Melanoma i/ˌmɛləˈnoʊmə/ (from Greek μέλας — melas, "dark")[1] is a malignant tumor of melanocytes.[2] Melanocytes produce the dark pigment, melanin, which is responsible for the color of skin. These cells 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 originate in any part of the body that contains melanocytes.
Melanoma is less common than other skin cancers. However, it is much more dangerous if it is not found early. It causes the majority (75%) of deaths related to skin cancer.[3] Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. In women, the most common site is the legs and melanomas in men are most common on the back.[4] It is particularly common among Caucasians, especially northwestern Europeans living in sunny climates. There are high rates of incidence in Oceania, Northern America, Europe, Southern Africa, and Latin America,[5] with a paradoxical decrease in southern Italy and Sicily.[6] This geographic pattern reflects the primary cause, ultraviolet light (UV) exposure[7]crossed with the amount of skin pigmentation in the population.[8][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 chemo- and immunotherapy, or 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 atumor. 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
See also: List of genes mutated in pigmented cutaneous lesions
A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. 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 lower elevated risk. Genetic testing can be used to determine whether a person has one of the currently known mutations.
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 nonfunctional inhibitor ofCDK4, 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 (meaning that the chances of a person carrying the mutation to express the phenotype is very high).
Familial melanoma is genetically heterogeneous,[14] 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 (disease development) of melanoma.[15] 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.[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.[18] The International Agency for Research on Cancer finds that tanning beds are "carcinogenic to humans" with people who begin using tanning devices before age 30 75% more likely to develop melanoma.[19]
In a study scientists reveal that the dose of UV radiation is deciding factor and can lead to different pathway. The p16 pathway is favored at low doses of UV radiation and results in cell-cycle arrest, to the contrary; the p53 pathway is more responsive to higher doses and induces apoptosis depending on p53 mutation status.[20]
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 epidermis) and the next layer (the dermis). This early stage of the disease is called the radial growth phase, and the tumor is less than 1 mm 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 tumor 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.[21]
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 tumor attains invasive potential, meaning it can 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),[22] 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 the melanoma 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 toMAP kinase pathway.[23]
Diagnosis
Visual diagnosis of melanomas is still the most common method employed by health professionals.[24] 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 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.[25][26]
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. 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 advocate the system "ABCDE",[27] 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][29] 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[29] 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".[30] 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, dermatofibromas, or lentigines.
Following a visual examination and a dermatoscopic exam,[30] or in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. 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. If the mole is malignant, the mole and an area around it need excision. Elliptical excisional biopsies may remove the tumor, followed by histological analysis and Breslow scoring. Punch biopsies are contraindicated in suspected melanomas, for fear of seeding tumor 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.[24] 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:[31]
•Lentigo maligna
•Lentigo maligna melanoma
•Superficial spreading melanoma
•Acral lentiginous melanoma
•Mucosal melanoma
•Nodular melanoma
•Polypoid melanoma
•Desmoplastic melanoma
•Amelanotic melanoma
•Soft-tissue melanoma
See also:[32]
•Melanoma with small nevus-like cells
•Melanoma with features of a Spitz nevus
•Uveal melanoma
Laboratory
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. 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 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.[33]
Melanoma stages:[34] 5 year survival rates:
Stage 0: Melanoma in situ (Clark Level I), 99.9% survival
Stage I / II: Invasive melanoma, 89–95% survival
•T1a: Less than 1.0 mm primary tumor thickness, without ulceration, and mitosis < 1/mm2
•T1b: Less than 1.0 mm primary tumor thickness, with ulceration or mitoses ≥ 1/mm2
•T2a: 1.01–2.0 mm primary tumor thickness, without ulceration
Stage II: High risk melanoma, 45–79% survival
•T2b: 1.01–2.0 mm primary tumor thickness, with ulceration
•T3a: 2.01–4.0 mm primary tumor thickness, without ulceration
•T3b: 2.01–4.0 mm primary tumor thickness, with ulceration
•T4a: Greater than 4.0 mm primary tumor thickness, without ulceration
•T4b: Greater than 4.0 mm primary tumor thickness, with ulceration
Stage III: Regional metastasis, 24–70% 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, 7–19% 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 from initial melanoma diagnosis with proper treatment.
Prevention
Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),[35] following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past, use of sunscreens with a sun protection factor (SPF) rating of 50 or higher on exposed areas were recommended; as older sunscreens more effectively blocked UVA with higher SPF.[36] 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.[37] This controversy is well discussed in numerous review articles, and is rejected by most dermatologists.[38] 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. Using artificial light for tanning was once believed to help prevent skin cancers, but it can actually lead to an increased incidence of melanomas.[39] 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.