Malignant Melanoma
Disease Details
Family Health Simplified
- Description
- Malignant melanoma is a serious type of skin cancer that originates in the melanocytes, which are the cells responsible for producing pigment in the skin.
- Type
- Malignant melanoma is a type of skin cancer. Its genetic transmission is typically sporadic, but it can also be inherited in an autosomal dominant pattern when it occurs as part of familial melanoma syndromes.
- 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
- Malignant melanoma can develop in individuals at any age but is more commonly diagnosed in older adults. The exact onset varies widely and can be influenced by genetic factors, sun exposure, and other risk factors. Detection often occurs when changes in skin lesions are observed. Early stages might not cause symptoms, but as it progresses, signs such as changes in the size, shape, or color of a mole may become evident.
- Prevalence
- Malignant melanoma is a type of skin cancer that originates in melanocytes, the cells that produce the pigment melanin. The prevalence of malignant melanoma varies by regions and populations, significantly influenced by factors such as UV radiation exposure and genetic susceptibility. In general, melanoma is more common among fair-skinned individuals and those living in areas with high sun exposure. In the United States, the lifetime risk of developing melanoma is about 2.6% for whites, 0.1% for African Americans, and 0.6% 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
- Malignant melanoma can be challenging to treat, especially in its advanced stages. While early-stage melanoma can often be effectively treated with surgical removal, advanced melanoma may require more complex treatments. These may include immunotherapy, targeted therapy, chemotherapy, and radiation therapy. Despite these options, metastatic melanoma (where the cancer has spread to other parts of the body) can be particularly difficult to manage and may have a poorer prognosis. Advances in treatments and early detection strategies continue to improve outcomes, but the disease can still be considered intractable in some cases, especially when not caught early.
- Disease Severity
- Malignant melanoma is a severe form of skin cancer that can spread to other parts of the body if not detected and treated early. The severity of malignant melanoma can vary, but it often requires prompt medical attention due to its potential for metastasis.
- 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
- Carrier status is not applicable to malignant melanoma, as this disease is not typically inherited in the manner that genetic carrier status would imply. Instead, malignant melanoma is a type of skin cancer primarily caused by genetic mutations resulting from ultraviolet (UV) exposure, rather than being passed from parent to child through specific carrier genes. However, there can be a familial predisposition due to inherited mutations in genes such as CDKN2A.
- Mechanism
-
Malignant melanoma is a type of skin cancer that arises from melanocytes, the pigment-producing cells in the skin. It is characterized by the uncontrolled growth of these cells.
Mechanism:
1. **Genetic Mutations**: Malignant melanoma often begins with DNA damage in melanocytes. Factors such as ultraviolet (UV) radiation from sunlight or tanning beds are common causes of this damage.
2. **Cellular Transformation**: The damage can lead to mutations in critical genes that regulate cell growth, division, and death.
3. **Uncontrolled Proliferation**: These mutations allow melanocytes to grow and divide uncontrollably, leading to the formation of a malignant tumor.
Molecular Mechanisms:
1. **BRAF Mutations**: One of the most common mutations in melanoma occurs in the BRAF gene, particularly the V600E mutation. BRAF is part of the MAPK/ERK signaling pathway that regulates cell division.
2. **NRAS Mutations**: Mutations in the NRAS gene, which also participates in the MAPK/ERK pathway, can lead to similar uncontrolled cell growth.
3. **CDKN2A Mutations**: This gene encodes the tumor suppressor proteins p16INK4a and p14ARF, which regulate the cell cycle. Mutations in CDKN2A can disable these tumor suppressor functions.
4. **PTEN Mutations**: Loss or mutation of PTEN can result in uncontrolled activation of the PI3K/AKT pathway, promoting cell survival and growth.
5. **TERT Promoter Mutations**: Mutations in the promoter region of the TERT gene can lead to increased telomerase activity, allowing melanocytes to evade normal senescence and become immortal.
Collectively, these molecular changes disrupt normal cellular regulatory mechanisms, leading to the development and progression of malignant melanoma. - 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 treatment for malignant melanoma involves providing patients access to investigational drugs outside of clinical trials, typically when no comparable or satisfactory alternative therapy options are available.
Off-label or experimental treatments may include:
1. **Checkpoint inhibitors**: While commonly approved for melanoma, off-label use might include different dosing regimens or combinations.
