Melanoma: Difference between revisions

Melanoma
Melanoma
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Melanoma (Template:Pron-en) is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye (see uveal melanoma). Melanoma can occur in any part of the body that contains melanocytes.

Melanoma is less common than other skin cancers. However, it is much more dangerous and causes the majority (75%) of deaths related to skin cancer.^[1] Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. The diagnosis is more frequent in women than in men and is particularly common among Caucasians living in sunny climates, with high rates of incidence in Australia, New Zealand, North America, and northern Europe.^[2] According to a WHO report about 48,000 melanoma related deaths occur worldwide per year.^[3]

The treatment includes surgical removal of the tumor, adjuvant treatment, chemo- and immunotherapy, or radiation therapy. The chance of a cure is greatest when the tumor is discovered while it is still small and thin, and can be entirely removed surgically.

Cause

In lay terms

All cancers are caused by damage to the DNA inside cells. This damage can be inherited in the form of genetic mutations, but in most cases it builds up over a person's lifetime and is caused by factors in their environment. DNA damage causes the cell to grow out of control, leading to a tumour. Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.^[4]

Natural history of melanoma

The earliest stage of melanoma starts when the melanocytes begin to grow out of control. Melanocytes are found between the outer layer of the skin (the epidermis) and the next layer (the dermis). This early stage of the disease is called the radial growth phase, and the tumour is less than 1mm thick. Because the cancer cells have not yet reached the blood vessels lower down in the skin it is very unlikely that this early-stage cancer 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 tumour cells start to move in a different direction — vertically up into the epidermis and into the papillary dermis - the behaviour of the cells changes dramatically.

The next step in the evolution is the invasive radial growth phase, which is a confusing term, however it explains the next step in the process of the radial growth, when individual cells start to acquire invasive potential. This step is important – from this point on the melanoma is capable of spreading. The Breslow's depth of the lesion is usually less than 1 mm (0.04 in), the Clark level is usually 2.

The following step in the process is the invasive melanoma — the vertical growth phase (VGP). The tumour attains invasive potential, meaning it can grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumour thickness is usually more than 1 mm (0.04 in), and the tumour involves the deeper parts of the dermis.

The host elicits an immunological reaction against the tumour (during the VGP),^[5] which is judged by the presence and activity of the TILs (tumour infiltrating lymphocytes). These cells sometimes completely destroy the primary tumour, this is called regression, which is the latest stage of the melanoma development. In certain cases the primary tumour is completely destroyed and only the metastatic tumour is discovered.

Genetics

In some cases, melanoma runs in families. Several different genes have been identified as increasing the risk of developing melanoma. Some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene called MC1R that causes red hair, have a relatively low risk. Genetic testing can be used to determine whether a person has one of the currently known mutations.

A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. 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 fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor of CDK4, a [cyclin-dependent kinase] that promotes cell division. Mutations that cause the skin condition Xeroderma Pigmentosum (XP) also seriously predispose one to melanoma. Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant^{[clarification needed]}.

Familial melanoma is genetically heterogeneous,^[6] and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma.^[7] The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a — a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs) — which has been localised to the p21 region of human chromosome 9.^[8]

Other mutations confer lower risk but are more prevalent in the population. People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type copies of the gene. MC1R mutations are very common; in fact, all people with red hair have a mutated copy of the gene.

Two-gene models of melanoma risk have already been created,^{[citation needed]} and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype.

In addition to identifying high-risk patients, researchers want to identify high-risk lesions within a given patient. Many new technologies, such as optical coherence tomography (OCT), are being developed to accomplish this. OCT allows pathologists to view 3-D reconstructions of the skin and offers more resolution than past techniques could provide. In vivo confocal microscopy and fluorescently tagged antibodies are also proving to be valuable diagnostic tools.

Mutation of the MDM2 SNP309 gene is associated with increased risk of melanoma in younger women.^[9]

UV radiation from tanning beds

In July 2009, the IARC released a report that categorized tanning beds as “carcinogenic to humans.” The agency, which is part of the World Health Organization (WHO), previously classified tanning beds as “probably carcinogenic.” The change comes after an analysis of more than 20 epidemiological studies indicating that people who begin using tanning devices before age 30 are 75% more likely to develop melanoma.^[10]

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 (such lesions should be referred without delay to a dermatologist). At later stages, the mole may itch, ulcerate or bleed.^[11] Early signs of melanoma are summarized by the mnemonic "ABCDE":

Asymmetry
Borders (irregular)
Color (variegated), and
Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser)
Evolving over time

These classifications do not however apply to the most dangerous form of melanoma nodular melanoma which has its own classifications:

Elevated above the skin surface
Firm to the touch
Growing.

Metastatic melanoma may cause non-specific paraneoplastic symptoms including loss of appetite, nausea, vomiting and fatigue. Metastasis of early melanoma is possible, but relatively rare: less than a fifth of melanomas diagnosed early become metastatic.

Classification

Melanoma is divided into the following stereotypes:^[12]

Diagnosis

Example where rule "D" failed: A 4mm nodular melanoma.

There is no blood test for detecting melanomas. Visual diagnosis of melanomas is still the most common method employed by health professionals.^[14] To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCD" mnemonic below), to be aware of moles and check for changes (shape, size, color, itching or bleeding) and to show any suspicious moles to a doctor with an interest and skills in skin malignancy.^[15]^[16]

A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCDE":

Asymmetrical skin lesion.
Border of the lesion is irregular.
Color: melanomas usually have multiple colors.
Diameter: moles greater than 6 mm are more likely to be melanomas than smaller moles.
Enlarging: Enlarging or evolving

A weakness in this system is the D. Many melanomas present themselves as lesions smaller than 6 mm in diameter; and all melanomas were malignant on day 1 of growth, which is merely a dot. An astute physician will examine all abnormal moles, including ones less than 6 mm in diameter. Seborrheic keratosis may meet some or all of the ABCD criteria, and can lead to false alarms among laypeople and sometimes even physicians. An experienced doctor can generally distinguish seborrheic keratosis from melanoma upon examination, or with dermatoscopy.

Some will advocate the system "ABCDE",^[17] with E for evolution. Certainly moles which change and evolve will be a concern. Alternately, some will refer to E as elevation. Elevation can help identify a melanoma, but lack of elevation does not mean that the lesion is not a melanoma. Most melanomas are detected in the very early stage, or in-situ stage, before they become elevated. By the time elevation is visible, they may have progressed to the more dangerous invasive stage.

However, Nodular melanomas do not fulfill these criteria, having their own mnemonic "EFG":

Elevated: the lesion is raised above the surrounding skin.
Firm: the nodule is solid to the touch.
Growing: the nodule is increasing in size.

A recent and novel method of melanoma detection is the "Ugly Duckling Sign"^[18]^[19] It is simple, easy to teach, and highly effective in detecting melanoma. Simply, correlation of common characteristics of a person's skin lesion is made. Lesions which greatly deviate from the common characteristics are labeled as an "Ugly Duckling", and further professional exam is required. The "Little Red Riding Hood" sign^[19] suggests that individuals with fair skin and light colored hair might have difficult-to-diagnose amelanotic melanomas. Extra care and caution should be rendered 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 non-melanomas or are considered to be "wolves in sheep clothing".^[20] These fair skinned individuals often have lightly pigmented or amelanotic melanomas which will not present easy-to-observe color changes and variation in colors. The borders of these amelanotic melanomas are often indistinct, making visual identification without a dermatoscope (dermatoscopy) very difficult.

People with a personal or family history of skin cancer or of dysplastic nevus syndrome (multiple atypical moles) should see a dermatologist at least once a year to be sure they are not developing melanoma.

Moles that are irregular in color or shape are often treated as candidates of melanoma. Following a visual examination and a dermatoscopic exam,^[20] or an in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. If the mole is malignant, the mole and an area around it need excision.

The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles or not have any color at all. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining the severity of the melanoma. Amelanotic melanomas and melanomas arising in fair skinned individuals (see the "Little Red Riding Hood" sign) 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 very hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines.

Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up of high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (being possible with the use of any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes.^[14] The diagnosis method should be used in conjunction with (and not as a replacement for) dermscopic imaging, with a combination of both methods appearing to give extremely high rates of detection.

Surgical Treatment

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.^[21] In order not to disrupt 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. Large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram directed lymphnode dissection. A small punch biopsy can be utilized 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.

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 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, PET and/or PET/CT 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.

Sometimes the skin lesion may bleed, itch, or ulcerate, although this is a very late sign. A slow-healing lesion should be watched closely, as that may be a sign of melanoma. Be aware also that in circumstances that are still poorly understood, melanomas may "regress" or spontaneously become smaller or invisible — however, the malignancy is still present. Amelanotic (colorless or flesh-colored) melanomas do not have pigment and may not even be visible. Lentigo maligna, a superficial melanoma confined to the topmost layers of the skin (found primarily in older patients) is often described as a "stain" on the skin. Some patients with metastatic melanoma do not have an obvious detectable primary tumor.

Staging

Further context on cancer staging is available at TNM.

Also of importance are the "Clark level" and "Breslow's depth" which refer to the microscopic depth of tumor invasion.^[22]

Melanoma stages:^[23]

Stage 0: Melanoma in Situ (Clark Level I), 99.9% Survival

Stage I/II: Invasive Melanoma, 85–99% Survival

T1a: Less than 1.00 mm primary tumor thickness, w/o Ulceration and mitosis < 1/mm2
T1b: Less than 1.00 mm primary tumor thickness, w/Ulceration or mitoses ≥ 1/mm2
T2a: 1.00–2.00 mm primary tumor thickness, w/o Ulceration

Stage II: High Risk Melanoma, 40–85% Survival

T2b: 1.00–2.00 mm primary tumor thickness, w/ Ulceration
T3a: 2.00–4.00 mm primary tumor thickness, w/o Ulceration
T3b: 2.00–4.00 mm primary tumor thickness, w/ Ulceration
T4a: 4.00 mm or greater primary tumor thickness w/o Ulceration
T4b: 4.00 mm or greater primary tumor thickness w/ Ulceration

Stage III: Regional Metastasis, 25–60% Survival

N1: Single Positive Lymph Node
N2: 2–3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis
N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases

Stage IV: Distant Metastasis, 9–15% Survival

M1a: Distant Skin Metastasis, Normal LDH
M1b: Lung Metastasis, Normal LDH
M1c: Other Distant Metastasis OR Any Distant Metastasis with Elevated LDH

Based Upon AJCC 5-Year Survival With Proper Treatment

Prevention

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),^[24] following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past it was recommended to use sunscreens with an SPF rating of 30 or higher on exposed areas as older sunscreens more effectively blocked UVA with higher SPF.^[25] Currently, newer sunscreen ingredients (avobenzone, zinc, and titanium) effectively block both UVA and UVB even at lower SPFs. However, there are questions about the ability of sunscreen to prevent melanoma.^[26] This controversy is well discussed in numerous review articles, and is refuted by most dermatologists.^[27]^[28] This correlation might be due to the confounding variable that individuals who used sunscreen to prevent burn might have a higher lifetime exposure to either UVA or UVB. See Sunscreen controversy for further references and discussions. Tanning, once believed to help prevent skin cancers, actually can lead to an increased incidence of melanomas.^[29] Even though tanning beds emit mostly UVA, which causes tanning, it by itself might be enough to induce melanomas.

A good rule of thumb for decreasing ultraviolet light exposure is to avoid the sun between the hours of 9 a.m. and 3 p.m. or avoid the sun when your shadow is shorter than your height. These are rough rules, however, and can vary depending on locality and individual skin cancer risk.

