Melanoma is a type ofcancer, typicallyskin cancer; it develops from themelanin-producing cells known asmelanocytes.[1] It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma).[1][2] In very rare cases melanoma can also happen in thelung, which is known as primary pulmonary melanoma and only happens in 0.01% of primarylung tumors.[7]
In females, melanomas most commonly occur on the legs; while in men, on the back.[2] Melanoma is frequently referred to asmalignant melanoma. However, the medical community stresses that there is no such thing as a 'benign melanoma' and recommends that the term 'malignant melanoma' should be avoided as it is redundant.[8][9][10]
About 30% of melanomas develop frommoles.[11] Changes in a mole that can indicate melanoma include increase—especially rapid increase—in size, irregular edges, change in color, itchiness, orskin breakdown.[1]
Avoiding UV light and usingsunscreen in UV-bright sun conditions may prevent melanoma.[2] Treatment typically is removal by surgery of the melanoma and the potentially affected adjacent tissue bordering the melanoma.[1] In those with slightly larger cancers, nearbylymph nodes may be tested for spread (metastasis).[1] Most people are cured if metastasis has not occurred.[1] For those in whom melanoma has spread,immunotherapy,biologic therapy,radiation therapy, orchemotherapy may improve survival.[1][14] With treatment, thefive-year survival rates in the United States are 100% among those with localized disease, 76% when the disease has spread to lymph nodes, and 35% among those with distant spread.[4] The likelihood that melanoma will reoccur or spread depends on itsthickness, how fast the cells are dividing, and whether or not the overlying skin has broken down.[2]
Melanoma is the most dangerous type of skin cancer.[2] In 2015, 3.1 million people had active disease, which resulted in 59,800 deaths.[5][6] The incidence of melanoma is expected to increase from 331,722 worldwide cases in 2022 to 510,000 cases in 2040.[11] However mortality is decreasing as newer treatments become available.[11] About 80% of all global cases occur in adults 50 years or older.[11] Australia and New Zealand have the highest rates of melanoma in the world.[2] High rates also occur in Northern Europe and North America, while it is less common in Asia, Africa, and Latin America.[2] In the United States, melanoma occurs about 1.6 times more often in men than women.[15] Melanoma has become more common since the 1960s in areas mostly populated bypeople of European descent.[2][13]
Early signs of melanoma are changes to the shape or color of existingmoles or, in the case ofnodular melanoma, the appearance of a new lump anywhere on the skin. At later stages, the mole mayitch,ulcerate, or bleed. Early signs of melanoma are summarized by the mnemonic "ABCDEEFG":[16][17]
Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser)
Evolving over time
This classification does not apply to nodular melanoma, which has its own classifications:[18]
Elevated above the skin surface
Firm to the touch
Growing
Metastatic melanoma may cause nonspecificparaneoplastic symptoms, including loss of appetite,nausea, vomiting, and fatigue.Brain metastases are particularly common in patients with metastatic melanoma.[19] Other common sites of metastasis of melanoma includeliver, intestines, bone,lungs and distant lymph nodes.[11]
Melanomas are typically caused by DNA damage resulting from exposure to UV light from the sun.Genetics also play a role.[20][21] Melanoma can also occur in skin areas with little sun exposure (i.e., mouth, soles of feet, palms of hands, genital areas).[22] People withdysplastic nevus syndrome, also known as familial atypical multiple mole melanoma, are at increased risk for the development of melanoma.[23]
Having more than 50 moles indicates an increased risk of melanoma. A weakened immune system makes cancer development easier due to the body's weakened ability to fight cancer cells.[20]
The main risk factor for melanoma formation is exposure to UV radiation, either from sunlight orindoor tanning. UV radiation exposure from tanning beds increases the risk of melanoma.[24][25] TheInternational 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.[26]
Those who work in airplanes also appear to have an increased risk, believed to be due to greater exposure to UV.[27]
UVB light, emanating from the sun at wavelengths between 315 and 280 nm, is absorbed directly by DNA in skin cells, which results in a type ofdirect DNA damage calledcyclobutane pyrimidine dimers.Thymine,cytosine, or cytosine-thyminedimers are formed by the joining of two adjacentpyrimidine bases within a strand of DNA.UVA light presents at wavelengths longer than UVB (between 400 and 315 nm); and it can also be absorbed directly by DNA in skin cells, but at lower efficiencies—about 1/100 to 1/1000 of UVB.[28]
Radiation exposure (UVA and UVB) is a major contributor to the development of melanoma.[29] Occasional extreme sun exposure that results in "sunburn" on areas of the human body is causally related to melanoma.[30] The risk appears to be strongly influenced by socioeconomic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than in unskilled workers.[31][32] Other factors aremutations in (or total loss of)tumor suppressor genes.
Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree ofskin pigmentation. Melanoma rates tend to be highest in countries settled by migrants from Europe, which have a large amount of direct, intense sunlight to which the skin of the settlers is not adapted, most notably Australia. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia.[33]
Incurring multiple severe sunburns increases the likelihood that future sunburns develop into melanoma due to cumulative damage. Living close to the equator increases exposure to UV radiation.[20]
It is believed that 5-12% of melanoma is hereditary.[11][34] Having a family history of melanoma increases one's risk, with having a first-degree relative increasing one's risk of developing melanoma by 1.74 times. Having a personal history of melanoma increases the risk of developing another melanoma in the future, by some estimates an 8.40 times increased risk.[35][11][20] Familial melanoma is more likely to present at an earlier age and more likely to present as multiple skin lesions than non-familial melanoma.[34] Familial melanoma is also more likely to present as thinner lesions (less depth of skin invasion.[34]
A number of rare mutations, which often run in families, greatly increase melanoma susceptibility.[36] Severalgenes increase risks. Some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene calledMC1R that causes red hair, have an elevated risk.Genetic testing can be used to search for the mutations.[37] Melanoma with genetic mutations in theBRAF genesV600E or V600K (proteins involved in cell growth) are more responsive to therapy with the BRAF inhibitordabrafenib plustrametinib.[11]
One class of mutations affects the geneCDKN2A. An alternativereading frame mutation in this gene leads to the destabilization ofp53, atranscription factor involved inapoptosis and in 50% of human cancers. Another mutation in the same gene results in a nonfunctional inhibitor ofCDK4, acyclin-dependentkinase that promotescell division. Mutations that cause the skin conditionxeroderma 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 highlypenetrant (the chances of a carrier expressing the phenotype are high).[citation needed]
Dysplastic nevus syndrome also known as FAMMM (familial atypical multiple mole-melanoma) is typically characterized by having 50 or more combined moles in addition to a family history of melanoma.[22] It is transmitted autosomal dominantly and mostly associated with theCDKN2A mutations.[22] People who have a CDKN2A mutation associated with FAMMM have a 38-fold increased risk of pancreatic cancer.[40] People with FAMMM also have a 30% lifetime risk of developing melanoma.[11]
People with mutations in theMC1R gene are two to 2.7-3.6 times more likely to develop melanoma than those with two wild-type (typical unaffected type) copies. Some MC1R gene variants are more common in those with red hair.[41][42] Mutation of theMDM2 SNP309 gene is associated with increased risks for younger women.[43]
Fair and red-haired people, persons with multiple atypicalnevi ordysplastic nevi, and persons born with giantcongenital melanocytic nevi are at increased risk.[44] Fair skin is the result of having less melanin in the skin, which means less protection from UV radiation exists.[20]
Where melanoma is most likely to developMolecular basis for melanoma cell motility: actin-richpodosomes (yellow), along withcell 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 (theepidermis) and the next layer (thedermis). This early stage of the disease is called the radial growth phase, when the tumor is less than 1 mm thick, and spreads at the level of the basal epidermis.[45] 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.[46]
When the tumor cells start to move in a different direction – vertically up into the epidermis and into thepapillary dermis – cell behaviour changes dramatically.[47]
The next step in the evolution is the invasive radial growth phase, in which individual cells start to acquire invasive potential. From this point on, melanoma is capable of spreading.[citation needed] TheBreslow's depth of the lesion is usually less than 1 mm (0.04 in), while theClark level is usually 2.
The vertical growth phase (VGP) following invasive melanoma. The tumor becomes able to grow into the surrounding tissue and can spread around the body through blood orlymph vessels. The tumor thickness is usually more than 1 mm (0.04 in), and the tumor involves the deeper parts of the dermis.
The host elicits an immunological reaction against the tumor during the VGP,[48] which is judged by the presence and activity of thetumor infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary tumor; this is called regression, which is the latest stage of development. In certain cases, the primary tumor is completely destroyed and only the metastatic tumor is discovered. About 40% of human melanomas contain activating mutations affecting the structure of the B-Rafprotein, resulting inconstitutive signaling through the Raf toMAP kinase pathway.[49]
A cause common to most cancers is damage to DNA.[50] UVA light mainly causesthymine dimers.[51] UVA also producesreactive oxygen species and these inflict other DNA damage, primarily single-strand breaks, oxidizedpyrimidines and the oxidizedpurine8-oxoguanine (a mutagenic DNA change) at 1/10, 1/10, and 1/3rd the frequencies of UVA-induced thymine dimers, respectively.
