Melanoma 716631 225626548 2008-07-14T16:55:08Z 75.131.228.158 /* Complications */ {{Mergefrom|ABCD guideline|date=June 2008}} {{Infobox_Disease | Name = Melanoma-Skin Cancer Disease | Image = WB032021.JPG| Caption = | Width = 225 | DiseasesDB = 7947 | ICD10 = {{ICD10|C|43||c|43}} | ICD9 = {{ICD9|172}} | ICDO = {{ICDO|8720|3}} | OMIM = 155600 | MedlinePlus = 000850 | eMedicineSubj = derm | eMedicineTopic = 257 | eMedicine_mult = {{eMedicine2|med|1386}} {{eMedicine2|ent|27}} {{eMedicine2|plastic|456}} | }} '''Melanoma''' is a malignant [[tumor]] of [[melanocyte]]s which are found predominantly in skin but also in the [[bowel]] and the [[eye]] (see [[uveal melanoma]]). It is one of the rarer types of [[skin cancer]] but causes the majority of skin cancer related deaths. Malignant melanoma is a serious type of skin cancer. It is due to uncontrolled growth of pigment cells, called melanocytes.<ref>[http://www.nlm.nih.gov/medlineplus/news/fullstory_34983.html Melanoma Death Rate Still Climbing]</ref><ref>[http://seer.cancer.gov/statfacts/html/melan.html Cancer Stat Fact Sheets]</ref> Despite many years of intensive laboratory and clinical research, the sole effective cure is surgical resection of the primary tumor before it achieves a [[Breslow thickness]] greater than 1&nbsp;mm. On June 23, 2008, Israeli scientists from the Oncology Institute of the Hadassa Medical Center in Jerusalem [http://www.israelnationalnews.com/News/Flash.aspx/148679 announced] they developed a vaccine that prevents recurrences of the disease among previous sufferers and increases chances of survival for current ones. Around 160,000 new cases of melanoma are diagnosed worldwide each year, and it is more frequent in males and caucasians.<ref name="Stat">Ries LAG, et al, eds. SEER Cancer Statistics Review, 1975-2000. Bethesda, MD: National Cancer Institute; 2003: Tables XVI-1-9.</ref> It is more common in caucasian populations living in sunny climates than other groups.<ref>{{cite journal | author = Parkin D, Bray F, Ferlay J, Pisani P | title = Global cancer statistics, 2002 | journal = CA Cancer J Clin | volume = 55 | issue = 2 | pages = 74–108 | year = | pmid = 15761078}}''[http://caonline.amcancersoc.org/cgi/content/full/55/2/74 Full text]''</ref> According to the [[WHO]] Report about 48,000 melanoma related deaths occur worldwide per annum.<ref name="who1">Lucas, R. Global Burden of Disease of Solar Ultraviolet Radiation, Environmental Burden of Disease Series, July 25, 2006; No. 13. News release, World Health Organization</ref> Malignant melanoma accounts for 75 percent of all deaths associated with skin cancer.<ref>[http://www.aafp.org/afp/20000715/357.html Treatment of Skin Cancer]</ref> The treatment includes surgical removal of the tumor; [[adjuvant]] treatment; [[chemotherapy|chemo-]] and [[Cancer immunotherapy|immunotherapy]], or [[radiation therapy]]. ==History== 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 [[Inca Empire|Inca]] 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 | author = 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 [[Royal College of Surgeons of England#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 = Ann R Coll Surg Engl | volume = 43 | issue = 4 | pages = 218–39 | year = 1968 | pmid = 5698493}}</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"> Norris, W. ''A case of fungoid disease.'', Edinb. Med. Surg. 1820, 16: 562-565.</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''). 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 benefit depends upon the early removal of the disease ...'<ref name="cooper">{{cite book | last = Cooper | first = Samuel | title = First lines of theory and practice of surgery | publisher = Longman, Orme, Brown, Green and Longman | date = 1840 | location = London}}</ref> More than one and a half centuries later this situation remains largely unchanged. In 1956, Australian professor Henry Oliver Lancaster discovered that melanomas were directly associated with [[latitude]] (ie, intensity of [[sunlight]]); and that exposure to the sun was a very high factor in the development of the cancer{{Fact|date=July 2007}}. ==Epidemiology & Causes== Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental.<ref>[http://www.skincarephysicians.com/skincancernet/who_is_most.html Who is Most at Risk for Melanoma?]</ref> "Intrinsic" factors are generally an individual's family history and inherited [[genotype]], while the most relevant environmental factor is sun exposure. [[Epidemiologic]] studies suggest that exposure to [[ultraviolet]] radiation (UVA<ref name="uva">{{cite journal | author = 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. 