Melanoma

Melanoma
Classification and external resources
a melanoma
10 C43
9 172.9
ICD-O: 8720/3
OMIM 155600
DiseasesDB 7947
MedlinePlus 000850
eMedicine derm/257 med/1386 ent/27 plastic/456
MeSH D008545

Melanoma (uveal melanoma). Melanoma can originate in any part of the body that contains melanocytes.

Melanoma is less common than other [9]

According to a WHO report, about 48,000 melanoma related deaths occur worldwide per year.[10]

The treatment includes surgical removal of the tumor. If melanoma is found early, while it is still small and thin, and if it is completely removed, then the chance of cure is high. The likelihood of the melanoma coming back or spreading depends on how deeply it has gone into the layers of the skin. For melanomas that come back or spread, treatments include radiation therapy.

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)
  • 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 nonspecific 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. Brain metastases are particularly common in patients with metastatic melanoma.[12] It can also spread to the liver, bones, abdomen or distant lymph nodes.

Cause

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 tumor. Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.[13]

Genetics

A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. Several different Genetic testing can be used to determine whether a person has one of the currently known mutations.

One class of mutations affects the gene 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 (meaning that the chances of a person carrying the mutation to express the phenotype is very high).

Familial melanoma is genetically heterogeneous,[16]

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 (typical unaffected type) copies of the gene. MC1R mutations are very common; in fact, all people with red hair have a mutated copy of the gene. Mutation of the MDM2 SNP309 gene is associated with increased risk of melanoma in younger women.[17]

UV radiation

The UV radiation from tanning beds increases the risk of melanoma.[19]

Pathophysiology

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 dermis). This early stage of the disease is called the radial growth phase, and the tumor 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.[20]

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 than1 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),[21] which is judged by the presence and activity of the tumour infiltrating lymphocytes (TILs). 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.

Diagnosis

ABCD rule illustration: On the left side from top to bottom: melanomas showing (A) Asymmetry, (B) a border that is uneven, ragged, or notched, (C) coloring of different shades of brown, black, or tan and (D) diameter that had changed in size. The normal moles on the right side do not have abnormal characteristics (no asymmetry, even border, even color, no change in diameter).

Melanoma in skin biopsy with H&E stain — this case may represent superficial spreading melanoma.

Lymph node with almost complete replacement by metastatic melanoma. The brown pigment is focal deposition of melanin

Visual diagnosis of melanomas is still the most common method employed by health professionals.[22] Moles that are irregular in color or shape are often treated as candidates of melanoma. The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles or not have any color at all. 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. There is no blood test for detecting melanomas.

To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see “ABCDE” mnemonic below), to be aware of [24]

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 diameter. 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. dermatoscopy.

Some advocate the system “ABCDE”,[25] with E for evolution. Certainly moles that change and evolve will be a concern. Alternatively, some 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.

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”.[28] 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 very difficult.

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, lentigines.

Following a visual examination and a dermatoscopic exam,Punch biopsies are contraindicated in suspected melanomas, for fear of seeding tumour cells and hastening the spread of the malignant cells.

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.[22] The diagnosis method should be used in conjunction with (and not as a replacement for) dermoscopic imaging, with a combination of both methods appearing to give extremely high rates of detection.

Classification

Melanoma is divided into the following types:[29]

See also:[30]

Laboratory

HMB-45 is a monoclonal antibody that reacts against an antigen present in melanocytic tumors such as melanomas, and stands for Human Melanoma Black. It is used in anatomic pathology as a marker for such tumors. The antibody was generated to an extract of melanoma. It reacts positively against melanocytic tumors but not other tumors, thus demonstrating specificity and sensitivity. The antibody also reacts positively against junctional nevus cells but not intradermal nevi, and against fetal melanocytes but not normal adult melanocytes. HMB-45 is nonreactive with almost all non-melanoma human malignancies, with the exception of rare tumors showing evidence of melanogenesis (e.g., pigmented schwannoma, clear cell sarcoma) or tumors associated with tuberous sclerosis complex (angiomyolipoma and lymphangiomyoma).

Staging

Further context on TNM.