Almost all melanomas start with altering the color and appearance of normal-looking skin. This area may be a dark spot or an abnormal new mole. Other melanomas form from a mole or freckle that is already present in the skin. It can be difficult to distinguish between a melanoma and a normal mole. When looking for danger signs in pigmented lesions of the skin a few simple rules are often used. The “ABCDE” list, the "ugly duckling sign", and the "red riding hood" rule are defined and discussed under the heading "Detection" earlier in this article.

“Melanoma Monday” is the kick-off of May Melanoma Month with special activities nationally and locally. Also known as National Skin Self-Examination Day. People are encouraged to examine their skin for skin cancer.^[30] Since 1985, this program has helped to detect more than 188,000 suspicious lesions, including more than 21,500 suspected melanomas.

Treatment

Confirmation of the clinical diagnosis is either done with an excisional skin biopsy or a small full thickness sampling with a punch skin biopsy. This is usually followed with a follow up wider excision of the scar or tumor. Depending on the stage a sentinel lymph node biopsy is done as well, although controversy exists around trial evidence for this procedure. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.

Surgery

Diagnostic punch or excisional biopsies may appear to excise (and in some cases may indeed actually 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 to 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2 to 0.5 cm.^[31] Many surgeons consider 0.5 cm the standard of care for standard excision of melanoma-in-situ,^[32] but 0.2 cm 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 tumour 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.^[33]

Mohs surgery has been reported with cure rate as low as 77%^[34] and as high as 98% for melanoma-in-situ.^[35] CCPDMA and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this "intra-epithelial" type of melanoma.

Melanomas which spread usually do so to the lymph nodes in the region of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications but unfortunately 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.^[36]

Although controversial and without prolonging survival, "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 in order 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 H&E staining, and immunoperoxidase staining will be adequate to rule out node involvement. PCR tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative SLN actually had a small number of positive cells in their nodes. Alternatively, a fine-needle aspiration 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.

Adjuvant treatment

High risk melanomas may require adjuvant treatment. 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.^[37] This claim is not supported by all research at this time, and in Europe interferon is usually not used outside the scope of clinical trials.^[38]^[39]

Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.^[40]

Chemotherapy and immunotherapy

Various chemotherapy agents are used, including dacarbazine (also termed DTIC), immunotherapy (with interleukin-2 (IL-2) or interferon (IFN)) as well as local perfusion are used by different centers. They can occasionally show dramatic success, but the overall success in metastatic melanoma is quite limited.^[41] IL-2 (Proleukin) is the first new therapy approved for the treatment of metastatic melanoma in 20 years. Studies have demonstrated that IL-2 offers the possibility of a complete and long-lasting remission in this disease, although only in a small percentage of patients.^[42] A number of new agents and novel approaches are under evaluation and show promise.^[43] Clinical trial participation should be considered the standard of care for metastatic melanoma.^[44]

Another molecule used in the immunotherapy is the lymphocyte cd4+. The lymphocyte cd4+ is isolated from the human body and produced in large amounts in laboratories. The cd4+ recognizes and kills the melanoma cells. It is used in melanoma metastasis and it gives good results in 2 months. Unfortunately this treatment is used only in some patients which their immune system recognizes the melanoma metastasis.^[45]

In 2005, a phase III clinical trial for a melanoma vaccine was halted after showing little benefit compared to placebo. On June 23, 2008, Israeli scientists from the Oncology Institute of the Hadassa Medical Center in Jerusalem announced they developed a vaccine that prevents recurrences of the disease among previous sufferers and increases chances of survival for current ones. One of the most promising current experimental treatment approaches, also an immunotherapy, is OncoVEX GM-CSF (BioVex Inc, Woburn, MA) which is currently in Phase 3 clinical trials following a very high level of efficacy having been observed in Phase 2.

Lentigo maligna treatment

Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceedingly high (up to 50%). This is due to the ill defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation of the standard bread loafing technique of fixed tissue histology — result in a high "false negative" error rate, and frequent recurrences. Margin controlled (peripheral margins) is necessary to eliminate the false negative errors. If breadloafing is utilized, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control.

Mohs surgery has been done with cure rate reported to be as low as 77%,^[34] and as high as 95% by another author.^[35] 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.^[46]

Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months.

Radiation therapy

Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. It may reduce the rate of local recurrence but does not prolong survival.^[47] Radioimmunotherapy of metastatic melanoma is currently under investigation. Radiotherapy has a role in the palliation of metastatic melanoma.^[48]

Cell and Targeted Therapies

In research setting other therapies, such as adoptive cell therapy or gene therapy, may be tested.^[49] Two kinds of experimental treatments developed at the National Cancer Institute (NCI), part of the National Institutes of Health in the US have been used in advanced (metastatic) melanoma with moderate success. The first treatment involves adoptive cell therapy using immune cells isolated from a patient's own melanoma tumor (TIL). 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 complete responses in highly pretreated patients.^[50] The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.^[51]

A new treatment that trains the immune system to fight cancer has shown modest benefit in late-stage testing against melanoma.^[52]

About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggest that B-Raf inhibitors including Plexxicon(R) can lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation.^[53] Large clinical trials are underway to more fully evaluate the efficacy and potency of B-Raf inhibitors. Sutent may be effective for patients with metastatic melanoma.^[54]

Ipilimumab

At the American Society of Clinical Oncology Conference in June 2010, pharmaceutical company reported the clinical findings of their drug ipilimumab. 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.^[55] 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.^[56]^[57]^[58] Meaning that the drug performed better than the vaccine, although the vaccine has not been tested before and may be causing toxicity — making the drug appear better by comparison.

Prognosis

Features that affect prognosis are tumor thickness in millimeters (Breslow's depth), depth related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion, presence of tumor-infiltrating lymphocytes (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant metastasis.^[59] Certain types of melanoma have worse prognoses but this is explained by their thickness. Interestingly, less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences tend to behave similarly to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.

When melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. Extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic have a more favorable prognosis than macrometastases. In some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely employed test known as the polymerase chain reaction (PCR), the prognosis is better. Macrometastases 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 still worse.

When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%.^[23] The median survival is 6 to 12 months. Treatment is palliative, focusing on life-extension and quality of life. In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis.

There is not enough definitive evidence to adequately stage, and thus give a prognosis for ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g. rectal melanoma), although these tend to metastasize more easily. Even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a pathology report might indicate.

Epidemiology

Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental.^[62] "Intrinsic" factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure.

Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA^[63] and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. 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;^[64]^[65]^[66] studies from mice on skin cancer tend to confirm a role for Activating Transcription Factor-2 in cancer progression.^[67]^[68] Occasional extreme sun exposure (resulting in "sunburn") is causally related to melanoma.^[69] Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers.^[70]^[71] Other factors are mutations in or total loss of tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.^[72]

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. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia^[73] where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that sunscreen — while preventing the sunburn — does not protect mice, injected with melanoma cells a day after UV exposure, from developing melanoma.^[74]

Fair and red-headed people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk.^[75]

A family history of melanoma greatly increases a person's risk because mutations in CDKN2A, CDK4 and several other genes have been found in melanoma-prone families.^[76] Patients with a history of one melanoma are at increased risk of developing a second primary tumour.^[77]

The incidence of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved.^[78]

To understand how sunscreen can reduce sunburn and at the same time cause melanoma it is necessary to distinguish between direct DNA damage and indirect DNA damage. Genetic analysis has shown that 92% of all melanoma are caused by the indirect DNA damage.^[79] Although some people believe that dark-skinned people such as those of African descent cannot get sunburns, they are in fact susceptible, and should use sunscreen accordingly, as sunscreen has been proven to protect against other cancers such as squamous cell carcinoma and basal cell carcinoma.^[80]

History

Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However, one example lies in a 1960s examination of nine Peruvian mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones.^[81]

John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not knowing precisely what it was, he described it as a "cancerous fungous excrescence". The excised tumor was preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma.^[82]

The French physician René Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculté de Médecine de Paris in 1804 and then published as a bulletin in 1806.^[83] The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820.^[84] In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and Therapeutical Remarks on That Disease).

The first formal acknowledgment of advanced melanoma as untreatable came from Samuel Cooper in 1840. He stated that the only chance for benefit depends upon the early removal of the disease ...'^[85] More than one and a half centuries later this situation remains largely unchanged.

Research

One important pathway in melanin synthesis involves the transcription factor MITF. The MITF gene is highly conserved and is found in people, mice, birds, and even fish. MITF production is regulated via a fairly straightforward pathway. UV radiation causes increased expression of transcription factor p53 in keratinocytes, and p53 causes these cells to produce melanocyte-stimulating hormone (MSH), which binds to melanocortin 1 receptors (MC1R) on melanocytes. Ligand-binding at MC1R receptors activates adenylate cyclases, which produce cAMP, which activates CREB, which promote MITF expression. The targets of MITF include p16 (a CDK inhibitor) and Bcl2, a gene essential to melanocyte survival. It is often difficult to design drugs that interfere with transcription factors, but perhaps new drugs will be discovered that can impede some reaction in the pathway upstream of MITF.

Studies of chromatin structure also promise to shed light on transcriptional regulation in melanoma cells. It has long been assumed that nucleosomes are positioned randomly on DNA, but murine studies of genes involved in melanin production now suggest that nucleosomes are stereotypically positioned on DNA. When a gene is undergoing transcription, its transcription start site is almost always nucleosome-free. When the gene is silent, however, nucleosomes often block the transcriptional start site, suggesting that nucleosome position may play a role in gene regulation.

Finally, given the fact that melanin helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce melanin synthesis in individuals who would otherwise get sunburns. Redheads, for example, do not tan because they have MC1R mutations. In mice, it has been shown that the melanin production pathway can be rescued downstream of MC1R.^{[citation needed]}

A study published on January 27, 2011, by M. Raza Zaidi et al. shows that interferon-γ links ultraviolet radiation to melanomagenesis in mice. Using a mouse model that allowed the visual tracking and purification of melanocytes using a green fluorescent dye, data showed that UVB-induced, macrophage-enhanced interferon-γ release results in melanoma growth, proliferation and immunoevasion. Based on these results, the interferon-γ pathway can potentially serve as part of new therapeutic measures to treat patients suffering from malignant melanoma, as well as a potential preventive strategy against UV-induced radiation.^[86]

