Understanding and Definition of Melanoma, Early signs of melanoma

Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They 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 occur in any part of the body that contains melanocytes.

Melanoma is less common than other skin cancers. However, it is much more dangerous and causes the majority (75%) of deaths related to skin cancer. Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. The diagnosis is more frequent in women than in men and is particularly common among Caucasians living in sunny climates, with high rates of incidence in Australia, New Zealand, North America, and northern Europe. According to a WHO report about 48,000 melanoma related deaths occur worldwide per year.

The treatment includes surgical removal of the tumor, adjuvant treatment, chemo- and immunotherapy, or radiation therapy. The chance of a cure is greatest when the tumor is discovered while it is still small and thin, and can be entirely removed surgically.

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

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 tumour 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.

The next step in the evolution is the invasive verical 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 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), which is judged by the presence and activity of the TILs (tumour infiltrating lymphocytes). 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.

In some cases, melanoma runs in families. 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 low risk. Genetic testing can be used to determine whether a person has one of the currently known mutations.

A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. 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 non-functional inhibitor of CDK4, 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.

Familial melanoma is genetically heterogeneous, 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 of melanoma. 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.

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 copies of the gene. MC1R mutations are very common; in fact, all people with red hair have a mutated copy of the gene.

Two-gene models of melanoma risk have already been created, and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype.

In addition to identifying high-risk patients, researchers want to identify high-risk lesions within a given patient. Many new technologies, such as optical coherence tomography (OCT), are being developed to accomplish this. OCT allows pathologists to view 3-D reconstructions of the skin and offers more resolution than past techniques could provide. In vivo confocal microscopy and fluorescently tagged antibodies are also proving to be valuable diagnostic tools.

Mutation of the MDM2 SNP309 gene is associated with increased risk of melanoma in younger women.

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. Early signs of melanoma are summarized by the mnemonic "ABCDE":

* Asymmetry

* Borders (irregular)

* Color (variegated), and

* 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 non-specific 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.

There is no blood test for detecting melanomas. Visual diagnosis of melanomas is still the most common method employed by health professionals. To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCD" 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.

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 D. 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 will advocate the system "ABCDE",[18] with E for evolution. Certainly moles which change and evolve will be a concern. Alternatively, some will 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.

However, 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" 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 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". 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 (dermatoscopy) very difficult.

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.

Moles that are irregular in color or shape are often treated as candidates of melanoma. Following a visual examination and a dermatoscopic exam, or an in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. If the mole is malignant, the mole and an area around it need excision.

The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles or not have any color at all. 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. 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.

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

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds), following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past it was recommended to use sunscreens with an SPF rating of 30 or higher on exposed areas as older sunscreens more effectively blocked UVA with higher SPF. 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. This controversy is well discussed in numerous review articles, and is refuted by most dermatologists. 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. Tanning, once believed to help prevent skin cancers, actually can lead to an increased incidence of melanomas. 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 your shadow is shorter than your 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. The “ABCDE” list, the "ugly duckling sign", and the "red riding hood" rule are defined and discussed under the heading "Detection" earlier in this article.

“Melanoma Monday” is the kick-off of May Melanoma Month with special activities nationally and locally. Also known as National Skin Self-Examination Day. People are encouraged to examine their skin for skin cancer. Since 1985, this program has helped to detect more than 188,000 suspicious lesions, including more than 21,500 suspected melanomas.

In research setting other therapies, such as adoptive cell therapy or gene therapy, may be tested. Two kinds of experimental treatments developed at the National Cancer Institute (NCI), part of the National Institutes of Health in the US have been used in advanced (metastatic) melanoma with moderate success. The first treatment involves adoptive cell therapy using immune cells isolated from a patient's own melanoma tumor (TIL). These cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily reduces normal T cells in the patient's body. TIL Therapy following lymphodepletion can result in complete responses in highly pretreated patients. The second treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.

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

About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggest that B-Raf inhibitors including Plexxicon(R) can lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation. Large clinical trials are underway to more fully evaluate the efficacy and potency of B-Raf inhibitors. Sutent may be effective for patients with metastatic melanoma.

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.

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.

The French physician René Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculté de Médecine de Paris in 1804 and then published as a bulletin in 1806. The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820. 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 ...' More than one and a half centuries later this situation remains largely unchanged.