If unrepaired, cyclobutane pyrimidine dimer (CPD) photoproducts can lead to mutations by inaccuratetranslesion synthesis during DNA replication or repair. The most frequent mutations due to inaccurate synthesis past CPDs are cytosine to thymine (C>T) or CC>TTtransition mutations. These are commonly referred to as UV fingerprint mutations, as they are the most specific mutation caused by UV, being frequently found in sun-exposed skin, but rarely found in internal organs.[52] Errors in DNA repair of UV photoproducts, or inaccurate synthesis past these photoproducts, can also lead to deletions, insertions, andchromosomal translocations.
The entire genomes of 25 melanomas were sequenced.[53] On average, about 80,000 mutated bases (mostly C>T transitions) and about 100 structural rearrangements were found per melanoma genome. This is much higher than the roughly 70 mutations across generations (parent to child).[54][55] Among the 25 melanomas, about 6,000 protein-coding genes hadmissense,nonsense, orsplice site mutations. The transcriptomes of over 100 melanomas has also been sequenced and analyzed. Almost 70% of all human protein-coding genes are expressed in melanoma. Most of these genes are also expressed in other normal and cancer tissues, with some 200 genes showing a more specific expression pattern in melanoma compared to other forms of cancer. Examples of melanoma specific genes aretyrosinase,MLANA, andPMEL.[56][57]
UV radiation causesdamage to the DNA of cells, typically thymine dimerization, which, when unrepaired, can create mutations in the cell's genes. This strong mutagenic factor makes cutaneous melanoma the tumor type with the highest number of mutations.[58] When the celldivides, these mutations are propagated to new generations of cells. If the mutations occur inprotooncogenes ortumor suppressor genes, the rate ofmitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of atumor. 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;[59][60][61] studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer progression.[62][63]
Large-scale studies, such asThe Cancer Genome Atlas, have characterized recurrentsomatic alterations likely driving initiation and development of cutaneous melanoma. The Cancer Genome Atlas study has established four subtypes:BRAF mutant,RAS mutant,NF1 mutant, and triple wild-type.[65]
The most frequent mutation occurs in the 600th codon ofBRAF (50% of cases).BRAF is normally involved in cell growth, and this specific mutation renders the protein constitutively active and independent of normal physiological regulation, thus fostering tumor growth.[66] RAS genes (NRAS,HRAS andKRAS) are also recurrently mutated (30% of TCGA cases) and mutations in the 61st or 12th codons trigger oncogenic activity. Loss-of-function mutations often affecttumor suppressor genes such asNF1,TP53 andCDKN2A. Other oncogenic alterations include fusions involving various kinases such as BRAF,[67] RAF1,[68] ALK, RET, ROS1, NTRK1.,[69] NTRK3[70] and MET[71] BRAF, RAS, andNF1 mutations and kinase fusions are remarkably mutually exclusive, as they occur in different subsets of patients. Assessment of mutation status can, therefore, improve patient stratification and inform targeted therapy with specific inhibitors.[citation needed]
The research done by Sarna's team proved that heavily pigmented melanoma cells haveYoung's modulus about 4.93, while in non-pigmented ones it was only 0.98.[72] In another experiment they found thatelasticity of melanoma cells is important for its metastasis and growth: non-pigmented tumors were bigger than pigmented and it was much easier for them to spread. They showed that there are both pigmented and non-pigmented cells in melanomatumors, so that they can both bedrug-resistant and metastatic.[72]
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).Variousdifferential diagnoses of pigmented skin lesions, by relativerates upon biopsy and malignancy potential, including "melanoma" at right
Visually inspecting the skin lesion in question is the first step in diagnosing a suspected a melanoma.[73] Moles that are irregular in color or shape are suspicious for melanoma. To detect melanomas, it is recommended to learn to recognize them (see"ABCDE" mnemonic), to regularly examinemoles for changes (shape, size, color, itching or bleeding) and to consult a qualified physician when a suspicious skin lesion appears.[74][75] In-person inspection of suspicious skin lesions is more accurate than visual inspection of images.[76]
When used by trained specialists, dermoscopy is more helpful to identify malignant lesions than use of the naked eye alone.[77] Reflectanceconfocal microscopy may have better sensitivity and specificity than dermoscopy in diagnosing cutaneous melanoma but more studies are needed to confirm this result.[78]
Many melanomas present as lesions smaller than 6 mm in diameter. Physicians typically examine all moles, including those less than 6 mm in diameter.Seborrheic keratosis may meet some or all of the ABCD criteria and may be sometimes mistaken for melanoma. Doctors can generally distinguish seborrheic keratosis from melanoma upon examination or withdermatoscopy.[79]
Total body photography, which involves photographic documentation of as much body surface as possible, is sometimes used to objectively observe the evolution of body moles over time, to potentially find moles that become suspicious. It is often used during follow-up for high-risk patients. The technique has been reported to enable early detection and provide a cost-effective approach, but its efficacy has been questioned due to its inability to detect microscopic changes.[73]
Melanoma in skin biopsy withH&E stain – this case may represent superficial spreading melanoma.
Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is a focal deposition of melanin.
One method of finding lesions that are suspected melanomas is the "ugly duckling sign".[80] People's moles tend to look like one another, but when there is a mole that looks different than someone's other moles, it is more likely to be a melanoma.[11] The "Little Red Riding Hood" sign suggests that individuals with fair skin and light-colored hair might have difficult-to-diagnoseamelanotic melanomas.[80] Extra care is required when examining such individuals, as they might have multiple melanomas and severely dysplastic nevi.
Amelanotic melanomas (a rare subtype) have very little to no pigmentation and are therefore more difficult to detect.[11] The acral subtype of melanoma presents in areas that do not usually get sun exposure and are difficult to see by a person (the soles of the feet, and palms of hand) making detection difficult. Thirty to 40% of acral melanomas are amelanotic (producing little to no pigment), also making the diagnosis challenging.[11]
Following a visual examination and a dermatoscopic exam, or other specialized tests such asconfocal microscopy, askin biopsy is done for lesions suspicious of being melanoma. A skin biopsy is required for definitive diagnosis of melanoma and staging the cancer.[11] Elliptical excisional biopsies may remove the tumor, followed byhistological analysis and Breslow scoring. Incisional biopsies such aspunch biopsies are usually contraindicated in suspected melanomas, because of the possibility of sampling error or local implantation causing misestimation of tumour thickness.[81][82][83] However, fears that such biopsies may increase the risk of metastatic disease seem unfounded.[84][85]
A melanomain situ has not invaded beyond thebasement membrane, whereas aninvasive melanoma has spread beyond it.
Some histopathological types of melanoma are inherently invasive, includingnodular melanoma andlentigo maligna melanoma, where thein situ counterpart to lentigo maligna melanoma islentigo maligna.[90] Lentigo maligna is sometimes classified as a very early melanoma,[91] and sometimes a precursor to melanoma.[92]
Melanomas are staged based on the depth of invasion in various layers of the skin, the presence of ulceration, spread to local lymph nodes or spread to distant lymph nodes and organs (metastasis).[11]
Metastatic melanomas can be detected by CT scans, MRIs, and PET/CTs, or ultrasound. PET/CT to assess for metastasis is generally recommended for people with stage IIB or greater melanoma.[11] If a person has an ulcerated lesion, or if the depth of tumor invasion is greater than 0.8 mm, then a sentinel lymph node biopsy is recommended.[11] LDH levels may sometimes be elevated in metastatic melanoma, but this is not required for the diagnosis nor staging.[11]
Melanoma stages according toAJCC, 8th edition:[95]
TX: Primary tumor thickness cannot be assessed (such as a diagnosis by curettage)
T0: No evidence of primary tumor (such as unknown primary or completely regressed melanoma)
Presence of in-transit, satellite, and/or microsatellite metastases
N/A
NX
Regional nodes not assessed (such as sentinel lymph node biopsy not performed, or regional nodes previously removed for another reason)[notes 2]
Stage III
N1
One involved lymph node, or any number of in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes.