Notes

^ Jerant AF, Johnson JT, Sheridan CD, Caffrey TJ (2000). "Early detection and treatment of skin cancer". Am Fam Physician. 62 (2): 357–68, 375–6, 381–2. PMID 10929700. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Parkin D, Bray F, Ferlay J, Pisani P (2005). "Global cancer statistics, 2002". CA Cancer J Clin. 55 (2): 74–108. doi:10.3322/canjclin.55.2.74. PMID 15761078.{{cite journal}}: CS1 maint: multiple names: authors list (link)Full text
^ Lucas, R. Global Burden of Disease of Solar Ultraviolet Radiation, Environmental Burden of Disease Series, July 25, 2006; No. 13. News release, World Health Organization
^ [1] IARC — Solar and ultraviolet radiation. Monographs on the evaluation of carcinogenic risks to humans
^ http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=34439
^ Greene MH. (1998). "The genetics of hereditary melanoma and nevi". Cancer. 86 (11): 2464–77. doi:10.1002/(SICI)1097-0142(19991201)86:11. PMID 10630172.
^ Halachmi S, Gilchrest BA. (2001). "Update on genetic events in the pathogenesis of melanoma". Curr Opin Oncol. 13 (2): 129–136. doi:10.1097/00001622-200103000-00008. PMID 11224711.
^ CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) from Entrez Gene
^ Firoz, EF; Warycha, M; Zakrzewski, J; Pollens, D; Wang, G; Shapiro, R; Berman, R; Pavlick, A; Manga, P (2009). "Association of MDM2 SNP309, Age of Onset, and Gender in Cutaneous Melanoma". Clinical cancer research : an official journal of the American Association for Cancer Research. 15 (7): 2573–80. doi:10.1158/1078-0432.CCR-08-2678. PMID 19318491.
^ WHO International Agency for Research on Cancer Monograph Working Group (August 2009). "A Review of Human Carcinogens—Part D:Radiation". The Lancet Oncology. 10 (8): 751–2. doi:10.1016/S1470-2045(09)70213-X. PMID 19655431.
^ MelanomaWarningSigns.com
^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. pp. 694–9. ISBN 0-7216-2921-0. {{cite book}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
^ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ ^a ^b Wurm, Elisabeth M and Soyer, H Peter (2010). Australian Prescriber (33): 150–5 http://www.australianprescriber.com/magazine/33/5/150/5. {{cite journal}}: Missing or empty |title= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ MelanomaFoundation.org
^ Friedman R, Rigel D, Kopf A (1985). "Early detection of malignant melanoma: the role of physician examination and self-examination of the skin". CA Cancer J Clin. 35 (3): 130–51. doi:10.3322/canjclin.35.3.130. PMID 3921200.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ AAD.org
^ SkinCancer.org
^ ^a ^b Mascaro JM, Mascaro JM (1998). "The dermatologist's position concerning nevi: a vision ranging from "the ugly duckling" to "little red riding hood"". Arch Dermatol. 134 (11): 1484–5. PMID 9828892. {{cite journal}}: Unknown parameter |month= ignored (help)
^ ^a ^b Dermnetnz.org
^ Swanson N, Lee K, Gorman A, Lee H (2002). "Biopsy techniques. Diagnosis of melanoma". Dermatol Clin. 20 (4): 677–80. doi:10.1016/S0733-8635(02)00025-6. PMID 12380054.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Malignant Melanoma: staging at Collaborative Hypertext of Radiology
^ ^a ^b Balch C, Buzaid A, Soong S, Atkins M, Cascinelli N, Coit D, Fleming I, Gershenwald J, Houghton A, Kirkwood J, McMasters K, Mihm M, Morton D, Reintgen D, Ross M, Sober A, Thompson J, Thompson J (2001). "Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma". J Clin Oncol. 19 (16): 3635–48. PMID 11504745.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Autier P (2005). "Cutaneous malignant melanoma: facts about sunbeds and sunscreen". Expert Rev Anticancer Ther. 5 (5): 821–33. doi:10.1586/14737140.5.5.821. PMID 16221052.
^ Can Melanoma Be Prevented?
^ Garland C, Garland F, Gorham E (1992). "Could sunscreens increase melanoma risk?". Am J Public Health. 82 (4): 614–5. doi:10.2105/AJPH.82.4.614. PMC 1694089. PMID 1546792.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ HighBeam.com
^ "Does sunscreen cause melanoma? Researchers now strongly say no". J Drugs Dermatol. 3 (3): 323–4. 2004. PMID 15176171.
^ Clough-Gorr KM, Titus-Ernstoff L, Perry AE, Spencer SK, Ernstoff MS (2008). "Exposure to sunlamps, tanning beds, and melanoma risk". Cancer Causes Control. 19 (7): 659–69. doi:10.1007/s10552-008-9129-6. PMID 18273687. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ melanomamonday.com
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^ ^a ^b Mikhail, G. Mohs Micrographic Surgery. 1991, Saunders, pp. 13–14
^ ^a ^b Bene NI, Healy C, Coldiron BM (2008). "Mohs micrographic surgery is accurate 95.1% of the time for melanoma in situ: a prospective study of 167 cases". Dermatol Surg. 34 (5): 660–4. doi:10.1111/j.1524-4725.2007.34124.x. PMID 18261099. Cure rate as high as 98% for small melanoma in situ, and as high as 95% noted for lentigo maligna variant of melanona in situ has been reported with Mohs surgery. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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^ Bhatia S, Tykodi SS, Thompson JA (2009). "Treatment of Metastatic Melanoma: An Overview". Oncology. 23 (6). PMID 19544689.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ An Overview Of The Melanoma Treatment And Therapy
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^ Primary Care Oncology. Ford. 1999. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)CS1 maint: others (link)
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^ Press release from the NIH
^ CBSnews.com
^ Harmon, Amy (February 21, 2010). "A Roller Coaster Chase for a Cure". The New York Times.
^ http://professional.cancerconsultants.com/oncology_melanoma_news.aspx?id=44063
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^ http://www.pharmalot.com/2010/06/bristol-myers-melanoma-med-and-wall-street-wags/
^ Forbes http://blogs.forbes.com/sciencebiz/2010/06/the-risk-for-bristol/. {{cite news}}: Missing or empty |title= (help)
^ http://www.news-medical.net/news/20100609/Phase-3-clinical-study-Ipilimumab-boosts-sustains-immune-system-responses-against-melanoma-tumors.aspx
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^ "CANCERMondial (GLOBOCAN)". GLOBOCAN. 2010. Retrieved 12 August 2010.
^ "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved Nov. 11, 2009. {{cite web}}: Check date values in: |accessdate= (help)
^ Who is Most at Risk for Melanoma?
^ Wang S, Setlow R, Berwick M, Polsky D, Marghoob A, Kopf A, Bart R (2001). "Ultraviolet A and melanoma: a review". J Am Acad Dermatol. 44 (5): 837–46. doi:10.1067/mjd.2001.114594. PMID 11312434.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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^ Bhoumik A, Singha N, O'Connell MJ, Ronai ZA (2008). "Regulation of TIP60 by ATF2 modulates ATM activation". J. Biol. Chem. 283 (25): 17605–14. doi:10.1074/jbc.M802030200. PMC 2427333. PMID 18397884. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ Bhoumik A, Jones N, Ronai Z (2004). "Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity". Proc. Natl. Acad. Sci. U.S.A. 101 (12): 4222–7. doi:10.1073/pnas.0400195101. PMC 384722. PMID 15010535. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V (2008). "The role of ATF-2 in oncogenesis". Bioessays. 30 (4): 314–27. doi:10.1002/bies.20734. PMID 18348191. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
^ Huang Y, Minigh J, Miles S, Niles RM (2008). "Retinoic acid decreases ATF-2 phosphorylation and sensitizes melanoma cells to taxol-mediated growth inhibition". J Mol Signal. 3: 3. doi:10.1186/1750-2187-3-3. PMC 2265711. PMID 18269766.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
^ Oliveria S, Saraiya M, Geller A, Heneghan M, Jorgensen C (2006). "Sun exposure and risk of melanoma". Arch Dis Child. 91 (2): 131–8. doi:10.1136/adc.2005.086918. PMC 2082713. PMID 16326797.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Lee J, Strickland D (1980). "Malignant melanoma: social status and outdoor work". Br J Cancer. 41 (5): 757–63. PMC 2010319. PMID 7426301.
^ Pion IA, Rigel DS, Garfinkel L, Silverman MK, Kopf AW (1995). "Occupation and the risk of malignant melanoma". Cancer. 75 (2 Suppl): 637–44. doi:10.1002/1097-0142(19950115)75:2. PMID 7804988. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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^ Miller A, Mihm M (2006). "Melanoma". N Engl J Med. 355 (1): 51–65. doi:10.1056/NEJMra052166. PMID 16822996.
^ Rhodes A, Weinstock M, Fitzpatrick T, Mihm M, Sober A (1987). "Risk factors for cutaneous melanoma. A practical method of recognizing predisposed individuals". JAMA. 258 (21): 3146–54. doi:10.1001/jama.258.21.3146. PMID 3312689.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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^ Cooper, Samuel (1840). First lines of theory and practice of surgery. London: Longman, Orme, Brown, Green and Longman.
^ Zaidi MR, Davis S, Noonan FP; et al. (2011). "Interferon-γ links ultraviolet radiation to melanomagenesis in mice". Nature. 469 (7331): 548–53. doi:10.1038/nature09666. PMID 21248750. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

External links

Template:Gonadal tumors, paraganglioma, glomus, nevi and melanomas

[1] Jerant AF, Johnson JT, Sheridan CD, Caffrey TJ (2000). "Early detection and treatment of skin cancer". Am Fam Physician. 62 (2): 357–68, 375–6, 381–2. PMID 10929700. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[globalca2001-2] Parkin D, Bray F, Ferlay J, Pisani P (2005). "Global cancer statistics, 2002". CA Cancer J Clin. 55 (2): 74–108. doi:10.3322/canjclin.55.2.74. PMID 15761078.{{cite journal}}: CS1 maint: multiple names: authors list (link)Full text

[who1-3] Lucas, R. Global Burden of Disease of Solar Ultraviolet Radiation, Environmental Burden of Disease Series, July 25, 2006; No. 13. News release, World Health Organization

[4] [1] IARC — Solar and ultraviolet radiation. Monographs on the evaluation of carcinogenic risks to humans

[5] ttp://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=34439

[6] Greene MH. (1998). "The genetics of hereditary melanoma and nevi". Cancer. 86 (11): 2464–77. doi:10.1002/(SICI)1097-0142(19991201)86:11. PMID 10630172.

[7] Halachmi S, Gilchrest BA. (2001). "Update on genetic events in the pathogenesis of melanoma". Curr Opin Oncol. 13 (2): 129–136. doi:10.1097/00001622-200103000-00008. PMID 11224711.

[8] CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4) from Entrez Gene

[9] Firoz, EF; Warycha, M; Zakrzewski, J; Pollens, D; Wang, G; Shapiro, R; Berman, R; Pavlick, A; Manga, P (2009). "Association of MDM2 SNP309, Age of Onset, and Gender in Cutaneous Melanoma". Clinical cancer research : an official journal of the American Association for Cancer Research. 15 (7): 2573–80. doi:10.1158/1078-0432.CCR-08-2678. PMID 19318491.

[10] WHO International Agency for Research on Cancer Monograph Working Group (August 2009). "A Review of Human Carcinogens—Part D:Radiation". The Lancet Oncology. 10 (8): 751–2. doi:10.1016/S1470-2045(09)70213-X. PMID 19655431.

