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Skin Melanoma

Disease Details

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Description: Skin melanoma is a type of cancer that begins in the melanocytes, the cells that produce the pigment melanin responsible for skin color.
Type: Skin melanoma is a type of cancer that develops in the melanocytes, the cells responsible for producing pigment in the skin. It can exhibit both sporadic and familial patterns. Sporadic melanoma occurs due to genetic mutations that happen during a person's lifetime, often influenced by environmental factors such as UV radiation. Familial melanoma, although less common, follows an autosomal dominant pattern of genetic transmission, where a mutation in a gene like CDKN2A or CDK4 can be inherited from one affected parent, increasing the risk of developing melanoma in the offspring.
Signs And Symptoms: Early signs of melanoma are changes to the shape or color of existing moles or, in the case of nodular melanoma, the appearance of a new lump anywhere on the skin. At later stages, the mole may itch, ulcerate, or bleed. Early signs of melanoma are summarized by the mnemonic "ABCDEEFG":
Asymmetry
Borders (irregular with edges and corners)
Colour (variegated)
Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser)
Evolving over timeThis classification does not apply to nodular melanoma, which has its own classifications:
Elevated above the skin surface
Firm to the touch
GrowingMetastatic melanoma may cause nonspecific paraneoplastic symptoms, including loss of appetite, nausea, vomiting, and fatigue. Metastasis (spread) 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. It can also spread to the liver, bones, abdomen, or distant lymph nodes.
Prognosis: Factors that affect prognosis include:

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.Certain types of melanoma have worse prognoses but this is explained by their thickness. 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. Macro-metastases 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 worse still. In addition to these variables, expression levels and copy number variations of a number of relevant genes may be used to support assessment of malignant melanoma prognosis.Stage IV melanoma, in which it has metastasized, is the most deadly skin malignancy: five-year survival is 22.5%. When there is distant metastasis, the cancer is generally considered incurable. The five-year survival rate is less than 10%. The median survival is 6–12 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. Survival is better with metastasis in which the location of the primary tumor is unknown.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.
About 200 genes are prognostic in melanoma, with both unfavorable genes where high expression is correlated to poor survival and favorable genes where high expression is associated with longer survival times. Examples of unfavorable genes are MCM6 and TIMELESS; an example of a favorable gene is WIPI1.An increased neutrophil-to-lymphocyte ratio is associated with worse outcomes.
Onset: Skin melanoma, commonly referred to as melanoma, is a type of skin cancer that develops in the melanocytes, the cells that produce the pigment melanin. The onset of melanoma can be influenced by various factors and may not have a specific timing. Key points about its onset include:

1. **Risk Factors**: These include excessive exposure to ultraviolet (UV) radiation from the sun or tanning beds, having fair skin, a history of sunburns, a large number of moles or atypical moles, a family history of melanoma, and a weakened immune system.

2. **Age and Gender**: Melanoma can occur at any age but is more common in older adults. It is one of the most common cancers in younger individuals, especially women under the age of 30.

3. **Genetics**: Certain genetic mutations and inherited conditions, such as familial atypical multiple mole melanoma (FAMMM) syndrome, increase the risk of developing melanoma.

4. **Early Signs**: The development of melanoma can begin with changes in an existing mole or the appearance of a new pigmented or unusual-looking growth on the skin. The ABCDE rule (Asymmetry, Border irregularity, Color variation, Diameter over 6mm, Evolving shape or size) is often used to identify potential melanomas.

