melanoma

For more information on melanoma, visit Britannica.com.

Key Terms: Adjuvant therapy, Dermis, Dysplastic nevus syndrome, Epidermis, Genome, Immunotherapy, Integument, Lymph node dissection, Lymphedema, Melanocyte, Metastasis, Nevus, Resection, Skin appendages, Systemic disease.

Definition

Malignant melanoma is a type of cancer arising from the melanocyte cells of the skin. The melanocytes are cells in the skin that produce the pigment melanin. Malignant melanoma develops when the melanocytes no longer respond to normal control mechanisms of cellular growth and are capable of invasion locally or spread to other organs in the body (metastasis), where again they invade and compromise the function of that organ.

Description

Melanocytes, embryologically derived from the neural crest, are distributed in the epidermis and thus are found throughout the skin. They produce a brown pigment known as melanin and are responsible for racial variation in skin color and also the color of moles. Malignant degeneration of the melanocyte gives rise to the tumor, melanoma, of which there are four subtypes. These are: superficial spreading, nodular, lentigo maligna, and acral lentiginous melanomas, accounting for 70%, 15% to 30%, 4% to 10%, and 2% to 8% of cases, respectively. Malignant melanoma may develop anywhere on the body. In men, it is most common on the trunk. In women, it is most common on the back or legs. The subtype also may influence where the tumor develops; lentigo melanoma is more common on the face while acral lentiginous melanoma is more common on the palms of the hand, soles of the feet, or in the nail beds.

The locally invasive characteristic of this tumor involves vertical penetration through the skin and into the dermis and subcutaneous (under-the-skin) tissues of the malignant melanocytes. With the exception of the nodular variety of melanoma, there is often a phase of radial or lateral growth associated with these tumors. Since it is the vertical growth that characterizes the malignancy, the nodular variant of melanoma carries the worst prognosis. Fortunately, the superficial spreading type is most common.

The primary tumor begins in the skin, often from the melanocytes of a pre-existing mole. Once it becomes invasive, it may progress beyond the site of origin to the regional lymph nodes or travel to other organ systems in the body and become systemic in nature.

The lymph is the clear, protein-rich fluid that bathes the cells throughout our body. Lymph will work its way back to the bloodstream via small channels known as lymphatics. Along the way, the lymph is filtered through cellular stations known as nodes, thus they are called lymph nodes. Nearly all organs in the body have a primary lymph node group filtering the tissue fluid, or lymph, that comes from that organ. Different areas of the skin have different primary nodal stations. For the leg, they are in the groin. For the arm, the armpit or axilla. For the face, it is the neck. Depending where on the torso the tumor develops, it may drain into one groin or armpit, or both.

Cancer, as it invades in its place of origin, may also work its way into blood vessels. If this occurs, it provides yet another route for the cancer to spread to other organs of the body. When the cancer spreads elsewhere in the body, it has become systemic in extent and the tumor growing elsewhere is known as a metastasis.

Untreated, malignant melanoma follows a classic progression. It begins and grows locally, penetrating vertically. It may be carried via the lymph to the regional nodes, known as regional metastasis. It may go from the lymph to the bloodstream or penetrate blood vessels, directly allowing it a route to go elsewhere in the body. When systemic disease or distant metastasis occur, melanoma commonly involves the lung, brain, liver, or occasionally bone. The malignancy causes death when its uncontrolled growth compromises vital organ function.

Demographics

In the United States, malignant melanoma will account for 5% of malignancies in men and 4% in women, being the sixth most common cancer in men and the seventh in women. There will be 553,400 total cancer deaths in the United States. Malignant melanoma will account for 7,800 for an incidence of 1.5% of total deaths related to cancer.

The incidence of primary cutaneous malignant melanoma has been steadily increasing, possibly related to increase of sun exposure. Currently, the risk is about 13 per 100,000 of the population. It affects all age groups but is most commonly seen in patients between 30 and 60 years of age.

Sun exposure definitely increases risk of developing melanoma. The melanocytes are part of the integument's photoprotective mechanism; in response to sunlight, they produce melanin that has a protective role from the sun's ultraviolet rays. For Caucasians, the amount of melanin present in the skin is directly related to sun exposure. However, it is not so much the total sun exposure that seems important, rather it is the history of sunburn, (especially if severe or at an early age), that correlates with the increased risk. On this basis populations of fair-skinned people living in areas of high sun exposure such as the southwest United States or Australia are subject to increased risk. Malignant melanoma also affects nonCaucasians—though sun exposure probably does not play a role—at a rate of 10% that of Caucasians. The most common form of melanoma in African Americans is acral lentiginous melanoma.

Malignant melanoma may arise in the skin anywhere on the body. It is estimated that 50% to 70% develop spontaneously while the remainder start in a pre-existing mole.

Causes and Symptoms

The predisposing causes to the development of malignant melanoma are environmental and genetic. The environmental factor is excessive sun exposure. There are also genetically transmitted familial syndromes with alterations in the CDKN2A gene, which encodes for the tumor-suppressing proteins p16 and p19. In 2003, a group of Swedish researchers reported that 63 out of a group of 71 melanoma patients, or 89% of the group, had mutations in either the NRAS or the BRAF gene. The researchers found that these mutations occur at an early point in the development of melanoma and remain as the tumor progresses.

As of early 2003, some researchers think there may be two pathways to malignant melanoma, one involving exposure to sunlight and the other with melanocyte proliferation triggered by other factors. This hypothesis is based on the difference in distribution of moles on the body between patients who develop melanomas on the face and neck, and those who develop melanomas on the trunk.

A small percentage of melanomas arise within burn scar tissue. As of 2003, researchers do not fully understand the relationship between deep burns and an increased risk of skin cancer.

As mentioned previously, melanin production in fair-skinned people is induced by sun exposure. An exposure substantial enough to result in a mild sunburn will be followed by melanin producing a tan that may last a few weeks. Both ultraviolet radiation and damaging oxygen radicals caused by sun exposure may damage cells, particularly their DNA. It is suspected that this damage induces mutations that result in the development of malignant melanoma. Though these mutations are alterations of the genome causing the melanoma, they are environmentally induced and account for sporadic or spontaneous cases of this disease.