N1a
One clinically occult (that is, detected by sentinel node biopsy)
No
N1b
One clinically detected
No
N1c
No regional lymph node disease
Yes
N2
Two or 3 tumor‐involved nodes or any number of in‐transit, satellite, and/or microsatellite metastases with one tumor‐involved node
N2a
Two or 3 clinically occult (that is, detected by sentinel node biopsy)
No
N2b
Two or 3, at least one of which was clinically detected
No
N2c
One clinically occult or clinically detected
Yes
N3
Four or more tumor‐involved nodes or any number of in‐transit, satellite, and/or microsatellite metastases with 2 or more tumor‐involved nodes, or any number of matted nodes without or with in‐transit, satellite, and/or microsatellite metastases
N3a
Four or more clinically occult (that is, detected by sentinel node biopsy)
No
N3b
Four or more, at least one of which was clinically detected, or the presence of any number of matted nodes
No
N3c
Two or more clinically occult or clinically detected and/or presence of any number of matted nodes
Yes
Stage 1, 2 and 3 require an M (metastasis status) of:
It is common for patients diagnosed with melanoma to have chest X-rays, and in some casesCT,MRI, and/orPET scans. Although controversial,sentinel lymph node biopsies and examination of thelymph nodes are also performed in patients to assess spread to the lymph nodes; this test is very sensitive, with a high negative predictive value, meaning that if no metastatic disease is detected then patients can be assured that the chance of spread is very low.[96] A diagnosis of melanoma is supported by the presence of theS-100 protein marker.[citation needed]
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 against 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.[citation needed]
HMB-45 is nonreactive with almost all non-melanoma human malignancies, except rare tumors showing evidence of melanogenesis (e.g., pigmentedschwannoma,clear cell sarcoma) or tumors associated withtuberous sclerosis complex (angiomyolipoma and lymphangiomyoma).[citation needed]
Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds) and other sun protection measures such as wearingsun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection.[98][11] Using artificial light for tanning was once believed to help prevent skin cancers, but it can lead to an increased incidence of melanomas.[99]
UV nail lamps, which are used in nail salons to dry nail polish, are another widespread source of UV radiation that could be avoided.[100][101] Although the risk of developing skin cancer through UV nail lamp use is low, it is still recommended to wear fingerless gloves and/or apply SPF 30 or greater sunscreen to the hands before using a UV nail lamp.[100][101]
The body uses UV light to generatevitamin 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.[102]
Sunscreen appears to be effective in preventing melanoma.[2][12] 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.[103] Currently, newer sunscreen ingredients (avobenzone,zinc oxide, andtitanium dioxide) effectively block both UVA and UVB even at lower SPFs. Sunscreen also protects againstsquamous cell carcinoma, another skin cancer.[104]
Concerns have been raised that sunscreen might create a false sense of security against sun damage.[105]
A 2005 review found tentative evidence thatstatin andfibrate medication may decrease the risk of melanoma.[106] A 2006 review however did not support any benefit.[107]
Confirmation of the clinical diagnosis is done with askin biopsy. This is usually followed up with a wider excision of the scar or tumor. Depending on the stage, asentinel lymph node biopsy may be performed. Controversy exists around benefit for sentinel lymph node biopsy; with unclear evidence of benefit as of 2015.[108][109]
Excisional biopsies may remove the tumor, but further surgery is often necessary to make sure all of the tumor is removed and reduce the risk of recurrence. Complete surgical excision with adequatesurgical margins is standard. Often this is done by awide local excision (WLE) with 5 mm to 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2 to 5 cm. A wide-local excision usually removes 5 mm to 2 cm around the tumor, with the margins determined by the Breslow Depth (2 cm margins are removed for a Breslow tumor Depth greater than 2 mm).[11]Mohs surgery, or the double-bladed technique with margin control is sometimes used. The sample is inspected histologically to make sure no tumor cells involve the cut margins, indicating an inadequate tumor of removal. The wide excision aims to reduce the rate of tumor recurrence at the site of the original lesion. A 2009 meta-analysis of randomized controlled trials found a small difference in survival rates favoring wide excision of primary cutaneous melanomas, but these results were not statistically significant.[110]
Mohs surgery has been reported with cure rate as low as 77% and as high as 98.0% for melanoma-in-situ.[111][112]CCPDMA and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in removal of melanoma in-situ.
Melanomas that spread usually do so to thelymph nodes in the area of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymph node dissection) were associated with many complications, but no overall survival benefit.[11]
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.[116] People with these conditions are unlikely to have the cancer spread to their lymph nodes or anywhere else and have a 5-year survival rate of 97%.[116]
Sentinel lymph node biopsy is indicated for ulcerated melanomas or melanomas of greater than 0.8 mm thickness.[11] A process calledlymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site to localize the sentinel node. Further precision is provided using a blue tracerdye, and surgery is performed to biopsy the node. Routinehematoxylin and eosin andimmunoperoxidase staining will be adequate to rule out node involvement.