[11] MelanomaWarningSigns.com

[12] James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. pp. 694–9. ISBN 0-7216-2921-0. {{cite book}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

[Bolognia-13] Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.{{cite book}}: CS1 maint: multiple names: authors list (link)

[ap01-14] Wurm, Elisabeth M and Soyer, H Peter (2010). Australian Prescriber (33): 150–5 http://www.australianprescriber.com/magazine/33/5/150/5. {{cite journal}}: Missing or empty |title= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[15] MelanomaFoundation.org

[16] Friedman R, Rigel D, Kopf A (1985). "Early detection of malignant melanoma: the role of physician examination and self-examination of the skin". CA Cancer J Clin. 35 (3): 130–51. doi:10.3322/canjclin.35.3.130. PMID 3921200.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[17] AAD.org

[18] SkinCancer.org

[ReferenceA-19] Mascaro JM, Mascaro JM (1998). "The dermatologist's position concerning nevi: a vision ranging from "the ugly duckling" to "little red riding hood"". Arch Dermatol. 134 (11): 1484–5. PMID 9828892. {{cite journal}}: Unknown parameter |month= ignored (help)

[dermnetnz.org-20] Dermnetnz.org

[21] Swanson N, Lee K, Gorman A, Lee H (2002). "Biopsy techniques. Diagnosis of melanoma". Dermatol Clin. 20 (4): 677–80. doi:10.1016/S0733-8635(02)00025-6. PMID 12380054.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[22] Malignant Melanoma: staging at Collaborative Hypertext of Radiology

[AJCC-23] Balch C, Buzaid A, Soong S, Atkins M, Cascinelli N, Coit D, Fleming I, Gershenwald J, Houghton A, Kirkwood J, McMasters K, Mihm M, Morton D, Reintgen D, Ross M, Sober A, Thompson J, Thompson J (2001). "Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma". J Clin Oncol. 19 (16): 3635–48. PMID 11504745.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[24] Autier P (2005). "Cutaneous malignant melanoma: facts about sunbeds and sunscreen". Expert Rev Anticancer Ther. 5 (5): 821–33. doi:10.1586/14737140.5.5.821. PMID 16221052.

[25] Can Melanoma Be Prevented?

[26] Garland C, Garland F, Gorham E (1992). "Could sunscreens increase melanoma risk?". Am J Public Health. 82 (4): 614–5. doi:10.2105/AJPH.82.4.614. PMC 1694089. PMID 1546792.{{cite journal}}: CS1 maint: multiple names: authors list (link)

[27] HighBeam.com

[28] "Does sunscreen cause melanoma? Researchers now strongly say no". J Drugs Dermatol. 3 (3): 323–4. 2004. PMID 15176171.

[29] Clough-Gorr KM, Titus-Ernstoff L, Perry AE, Spencer SK, Ernstoff MS (2008). "Exposure to sunlamps, tanning beds, and melanoma risk". Cancer Causes Control. 19 (7): 659–69. doi:10.1007/s10552-008-9129-6. PMID 18273687. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