A positive family history of one or two first-degree relatives having had melanoma substantially increases the risk on a genetic basis. A family tendency is observed in 8% to 12% of patients. There is a syndrome known as the dysplastic (atypical) nevus syndrome that is characterized by atypical moles with bothersome clinical features in children under age 10. Such individuals have to be observed closely for the development of malignant melanoma. Chromosome 9p has been identified as being involved in familial predisposition. There are mutations in up to 50% of familial melanoma patients of the tumor-suppressing gene CDKN2A. The actual number of moles increases risk, but the size of the moles needs be considered. Those with 10 larger moles of over 1 cm (0.4 in.) are at more risk than those with a higher number (50–99) of smaller moles. Finally, when a child is born with a large congenital mole, careful observation for change is appropriate because of increased risk.

An excellent way of identifying changes of significance in a mole is the ABCDE rule:

• Assymetry
• Border irregularity
• Color variegation
• Diameter exceeding 6 mm (0.24 in.)
• Elevation above surrounding tissue.

Notice that three of the criteria refer to variability of the lesion (color variegation refers to areas of light color and black scattered within the mole). Thus small, uniform regular lesions have less cause for concern. It is important to realize that change in a mole or the rapid development of a new one are very important symptoms.

Another summary of important changes in a mole is the Glasgow 7-point scale. The symptoms and signs below can occur anywhere on the skin, including the palms of the hands, soles of the feet, and also the nail beds:

• change in size
• change in shape
• change in color
• inflammation
• crusting and bleeding
• sensory change
• diameter more than 7 mm (0.28 in.)

In this scheme, change is emphasized along with size. Bleeding and sensory changes are relatively late symptoms.

Symptoms related to the presence of regional disease are mostly those of nodules or lumps in the areas containing the lymph nodes draining the area. Thus nodularity can be found in the armpit, the groin, or the neck if regional nodes are involved. There is also a special type of metastasis that can occur regionally with malignant melanoma; it is known as an in-transit metastasis. If the melanoma is spreading through the lymph system, some of the tumor may grow there, resulting in a nodule part way between the primary site and the original lymph node. These in-transit metastasis are seen both at the time of original presentation or later after primary treatment has been rendered, the latter being a type of recurrence.

Finally, in those who either are diagnosed with or progress to widespread or systemic disease, symptoms and signs are related to the affected organ. Thus neurologic problems, lung problems, or liver problems develop depending on the organ involved.

Diagnosis

None of the clinical signs or symptoms discussed above are absolute indications that a patient has malignant melanoma. The actual diagnosis is accomplished by biopsy, a procedure that removes tissue to examine under a microscope. It is important that the signs and symptoms are used to develop a suspicion of the diagnosis because the way the biopsy is performed for melanoma may be different than for other lesions of the skin.

When dealing with an early malignant melanoma, it is very important to establish the exact thickness of penetration of the primary tumor. Any biopsy that doesn't remove the full vertical extent of the primary is inadequate. Therefore, if a skin lesion is suspicious, full thickness excisional biopsy is the approach recommended. Shave biopsies and biopsies that remove only a portion of the suspect area are inappropriate. Often, in an early case, the excision involves just the suspicious lesion with minimal normal skin, but it should be a full vertical excision of the skin. If a melanoma is diagnosed, further treatment of this area will often be necessary but doesn't compromise outcome (prognosis). In some special areas of the body, minor modifications may be necessary about initial total excision, but full thickness excision should always be the goal. (See staging, below.)

Once the diagnosis is obtained, careful examination of the patient for regional lymph node involvement should be done. A careful review to uncover any symptoms of widespread disease is also appropriate.

The more common patient has an early melanoma, and extensive testing is not usually warranted. Routine testing in this situation involves a complete blood count, a chest x ray, and determinations of blood enzymes including lactic dehydrogenase and alkaline phosphatase.

If the patient has signs or symptoms of more advanced disease, or if the lesion's depth of penetration is sizeable, further imaging studies may be appropriate. These would involve CAT scans of the abdomen, the chest, or regional nodal areas, or a CT or MRI of the brain.

Treatment Team

The treatment of malignant melanoma is primarily surgical. Newer, more effective protocols involving the medical oncologist are being developed for the patient with systemic disease. Radiation therapy has a limited role in the treatment of melanoma, primarily that of helping to ease the effects of metastasis to the brain or sometimes the skeleton.

Clinical Staging, Treatments, and Prognosis

The key to successful treatment is early diagnosis. Patients identified with localized, thin, small lesions (typified by superficial spreading subtype) nearly always survive. For those with advanced lesions, the outcome is poor in spite of progress in systemic therapy.

Clinical Staging

Malignant melanoma is locally staged based on the depth of penetration through the skin and its appendages. There are two ways of looking at the depth of penetration. The Clarke system utilizes the layers of the dermis and the skin appendages present at that layer to identify the depth of penetration. The Breslow system uses the absolute measurement of depth. Though useful conceptually, the Clarke system is used less frequently because of the fact that skin is of different thickness in different regions of the body. The depth of penetration is much greater when the tumor reaches the subcutaneous fat when the skin involved is the back as opposed to the face. It turns out that the Breslow measurement is more reproducible and thus more useful; therefore, for purposes here, depth of penetration by absolute measurement (Breslow) is used in local staging.

Stage I and stage II have no involvement of the regional lymph nodes and are thus localized to the site of origin. These stages are subdivided on the basis of penetration. Stage Ia is 0.75 mm or less (1 mm = 0.04 in), and Stage Ib is 0.75 mm to 1.5 mm penetration. Stage IIa is 1.5 mm to 4.0 mm and Stage IIb is over 4.0 mm or into the subcutaneous fat. In stage III and IV, there is disease beyond the primary site. Stage III is defined by the presence of in-transit or regional nodal metastasis or both. Stage IV is defined by the presence of distant metastasis.