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 [[oncogene]]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]]. Occasional extreme sun exposure (resulting in "[[sunburn]]") is causally related to melanoma.<ref>{{cite journal | author = 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}}</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 | author = 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}}</ref><ref>{{cite journal |author=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 |year=1995 |month=January |pmid=7804988 |doi= |url=}}</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. 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]]. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in [[Australia]]<ref>{{cite journal | author = 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> where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that [[sunscreen]] - while preventing the sunburn - does not protect from melanoma. <ref name=Wolf1993> {{cite journal |author= Wolf P; Donawho C K; Kripke M L |title= Effect of Sunscreens on UV radiation-induced enhancements of melanoma in mice | journal= J. nat. Cancer. Inst. |volume=86 |pages=99–105 |year=1994 |doi= 10.1093/jnci/86.2.99 |pmid= 8271307}}</ref> Many researchers say that sunscreen can even increase the melanoma risk (see [http://vvv.com/healthnews/dsunscre.html Sunscreens and Cancer by Hans R Larsen]). Fair and red-headed 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 | author = 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 ''[[CDKN2A]]'', ''[[CDK4]]'' and several other genes have been found in melanoma-prone families.<ref>{{cite journal | author = 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> Patients with a history of one melanoma are at increased risk of developing a second primary tumour.<ref>{{cite journal | author = 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> The incidence 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 | author = Berwick M, Wiggins C | title = The current epidemiology of cutaneous malignant melanoma | journal = Front Biosci | volume = 11 | issue = | pages = 1244–54 | year = 2006| pmid = 16368510 | doi = 10.2741/1877}}</ref> To understand how sunscreen can reduce sunburn and at the same time cause melanoma it is necessary to distinguish between [[direct DNA damage]] and [[indirect DNA damage]]. Genetic analysis has shown, that 92% of all melanoma are caused by the indirect DNA damage.<ref name=Davies> {{cite journal |author=Davies H.; Bignell G. R.; Cox C.; |year= 2002 |month=6 |title= Mutations of the BRAF gene in human cancer |journal= Nature |volume= 417 |issue= |pages=949–954 |id= |url= http://www.nature.com/nature/journal/v417/n6892/full/nature00766.html |doi=10.1038/nature00766}}</ref> Though some people don't think African American people can get sun burns they can get them as well as any other person could. They too should use sun block. The recommended amount of sun blocks for adults is 4 oz which is enough to fill a shot glass. ==Genetics== 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 = 2464–2477 | year = 1998 | pmid = 10630172 | doi = 10.1002/(SICI)1097-0142(19991201)86:11 <2464::AID-CNCR3>3.0.CO;2-F | doi_brokendate = 2008-06-21}}</ref> and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma.<ref>{{cite journal | author = Halachmi S, Gilchrest BA. | title = Update on genetic events in the pathogenesis of melanoma | journal = Curr Opin Oncol | 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>[http://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)] from Entrez Gene</ref> Today, melanomas are diagnosed only after they become visible on the skin. In the future, however, physicians will hopefully be able detect melanomas based on a patient’s [[genotype]], not just his or her [[phenotype]]. Recent genetic advances promise to help doctors to identify people with high-risk genotypes and to determine which of a person’s lesions have the greatest chance of becoming cancerous. A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. One class of mutations affects the gene [[CDKN2A]]. An alternative [[reading frame]] mutation in this gene leads to the destabilization of [[p53]], a [[transcription factor]] involved in [[apoptosis]] and in fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor of [[CDK4]], a [cyclin-dependent kinase] that promotes cell division. Mutations that cause the skin condition [[Xeroderma Pigmentosum]] (XP) also seriously predispose one to melanoma. Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant. Other mutations confer lower risk but are more prevalent 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 copies of the gene. [[Melanocortin 1 receptor|MC1R]] mutations are very common; in fact, all people with red hair have a mutated copy of the gene. Two-gene models of melanoma risk have already been created, and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype. In addition to identifying high-risk patients, researchers also want to identify high-risk lesions within a given patient. Many new technologies, such as [[optical coherence tomography]] (OCT), are being developed to accomplish this. OCT allows pathologists to view 3-D reconstructions of the skin and offers more resolution than past techniques could provide. In vivo [[confocal microscopy]] and fluorescently tagged [[antibodies]] are also proving to be valuable diagnostic tools. ==Detection and prevention== 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. In the past it was recommended to use [[sunscreen]]s with an [[sunscreen|SPF]] rating of 30 or higher on exposed areas.<ref>[http://www.cancer.org/docroot/cri/content/cri_2_4_2x_can_melanoma_be_prevented_50.asp Can Melanoma Be Prevented?]</ref> However, there are severe doubts about the ability of [[sunscreen]] to prevent melanoma.<ref>{{cite journal |author=Garland C, Garland F, Gorham E |title=Could sunscreens increase melanoma risk? |url= http://www.ajph.org/cgi/reprint/82/4/614| journal=Am J Public Health |volume=82 |issue=4 |pages=614–5 |year=1992 |pmid=1546792 |issn=}}</ref> [[Image:WB032021.JPG|thumb|230px|A melanoma showing irregular borders and colour, diameter over 10&nbsp;mm and asymmetry (ie A, B, C and D.)]] To prevent or detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCDE" mnemonic below), to be aware of [[Melanocytic nevus|moles]] and check for changes (shape, size, color, itching or bleeding) and to show any suspicious moles to a doctor with an interest and skills in skin malignancy.<ref>{{cite journal | author = 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 | doi = 10.3322/canjclin.35.3.130}}</ref> A popular method for remembering the signs and symptoms of melanoma is the mneumonic "ABCDE": * '''A'''symmetrical skin lesion. * '''B'''order of the lesion is irregular. * '''C'''olor: melanomas usually have multiple colors. * '''D'''iameter: moles greater than 5&nbsp;mm are more likely to be melanomas than smaller moles. * '''E'''volution: The evolution (ie change) of a mole or lesion may be a hint that the lesion is becoming malignant --or-- '''E'''levation: The mole is raised or elevated above the skin. The '''E''' is sometimes omitted, as in the [[ABCD guideline]]. People with a personal or family history of skin cancer or of [[dysplastic nevus syndrome]] (multiple atypical moles) should see a dermatologist at least once a year to be sure they are not developing melanoma. ==Diagnosis== Moles that are irregular in color or shape are suspicious of a malignant or a premalignant melanoma. Following a visual examination and a [[Dermatoscopy|dermatoscopic exam]] (an instrument that illuminates a mole, revealing its underlying pigment and vascular network structure), or an examination using other ''in vivo'' diagnostic tools, such as a confocal microscope, the doctor may biopsy the suspicious mole. If it is malignant, the mole and an area around it needs excision. The diagnosis of melanoma requires experience, as early stages may look identical to harmless [[Mole (skin marking)|moles]] or not have any color at all. A [[biopsy]] performed under [[local anesthesia]] is often required to assist in making or confirming the [[diagnosis]] and in defining the severity of the melanoma. ''Excisional biopsy'' is the management of choice; this is where the suspect lesion is totally removed with an adequate ellipse of surrounding skin and tissue.<ref>{{cite journal | author = Swanson N, Lee K, Gorman A, Lee H | title = Biopsy techniques. Diagnosis of melanoma | journal = Dermatol Clin | volume = 20 | issue = 4 | pages = 677–80 | year = 2002 | pmid = 12380054 | doi = 10.1016/S0733-8635(02)00025-6}}</ref> The biopsy will include the epidermal, dermal, and subcutaneous layers of the skin, enabling the [[pathology|histopathologist]] to determine the depth of penetration of the melanoma by microscopic examination. This is described by [[Clark's level]] (involvement of skin structures) and [[Breslow's depth]] (measured in millimeters). [[Image:Malignant melanoma (1) at thigh Case 01.jpg|100px|Malignant melanoma in skin biopsy with [[Hematoxylin|H]] and [[eosin|E]] stain.]] [[Image:Malignant melanoma (2) at thigh Case 01.jpg|100px|This case may represent superficial spreading melanoma.]] [[Image:Malignant melanoma (3) at thigh Case 01.jpg|100px|The same case as the last one.]] [[Image:Malignant melanoma (4) at thigh Case 01.jpg|100px|Enlargement of the image.]] If an excisional biopsy is not possible in certain larger pigmented lesions, a ''punch biopsy'' may be performed using a surgical punch (an instrument similar to a tiny cookie cutter with a handle, with