Malignant MelanomaFaith DurhamBio 24510/17/2011Dr. C.A.C. Dike |
Table of Contents
Definition Pg. 1
Introduction Pg. 1
Signs and symptoms Pg. 1-4
Pathophysiology( Intrinsic factors) Pg. 4-5
Environmental factors Pg. 5-6
Types of Melanoma Pg. 6-7
4 Stages and Evolution of Melanoma Pg. 7-9
Prevention of Melanoma Pg. 9
References Pg. 10
Definition
Malignant melanoma is a neoplasm of melanocytes or of the cells that develop from melanocytes. Melanocytes are cells predominantly in the skin, but are also found in other parts of the body that produce a pigment called melanin that colors our skin, hair, and eyes. Malignant melanoma develops when the melanocytes no longer respond to normal control mechanisms of cellular growth. They may then invade nearby structures or spread to other organs in the body, where again they invade and compromise the function of that organ. Melanoma can occur in any part of the body that contains melanocytes.
Introduction
Melanoma is less common than other skin cancers, but it is the most serious form of skin cancer and causes the majority of deaths related to skin cancer. If it is recognized and treated early, it is almost always curable, but if it is not, the cancer can advance and spread to other parts of the body, where it becomes hard to treat and can be fatal.
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, Latin America, and northern Europe. Solar exposure and genetic factors are responsible for the majority of these cases of melanoma. The majority of melanomas are black or brown, but often they can also be skin-colored, pink, red, purple, blue or white.
Signs and symptoms
The key to treating melanoma is recognizing symptoms early. You might not notice a small spot of concern if you don't look carefully, so perform thorough self-examinations. 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. The primary symptom of any skin cancer is usually a mole, sore, lump, or growth on the skin. Any change in appearance of a pigmented skin sore over time is a warning sign. Also, watch for any bleeding from a skin growth. At later stages, the mole may itch, ulcerate or bleed. Early signs of melanoma are summarized by the mnemonic "ABCDE".
The ABCD mnemonic system may help you remember features that might be symptoms of melanoma:
•Asymmetry: One half of the abnormal area is different from the other half.
•Borders: The lesion or growth has irregular edges.
•Color: Color changes from one area to another, with shades of tan, brown, or black sometimes white, red, or blue. A mixture of colors may appear within one sore.
•Diameter: The trouble spot is usually but not always larger than 6 mm in diameter -- about the size of a pencil eraser.
•Enlarging: Enlarging or evolving
Generally, an individual's risk for developing melanoma depends on intrinsic and environmental factors. Intrinsic factors are generally an individual's family history and inherited genotype, while the environmental factor is sun exposure. 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 a tumor. Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.
Pathophysiology( Intrinsic factors)
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 low risk. Genetic testing can be used to determine whether a person has one of the currently known mutations.
About 60% of melanomas contain a mutation in the B-Raf gene. Early clinical trials suggested that B-Raf inhibitors including Plexxicon(R)'s vemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation. A family history of melanoma greatly increases a person's risk because mutations in CDKN2A,CDK4 and several other genes have been found in melanoma-prone families. Patients with a history of one melanoma are at increased risk of developing a second primary tumor.
One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of tumor protein 53, a transcription factor involved in apoptosis and in fifty percent of human cancers. Another mutation in the same gene results in a nonfunctional 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.
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 (disease development) 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. Mutation of the MDM2 SNP309 gene is associated with increased risk of melanoma in younger women.
Environmental factors
Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in proto-oncogenes 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 abnormal 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. Occasional extreme sun exposure resulting in sunburn is causally related to melanoma. Melanoma is most common on the back in men and on legs in women. Other factors are mutations in or total loss of tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma. Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns have a significantly greater risk for melanoma. The cause is the exaggerated UV-exposure.