[30] y.com

[31] LabPath.com

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@@ Line 18: / Line 18: @@
 '''Melanoma''' ({{pron-en|ˌmɛləˈnoʊmə|melanoma-pronunciation.ogg}}) is a [[malignant]] [[tumor]] of [[melanocyte]]s.  Melanocytes are cells that produce the dark pigment, [[melanin]], which is responsible for the color of skin.  They predominantly occur in skin, but are also found in other parts of the body, including the [[bowel]] and the [[human eye|eye]] (see [[uveal melanoma]]).  Melanoma can occur in any part of the body that contains melanocytes.
-Melanoma is less common than other [[skin cancer]]s. However, it is much more dangerous and causes the majority (75%) of deaths related to skin cancer.<ref>{{Cite web|title=Early Detection and Treatment of Skin Cancer|work=[[American Family Physician]]|date=July 15, 2000|url=http://www.aafp.org/afp/20000715/357.html |accessdate=2010-02-08}}</ref>  Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. The diagnosis is more frequent in women than in men and is particularly common among [[Caucasian race|Caucasians]] living in sunny climates, with high rates of incidence in Australia, New Zealand, North America, and northern Europe.<ref name="globalca2001">{{Cite journal| author = Parkin D, Bray F, Ferlay J, Pisani P | title = Global cancer statistics, 2002 | journal = CA Cancer J Clin | volume = 55 | issue = 2 | pages = 74–108 | year = 2005| pmid = 15761078 | doi = 10.3322/canjclin.55.2.74}}''[http://caonline.amcancersoc.org/cgi/content/full/55/2/74 Full text]''</ref>
+Melanoma is less common than other [[skin cancer]]s. However, it is much more dangerous and causes the majority (75%) of deaths related to skin cancer.<ref>{{cite journal |author=Jerant AF, Johnson JT, Sheridan CD, Caffrey TJ |title=Early detection and treatment of skin cancer |journal=Am Fam Physician |volume=62 |issue=2 |pages=357–68, 375–6, 381–2 |year=2000 |month=July |pmid=10929700 |url=http://www.aafp.org/afp/20000715/357.html }}</ref>  Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. The diagnosis is more frequent in women than in men and is particularly common among [[Caucasian race|Caucasians]] living in sunny climates, with high rates of incidence in Australia, New Zealand, North America, and northern Europe.<ref name="globalca2001">{{Cite journal| author = Parkin D, Bray F, Ferlay J, Pisani P | title = Global cancer statistics, 2002 | journal = CA Cancer J Clin | volume = 55 | issue = 2 | pages = 74–108 | year = 2005| pmid = 15761078 | doi = 10.3322/canjclin.55.2.74}}''[http://caonline.amcancersoc.org/cgi/content/full/55/2/74 Full text]''</ref>
 According to a [[WHO]] report about 48,000 melanoma related deaths occur worldwide per year.<ref name="who1">Lucas, R. Global Burden of Disease of Solar Ultraviolet Radiation, Environmental Burden of Disease Series, July 25, 2006; No. 13. News release, World Health Organization</ref>
@@ Line 26: / Line 26: @@
 ===In lay terms===
 <!-- References: all material here has been sourced from allied/related articles in Wikipedia.  However, since Wikipedia is only a third-class reference, the sources should probably not be cited. -->
-All cancers are caused by damage to the [[DNA]] inside cells. This damage can be inherited in the form of [[genetic mutations]], but in most cases it builds up over a person's lifetime and is caused by factors in their environment. DNA damage causes the cell to grow out  of control, leading to a tumour. Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.<ref>[http://monographs.iarc.fr/ENG/Monographs/vol55/] IARC - Solar and ultraviolet radiation. Monographs on the evaluation of carcinogenic risks to humans</ref>
+All cancers are caused by damage to the [[DNA]] inside cells. This damage can be inherited in the form of [[genetic mutations]], but in most cases it builds up over a person's lifetime and is caused by factors in their environment. DNA damage causes the cell to grow out  of control, leading to a tumour. Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.<ref>[http://monographs.iarc.fr/ENG/Monographs/vol55/] IARC — Solar and ultraviolet radiation. Monographs on the evaluation of carcinogenic risks to humans</ref>
 ====Natural history of melanoma====
@@ Line 32: / Line 32: @@
 The earliest stage of melanoma starts when the melanocytes begin to grow out of control. Melanocytes are found between the outer layer of the skin (the [[epidermis]]) and the next layer (the [[dermis]]). This early stage of the disease is called the radial growth phase, and the tumour is less than 1mm thick. Because the cancer cells have not yet reached the blood vessels lower down in the skin it is very unlikely that this early-stage cancer 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 tumour cells start to move in a different direction - vertically up into the [[epidermis]] and into the [[papillary dermis]] - the behaviour of the cells changes dramatically.
+When the tumour cells start to move in a different direction — vertically up into the [[epidermis]] and into the [[papillary dermis]] - the behaviour of the cells changes dramatically.
-The next step in the evolution is the invasive radial growth phase, which is a confusing term, however it explains the next step in the process of the radial growth, when individual cells start to acquire invasive potential. This step is important - from this point on the melanoma is capable of spreading. The [[Breslow's depth]] of the lesion is usually less than {{convert|1|mm|2|abbr=on|lk=out}}, the [[Clark level]] is usually 2.
+The next step in the evolution is the invasive radial growth phase, which is a confusing term, however it explains the next step in the process of the radial growth, when individual cells start to acquire invasive potential. This step is important – from this point on the melanoma is capable of spreading. The [[Breslow's depth]] of the lesion is usually less than {{convert|1|mm|2|abbr=on|lk=out}}, the [[Clark level]] is usually 2.
-The following step in the process is the invasive melanoma - the vertical growth phase (VGP). The tumour attains invasive potential, meaning it can grow into the surrounding tissue and can spread around the body through blood or [[lymph vessels]]. The tumour thickness is usually more than {{convert|1|mm|2|abbr=on|lk=out}}, and the tumour involves the deeper parts of the dermis.
+The following step in the process is the invasive melanoma — the vertical growth phase (VGP). The tumour attains invasive potential, meaning it can grow into the surrounding tissue and can spread around the body through blood or [[lymph vessels]]. The tumour thickness is usually more than {{convert|1|mm|2|abbr=on|lk=out}}, and the tumour involves the deeper parts of the dermis.
 The host elicits an immunological reaction against the tumour (during the VGP),<ref>http://www.asco.org/ascov2/Meetings/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=34439</ref> which is judged by the presence and activity of the TILs ([[tumour infiltrating lymphocyte]]s). These cells sometimes completely destroy the primary tumour, this is called regression, which is the latest stage of the melanoma development. In certain cases the primary tumour is completely destroyed and only the metastatic tumour is discovered.
@@ Line 45: / Line 45: @@
 A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma.  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 fifty percent of human cancers.  Another mutation in the same gene results in a non-functional inhibitor of [[CDK4]], a [cyclin-dependent kinase] that promotes cell division.  Mutations that cause the skin condition [[Xeroderma Pigmentosum]] (XP) also seriously predispose one to melanoma.  Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA.  Both CDKN2A and XP mutations are ''highly penetrant''{{clarify|date=November 2010}}.
-Familial melanoma is genetically heterogeneous,<ref>{{Cite journal| author = Greene MH. | title = The genetics of hereditary melanoma and nevi | journal = Cancer | volume = 86 | issue = 11 | pages = 2464–2477 | year = 1998 | pmid = 10630172 | doi = 10.1002/(SICI)1097-0142(19991201)86:11 | doi_brokendate = 2009-04-03}}</ref> and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma.<ref>{{Cite journal| author = Halachmi S, Gilchrest BA. | title = Update on genetic events in the pathogenesis of melanoma | journal = Curr Opin Oncol | volume = 13 | issue = 2 | pages = 129–136 | year = 2001 | pmid = 11224711 | doi = 10.1097/00001622-200103000-00008}}</ref> The multiple [[Tumor suppressor gene|tumor suppressor]] 1 (CDKN2A/MTS1) gene encodes p16INK4a - a low-molecular weight protein inhibitor of [[cyclin-dependent kinase|cyclin-dependent protein kinases]] (CDKs) - which has been localised to the p21 region of [[Chromosome 9 (human)|human chromosome 9]].<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=1029 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)] from Entrez Gene</ref>
+Familial melanoma is genetically heterogeneous,<ref>{{Cite journal| author = Greene MH. | title = The genetics of hereditary melanoma and nevi | journal = Cancer | volume = 86 | issue = 11 | pages = 2464–77 | year = 1998 | pmid = 10630172 | doi = 10.1002/(SICI)1097-0142(19991201)86:11 }}</ref> and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma.<ref>{{Cite journal| author = Halachmi S, Gilchrest BA. | title = Update on genetic events in the pathogenesis of melanoma | journal = Curr Opin Oncol | volume = 13 | issue = 2 | pages = 129–136 | year = 2001 | pmid = 11224711 | doi = 10.1097/00001622-200103000-00008}}</ref> The multiple [[Tumor suppressor gene|tumor suppressor]] 1 (CDKN2A/MTS1) gene encodes p16INK4a — a low-molecular weight protein inhibitor of [[cyclin-dependent kinase|cyclin-dependent protein kinases]] (CDKs) — which has been localised to the p21 region of [[Chromosome 9 (human)|human chromosome 9]].<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=1029 CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)] from Entrez Gene</ref>
 Other mutations confer lower risk but are more prevalent in the population.  People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type copies of the gene.   [[Melanocortin 1 receptor|MC1R]] mutations are very common; in fact, all people with red hair have a mutated copy of the gene.
@@ Line 58: / Line 58: @@
 In July 2009, the [[International Agency for Research on Cancer|IARC]] released a report that categorized tanning beds as “carcinogenic to humans.” The agency, which is part of the [[World Health Organization]] (WHO), previously classified tanning beds as “probably carcinogenic.” The change comes after an analysis of more than 20 epidemiological studies indicating that people who begin using tanning devices before age 30 are 75% more likely to develop melanoma.<ref>{{Cite journal
 |author=WHO International Agency for Research on Cancer Monograph Working Group
-|title=A Review of Human Carcinogens--Part D:Radiation
+|title=A Review of Human Carcinogens—Part D:Radiation
 | journal=[[The Lancet Oncology]]
 |date = August 2009| volume=10
 | issue=8
-| pages=751–752
+| pages=751–2
 | doi=10.1016/S1470-2045(09)70213-X
 | pmid=19655431}}</ref>
@@ Line 81: / Line 81: @@
 ==Classification==
-Melanoma is divided into the following stereotypes:<ref name="Andrews">{{Cite book|author=James, William D.; Berger, Timothy G.; et al. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |location= |year=2006 |pages= |isbn=0-7216-2921-0 |oclc= |doi= |accessdate=}}</ref>{{rp|694-699}}
+Melanoma is divided into the following stereotypes:<ref>{{Cite book|author=James, William D.; Berger, Timothy G.; et al. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |location= |year=2006 |isbn=0-7216-2921-0 |pages=694–9}}</ref>
 * [[Lentigo maligna]]
@@ Line 94: / Line 94: @@
 * [[Soft-tissue melanoma]]
-See also:<ref name="Bolognia">{{Cite book|author=Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. |title=Dermatology: 2-Volume Set |publisher=Mosby |location=St. Louis |year=2007 |pages= |isbn=1-4160-2999-0 |oclc= |doi= |accessdate=}}</ref>
+See also:<ref name="Bolognia">{{Cite book|author=Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. |title=Dermatology: 2-Volume Set |publisher=Mosby |location=St. Louis |year=2007 |isbn=1-4160-2999-0 }}</ref>
 * [[Melanoma with small nevus-like cells]]
@@ Line 107: / Line 107: @@
 [[File:Malignant melanoma (1) at thigh Case 01.jpg|thumb|225px|Melanoma in skin biopsy with [[H&E stain]]. This case may represent superficial spreading melanoma]]
-There is no blood test for detecting melanomas. Visual diagnosis of melanomas is still the most common method employed by health professionals.<ref name="ap01">{{cite journal |author=Wurm, Elisabeth M and Soyer, H Peter |year=2010 |month=October |journal=Australian Prescriber |issue=33 |pages=150–155 |url=http://www.australianprescriber.com/magazine/33/5/150/5}}</ref> To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCD" mnemonic below), to be aware of [[Melanocytic nevus|moles]] and check for changes (shape, size, color, itching or bleeding) and to show any suspicious moles to a doctor with an interest and skills in skin malignancy.<ref>[http://www.melanomafoundation.org/prevention/abcd.htm MelanomaFoundation.org]</ref><ref>{{Cite journal| author = Friedman R, Rigel D, Kopf A | title = Early detection of malignant melanoma: the role of physician examination and self-examination of the skin | journal = CA Cancer J Clin | volume = 35 | issue = 3 | pages = 130–51 | year = 1985| pmid = 3921200 | doi = 10.3322/canjclin.35.3.130}}</ref>