Treatments

Once the diagnosis of malignant melanoma has been established by biopsy and the stage has been identified using the results of the examination and studies, a treatment plan is developed. Melanoma is not cured unless it is diagnosed at a stage when it can be isolated and removed surgically. Considerations revolve around the extent of the local and regional nodal surgery for stages I through III. For stage IV patients, or those that are treated and then develop recurrence at distant sites, chemotherapy or immunotherapy is planned. Studies are in progress to improve the results from traditional chemotherapeutic regimens. Adjuvant therapy (auxiliary drug treatment used to make possibility of relapse less for those at high risk) is also considered.

Surgical therapy for the primary site is that of wide local removal of the skin including subcutaneous tissue surrounding the lesion. In the past, wide excisions were large and encompassed 2 in. of tissue in all directions wherever feasible. It has been shown that such wide local excisions are not necessary and the question has become how wide is necessary? Studies from the World Health Organization Melanoma Group and by the Melanoma Intergroup Committee in the United States have provided general guidelines based on the depth of penetration of the melanoma. These guidelines and anatomic considerations need to be kept in mind by the surgeon.

The next issue in primary management is whether or not the patient needs to have the regional lymph nodes removed in addition to treatment of the primary tumor. The problems associated with the resection of regional lymph nodes are those of lifelong edema or swelling in the extremity. Though it does not occur in all patients (5% to 20%, depending on the extremity and extent of the dissection), it can be a disabling symptom. Certainly, if it could be ascertained that there was disease in the nodes, resection (removal) would be appropriate. However, if there was no disease, the risk of edema should be avoided. In patients with no signs of regional disease, depth of penetration of the primary tumor helps guide the decision. If the tumor penetrates less than 1mm, dissection is not usually done. If it is 1-2 mm, node dissection may be done at the time of primary treatment or the patient may be observed and only undergo lymph node dissection if the area later shows signs of disease. If the patient has enlarged lymph nodes or the depth of the tumor has led to the evaluation by CAT scan showing enlarged nodes, resection of the nodes will be considered. In the latter case, more extensive imaging of the lung, liver, or brain may be appropriate to be sure the patient doesn't already have stage IV disease.

Questions related to which patients should have resection of regional lymph nodes have led to an intermediary procedure known as sentinel lymph node mapping and biopsy. Intermediate thickness melanomas between 1 and 4 mm deep (0.04 and 0.16 in.) may have nodal involvement even if the exam and any other studies done are normal. If a radioisotope tracer or blue dye is injected into the area of the primary tumor, very shortly it will travel to the lymph nodes draining that area. These sentinel nodes are thus identifiable and are the most likely to harbor any regional metastatic disease. If these nodes alone are biopsied and are normal, the rest of the lymph node group can be spared. If they show microscopic deposits of tumor, then the full resection of the lymph node group may be completed. This procedure allows selection of those patients with intermediate thickness melanoma who will benefit from the regional lymph node dissection.

Patients with metastatic melanoma who do not respond well to other therapies may be candidates for treatment with aldesleukin (also called interleukin-2), a specific kind of biological response modifier that promotes the development of T cells. These cells are part of the lymphatic system and can directly interact with and fight cancer cells. Although interleukin is produced naturally in the body, its therapeutic form is developed via biotechnology in a laboratory setting. In some patients, this medication has helped shrink tumors. Side effects, however, can be severe, and range from flu-like symptoms to whole-body infection (sepsis) and coma.

Some patients, such as those with IIb or stage III melanoma, are at high risk for the development of recurrence after treatment. Although these patients are clinically free of disease after undergoing primary treatment, they are more likely to have some microscopic disease in the body that studies have not yet been able to identify. In an effort to decrease the rate of relapse, adjuvant therapy may be considered. Interferon alpha 2a is an agent that stimulates the immune system. This adjuvant therapy may slightly increase the duration of a patient's disease-free state and lengthen overall survival. However, interferon alpha 2a has high toxicity and patients may not tolerate the side effects.

Unfortunately, treatment for those patients who present with or go on to develop systemic disease usually fails; melanoma that has metastasized to the brain is particularly difficult to treat. The chemotherapeutic agent dacarbazine, or DTIC, seems to be the most active agent. Overall responses are noted in about 20% of patients, and they last only two to six months. Combination therapy may be an option. The regimen of DTIC + BCNU (carmustine)+ cisplatin + tamoxifen delivers a response rate of 40%. Combining biologic or immunologic agents such as interferon with standard chemotherapeutic agents is under study and showing improved response rates, though toxicity is substantial and only the healthier, younger patients tolerate the treatment.

Some researchers are investigating the reasons why melanomas are so resistant to chemotherapy. One suggestion as of late 2003 is that the genes ordinarily responsible for apoptosis (cell self-destruction) do not function normally in melanomas. The development of new drugs to treat melanoma depends on a better understanding of the complex processes involved in apoptosis.

Prognosis

Almost all patients survive stage Ia malignant melanoma, and the suvivorship for stage I overall is more than 90%. Survival drops in stage IIa to about 65% at five years and is worse yet for stage IIb at slightly over 50%. Stage III has a survival rate at 5 years of 10% to 47%, depending on the size and number of regional nodes involved. Stage IV malignant melanoma is almost always a fatal disease.

Alternative and Complementary Therapies

Though radiation therapy has a minimal role in the primary treatment of malignant melanoma, for patients who have metastatic disease, radiation may be helpful. This is true in patients who have developed tumor deposits in areas such as the brain or the bone.

Coping With Cancer Treatment

For those with familial tendencies for malignant melanoma, genetic counseling may be appropriate. Psychological counseling may be appropriate for anyone having trouble coping with a potentially fatal disease. Local cancer support groups may be helpful and are often identified by contacting local hospitals or the American Cancer Society.

Clinical Trials

Clinical trials are studies of new modes of therapy in an effort to improve results of treatment. For those wishing to find a trial related to their particular situation, the National Cancer Institute lists those available at: .

