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In This Report

•	Highlights
•	Introduction
•	Other Skin Cancers
•	Causes
•	Risk Factors
•	Prognosis
•	Prevention
•	Diagnosis
•	Treatment for Melanoma
•	Treatment for Other Skin Ca...
•	Resources
•	References

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Melanoma and Other Skin Cancers

Highlights

Immune-Suppressing Drugs and Skin Cancer Risk

• In 2005, the FDA warned that two immune-suppressing drugs used to treat eczema may increase the risk for skin cancer. The manufacturers of pimecrolimus (Elidel) and tacrolimus (Protopic) have put a strong warning on these drugs’ labels. These drugs are ointments that are rubbed on the skin. The FDA recommends that patients limit the amount of ointment they apply, and avoid direct exposure to sunlight.
• The rheumatoid arthritis drug etanercept (Enbrel) does not raise the risk for developing squamous cell skin cancer, according to research published in 2005 in the Archives of Dermatology. Researchers analyzed data from more than 1400 patients who used etanercept for up to five years. Etanercept works by blocking tumor necrosis factor (TNF), an immune system chemical messenger that is involved in inflammatory processes and diseases. Previous reports had indicated a possible association between etanercept use and skin cancer risk.

Tanning Devices

• Tanning beds and sunlamps increase the risk for developing melanoma, according to a 2005 review of epidemiologic studies. Previous findings have suggested that women who use tanning devices more than once a month significantly increase their melanoma risk. Women in their 20s, as well as blondes and redheads, are especially at risk.

Immunotherapy

• A new type of immunotherapy may help patients with advanced melanoma who have failed to respond to other treatments. T-cell therapy removes a patient’s white blood cells, activates them to fight tumors, and then infuses the cells back into the patient. Patients also receive chemotherapy. A 2005 study, published in the Journal of the National Cancer Institute, confirms the promising results of an earlier trial.

Curcumin

• The yellow pigment found in turmeric and curry spices may have anti-cancer properties. In a laboratory study, curmeric stopped melanoma cell growth.

Introduction

Melanoma is the most deadly form of skin cancer, although it can often be cured if caught very early. To understand how melanomas form, it is useful to know something about the skin.

The Skin. The skin is the largest organ in the body and consists of layers.

• The outermost layer of the skin, the epidermis, is only about 20 cells deep, roughly as thick as a sheet of paper.
• The dermis ranges in thickness from one to four millimeters (about 1/32 to 1/8 inch). The dermis contains tiny blood and lymph vessels, which increase in number deeper in the skin.

The skin is the largest organ of the body. The skin and its derivatives (hair, nails, sweat and oil glands) make up the integumentary system. One of the main functions of the skin is protection. It protects the body from external factors such as bacteria, chemicals, and temperature. The skin contains secretions that can kill bacteria and the pigment melanin provides a chemical pigment defense against ultraviolet light that can damage skin cells. The skin also helps control body temperature.

Melanocytes. Between the epidermis and the dermis are a layer of cells called melanocytes, which produce a brown-black skin pigment called melanin that determines skin and hair coloring. Melanin also helps protect against the damaging rays of the sun.

Melanoma. Melanocytes give melanoma its name. As a person ages, melanocytes often proliferate, forming concentrated clusters that appear on the surface as small, dark, flat or dome-shaped spots, which are usually harmless moles or liver spots.

• When cell proliferation occurs in a controlled and contained manner, the resulting lesion is benign and is commonly referred to as a mole or nevus. Most adults have at least several dozen benign moles.
• Sometimes, however, pigment cells grow out of control and become a malignant and life-threatening melanoma.

Click the icon to see an image of melanin.

At first, melanoma cells grow sideways (laterally), and so are confined to the epidermis and to the top layers of the dermis. However, once they grow downward into the dermis, the cancer will come into contact with lymph and blood vessels. The thicker the melanoma, the greater the likelihood that it could spread through these vessels to distant sites. Removal of the lesion before it penetrates to the deeper layers of the skin is crucial for achieving a cure. Early detection is very important.

Significant Features

People who regularly check moles on their skin may have a lower risk of developing advanced melanoma, but people should not panic over every skin irregularity. A doctor should examine any suspicious lesion with one or more of the features discussed below or that changes noticeably in size, color, or shape. Itching, tenderness, scaling, bleeding, crusting, or sores can signal potentially cancerous changes in any mole.

A mnemonic device, ABCD, is used to describe several features that help to distinguish melanomas from noncancerous growths:

• Asymmetry (A). About half the time, a melanoma develops in an existing mole; in other cases, it arises as a new lesion that can resemble an ordinary mole. A noncancerous mole, however, is generally symmetric and circular in shape, while melanoma usually grows in an irregular, asymmetric fashion.
• Border Irregularity (B). Benign lesions generally have clearly defined borders that mark the boundary between mole and skin. A melanoma, in contrast, often has notched or indistinct borders that may signal ongoing growth and spread of the cancer.
• Color Variation (C). One of the earliest signs of melanoma may be the appearance of various colors within the lesion. Because melanomas arise within pigment-forming cells, they are often varicolored lesions of tan, dark brown, or black, reflecting the production of melanin pigment at different depths within the skin. Occasionally, lesions are flesh colored or surrounded by redness or lighter areas of depigmentation. Pink or red areas may result from inflammation of blood vessels within the skin; blue areas reflect pigment in the deeper layers of the skin; and white areas can arise from dead cancerous tissue.
• Diameter (D). A diameter of 6 millimeters or larger (about the size of a pencil eraser) is worrisome. Melanomas start out small; by the time a lesion has grown this large, other abnormalities will most likely be present. No matter what size, a doctor should examine any suspicious lesion.

Growth Pattern

Melanomas tend to grow in stages:

• Most melanomas tend to be flat initially and spread laterally across the skin surface as they grow. At this early stage, which can last from one to five years or longer, removal of the growth has an excellent chance of curing the melanoma. Still, there is a chance that some of these melanomas are invasive and they should be treated aggressively.
• Lesions that become raised or dome-shaped over at least part of their surface indicate that downward growth has occurred. In some cases, this growth is very rapid, occurring over a period of weeks to months.

