw E |title=Melanoma tumor seeding after punch biopsy. |journal=Dermatol Surg |volume=38 |issue=7 pt 1 |pages=1083–5 |date=July 2012 |pmid=22471244 |doi=10.1111/j.1524-4725.2012.02384.x}}</ref> However, fears that such biopsies may increase the risk of metastatic disease seem unfounded.<ref name="pmid16307945">{{cite journal |vauthors=Martin RC 2nd, Scoggins CR, Ross MI, Reintgen DS, Noyes RD, Edwards MJ, McMasters KM |title=Is incisional biopsy of melanoma harmful? |journal=Am J Surg |volume=190 |issue=6 |pages=913–7 |date=December 2005 |pmid=16307945 |doi=10.1016/j.amjsurg.2005.08.020}}</ref><ref name="pmid24665419">{{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=Arch Plast Surg |volume=41 |issue=2 |pages=122–5 |date=March 2014 |pmid=24665419 |doi=10.5999/aps.2014.41.2.122 |pmc=3961608}}</ref>

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.<ref name="ap01" /> 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.

===Classification===
[[File:Anal Melanoma.JPG|thumb|An anal melanoma]]
Melanoma is divided into the following types:<ref>{{Cite book|author1=James, William D. |author2=Berger, Timothy G. |title=Andrews' Diseases of the Skin: clinical Dermatology|publisher=Saunders Elsevier |year=2006 |isbn=0-7216-2921-0 |pages=694–9|display-authors=etal}}</ref>

* [[Lentigo maligna]]
* [[Lentigo maligna melanoma]]
* [[Superficial spreading melanoma]]
* [[Acral lentiginous melanoma]]
* [[Mucosal melanoma]]
* [[Nodular melanoma]]
* [[Polypoid melanoma]]
* [[Desmoplastic melanoma]]

See also:<ref name="Bolognia">{{Cite book|author1=Rapini, Ronald P. |author2=Bolognia, Jean L. |author3=Jorizzo, Joseph L. |title=Dermatology: 2-Volume Set |publisher=Mosby |year=2007 |isbn=1-4160-2999-0 }}</ref>

* [[Melanoma with small nevus-like cells]]
* [[Melanoma with features of a Spitz nevus]]
* [[Uveal melanoma]]

===Laboratory===
[[Lactate dehydrogenase]] (LDH) tests are often used to screen for [[metastasis|metastases]], although many patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates 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 [[computed tomography|CT]], [[MRI]], [[Positron emission tomography|PET]] and/or PET/CT scans. Although controversial, [[sentinel lymph node]] biopsies and examination of the [[lymph node]]s 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).

===Staging===
''Further context on [[cancer staging]] is available at [[TNM staging system|TNM]].''

Also of importance are the "[[Clark level]]" and "[[Breslow's depth]]", which refer to the microscopic depth of tumor invasion.<ref>{{cite web|title=Malignant Melanoma: staging |date=1 September 2006 |work=Collaborative Hypertext of Radiology |publisher=Medical College of Wisconsin |url=http://chorus.rad.mcw.edu/doc/00955.html |deadurl=yes |archiveurl=https://web.archive.org/web/20100718150647/http://chorus.rad.mcw.edu/doc/00955.html |archivedate=2010-07-18 |df= }}</ref>

Melanoma stages:<ref name=AJCC />
5 year survival rates:

[[File:Diagram showing the T stages of melanoma CRUK 373.svg|thumb|right|T stages of melanoma]]

'''Stage 0''': Melanoma ''in situ'' (Clark Level I), 99.9% survival

'''Stage I / II''': Invasive melanoma, 89–95% survival
*T1a: Less than 1.0&nbsp;mm primary tumor thickness, without ulceration, and mitosis < 1/mm2
*T1b: Less than 1.0&nbsp;mm primary tumor thickness, with ulceration or mitoses ≥ 1/mm2
*T2a: 1.01–2.0&nbsp;mm primary tumor thickness, without ulceration

[[File:Malignes Melanom.jpg|thumb|F18-FDG PET/CT in a melanoma patient showing multiple lesions, most likely metastases]]
'''Stage II''': High risk melanoma, 45–79% survival
*T2b: 1.01–2.0&nbsp;mm primary tumor thickness, with ulceration
*T3a: 2.01–4.0&nbsp;mm primary tumor thickness, without ulceration
*T3b: 2.01–4.0&nbsp;mm primary tumor thickness, with ulceration
*T4a: Greater than 4.0&nbsp;mm primary tumor thickness, without ulceration
*T4b: Greater than 4.0&nbsp;mm primary tumor thickness, with ulceration

'''Stage III''': Regional metastasis, 24–70% survival
*N1: Single positive lymph node
*N2: Two to three positive lymph nodes ''or'' regional skin/in-transit metastasis
*N3: Four positive lymph nodes ''or'' one lymph node and regional skin/in-transit metastases

'''Stage IV''': Distant metastasis, 7–19% survival
*M1a: Distant skin metastasis, normal [[Lactate dehydrogenase|LDH]]
*M1b: Lung metastasis, normal LDH
*M1c: Other distant metastasis ''or'' any distant metastasis with elevated LDH

''Based upon AJCC five-year survival from initial melanoma diagnosis with proper treatment.''