If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection may be performed in which affected lymph nodes are surgically removed. Lymph node dissection is not associated with a survival benefit in those with melanoma and is no longer recommended.[11]
Adjuvant treatment after surgery may reduce the risk of recurrence, especially in high-risk melanomas. The most common adjuvant treatment is immune checkpoint inhibitor treatment for up to a year post-surgery.[117]
In the early 2000s, a relatively common strategy was to treat patients with a high risk of recurrence with up to a year of high-doseinterferon treatment.[118] A 2013 meta-analysis suggested that the addition of interferon alpha increased disease-free and overall survival for people with AJCC TNM stage II-III cutaneous melanoma.[119] 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 the quality of life.[120] Interferon is no longer routinely used in the treatment of melanoma outside of clinical trials.[121][122]
Chemotherapy drugs such asdacarbazine have been commonly used for metastatic melanoma since the 1970s; however, their efficacy in terms of survival has never been proven in anRCT.[123] Since the approval of immune checkpoint inhibitors, dacarbazine and its oral counterpart, temozolomide, constitute potential treatment options in later lines of therapy.[124]
Multiple drugs are available to patients to decrease the size of the tumor. By lessening the size of the tumor, some symptoms can be relieved; however, this does not necessarily lead to remission. Some of these drugs aredacarbazine,temozolomide, andfotemustine. Combinations of drugs are also used and, in some cases, present higher remission rates. Although combinations of drugs increase remission rates, the survival rate does not show an increase.[125]
In people with locally advanced cutaneous malignancies and sarcoma, isolated limb infusion (ILI) has been found to be a minimally invasive and well-tolerated procedure for delivering regional chemotherapy.[126][127]
Melanoma cells have mutations that allow them to survive and grow indefinitely in the body.[123] Small-molecule targeted therapies work by blocking the genes involved in pathways for tumor proliferation and survival.[123] The main treatments are BRAF,C-Kit andNRAS inhibitors.[128] These inhibitors work to inhibit the downstream pathways involved in cell proliferation and tumour development due to specific gene mutations.[129] People can be treated with small-molecule targeted inhibitors if they are positive for the specific mutation.[123]BRAF inhibitors, such asvemurafenib anddabrafenib and aMEK inhibitortrametinib are the most effective, approved treatments for BRAF positive melanoma.[130][123] Melanoma tumors can developresistance during therapy which can make therapy no longer effective, but combining the use of BRAF and MEK inhibitors may create a fast and lasting melanoma therapy response.[131]
Several treatments improve survival over traditional chemotherapy.[123] Biochemotherapy (chemotherapy with cytokines IL-2 and IFN-α) combined with BRAF inhibitors improved survival for people with BRAF-positive melanoma.[123] Biochemotherapy alone did not improve overall survival and had higher toxicity than chemotherapy.[123] Combining multiple chemotherapy agents (polychemotherapy) did not improve survival over monochemotherapy.[123] Targeted therapies result in relatively shortprogression-free survival (PFS) times. The therapy combination of dabrafenib and trametinib has a 3-year PFS of 23% and a 5-year PFS of 13%.[132]
Lifileucel (Amtagvi) is a tumor-derived autologous T-cell immunotherapy that was approved for medical use in the United States in February 2024.[133][134]
Immunotherapy is aimed at stimulating the person's immune system against the tumor to enhance the body's ability to recognize and kill cancer cells.[135] The current approach to treating melanoma with immunotherapy includes three broad categories of treatments, includingcytokines, immune checkpoint inhibitors, andadoptive cell transfer.[135] These treatment options are most often used in people with metastatic melanoma and significantly improve overall survival.[123]
Cytokine therapies used for melanoma includeIFN-a andIL-2.[136] IL-2 (Proleukin) was the first new therapy approved (1990 EU, 1992 US) for the treatment of metastatic melanoma in 20 years.[137] IL-2 may offer the possibility of a complete and long-lasting remission in this disease in a small percentage of people with melanoma.[138] Intralesional IL-2 for in-transit metastases has a high complete response rate ranging from 40 to 100%.[130] Similarly, IFN-α has shown only modest survival benefits and high toxicity, limiting its use as a stand-alone therapy.[123][136]
Immune check point inhibitors include anti-CTLA-4 monoclonal antibodies (ipilimumab andtremelimumab),toll-like receptor (TLR) agonists,CD40 agonists, anti-PD-1 (pembrolizumab,pidilizumab, andnivolumab) andPD-L1 antibodies.[135][136] Evidence suggests that anti-PD-1 antibodies are more effective than anti-CTLA4 antibodies with less systemic toxicity.[123] The five-year progression-free survival for immunotherapy with pembrolizumab is 21%.[132] Nivolumab or pembrolizumab was associated with increased recurrence free survival at 12 months of treatment. These medications block PD-1 to inhibitT-cell inactivation, this leads to more T-cell proliferation and activity against melanoma cells.[11] Either medication is indicated in Stage IIB-C disease (or observation after resection without using medication is also a treatment option).[11]
For stage IIIA-D disease, resection of tumor may be followed by 12 months of treatment with nivolumab or pembrolizumab ordabrafenib (BRAF inhibitor) plustrametinib (MEK inhibitor)in BRAF gene positive disease. Observation after resection (without using immunotherapy) is also an option, but immunotherapy after resection is associated with an improved cancer-free survival rate at 5 years.[11]
In those with stage III or IV disease that cannot be surgically removed, dual checkpoint blockade by combining nivolumab andipilimumab (anti-CTLA4 inhibitor) followed by maintenance nivolumab is associated with increased survival and has a lower mortality than using either agent alone.[11]