Any suspicious lesion should be checked immediately, particularly if it has grown quickly or is partially flat and partially raised.

Location

Common sites of melanoma in men are the head, neck, and trunk, and in women, the arms or legs. Any area of the skin may be affected, however, in either gender. Melanomas may not be noticed if they appear on areas that are difficult to examine, such as the scalp or the back. Less common sites for melanoma include the fingers, palms, soles of the feet, the genitals, lips, or under the fingernails or toenails. The presence of a dark lesion under the nail that runs into the adjoining skin and doesn't heal may signal melanoma. Rarely, melanomas appear in the mouth, in the iris of the eye, or in the retina at the back of the eye, where they may be detected during dental or eye examinations.

Click the icon to see an image of melanoma.

Specific Melanomas

Superficial Spreading Melanoma. Superficial spreading melanoma is the most common and most curable. It is flat, asymmetrical, unevenly colored, and usually grows outward across the surface of the skin.

Nodular Melanoma. Nodular melanoma appears as a fast-growing brown or black lump and its characteristics do not always fit the definitions described above. It is important to check for this type of melanoma, because it is associated with an outbreak of other tumors.

Lentigo Maligna. Lentigo maligna (sometimes called Hutchinson's freckle) usually occurs in elderly people and is marked by flat, mottled, tan-to-brown freckle-like spots with irregular borders. These lesions often appear on the face or other sun-exposed areas and typically enlarge slowly for five to fifteen years before cancer appears.

Acral Lentiginous Melanoma. Although rare, acral lentiginous melanoma is the most common melanoma among African and Asian populations. It commonly appears as a dark patch on the palms, soles, fingers, toes, under fingernails or toenails, or mucous membranes.

Other Skin Cancers

There are two other types of skin cancers: Basal Cell and Squamous Cell. Basal cell is the most common form of skin cancer.

Basal Cell Carcinomas

Basal cell carcinoma (BCC) is named for the round basal cells located in the lower part of the epidermis (the outermost layer of the skin), from which it arises. Like melanoma, the cancer has been increasing at a dramatic rate.

Prevalence and Risk Factors. Basal cell carcinoma occurs in 800,000 people every year, and 30% of people, almost exclusively Caucasians, can expect to have basal cell carcinoma, on average, by age 55. Some experts posit that genetic mutations caused by factors other than sunlight may also contribute to basal cell cancer.

Interestingly, a 2001 study reported that people with more wrinkles were less likely to develop basal cell carcinomas, even among high-risk groups. Some experts suggest that people prone to wrinkles may respond to sun exposure with biologic mechanisms that protect against basal cell carcinoma. More research is needed confirm this.

Characteristics. The lesions usually develop later in life in areas that have received the most sun exposure, such as the head, neck and back, and especially the nose. About a third of basal cell carcinomas appear in areas not exposed to the sun.

Basal cell carcinomas (BCCs) have many different appearances:

• They usually appear as a round area of thickened skin that does not change color or cause pain or itching.
• Very slowly, the lesion spreads out and develops a slightly raised edge, which may be translucent and smooth. Infrequently, basal cell carcinomas resemble malignant melanomas in color.
• Eventually, the center becomes hollowed and covered with a thin skin, which can become sore and open.
• A form known as aggressive-growth basal cell carcinoma resembles a scar with a hard base. This is type is more likely to spread and must be treated very aggressively.

Basal cell cancer is a malignant skin tumor involving cancerous changes of basal skin cells. Basal cell skin cancers usually occur on areas of skin that are regularly exposed to sunlight or other ultraviolet radiation. Once a suspicious lesion is found, a biopsy is needed to prove the diagnosis of basal cell carcinoma. Treatment varies depending on the size, depth, and location of the cancer. Early treatment by a dermatologist may result in a cure rate of more than 95%, but regular examination by a health care provider is required to watch for new sites of basal cell cancer.

They are sometimes hard to tell from benign skin conditions. For instance, occasionally they arise in unexposed skin, where they may mimic an ordinary mole, cyst, or pimple. They may be particularly difficult to distinguish from benign cysts when they occur near the eyes.

Outlook. Usually, basal cells are slow growing and they are rarely fatal. Most basal cell carcinomas need not be treated as an emergency, although late treatment can cause disfigurement, so they should be removed as early as possible.

The basal cell carcinomas that are most likely to spread are larger ones (more than 1 centimeter), scar-like BCCs, particularly those located on the cheek, and any BCC on the nose, neck, earlobe, eyelid, or temple.

Some studies are indicating that people with basal cell carcinoma may be at higher risk for second cancers, including melanoma, cancer of the lip, salivary glands, larynx, lung, breast, and kidney and non-Hodgkin's lymphoma. Those at higher risk for such cancers appear to be men and anyone diagnosed before 60 with BCC.

Squamous Cell Carcinoma and Bowen's Disease

Characteristics. Squamous cell carcinoma (SCC) develops from keratinocytes, flat, scale-like skin cells that lie under the top layer of the epidermis. The majority of squamous cell carcinomas occur on sun-exposed areas, especially the forehead, temple, ears, neck, and back of the hands. People who have spent considerable time sunbathing may develop them on their lower legs. Their appearance changes with its stage:

• Squamous cell carcinoma in situ (often referred to as Bowen's disease). This is the earliest stage when the cancer is local and has not spread. Lesions are typically large reddish patches (often over one inch) that are scaly and crusted.
• Invasive squamous cell carcinoma. These are lesions that are highly likely to spread (metastasize). They enlarge either rapidly (over months) or slowly (over years). Eventually they become ulcerated.

Click the icon to see an image of squamous cell cancer.

Prevalence and Risk Factors. About 160,000 people develop squamous cell carcinomas every year. The incidence of this cancer is increasing.

Sun exposure and sun damage are the greatest risk factors, and the addition of other factors compound the risk:

• Older age.
• Being fair skinned, particularly having red hair.
• Living in sunny climates.
• Treatments for psoriasis, including PUVA (psoralen and UVA radiation) and immunosuppressant agents, such as cyclosporine, also pose a risk for squamous cell carcinoma (SCC). (A 2005 study found that the rheumatoid arthritis drug etanercept (Enbrel) does not increase squamous cell cancer risk.)
• Genital warts (human papillomavirus) may also increase the risk in the genital and anal areas and around fingernails.