==Prevention==

===Avoiding ultraviolet radiation===
Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),<ref>{{Cite journal| author = Autier P | title = Cutaneous malignant melanoma: facts about sunbeds and sunscreen | journal = Expert Rev Anticancer Ther | volume = 5 | issue = 5 | pages = 821–33 | year = 2005 | pmid = 16221052 | doi = 10.1586/14737140.5.5.821}}</ref> 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.<ref>{{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=659–69|date=September 2008 |pmid=18273687 |doi=10.1007/s10552-008-9129-6 }}</ref>

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.<ref>{{cite journal|last1=Greinert|first1=R|last2=de Vries|first2=E|last3=Erdmann|first3=F|last4=Espina|first4=C|last5=Auvinen|first5=A|last6=Kesminiene|first6=A|last7=Schüz|first7=J|title=European Code against Cancer 4th Edition: Ultraviolet radiation and cancer.|journal=Cancer epidemiology|date=December 2015|volume=39 |issue=Suppl 1|pages=S75–83|pmid=26096748|url=http://www.cancerepidemiology.net/article/S1877-7821(15)00002-8/fulltext|doi=10.1016/j.canep.2014.12.014}}</ref>

===Sunscreen===
[[Sunscreen]] appears to be effective in preventing melanoma.<ref name=WCR2014/><ref name=SunM>{{cite journal |vauthors=Kanavy HE, Gerstenblith MR | title = Ultraviolet radiation and melanoma | journal = Semin Cutan Med Surg | volume = 30 | issue = 4| pages = 222–8 |date=December 2011 | pmid = 22123420 | doi = 10.1016/j.sder.2011.08.003 }}</ref> 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.<ref>[http://www.cancer.org/docroot/cri/content/cri_2_4_2x_can_melanoma_be_prevented_50.asp Can Melanoma Be Prevented?] {{webarchive |url=https://web.archive.org/web/20060627025413/http://www.cancer.org/docroot/cri/content/cri_2_4_2x_can_melanoma_be_prevented_50.asp |date=June 27, 2006 }}</ref> 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.<ref name=SunS>{{cite journal |author1=Burnett M.E. |author2=Wang S.Q. | 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 }}</ref>

Concerns have been raised that sunscreen might create a false sense of security against sun damage.<ref>{{Cite journal|last=Planta|first=Margaret B.|date=2011-11-01|title=Sunscreen and Melanoma: Is Our Prevention Message Correct?|url=http://www.jabfm.org/content/24/6/735|journal=The Journal of the American Board of Family Medicine |volume=24|issue=6|pages=735–9|doi=10.3122/jabfm.2011.06.100178 |pmid=22086817|deadurl=no|archiveurl=https://web.archive.org/web/20140810061440/http://www.jabfm.org/content/24/6/735|archivedate=2014-08-10|df=}}</ref>

==Treatment==
[[File:Malignant melanoma on chest.jpg|thumb|Extensive malignant melanoma on a person's chest]]
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 is done, as well, although controversy exists around trial evidence for this procedure.<ref>{{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=2008-01-08 |accessdate=2012-08-13 |deadurl=yes |archiveurl=https://web.archive.org/web/20120711150413/http://www.malignant-melanoma.org/sentinel-node-biopsy/sentinel-node-biopsy-false-positivity/ |archivedate=2012-07-11 |df= }}</ref> Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.

===Surgery===

Excisional biopsies may remove the tumor, but further surgery is often necessary to reduce the risk of recurrence. Complete surgical excision with adequate [[surgical margin]]s 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 1 to 2&nbsp;cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2 to 0.5&nbsp;cm. Many surgeons consider 0.5&nbsp;cm the standard of care for standard excision of melanoma-in-situ,<ref>{{cite journal |vauthors=Clark GS, Pappas-Politis EC, Cherpelis BS, etal |title=Surgical management of melanoma in situ on chronically sun-damaged skin |journal=Cancer Control |volume=15 |issue=3 |pages=216–24 |date=July 2008 |pmid=18596673}}</ref> but 0.2&nbsp;cm 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.<ref>{{cite journal |vauthors=Balch C, Urist M, Karakousis C, Smith T, Temple W, Drzewiecki K, Jewell W, Bartolucci A, Mihm M, 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 = Ann Surg | volume = 218 | issue = 3 | pages = 262–7; discussion 267–9 | year = 1993 | pmid = 8373269 | doi = 10.1097/00000658-199309000-00005 | pmc = 1242959}}</ref>

Mohs surgery has been reported with cure rate as low as 77%<ref name=Mikhail91>{{cite book|first1=Frederic Edward|last1=Mohs|first2=George R.|last2=Mikhail|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|deadurl=no|archiveurl=https://web.archive.org/web/20160107215207/https://books.google.com/books?id=8j9sAAAAMAAJ|archivedate=2016-01-07|df=}}</ref> and as high as 98.0% for melanoma-in-situ.<ref name=Bene08>{{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=Dermatol Surg |volume=34 |issue=5 |pages=660–4 |date=May 2008 |pmid=18261099 |doi=10.1111/j.1524-4725.2007.34124.x |url=http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1076-0512&date=2008&volume=34&issue=5&spage=660 |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]].}}</ref> [[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.<ref>{{cite web|url=http://www.malignant-melanoma.org/surgery/lymph-node-dissection-surgery/ |title=The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) |publisher= |deadurl=yes |archiveurl=https://web.archive.org/web/20090106181514/http://www.malignant-melanoma.org/surgery/lymph-node-dissection-surgery/ |archivedate=2009-01-06 |df= }}</ref>

Biopsy of sentinel lymph nodes is a widely used procedure when treating cutaneous melanoma.<ref>{{cite journal|last=Crowson|first=AN|author2=Haskell, H|title=The role of sentinel lymph-node biopsy in the management of cutaneous melanoma.|journal=Giornale italiano di dermatologia e venereologia : organo ufficiale, Societa italiana di dermatologia e sifilografia|date=Oct 2013|volume=148|issue=5|pages=493–9|pmid=24005142}}</ref><ref>{{cite journal|last=Ross|first=MI|author2=Gershenwald, JE|title=Sentinel lymph node biopsy for melanoma: a critical update for dermatologists after two decades of experience.|journal=Clinics in dermatology|date=May–Jun 2013|volume=31|issue=3|pages=298–310|pmid=23608449|doi=10.1016/j.clindermatol.2012.08.004}}</ref>