Early detection and prompt treatment are crucial in improving outcomes for those diagnosed with melanoma.
Prevalence: The prevalence of skin melanoma varies by region and population. In the United States, melanoma represents about 1% of all skin cancers but causes the majority of skin cancer deaths. The lifetime risk of developing melanoma is approximately 1 in 38 for whites, 1 in 1,000 for African Americans, and 1 in 167 for Hispanics.
Epidemiology: Globally, in 2012, melanoma occurred in 232,000 people and resulted in 55,000 deaths. Australia and New Zealand have the highest rates of melanoma in the world. It has become more common in the last 20 years in areas that are mostly Caucasian.The rate 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.
Intractability: Skin melanoma can be challenging to treat, especially in advanced stages. Early-stage melanoma is often treatable with surgical removal. However, advanced melanoma that has spread to other parts of the body (metastatic melanoma) can be more difficult to manage and may require a combination of treatments including immunotherapy, targeted therapy, radiation, and chemotherapy. Advances in medical treatments have improved outcomes for many patients, but some cases may still be resistant to treatment.
Disease Severity: Skin melanoma is a type of skin cancer that originates in the melanocytes, the cells responsible for producing melanin, which gives skin its color.

- Disease Severity: Skin melanoma can range from less severe (localized and treatable when caught early) to very severe (spreading to other parts of the body, making it more difficult to treat and potentially life-threatening).
Healthcare Professionals: Disease Ontology ID - DOID:8923
Pathophysiology: The earliest stage of melanoma starts when melanocytes begin out-of-control growth. 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, when the tumor is less than 1 mm thick, and spreads at the level of the basal epidermis. Because the cancer cells have not yet reached the blood vessels deeper in the skin, it is very unlikely that this early-stage melanoma will spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely removed with surgery.When the tumor cells start to move in a different direction – vertically up into the epidermis and into the papillary dermis – cell behaviour changes dramatically.The next step in the evolution is the invasive radial growth phase, in which individual cells start to acquire invasive potential. From this point on, melanoma is capable of spreading. The Breslow's depth of the lesion is usually less than 1 mm (0.04 in), while the Clark level is usually 2.
The vertical growth phase (VGP) following is invasive melanoma. The tumor becomes able to grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumor thickness is usually more than 1 mm (0.04 in), and the tumor involves the deeper parts of the dermis.
The host elicits an immunological reaction against the tumor during the VGP, which is judged by the presence and activity of the tumor infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary tumor; this is called regression, which is the latest stage of development. In certain cases, the primary tumor is completely destroyed and only the metastatic tumor is discovered. About 40% of human melanomas contain activating mutations affecting the structure of the B-Raf protein, resulting in constitutive signaling through the Raf to MAP kinase pathway.A cause common to most cancers is damage to DNA. UVA light mainly causes thymine dimers. UVA also produces reactive oxygen species and these inflict other DNA damage, primarily single-strand breaks, oxidized pyrimidines and the oxidized purine 8-oxoguanine (a mutagenic DNA change) at 1/10, 1/10, and 1/3rd the frequencies of UVA-induced thymine dimers, respectively.
If unrepaired, cyclobutane pyrimidine dimer (CPD) photoproducts can lead to mutations by inaccurate translesion synthesis during DNA replication or repair. The most frequent mutations due to inaccurate synthesis past CPDs are cytosine to thymine (C>T) or CC>TT transition mutations. These are commonly referred to as UV fingerprint mutations, as they are the most specific mutation caused by UV, being frequently found in sun-exposed skin, but rarely found in internal organs. Errors in DNA repair of UV photoproducts, or inaccurate synthesis past these photoproducts, can also lead to deletions, insertions, and chromosomal translocations.
The entire genomes of 25 melanomas were sequenced. On average, about 80,000 mutated bases (mostly C>T transitions) and about 100 structural rearrangements were found per melanoma genome. This is much higher than the roughly 70 mutations across generations (parent to child). Among the 25 melanomas, about 6,000 protein-coding genes had missense, nonsense, or splice site mutations. The transcriptomes of over 100 melanomas has also been sequenced and analyzed. Almost 70% of all human protein-coding genes are expressed in melanoma. Most of these genes are also expressed in other normal and cancer tissues, with some 200 genes showing a more specific expression pattern in melanoma compared to other forms of cancer. Examples of melanoma specific genes are tyrosinase, MLANA, and PMEL.UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. This strong mutagenic factor makes cutaneous melanoma the tumor type with the highest number of mutations. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Data from patients suggest that aberrant levels of activating transcription factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells; studies from mice on skin cancer tend to confirm a role for activating transcription factor-2 in cancer progression.Cancer stem cells may also be involved.
Carrier Status: Skin melanoma is not typically described in terms of "carrier status," as it is not a condition passed down through a simple inheritance pattern like some genetic disorders. Instead, skin melanoma is a type of skin cancer that begins in melanocytes, the cells that produce the pigment melanin. Risk factors include exposure to ultraviolet (UV) radiation from the sun or tanning beds, having fair skin, a family history of melanoma, and the presence of many moles or atypical moles. Genetic mutations, such as those in the BRAF gene, can also play a role in the development of melanoma.
Mechanism: Skin melanoma is a type of cancer originating from melanocytes, the cells responsible for producing melanin, the pigment that gives skin its color.