Outlook and Severity. Prompt treatment is desirable because squamous cell carcinomas are more likely to spread to local lymph nodes than are basal cell carcinomas, the other common skin cancer. Mortality rates for this cancer are very low, although squamous cell cancer still kills between 2,000 and 2,500 Americans each year. The risk for metastases (the spread of cancer to other organs) ranges from 0.5% to 16%, depending on risk factors. Squamous cell carcinomas most likely to spread include the following:

• Deep lesions, those larger than 2 cm in diameter, or patches with poorly defined margins.
• Recurrent lesions.
• SCC on neck, earlobe, eyelid, lips, or temple.
• SCC that develop in ulcers.
• SCC that develops on skin areas that have been previously treated with radiation or exposed to carcinogenic chemicals.

People with squamous cell carcinomas seem to be at higher risk for other cancers, including melanoma itself, lung cancer, non-Hodgkin lymphoma, bladder cancer, leukemia, and testicular and prostate cancer in men and breast cancer in women.

Precancerous Skin Disorders

Actinic (Solar) Keratoses. Actinic (also called solar) keratoses are the most common of all precancerous skin lesions. In fact, evidence now strongly supports the belief that actinic keratoses are actually squamous cell carcinomas in situ (the early stage of SCC). It should be noted, however, that not all actinic keratoses progress to carcinomas. One long-term study in 1999 indicated that the rate of malignant transformation might be about 10% over a 10-year period, while other studies show higher rates of progression to SCC.

Actinic keratoses occur after years of sun exposure and afflict over half of Caucasian persons aged 40 or older who live in hot sunny climates. They occur predominantly on sun-exposed skin such as the face, neck, back of the hands and forearms, upper chest, and upper back. Men may develop keratoses along the rim of the ear.

Actinic keratoses have the following characteristics:

• Lesions typically occur on the surface of the skin and have a sandpaper-like feel. In fact, they are sometimes more easily felt than seen.
• Most lesions are pink and even flesh-colored. Some are red or brown, scaly, and tender. At times, they can resemble melanomas and even dermatologists may have trouble telling the two apart.
• They can range in size from microscopic to several inches in diameter.

Keratoacanthomas. Keratoacanthomas closely resemble squamous cell carcinomas but they are not malignant. The majority arises in sun-exposed skin, usually on the hands or face. They are typically skin colored or slightly reddish when they first develop but their appearance typically changes:

• In the early stages, keratoacanthomas are smooth, red, and dome shaped.
• Within a few weeks, they can grow rapidly, usually to one or two centimeters. Some reach the size of a quarter in less than a month and can be rather disfiguring.
• They eventually stop growing and become crater-like with an outer rim of tissue surrounding and a sometimes crusty interior.

Most will spontaneously regress within a year but they almost always scar after healing. Also about 25% develop into squamous cell carcinomas, most frequently in older people and in sun-exposed areas. Removal by surgery (sometimes by radiation) is recommended. They may also be treated with 5-fluorouracil, either as a cream (Efudex) or with injections.

Causes

The role of the sun cannot be overestimated as the most important cause of prematurely aging skin (called photoaging) and skin cancers. Overall, exposure to ultraviolet (referred to as UVA or UVB) radiation emanating from sunlight accounts for about 90% of the symptoms of premature skin aging, and most of these effects occur by age 20:

• Even small amounts of UV radiation trigger process leading to skin wrinkles.
• Long-term repetitive and cumulative exposure to sunlight appears to be responsible for the vast majority of undesirable consequences of aging skin, including basal cell and squamous cell carcinomas.
• Melanoma is more likely to be caused by intense exposure to sunlight in early life.

UVA and UVB Radiation. When sunlight penetrates the top layers of the skin, ultraviolet (referred to as UVA or UVB) radiation bombards the genetic material, the DNA, inside the skin cells and damages it.

• UVB is the primary agent in sunburning and primarily affects the outer skin layers. UVB is most intense at midday when sunlight is brightest.Slightly over 70% of the yearly UVB dose is received during the summer and only 28% is received during the remainder of the year.
• UVA penetrates more deeply and efficiently, however. UVA's intensity also tends to be less variable both during the day and throughout the year than UVB's. For example, only about half of the yearly UVA dose is received during the summer months and the balance is spread over the rest of the year. UVA is also not filtered through window glass (as UVB is).

Damaging Effects of UV Radiation. Both UVA and UVB rays cause damage, including genetic injury, wrinkles, lower immunity against infection, aging skin disorders, and cancer, although the mechanisms are not yet fully clear. The following are some ways in which cancer may develop and some defensive actions that the skin uses to defend itself against DNA damage.

• Oxidation and Antioxidants. The effects of UV radiation are implicated in the production of oxidants, also called free radicals. These are unstable molecules produced by normal chemical processes in the body that, in excess, can damage the body's cells and even alter their genetic material, contributing to the aging process and sometimes to cancer. The large surface area of the skin makes this organ a prime target for oxidants.
• Defective DNA Repair and Protective Enzymes. Some melanomas and other skin cancers are caused by a breakdown in the mechanisms that help repair DNA damage. This can occur from various causes including an inherited condition called xeroderma pigmentosum (XP). A number of enzymes in the skin help protect against this damage. One repair enzyme called T4 endonuclease 5 (T4N5) is, in fact, being investigated in lotions to protect against skin cancers.
• Breakdown of Immune Protection. Specific immune factors protect the skin, including white blood cells called T lymphocytes and specialized skin cells called Langerhans cells. Such immune factors attack developing cancer cells at the very earliest stages. Unfortunately, certain substances in the skin--of note a chemical called urocanic acid--suppress such immune factors when exposed to sunlight, setting the stage for skin cancers.

Defective Cell Death (Apoptosis). Apoptosis is the last defense of the immune system. It is a natural process of cell-suicide, which occurs when cells are very severely damaged. Apoptosis in the skin kills off cells harmed by UVA so that they do not turn cancerous. (The peeling after sunburn is the result of these dead skin cells.) In some cases, however, genetic mutations or other factors derail apoptosis. If this occurs, the cells can become immortal and continue to proliferate, resulting in skin cancers.