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.<ref name="AADfive">{{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/ |accessdate=5 December 2013 |deadurl=no |archiveurl=https://web.archive.org/web/20131201171621/http://www.choosingwisely.org/doctor-patient-lists/american-academy-of-dermatology/ |archivedate=1 December 2013 |df= }}, which cites
*{{cite journal |last1=Bichakjian |first1=CK |last2=Halpern |first2=AC |last3=Johnson |first3=TM |last4=Foote Hood |first4=A |last5=Grichnik |first5=JM |last6=Swetter |first6=SM |last7=Tsao |first7=H |last8=Barbosa |first8=VH |last9=Chuang |first9=TY |last10=Duvic |first10=M |last11=Ho |first11=VC |last12=Sober |first12=AJ |last13=Beutner |first13=KR |last14=Bhushan |first14=R |last15=Smith Begolka |first15=W |author16=American Academy of Dermatology |title=Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. |journal=Journal of the American Academy of Dermatology |date=Nov 2011 |volume=65 |issue=5 |pages=1032–47 |pmid=21868127 |doi=10.1016/j.jaad.2011.04.031}}
*{{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 |editor-first=Stephen B. |editor-last=Edge}}
*{{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 |publication-place=[[Fort Washington, Pennsylvania]] |url=https://subscriptions.nccn.org/gl_login.aspx?ReturnURL=http://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf |accessdate=5 December 2013 |deadurl=yes |archiveurl=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 |archivedate=28 December 2013 |df= }}{{closed access}}</ref> People with these conditions are unlikely to have the cancer spread to their lymph nodes or anywhere else and already have a 97% 5-year survival rate.<ref name="AADfive"/> Because of these things, sentinel lymph node biopsy is [[unnecessary health care]] for them.<ref name="AADfive"/> 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.<ref name="AADfive"/> To potentially correct false positives, gene expression profiling may be used as auxiliary testing for ambiguous and small lesions.<ref name=":0" /><ref name=Brunner13 />

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 [[H&E stain|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&nbsp;mm) ellipse of surrounding skin and tissue.<ref>{{Cite journal|vauthors=Swanson N, Lee K, Gorman A, Lee H | title = Biopsy techniques. Diagnosis of melanoma | journal = Intensive 2011: The Third International Conference on Resource Intensive Applications and Services | volume = 20 | issue = 4 |pages = 677–80 | year = 2002 | pmid = 12380054 | doi = 10.1016/S0733-8635(02)00025-6}}</ref> To avoid disruption of the local lymphatic drainage, the preferred surgical margin for the initial biopsy should be narrow (1&nbsp;mm). The biopsy should include the epidermal, dermal, and subcutaneous layers of the skin. This enables the [[pathology|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&nbsp;cm, 1.0&nbsp;cm, or 2&nbsp;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.

===Add on treatment===
High-risk melanomas may require [[adjuvant therapy|adjuvant]] treatment, although attitudes to this vary in different countries. In the United States, most patients in otherwise good health will begin up to a year of high-dose [[interferon]] treatment, which has severe side effects, but may improve the patient's prognosis slightly.<ref>{{cite journal |vauthors=Kirkwood J, Strawderman M, Ernstoff M, Smith T, Borden E, Blum R | title = Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684 | journal = J Clin Oncol | volume = 14 | issue = 1 | pages = 7–17 | year = 1996 | pmid = 8558223}}</ref> However, the [[British Association of Dermatologists]] guidelines on melanoma state that interferon is not recommended as a standard adjuvant treatment for melanoma.<ref name="Dermatologists' Management Guidelines">{{cite book|last=English|title=British Association of Dermatologists' management guidelines|year=2010|publisher=Wiley-Blackwell |isbn=978-1-4443-3552-1|url=http://as.wiley.com/WileyCDA/WileyTitle/productCd-1444335529,descCd-buy.html|editor1=Neil H. Cox |editor2=John S.C. |accessdate=19 August 2013}}</ref> 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.<ref>{{cite journal |vauthors=Wheatley K, Ives N, Eggermont A, etal | 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 |url=http://ascopubs.org/doi/abs/10.1200/jco.2007.25.18_suppl.8526}}</ref>

In Europe, interferon is usually not used outside the scope of clinical trials.<ref>{{cite journal |vauthors=Kirkwood J, Ibrahim J, Sondak V, Richards J, Flaherty L, Ernstoff M, Smith T, Rao U, Steele M, Blum R | title = High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190 | journal = J Clin Oncol | volume = 18 | issue = 12 | pages = 2444–58 | year = 2000 | pmid = 10856105}}</ref><ref>{{cite journal |vauthors=Kirkwood J, Ibrahim J, Sondak V, Ernstoff M, Ross M | title = Interferon alfa-2a for melanoma metastases | journal = Lancet | volume = 359 | issue = 9310 | pages = 978–9 | year = 2002 | pmid = 11918944 | doi = 10.1016/S0140-6736(02)08001-7}}</ref>

Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.<ref>{{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 = Opt Lett.| volume = 31 | issue = 20 | pages = 2998–3000 | year = 2006 | pmid = 17001379 | doi = 10.1364/OL.31.002998}}</ref>

===Chemotherapy and immunotherapy===
Various [[chemotherapy]] agents, including [[temozolomide]], [[dacarbazine]] (also termed DTIC), [[Cancer immunotherapy|immunotherapy]] (with [[interleukin-2]] (IL-2) or [[interferon]] (IFN)), as well as local perfusion, are used by different centers. The overall success in metastatic melanoma is quite limited.<ref>{{cite journal |vauthors=Bajetta E, Del Vecchio M, Bernard-Marty C, Vitali M, Buzzoni R, Rixe O, Nova P, Aglione S, Taillibert S, Khayat D |title=Metastatic melanoma: chemotherapy |journal=Semin Oncol |volume=29 |issue=5 |pages=427–45 |year=2002 |pmid=12407508 |doi=10.1053/sonc.2002.35238}}</ref>

IL-2 ([[Proleukin]]) was the first new therapy approved (1990 Europe, 1992 USA) for the treatment of metastatic melanoma in 20 years. Studies have demonstrated that IL-2 offers the possibility of a complete and long-lasting remission in this disease, although only in a small percentage of patients.<ref>{{cite journal |author=Buzaid A |title=Management of metastatic cutaneous melanoma |journal=Oncology (Williston Park) |volume=18 |issue=11 |pages=1443–50; discussion 1457–9 |year=2004 |pmid=15609471}}</ref> Intralesional IL-2 for in-transit metastases has a high complete response rate ranging from 40 to 100%.<ref name="Current_Future_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 Derm Venereol |volume=95 |issue=5 |pages=516–524 |year=2015 |pmid=25520039 |doi=10.2340/00015555-2035}}</ref>