**Mechanism:**
Melanoma develops when melanocytes undergo genetic mutations that lead to uncontrolled cell growth and division. These mutations can be triggered by factors such as ultraviolet (UV) radiation from the sun or tanning beds, leading to DNA damage in skin cells.

**Molecular Mechanisms:**
1. **BRAF Mutations:** About 50% of melanomas have mutations in the BRAF gene, particularly the V600E mutation. This mutation results in the continuous activation of the MAPK/ERK signaling pathway, promoting cell proliferation and survival even in the absence of growth signals.

2. **NRAS Mutations:** NRAS mutations are another common alteration in melanoma, contributing to approximately 15-20% of cases. These mutations also activate the MAPK pathway, similar to BRAF mutations, leading to increased cell growth and survival.

3. **PTEN Loss:** PTEN is a tumor suppressor gene that negatively regulates the PI3K/AKT signaling pathway. Loss of PTEN function results in the activation of this pathway, enhancing cell survival and proliferation.

4. **CDKN2A Mutations:** The CDKN2A gene encodes p16INK4a and p14ARF, proteins that are involved in cell cycle regulation. Mutations or deletions in CDKN2A disrupt normal cell cycle control, leading to unchecked cell division and tumor formation.

5. **KIT Mutations:** KIT mutations are less common but can be found in certain subtypes of melanoma, such as acral and mucosal melanomas. KIT is a receptor tyrosine kinase, and its mutations lead to activation of downstream signaling pathways that promote tumor growth.

6. **TERT Promoter Mutations:** Mutations in the promoter region of the TERT gene lead to increased telomerase activity, allowing melanoma cells to maintain telomere length and thereby promote unlimited cell division.

These molecular mechanisms collectively contribute to the initiation and progression of skin melanoma, making them targets for therapeutic intervention.
Treatment: Confirmation of the clinical diagnosis is done with a skin biopsy. This is usually followed up with a wider excision of the scar or tumor. Depending on the stage, a sentinel lymph node biopsy may be performed. Controversy exists around trial evidence for sentinel lymph node biopsy; with unclear evidence of benefit as of 2015. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.
Compassionate Use Treatment: Compassionate use, also known as expanded access, allows patients with serious or life-threatening conditions, like advanced skin melanoma, to gain access to investigational drugs or treatments outside of clinical trials when no comparable or satisfactory therapies are available. This typically involves treatments that are still in the experimental phase but have shown promise in initial studies.

Off-label treatments for skin melanoma might include the use of FDA-approved drugs typically intended for other conditions but found to be effective in treating melanoma. Examples could include certain chemotherapeutic agents, immunotherapies, or targeted therapies that are not specifically approved for melanoma but might show efficacy in individual cases based on emerging studies or clinical judgment.

Experimental treatments for skin melanoma often involve participation in clinical trials testing novel therapies. These can include new immunotherapies (like checkpoint inhibitors), targeted therapies, combination treatments, or gene therapy approaches that are currently in the research phase.