an opening ranging in size from 1 to 6&nbsp;mm). The punch is used to remove a plug of skin (down to the subcutaneous layer) from a portion of a large suspicious lesion, for histopathological examination. [[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 nodes are also performed in patients to assess spread to the lymph nodes. Sometimes the skin lesion may bleed, itch, or ulcerate, although this is a very late sign. A slow-healing lesion should be watched closely, as that may be a sign of melanoma. Be aware also that in circumstances that are still poorly understood, melanomas may "regress" or spontaneously become smaller or invisible - however the malignancy is still present. '''Amelanotic''' (colorless or flesh-colored) melanomas do not have pigment and may not even be visible. '''[[Lentigo]] maligna''', a superficial melanoma confined to the topmost layers of the skin (found primarily in older patients) is often described as a "stain" on the skin. Some patients with metastatic melanoma do not have an obvious detectable primary tumor. ==Types of primary melanoma== The most common types of Melanoma in the skin: * [[superficial spreading melanoma]] (SSM) * [[nodular melanoma]] * [[acral lentiginous melanoma]] * [[lentigo maligna melanoma|lentigo maligna (melanoma)]] Any of the above types may produce melanin (and be dark in colour) or not (and be amelanotic - not dark). Similarly any subtype may show desmoplasia (dense fibrous reaction with neurotropism) which is a marker of aggressive behaviour and a tendency to local recurrence. Elsewhere: * [[clear cell tumor|clear cell sarcoma]] (Melanoma of Soft Parts) * [[mucosal melanoma]] * [[uveal melanoma]] ==Prognostic factors== {{see also|Breslow's depth}} 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 | author = 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}}''[https://www.moffitt.usf.edu/pubs/ccj/v12n4/pdf/223.pdf Full text (PDF)]''</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 still worse. 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 | author = 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}}''[http://www.jco.org/cgi/content/full/19/16/3635 Full text]''</ref> The median survival is 6 to 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. 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. ==Staging== ''Further context on [[cancer staging]] is available at [[TNM]].'' Also of importance are the "Clark level" and "Breslow depth" which refer to the microscopic depth of tumor invasion.<ref> [http://chorus.rad.mcw.edu/doc/00955.html Malignant melanoma: staging] at Collaborative Hypertext of Radiology</ref> Melanoma stages:<ref name=AJCC /> '''Stage 0''': Melanoma in Situ (Clark Level I), 100% Survival '''Stage I/II''': Invasive Melanoma, 85-95% Survival *T1a: Less than 1.00&nbsp;mm primary, w/o Ulceration, Clark Level II-III *T1b: Less than 1.00&nbsp;mm primary, w/Ulceration or Clark Level IV-V *T2a: 1.00-2.00&nbsp;mm primary, w/o Ulceration '''Stage II''': High Risk Melanoma, 40-85% Survival *T2b: 1.00-2.00&nbsp;mm primary, w/ Ulceration *T3a: 2.00-4.00&nbsp;mm primary, w/o Ulceration *T3b: 2.00-4.00&nbsp;mm primary, w/ Ulceration *T4a: 4.00&nbsp;mm or greater primary w/o Ulceration *T4b: 4.00&nbsp;mm or greater primary w/ Ulceration '''Stage III''': Regional Metastasis, 25-60% Survival *N1: Single Positive Lymph Node *N2: 2-3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis *N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases '''Stage IV''': Distant Metastasis, 9-15% Survival *M1a: Distant Skin Metastasis, Normal [[Lactate dehydrogenase|LDH]] *M1b: Lung Metastasis, Normal [[Lactate dehydrogenase|LDH]] *M1c: Other Distant Metastasis OR Any Distant Metastasis with Elevated [[Lactate dehydrogenase|LDH]] ''Based Upon AJCC 5-Year Survival With Proper Treatment'' ==Treatment== Surgery is the first choice therapy for localized cutaneous melanoma. Depending on the stage a [[sentinel lymph node]] biopsy is done as well, although [http://www.malignant-melanoma.org/sentinel-node-biopsy/sentinel-node-biopsy-false-positivity/ controversy exists around trial evidence] for this procedure. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach. ===Surgery=== [[Image:Sentinel lymph node (axilla).jpg|thumb|370px|A blue stained sentinel lymph node in the [[axilla]].]] Diagnostic punch or excisional biopsies may appear to excise (and in some cases may indeed actually remove) the tumor, but further surgery is often necessary to reduce the risk of recurrence. Complete surgical excision with adequate margins and assessment for the presence of detectable metastatic disease along with short- and long-term followup is standard. Often this is done by a "wide local excision" (WLE) with 1 to 2&nbsp;cm margins. The wide excision aims to reduce the rate of tumour 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. There of 2&nbsp;cm margins for even the thickest tumors.