By 2005 a number of new agents and novel approaches were under evaluation and showed promise.<ref>{{cite journal |vauthors=Danson S, Lorigan P |title=Improving outcomes in advanced malignant melanoma: update on systemic therapy |journal=Drugs |volume=65 |issue=6 |pages=733–43 |year=2005 |pmid=15819587 |doi=10.2165/00003495-200565060-00002}}</ref>

In 2009 Clinical trial participation was considered the standard of care for metastatic melanoma.<ref>{{cite journal |vauthors=Bhatia S, Tykodi SS, Thompson JA |title=Treatment of Metastatic Melanoma: An Overview |journal=Oncology |volume=23 |issue=6 |year=2009 |url=http://www.cancernetwork.com/display/article/10165/1413720 |pmid=19544689 |pages=488–96 |pmc=2737459 |deadurl=no |archiveurl=https://web.archive.org/web/20090530081051/http://www.cancernetwork.com/display/article/10165/1413720 |archivedate=2009-05-30 |df= }}</ref>

Therapies for metastatic melanoma include biologic immunotherapy agents [[ipilimumab]], [[pembrolizumab]], and [[nivolumab]];<ref name=Syn2017/> [[BRAF inhibitor]]s, such as [[vemurafenib]] and [[dabrafenib]]; and a [[MEK inhibitor]] [[trametinib]].<ref name="Current_Future_Melanoma"/>

Ongoing research is looking at treatment by [[adoptive cell transfer]].<ref>{{cite journal|last1=Rosenberg|first1=SA|last2=Restifo|first2=NP|title=Adoptive cell transfer as personalized immunotherapy for human cancer.|journal=Science|date=3 April 2015|volume=348|issue=6230|pages=62–8|pmid=25838374|doi=10.1126/science.aaa4967}}</ref> For this purpose, application of prestimulated or modified [[T cells]]<ref>{{cite journal |vauthors=Zang YW, Gu XD, Xiang JB, Chen ZY |title=Clinical application of adoptive T cell therapy in solid tumors |journal=Med. Sci. Monit. |volume=20 |pages=953–9 |year=2014 |pmid=24912947 |pmc=4063985 |doi=10.12659/MSM.890496 |url=http://www.medscimonit.com/download/index/idArt/890496 |deadurl=no |archiveurl=https://web.archive.org/web/20170629085737/http://medscimonit.com/download/index/idArt/890496 |archivedate=2017-06-29 |df= }}</ref> or [[dendritic cells]] is possible.<ref>{{cite journal |last1=Van Lint |first1=S |last2=Wilgenhof |first2=S |last3=Heirman |first3=C |last4=Corthals |first4=J |last5=Breckpot |first5=K |last6=Bonehill |first6=A |last7=Neyns |first7=B |last8=Thielemans |first8=K |title=Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula. |journal=Cancer immunology, immunotherapy : CII |date=September 2014 |volume=63 |issue=9 |pages=959–67 |pmid=24878889 |doi=10.1007/s00262-014-1558-3}}</ref>

===Lentigo maligna===

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&nbsp;mm to assure that the method approaches complete margin control.

[[Mohs surgery]] has been done with cure rate reported to be as low as 77%,<ref name=Mikhail91/> and as high as 95% by another author.<ref name=Bene08/> 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.<ref>{{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=J. Am. Acad. Dermatol. |volume=37 |issue=5 Pt 1 |pages=758–64 |date=November 1997 |pmid=9366823 |url=http://linkinghub.elsevier.com/retrieve/pii/S0190-9622(97)70114-2 |doi=10.1016/S0190-9622(97)70114-2}}</ref>

Some melanocytic nevi, and melanoma-in-situ ([[lentigo maligna]]) have resolved with an experimental treatment, [[imiquimod]] (Aldara) topical cream, an immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months.

===Radiation therapy===
[[Radiation therapy]] is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable 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.<ref>{{cite journal|last1=Hill|first1=R|last2=Healy|first2=B|last3=Holloway|first3=L|last4=Kuncic|first4=Z|last5=Thwaites|first5=D|last6=Baldock|first6=C|title=Advances in kilovoltage x-ray beam dosimetry.|journal=Physics in medicine and biology|date=21 March 2014|volume=59|issue=6|pages=R183–231|pmid=24584183|doi=10.1088/0031-9155/59/6/r183}}</ref> It may reduce the rate of local recurrence but does not prolong survival.<ref>{{cite journal |vauthors=Bastiaannet E, Beukema J, Hoekstra H | title = Radiation therapy following lymph node dissection in melanoma patients: treatment, outcome and complications | journal = Cancer Treat Rev | volume = 31 | issue = 1 | pages = 18–26 | year = 2005 | pmid = 15707701 | doi = 10.1016/j.ctrv.2004.09.005}}</ref> [[Radioimmunotherapy]] of metastatic melanoma is currently under investigation.
Radiotherapy has a role in the palliation of metastatic melanoma.<ref>{{cite book|author=Boyer|others=Ford|title=Primary Care Oncology|year=1999}}</ref>

==Prognosis==
[[File:Diagram showing the most common places for melanoma to spread to CRUK 312.svg|thumb|right|A diagram showing the most common sites for melanoma to spread]]
Features that affect [[prognosis]] are [[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 [[lymphocyte]]s (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant [[metastasis]].<ref>{{Cite journal |vauthors=Homsi J, Kashani-Sabet M, Messina J, Daud A |title=Cutaneous melanoma: prognostic factors |journal=Cancer Control |volume=12 |issue=4 |pages=223–9 |year=2005 |pmid=16258493 |url=https://www.moffitt.usf.edu/pubs/ccj/v12n4/pdf/223.pdf |archive-url=https://wayback.archive-it.org/all/20080216112052/https://www.moffitt.usf.edu/pubs/ccj/v12n4/pdf/223.pdf |dead-url=yes |archive-date=2008-02-16 |format=PDF |df= }}</ref> Certain types of melanoma have worse prognoses but this is explained by their [[Breslow's depth|thickness]]. Interestingly, 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 node]]s, 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. Macrometastases 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 malignant melanoma prognosis.<ref name=":0">{{Cite journal|last=van Kempen|first=Leon|date=2014|title=Molecular pathology of cutaneous melanoma|url=|journal=Melanoma Management|volume=1 | issue = 2 |pages=151–164}}</ref><ref name=Brunner13>{{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=J. Cancer Res. Clin. Oncol. |volume=139 |issue=2 |pages=249–58 |year=2013 |pmid=23052696 |doi=10.1007/s00432-012-1322-z |url=https://dx.doi.org/10.1007/s00432-012-1322-z}}</ref>

