Melanoma
Melanoma is a type of cancer, typically skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye. In very rare cases melanoma can also happen in the lung, which is known as primary pulmonary melanoma and only happens in 0.01% of primary lung tumors.
In females, melanomas most commonly occur on the legs; while in men, on the back. Melanoma is frequently referred to as malignant 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.
About 30% of melanomas develop from moles. Changes in a mole that can indicate melanoma include increaseespecially rapid increasein size, irregular edges, change in color, itchiness, or skin breakdown.
The primary cause of melanoma is ultraviolet light exposure in those with low levels of the skin pigment melanin. The UV light may be from the sun or other sources, such as tanning devices. Those with many moles, a history of affected family members, and poor immune function are at greater risk. A number of rare genetic conditions, such as xeroderma pigmentosum, also increase the risk. Diagnosis is by biopsy and analysis of any skin lesion that has signs of being potentially cancerous.
Avoiding UV light and using sunscreen in UV-bright sun conditions may prevent melanoma. Treatment typically is removal by surgery of the melanoma and the potentially affected adjacent tissue bordering the melanoma. In those with slightly larger cancers, nearby lymph nodes may be tested for spread. Most people are cured if metastasis has not occurred. For those in whom melanoma has spread, immunotherapy, biologic therapy, radiation therapy, or chemotherapy may improve survival. With treatment, the five-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. The likelihood that melanoma will reoccur or spread depends on its thickness, how fast the cells are dividing, and whether or not the overlying skin has broken down.
Melanoma is the most dangerous type of skin cancer. In 2015, 3.1 million people had active disease, which resulted in 59,800 deaths. The incidence of melanoma is expected to increase from 331,722 worldwide cases in 2022 to 510,000 cases in 2040. However mortality is decreasing as newer treatments become available. About 80% of all global cases occur in adults 50 years or older. Australia and New Zealand have the highest rates of melanoma in the world. High rates also occur in Northern Europe and North America, while it is less common in Asia, Africa, and Latin America. In the United States, melanoma occurs about 1.6 times more often in men than women. Melanoma has become more common since the 1960s in areas mostly populated by people of European descent.
Signs and symptoms
Early signs of melanoma are changes to the shape or color of existing moles or, in the case of nodular melanoma, the appearance of a new lump anywhere on the skin. At later stages, the mole may itch, ulcerate, or bleed. Early signs of melanoma are summarized by the mnemonic "ABCDEEFG":- Asymmetry
- Borders
- Colour
- Diameter
- Evolving over time
- Elevated above the skin surface
- Firm to the touch
- Growing
Cause
Melanomas are typically caused by DNA damage resulting from exposure to UV light from the sun. [|Genetics] also play a role. Melanoma can also occur in skin areas with little sun exposure. People with dysplastic nevus syndrome, also known as familial atypical multiple mole melanoma, are at increased risk for the development of melanoma.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.
UV radiation
The main risk factor for melanoma formation is exposure to UV radiation, either from sunlight or indoor tanning. UV radiation exposure from tanning beds increases the risk of melanoma. The International Agency for Research on Cancer finds that tanning beds are "carcinogenic to humans" and that people who begin using tanning devices before the age of thirty years are 75% more likely to develop melanoma.Those who work in airplanes also appear to have an increased risk, believed to be due to greater exposure to UV.
UVB light, emanating from the sun at wavelengths between 315 and 280 nm, is absorbed directly by DNA in skin cells, which results in a type of direct DNA damage called cyclobutane pyrimidine dimers. Thymine, cytosine, or cytosine-thymine dimers are formed by the joining of two adjacent pyrimidine bases within a strand of DNA. UVA light presents at wavelengths longer than UVB ; and it can also be absorbed directly by DNA in skin cells, but at lower efficienciesabout 1/100 to 1/1000 of UVB.
Radiation exposure is a major contributor to the development of melanoma. Occasional extreme sun exposure that results in "sunburn" on areas of the human body is causally related to melanoma. 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. Other factors are mutations in 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 of skin pigmentation. Melanoma rates tend to be highest in countries settled by migrants from Europe, which have a large amount of direct, intense sunlight to which the skin of the settlers is not adapted, most notably Australia. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia.
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.