Genetic Factors

A number of genetic factors are being investigated for their role in melanomas, including inherited genes and genetic defects that are acquired from environmental assaults (particularly sunlight).

Mutations in Genes that Regulate Cell Growth. Noninherited mutations in a number of genes that inhibit tumor growth or other cell-protecting properties may account for cancerous changes in moles and for aggressive melanomas. The following are some examples.

• Important studies have now identified a mutation in the BRAF gene that appears to be the most common event in the process that leads to melanoma. Some researchers have observed mutations in 66% of malignant melanomas. Researchers hope that agents that block this gene may be a viable treatment path.
• P16 is a tumor suppressive gene that may be abnormal in some melanoma cases.
• Genetic mutations that regulate Ku70 and Ku80 proteins may disrupt processes that repair strands of DNA.
• Researchers are also studying mutations in a gene that encodes for a substance called epidermal growth factor (EGF). EGF plays a role in skin cell growth and wound healing, and may account for many sporadic (non-inherited) cases of melanoma.
• Of further interest are mutations in genes that regulate Fas proteins, which are involved in apoptosis, a natural process of cell self-destruction. When it goes awry in melanoma cells, proliferation can become rampant.

CDKN2A Mutations. Mutations in a genetic regulator called CDKN2A are the most common causes of inherited melanoma (which are still very uncommon). (Mutations in this gene also appear in non-inherited cases of melanoma.) Genetic tests are being developed for CDKN2A, although it is not clear if knowing the results of the test would benefit people carrying the gene.

Variations in the Melanocortin-1 Receptor Gene. One study found that the greater the number of variations from normal in a gene called the melanocortin-1 receptor gene, the greater the risk for melanoma. The gene plays an important role in determining if a person has red hair, fair skin, and sensitivity to UV radiation. Interestingly, people who had olive and darker skin and who carried one or more variations of the gene had a higher than average risk for melanoma.

Aging

Aging may weaken the body's ability to fend off impending cancers, including melanomas. As a person ages, they lose specialized immune cells in the skin (Langerhans cells) that are thought to be responsible for eliminating skin cancers at the very earliest stage when only one or two cancer cells are present. The number of these immune cells decreases with age, possibly setting the stage for skin cancers to take root and thrive in later life.

Risk Factors

In the US, the incidence of melanoma is rising more rapidly than any other cancer. According to the American Cancer Society, about 59,580 new melanomas will be diagnosed in the United States in 2005, and 7,700 people will die from it.

Survival rates have been improving, however, and the increase in melanomas has occurred principally with thin, less aggressive forms of the disease. Some experts believe this is due to the increased awareness from effective public programs and earlier diagnosis.

Age and Gender

Melanoma in Adults. Melanoma is most common in people over 40 and the incidence increases significantly as people get older. Before age 40, melanomas are slightly more common in women than men, but after age 40 men are more often affected. Men are also more likely to have invasive and fatal melanoma than are women, although some research suggests that the higher rates are only because men fail to seek a diagnosis of suspicious skin changes before they become dangerous. The rate in women levels off somewhat between age 45 and 60; researchers speculate that menopause could have some sort of protective effect during those years.

Melanoma in Children. Melanoma is rare in children under age 10. Among children ages 10 to 14 the incidence is only 0.3 per 100,000 and between ages 14 and 19, it is still very rare, 1.3 per 100,000. Parents, then, should not be unduly alarmed by every minor skin imperfection in their children. Nevertheless, melanoma is as serious in children as in adults and early detection is still critical.

Intense Exposure to Sunlight and Ultraviolet Radiation

Ethnic Groups and Complexion. People with light skin, blue, gray, or green eyes, red or blond hair, and lots of freckles are at highest risk than people with other skin types for developing melanoma. The risk increases for those who are easily sunburned and rarely tan, particularly if they live close to the equator where sunlight is most intense. Darker ethnic groups or those with swarthy complexions are not immune, however.

Experts have devised a classification system for skin phototypes (SPTs) based on the sensitivity to sunlight. It ranges from SPT I (lightest skin plus other factors) to IV (darkest skin). Tanning and Sunburn Risk People with skin types I and II are at highest risk for photoaging skin diseases, including cancer. It should be noted, however, that premature aging from sunlight can affect people of all skin shades.

People Exposed to Intermittent Intense Sunburns. Whereas some skin cancers, such as squamous cell and basal cell carcinomas, are associated with cumulative lifetime exposure to the sun, melanoma is more often linked to intermittent intense exposure to sunlight, particularly during childhood and adolescence. Cancer typically arises many years later.

Fortunately, many parents are now taking effective steps to protect their children, although experts worry that they are relying too much sunscreen and less on other protective measures. Adolescents, however, are at special risk for sun-related cancers because, according to a 2002 study, the majority fails to take protective measures when out in the sun. According to the study, boys are less likely to use sunscreen than girls, but girls have more sunburns and use tanning salons more often. Adults who work indoors and experience the occasional weekend sunburn may also be at increased danger.

Interestingly, a number of studies report that continuous exposure to sunlight during adolescence or adulthood may be protective.

Tanning Devices. Tanning beds have been linked to a higher incidence of skin cancers. A 2003 study of Scandinavian women found that women who visited a tanning salon at least once a month were 55% more likely to develop malignant melanoma compared to women who did not use these devices. The risk was highest for women in their 20s.

Personal or Family History of Melanoma

Individuals who have been diagnosed with melanoma are at increased risk for a second primary melanoma. According to one 2003 study, the risk over time for developing a second melanoma is 1% in the first year after diagnosis, 2.1% at five years, 3.2% at 10 years, and 5.3% at 20 years. The risk is especially higher in older men and in those with first melanomas on the upper body and face.

People with family members who have or had melanoma should also be considered at high risk and examined on a regular basis.

Other Skin Conditions That Increase the Risk for Melanoma

Nonmelanoma Skin Cancers. Nonmelanoma skin cancers, including basal and squamous cell carcinomas, increase the risk of dying from other cancers, including melanoma itself, lung cancer, non-Hodgkin's lymphoma, bladder cancer, and leukemia as well as testicular and prostate cancers (in men) and breast cancer (in women).