When there is distant metastasis, the cancer is generally considered incurable. The five-year survival rate is less than 10%.<ref name=AJCC>{{Cite journal | vauthors = Balch C, Buzaid A, Soong S, Atkins M, Cascinelli N, Coit D, Fleming I, Gershenwald J, Houghton A, Kirkwood J, McMasters K, Mihm M, Morton D, Reintgen D, Ross M, Sober A, Thompson J, Thompson J | title = Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma | journal = J Clin Oncol | volume = 19 | issue = 16 | pages = 3635–48 | year = 2001 | pmid = 11504745 | url = http://www.jco.org/cgi/content/full/19/16/3635 | deadurl = no | archiveurl = https://web.archive.org/web/20060305151011/http://www.jco.org/cgi/content/full/19/16/3635 | archivedate = 2006-03-05 | df = }}</ref> The median survival is 6–12 months. Treatment is [[Palliative care|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.<ref>{{cite journal|last1=Bae|first1=JM|last2=Choi|first2=YY|last3=Kim|first3=DS|last4=Lee|first4=JH|last5=Jang|first5=HS|last6=Lee|first6=JH|last7=Kim|first7=H|last8=Oh|first8=BH|last9=Roh|first9=MR|last10=Nam|first10=KA|last11=Chung|first11=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|date=January 2015|volume=72|issue=1|pages=59–70|pmid=25440435|doi=10.1016/j.jaad.2014.09.029}}</ref>

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|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 (gene)|TIMELESS]] and an example of a favorable gene is [[WIPI1]].<ref name="proteinatlas.org"/><ref name="Uhlen eaan2507"/>

==Epidemiology==
[[File:Worldwide Melanoma of Skin Cancer Incidence - 2008 Globocan.svg|thumb|upright=1.3|[[Age adjustment|Age-standardized]] [[Incidence (epidemiology)|new cases per year]] of melanoma of the skin per 100,000 inhabitants in 2008.<ref>{{cite web|url=http://www-dep.iarc.fr/|title=CANCERMondial (GLOBOCAN)|year=2010|work=[[GLOBOCAN]]|accessdate=12 August 2010|deadurl=no|archiveurl=https://web.archive.org/web/20120217163455/http://www-dep.iarc.fr/|archivedate=17 February 2012|df=}}</ref>{{refbegin|2}}
{{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}}
{{refend}}]]
[[File:Melanoma and other skin cancers world map-Deaths per million persons-WHO2012.svg|thumb|upright=1.3|Deaths from melanoma and other skin cancers per million persons in 2012 {{refbegin|3}}{{legend|#ffff20|0–2}}{{legend|#ffe820|3–5}}{{legend|#ffd820|6-6}}{{legend|#ffc020|7–8}}{{legend|#ffa020|9-9}}{{legend|#ff9a20|10–13}}{{legend|#f08015|14–18}}{{legend|#e06815|19–37}}{{legend|#d85010|38–51}}{{legend|#d02010|52–114}}{{refend}}]]

Globally, in 2012, melanoma occurred in 232,000 people and resulted in 55,000 deaths.<ref name=WCR2014/> Australia and New Zealand have the highest rates of melanoma in the world.<ref name=WCR2014/> It has become more common in the last 20 years in areas that are mostly [[White people|Caucasian]].<ref name=WCR2014/>

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.<ref>{{Cite journal|vauthors=Berwick M, Wiggins C | title = The current epidemiology of cutaneous malignant melanoma | journal = Front Biosci | volume = 11 | pages = 1244–54 | year = 2006| pmid = 16368510 | doi = 10.2741/1877}}</ref>

===Australia===
[[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.<ref name="aihw2012">{{cite web|url=http://aihw.gov.au/cancer/cancer-in-australia-overview-2012/|title=Cancer in Australia: an overview 2012|publisher=AIHW|deadurl=no|archiveurl=https://web.archive.org/web/20140602195619/http://aihw.gov.au/cancer/cancer-in-australia-overview-2012/|archivedate=2014-06-02|df=}}</ref> 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-standardised 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-standardised cancer incidence in Australia is the highest in the world, and this is attributable to melanoma alone. Age-standardised 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.

===United States===
In the United States about 9,000 people die from melanoma a year.<ref name=Vital2015/> In 2011 it affected 19.7 per 100,000, and resulted in death in 2.7 per 100,000.<ref name=Vital2015>{{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 Morb. Mortal. Wkly. Rep. |volume=64 |issue=21 |pages=591–6 |year=2015 |pmid=26042651 |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6421a6.htm |deadurl=no |archiveurl=https://web.archive.org/web/20170531141344/https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6421a6.htm |archivedate=2017-05-31 |df= }}</ref>

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.<ref>{{Cite web|url=https://www.cdc.gov/cancer/skin/statistics/|title=CDC – Skin Cancer Statistics|website=www.cdc.gov |access-date=2017-04-10|deadurl=no|archiveurl=https://web.archive.org/web/20170410214142/https://www.cdc.gov/cancer/skin/statistics/|archivedate=2017-04-10|df=}}</ref>
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 Hispanics.