In an attempt to develop a new type of immunotherapy, melanoma-specific vaccines are being developed. Antigens specific to melanoma cells and other tumorassociated antigens are being used to stimulate the body's own natural immune system to attack and kill the cells of malignant melanoma. Though experimental, this type of therapy offers hope and clinical trials are underway. In 2003 a team of researchers in New York reported that vaccines made from poxviruses show promise as a treatment for melanoma.

Prevention

Though it is difficult to prove that sunscreens statistically reduce the frequency of malignant melanoma at this time, most authorities recommend use as protection from ultraviolet light (considered a major factor in the development of melanoma.) Avoidance of severe sunburns is recommended.

Special Concerns

Sub-ungal melanoma is a type of acral lentiginous melanoma that occurs in the nail beds. Any pigmented lesion in these areas needs evaluation. They are commonly mistaken for bruises or infection. The main concern is to know they exist so that proper evaluation is performed as early as possible.

Malignant melanoma may also involve the eye, as melanin-producing cells exist there also. Again, familiarity with these spots is important so that pigmented growths are not ignored but evaluated early.

Questions to Ask the Doctor

• What stage of cancer do I have?
• Has the cancer spread? What tests will be used to determine this?
• What are my treatment options?
• Is adjuvant therapy really necessary in my case?
• What are the risks and side effects of these treatments?
• What medications can I take to relieve treatment side effects?
• Are there any clinical studies underway that would be appropriate for me?
• What effective alternative or complementary treatments are available for this type of cancer?
• How debilitating is the treatment? Will I be able to continue working?
• How will the treatment affect my sexuality?
• Are there any local support groups for melanoma patients?
• What is the chance that the cancer will recur?
• Is there anything I can do to prevent recurrence?
• How often will I have follow-up examinations?

Rarely, a patient presents with regional lymph node involvement, but the primary site of the tumor cannot be identified. The primary may not be producing pigment and is known as an amelanonic melanoma. Because these patients present with stage III disease, they do less well as a group overall.

Resources

Books

Abeloff, Armitage, Lichter, and Niederhuber. Clinical Oncology Library. 2nd ed. London: Churchill Livingstone, 2004.

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Dermatologic Disorders: Malignant Tumors." Section 10, Chapter 126 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Dermatologic Disorders: Moles." Section 10, Chapter 125 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Dermatologic Disorders: Reactions to Sunlight." Section 10, Chapter 119 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Periodicals

Brown, C. K., and J. M. Kirkwood. "Medical Management of Melanoma." Surgical Clinics of North America 83 (April 2003): 283–322.

Carlson, J. A., A. Slominski, G. P. Linette, et al. "Malignant Melanoma 2003: Predisposition, Diagnosis, Prognosis, and Staging." American Journal of Clinical Pathology 120, Supplement (December 2003): S101–S127.

Eigentler, T. K., U. M. Caroli, P. Radny, and C. Garbe. "Palliative Therapy of Disseminated Malignant Melanoma: A Systematic Review of 41 Randomised Clinical Trials." Lancet Oncology 4 (December 2003): 748–759.

Halder, R. M., and C. J. Ara. "Skin Cancer and Photoaging in Ethnic Skin." Dermatologic Clinics 21 (October 2003): 725–732.

Horig, H., and H. L. Kaufman. "Local Delivery of Poxvirus Vaccines for Melanoma." Seminars in Cancer Biology 13 (December 2003): 417–422.

Jellouli-Elloumi, A., L. Kochbati, S. Dhraief, et al. "Cancers Arising from Burn Scars: 62 Cases." [in French] Annales de dermatologie et de venereologie 130 (April 2003): 413–416.

McWilliams, R. R., P. D. Brown, J. C. Buckner, et al. "Treatment of Brain Metastases from Melanoma." Mayo Clinic Proceedings 78 (December 2003): 1529–1536.

Omholt, K., A. Platz, L. Kanter, et al. "NRAS and BRAF Mutations Arise Early During Melanoma Pathogenesis and Are Preserved Throughout Tumor Progression." Clinical Cancer Research 9 (December 15, 2003): 6483–6488.

Rockmann, H., and D. Schadendorf. "Drug Resistance in Human Melanoma: Mechanisms and Therapeutic Opportunities" Onkologie 26 (December 2003): 581–587.

Weinstock, Martin A. "Early Detection of Melanoma." JAMA, The Journal of the American Medical Association 284 (16 August 2000): 886.

Whiteman, D. C., P. Watt, D. M. Purdie, et al. "Melanocytic Nevi, Solar Keratoses, and Divergent Pathways to Cutaneous Melanoma." Journal of the National Cancer Institute 95 (June 4, 2003): 806–812.

Other

Cancer Resource Center American Cancer Society. [cited June 20, 2005]. .

Melanoma Patient's Information Page. [cited June 20, 2005]. .

National Cancer Institute. [cited June 13, 2005]. .

—Richard A. McCartney, MD; Rebecca J. Frey, PhD

A malignant neoplasm characterized by pigment-producing cells. It usually is dark in color but may be amelanotic, that is, free of pigment.

Melanoma is a cancer that forms in the pigment cells (melanocytes) of the skin. There were approximately forty-seven thousand new cases in the United States in the year 2000, nearly eight thousand of which were fatal, mostly due to metastases. Reports of melanoma cases doubled in frequency during the last decade of the twentieth century. Solar exposure and genetic factors are responsible for the majority of cases.

Reduction in exposure to ultraviolet light, especially early in life, and regular screening of those at increased risk are the best approaches to reducing mortality from melanomas. The overall five-year survival rate is 85 percent, and surgical excision of early tumors is usually curative. More effective treatment for advanced malignant melanoma is needed, however.

(SEE ALSO: Cancer; Skin Cancer; Ultraviolet Radiation)

Bibliography

Balch, C. M.; Houghton, A.; Sober, A. J.; and Soong, S. J., eds. (1998). Cutaneous Melanoma, 3rd edition. St. Louis, MO: Quality Medical Publishing.

