soft tissue including muscle, and/or non-regional lymph nodenot recorded or unspecified m1a(0)not elevated m1a(1)elevated m1b distant metastasis to lung with or without metastasis at m1a sitesnot recorded or unspecified m1b(0)not elevated m1b(1)elevated m1c distant metastasis to non‐cns visceral sites, with or without metastasis to m1a or m1b sitesnot recorded or unspecified m1c(0)not elevated m1c(1)elevated m1d distant metastasis to cns, with or without metastasis to m1a, m1b, or m1c sitesnot recorded or unspecified m1d(0)not elevated m1d(1)elevated older systems include "clark level" and "breslow's depth", quantifying microscopic depth of tumor invasion. f18-fdg pet/ct in a melanoma patient showing multiple lesions, most likely metastases laboratory lactate dehydrogenase (ldh) tests are often used to screen for metastases, although many patients with metastases (even end-stage) have a normal ldh; extraordinarily high ldh often indicates the metastatic spread of the disease to the liver. it is common for patients diagnosed with melanoma to have chest x-rays and an ldh test, and in some cases ct, mri, and/or pet scans. although controversial, sentinel lymph node biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph nodes. a diagnosis of melanoma is supported by the presence of the s-100 protein marker. 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 to 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. hmb-45 is nonreactive with almost all non-melanoma human malignancies, with the exception of rare tumors showing evidence of melanogenesis (e.g., pigmented schwannoma, clear cell sarcoma) or tumors associated with tuberous sclerosis complex (angiomyolipoma and lymphangiomyoma). prevention there is no evidence to support or refute adult population screening for malignant melanoma. ultraviolet radiation minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds), following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. using artificial light for tanning was once believed to help prevent skin cancers, but it can actually lead to an increased incidence of melanomas. uv nail lamps, which are used in nail salons to dry nail polish, are another common and widespread source of uv radiation that could be avoided. 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. the body uses uv light to generate vitamin 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. sunscreen sunscreen appears to be effective in preventing melanoma. 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. currently, newer sunscreen ingredients (avobenzone, zinc oxide, and titanium dioxide) effectively block both uva and uvb even at lower spfs. sunscreen also protects against squamous cell carcinoma, another skin cancer. concerns have been raised that sunscreen might create a false sense of security against sun damage. medications a 2005 review found tentative evidence that statin and fibrate medication may decrease the risk of melanoma. a 2006 review however did not support any benefit. treatment extensive malignant melanoma on a person's chest confirmation of the clinical diagnosis is done with a skin biopsy. this is usually followed up with a wider excision of the scar or tumor. depending on the stage, a sentinel lymph node biopsy may be performed. controversy exists around trial evidence for sentinel lymph node biopsy; with unclear evidence of benefit as of 2015. treatment of advanced malignant melanoma is performed from a multidisciplinary approach. surgery excisional biopsies may remove the tumor, but further surgery is often necessary to reduce the risk of recurrence. complete surgical excision with adequate surgical margins and assessment for the presence of detectable metastatic disease along with short- and long-term followup is standard. often this is done by a wide local excision (wle) with 1–2 cm (0.4–0.8 in) margins. melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2–0.5 cm (0.1–0.2 in). many surgeons consider 0.5 cm (0.2 in) the standard of care for standard excision of melanoma-in-situ, but 0.2 cm (0.1 in) margin might be acceptable for margin controlled surgery (mohs surgery, or the double-bladed technique with margin control). the wide excision aims to reduce the rate of tumor recurrence at the site of the original lesion. this is a common pattern of treatment failure in melanoma. considerable research has aimed to elucidate appropriate margins for excision with a general trend toward less aggressive treatment during the last decades. 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. mohs surgery has been reported with cure rate as low as 77% and as high as 98.0% for melanoma-in-situ. ccpdma and the "double scalpel" peripheral margin controlled surgery is equivalent to mohs surgery in effectiveness on this "intra-epithelial" type of melanoma. melanomas that spread usually do so to the lymph nodes in the area of the tumor before spreading elsewhere. attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications, but no overall survival benefit. recently, the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumor. biopsy of sentinel lymph nodes is a widely used procedure when treating cutaneous melanoma. 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. 