(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). 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. gene mutations large-scale studies, such as the cancer genome atlas, have characterized recurrent somatic 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. the most frequent mutation occurs in the 600th codon of braf (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. ras genes (nras, hras and kras) are also recurrently mutated (30% of tcga cases) and mutations in the 61st or 12th codons trigger oncogenic activity. loss-of-function mutations often affect tumor suppressor genes such as nf1, tp53 and cdkn2a. other oncogenic alterations include fusions involving various kinases such as braf, raf1, alk, ret, ros1, ntrk1., ntrk3 and met braf, ras, and nf1 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. in some cases (3-7%) mutated versions of braf and nras undergo copy-number amplification. metastasis the research done by sarna's team proved that heavily pigmented melanoma cells have young's modulus about 4.93, when in non-pigmented ones it was only 0.98. in another experiment they found that elasticity 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 shown that there are both pigmented and non-pigmented cells in melanoma tumors, so that they can both be drug-resistant and metastatic. diagnosis 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). various differential diagnoses of pigmented skin lesions, by relative rates upon biopsy and malignancy potential, including "melanoma" at right. looking at the area in question is the most common method of suspecting a melanoma. moles that are irregular in color or shape are typically treated as candidates. to detect melanomas (and increase survival rates), it is recommended to learn to recognize them (see "abcde" mnemonic), to regularly examine moles for changes (shape, size, color, itching or bleeding) and to consult a qualified physician when a candidate appears. however, many melanomas present as lesions smaller than 6 mm in diameter, and all melanomas are malignant when they first appear as a small dot. physicians typically examine all moles, including those less than 6 mm in diameter. seborrheic keratosis may meet some or all of the abcd criteria, and can lead to false alarms. doctors can generally distinguish seborrheic keratosis from melanoma upon examination or with dermatoscopy. some advocate replacing "enlarging" with "evolving": moles that change and evolve are a concern. alternatively, some practitioners prefer "elevation". elevation can help identify a melanoma, but lack of elevation does not mean that the lesion is not a melanoma. most melanomas in the us are detected before they become elevated. by the time elevation is visible, they may have progressed to the more dangerous invasive stage. in-person inspection of suspicious skin lesions is more accurate than visual inspection of images of suspicious skin lesions. when used by trained specialists, dermoscopy is more helpful to identify malignant lesions than use of the naked eye alone. reflectance confocal microscopy may have better sensitivity and specificity than dermoscopy in diagnosing cutaneous melanoma but more studies are needed to confirm this result. melanoma in skin biopsy with h&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. a dermatoscope malignant melanoma, right posterior thigh melanoma in situ, vertex scalp marked for biopsy malignant melanoma in situ, evolving, right clavicle marked for biopsy malignant melanoma, vertex scalp marked for biopsy malignant melanoma, right medial thigh marked for biopsy malignant melanoma, right posterior shoulder circled for biopsy malignant melanoma, left forearm marked for biopsy malignant melanoma left forearm post excision with purse-string closure melanoma in situ, right forehead marked for biopsy melanoma in situ, dermatoscope image, right forehead marked for biopsy malignant melanoma in situ, evolving, a medial right temple with adjacent sebaceous hyperplasia, lateral malignant melanoma in situ, left anterior shoulder marked for biopsy malignant melanoma in situ, right anterior shoulder marked for biopsy malignant melanoma in situ, left upper inner arm malignant melanoma in situ marked for biopsy, left forearm malignant melanoma in situ, right upper medial back, marked for biopsy malignant melanoma, mid frontal scalp malignant melanoma, left mid-back marked for biopsy malignant melanoma, left mid-back marked for biopsy, through dermatoscope gross pathology of melanoma metastasis, which is pigment-forming in a vast majority of cases, giving it a dark appearance. ugly duckling one method is the "ugly duckling sign". correlation of common lesion characteristics is made. lesions that deviate from the common characteristics are labeled an "ugly duckling", and a further professional exam is required. the "little red riding hood" sign suggests that individuals with fair skin and light-colored hair might have difficult-to-diagnose amelanotic