— ARTHUR J. SOBER

A dark pigmented mole on the skin, some forms of which can be very invasive and malignant. Malignant melanoma is a cancerous tumour of melanocytes that usually occurs in the skin and sometimes in the retina of the eye. It is often associated with intermittent excessive exposure to ultraviolet light from the sun, especially in youth. Malignant cells often spread quickly to other parts of the body. Melanomas usually have an irregular shape and irregular border; they are often multicoloured and measure more than 0.5 cm (quarter of an inch) in diameter. Anyone with a suspicious skin growth should contact their doctor immediately. Superficial malignant melanomas can often be treated successfully by surgery, but once the disease spreads the prognosis is poor. Anyone who spends a lot of time outdoors, and that includes most sportspeople, should be aware of the potential risk and wear protective clothing and high factor sunscreen on areas exposed to sunlight. See also cyclist's melanoma.

A serious, often lethal, form of skin cancer.

A tumor arising from melanocytes, dendritic cells of neuroectodermal origin, or melanoblasts. They are most common in the skin, eye and oral cavity of dogs and aged gray horses, but occur occasionally as congenital lesions in pigs, goats and cattle. An inherited, malignant melanoma is recorded in swordtail–platyfish hybrids.

• amelanotic m. — one containing little or no melanin.
• benign m's — usually pigmented plaques or nodules. Those with junctional activity are analogous to the human compound junctional nevus.
• congenital m. of pigs — a single or multiple pigmented tumor of the skin or viscera that grows slowly and may metastasize. Spontaneous regression is common. An inherited form seen in Sinclair miniature pigs.
• dermal m. — a tumor which arises from rests of melanocytes in the dermis, remnants of neural crest precursors. Pigmentation is variable. It is usually benign.
• malignant m. — a malignant, rapidly growing, frequently ulcerated mass, consisting of either spindle cells or epithelioid cells or a mixture of the two, with a marked tendency to metastasize. The tumor cells may or may not (amelanotic) be pigmented. Although melanomas in pigs and cattle are usually benign and are not treated, those in horses, dogs, cats and occasional cases in sheep, goats and pigs are malignant. Called also nevocarcinoma.

Melanoma-Skin Cancer Disease
Classification and external resources
ICD-10	C43.
ICD-9	172
ICD-O:	M8720/3
OMIM	155600
DiseasesDB	7947
MedlinePlus	000850
eMedicine	derm/257 med/1386 ent/27 plastic/456
MeSH	D008545

Melanoma (pronounced /ˌmɛləˈnoʊmə/ ( listen)) is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye (see uveal melanoma). It is one of the less common types of skin cancer but causes the majority (75%) of skin cancer related deaths^[1]. Melanocytes are normally present in skin, being responsible for the production of the dark pigment melanin.^[2] Despite many years of intensive laboratory and clinical research, the greatest chance of cure is in the early surgical resection of thin tumours.

Around 60,000 new cases of melanoma invasive melanoma are diagnosed in the US each year, more frequently in males and in Caucasians.^[3] It is more common in Caucasian populations living in sunny climates than in other groups, or in those who use tanning salons.^[4] According to a WHO report about 48,000 melanoma related deaths occur worldwide per year.^[5]

The treatment includes surgical removal of the tumor, adjuvant treatment, chemo- and immunotherapy, or radiation therapy.

Contents 1 Classification 2 Signs and symptoms 3 Cause 3.1 Genetics 4 Diagnosis 4.1 Staging 5 Prevention 6 Management 6.1 Surgery 6.2 Adjuvant treatment 6.2.1 Chemotherapy and immunotherapy 6.3 Lentigo maligna treatment 6.4 Radiation and other therapies 7 Prognosis 8 Epidemiology 9 History 10 Research 11 See also 12 References 13 External links

Classification

Melanoma may be divided into the following stereotypes:^[6]:694-699

• Lentigo maligna
• Lentigo maligna melanoma
• Superficially spreading melanoma
• Acral lentiginous melanoma
• Mucosal melanoma
• Nodular melanoma
• Polypoid melanoma
• Desmoplastic melanoma
• Amelanotic melanoma
• Soft-tissue melanoma

See also:

• Uveal melanoma

Signs and symptoms

Early signs of melanoma are changes to the shape or color of existing moles. The mole may itch, ulcerate or bleed.[1]

Metastatic melanoma may cause general symptoms like loss of apetite, nausea, vomiting and fatigue. Metastasis as the first symptom of melanoma is possible, however, fortunately less than a fifth of melanomas diagnosed yearly become metastatic.

Cause

Genetics

Familial melanoma is genetically heterogeneous,^[7] 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.^[8] 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.^[9] Today, melanomas are diagnosed only after they become visible on the skin. In the future, however, physicians will hopefully be able detect melanomas based on a patient’s genotype, not just his or her phenotype. Recent genetic advances promise to help doctors to identify people with high-risk genotypes and to determine which of a person’s lesions have the greatest chance of becoming cancerous. 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. 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 also 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.^[10]

Diagnosis

ABCD rule illustration. On the left side from top to bottom: melanomas showing (A) Asymmetry, (B) a border that is uneven, ragged, or notched, (C) coloring of different shades of brown, black, or tan and (D) diameter that had changed in size. The normal moles on the right side do not have abnormal characteristics (no asymmetry, even border, even color, no change in diametry).

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.^[11][12]

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 likely 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. An experienced doctor can distinguish seborrheic keratosis from melanoma upon examination, or with dermatoscopy.

Some will advocate the system "ABCDE",^[13] with E for evolution. Certainly moles which change and evolve will be a concern. Alternately, 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.

A recent and novel method of melanoma detection is the "Ugly Duckling Sign"^[14][15] 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^[15] suggests that individuals with fair skin and light colored hair might have difficult-to-diagnose 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".^[16] 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.

A dermatoscope.

A modern polarized dermatoscope.