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.[123] However, combination therapy also has a higher risk of immune-related adverse reactions (due to hyperactivity of the immune system).[11]
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, results in a high "false negative" error rate and frequent recurrences. Margin control (peripheral margins) is necessary to eliminate the false-negative errors. Ifbread 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.[142]
Mohs surgery has been done with cure rate reported to be as low as 77%,[111] and as high as 95% by another author.[112] 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.[143]
Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment,imiquimod (Aldara) topical cream, an immune enhancing agent. Some derma-surgeons are combining the two methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months. While some studies have suggested the adjuvant use of topical tazarotene, the current evidence is insufficient to recommend it and suggests that it increases topical inflammation, leading to lower patient compliance.[142]
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 that the maximum radiation dose occurs close to the skin surface.[144] It may reduce the rate of local recurrence but does not prolong survival.[145]Radioimmunotherapy of metastatic melanoma is currently under investigation.Radiotherapy has a role in the palliation of metastatic melanoma.[146]
A diagram showing the most common sites for melanoma to spread5-year relative survival by stage at diagnosis for melanoma of the skin in the United States as of 2014
Certain types of melanoma have worse prognoses, but this is explained by theirthickness. Less invasive melanomas, even with lymph node metastases, carry a better prognosis than deep melanomas without regional metastasis at the time of staging. Local recurrences tend to behave similarly to a primary unless they are at the site of awide 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 thelymph nodes, one of the most important factors is the number of nodes with malignancy. The 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 bypolymerase 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 several relevant genes may be used to support assessment of melanoma prognosis.[148][149]
Stage IV melanoma, in which it has metastasized, is the most deadly skin malignancy:[132] five-year survival in the United States was 34.6% for people diagnosed between 2015 and 2021.[4] Metastases to the skin and lungs have a better prognosis. Metastases to the 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.[150] Survival rates have rapidly increased in the decade leading up to 2025.[151]
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 apathology 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 areMCM6 andTIMELESS; an example of a favorable gene isWIPI1.[56][57]
An increased neutrophil-to-lymphocyte ratio is associated with worse outcomes.[152][153][154]
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.[2] Australia and New Zealand have the highest rates of melanoma in the world.[2] It has become more common in the last 20 years in areas that are mostlyCaucasian.[2]
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 both sexes; indeed, its incidence is higher than forlung 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.[156] Melanoma incidence in Australia is a 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.
Melanomas diagnosed in the US per 100,000 people in 2018.[157] Melanomas affect white people much more often than people in any other racial or ethnic classification.
In the United States, about 8-9,000 people die from melanoma a year, and the death rate from melanoma is 1.40 deaths per 100,000 people.[11][158]
The incidence of melanoma in the United States increased from 8.8 cases per 100,000 people in 1975 to 27.7 cases per 100,000 people in 2021.[11] The annual mortality from melanoma decreased 6.1% annually from 2013 to 2017 and 1.4% annually from 2017 to 2022. Advances in treatment are believed to have caused the rapid decline in mortality over the last decade.[159][11] In 2024, in the United States, there were 100,640 cases of melanoma and 8290 deaths.[11] There were also 107,240 cases of melanoma in situ, in which melanoma is confined to the epidermis.[11]
Melanoma is more than 20 times more common in whites than in African Americans. Overall, the lifetime risk of getting melanoma is about 2.5% (1 in 40) for whites, 0.1% (1 in 1,000) for African Americans, and 0.5% (1 in 200) for Mexicans.
The risk of melanoma increases as people age. The average age of people when the disease is diagnosed is 63.[160] 80% of all cases of melanoma (globally) are diagnosed in people older than 50 years.[11]
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 ninePeruvian 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.[161]
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 theHunterian Museum of theRoyal 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.[162]
The French physicianRené 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.[163]
The first English-language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris, in 1820.[164] In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases ofMelanosis 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.[165] 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 fromSamuel 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) ...'[166]
More than one and a half centuries later, this situation remains largely unchanged.
The wordmelanoma came to English from 19th-centuryNeo-Latin[167] and usescombining forms derived fromancient Greek roots:melano- (denotingmelanin) +-oma (denoting a tissue mass and especially aneoplasm), in turn fromGreekμέλαςmelas, "dark",[168] and-ωμαoma, "process". The wordmelanoma has a long history of being usedin a broader sense to refer to anymelanocytic tumor, typically, but not always malignant,[169][170] but today the narrower sense referring only to malignant types has become so dominant that benign tumors are usually not called melanomas anymore and the wordmelanoma is now usually taken to mean malignant melanoma unless otherwise specified. Terms such as "benignmelanocytic tumor" unequivocally label the benign types, and modern histopathologic tumor classifications used in medicine do not use the word for benign tumors.