<ref>{{cite journal | author = 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}}</ref> Melanomas which spread usually do so to the [[lymph nodes]] in the region of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically ([[lymphadenectomy]]) were associated with many complications but unfortunately 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.[http://www.malignant-melanoma.org/surgery/lymph-node-dissection-surgery/] Although controversial and without prolonging survival, "sentinel lymph node" biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. A process called [[lymphoscintigraphy]] is performed in which a radioactive tracer is injected at the tumor site in order 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 staining, 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 SLN actually had a small number of positive cells in their nodes. Alternatively, a fine-needle aspiration 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. ===Adjuvant treatment=== High risk melanomas may require adjuvant treatment. 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.<ref>{{cite journal | author = 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> This claim is not supported by all research at this time, and in Europe interferon is usually not used outside the scope of clinical trials.<ref>{{cite journal | author = 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 | author = 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 | author = 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 are used, including [[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. They can occasionally show dramatic success, but the overall success in metastatic melanoma is quite limited.<ref>{{cite journal | author = 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) is the first new therapy approved 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> A number of new agents and novel approaches are under evaluation and show promise.<ref>{{cite journal | author = 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> ===Lentigo maligna treatment=== Some superficial melanomas (lentigo maligna) have resolved with an experimental treatment, [[imiquimod]] (Aldara) topical cream, an immune enhancing agent. Application of this cream has been shown to decrease tumor size prior to surgery, reducing the invasiveness of the procedure. This treatment is used especially for smaller melanoma in situ lesions located in cosmetically sensitive regions. Several published studies demonstrate a 70% cure rate with this topical treatment. With lentigo maligna, surgical cure rates are no higher. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months. ===Radiation and other therapies=== [[Radiation therapy]] is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. It may reduce the rate of local recurrence but does not prolong survival.<ref>{{cite journal | author = 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> In research setting other therapies, such as [[gene therapy]], may be tested.<ref>{{cite journal | author = 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 = | pmid = 11907465}}''[https://www.moffitt.usf.edu/pubs/ccj/v9n1/pdf/39.pdf Full text (PDF)]''</ref> [[Radioimmunotherapy]] of metastatic melanoma is currently under investigation. Experimental treatment developed at the National Cancer Institute (NCI), part of the National Institutes of Health in the US was used in advanced (metastatic) melanoma with moderate success. The treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.<ref name="nih">[http://www.nih.gov/news/pr/aug2006/nci-31b.htm Press release from the NIH]</ref> ==Complications== People with melanoma may not feel like eating, especially if they are uncomfortable or tired. Foods may taste different than they did previously. Poor appetite, nausea, or vomiting are all side-effects of melanoma. Good nutrition however often helps people with cancer feel better and have more energy.<ref>{{cite web |url=http://www.nci.nih.gov/cancertopics/wyntk/melanoma/page28 |title=What You Need To Know About™ Melanoma - Nutrition |accessdate=2008-05-18 |publisher=[[National Cancer Institute]]}}</ref> ==Future thought== One important pathway in [[melanin]] synthesis involves the 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 [[adenyl cyclases]], which produce [[cAMP]], which activates [[CREB]], which promotes [[MITF]] expression. The targets of MITF include [[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. 