Basal cell cancer is a malignant skin tumor involving cancerous changes of basal skin cells. Basal cell skin cancers usually occur on areas of skin that are regularly exposed to sunlight or other ultraviolet radiation. Once a suspicious lesion is found, a biopsy is needed to prove the diagnosis of basal cell carcinoma. Treatment varies depending on the size, depth, and location of the cancer. Early treatment by a dermatologist may result in a cure rate of more than 95%, but regular examination by a health care provider is required to watch for new sites of basal cell cancer.

Click the icon to see an image of squamous cell cancer.

Moles (Nevi) and Other Dark Blemishes. Any mole (called a nevus) or other blemish that seems new, changing, or unusual in any way should raise suspicion, but one should not be alarmed by every rash or bump. Benign (noncancerous) moles (nevi) typically have the following characteristics:

• Benign moles generally remain small with clearly defined, regular borders and uniform coloration. Some have a regular stippled or net-like pattern of pigmentation, however, and may even resemble early melanoma.
• They typically first appear during childhood, puberty, or young adulthood. They may naturally grow, darken, or increase in number at certain times of life, such as adolescence or pregnancy.

Some specific moles or dark blemishes that either resemble melanomas, are risk factors for melanoma, or both include the following:

• Freckles. Freckles typically appear in children on sun-exposed areas and are usually evenly brown or tan. The more freckles a person develops as a child, the greater the risk for melanoma in adulthood.
• Liver Spots. Liver spots are usually evenly brown or tan sun-induced lesions that are universal signs of aging. Occurring most noticeably on the hands and face, these harmless blemishes tend to enlarge and darken over time.
• Dysplastic (or Atypical) Nevi. About 30% of the population has moles called dysplastic nevi, or atypical moles. They are larger than ordinary moles (most are 5 mm across, about the size of a pencil eraser, or larger), have irregular borders, and are various shades or colors. Individuals who have dysplastic nevi plus a family history of melanoma (a syndrome known as FAMM) are at a high risk for developing melanoma at an early age (younger than 40) and often develop subsequent melanomas at additional locations. The risk for those with atypical moles and no family history of melanoma is less clear.
• Blue Nevus. The blue nevus is a benign mole that may easily be mistaken for melanoma. It is a blue-black, smooth, raised nodule and commonly occurs on the buttocks, hands, or feet.
• Spindle Cell (Spitz) Nevus. Children may develop a benign lesion called a spindle cell (or Spitz) nevus. The mole is firm, raised, and pink or reddish-brown. It may be smooth or scaly and usually appears on the face, particularly the cheeks. It is not harmful, but it may be difficult to differentiate from a melanoma, even for experts.
• Congenital Nevi (Birthmarks). Whenever possible, very large birthmarks should be removed during infancy. Those known as giant congenital nevi are more than eight inches across and are major risk factors for melanoma. In such cases, cancer usually appears by age 10. Medium-sized congenital nevi do not appear to increase the risk for melanoma. Experts disagree, however, about whether small birthmarks need to be removed. Parents are advised to watch any birthmark for changes.

The more moles one has the higher the risk that one of them will become cancerous, although the danger is still very small. A 2003 study estimated that the risk for a single mole to develop into melanoma by age 80 is 1 in 3164 in men and 1 in 10,800 for women. (The risk is higher, however, with atypical moles. One study of people with melanoma indicated that the presence of even one atypical mole doubled the normal risk and having 10 or more increased the chance 12-fold.) Any moles should be watched for changes, particularly in people with fair skin and other risk factors. However, simply having them should not cause alarm.

Psoriasis and Its Treatments. Psoriasis increases the risk for squamous cell carcinoma, but studies conflict on whether it has any effect on melanoma. One study, in fact, reported a lower risk. Nevertheless, there is some evidence that long-term treatment for psoriasis using UVA radiation (PUVA) may increase the risk for melanoma. In one study, there was a significantly higher risk even with relatively few treatments. In one study, invasive melanoma had occurred in 2.8% of patients 15 or more years after the initial treatment.

Non-Skin Medical Conditions

• Non-Hodgkin's Lymphoma. Survivors of either non-Hodgkin's lymphoma or melanoma face a higher risk for the other malignancy. These may have common causes, such as exposure to UV radiation or shared genetic factors.
• Immunosuppressed Patients. Individuals whose immune systems are suppressed because of certain medications, organ transplantation, or specific medical conditions such as AIDS are also at risk. (Melanoma has also developed in patients who received heart transplants from donors who had the disease.) Immune-suppressing drugs used to treat autoimmune disorders may increase risk. In 2005, the FDA warned of potential skin cancer risks associated with the eczema drugs pimecrolimus (Elidel) and tacrolimus (Protopic).
• Endometriosis. Endometriosis may put women with this condition at higher risk for melanoma, although more research is needed to confirm this.

Geographic Location

Australia has the highest melanoma rate in the world. In the US the incidence is highest in California, Florida, and Texas. The disease is by no means limited to such sunny states and countries, however. In general, the risks are highest in regions where the population tends to be blonde and fair-skinned. Norway, for example, has had the highest rate of melanoma in Europe, and rates are soaring in the UK, particularly among men, perhaps because Britons are increasingly vacationing in sunny climates.

Other Forms of Radiation Exposure

Occupational exposure to radiation, such as in health-care or industrial settings, may increase the risk for melanoma. Airline pilots, too, are at increased risk for melanoma. It is uncertain, however, whether this higher risk is from excessive exposure to ionizing radiation at high altitudes or because they have more opportunity to spend time in sunny regions. Experts disagree over whether frequent flyers are also at increased jeopardy.

Prognosis

Melanoma presents a case of extremes. If detected while it is still local (called melanoma in situ), the five-year survival rate is over 95%. And, fortunately, about 80% of melanomas are diagnosed in this early stage.

If the cancer is more advanced, however, survival drops below 60%. Its deadly nature is due to the spread of cancerous melanoma cells to other parts of the body. Cancer cells that spread in this fashion are known as metastases and are very difficult to treat. Melanoma cells usually spread first via lymph vessels (channels that carry immune system cells and fluids to the lymph nodes) or glands. Melanoma cells can also spread via blood vessels to various organs, causing metastatic tumors in the liver, lungs, brain, or other sites.