In clinical research, adoptive cell therapy andgene therapy, are being tested.[172]
Two kinds of experimental treatments developed at theNational Cancer Institute (NCI) have been used in metastatic melanoma with tentative success.[47]
The first treatment involves adoptive cell therapy (ACT) using TILs, immune cells (tumor-infiltrating lymphocytes) isolated from a person's own melanoma tumor.[130] 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.[173][174]
The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so-calledT cell receptors (TCRs) into the patient's lymphocytes.[130] After that manipulation, lymphocytes recognize and bind to certainmolecules found on the surface of melanoma cells and kill them.[175]
About 60% of melanomas contain a mutation in theB-Raf gene. Early clinical trials suggested that B-Raf inhibitors including Plexxicon'svemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation.[178] In June 2011, a largeclinical trial confirmed the positive findings from those earlier trials.[179][180]
In August 2011, Vemurafenib received FDA approval for the treatment of late-stage melanoma. In May 2013, theUS FDA approved dabrafenib as a single-agent treatment for patients with BRAF V600E mutation-positive advanced melanoma.[181]
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 aMEK inhibitortrametinib led to even better outcomes. Compared to Dabrafenib alone, progression-free survival was increased to 41% from 9%, and the medianprogression-free survival increased to 9.4 months versus 5.8 months. Some side effects were, however, increased in the combined study.[182][183]
In January 2014, the FDA approved the combination of dabrafenib and trametinib for the treatment of people with BRAF V600E/K-mutant metastatic melanoma.[184] In June 2018, the FDA approved the combination of a BRAF inhibitorencorafenib and a MEK inhibitorbinimetinib for the treatment of un-resectable or metastatic melanoma with a BRAF V600E or V600K mutation.[185]
Eventual resistance to BRAF and MEK inhibitors may be due to a cell surface protein known asEphA2 which is now being investigated.[186]
At theAmerican Society of Clinical Oncology Conference in June 2010, theBristol Myers Squibb pharmaceutical company reported the clinical findings of their drugipilimumab. 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.[187] 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.[188][189] 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.[190][191][192]
In June 2011, a clinical trial of ipilimumab plusdacarbazine combined this immune system booster with the standard chemotherapy drug that targets cell division. It showed an increase in median survival for these late-stage patients to 11 months instead of the 9 months normally seen. Researchers were also hopeful of improving the five-year survival rate, though serious adverse side effects were seen in some patients. A course of treatment costs $120,000. The drug's brandname is Yervoy.[179][193]
Advances in high-resolution ultrasound scanning have enabled surveillance of metastatic burden to the sentinel lymph nodes.[194] The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) is evaluating ultrasound as an alternative to invasive surgical methods.[195]
In some countries, oncolytic virotherapy methods are studied and used to treat melanoma. Oncolytic virotherapy is a promising branch ofvirotherapy, whereoncolytic viruses are used to treat diseases; viruses can increase metabolism, reduce anti-tumor immunity, and disorganize vasculature.[196] 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.[197][14]
Antiretrovirals have been testedin vitro against melanoma. The rationale behind this lies in their potential to inhibit human endogenousretroviruses, whose activity has been associated with the development of melanoma.[198][199] Evidence from studies on melanoma cell lines indicates that antiretroviral drugs, including lamivudine, doravirine, and cabotegravir, can effectively downregulate the expression of human endogenous retroviruses (HERV-K). These drugs not only reduce cell growth and invasiveness but also enhance the potential of immune checkpoint therapies.[200] Furthermore, they have shown promise in addressing resistance mechanisms that emerge following prolonged treatment with BRAF inhibitors like dabrafenib and AZ628. By restoring apoptosis, decreasing cell viability, and influencing tumor suppressor proteins, these antiretrovirals offer a compelling strategy to tackle therapeutic resistance in melanoma.[201] Further developments are awaited through animal model testing.
Recent research has identified miR-139-5p, a small noncoding RNA, as a potential tumor suppressor in melanoma. Overexpression of miR-139-5p has been shown to inhibit cell proliferation, migration, and invasion while inducing apoptosis in melanoma cells. These effects are associated with the downregulation of IGF1R, a receptor that activates the PI3K/AKT signaling pathway. By suppressing IGF1R-mediated signaling, miR-139-5p reduces melanoma cell aggressiveness. These findings highlight miR-139-5p as a potential therapeutic agent and emphasize the significance of miRNA regulation in melanoma development and treatment.[202]
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