Patients interested in these options should discuss them with their healthcare provider, who can consider their individual case details and eligibility for such treatments.
Lifestyle Recommendations: For skin melanoma, the following lifestyle recommendations can help reduce the risk and support overall health:

1. **Sun Protection:**
- Regularly use broad-spectrum sunscreen with an SPF of at least 30.
- Wear protective clothing, including hats and sunglasses.
- Seek shade, especially during peak sun hours (10 AM to 4 PM).
- Avoid tanning beds and artificial UV exposure.

2. **Regular Skin Checks:**
- Perform self-examinations monthly to look for new or changing moles.
- Schedule annual skin exams with a dermatologist.

3. **Healthy Diet:**
- Eat a balanced diet rich in fruits, vegetables, lean proteins, and whole grains.
- Consider foods high in antioxidants, such as berries and leafy greens.

4. **Avoid Smoking and Limit Alcohol:**
- Smoking cessation and moderating alcohol intake can improve overall health.

5. **Exercise Regularly:**
- Engage in regular physical activity to maintain overall health and boost the immune system.

6. **Monitor Immunosuppressive Medications:**
- If taking immunosuppressive drugs, follow your doctor's advice closely, as these can increase melanoma risk.

7. **Stay Informed:**
- Keep updated on the latest guidelines and recommendations from healthcare providers regarding skin cancer prevention.

By adopting these lifestyle habits, you can help minimize the risk of skin melanoma and promote general well-being.
Medication: A 2005 review found tentative evidence that statin and fibrate medication may decrease the risk of melanoma. A 2006 review however did not support any benefit.
Repurposable Drugs: There is ongoing research on repurposing existing drugs for the treatment of skin melanoma. Some drugs being investigated include:

1. **Metformin**: Primarily used for type 2 diabetes, metformin has shown potential anti-cancer properties by inhibiting melanoma cell growth.
2. **Statins**: Used to lower cholesterol, statins may have a role in inducing apoptosis in melanoma cells.
3. **Aspirin**: This anti-inflammatory drug has been studied for its potential to reduce melanoma risk and inhibit tumor growth.

It is important to consult scientific literature and clinical trials for the latest updates on these and other repurposable drugs.
Metabolites: Metabolites associated with skin melanoma include various amino acids, lipids, and organic acids. Some of the notable ones are lactic acid, alanine, and glutamine. Detailed metabolomic profiling can help in understanding the metabolic reprogramming in melanoma cells and might be useful for diagnostic and therapeutic purposes.
Nutraceuticals: Nutraceuticals are food-derived products that offer health benefits beyond basic nutrition, including potential roles in the prevention or treatment of diseases like skin melanoma. Examples include:

1. **Curcumin**: Extracted from turmeric, it has anti-inflammatory and antioxidant properties that may reduce melanoma growth.
2. **Green Tea Polyphenols**: Compounds like EGCG in green tea possess anti-cancer properties.
3. **Resveratrol**: Found in grapes and berries, it exhibits anti-tumor activity.
4. **Omega-3 Fatty Acids**: These have anti-inflammatory effects and can be found in fish oil.
5. **Vitamin D**: Adequate levels might help in melanoma prevention, given its role in cell growth regulation.

While these nutraceuticals show potential, more research is needed to confirm their efficacy in clinical settings for melanoma.
Peptides: In the context of skin melanoma, peptides refer to short chains of amino acids that can be used in various therapeutic approaches, including immunotherapy and vaccine development. These peptides can stimulate an immune response against melanoma cells, potentially aiding in the treatment of the disease.

Nanotechnology involves using nanoparticles for improved diagnosis and treatment of melanoma. Nanoparticles can be engineered to deliver drugs directly to melanoma cells, enhancing the effectiveness of treatment while minimizing side effects. They can also be used in imaging techniques to provide better detection and monitoring of melanoma progression.