In general, after patients are treated for melanoma, the longer they remain free of cancer recurrence following treatment, the better the chance of remaining disease-free. However, relapses are not uncommon in those whose initial melanoma was large. (Current research suggests that even many local melanomas may be more dangerous than previously thought. Even after small melanomas have been completely removed, patients must be monitored for recurrence.)

Anyone who has recovered from melanoma should be especially strict about adhering to preventive guidelines and remain vigilant for suspicious lesions, since the risk for developing a new melanoma is increased even if the first one was successfully cured. Such relapses may occur years after the original diagnosis.

Prevention

Australia and Scotland have reported improved survival rates from melanoma after aggressive detection and prevention programs were started. In addition to encouraging regular self-examination, such programs include eliminating the sales tax on sunscreens, discouraging suntans and midday sports, and planting trees and placing canopies over children's playgrounds.

Self-Examinations for General Population

Anyone with risk factors for this cancer should be vigilant and check the entire body every month or so. Some experts have defined three specific areas for locating melanomas:

• Areas visible to anyone, such as the arms or face. (About 60% of melanomas are found here.)
• Areas usually covered with clothing and visible only to the patients or their partners. (About 34% of melanomas are detected in these areas.)
• Hidden areas usually found by health professionals (scalp, buttock folds, oral cavity.) About 6% are found here, but they also most likely to be more advanced and dangerous. Partners are useful in checking these areas. (A hair dryer to separate hair is useful for examining examine the scalp.)

Experts suggest drawing a map of the body indicating locations of moles, areas of discoloration, lumps, or other blemishes. Whenever a person conducts a self-examination, the map is checked for new lesions, lumps, or moles and for changes in shape, color, and size.

Professional Examination for High-Risk Individuals

Some experts recommend regular full-body screening by a trained health professional in high-risk individuals, which include people with personal or family history of melanoma and individuals with atypical nevi (irregular moles that are also larger than normal).

Such people should protect themselves from overexposure to sunlight and have a medical examination of the entire skin surface every three to 12 months, with the frequency depending on risk factors. Doctors may take photographs of any moles at each visit and compare them with previous photos for any changes. A self-examination should be performed every two months.

Routine screening for everyone does not appear to save many additional lives. In any case, individuals who are worried about any suspicious areas should see a dermatologist or be sure their primary care doctor is able to recognize skin cancers.

Examinations for Patients Previously Treated for Melanoma. People who have had melanoma and been treated successfully are at risk for recurrence or a second primary melanoma. Based on recurrence rates by cancer stage, a team of researchers suggested the following guidelines for being reexamined by the doctor after treatment:

• Stage I patients: Annual examinations.
• Stage II patients: Every six months for years one and two and annually thereafter.
• Stage III patients: Every three months for the first year, every four months for year two, and every six months for years three to five.

All patients should be checked annually from the sixth year onward. These are guidelines only and may be modified, depending on individual patient characteristics. Some studies also indicate that regular screening of family members of people with melanoma could prevent a number of serious cases.

General Guidelines for Avoiding the Sun and UV Radiation

The best way to prevent skin damage in any case is to avoid episodes of excessive sun exposure. The following are some specific guidelines:

• Use sunscreens that block out both UVA and UVB radiation. However, do not rely on them only for sun protection. Also wear protective clothing and sunglasses.
• Avoid exposure particularly during the hours of 10 AM to 4 PM when sunlight pours down 80% of its daily UV dose.
• Avoid reflective surfaces, such as water, sand, concrete, and white-painted areas. (Clouds and haze are not protective and in some cases may intensify UVB rays.)
• Ultraviolet intensity depends on the angle of the sun, not heat or brightness. So the dangers are greater the closer to the summer-start date. For example, in the Northern Hemisphere, UV intensity in April (two months before summer starts) is equal to that in August (two months after summer begins).
• The higher the altitude the quicker one sunburns. (One study suggested, for example, that an average complexion burns at six minutes at 11,000 feet at noon compared to 25 minutes at sea level in a temperate climate.)
• Avoid sun lamp, and tanning beds or salons. They provide mostly high-output UVA rays. Some experts believe that 15 to 30 minutes at a tanning salon are as dangerous as a day spent in the sun. People should not be misled by advertising claims of "safe" tanning or promotions offering unlimited tanning.

Sunscreens. The use of sunscreens is complex and everyone should understand how and when to use them. The bottom line is not that people should avoid sunscreens or sunblocks, but that they should always use them in combination with other sun-protective measures.

Protective Clothing. Wearing sun-protective clothing is extremely important and protects even better than sunscreens. Special clothing is now available for blocking UV rays and is rated using SPF ratings or a system called the UPF (ultraviolet protection factor) index, with 50 UPF being the highest. (According to one study, this is a very reliable indicator of protection.) The clothing is expensive, however. The following are some tips for anyone:

• Everyone, including children, should wear hats with wide brims. (Even wearing a hat, however, may not be fully protective against skin cancers on the head and neck.)
• People should look for loosely fitted, unbleached, tightly woven fabrics. The tighter the weave the more protective the garment.
• Washing clothes over and over improves UPF by drawing fabrics together during shrinkage. An easy way to assess protection is simply to hold the garment up to a window or lamp and see how much light comes through. The less the better.
• Everyone over age one should wear sunglasses that block all UVA and UVB rays when in the sun.

Click the icon to see a depiction of sun protection.

Chemical Tanners

Some research suggests that melanin and dihydroxyacetone (DHA), the active ingredients in many self-tanning lotions, may help filter out UVA and UVB radiation and so be protective. More research is underway.

Role of Fats

One study indicated that people who reduced their intake of fat to 20% of their daily diet were significantly less likely than those on a high-fat diet to develop actinic keratosis, a common aging skin disorder that can also be a precursor to nonmelanoma skin cancer. Low-fat diets, however, appear to have no effect on basal cell carcinoma. In fact, some studies have suggested that certain fatty acids, such as those found in monounsaturated fats (e.g., olive and canola oils) or fish oils, may help protect the skin against sun-related diseases.