Types of Melanoma
There are four major types of melanoma. Superficial spreading melanoma (SSM) is the most common type of melanoma. It is usually flat and irregular in shape and color, with different shades of black and brown. It may occur at any age or body site, and is most common in Caucasians. Approximately 70% of cutaneous malignant melanomas are the superficial spreading melanoma (SSM) type and often arise from a pigmented dysplastic nevus. SSMs typically develop after a long-standing stable nevus changes. Typical changes include ulceration, enlargement, or color changes. An SSM may be found on any body surface but are common in the head, neck, and trunk of males and the lower extremities of females. Nodular melanoma (NMs) usually starts as a raised area that is dark blackish-blue or bluish-red. However, some do not have any color. Nodular melanomas represent approximately 10-15% of melanomas and also are found commonly on all body surfaces, especially the trunk of males. These lesions are the most symmetrical and uniform of the melanomas and are dark brown or black. The radial growth phase may not be evident in NMs. However, if this phase is evident, it is short-lived, because the tumor advances rapidly to the vertical growth phase, thus making the NM a high-risk lesion. Approximately 5% of all NMs are amelanotic melanomas. Lentigo maligna melanoma (LMMs) usually occurs in the elderly. It is most common in sun-damaged skin on the face, neck, and arms. The abnormal skin areas are usually large, flat, and tan with areas of brown. Lentigo maligna melanomas also account for 10-15% of melanomas. LMMs may have areas of hypopigmentation and often are quite large. LMMs arise from a lentigo maligna precursor lesion. Acral lentiginous melanoma (ALMs) is the least common form of melanoma. It usually occurs on the palms, soles, or under the nails and is more common in African Americans. Acral lentiginous melanomas are the only melanomas that have an equal frequency among blacks and whites. They occur on the palms, soles, and subungual areas. Subungual melanomas often are mistaken for subungual hematomas (splinter hemorrhages). ALM is extremely aggressive, with rapid progression from the radial to vertical growth phase.
4 Stages and Evolution of Melanoma
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 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 tumor cells start to move in a different direction — vertically up into the epidermis and into the papillary dermis — the behavior of the cells changes dramatically. 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 than1 mm. The following step in the process is the invasive melanoma — the vertical growth phase. 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 and the tumor involves the deeper parts of the dermis. The host elicits an immunological reaction against the tumor, which is judged by the presence and activity of the tumor infiltrating lymphocytes. 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.
Stages of Melanoma
Level I - All tumor cells above basement membrane (in situ) Melanoma is confined to the skin, but has grown thicker. It can be as thick as 1.0 millimeter. In stage IA, the skin covering the melanoma remains intact.
Level II - Tumor extends into papillary dermis Melanoma has grown thicker. The thickness ranges from 1.01 millimeters to greater than 4.0 millimeters. The skin covering the melanoma may have broken open (ulcerated). While thick, the cancer has not spread.
Level III - Tumor extends to interface between papillary and reticular dermis. Melanoma has spread to either: 1) one or more nearby lymph node (often called lymph gland) or 2) nearby skin.
Level IV - Tumor extends between bundles of collagen of reticular dermis.
Level V - Tumor invasion of subcutaneous tissue. Melanoma has spread to an internal organ, lymph nodes further from the original melanoma, or is found on the skin far from the original melanoma.
Prevention of Melanoma
Minimizing exposure to sources of ultraviolet radiation following sun protection measures and wearing sun protective clothing can offer protection against developing melanoma. In the past, use of sunscreens with a SPF rating of 50 or higher on exposed areas were recommended, 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. 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 prime factor 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.
References
Paul B. Chapman et al (2011-06-05). "Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation". New England Journal of Medicine
Blackledge J, Dubovitski D (2011 [1]). "MoleTest: A Web-based Skin Cancer Screening System". Intensive 2011: The Third International Conference on Resource Intensive Applications and Services: 22–29
Firoz, EF; Warycha, M; Zakrzewski, J; Pollens, D; Wang, G; Shapiro, R; Berman, R; Pavlick, A et al. (2009). "Association of MDM2 SNP309, Age of Onset, and Gender in Cutaneous Melanoma.". Clinical cancer research : an official journal of the American Association for Cancer Research 15 (7): 2573–80
The Incidence of Second Primary Invasive Melanoma in Queensland, 1982-2003
Kieran A. McCaul, Lin Fritschi, Peter Baade and Michael Coory
Cancer Causes & Control Vol. 19, No. 5 (Jun., 2008), pp. 451-458
Exposure to Sunlamps, Tanning Beds, and Melanoma Risk
Kerri M. Clough-Gorr, Linda Titus-Ernstoff, Ann E. Perry, Steven K. Spencer and Marc S. Ernstoff
Cancer Causes & Control Vol. 19, No. 7 (Sep., 2008), pp. 659-669
Acral Lentiginous Melanoma Presents Distinct Clinical Profile with High Cancer Susceptibility
Eduardo Nagore, Carolina Pereda, Rafael Botella-Estrada, Celia Requena and Carlos Guillén
Cancer Causes & Control Vol. 20, No. 1 (Feb., 2009), pp. 115-119