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%. because of these considerations, sentinel lymph node biopsy is considered unnecessary health care for them. furthermore, baseline blood tests and radiographic studies should not be performed only based on identifying this kind of melanoma, as there are more accurate tests for detecting cancer and these tests have high false-positive rates. to potentially correct false positives, gene expression profiling may be used as auxiliary testing for ambiguous and small lesions. sentinel lymph node biopsy is often performed, especially for t1b/t2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. a process called lymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site to localize the sentinel node(s). further precision is provided using a blue tracer dye, and surgery is performed to biopsy the node(s). routine hematoxylin and eosin (h&e) and immunoperoxidase staining will be adequate to rule out node involvement. polymerase chain reaction (pcr) tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative sentinel lymph node actually had a small number of positive cells in their nodes. alternatively, a fine-needle aspiration biopsy may be performed and is often used to test masses. if a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. if the disease is completely resected, the patient will be considered for adjuvant therapy. excisional skin biopsy is the management of choice. here, the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue. to avoid disruption of the local lymphatic drainage, the preferred surgical margin for the initial biopsy should be narrow (1 mm). the biopsy should include the epidermal, dermal, and subcutaneous layers of the skin. this enables the histopathologist to determine the thickness of the melanoma by microscopic examination. this is described by breslow's thickness (measured in millimeters). however, for large lesions, such as suspected lentigo maligna, or for lesions in surgically difficult areas (face, toes, fingers, eyelids), a small punch biopsy in representative areas will give adequate information and will not disrupt the final staging or depth determination. in no circumstances should the initial biopsy include the final surgical margin (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. a large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram-directed lymphnode dissection. a small punch biopsy can be used at any time where for logistical and personal reasons a patient refuses more invasive excisional biopsy. small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring. add on treatment high-risk melanomas may require adjuvant treatment, although attitudes to this vary in different countries. in the united states, most patients in otherwise good health will begin up to a year of high-dose interferon treatment, which has severe side effects, but may improve the patient's prognosis slightly. however, the british association of dermatologists guidelines on melanoma state that interferon is not recommended as a standard adjuvant treatment for melanoma. 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. 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 quality of life. in the european union, interferon is usually not used outside the scope of clinical trials. chemotherapy chemotherapy drugs such as dacarbazine have been the backbone of metastatic melanoma treatment since fda approval in 1975; however, its efficacy in terms of survival has never been proven in an rct. 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. targeted therapy melanoma cells have mutations that allow them to survive and grow indefinitely in the body. small-molecule targeted therapies work by blocking the genes involved in pathways for tumor proliferation and survival. the main treatments are braf, c-kit and nras inhibitors. these inhibitors work to inhibit the downstream pathways involved in cell proliferation and tumour development due to specific gene mutations. people can be treated with small-molecule targeted inhibitors if they are positive for the specific mutation. braf inhibitors, such as vemurafenib and dabrafenib and a mek inhibitor trametinib are the most effective, approved treatments for braf positive melanoma. melanoma tumors can develop resistance 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. a number of treatments improve survival over traditional chemotherapy. biochemotherapy (chemotherapy with cytokines il-2 and ifn-α) combined with braf inhibitors improved survival for people with braf positive melanoma. biochemotherapy alone did not improve overall survival and had higher toxicity than chemotherapy. combining multiple chemotherapy agents (polychemotherapy) did not improve survival over monochemotherapy. targeted therapies result in relatively short progression-free survival (pfs) times. the therapy combination of dabrafenib and trametinib has a 3-year pfs of 23%, and 5-year pfs of 13%. immunotherapy immunotherapy is aimed at stimulating the person's immune system against the tumor, by enhancing the body's own ability to recognize and kill cancer cells. the current approach to treating melanoma with immunotherapy includes three broad categories of treatments including cytokines, immune check point inhibitors, and adoptive cell transfer. these treatment options are most often used in people with metastatic melanoma and significantly improves overall survival. however, these treatments are often costly. for example, one immune check point inhibitor treatment, pembrolizumab, costs $10,000 to us$12,000 for a single dose administered every 3 weeks. cytokine therapies used for melanoma include ifn-a and il-2. il-2