Antioxidants and other Natural Substances

Antioxidants are substances that act as scavengers of free radicals, mopping up unstable particles that, in excess, can damage the basic structure of cells, including their genetic material (DNA). Nevertheless, it is not yet known whether antioxidants can effectively protect against cancer, heart disease, premature aging, and other maladies. Among the most well-known antioxidants for the skin are vitamins C and E, and coenzyme Q10 (CoQ10).

Antioxidants are substances that act as scavengers of oxygen-free radicals, the unstable particles that can damage cells and which are implicated in sun damage and even skin cancers. Antioxidants in the skin are depleted when exposed to sunlight and must be replaced. The antioxidants studied for skin protection include vitamins A, C, E, selenium, coenzyme Q10 (CoQ10), and alpha-lipoic acid.

Click the icon to read about the antioxidant selenium.

Topical Antioxidants. Although there are wide claims about the benefits of antioxidants for wrinkles when used in skin creams, to date, only vitamins E and C and selenium applied topically have been proven to have any benefits for reducing sun damage in the skin. Even with these antioxidants, however most available brands contain very low concentrations of them. In addition, they are also not well absorbed and they have a short-term effect. New delivery techniques, however, may prove to offset some of these problems.

• Vitamin E. Studies suggest that topical vitamin E, particularly alpha tocopherol (a form of vitamin E) cream decreased skin roughness, length of facial lines, and wrinkle depth. Studies on mice have also reported reductions in UV-induced skin cancer with its use.
• Vitamin C, or ascorbic acid. This is a very potent antioxidant and most studies on the effects of antioxidants on the skin have used this vitamin. In laboratory studies, large amounts reduced skin swelling and protected immune factors from sunlight. It may even promote collagen production. Vitamin C by itself is unstable, but products that solve the delivery problem are now available (e.g., Cellex-C, Avon's Anew Formula C Treatment Capsules, and others).
• Selenium in the form of L-selenomethionine has protected against sun damage and even delayed skin cancer in animal studies. It is not known if such benefits apply to people.

Oral Antioxidants. One small study found that taking a combination of vitamins oral C and E supplements may help reduce sunburn reactions, although the protection is much less than from sunscreens. (Taking the vitamins singly does not appear to have the same effect.)

Other Natural Substances. The following natural substances have antioxidant properties and are being tried for sun-protection:

• Both green and black tea and ginger appear to have properties that may provide some protection against skin cancers and photoaging. A 2001 study using extracts of topical green tea suggested that it might protect against ultraviolet damage. More research is warranted. Green tea skin care products are now available, but their quality is unregulated.
• The substance silymarin, found in the milk thistle family (which includes artichokes), may inhibit UVB-promoted cancers in animals.
• In one interesting study, eating garlic protected animals very effectively against UVB damage by interfering with urocanic acid in the skin. Whether these results may be applied to humans, and what quantities of garlic might be beneficial, is still unknown.

Warning Note: A wide range of herbal products--both oral and topical--may contribute to dermatological problems. Some Chinese herbal creams have been found to contain corticosteroids, and some may contain mercury or arsenic contaminants have been reported in some Ayurvedic therapies. In addition, a number of oral herbal remedies used for medical or emotional conditions may produce irritation in reaction to sunlight (photosensitivity). The include but are not limited to St. John's Wort, kava, and yohimbe.

Experimental Agents

Ointments that Prevent Skin Cancers on a Molecular Level. Of interest are studies suggesting the compounds that target genetic mechanisms in the skin may prove to be beneficial ingredients in topical products (e.g., creams, lotions) that prevent skin cancers on a molecular level. They include the cytokine interleukin-12 and an enzyme called T4 endonuclease 5 (T4N5).

Specific Cholesterol-Lowering Drugs. Some interesting but preliminary reports suggest that specific cholesterol-lowering medications, including the popular drug lovastatin (Mevacor) and Apomine (a drug originally developed to treat high cholesterol) may have some benefits for preventing or even treating melanoma. Further research is needed, however, to determine if there is indeed a link between cholesterol and melanoma and if these and similar medications actually help prevent the disease.

Like most vitamins, vitamin D may be obtained in the recommended amount with a well-balanced diet, including some enriched or fortified foods. In addition, the body manufactures vitamin D when exposed to sunshine. It is recommended people get 10 to 15 minutes of sunshine, 3 times a week.

Diagnosis

An experienced doctor should first rule out benign conditions that resemble melanoma, such as a noncancerous mole called a melanocytic nevi. In rare instances, a melanoma will be difficult to detect. For example, an uncommon form of melanomas called a myxoid melanoma may be mistaken for a benign skin disorder known as a myxoid fibrohistiocytic lesion. Another opinion from a second pathologist, computerized image processing, or advanced staining techniques may help to confirm the diagnosis.

Some doctors now employ dermoscopy (also called dermatoscopy or epiluminescence microscopy), which uses a hand-held scope-like device that enhances the suspected lesion. It is still not clear if such devices are any better than the naked eye of a trained professional. Of interest, however, was a 2002 study suggesting that it was very useful in identifying possible melanomas in suspicious nail abnormalities and therefore avoiding many painful biopsies in this area. A 2004 study confirmed that adding dermoscopy to conventional naked-eye examination leads to fewer biopsies than using naked-eye examination alone.

A recently developed Australian device (the Solarscan) may improve detection. It is shaped like a hair dryer and takes an image of the suspicious lesion; it then reads the image and compares it with a databank of melanoma images to help determine if it is cancerous. It can also store the image of lesion and compare it for changes with later images taken at subsequent check ups.

Biopsy

Biopsy of the Melanoma. Melanoma is diagnosed by biopsy (excision) of suspicious lesions. With this procedure, the doctor will anesthetize the area around the lesion and, depending on size and site, remove all or part of it. The biopsy specimen will be sent to a lab for analysis, where a pathologist will take thin slices of the lesion and examine the cell structure under a microscope. If melanoma is found, it will be staged and its depth and probability of spreading will be assessed.