The risk of melanoma increases as people age. The average age of people when the disease is diagnosed is 63.<ref>{{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=2017-04-10|deadurl=no|archiveurl=https://web.archive.org/web/20170410135926/https://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html|archivedate=2017-04-10|df=}}</ref>

==History==
{{see also|Timeline of melanoma}}
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 [[Peru]]vian 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.<!--
--><ref name="urteaga">{{Cite journal|vauthors=Urteaga O, Pack G | title = On the antiquity of melanoma | journal = Cancer | volume = 19 | issue = 5 | pages = 607–10 | year = 1966 | pmid = 5326247 | doi = 10.1002/1097-0142(196605)19:5<607::AID-CNCR2820190502>3.0.CO;2-8}}</ref>

[[John Hunter (surgeon)|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 and Wellcome Museums|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.<!--
--><ref name="bodenham">{{Cite journal| author = Bodenham D | 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 = 218–39 | year = 1968 | pmid = 5698493 | pmc = 2312310}}</ref>

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.<!--
--><ref name="laennec">{{Cite journal| author = Laennec RTH | year = 1806 | title = Sur les melanoses | journal = Bulletin de la Faculte de Medecine de Paris | volume = 1 | pages = 24–26}}</ref>
The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820.<ref name="norris1">{{cite journal |author=Norris, W. |title=A case of fungoid disease |journal=Edinb. Med. Surg. J. |volume=16 |pages=562–5 |year=1820 }}</ref> 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.<ref>Norris W. Eight cases of Melanosis with pathological and therapeutical remarks on that disease. London: Longman; 1857.</ref> 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 (surgeon)|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) ...'<ref name="cooper">{{cite book|last=Cooper|first=Samuel|title=The First Lines of the Theory and Practice of Surgery: Including the Principle Operations|url={{google books |plainurl=y |id=hgE0AQAAMAAJ}}|year=1844|publisher=S.S. and W. Wood}}</ref>

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

The word melanoma is from the [[Greek language|Greek]] μέλας ''melas'' meaning "dark".<ref>[http://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dme%2Flas μέλας] {{webarchive|url=https://web.archive.org/web/20110605183904/http://www.perseus.tufts.edu/hopper/text?doc=Perseus%3Atext%3A1999.04.0057%3Aentry%3Dme%2Flas |date=2011-06-05 }}, Henry George Liddell, Robert Scott, ''A Greek-English Lexicon'', on Perseus</ref>

==Research==
Pharmacotherapy research for unresectable or metastatic malignant melanoma offers new treatment possibilities.<ref name="melanoma2012">{{cite journal|title=Drugs in Clinical Development for Melanoma|journal=Pharmaceutical Medicine|date=23 December 2012|volume=26|issue=3|pages=171–183|doi=10.1007/BF03262391|url=http://adisonline.com/pharmaceuticalmedicine/Abstract/2012/26030/Drugs_in_Clinical_Development_for_Melanoma__.4.aspx}}</ref> In addition to the advances with recently approved agents, ongoing research into combination therapy, such as dabrafenib and trametinib, may reveal a more effective and better-tolerated option for patients with metastatic melanoma. One important pathway in [[melanin]] synthesis involves the transcription factor [[Microphthalmia-associated transcription factor|MITF]]. The [[MITF gene]] is highly conserved and is found in people, mice, birds, and even fish. MITF production is regulated via a fairly straightforward pathway. [[UV radiation]] causes increased expression of transcription factor [[p53]] in [[keratinocytes]], and p53 causes these cells to produce [[melanocyte-stimulating hormone]] (MSH), which binds to [[melanocortin 1 receptor]]s (MC1R) on [[melanocytes]]. Ligand-binding at MC1R receptors activates [[adenylate cyclase]]s, which produce [[Cyclic adenosine monophosphate|cAMP]], which activates [[CREB]], which promote MITF expression. The targets of MITF include [[p16 (gene)|p16]] (a [[CDK inhibitor]]) and [[Bcl2]], a gene essential to melanocyte survival. It is often difficult to design drugs that interfere with transcription factors, but perhaps new drugs will be discovered that can impede some reaction in the pathway upstream of MITF.

Studies of [[chromatin]] structure also promise to shed light on transcriptional regulation in melanoma cells.<ref>{{cite journal | author = Bastonini E | date = Sep 2014 | title = Chromatin barcodes as biomarkers for melanoma | journal = Pigment Cell Melanoma Res | volume = 27 | issue = 5| pages = 788–800 | doi = 10.1111/pcmr.12258 |pmid=24807349 |display-authors=etal}}</ref> It has long been assumed that [[nucleosomes]] are positioned randomly on [[DNA]], but [[murine]] studies of genes involved in melanin production now suggest that nucleosomes are stereotypically positioned on DNA. When a gene is undergoing transcription, its transcription start site is almost always nucleosome-free. When the gene is silent, however, nucleosomes often block the transcriptional start site, suggesting that nucleosome position may play a role in gene regulation. In addition to genetic mutations, evidence demonstrates that epigenetic events (e.g. loss of DNA hydroxymethylation 5-hydroxymethylcytosine) also play roles in melanoma tumorigenesis.<ref>{{Cite journal|title = Loss of 5-Hydroxymethylcytosine Is an Epigenetic Hallmark of Melanoma|url = http://www.cell.com/article/S0092867412010124/abstract|journal = Cell |pmc = 3770275 |pmid = 22980977|pages = 1135–46|volume = 150|issue = 6|doi = 10.1016/j.cell.2012.07.033|language = English|first = Christine Guo|last = Lian|first2 = Yufei|last2 = Xu|first3 = Craig|last3 = Ceol|first4 = Feizhen|last4 = Wu|first5 = Allison|last5 = Larson|first6 = Karen|last6 = Dresser|first7 = Wenqi|last7 = Xu|first8 = Li|last8 = Tan|first9 = Yeguang|last9 = Hu}}</ref>

===Targeted therapies===

In clinical research setting other therapies, such as adoptive cell therapy or [[gene therapy]], are being tested.<ref>{{cite journal |vauthors=Sotomayor M, Yu H, Antonia S, Sotomayor E, Pardoll D | title = Advances in gene therapy for malignant melanoma | journal = Cancer Control | volume = 9 | issue = 1 | pages = 39–48 | year = 2002| pmid = 11907465}}</ref>