+There is no blood test for detecting melanomas. Visual diagnosis of melanomas is still the most common method employed by health professionals.<ref name="ap01">{{cite journal |author=Wurm, Elisabeth M and Soyer, H Peter |year=2010 |month=October |journal=Australian Prescriber |issue=33 |pages=150–5 |url=http://www.australianprescriber.com/magazine/33/5/150/5}}</ref> To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCD" mnemonic below), to be aware of [[Melanocytic nevus|moles]] and check for changes (shape, size, color, itching or bleeding) and to show any suspicious moles to a doctor with an interest and skills in skin malignancy.<ref>[http://www.melanomafoundation.org/prevention/abcd.htm MelanomaFoundation.org]</ref><ref>{{Cite journal| author = Friedman R, Rigel D, Kopf A | title = Early detection of malignant melanoma: the role of physician examination and self-examination of the skin | journal = CA Cancer J Clin | volume = 35 | issue = 3 | pages = 130–51 | year = 1985| pmid = 3921200 | doi = 10.3322/canjclin.35.3.130}}</ref>
 A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCDE":
@@ Line 126: / Line 126: @@
 * ''G''rowing: the nodule is increasing in size.
-A recent and novel method of melanoma detection is the '''"Ugly Duckling Sign"'''<ref>[http://www.skincancer.org/the-ugly-duckling-sign.html SkinCancer.org]</ref><ref name="ReferenceA">Mascaro JM Jr, Mascaro JM. The dermatologist's position concerning nevi: a vision ranging from 'the ugly duckling' to 'little red riding hood'. Arch Dermatol 1998; 134:1484–5.
+A recent and novel method of melanoma detection is the '''"Ugly Duckling Sign"'''<ref>[http://www.skincancer.org/the-ugly-duckling-sign.html SkinCancer.org]</ref><ref name="ReferenceA">{{cite journal |author=Mascaro JM, Mascaro JM |title=The dermatologist's position concerning nevi: a vision ranging from "the ugly duckling" to "little red riding hood" |journal=Arch Dermatol |volume=134 |issue=11 |pages=1484–5 |year=1998 |month=November |pmid=9828892 |url=http://archderm.ama-assn.org/cgi/pmidlookup?view=long&pmid=9828892}}
 </ref>  It is simple, easy to teach, and highly effective in detecting melanoma.  Simply, correlation of common characteristics of a person's skin lesion is made.  Lesions which greatly deviate from the common characteristics are labeled as an "Ugly Duckling", and further professional exam is required.  The '''"Little Red Riding Hood"''' sign<ref name="ReferenceA"/> suggests that individuals with fair skin and light colored hair might have difficult-to-diagnose amelanotic melanomas.  Extra care and caution should be rendered 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 non-melanomas or are considered to be "wolves in sheep clothing".<ref name="dermnetnz.org">[http://dermnetnz.org/doctors/dermoscopy-course/introduction.html Dermnetnz.org]</ref>  These fair skinned individuals often have lightly pigmented or amelanotic melanomas which will not present easy-to-observe color changes and variation in colors.  The borders of these amelanotic melanomas are often indistinct, making visual identification without a dermatoscope ([[dermatoscopy]]) very difficult.
@@ Line 142: / Line 142: @@
 [[Lactate dehydrogenase]] (LDH) tests are often used to screen for [[metastasis|metastases]], although many patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates 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 [[computed tomography|CT]], [[MRI]], [[Positron emission tomography|PET]] and/or PET/CT 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.
-Sometimes the skin lesion may bleed, itch, or ulcerate, although this is a very late sign.  A slow-healing lesion should be watched closely, as that may be a sign of melanoma.  Be aware also that in circumstances that are still poorly understood, melanomas may "regress" or spontaneously become smaller or invisible - however, the malignancy is still present.  '''Amelanotic''' (colorless or flesh-colored) melanomas do not have pigment and may not even be visible.  '''[[Lentigo maligna]]''', a superficial melanoma confined to the topmost layers of the skin (found primarily in older patients) is often described as a "stain" on the skin. Some patients with metastatic melanoma do not have an obvious detectable primary tumor.
+Sometimes the skin lesion may bleed, itch, or ulcerate, although this is a very late sign.  A slow-healing lesion should be watched closely, as that may be a sign of melanoma.  Be aware also that in circumstances that are still poorly understood, melanomas may "regress" or spontaneously become smaller or invisible — however, the malignancy is still present.  '''Amelanotic''' (colorless or flesh-colored) melanomas do not have pigment and may not even be visible.  '''[[Lentigo maligna]]''', a superficial melanoma confined to the topmost layers of the skin (found primarily in older patients) is often described as a "stain" on the skin. Some patients with metastatic melanoma do not have an obvious detectable primary tumor.
 ===Staging===
@@ Line 153: / Line 153: @@
 '''Stage 0''': Melanoma in Situ (Clark Level I), 99.9% Survival
-'''Stage I/II''': Invasive Melanoma, 85-99% Survival
+'''Stage I/II''': Invasive Melanoma, 85–99% Survival
 *T1a: Less than 1.00&nbsp;mm primary tumor thickness, w/o Ulceration and mitosis < 1/mm2
 *T1b: Less than 1.00&nbsp;mm primary tumor thickness, w/Ulceration or mitoses ≥ 1/mm2
-*T2a: 1.00-2.00&nbsp;mm primary tumor thickness, w/o Ulceration
+*T2a: 1.00–2.00&nbsp;mm primary tumor thickness, w/o Ulceration
-'''Stage II''': High Risk Melanoma, 40-85% Survival
+'''Stage II''': High Risk Melanoma, 40–85% Survival
-*T2b: 1.00-2.00&nbsp;mm primary tumor thickness, w/ Ulceration
+*T2b: 1.00–2.00&nbsp;mm primary tumor thickness, w/ Ulceration
-*T3a: 2.00-4.00&nbsp;mm primary tumor thickness, w/o Ulceration
+*T3a: 2.00–4.00&nbsp;mm primary tumor thickness, w/o Ulceration
-*T3b: 2.00-4.00&nbsp;mm primary tumor thickness, w/ Ulceration
+*T3b: 2.00–4.00&nbsp;mm primary tumor thickness, w/ Ulceration
 *T4a: 4.00&nbsp;mm or greater primary tumor thickness w/o Ulceration
 *T4b: 4.00&nbsp;mm or greater primary tumor thickness w/ Ulceration
-'''Stage III''': Regional Metastasis, 25-60% Survival
+'''Stage III''': Regional Metastasis, 25–60% Survival
 *N1: Single Positive Lymph Node
-*N2: 2-3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis
+*N2: 2–3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis
 *N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases
-'''Stage IV''': Distant Metastasis, 9-15% Survival
+'''Stage IV''': Distant Metastasis, 9–15% Survival
 *M1a: Distant Skin Metastasis, Normal [[Lactate dehydrogenase|LDH]]
 *M1b: Lung Metastasis, Normal [[Lactate dehydrogenase|LDH]]
@@ Line 178: / Line 178: @@
 ==Prevention==
-Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),<ref>{{Cite journal| author = Autier P | title = Cutaneous malignant melanoma: facts about sunbeds and sunscreen | journal = Expert Rev Anticancer Ther | volume = 5 | issue = 5 | pages = 821–33 | year = 2005 | pmid = 16221052 | doi = 10.1586/14737140.5.5.821}}</ref> following sun protection measures and wearing [[sun protective clothing]] (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past it was recommended to use  [[sunscreen]]s with an [[sunscreen|SPF]] rating of 30 or higher on exposed areas as older sunscreens more effectively blocked UVA with higher SPF.<ref>[http://www.cancer.org/docroot/cri/content/cri_2_4_2x_can_melanoma_be_prevented_50.asp Can Melanoma Be Prevented?]</ref> Currently, newer sunscreen ingredients (avobenzone, zinc, and titanium) effectively block both UVA and UVB even at lower SPFs. However, there are questions about the ability of [[sunscreen]] to prevent melanoma.<ref>{{Cite journal|author=Garland C, Garland F, Gorham E |title=Could sunscreens increase melanoma risk? |url= http://www.ajph.org/cgi/reprint/82/4/614| journal=Am J Public Health |volume=82 |issue=4 |pages=614–5 |year=1992 |pmid=1546792 |doi=10.2105/AJPH.82.4.614 |pmc=1694089}}</ref> This controversy is well discussed in numerous review articles, and is refuted by most dermatologists.<ref>[http://www.highbeam.com/doc/1G1-117775410.html HighBeam.com]</ref><ref>[http://findarticles.com/p/articles/mi_m0PDG/is_3_3/ai_n6056512 FindArticles.com]</ref>  This correlation might be due to the confounding variable that individuals who used sunscreen to prevent burn might have a higher lifetime exposure to either UVA or UVB.  See [[Sunscreen controversy]] for further references and discussions.
+Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),<ref>{{Cite journal| author = Autier P | title = Cutaneous malignant melanoma: facts about sunbeds and sunscreen | journal = Expert Rev Anticancer Ther | volume = 5 | issue = 5 | pages = 821–33 | year = 2005 | pmid = 16221052 | doi = 10.1586/14737140.5.5.821}}</ref> following sun protection measures and wearing [[sun protective clothing]] (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past it was recommended to use  [[sunscreen]]s with an [[sunscreen|SPF]] rating of 30 or higher on exposed areas as older sunscreens more effectively blocked UVA with higher SPF.<ref>[http://www.cancer.org/docroot/cri/content/cri_2_4_2x_can_melanoma_be_prevented_50.asp Can Melanoma Be Prevented?]</ref> Currently, newer sunscreen ingredients (avobenzone, zinc, and titanium) effectively block both UVA and UVB even at lower SPFs. However, there are questions about the ability of [[sunscreen]] to prevent melanoma.<ref>{{Cite journal|author=Garland C, Garland F, Gorham E |title=Could sunscreens increase melanoma risk? |url= http://www.ajph.org/cgi/reprint/82/4/614| journal=Am J Public Health |volume=82 |issue=4 |pages=614–5 |year=1992 |pmid=1546792 |doi=10.2105/AJPH.82.4.614 |pmc=1694089}}</ref> This controversy is well discussed in numerous review articles, and is refuted by most dermatologists.<ref>[http://www.highbeam.com/doc/1G1-117775410.html HighBeam.com]</ref><ref>{{cite journal |author= |title=Does sunscreen cause melanoma? Researchers now strongly say no |journal=J Drugs Dermatol |volume=3 |issue=3 |pages=323–4 |year=2004 |pmid=15176171 |doi= |url=http://findarticles.com/p/articles/mi_m0PDG/is_3_3/ai_n6056512}}</ref>  This correlation might be due to the confounding variable that individuals who used sunscreen to prevent burn might have a higher lifetime exposure to either UVA or UVB.  See [[Sunscreen controversy]] for further references and discussions.
-Tanning, once believed to help prevent skin cancers, actually can lead to an increased incidence of melanomas.<ref>Exposure to sunlamps, tanning beds, and melanoma risk
+Tanning, once believed to help prevent skin cancers, actually can lead to an increased incidence of melanomas.<ref>{{cite journal |author=Clough-Gorr KM, Titus-Ernstoff L, Perry AE, Spencer SK, Ernstoff MS |title=Exposure to sunlamps, tanning beds, and melanoma risk |journal=Cancer Causes Control |volume=19 |issue=7 |pages=659–69 |year=2008 |month=September |pmid=18273687 |doi=10.1007/s10552-008-9129-6 }}
-Journal Cancer Causes and Control.  Springer, Netherlands. ISSN 0957-5243 (Issue Volume 19, Number 7 / September, 2008. pp.659-69.</ref>  Even though tanning beds emit mostly UVA, which causes tanning, it by itself might be enough to induce melanomas.
+</ref>  Even though tanning beds emit mostly UVA, which causes tanning, it by itself might be enough to induce melanomas.
 A good rule of thumb for decreasing ultraviolet light exposure is to avoid the sun between the hours of 9 a.m. and 3 p.m. or avoid the sun when your shadow is shorter than your height. These are rough rules, however, and can vary depending on locality and individual skin cancer risk.
@@ Line 186: / Line 186: @@
 Almost all melanomas start with altering the color and appearance of normal-looking skin. This area may be a dark spot or an abnormal new mole. Other melanomas form from a mole or freckle that is already present in the skin. It can be difficult to distinguish between a melanoma and a normal mole. When looking for danger signs in pigmented lesions of the skin a few simple rules are often used.  The “ABCDE” list, the "ugly duckling sign", and the "red riding hood" rule are defined and discussed under the heading "Detection" earlier in this article.
-“Melanoma Monday” is the kick-off of May Melanoma Month with special activities nationally and locally.  Also known as National Skin Self-Examination Day. People are encouraged to examine their skin for skin cancer.<ref>[http://www.melanomamonday.com]</ref>  Since 1985, this program has helped to detect more than 188,000 suspicious lesions, including more than 21,500 suspected melanomas.
+“Melanoma Monday” is the kick-off of May Melanoma Month with special activities nationally and locally.  Also known as National Skin Self-Examination Day. People are encouraged to examine their skin for skin cancer.<ref>[http://www.melanomamonday.com melanomamonday.com]</ref>  Since 1985, this program has helped to detect more than 188,000 suspicious lesions, including more than 21,500 suspected melanomas.
 ==Treatment==
@@ Line 195: / Line 195: @@
 Diagnostic punch or excisional biopsies may appear to excise (and in some cases may indeed actually remove) the tumor, but further surgery is often necessary to reduce the risk of recurrence.
-Complete surgical excision with adequate [[surgical margin]]s 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 to 2&nbsp;cm margins.  Melanoma-in-situ and lentigo malignas are treated with narrower [[surgical margin]]s, usually 0.2 to 0.5&nbsp;cm.<ref>[http://www.labpath.com/new7.html LabPath.com]</ref>  Many surgeons consider 0.5&nbsp;cm the standard of care for standard excision of melanoma-in-situ,<ref>[http://www.moffitt.org/moffittapps/ccj/v15n3/pdf/216.pdf Moffitt.org]</ref> but 0.2&nbsp;cm 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 tumour 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.<ref>{{cite journal | author = Balch C, Urist M, Karakousis C, Smith T, Temple W, Drzewiecki K, Jewell W, Bartolucci A, Mihm M, Barnhill R | title = Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial | journal = Ann Surg | volume = 218 | issue = 3 | pages = 262–7; discussion 267–9 | year = 1993 | pmid = 8373269 | doi = 10.1097/00000658-199309000-00005 | pmc = 1242959}}</ref>