Moles that are irregular in color or shape are suspicious of a malignant or a premalignant melanoma. Following a visual examination and a dermatoscopic exam,^[16] used routinely by one in 4 dermatologists in the United States,^[17] or an examination using other in vivo diagnostic tools, such as a confocal microscope, the doctor may biopsy the suspicious mole. If it is malignant, the mole and an area around it needs 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, and breaks the "Ugly Duckling" sign. These melanomas are often light brown, or pink in color - and very hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines. There is no blood test for detecting melanomas.

Malignant melanoma in skin biopsy with H&E stain. This case may represent superficial spreading melanoma.

Excisional skin biopsy is the management of choice; this is where the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue.^[18] The preferred surgical margin for the initial biopsy should be narrow (1 mm) in order to prevent the disruption of the local lymphatic drainage. The biopsy will include the epidermal, dermal, and subcutaneous layers of the skin, enabling the histopathologist to determine the thickness of the melanoma by microscopic examination. This is described by Breslow's thickness (measured in millimeters). However, for large lesions such as suspected lentigo maligna, or for lesions in surgically difficult areas (face, toes, fingers, eyelids), a small punch biopsy in representative areas will give adequate information and will not disrupt the final staging or depth determination. In no circumstances should the initial biopsy include the final surgical margin (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. Large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram directed lymphnode dissection. A small punch biopsy can be utilized at any time where for logistical and personal reasons a patient refuses more invasive excisional biopsy. Small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring.

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.

Sometimes the skin lesion may bleed, itch, or ulcerate, although this is a very late sign. A slow-healing lesion should be watched closely, as that may be a sign of melanoma. Be aware also that in circumstances that are still poorly understood, melanomas may "regress" or spontaneously become smaller or invisible - however the malignancy is still present. Amelanotic (colorless or flesh-colored) melanomas do not have pigment and may not even be visible. Lentigo maligna, a superficial melanoma confined to the topmost layers of the skin (found primarily in older patients) is often described as a "stain" on the skin. Some patients with metastatic melanoma do not have an obvious detectable primary tumor.

Staging

Further context on cancer staging is available at TNM.

Also of importance are the "Clark level" and "Breslow depth" which refer to the microscopic depth of tumor invasion.^[19]

Melanoma stages:^[20]

Stage 0: Melanoma in Situ (Clark Level I), 99.9% Survival

Stage I/II: Invasive Melanoma, 85-95% Survival

• T1a: Less than 1.00 mm primary, w/o Ulceration, Clark Level II-III
• T1b: Less than 1.00 mm primary, w/Ulceration or Clark Level IV-V
• T2a: 1.00-2.00 mm primary, w/o Ulceration

Stage II: High Risk Melanoma, 40-85% Survival

• T2b: 1.00-2.00 mm primary, w/ Ulceration
• T3a: 2.00-4.00 mm primary, w/o Ulceration
• T3b: 2.00-4.00 mm primary, w/ Ulceration
• T4a: 4.00 mm or greater primary w/o Ulceration
• T4b: 4.00 mm or greater primary w/ Ulceration

Stage III: Regional Metastasis, 25-60% Survival

• N1: Single Positive Lymph Node
• N2: 2-3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis
• N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases

Stage IV: Distant Metastasis, 9-15% 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 5-Year Survival With Proper Treatment

Prevention

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),^[21] 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.^[22] 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.^[23] This controversy is well discussed in numerous review articles, and is refuted by most dermatologists.^[24][25] 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 increase incidence of melanomas.^[26] 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 malignant 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 is very hard to distinguish the difference between a malignant 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.

Management

Surgery is the first choice therapy for localized cutaneous melanoma. Depending on the stage a sentinel lymph node biopsy is done as well, although controversy exists around trial evidence for this procedure. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.

Surgery

Diagnostic punch or excisional biopsies may appear to excise (and in some cases may indeed actually remove) the tumor, but further surgery is often necessary to reduce the risk of recurrence.

Complete surgical excision with adequate margins and assessment for the presence of detectable metastatic disease along with short- and long-term followup is standard. Often this is done by a "wide local excision" (WLE) with 1 to 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2 to 0.5 cm^[27]. Many surgeons consider 0.5 cm the standard of care for standard excision of melanoma-in-situ,^[28] but 0.2 cm margin might be acceptable for margin controlled surgery (Mohs surgery, or the double bladed technique with margin control). The wide excision aims to reduce the rate of tumour recurrence at the site of the original lesion. This is a common pattern of treatment failure in melanoma. Considerable research has aimed to elucidate appropriate margins for excision with a general trend toward less aggressive treatment during the last decades.^[29]

Mohs surgery has been reported with cure rate as low as 77%^[30] and as high as 98% for melanoma-in-situ.^[31]

Melanomas which spread usually do so to the lymph nodes in the region of the tumor before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications but unfortunately no overall survival benefit. Recently the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumor.[2]

Although controversial and without prolonging survival, "sentinel lymph node" biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. A process called lymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site in order to localize the "sentinel node(s)". Further precision is provided using a blue tracer dye and surgery is performed to biopsy the node(s). Routine H&E staining, and immunoperoxidase staining will be adequate to rule out node involvement. PCR tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative SLN actually had a small number of positive cells in their nodes. Alternatively, a fine-needle aspiration may be performed and is often used to test masses.

If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed. If the disease is completely resected, the patient will be considered for adjuvant therapy.