Also of importance are the “Clark level” and “Breslow's depth“, which refer to the microscopic depth of tumor invasion.[31]

Melanoma stages:[32] 5 year survival rates:

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, without ulceration, and mitosis < 1/mm2
  • T1b: Less than 1.00 mm primary tumor thickness, with ulceration or mitoses ≥ 1/mm2
  • T2a: 1.00–2.00 mm primary tumor thickness, without ulceration

F18-FDG PET/CT in a melanoma patient showing multiple lesions, most likely metastases

Stage II: High risk melanoma, 40–85% survival

  • T2b: 1.00–2.00 mm primary tumor thickness, with ulceration
  • T3a: 2.00–4.00 mm primary tumor thickness, without ulceration
  • T3b: 2.00–4.00 mm primary tumor thickness, with ulceration
  • T4a: 4.00 mm or greater primary tumor thickness without ulceration
  • T4b: 4.00 mm or greater primary tumor thickness with ulceration

Stage III: Regional metastasis, 25–60% survival

  • N1: Single positive lymph node
  • N2: Two to three positive lymph nodes or regional skin/in-transit metastasis
  • N3: Four positive lymph nodes or one 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 five-year survival with proper treatment

Prevention

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),[37] 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 one's shadow is shorter than one's 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.

Treatment

Extensive malignant melanoma on a patient's chest

Confirmation of the clinical diagnosis is done with a skin biopsy. This is usually followed up with a wider excision of the scar or tumor. Depending on the stage, a sentinel lymph node biopsy is done, as well, although controversy exists around trial evidence for this procedure.[38] Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.

Surgery

Excisional biopsies may remove the tumor, but further surgery is often necessary to reduce the risk of recurrence. Complete surgical excision with adequate [41]

Mohs surgery has been reported with cure rate as low as 77%CCPDMA and the “double scalpel” peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this “intra-epithelial” type of melanoma.

Melanomas that spread usually do so to the lymph nodes in the area of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications, but no overall survival benefit. Recently, the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumor.[44]

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 fine-needle aspiration biopsy may be performed and is often used to test masses.

If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. If the disease is completely resected, the patient will be considered for adjuvant therapy. Excisional morbidity from the procedure. A large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram-directed lymphnode dissection. A small punch biopsy can be used at any time where for logistical and personal reasons a patient refuses more invasive excisional biopsy. Small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring.

Adjuvant treatment

High-risk melanomas may require [48]

In Europe, interferon is usually not used outside the scope of clinical trials.[50]

Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.[51]

Chemotherapy and immunotherapy

Various [55]

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 control (peripheral margins) is necessary to eliminate the false negative errors. If bread loafing is used, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control.

[56]

Some melanocytic nevi, and melanoma-in-situ (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

[58]

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 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%.[32] 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

Age-standardized incidence rate of melanoma of the skin per 100,000 inhabitants in 2008.[60]

  no data
  less than 1.75
  1.76–3.50
  3.51–5.25
  5.26–7.00
  7.01–8.75
  8.76–10.50
  10.51–12.25
  12.26–14.00
  14.01–15.75
  15.76–17.50
  17.76–19.25
  more than 19.25

[61]

  no data
  less than 0.7
  0.7–1.4
  1.4–2.1
  2.1–2.8
  2.8–3.5
  3.5–4.2
  4.2–4.9
  4.9–5.6
  5.6–6.3
  6.3–7
  7–7.7
  more than 7.7

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.

[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 [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 [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 [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 [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

Pharmacotherapy research for unresectable or metastatic malignant melanoma offers new treatment possibilities.[2] In addition to the advances with recently approved agents, ongoing research into combination therapy, such as dabrafenib and trametinib, may reveal a more effective and better-tolerated option for patients with metastatic melanoma. 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 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]

BRAF

About 60% of melanomas contain a mutation in the [89]

In June 2012 a study reported that patients taking a different B-Raf inhibitor, Dabrafenib, did better than patients taking a chemotherapy agent. [90]

Some researchers believe that combination therapies that simultaneously block multiple pathways may improve efficacy by making it more difficult for the tumor cells to mutate before being destroyed. In October 2012 a study reported that combining Dabrafenib with a MEK inhibitor led to even better outcomes. Compared to Dabrafenib alone, progression-free survival was increased to 41% from 9%, and the median progression-free survival increased to 9.4 months versus 5.8 months. Some side effects were, however, increased in the combined study. [92]

Ipilimumab

At the [96] The criticism was that although Ipilimumab performed better than the vaccine, the vaccine has not been tested before and may be causing toxicity, making the drug appear better by comparison.

In June 2011, a clinical trial of ipilimumab plus [97]

Targeted therapies

In clinical research setting other therapies, such as [101]

A new treatment that trains the immune system to fight cancer has shown modest benefit in late-stage testing against melanoma.[103]

Surveillance methods

Advances in high resolution ultrasound scanning have enabled surveillance of metastatic burden to the sentinel lymph nodes.[105]

See also

References

Notes
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External links

This article uses material from the Wikipedia article Melanoma, which is released under the Creative Commons Attribution-Share-Alike License 3.0.

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