+Complete surgical excision with adequate [[surgical margin]]s 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 to 2&nbsp;cm margins.  Melanoma-in-situ and lentigo malignas are treated with narrower [[surgical margin]]s, usually 0.2 to 0.5&nbsp;cm.<ref>[http://www.labpath.com/new7.html LabPath.com]</ref>  Many surgeons consider 0.5&nbsp;cm the standard of care for standard excision of melanoma-in-situ,<ref>{{cite journal |author=Clark GS, Pappas-Politis EC, Cherpelis BS, ''et al.'' |title=Surgical management of melanoma in situ on chronically sun-damaged skin |journal=Cancer Control |volume=15 |issue=3 |pages=216–24 |year=2008 |month=July |pmid=18596673 |format=PDF |url=http://www.moffitt.org/CCJRoot/v15n3/pdf/216.pdf}}</ref> but 0.2&nbsp;cm 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 tumour 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.<ref>{{cite journal | author = Balch C, Urist M, Karakousis C, Smith T, Temple W, Drzewiecki K, Jewell W, Bartolucci A, Mihm M, Barnhill R | title = Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial | journal = Ann Surg | volume = 218 | issue = 3 | pages = 262–7; discussion 267–9 | year = 1993 | pmid = 8373269 | doi = 10.1097/00000658-199309000-00005 | pmc = 1242959}}</ref>
-[[Mohs surgery]] has been reported with cure rate as low as 77%<ref name="Mikhail, G. Mohs Micrographic Surgery 1991, pp. 13">Mikhail, G. Mohs Micrographic Surgery. 1991, Saunders, pp. 13–14</ref> and as high as 98% for melanoma-in-situ.<ref>Bene, NI, et al. Mohs micrographic surgery is accurate 95.1% of the time for melanoma in situ: a prospective study of 167 cases Dermatol Surg. 2008 May;34(5):660-4.Cure rate as high as 98% for small melanoma in situ, and as high as 95% noted for lentigo maligna variant of melanona in situ has been reported with [[Mohs surgery]].</ref>  [[CCPDMA]] and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this "intra-epithelial" type of melanoma.
+[[Mohs surgery]] has been reported with cure rate as low as 77%<ref name="Mikhail, G. Mohs Micrographic Surgery 1991, pp. 13">Mikhail, G. Mohs Micrographic Surgery. 1991, Saunders, pp. 13–14</ref> and as high as 98% for melanoma-in-situ.<ref name=Bene08>{{cite journal |author=Bene NI, Healy C, Coldiron BM |title=Mohs micrographic surgery is accurate 95.1% of the time for melanoma in situ: a prospective study of 167 cases |journal=Dermatol Surg |volume=34 |issue=5 |pages=660–4 |year=2008 |month=May |pmid=18261099 |doi=10.1111/j.1524-4725.2007.34124.x |url=http://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1076-0512&date=2008&volume=34&issue=5&spage=660 |quote=Cure rate as high as 98% for small melanoma in situ, and as high as 95% noted for lentigo maligna variant of melanona in situ has been reported with [[Mohs surgery]].}}</ref>  [[CCPDMA]] and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this "intra-epithelial" type of melanoma.
 Melanomas which spread usually do so to the [[lymph nodes]] in the region of the tumor before spreading elsewhere.  Attempts to improve survival by removing lymph nodes surgically ([[lymphadenectomy]]) were associated with many complications but unfortunately 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.<ref>[http://www.malignant-melanoma.org/surgery/lymph-node-dissection-surgery/ Malignant-Melanoma.org]</ref>
@@ Line 220: / Line 220: @@
 ===Lentigo maligna treatment===
-Standard excision is still being done by most surgeons.  Unfortunately, the recurrence rate is exceedingly high (up to 50%).  This is due to the ill defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin).  The narrow surgical margin used, combined with the limitation of the standard bread loafing technique of fixed tissue histology - result in a high "false negative" error rate, and frequent recurrences.  Margin controlled (peripheral margins) is necessary to eliminate the false negative errors.  If breadloafing is utilized, distances from sections should approach 0.1&nbsp;mm to assure that the method approaches complete margin control.
+Standard excision is still being done by most surgeons.  Unfortunately, the recurrence rate is exceedingly high (up to 50%).  This is due to the ill defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin).  The narrow surgical margin used, combined with the limitation of the standard bread loafing technique of fixed tissue histology — result in a high "false negative" error rate, and frequent recurrences.  Margin controlled (peripheral margins) is necessary to eliminate the false negative errors.  If breadloafing is utilized, distances from sections should approach 0.1&nbsp;mm to assure that the method approaches complete margin control.
-[[Mohs surgery]] has been done with cure rate reported to be as low as  77%,<ref name="Mikhail, G. Mohs Micrographic Surgery 1991, pp. 13"/> and as high as 95% by another author.<ref>Bene, NI, et al. Mohs micrographic surgery is accurate 95.1% of the time for melanoma in situ: a prospective study of 167 cases Dermatol Surg. 2008 May;34(5):660-4.</ref>  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.<ref>Usefulness of the Staged Excision for Lentigo Maligna and Lentigo Maligna Melanoma: The 'Square' Procedure" (J Am Acad Dermatol 1997;37:758-63)</ref>
+[[Mohs surgery]] has been done with cure rate reported to be as low as  77%,<ref name="Mikhail, G. Mohs Micrographic Surgery 1991, pp. 13"/> and as high as 95% by another author.<ref name=Bene08/> 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.<ref>{{cite journal |author=Johnson TM, Headington JT, Baker SR, Lowe L |title=Usefulness of the staged excision for lentigo maligna and lentigo maligna melanoma: the "square" procedure |journal=J. Am. Acad. Dermatol. |volume=37 |issue=5 Pt 1 |pages=758–64 |year=1997 |month=November |pmid=9366823 |url=http://linkinghub.elsevier.com/retrieve/pii/S0190-9622(97)70114-2}}</ref>
 Some melanocytic nevi, and melanoma-in-situ ([[lentigo maligna]]) have resolved with an experimental treatment,  [[imiquimod]] (Aldara) topical cream, an immune enhancing agent.  Some dermasurgeons are combining the 2 methods:  surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months.
@@ Line 232: / Line 232: @@
 ===Cell and Targeted Therapies===
-In research setting other therapies, such as adoptive cell therapy or [[gene therapy]], may be tested.<ref>{{cite journal | author = Sotomayor M, Yu H, Antonia S, Sotomayor E, Pardoll D | title = Advances in gene therapy for malignant melanoma | journal = Cancer Control | volume = 9 | issue = 1 | pages = 39–48 | year = 2002| pmid = 11907465}}''[https://www.moffitt.usf.edu/pubs/ccj/v9n1/pdf/39.pdf Full text (PDF)]''</ref>
+In research setting other therapies, such as adoptive cell therapy or [[gene therapy]], may be tested.<ref>{{cite journal | author = Sotomayor M, Yu H, Antonia S, Sotomayor E, Pardoll D | title = Advances in gene therapy for malignant melanoma | journal = Cancer Control | volume = 9 | issue = 1 | pages = 39–48 | year = 2002| pmid = 11907465 |url=https://www.moffitt.usf.edu/pubs/ccj/v9n1/pdf/39.pdf |format=PDF}}</ref>
 Two kinds of experimental treatments developed at the National Cancer Institute (NCI), part of the National Institutes of Health in the US have been used in advanced (metastatic) melanoma with moderate success.
-The first treatment involves adoptive cell therapy using immune cells isolated from a patient's own melanoma tumor (TIL). 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 complete responses in highly pretreated patients.<ref>[http://jco.ascopubs.org/cgi/content/abstract/26/32/5233]</ref> The second treatment, adoptive transfer of genetically altered autologous lymphocytes,
+The first treatment involves adoptive cell therapy using immune cells isolated from a patient's own melanoma tumor (TIL). 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 complete responses in highly pretreated patients.<ref>{{cite journal |author=Dudley ME, Yang JC, Sherry R, ''et al.'' |title=Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens |journal=J. Clin. Oncol. |volume=26 |issue=32 |pages=5233–9 |year=2008 |month=November |pmid=18809613 |pmc=2652090 |doi=10.1200/JCO.2008.16.5449 |url=http://jco.ascopubs.org/content/26/32/5233.full}}</ref> The second treatment, adoptive transfer of genetically altered autologous lymphocytes,
 depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.<ref name="nih">[http://www.nih.gov/news/pr/aug2006/nci-31b.htm Press release from the NIH]</ref>
@@ Line 244: / Line 244: @@
 ==Ipilimumab==
-At the American Society of Clinical Oncology Conference in June 2010, pharmaceutical company reported the clinical findings of their drug [[ipilimumab]]. 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.<ref>{{cite news | title = Bristol drug cuts death risk in advanced melanoma | url = http://www.reuters.com/article/idUSN0218461520100605 | work=Reuters | date=June 5, 2010}}</ref> 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.<ref>http://www.pharmalot.com/2010/06/bristol-myers-melanoma-med-and-wall-street-wags/</ref><ref>{{cite news| url=http://blogs.forbes.com/sciencebiz/2010/06/the-risk-for-bristol/ | work=Forbes}}</ref><ref>http://www.news-medical.net/news/20100609/Phase-3-clinical-study-Ipilimumab-boosts-sustains-immune-system-responses-against-melanoma-tumors.aspx</ref> Meaning that the drug performed better than the vaccine, although the vaccine has not been tested before and may be causing toxicity - making the drug appear better by comparison.
+At the American Society of Clinical Oncology Conference in June 2010, pharmaceutical company reported the clinical findings of their drug [[ipilimumab]]. 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.<ref>{{cite news | title = Bristol drug cuts death risk in advanced melanoma | url = http://www.reuters.com/article/idUSN0218461520100605 | work=Reuters | date=June 5, 2010}}</ref> 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.<ref>http://www.pharmalot.com/2010/06/bristol-myers-melanoma-med-and-wall-street-wags/</ref><ref>{{cite news| url=http://blogs.forbes.com/sciencebiz/2010/06/the-risk-for-bristol/ | work=Forbes}}</ref><ref>http://www.news-medical.net/news/20100609/Phase-3-clinical-study-Ipilimumab-boosts-sustains-immune-system-responses-against-melanoma-tumors.aspx</ref> Meaning that the drug performed better than the vaccine, although the vaccine has not been tested before and may be causing toxicity — making the drug appear better by comparison.
 ==Prognosis==
 {{See also|Breslow's depth}}
-Features that affect [[prognosis]] are [[tumor]] thickness in millimeters ([[Breslow's depth]]), depth related to skin structures ([[Clark level]]), type of melanoma, presence of ulceration, presence of lymphatic/[[perineural invasion]], presence of tumor-infiltrating [[lymphocyte]]s (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant [[metastasis]].<ref>{{Cite journal| author = Homsi J, Kashani-Sabet M, Messina J, Daud A | title = Cutaneous melanoma: prognostic factors | journal = Cancer Control | volume = 12 | issue = 4 | pages = 223–9 | year = 2005 | pmid = 16258493 |url=http://www.medscape.com/viewarticle/516206 }}''[https://www.moffitt.usf.edu/pubs/ccj/v12n4/pdf/223.pdf Full text (PDF)]''</ref> Certain types of melanoma have worse prognoses but this is explained by their [[Breslow's depth|thickness]]. Interestingly, less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging.  Local recurrences tend to behave similarly to a primary unless they are at the site of a [[wide local excision]] (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.
+Features that affect [[prognosis]] are [[tumor]] thickness in millimeters ([[Breslow's depth]]), depth related to skin structures ([[Clark level]]), type of melanoma, presence of ulceration, presence of lymphatic/[[perineural invasion]], presence of tumor-infiltrating [[lymphocyte]]s (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant [[metastasis]].<ref>{{Cite journal| author = Homsi J, Kashani-Sabet M, Messina J, Daud A | title = Cutaneous melanoma: prognostic factors | journal = Cancer Control | volume = 12 | issue = 4 | pages = 223–9 | year = 2005 | pmid = 16258493 |url=http://www.medscape.com/viewarticle/516206 |url=https://www.moffitt.usf.edu/pubs/ccj/v12n4/pdf/223.pdf |format=PDF}}</ref> Certain types of melanoma have worse prognoses but this is explained by their [[Breslow's depth|thickness]]. Interestingly, less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging.  Local recurrences tend to behave similarly to a primary unless they are at the site of a [[wide local excision]] (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.
 When melanomas have spread to the [[lymph node]]s, one of the most important factors is the number of nodes with malignancy.  Extent of malignancy within a node is also important; micrometastases in which malignancy is only microscopic have a more favorable prognosis than macrometastases.  In some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely employed test known as the [[polymerase chain reaction]] (PCR), the prognosis is better. Macrometastases 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 still worse.
-When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%.<ref name=AJCC>{{Cite journal| author = Balch C, Buzaid A, Soong S, Atkins M, Cascinelli N, Coit D, Fleming I, Gershenwald J, Houghton A, Kirkwood J, McMasters K, Mihm M, Morton D, Reintgen D, Ross M, Sober A, Thompson J, Thompson J | title = Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma | journal = J Clin Oncol | volume = 19 | issue = 16 | pages = 3635–48 | year = 2001 | pmid = 11504745}}''[http://www.jco.org/cgi/content/full/19/16/3635 Full text]''</ref> The median survival is 6 to 12 months. Treatment is [[Palliative care|palliative]], focusing on life-extension and [[quality of life]].  In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment).  Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis.