Two kinds of experimental treatments developed at the [[National Cancer Institute]] (NCI), have been used in metastatic melanoma with tentative success.<ref name=Hershkovitz10>{{cite journal |vauthors=Hershkovitz L, Schachter J, Treves AJ, Besser MJ |title=Focus on adoptive T cell transfer trials in melanoma |journal=Clin. Dev. Immunol. |volume=2010 |page=260267 |year=2010 |pmid=21234353 |pmc=3018069 |doi=10.1155/2010/260267 }}</ref>

The first treatment involves adoptive cell therapy (ACT) using TILs immune cells (tumor infiltrating lymphocytes) isolated from a person's own melanoma tumor.<ref name="Current_Future_Melanoma"/> 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.<ref>{{cite journal |vauthors=Dudley ME, Yang JC, Sherry R, etal |title=Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens |journal=J. Clin. Oncol. |volume=26 |issue=32 |pages=5233–9 |date=November 2008 |pmid=18809613 |pmc=2652090 |doi=10.1200/JCO.2008.16.5449 |url=http://jco.ascopubs.org/content/26/32/5233.full |deadurl=no |archiveurl=https://web.archive.org/web/20150210005932/http://jco.ascopubs.org/content/26/32/5233.full |archivedate=2015-02-10 |df= }}</ref><ref name=Besser10>{{cite journal |vauthors=Besser MJ, Shapira-Frommer R, Treves AJ, etal |title=Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients |journal=Clin. Cancer Res. |volume=16 |issue=9 |pages=2646–55 |date=May 2010 |pmid=20406835 |doi=10.1158/1078-0432.CCR-10-0041 |url=http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=20406835}}</ref>

The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called [[T cell receptor]]s (TCRs), into patient's lymphocytes.<ref name="Current_Future_Melanoma"/> After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.<ref name="nih">{{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|publisher=|deadurl=no|archiveurl=https://web.archive.org/web/20060928214625/http://www.nih.gov/news/pr/aug2006/nci-31b.htm|archivedate=28 September 2006|df=}}</ref>

A vaccine to train the immune system to fight cancer showed modest benefit in late-stage testing in 2009 against melanoma.<ref>{{cite news |title=Immune System Taught To Fight Melanoma |date=30 May 2009 |publisher=CBSNews |url=http://www.cbsnews.com/stories/2009/05/30/health/main5050957.shtml |deadurl=no |archiveurl=https://web.archive.org/web/20101029214646/http://www.cbsnews.com/stories/2009/05/30/health/main5050957.shtml |archivedate=29 October 2010 |df= }}</ref><ref>{{Cite journal | doi = 10.1056/NEJMoa1012863| pmid=21631324 |pmc=3517182 |title = Gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma| journal = New England Journal of Medicine| volume = 364| issue = 22| pages = 2119–27| year = 2011| last1 = Schwartzentruber | first1 = D. J. | last2 = Lawson | first2 = D. H. | last3 = Richards | first3 = J. M. | last4 = Conry | first4 = R. M. | last5 = Miller | first5 = D. M. | last6 = Treisman | first6 = J. | last7 = Gailani | first7 = F. | last8 = Riley | first8 = L. | last9 = Conlon | first9 = K. | last10 = Pockaj | first10 = B. | last11 = Kendra | first11 = K. L. | last12 = White | first12 = R. L. | last13 = Gonzalez | first13 = R. | last14 = Kuzel | first14 = T. M. | last15 = Curti | first15 = B. | last16 = Leming | first16 = P. D. | last17 = Whitman | first17 = E. D. | last18 = Balkissoon | first18 = J. | last19 = Reintgen | first19 = D. S. | last20 = Kaufman | first20 = H. | last21 = Marincola | first21 = F. M. | last22 = Merino | first22 = M. J. | last23 = Rosenberg | first23 = S. A. | last24 = Choyke | first24 = P. | last25 = Vena | first25 = D. | last26 = Hwu | first26 = P. }}</ref>

===BRAF inhibitors===
About 60% of melanomas contain a mutation in the [[BRAF (gene)|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.<ref>{{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 | first=Amy | last=Harmon | date=February 21, 2010 | deadurl=no | archiveurl=https://web.archive.org/web/20170210085433/http://www.nytimes.com/2010/02/22/health/research/22trial.html | archivedate=February 10, 2017 | df= }}</ref> In June 2011, a large [[clinical trial]] confirmed the positive findings from those earlier trials.<ref name="studies">{{cite news|publisher=New York Times|author=Andrew Pollack|date=June 5, 2011|title=Drugs Show Promise Slowing Advanced Melanoma|url=https://www.nytimes.com/2011/06/06/health/research/06melanoma.html|deadurl=no|archiveurl=https://web.archive.org/web/20170131105246/http://www.nytimes.com/2011/06/06/health/research/06melanoma.html|archivedate=January 31, 2017|df=}}</ref><ref name="pmid21639808">{{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, ((BRIM-3 Study Group)) |title=Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation|journal=New England Journal of Medicine|date=30 June 2011|volume=364|issue=26|pages=2507–16|doi=10.1056/NEJMoa1103782|pmid=21639808|pmc=3549296}}</ref>

In August 2011 Vemurafenib received FDA approval for the treatment of late-stage melanoma. In May 2013 the [[Food and Drug Administration|US FDA]] approved dabrafenib as a single agent treatment for patients with BRAF V600E mutation-positive advanced melanoma.<ref name=r20150530>{{cite news | url = https://www.reuters.com/article/2013/05/30/us-glaxosmithkline-approvals-idUSBRE94S1A020130530 | title = GSK melanoma drugs add to tally of U.S. drug approvals | publisher = Reuters | date = May 30, 2013 | deadurl = no | archiveurl = https://web.archive.org/web/20150924181713/http://www.reuters.com/article/2013/05/30/us-glaxosmithkline-approvals-idUSBRE94S1A020130530 | archivedate = September 24, 2015 | df = }}</ref>

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.
<ref>{{cite news|publisher=News Medical|date=October 1, 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|deadurl=no|archiveurl=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|archivedate=May 14, 2013|df=}}</ref><ref name="pmid23020132">{{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 3rd, 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=New England Journal of Medicine|date=1 November 2012|volume=367|issue=18|pages=1694–1703|doi=10.1056/NEJMoa1210093|pmid=23020132|pmc=3549295}}</ref>