Adjuvant treatment

High risk melanomas may require adjuvant treatment. In the United States most patients in otherwise good health will begin up to a year of high-dose interferon treatment, which has severe side effects but may improve the patient's prognosis.^[32] This claim is not supported by all research at this time, and in Europe interferon is usually not used outside the scope of clinical trials.^[33][34]

Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.^[35]

Chemotherapy and immunotherapy

Various chemotherapy agents are used, including dacarbazine (also termed DTIC), immunotherapy (with interleukin-2 (IL-2) or interferon (IFN)) as well as local perfusion are used by different centers. They can occasionally show dramatic success, but the overall success in metastatic melanoma is quite limited.^[36] IL-2 (Proleukin) is the first new therapy approved for the treatment of metastatic melanoma in 20 years. Studies have demonstrated that IL-2 offers the possibility of a complete and long-lasting remission in this disease, although only in a small percentage of patients.^[37] A number of new agents and novel approaches are under evaluation and show promise.^[38] Clinical trial participation should be considered the standard of care for metastatic melanoma.^[39]

In 2005, a phase III clinical trial for a melanoma vaccine was halted after showing little benefit compared to placebo. On June 23, 2008, Israeli scientists from the Oncology Institute of the Hadassa Medical Center in Jerusalem announced they developed a vaccine that prevents recurrences of the disease among previous sufferers and increases chances of survival for current ones. One of the most promising current experimental treatment approaches, also an immunotherapy, is OncoVEX GM-CSF (BioVex Inc, Woburn, MA) which is currently in Phase 3 clinical trials following a very high level of efficacy having been observed in Phase 2.

Lentigo maligna treatment

Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceeding high (up to 50%). This is due to the ill defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation of the standard bread loafing technique of fixed tissue histology - result in a high "false negative" error rate, and frequent recurrences. Margin controlled (peripheral margins) is necessary to eliminate the false negative errors. If breadloafing is utilized, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control.

Mohs surgery has been done with cure rate reported to be as low as 77%,^[30] and as high as 95% by another author.^[40] The "double scalpel" peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods.^[41]

Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months. Considering the very poor cure rate with standard excision, it might not be a bad idea to follow up all surgical excisions with topical imiquimod treatments.

Radiation and other therapies

Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. It may reduce the rate of local recurrence but does not prolong survival.^[42]

In research setting other therapies, such as gene therapy, may be tested.^[43] Radioimmunotherapy of metastatic melanoma is currently under investigation. Experimental treatment developed at the National Cancer Institute (NCI), part of the National Institutes of Health in the US was used in advanced (metastatic) melanoma with moderate success. The 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.^[44]

A new treatment that trains the immune system to fight cancer has shown modest benefit in late-stage testing against melanoma.^[45]

Prognosis

See also: Breslow's depth

Features that affect prognosis are 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.^[46]

Certain types of melanoma have worse prognoses but this is explained by their thickness. Interestingly, 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. Macrometastases 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 still worse.

When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%.^[20] The median survival is 6 to 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.

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.

Epidemiology

Age-standardized death from melanoma and other skin cancers per 100,000 inhabitants in 2004.^[47]

     no data      less than 0.7      0.7-1.4      1.4-2.1      2.1-2.8      2.8-3.5      3.5-4.2      4.2-4.9      4.9-5.6      5.6-6.3      6.3-7      7-7.7      more than 7.7

Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental.^[48] "Intrinsic" factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure.

Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA^[49] 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 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;^[50][51][52] studies from mice on skin cancer tend to confirm a role for Activating Transcription Factor-2 in cancer progression.^[53][54] Occasional extreme sun exposure (resulting in "sunburn") is causally related to melanoma.^[55] Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers.^[56][57] 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.^[58]

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^[59] 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 (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that sunscreen - while preventing the sunburn - does not protect mice, injected with melanoma cells a day after UV exposure, from developing melanoma.^[60]

Fair and red-headed people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk.^[61]

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.^[62] Patients with a history of one melanoma are at increased risk of developing a second primary tumour.^[63]

The incidence 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.^[64]

To understand how sunscreen can reduce sunburn and at the same time cause melanoma it is necessary to distinguish between direct DNA damage and indirect DNA damage. Genetic analysis has shown that 92% of all melanoma are caused by the indirect DNA damage.^[65] Although some people believe that dark-skinned people such as those of African descent cannot get sunburns, they are in fact susceptible, and may sunscreen accordingly, as sunscreen has been proven to protect against other cancers such as squamous cell carcinoma and basal cell carcinoma.^[66]

History

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 Inca 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.^[67]

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.^[68]

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.^[69] The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820.^[70] 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 ...'^[71] More than one and a half centuries later this situation remains largely unchanged.

Research

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One important pathway in melanin synthesis involves the transcription factor MITF. The MITF gene is highly conserved and is found in people, mice, birds, and even fish. MITF production is regulated via a fairly straightforward pathway. UV radiation causes increased expression of transcription factor p53 in keratinocytes, and p53 causes these cells to produce melanocyte stimulating hormone (MSH), which binds to melanocortin 1 receptors (MC1R) on melanocytes. Ligand-binding at MC1R receptors activates adenylate cyclases, which produce cAMP, which activates CREB, which promote MITF expression. The targets of MITF include p16 (a CDK inhibitor) and Bcl2, a gene essential to melanocyte survival. It is often difficult to design drugs that interfere with transcription factors, but perhaps new drugs will be discovered that can impede some reaction in the pathway upstream of MITF. Studies of chromatin structure also promise to shed light on transcriptional regulation in melanoma cells. It has long been assumed that nucleosomes are positioned randomly on DNA, but murine studies of genes involved in melanin production now suggest that nucleosomes are stereotypically positioned on DNA. When a gene is undergoing transcription, its transcription start site is almost always nucleosome-free. When the gene is silent, however, nucleosomes often block the transcriptional start site, suggesting that nucleosome position may play a role in gene regulation. Finally, given the fact that melanin helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce melanin synthesis in individuals who would otherwise get sunburns. Redheads, for example, do not tan because they have MC1R mutations. In mice, it has been shown that the melanin production pathway can be rescued downstream of MC1R. Perhaps such a strategy will eventually be used to protect humans from melanoma.