+When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%.<ref name=AJCC>{{Cite journal| author = Balch C, Buzaid A, Soong S, Atkins M, Cascinelli N, Coit D, Fleming I, Gershenwald J, Houghton A, Kirkwood J, McMasters K, Mihm M, Morton D, Reintgen D, Ross M, Sober A, Thompson J, Thompson J | title = Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma | journal = J Clin Oncol | volume = 19 | issue = 16 | pages = 3635–48 | year = 2001 | pmid = 11504745 |url=http://www.jco.org/cgi/content/full/19/16/3635}}</ref> The median survival is 6 to 12 months. Treatment is [[Palliative care|palliative]], focusing on life-extension and [[quality of life]].  In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment).  Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis.
 There is not enough definitive evidence to adequately stage, and thus give a prognosis for ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g. rectal melanoma), although these tend to metastasize more easily.  Even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a [[Pathology|pathology report]] might indicate.
@@ Line 290: / Line 290: @@
 Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental.<ref>[http://www.skincarephysicians.com/skincancernet/who_is_most.html  Who is Most at Risk for Melanoma?]</ref> "Intrinsic" factors are generally an individual's family history and inherited [[genotype]], while the most relevant environmental factor is sun exposure.
-[[Epidemiologic]] studies suggest that exposure to [[ultraviolet]] radiation (UVA<ref name="uva">{{Cite journal| author = Wang S, Setlow R, Berwick M, Polsky D, Marghoob A, Kopf A, Bart R | title = Ultraviolet A and melanoma: a review | journal = J Am Acad Dermatol | volume = 44 | issue = 5 | pages = 837–46 | year = 2001 | pmid = 11312434 | doi = 10.1067/mjd.2001.114594}}</ref> and UVB) is one of the major contributors to the development of melanoma. UV radiation causes [[DNA damage|damage]] to the [[DNA]] of cells, typically [[thymine]] dimerization, which when unrepaired can create [[mutation]]s in the cell's [[gene]]s. When the cell [[cell division|divides]], these mutations are propagated to new generations of cells. If the mutations occur in [[protooncogene]]s or [[tumor suppressor gene]]s, 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;<ref>Leslie MC, Bar-Eli M.Regulation of gene expression in melanoma: new approaches for treatment.J Cell Biochem. 2005 Jan 1;94(1):25-38.PMID: 15523674</ref><ref>Bhoumik A, Singha N, O'Connell MJ, Ronai ZA.Regulation of TIP60 by ATF2 modulates ATM activation.J Biol Chem. 2008 Jun 20;283(25):17605-14.</ref><ref>Bhoumik A, Jones N, Ronai Z.Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity.Proc Natl Acad Sci U S A. 2004 Mar 23;101(12):4222-7.</ref> studies from mice on skin cancer tend to confirm a role for Activating Transcription Factor-2 in cancer progression.<ref>Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V.The role of ATF-2 in oncogenesis.Bioessays. 2008 Apr;30(4):314-27.</ref><ref>Huang Y, Minigh J, Miles S, Niles RM.Retinoic acid decreases ATF-2 phosphorylation and sensitizes melanoma cells to taxol-mediated growth inhibition.J Mol Signal. 2008 Feb 12;3:3.PMID: 18269766</ref> Occasional extreme sun exposure (resulting in "[[sunburn]]") is causally related to melanoma.<ref>{{Cite journal| author = Oliveria S, Saraiya M, Geller A, Heneghan M, Jorgensen C | title = Sun exposure and risk of melanoma | journal = Arch Dis Child | volume = 91 | issue = 2 | pages = 131–8 | year = 2006 | pmid = 16326797 | doi = 10.1136/adc.2005.086918 | pmc = 2082713}}</ref> Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers.<ref>{{Cite journal| author = Lee J, Strickland D | title = Malignant melanoma: social status and outdoor work | journal = Br J Cancer | volume = 41 | issue = 5 | pages = 757–63 | year = 1980 | pmid = 7426301 | pmc = 2010319}}</ref><ref>{{Cite journal|author=Pion IA, Rigel DS, Garfinkel L, Silverman MK, Kopf AW |title=Occupation and the risk of malignant melanoma |journal=Cancer |volume=75 |issue=2 Suppl |pages=637–44 |year=1995 |month=January |pmid=7804988 |doi= 10.1002/1097-0142(19950115)75:2|url= |doi_brokendate=2009-04-03}}</ref> Other factors are [[mutation]]s in or total loss of [[tumor suppressor gene]]s.  Use of [[sunbed]]s (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.<ref>[http://www.who.int/mediacentre/news/notes/2005/np07/en/ The World Health Organization recommends that no person under 18 should use a sunbed]</ref>
+[[Epidemiologic]] studies suggest that exposure to [[ultraviolet]] radiation (UVA<ref name="uva">{{Cite journal| author = Wang S, Setlow R, Berwick M, Polsky D, Marghoob A, Kopf A, Bart R | title = Ultraviolet A and melanoma: a review | journal = J Am Acad Dermatol | volume = 44 | issue = 5 | pages = 837–46 | year = 2001 | pmid = 11312434 | doi = 10.1067/mjd.2001.114594}}</ref> and UVB) is one of the major contributors to the development of melanoma. UV radiation causes [[DNA damage|damage]] to the [[DNA]] of cells, typically [[thymine]] dimerization, which when unrepaired can create [[mutation]]s in the cell's [[gene]]s. When the cell [[cell division|divides]], these mutations are propagated to new generations of cells. If the mutations occur in [[protooncogene]]s or [[tumor suppressor gene]]s, 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;<ref>{{cite journal |author=Leslie MC, Bar-Eli M |title=Regulation of gene expression in melanoma: new approaches for treatment |journal=J. Cell. Biochem. |volume=94 |issue=1 |pages=25–38 |year=2005 |month=January |pmid=15523674 |doi=10.1002/jcb.20296 |url=http://dx.doi.org/10.1002/jcb.20296}}</ref><ref>{{cite journal |author=Bhoumik A, Singha N, O'Connell MJ, Ronai ZA |title=Regulation of TIP60 by ATF2 modulates ATM activation |journal=J. Biol. Chem. |volume=283 |issue=25 |pages=17605–14 |year=2008 |month=June |pmid=18397884 |pmc=2427333 |doi=10.1074/jbc.M802030200 |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18397884}}</ref><ref>{{cite journal |author=Bhoumik A, Jones N, Ronai Z |title=Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=12 |pages=4222–7 |year=2004 |month=March |pmid=15010535 |pmc=384722 |doi=10.1073/pnas.0400195101 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15010535}}</ref> studies from mice on skin cancer tend to confirm a role for Activating Transcription Factor-2 in cancer progression.<ref>{{cite journal |author=Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V |title=The role of ATF-2 in oncogenesis |journal=Bioessays |volume=30 |issue=4 |pages=314–27 |year=2008 |month=April |pmid=18348191 |doi=10.1002/bies.20734 }}</ref><ref>{{cite journal |author=Huang Y, Minigh J, Miles S, Niles RM |title=Retinoic acid decreases ATF-2 phosphorylation and sensitizes melanoma cells to taxol-mediated growth inhibition |journal=J Mol Signal |volume=3 |issue= |pages=3 |year=2008 |pmid=18269766 |pmc=2265711 |doi=10.1186/1750-2187-3-3 |url=http://www.jmolecularsignaling.com/content/3//3}}</ref> Occasional extreme sun exposure (resulting in "[[sunburn]]") is causally related to melanoma.<ref>{{Cite journal| author = Oliveria S, Saraiya M, Geller A, Heneghan M, Jorgensen C | title = Sun exposure and risk of melanoma | journal = Arch Dis Child | volume = 91 | issue = 2 | pages = 131–8 | year = 2006 | pmid = 16326797 | doi = 10.1136/adc.2005.086918 | pmc = 2082713}}</ref> Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers.<ref>{{Cite journal| author = Lee J, Strickland D | title = Malignant melanoma: social status and outdoor work | journal = Br J Cancer | volume = 41 | issue = 5 | pages = 757–63 | year = 1980 | pmid = 7426301 | pmc = 2010319}}</ref><ref>{{Cite journal|author=Pion IA, Rigel DS, Garfinkel L, Silverman MK, Kopf AW |title=Occupation and the risk of malignant melanoma |journal=Cancer |volume=75 |issue=2 Suppl |pages=637–44 |year=1995 |month=January |pmid=7804988 |doi= 10.1002/1097-0142(19950115)75:2}}</ref> Other factors are [[mutation]]s in or total loss of [[tumor suppressor gene]]s.  Use of [[sunbed]]s (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.<ref>[http://www.who.int/mediacentre/news/notes/2005/np07/en/ The World Health Organization recommends that no person under 18 should use a sunbed]</ref>
-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]]. Exposure during childhood is a more important risk factor than exposure in adulthood.  This is seen in migration studies in [[Australia]]<ref>{{Cite journal| author = Khlat M, Vail A, Parkin M, Green A | title = Mortality from melanoma in migrants to Australia: variation by age at arrival and duration of stay | journal = Am J Epidemiol | volume = 135 | issue = 10 | pages = 1103–13 | year = 1992 | pmid = 1632422}}</ref> where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that [[sunscreen]] - while preventing the sunburn - does not protect mice, injected with melanoma cells a day after UV exposure, from developing melanoma.<ref name=Wolf1993>{{Cite journal|author= Wolf P;  Donawho C K; Kripke M L |title= Effect of Sunscreens on UV radiation-induced enhancements of melanoma in mice  | journal= J. Nat. Cancer. Inst. |volume=86 |pages=99–105 |year=1994  |doi= 10.1093/jnci/86.2.99 |pmid= 8271307 |issue= 2}}</ref>
+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]]. Exposure during childhood is a more important risk factor than exposure in adulthood.  This is seen in migration studies in [[Australia]]<ref>{{Cite journal| author = Khlat M, Vail A, Parkin M, Green A | title = Mortality from melanoma in migrants to Australia: variation by age at arrival and duration of stay | journal = Am J Epidemiol | volume = 135 | issue = 10 | pages = 1103–13 | year = 1992 | pmid = 1632422}}</ref> where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that [[sunscreen]] — while preventing the sunburn — does not protect mice, injected with melanoma cells a day after UV exposure, from developing melanoma.<ref name=Wolf1993>{{Cite journal|author= Wolf P;  Donawho C K; Kripke M L |title= Effect of Sunscreens on UV radiation-induced enhancements of melanoma in mice  | journal= J. Nat. Cancer. Inst. |volume=86 |pages=99–105 |year=1994  |doi= 10.1093/jnci/86.2.99 |pmid= 8271307 |issue= 2}}</ref>
 Fair and red-headed people, persons with multiple atypical [[nevi]] or [[dysplastic nevus|dysplastic nevi]] and persons born with giant [[congenital melanocytic nevi]] are at increased risk.<ref name="IMAGE">{{Cite journal| author = Bliss J, Ford D, Swerdlow A, Armstrong B, Cristofolini M, Elwood J, Green A, Holly E, Mack T, MacKie R | title = Risk of cutaneous melanoma associated with pigmentation characteristics and freckling: systematic overview of 10 case-control studies. The International Melanoma Analysis Group (IMAGE) | journal = Int J Cancer | volume = 62 | issue = 4 | pages = 367–76 | year = 1995 | pmid = 7635560 | doi = 10.1002/ijc.2910620402}}</ref>
@@ Line 323: / Line 323: @@
 Finally, given the fact that melanin helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce melanin synthesis in individuals who would otherwise get sunburns.  Redheads, for example, do not tan because they have MC1R mutations.  In mice, it has been shown that the melanin production pathway can be rescued downstream of MC1R.{{citation needed|date=November 2010}}
-A study published on January 27, 2011, by M. Raza Zaidi et al. shows that interferon-γ links ultraviolet radiation to melanomagenesis in mice. Using a mouse model that allowed the visual tracking and purification of melanocytes using a green fluorescent dye, data showed that UVB-induced, macrophage-enhanced interferon-γ release results in melanoma growth, proliferation and immunoevasion. Based on these results, the interferon-γ pathway can potentially serve as part of new therapeutic measures to treat patients suffering from malignant melanoma, as well as a potential preventive strategy against UV-induced radiation.<ref>Zaidi, M.R. et al. 2011. Interferon-gamma Links Ultraviolet Radiation to Melanomagenesis in Mice. Nature. 469: 548 – 553. (http://www.nature.com/nature/journal/v469/n7331/full/nature09666.html)</ref>
+A study published on January 27, 2011, by M. Raza Zaidi et al. shows that interferon-γ links ultraviolet radiation to melanomagenesis in mice. Using a mouse model that allowed the visual tracking and purification of melanocytes using a green fluorescent dye, data showed that UVB-induced, macrophage-enhanced interferon-γ release results in melanoma growth, proliferation and immunoevasion. Based on these results, the interferon-γ pathway can potentially serve as part of new therapeutic measures to treat patients suffering from malignant melanoma, as well as a potential preventive strategy against UV-induced radiation.<ref>{{cite journal |author=Zaidi MR, Davis S, Noonan FP, ''et al.'' |title=Interferon-γ links ultraviolet radiation to melanomagenesis in mice |journal=Nature |volume=469 |issue=7331 |pages=548–53 |year=2011 |month=January |pmid=21248750 |doi=10.1038/nature09666 |url=http://www.nature.com/nature/journal/v469/n7331/full/nature09666.html}}</ref>
 ==See also==
@@ Line 342: / Line 342: @@
 *[http://www.mmmp.org/MMMP/import.mmmp?page=targetedtherapydatabase.mmmp Targeted Therapy Database (TTD) for Melanoma ]
 *[http://therapy.collabrx.com/ Targeted Therapy Finder for Melanoma]
-*[http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=39 American Cancer Society's Detailed Guide: Skin Cancer - Melanoma]
+*[http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=39 American Cancer Society's Detailed Guide: Skin Cancer — Melanoma]
 *[http://www.unboundmedicine.com/5minute/ub/view/5-Minute-Clinical-Consult/116371/all/melanoma Melanoma Diagnosis & Treatment:  5-Minute Clinical Consult]
 {{Diseases of the skin and appendages by morphology}}