Genetics
It is believed that 5-12% of melanoma is hereditary. 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. Familial melanoma is more likely to present at an earlier age and more likely to present as multiple skin lesions than non-familial melanoma. Familial melanoma is also more likely to present as thinner lesions are more responsive to therapy with the BRAF inhibitor dabrafenib plus trametinib.One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in 50% of human cancers. Another mutation in the same gene results in a nonfunctional inhibitor of CDK4, a cyclin-dependent kinase that promotes cell division. Mutations that cause the skin condition xeroderma pigmentosum also increase melanoma susceptibility. Scattered throughout the genome, these mutations reduce a cell's ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant.
Familial melanoma is genetically heterogeneous, and loci for familial melanoma appear on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to melanoma's pathogenesis. The multiple tumor suppressor 1 gene encodes p16INK4a – a low-molecular weight protein inhibitor of cyclin-dependent protein kinases – which has been localised to the p21 region of human chromosome 9.
Dysplastic nevus syndrome also known as FAMMM is typically characterized by having 50 or more combined moles in addition to a family history of melanoma. It is transmitted autosomal dominantly and mostly associated with the CDKN2A mutations. People who have a CDKN2A mutation associated with FAMMM have a 38-fold increased risk of pancreatic cancer. People with FAMMM also have a 30% lifetime risk of developing melanoma.
People with mutations in the MC1R gene are two to 2.7-3.6 times more likely to develop melanoma than those with two wild-type copies. Some MC1R gene variants are more common in those with red hair. Mutation of the MDM2 SNP309 gene is associated with increased risks for younger women.
Fair and red-haired people, persons with multiple atypical nevi or dysplastic nevi, and persons born with giant congenital melanocytic nevi are at increased risk. Fair skin is the result of having less melanin in the skin, which means less protection from UV radiation exists.
Pathophysiology
The earliest stage of melanoma starts when melanocytes begin out-of-control growth. Melanocytes are found between the outer layer of the skin and the next layer. 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. Because the cancer cells have not yet reached the blood vessels deeper in the skin, it is very unlikely that this early-stage melanoma will spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely removed with surgery.When the tumor cells start to move in a different direction – vertically up into the epidermis and into the papillary dermis – cell behaviour changes dramatically.
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. The Breslow's depth of the lesion is usually less than, while the Clark level is usually 2.
The vertical growth phase following invasive melanoma. The tumor becomes able to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than, and the tumor involves the deeper parts of the dermis.
The host elicits an immunological reaction against the tumor during the VGP, which is judged by the presence and activity of the tumor infiltrating lymphocytes. These cells sometimes completely destroy the primary tumor; this is called regression, which is the latest stage of development. In certain cases, the primary tumor is completely destroyed and only the metastatic tumor is discovered. About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the Raf to MAP kinase pathway.
A cause common to most cancers is damage to DNA. UVA light mainly causes thymine dimers. UVA also produces reactive oxygen species and these inflict other DNA damage, primarily single-strand breaks, oxidized pyrimidines and the oxidized purine 8-oxoguanine at 1/10, 1/10, and 1/3rd the frequencies of UVA-induced thymine dimers, respectively.
If unrepaired, cyclobutane pyrimidine dimer photoproducts can lead to mutations by inaccurate translesion synthesis during DNA replication or repair. The most frequent mutations due to inaccurate synthesis past CPDs are cytosine to thymine or CC>TT transition mutations. These are commonly referred to as UV fingerprint mutations, as they are the most specific mutation caused by UV, being frequently found in sun-exposed skin, but rarely found in internal organs. Errors in DNA repair of UV photoproducts, or inaccurate synthesis past these photoproducts, can also lead to deletions, insertions, and chromosomal translocations.
The entire genomes of 25 melanomas were sequenced. On average, about 80,000 mutated bases and about 100 structural rearrangements were found per melanoma genome. This is much higher than the roughly 70 mutations across generations. Among the 25 melanomas, about 6,000 protein-coding genes had missense, nonsense, or splice site mutations. The transcriptomes of over 100 melanomas has also been sequenced and analyzed. Almost 70% of all human protein-coding genes are expressed in melanoma. Most of these genes are also expressed in other normal and cancer tissues, with some 200 genes showing a more specific expression pattern in melanoma compared to other forms of cancer. Examples of melanoma specific genes are tyrosinase, MLANA, and PMEL.
UV radiation causes damage to the DNA of cells, typically thymine dimerization, which, when unrepaired, can create mutations in the cell's genes. This strong mutagenic factor makes cutaneous melanoma the tumor type with the highest number of mutations. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of activating transcription factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells; studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer progression.
Cancer stem cells may also be involved.