See also

• Oncophage
• Spitz nevus

References

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External links

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• American Cancer Society's Detailed Guide: Skin Cancer - Melanoma
• skintumor.info Gallery
• Skin Cancer Signs Melanoma Detection and Prevention.

v • d • e Diseases of the skin and appendages by morphology Growths Epidermal wart · callus · seborrheic keratosis · acrochordon · molluscum contagiosum · actinic keratosis · squamous cell carcinoma · basal cell carcinoma · merkel cell carcinoma · nevus sebaceous · trichoepithelioma Pigmented Freckles · lentigo · melasma · nevus · melanoma Dermal and subcutaneous epidermal inclusion cyst · hemangioma · dermatofibroma · keloid · lipoma · neurofibroma · xanthoma · Kaposi's sarcoma · infantile digital fibromatosis · granular cell tumor · leiomyoma · lymphangioma circumscriptum · myxoid cyst Rashes With epidermal involvement Eczematous contact dermatitis · atopic dermatitis · seborrheic dermatitis · stasis dermatitis · lichen simplex chronicus · Darier's disease · glucagonoma syndrome · langerhans cell histiocytosis · lichen sclerosus · pemphigus foliaceus · Wiskott-Aldrich syndrome · Zinc deficiency Scaling psoriasis · tinea (corporis · cruris · pedis · manuum · faciei) · pityriasis rosea · secondary syphillis · mycosis fungoides · systemic lupus erythematosus · pityriasis rubra pilaris · parapsoriasis · ichthyosis Blistering herpes simplex · herpes zoster · varicella · bullous impetigo · acute contact dermatitis · pemphigus vulgaris · bullous pemphigoid · dermatitis herpetiformis · porphyria cutanea tarda · epidermolysis bullosa simplex Papular scabies · insect bite reactions · lichen planus · miliaria · keratosis pilaris · lichen spinulosus · transient acantholytic dermatosis · lichen nitidus · pityriasis lichenoides et varioliformis acuta Pustular acne vulgaris · acne rosacea · folliculitis · impetigo · candidiasis · gonococcemia · dermatophyte · coccidioidomycosis · subcorneal pustular dermatosis Hypopigmented tinea versicolor · vitiligo · pityriasis alba · postinflammatory hyperpigmentation · tuberous sclerosis · idiopathic guttate hypomelanosis · leprosy · hypopigmented mycosis fungoides Without epidermal involvement Red Blanchable Erythema Generalized drug eruptions · viral exanthems · toxic erythema · systemic lupus erythematosus Localized cellulitis · abscess · boil · erythema nodosum · carcinoid syndrome · fixed drug eruption Specialized urticaria · erythema (multiforme · migrans · gyratum repens · annulare centrifugum · ab igne) Nonblanchable Purpura Macular thrombocytopenic purpura · actinic purpura Papular disseminated intravascular coagulation · vasculitis Indurated scleroderma/morphea · granuloma annulare · lichen sclerosis et atrophicus · necrobiosis lipoidica Miscellaneous disorders Ulcers Hair telogen effluvium · androgenic alopecia · trichotillomania · alopecia areata · systemic lupus erythematosus · tinea capitis · loose anagen syndrome · lichen planopilaris · folliculitis decalvans · acne keloidalis nuchae Nail onychomycosis · psoriasis · paronychia · ingrown nail Mucous membrane aphthous stomatitis · oral candidiasis · lichen planus · leukoplakia · pemphigus vulgaris · mucous membrane pemphigoid · cicatricial pemphigoid · herpesvirus · coxsackievirus · syphilis · systemic histoplasmosis · squamous cell carcinoma

v • d • e Gonadal tumors, paraganglioma, glomus, nevi and melanomas (ICD-O 8590-8799) Gonadal/ sex cord-gonadal stromal (8590-8679) sex cord (Granulosa cell tumour, Sertoli cell tumor) stroma (Thecoma, Leydig cell tumor) both (Sertoli-Leydig cell tumour, Luteoma) Paragangliomas And Glomus tumors (8680-8719) Neuroendocrine tumor: Paraganglioma (Pheochromocytoma) Vascular tissue neoplasm: Glomus tumor (Glomangiosarcoma) Nevi and melanomas (8720-8799) Nevi Melanocytic/pigmented nevus (Mongolian spot, Blue nevus, Nevus of Ota, Spitz nevus) location (Junctional nevus, Compound nevus) Halo nevus · Dysplastic nevus Melanomas (NE) Superficial spreading melanoma · Nodular melanoma · lentigo (Lentigo maligna/Lentigo maligna melanoma, Acral lentiginous melanoma)

v • d • e Tumors: skin cancer (C43-C44/D22-D23, 172-173/216) Epidermis Basal cell carcinoma · Squamous cell carcinoma (Acanthoma) Bowen's disease Dermis Benign fibrous histiocytoma/dermatofibrosarcoma · Dermatofibrosarcoma protuberans Nevi and melanomas Nevus: Melanocytic nevus · Dysplastic nevus · Halo nevus · Spitz nevus Melanoma: Superficial spreading melanoma · Nodular melanoma · lentigo (Lentigo maligna/Lentigo maligna melanoma, Acral lentiginous melanoma) integument, SF, LCT navs: anat/physio, noncongen/congen/neoplasia, symptoms+signs/eponymous, proc

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Dansk (Danish)
n. - melanom, pigmentsvulst

Nederlands (Dutch)
huidkanker, tumor met donker pigment

Français (French)
n. - mélanome

Deutsch (German)
n. - (meist) bösartiger Tumor von Melanin-Zellen

Ελληνική (Greek)
n. - (παθολ.) μελάνωμα

Italiano (Italian)
melanoma

Português (Portuguese)
n. - melanoma (m) (Med.)

Русский (Russian)
меланома

Español (Spanish)
n. - melanoma

Svenska (Swedish)
n. - melanom

中文（简体）(Chinese (Simplified))
黑素瘤, 胎记瘤

中文（繁體）(Chinese (Traditional))
n. - 黑素瘤, 胎記瘤

한국어 (Korean)
n. - 흑색종

日本語 (Japanese)
n. - 黒色腫

العربيه (Arabic)
‏(الاسم) الورم القيتاميني‏

עברית (Hebrew)
n. - ‮גידול כהה (בדר"כ ממאיר) בעור‬

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