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Melanoma

Disease Details

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Description: Melanoma is a type of skin cancer that originates in the melanocytes, the cells responsible for producing the pigment melanin.
Type: Melanoma is a type of skin cancer that arises from the pigment-producing cells known as melanocytes. The genetic transmission of melanoma can occur in a hereditary pattern, particularly in familial cases, where mutations in certain genes such as CDKN2A (p16) and CDK4 increase susceptibility. However, most cases of melanoma are sporadic and are primarily linked to environmental factors such as UV radiation from sun exposure.
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: Melanoma is a type of skin cancer that originates in melanocytes, the cells responsible for producing melanin, which gives skin its color. The onset of melanoma often involves the appearance of a new mole or a change in an existing mole. Signs can include alterations in size, shape, or color, asymmetry, irregular borders, multiple colors, and a diameter larger than 6mm. Early detection is crucial for effective treatment, making regular skin examinations important.
Prevalence: The prevalence of melanoma varies by region and population but is generally increasing worldwide. In the United States, the American Cancer Society estimates that about 1 in 27 men and 1 in 40 women will develop melanoma at some point in their lives. It is one of the most common cancers in young adults, particularly among young women. Early detection significantly improves prognosis.
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: Melanoma is a type of skin cancer that is potentially treatable, especially when detected early. Early-stage melanoma can often be cured with surgical removal. However, advanced melanoma, which has spread to other parts of the body, can be more challenging to treat. While advanced melanoma was once considered highly intractable, recent advances in targeted therapies and immunotherapies have improved outcomes significantly, making the disease more manageable. Nonetheless, the prognosis becomes more uncertain as the disease progresses.
Disease Severity: Melanoma is a type of skin cancer that can be very serious. The severity of melanoma is typically classified based on the following stages:

- **Stage 0 (in situ):** The melanoma is only in the outer layer of the skin and has not spread.
- **Stage I:** The melanoma is small (less than 2mm thick) and may or may not be ulcerated but hasn't spread to lymph nodes or distant sites.
- **Stage II:** The melanoma is thicker (over 2mm) and may be ulcerated but still hasn't spread to lymph nodes or distant sites.
- **Stage III:** The melanoma has spread to one or more nearby lymph nodes or to nearby skin or lymphatic channels.
- **Stage IV:** The melanoma has spread to distant organs, including the liver, lungs, brain, or distant skin and/or lymph nodes.

The severity of melanoma typically increases with higher stages, indicating a more advanced and potentially life-threatening disease that requires more aggressive treatment.
Healthcare Professionals: Disease Ontology ID - DOID:1909
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: Melanoma is a type of skin cancer that occurs when the pigment-producing cells called melanocytes mutate and become cancerous. There is no carrier status for melanoma since it is not a genetic condition that is passed down in a simple inherited manner like some other diseases. However, there are genetic factors that can increase an individual's risk of developing melanoma, and families may have a higher incidence of the disease due to shared genetic mutations, such as those in the CDKN2A gene.
Mechanism: Melanoma is a type of skin cancer that originates in melanocytes, the cells responsible for producing melanin, which gives skin its color.

**Mechanism:**
Melanoma develops when DNA damage—typically caused by ultraviolet (UV) radiation from sun exposure or tanning beds—induces mutations in the melanocytes. These mutations lead to uncontrolled cell growth and the formation of malignant tumors. If not detected early, melanoma can invade nearby tissues and metastasize to other parts of the body, making it more difficult to treat.

**Molecular Mechanisms:**
Several key molecular pathways and mutations are implicated in melanoma:

1. **BRAF Mutations:** Roughly 50% of melanomas contain mutations in the BRAF gene, most commonly the V600E mutation. This mutation results in the continuous activation of the BRAF protein, leading to uncontrolled cell proliferation via the MAPK/ERK signaling pathway.

2. **NRAS Mutations:** About 15-20% of melanomas show mutations in the NRAS gene, which also activates the MAPK pathway and contributes to cell growth and survival.

3. **PTEN Loss:** PTEN is a tumor suppressor gene that antagonizes the PI3K/AKT pathway. Loss or mutation of PTEN can lead to enhanced survival and growth of melanoma cells.

4. **KIT Mutations:** Mutations or amplifications in the KIT gene are particularly common in certain subtypes of melanoma, such as acral and mucosal melanomas. KIT mutations activate multiple signaling pathways, including the MAPK and PI3K pathways.

5. **CDKN2A Mutations:** The CDKN2A gene encodes p16INK4a and p14ARF, both of which act as tumor suppressors. Mutations or deletions in CDKN2A disrupt the cell cycle regulation, leading to increased cell division and tumor progression.

6. **TERT Promoter Mutations:** Mutations in the promoter region of the TERT gene, which encodes the enzyme telomerase, are common in melanoma. These mutations lead to increased TERT expression, contributing to the immortality of cancer cells by maintaining telomere length.