In January 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of patients with BRAF V600E/K-mutant metastatic melanoma.<ref>{{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 = January 9, 2014 | deadurl = no | archiveurl = https://web.archive.org/web/20140125190539/http://www.onclive.com/web-exclusives/FDA-Approves-First-Ever-Combination-for-Metastatic-Melanoma | archivedate = January 25, 2014 | df = }}</ref>

Eventual resistance to BRAF and MEK inhibitors may be due to a cell surface protein known as [[EPH receptor A2|EphA2]] which is now being investigated.<ref>{{cite web |url=http://www.oncotherapynetwork.com/skin-cancer-melanoma-targets/counteracting-drug-resistance-melanoma |title=Counteracting Drug Resistance in Melanoma |year=2015 |deadurl=no |archiveurl=https://web.archive.org/web/20150204044952/http://www.oncotherapynetwork.com/skin-cancer-melanoma-targets/counteracting-drug-resistance-melanoma |archivedate=2015-02-04 |df= }}</ref>

===Ipilimumab===
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.<ref>{{cite news | title = Bristol drug cuts death risk in advanced melanoma | url = https://www.reuters.com/article/idUSN0218461520100605 | work = Reuters | date = June 5, 2010 | deadurl = no | archiveurl = https://web.archive.org/web/20101109095301/http://www.reuters.com/article/idUSN0218461520100605 | archivedate = November 9, 2010 | df = }}</ref> 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.<ref>{{cite news |url=https://blogs.forbes.com/sciencebiz/2010/06/the-risk-for-bristol/ |title=The Risk For Bristol |work=Forbes |deadurl=yes |archiveurl=https://web.archive.org/web/20110315041905/http://blogs.forbes.com/sciencebiz/2010/06/06/the-risk-for-bristol/ |archivedate=2011-03-15 }}</ref><ref>{{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=2010-06-09 |accessdate=2012-08-13 |deadurl=no |archiveurl=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 |archivedate=2012-10-19 |df= }}</ref> 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.<ref>{{cite press release |url=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm |title=FDA approves new treatment for a type of late-stage skin cancer |author=Jefferson E |date=2011-03-25 |publisher=[[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) |accessdate=2011-03-25 |deadurl=no |archiveurl=https://web.archive.org/web/20110327063147/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm1193237.htm |archivedate=2011-03-27 |df= }}</ref><ref>{{cite news |url=https://www.nytimes.com/2011/03/26/business/26drug.html |title=Approval for Drug That Treats Melanoma |author=Pollack, Andrew |date=2011-03-25 |work=[[The New York Times]] |accessdate=2011-03-27 |deadurl=no |archiveurl=https://web.archive.org/web/20110401011816/http://www.nytimes.com/2011/03/26/business/26drug.html |archivedate=2011-04-01 |df= }}</ref><ref name="Drugs.com">Drugs.com: [http://www.drugs.com/yervoy.html Yervoy] {{webarchive|url=https://web.archive.org/web/20110809231412/http://www.drugs.com/yervoy.html |date=2011-08-09 }}</ref>

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 that perhaps 10–20% of patients could live a long time. Some serious side-effects of revving up the immune system were seen in some patients. A course of treatment costs $120,000. The drug's brandname is Yervoy.<ref name="studies"/><ref>{{cite journal |vauthors=Robert C, Thomas L, Bondarenko I, etal |title=Ipilimumab plus dacarbazine for previously untreated metastatic melanoma |journal=N. Engl. J. Med. |volume=364 |issue=26 |pages=2517–26 |date=June 2011 |pmid=21639810 |doi=10.1056/NEJMoa1104621 |url=http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 |deadurl=no |archiveurl=https://web.archive.org/web/20110609014640/http://www.nejm.org/doi/full/10.1056/NEJMoa1104621 |archivedate=2011-06-09 |df= }}</ref>

===Surveillance methods===
Advances in high resolution ultrasound scanning have enabled surveillance of metastatic burden to the sentinel lymph nodes.<ref>{{cite journal |vauthors=Voit C, Van Akkooi AC, Schäfer-Hesterberg G, etal |title=Ultrasound morphology criteria predict metastatic disease of the sentinel nodes in patients with melanoma |journal=J. Clin. Oncol. |volume=28 |issue=5 |pages=847–52 |date=February 2010 |pmid=20065175 |doi=10.1200/JCO.2009.25.7428 |url=http://www.jco.org/cgi/pmidlookup?view=long&pmid=20065175}}</ref> The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) is evaluating ultrasound as an alternative to invasive surgical methods.<ref>{{cite web|url=http://www.malignant-melanoma.org/sunmel |title=malignant-melanoma.org |publisher= |deadurl=yes |archiveurl=https://web.archive.org/web/20111014181613/http://www.malignant-melanoma.org/sunmel/ |archivedate=2011-10-14 |df= }}</ref>

===Oncolytic virotherapy===
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.<ref>{{cite journal|last=Forbes|first=NE|author2=Abdelbary, H|author3= Lupien, M|author4= Bell, JC|author5= Diallo, JS|title=Exploiting tumor epigenetics to improve oncolytic virotherapy.|journal=Frontiers in Genetics|date=Sep 20, 2013|volume=4|page=184|pmid=24062768|doi=10.3389/fgene.2013.00184|pmc=3778850}}</ref> 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.<ref>{{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 Jr, 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|date=2015|doi=10.1200/JCO.2014.58.3377|volume=33 |issue=25|pages=2780–8 |pmid=26014293}}</ref><ref name=Syn2017/>

==References==
{{Reflist}}

==External links==
{{Medical condition classification and resources

| DiseasesDB = 7947
| ICD10 = {{ICD10|C|43||c|43}}
| 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
}}

{{Wiktionary-inline|melanoma}}

{{Commons category-inline|Melanoma}}
* {{DMOZ|Health/Conditions_and_Diseases/Cancer/Melanoma/}}

{{Diseases of the skin and appendages by morphology}}
{{Skin tumors, nevi and melanomas}}

{{Authority control}}

[[Category:Melanoma]]
[[Category:RTT]]

Revision as of 22:29, 12 January 2018

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