2. **Targeted therapy**: BRAF and MEK inhibitors are FDA-approved for BRAF-mutant melanoma but might be used in novel combinations.
3. **Adoptive cell transfer therapy**: Using tumor-infiltrating lymphocytes (TILs) outside of clinical trials.
4. **Oncolytic virus therapy**: Talimogene laherparepvec (T-VEC) may be used off-label for specific patient situations.
5. **New investigational drugs**: Access to agents in late-stage development through expanded access programs.
Consultation with a healthcare provider specialized in oncology is crucial for pursuing these options. - Lifestyle Recommendations
-
For malignant melanoma, here are some lifestyle recommendations:
1. **Sun Protection**: Regularly use broad-spectrum sunscreen with at least SPF 30, wear protective clothing, hats, and sunglasses, and seek shade, especially during peak sun hours (10 AM to 4 PM).
2. **Avoid Tanning Beds**: Refrain from using tanning beds, as they increase the risk of melanoma.
3. **Regular Skin Checks**: Perform monthly self-examinations of your skin for new or changing moles, and see a dermatologist annually for a professional skin check.
4. **Healthy Diet**: Maintain a balanced diet rich in fruits, vegetables, and lean proteins to support overall health and immune function.
5. **Avoid Smoking**: Quit smoking, as it can compromise the immune system and overall skin health.
6. **Exercise**: Engage in regular physical activity to boost immune function and general well-being.
7. **Vitamin D**: Obtain vitamin D safely through diet and supplements rather than excessive sun exposure.
8. **Stay Informed**: Keep updated on the latest skin cancer prevention and treatment options and maintain regular follow-ups with healthcare providers if diagnosed with or at risk for melanoma.
These recommendations can help in reducing the risk of developing melanoma and support overall 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
-
While repurposable drugs for malignant melanoma are being researched, some existing drugs already show promise in treatment. These include:
1. **Metformin:** Commonly used for type 2 diabetes, it has shown potential in inhibiting melanoma cell growth in preclinical studies.
2. **Statins:** Frequently prescribed to lower cholesterol, certain statins like lovastatin have demonstrated anticancer properties against melanoma.
3. **Aspirin:** Known for its anti-inflammatory effects, aspirin has been studied for its potential to reduce melanoma risk and improve patient outcomes.
4. **Mefloquine:** Primarily an antimalarial drug, it has shown some efficacy in targeting and killing melanoma cells in laboratory settings.
These repurposed drugs are being explored for their potential to enhance treatment outcomes in melanoma patients. However, clinical trials and further research are necessary to validate their effectiveness and safety in this new context. - Metabolites
-
The metabolic profile of malignant melanoma is complex, but several key metabolites have been identified as being involved in melanoma progression and survival. These include:
1. **Lactate**: Increased due to upregulated glycolysis (Warburg effect), supporting rapid cancer cell proliferation.
2. **Glucose**: Elevated uptake and consumption for energy and biosynthesis.
3. **Acetate**: Utilized in lipid synthesis and can act as an alternative energy source.
4. **Glutamine**: Serves as a carbon and nitrogen source for nucleotide and amino acid biosynthesis.
5. **Fatty Acids**: Increased synthesis and uptake, important for membrane synthesis and signaling.
6. **Oncometabolites**: Such as 2-hydroxyglutarate, which can impact gene expression and cell differentiation.
These metabolites play roles in melanoma cell metabolism, growth, and survival, contributing to the disease's aggressiveness and resistance to therapy. - Nutraceuticals
- Nutraceuticals are products derived from food sources with extra health benefits, often used to promote overall health or prevent disease. For malignant melanoma, there is limited scientific evidence supporting the use of nutraceuticals for treatment. Some studies suggest potential benefits from certain compounds, such as antioxidants, but they should not replace conventional treatments. More research is needed to confirm their efficacy and safety in melanoma management. Always consult a healthcare professional before starting any new supplement.
- Peptides
- For malignant melanoma, peptides such as melanoma-associated antigen (MAGE) peptides, gp100, and tyrosinase peptides are of considerable interest in immunotherapy. These peptides can help in developing cancer vaccines that aim to stimulate the immune system to target and destroy melanoma cells. Additionally, nanoparticle (nan) delivery systems are being investigated to improve the effectiveness of these peptide-based therapies by enhancing targeted delivery, uptake, and immune response, while minimizing side effects.