Understanding these molecular mechanisms has led to the development of targeted therapies, such as BRAF inhibitors (e.g., vemurafenib) and MEK inhibitors (e.g., trametinib), which specifically target pathways involved in melanoma progression.
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: For melanoma, compassionate use treatments refer to therapies that are not yet approved by regulatory agencies but are made available to patients with serious or life-threatening conditions when no other options are viable. These treatments are typically in the experimental phase and are provided on a case-by-case basis through special programs.

Off-label treatments for melanoma involve the use of FDA-approved drugs for purposes that are not included in their approved labeling. Examples may include the use of certain immunotherapies, targeted therapies, or chemotherapeutic agents that are approved for other types of cancer but are prescribed for melanoma based on emerging research or clinical judgment.

Experimental treatments for melanoma include those that are still under investigation in clinical trials and have not yet received regulatory approval. These can include novel immunotherapies, targeted therapies, combination therapies, and other innovative approaches being studied for their effectiveness and safety in treating melanoma. Patients may access these treatments through participation in clinical trials.
Lifestyle Recommendations: ### Lifestyle Recommendations for Melanoma:

1. **Sun Protection:**
- **Use Sunscreen:** Apply a broad-spectrum sunscreen with SPF 30 or higher.
- **Wear Protective Clothing:** Long sleeves, wide-brimmed hats, and UV-blocking sunglasses.
- **Seek Shade:** Especially during peak sunlight hours (10 AM to 4 PM).

2. **Avoid Tanning Beds:**
- Tanning beds emit UV radiation, increasing the risk of melanoma.

3. **Regular Skin Checks:**
- **Self-Examinations:** Check your skin monthly for new moles or changes in existing ones.
- **Professional Exams:** Schedule annual dermatological check-ups.

4. **Healthy Diet:**
- Incorporate plenty of fruits, vegetables, and whole grains.
- Limit the intake of processed foods and sugary drinks.

5. **Avoid Smoking:**
- Smoking can negatively affect skin health and overall immune function.

6. **Exercise Regularly:**
- Aim for at least 150 minutes of moderate aerobic activity, or 75 minutes of vigorous activity, each week.

7. **Stay Hydrated:**
- Drink plenty of water throughout the day to maintain healthy skin.

By following these lifestyle recommendations, individuals can help lower their risk of developing melanoma and improve their overall skin health.
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: For melanoma, repurposable drugs include:

1. **Metformin**: Originally used for type 2 diabetes, studies suggest potential antitumor effects.
2. **Aspirin**: Commonly used as an anti-inflammatory and antiplatelet agent, it may have chemopreventive properties.
3. **Statins**: Primarily used for lowering cholesterol, they have shown potential antiproliferative effects on melanoma cells.

These drugs are being researched for their efficacy and safety in treating melanoma beyond their initial indications.
Metabolites: Melanoma, a type of skin cancer, is influenced by various metabolic pathways. Metabolites such as lactate, succinate, and fumarate can play significant roles in melanoma progression and metastasis. These metabolites are involved in cellular processes like glycolysis, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. Abnormal metabolic activities, often referred to as the "Warburg effect," include increased glycolysis and lactate production even in the presence of oxygen, contributing to the cancer's growth and survival.

Regarding nanotechnology (nan), it offers promising approaches for melanoma diagnosis and treatment. Nanoparticles can be engineered to target melanoma cells selectively, delivering therapeutic agents directly to the tumor, which minimizes damage to healthy tissues. Nanotechnologies are also being developed to enhance imaging techniques for early melanoma detection and monitoring.

Both metabolite profiling and nanotechnology are at the forefront of research, aiming to improve melanoma outcomes through better diagnostic, prognostic, and therapeutic strategies.
Nutraceuticals: Nutraceuticals like omega-3 fatty acids, green tea polyphenols, and curcumin have shown potential in supporting skin health and may have anti-cancer properties, including effects on melanoma. However, their efficacy in treating melanoma is not well-established and should not replace conventional treatments.

Nanotechnology is being investigated for melanoma treatment, utilizing nanoparticles to deliver drugs more effectively and target cancer cells specifically. This approach aims to enhance the therapeutic efficacy while minimizing side effects. Clinical trials and research are ongoing to determine the safety and effectiveness of these nanotechnology-based therapies.
Peptides: Peptides have emerged as a potential therapeutic approach for melanoma, particularly in the form of peptide-based vaccines and targeted therapies. These peptides can stimulate the immune system to recognize and attack melanoma cells or directly inhibit cancer cell growth and survival.

Nanotechnology offers novel strategies for melanoma treatment through the development of nanoparticles that can deliver drugs, genes, or imaging agents specifically to melanoma cells. This targeted approach helps to increase the efficacy of treatments while minimizing side effects. Nanoparticles can also protect therapeutic agents from degradation and improve their stability and bioavailability.