(proleukin) was the first new therapy approved (1990 eu, 1992 us) for the treatment of metastatic melanoma in 20 years. il-2 may offer the possibility of a complete and long-lasting remission in this disease in a small percentage of people with melanoma. intralesional il-2 for in-transit metastases has a high complete response rate ranging from 40 to 100%. similarly, ifn-a has shown only modest survival benefits and high toxicity, limiting its use as a stand-alone therapy. immune check point inhibitors include anti-ctla-4 monoclonal antibodies (ipilimumab and tremelimumab), toll-like receptor (tlr) agonists, cd40 agonists, anti-pd-1 (pembrolizumab, pidilizumab, and nivolumab) and pd-l1 antibodies. evidence suggests that anti-pd-1 antibodies are more effective than anti-ctla4 antibodies with less systemic toxicity. the five-year progression-free survival for immunotherapy with pembrolizumab is 21%. a therapeutic approach that includes the combination of different therapies improves overall survival and progression-free survival compared to treatment with the separate immunotherapy drugs alone. ongoing research is looking at treatment by adoptive cell transfer. adoptive cell transfer refers to the application of pre-stimulated, modified t cells or dendritic cells and is presently used to minimize complications from graft-versus-host disease. the combination nivolumab/relatlimab (opdualag) was approved for medical use in the united states in march 2022. 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 mm to assure that the method approaches complete margin control. a meta-analysis of the literature in 2014 found no randomized controlled trials of surgical interventions to treat lentigo maligna or melanoma in-situ, even though surgery is the most widely used treatment. mohs surgery has been done with cure rate reported to be as low as 77%, and as high as 95% by another author. the "double scalpel" peripheral margin controlled excision method approximates the mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods. some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (aldara) topical cream, an immune enhancing agent. some derma-surgeons are combining the 2 methods: surgically excising the cancer and then treating the area with aldara cream postoperatively for three months. while some studies have suggested the adjuvant use of topical tazarotene, the current evidence is insufficient to recommend it and suggests that it increases topical inflammation, leading to lower patient compliance. radiation radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with un-resectable distant metastases. kilovoltage x-ray beams are often used for these treatments and have the property of the maximum radiation dose occurring close to the skin surface. it may reduce the rate of local recurrence but does not prolong survival. radioimmunotherapy of metastatic melanoma is currently under investigation. radiotherapy has a role in the palliation of metastatic melanoma. prognosis a diagram showing the most common sites for melanoma to spread 5 year relative survival by stage at diagnosis for melanoma of the skin in the united states as of 2014 factors that affect prognosis include: tumor thickness in millimeters (breslow's depth), depth related to skin structures (clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion, presence of tumor-infiltrating lymphocytes (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant metastasis. certain types of melanoma have worse prognoses but this is explained by their thickness. less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. local recurrences tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion. when melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic have a more favorable prognosis than macrometastases. in some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely employed test known as the polymerase chain reaction (pcr), the prognosis is better. macro-metastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extracapsular extension, the prognosis is worse still. in addition to these variables, expression levels and copy number variations of a number of relevant genes may be used to support assessment of malignant melanoma prognosis. stage iv melanoma, in which it has metastasized, is the most deadly skin malignancy: five-year survival is 22.5%. when there is distant metastasis, the cancer is generally considered incurable. the five-year survival rate is less than 10%. the median survival is 6–12 months. treatment is palliative, focusing on life extension and quality of life. in some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). metastases to skin and lungs have a better prognosis. metastases to brain, bone and liver are associated with a worse prognosis. survival is better with metastasis in which the location of the primary tumor is unknown. there is not enough definitive evidence to adequately stage, and thus give a prognosis for, ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g., rectal melanoma), although these tend to metastasize more easily. even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a pathology report might indicate. about 200 genes are prognostic in melanoma, with both unfavorable genes where high expression is correlated to poor survival and favorable genes where high expression is associated with longer survival times. examples of unfavorable genes are mcm6 and timeless; an example of a favorable gene is wipi1. an increased neutrophil-to-lymphocyte ratio is associated with worse outcomes. epidemiology age-standardized new cases per year of melanoma of the skin per 100,000 inhabitants in 2008. no data less than 1.75 1.76–3.50 3.51–5.25 5.26–7.00 7.01–8.75 8.76–10.50 10.51–12.25 12.26–14.00 14.01–15.75 15.76–17.50 17.76–19.25 more than 19.25 deaths from melanoma and other skin cancers per million persons in 2012 0–2 3–5 6-6 7–8 9-9 10–13 14–18 19–37 38–51 52–114 globally, in 2012, melanoma occurred in 232,000 people and resulted in 55,000 deaths. australia and new zealand have the highest rates of melanoma in the world. it has become more common in the last 20 years in areas that are mostly caucasian. the rate of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved. 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. melanoma incidence in australia is matter of significance, for the following reasons: australian melanoma incidence has increased by more than 30 per cent between 1991 and 2009. australian melanoma age-standardized incidence rates were, as of 2008, at least 12 times higher than the world average. australian melanoma incidence is, by some margin, the highest in the world. overall age-standardized cancer incidence in australia is the highest in the world, and this is attributable to melanoma alone. age-standardized overall cancer incidence is similar to new zealand, but there is a statistically significant difference between australia and all other parts of the developed world including north america, western europe, and the mediterranean. united states melanoma rates by race and ethnicity in the us race white 25 american indian 5 hispanic 4 asian 1 black 1 melanomas diagnosed in the us per 100,000 people in 2018. melanomas affect white people much more often than people in any other racial or ethnic classification. in the united states, about 9,000 people die from melanoma a year. in 2011, it affected 19.7 per 100,000, and resulted in death in 2.7 per 100,000. 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. 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. 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 peruvian mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones. john hunter is reported to be the first to operate on metastatic melanoma in 1787. although not knowing precisely what it was, he described it as a "cancerous fungous excrescence". the excised tumor was preserved in the hunterian museum of the royal college of surgeons of england. it was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma. 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. the first english-language report of melanoma was presented by an english general practitioner from stourbridge, william norris in 1820. 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. he also described that melanomas could be amelanotic and later showed the metastatic nature of melanoma by observing that they can disseminate to other visceral organs. the first formal acknowledgment of advanced melanoma as untreatable came from samuel cooper in 1840. he stated that the only chance for a cure depends upon the early removal of the disease (i.e., early excision of the malignant mole) ...' more than one and a half centuries later this situation remains largely unchanged. terminology the word melanoma came to english from 19th-century neo-latin and uses combining forms derived from ancient greek roots: melano- (denoting melanin) + -oma (denoting a tissue mass and especially a neoplasm), in turn from greek μέλας melas, "dark", and -ωμα oma, "process". the word melanoma has a long history of being used in a broader sense to refer to any melanocytic tumor, typically, but not always malignant, but today the narrower sense referring only to malignant types has become so dominant that