melanomas. extra care is required when examining such individuals, as they might have multiple melanomas and severely dysplastic nevi. a dermatoscope must be used to detect "ugly ducklings", as many melanomas in these individuals resemble nonmelanomas or are considered to be "wolves in sheep's clothing". these fair-skinned individuals often have lightly pigmented or amelanotic melanomas that do not present easy-to-observe color changes and variations. their borders are often indistinct, complicating visual identification without a dermatoscope. amelanotic melanomas and melanomas arising in fair-skinned individuals are very difficult to detect, as they fail to show many of the characteristics in the abcd rule, break the "ugly duckling" sign, and are hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines. biopsy following a visual examination and a dermatoscopic exam, or in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. a skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining severity. elliptical excisional biopsies may remove the tumor, followed by histological analysis and breslow scoring. incisional biopsies such as punch biopsies are usually contraindicated in suspected melanomas, because of the possibility of sampling error or local implantation causing misestimation of tumour thickness. however, fears that such biopsies may increase the risk of metastatic disease seem unfounded. total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up for high-risk patients. the technique has been reported to enable early detection and provides a cost-effective approach (with any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes. the diagnosis method should be used in conjunction with (and not as a replacement for) dermoscopic imaging, with a combination of both methods appearing to give extremely high rates of detection. histopathologic types melanoma is a type of neuroectodermal neoplasm. there are four main types of melanoma: sn typefeaturesincidencephotographmicrograph 1. superficial spreading melanoma melanoma cells with nest formation along the dermo-epidermal junction. 70% 2. nodular melanoma grows relatively more in depth than in width. 15% - 20% 3. lentigo maligna melanoma linear spread of atypical epidermal melanocytes as well as invasion into the dermis. 5% - 10% 4. acral lentiginous melanoma continuous proliferation of atypical melanocytes at the dermoepidermal junction. 7% - 10% other histopathologic types are: an anal melanoma mucosal melanoma; when melanoma occurs on mucous membranes. desmoplastic melanoma melanoma with small nevus-like cells melanoma with features of a spitz nevus uveal melanoma vaginal melanoma polypoid melanoma, a subclass of nodular melanoma. in situ or invasive a melanoma in situ has not invaded beyond the basement membrane, whereas an invasive melanoma has spread beyond it. some histopathological types of melanoma are inherently invasive, including nodular melanoma and lentigo maligna melanoma, where the in situ counterpart to lentigo maligna melanoma is lentigo maligna. lentigo maligna is sometimes classified as a very early melanoma, and sometimes a precursor to melanoma. superficial spreading melanomas and acral lentiginous melanomas can be either in situ or invasive, but acral lentiginous melanomas are almost always invasive. staging further context on cancer staging is available at tnm. t stages of melanoma metastatic melanomas can be detected by x-rays, ct scans, mris, pet and pet/cts, ultrasound, ldh testing and photoacoustic detection. however, there is lack of evidence in the accuracy of staging of people with melanoma with various imaging methods. melanoma stages according to ajcc, 8th edition: 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) t (tumor) staget categorythicknessulceration stage 0 melanoma in situ stage i t1a less than 0.8 mmno t1b less than 0.8 mmyes >0.8 to 1.0 mmyes or no t2a >1.0 to 2.0 mmno stage ii t2b >1.0 to 2.0 mmyes t3a >2.0 to 4.0 mmno t3b >2.0 to 4.0 mmyes t4a >4.0 mmno t4b >4.0 mmyes stage 1 and 2 require an n (lymph node) class of: n0 – no regional metastases. n (lymph nodes) stagen categorynumber of tumor-involved regional lymph nodespresence of in-transit, satellite, and/or microsatellite metastases n/a nxregional nodes not assessed (such as sentinel lymph node biopsy not performed, or regional nodes previously removed for another reason) 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 detectedno n1c no regional lymph node diseaseyes 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 detectedno n2c one clinically occult or clinically detectedyes 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 nodesno n3c two or more clinically occult or clinically detected and/or presence of any number of matted nodesyes stage 1, 2 and 3 require an m (metastasis status) of: m0: no evidence of distant metastasis stagem categoryanatomic sitelactate dehydrogenase (ldh) level stage iv m1 evidence of distant metastasis m1a distant metastasis to the skin,