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. Finally, given the fact that tanning helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce tanning in individuals who would otherwise get sunburns. Redheads, for example, do not tan because they have MC1R mutations. In mice, it has been shown that the melanin production pathway can be rescued downstream of MC1R. Perhaps such a strategy will eventually be used to protect humans from melanoma. ==References== {{Reflist|2}} ==External links== {{commonscat|Melanoma}} ;Advocate organizations * [http://www.melanomainternational.org/ Melanoma International Foundation] * [http://www.melanoma.org/ Melanoma Research Foundation] * [http://www.skincheck.org/ Melanoma Education Foundation] * [http://www.melanoma.com/ melanoma.com] (commercially supported site) ;Forums for patients, families, and survivors * [http://www.melanomaforum.org/ Melanoma International Foundation] * [http://www.mpip.org/ Melanoma Research Foundation] ;Medical information *[http://www.israelnationalnews.com/News/Flash.aspx/148679 Israeli scientists develop Vaccine against Melanoma] *[http://www.mmmp.org Melanoma Molecular Map Project _ The first interactive website for translational oncology research] *[http://www.proleukin.com Proleukin] *[http://www.melanomaperspectives.com Melanoma Perspectives] *[http://www.skincancer.org/melanoma/index.php Information on Melanoma from The Skin Cancer Foundation] * [http://www.cimit.org/ CIMIT Center for Integration of Medicine and Innovative Technology - New Advances and Research in Melanoma] * [http://www.newsmonster.co.uk/sunlight-prevents-and-cures-cancer-and-a-healthy-tan-makes-you-look-good.html Sunbathing helps prevent cancer: UK newspaper article] * [http://www.dermnetnz.org/lesions/melanoma.html DermNet NZ: Melanoma] * [http://www.startoncology.net/capitoli/interno_capitoli/default.jsp?menu=professional&ID=32&language=eng Professional melanoma information] * [http://www.rah.sa.gov.au/cancer/melanoma/ Adelaide Melanoma Unit] (free information on diagnosis, prevention, treatment of melanoma; booklet available at cost) * [http://copublications.greenfacts.org/en/sunbeds/index.htm Assessing health risks of sunbeds and UV exposure] summary by [[GreenFacts]] of the European Commission SCCP assessment * [http://www.theschlip.com/ James A. Schlipmann Melanoma Cancer Foundation] ;Patient information * [http://www.melanomaintl.org/ MIF Patient & Family Toll-Free Helpline: 1-866-463-6663] * [http://www.cancer.gov/pdf/WYNTK/WYNTK_moles.pdf What You Need To Know About Moles and Dysplastic Nevi] - patient information booklet from cancer.gov (PDF) * [http://www.mpip.org/ MPIP: Melanoma patients information page] * [http://www.MelanomaSupport.org.au/ Melanoma Support Organisation (Victoria, Australia)] - Ran by Melanoma Survivors with strong links to Cancer Institutes in Victoria, Australia * [http://www.melanomapatients.org/ Melanoma Patients Australia] * [http://www.tustison.com/interests1.shtml/ Mikes Page - The Melanoma Resource Center] * [http://listserv.icors.org/SCRIPTS/WA-ICORS.EXE?SUBED1=mel-l&A=1/ MEL-L - Melanoma e-mail list for patients, caregivers and healthcare professionals] - Supporting the Melanoma Patient since 1996 * [http://www.malignant-melanoma.org Malignant-Melanoma.org] - An evidence based site explaining trial results to patients in simplified language ;Images and photographs *[http://www.dermnet.com/thumbnailIndex.cfm?moduleID=14&moduleGroupID=427&groupIndex=0&numcols=0 Melanoma photo library at Dermnet] * [http://dermatlas.med.jhmi.edu/derm/result.cfm?Diagnosis=53 DermAtlas: Melanoma images] * [http://www.lumen.luc.edu/lumen/MedEd/medicine/dermatology/melton/melcont.htm Photographs of melanoma] * [http://melanoma.blogsome.com/ Skin imaging methods for melanoma diagnosis](commercial advertising) * [http://dermatologie.free.fr/cas21b.htm Pictures of melanomas] * [http://dermatologie.free.fr/cas183re.htm Pictures of amelanotic melanomas] * [http://dermoscopic.blogspot.com Dermoscopy pictures] ;Videos * [http://revver.com/video/700464/melanoma/ MELANOMA] * [http://www.healthination.com/skin_cancer.php Health Video: Melanoma and Non-Melanoma Skin Cancers - Overview, Prevention, and Treatment] * [http://www.healthination.com/skin_self_exam.php Health Video: How to Perform a Skin Self Exam] {{Epithelial neoplasms}} [[Category:Skin diseases]] [[Category:Types of cancer]] [[be-x-old:Мэлянома]] [[bg:Меланома]] [[ca:Melanoma]] [[da:Malignt melanom]] [[de:Malignes Melanom]] [[et:Melanoom]] [[el:Μελάνωμα]] [[es:Melanoma]] [[eo:Melanomo]] [[fa:ملانوما]] [[fr:Mélanome]] [[gl:Melanoma maligno]] [[it:Melanoma]] [[he:מלנומה]] [[la:Melanoma Malignum]] [[lv:Melanoma]] [[nl:Melanoom]] [[ja:悪性黒色腫]] [[no:Malignt melanom]] [[pl:Czerniak złośliwy]] [[pt:Melanoma maligno]] [[ru:Меланома]] [[sr:Меланом]] [[fi:Melanooma]] [[sv:Malignt melanom]] [[zh:黑色素瘤]]