• Melanomas less than 4 mm thick suggest Stage I or II cancers, and the next step is to attempt to determine if they have spread or are likely to spread to the lymph nodes.
• Melanomas that are over 4 mm thick indicated later stages. In such cases, the lymph nodes are sometimes removed to attempt to prevent the cancer from spreading, although about 70% of these melanomas have already metastasized (spread).

Sentinel Lymph Node (SLN) Biopsy. When Stage I and II melanomas metastasize, they most often spread first to nearby lymph nodes. A procedure called sentinel lymph node (SLN) biopsy helps determine whether lymph nodes might be involved and how far it may have spread. SLN biopsy is now recommended for cancers that are thicker than 1 mm (millimeter) and generally unnecessary for those thinner than 0.75 mm (unless they are ulcerated). Although some evidence suggests this procedure may improve survival, no clinical trials have proven to date that this procedure improves the prognosis in melanoma.

Sentinel node biopsy is a technique which helps determine if a cancer has spread (metastisized), or is contained locally. When a cancer has been detected, often the next step is to find the lymph node closest to the tumor site and retrieve it for analysis. The concept of the "sentinel" node, or the first node to drain the area of the cancer, allows a more accurate staging of the cancer, and leaves unaffected nodes behind to continue the important job of draining fluids. The procedure involves the injection of a dye (sometimes mildly radioactive) to pinpoint the lymph node which is closest to the cancer site. Sentinel node biopsy is used to stage many kinds of cancer, including lung and skin (melanoma).

This procedure involves the following:

• A tiny amount of a tracer, either a radioactively labeled substance (radioisotope) or a blue dye, is injected into the tumor site.
• These substances then flow via the lymphatic system into the so-called sentinel node. This is the first lymph node to which any cancer would spread.
• The sentinel lymph node and possibly one or two others are then removed and biopsied.

The results of the biopsy can help doctors decide whether to remove other lymph nodes or not. The choices are not always clear cut, however:

• If the sentinel node and others shows signs of cancer then the nearby lymph nodes are removed.
• If they do not, particularly in Stage I, then it is highly likely that the remainder of the lymph nodes will be cancer free and further surgery becomes unnecessary.

Controversy exists over the best approach for patients with Stage II cancers when the sentinel node test has found no evidence of cancer. These melanomas are usually between 1 mm and 4 mm thick, and tumors at this stage carry a risk for sending microscopic cancer cells out into the lymph system unnoticed. However, new methods of examining sentinel lymph node biopsies are improving the ability to identify these cells, called micrometastases. Still, in such cases, removal of lymph nodes would probably have no impact on survival.

Biologic markers in blood tests may also prove to identify microscopic cancers if sentinel node biopsy results are uncertain.

Secondary Tests

If melanoma has been diagnosed, the doctor will perform others tests to see if the cancer has spread. They typically include the following:

• A chest x-ray.
• Blood tests that show high levels of lactate dehydrogenase suggest metastasis.
• Blood tests to assess liver function and other factors to help determine specific sites where the cancer may have spread.
• Advanced imaging techniques, such as computed tomography (CT) or positron emission tomography (PET), may also be used. PET is particularly accurate. One study reported that PET was able to diagnose melanoma that had spread even when other tests, including CT, did not. PET can also be very accurate for identifying recurrent melanomas.

Biologic Markers for Metastasis

Researchers are continually looking for other biologic factors, or markers, that would indicate whether the cancer had metastasized (even if sentinel node biopsies are negative). They also might suggest the severity of the cancer, which would help determine whether treatments should be more or less aggressive. A number of proteins and other factors detected in blood tests are showing promise as markers for microscopic metastasis. Examples include antibodies to MART-1, Melan-A, tyrosinase, and microphthalmia transcription factor (Mitf). Combinations of some of these factors may improve detection rates.

Risk Factors for Determining Prognosis

To reach a prognosis, other factors in addition to staging must be considered such as gender, age, and location of the melanoma. All cases are unique, however, and the presence of any of these factors should not discourage people from seeking all possible treatment options.

• Age. Patients older than 50 generally have the worst prognosis, perhaps because they tend to wait to see the doctor and thus have the thickest lesions.
• Gender. Although women and men fare equally well in the first two years after diagnosis, women appear to do a bit better after that time, particularly younger women. Prepubescent girls have a poorer prognosis than boys do (although it is very rare in children). This suggests, but does not prove, that estrogen may have some protective properties. The difference in gender may simply be due to women giving more attention to their skin.
• Melanoma Characteristics. Thick melanomas, those that are ulcerated (in which skin layers over the tumor appear indistinct on pathologic examination), and those that have invaded blood vessels tend to have a worse prognosis.
• Original Site. Patients with melanomas that arise within preexisting moles may fare better than those with new lesions. Some studies indicate that melanomas furthest away from the trunk, particularly the feet, were associated with poorer survival, but this may be because such areas are less likely to be observed and so such melanomas tend to be diagnosed at a late stage.
• Metastasis. Survival rates are worse if the cancer has spread, particularly to the gastrointestinal tract, liver, or lung. In any case, the more sites that the cancer has spread to, the poorer the prognosis.
• Regression. In some people, melanomas spontaneously stop growing for a time and may actually shrink in size, which is a favorable sign.

Treatment for Melanoma

Treatment depends on various factors, including the following:

• The site of the original lesion.
• The stage of the cancer.
• The patient's age and general health.

Treatment options include the following:

• Surgery is performed at every stage to remove the melanoma cancer cells.
• Melanoma that has spread to lymph nodes or additional nearby sites usually requires additional forms of treatment including chemotherapy, immunotherapy, and radiation therapy.
• Advanced melanoma that has spread to distant sites often cannot be cured, although surgical removal of metastatic tumors may provide some benefit by easing pain, increasing the general quality of life, and lengthening survival. Patients should seek to enter clinical trials, studies that examine new immunotherapies (vaccines, cytokines), gene therapies, chemotherapy combinations, or other treatments.

Surgery

Surgery is the primary treatment for all stages of melanoma.

Removal of the Melanoma. Some or all of the melanoma is often been removed during the biopsy. If cancerous tissue still remains after a diagnosis of melanoma, a surgeon will cut away additional tissue from the surrounding area to remove any stray cancer cells.

Mohs micrographic surgery was developed to allow meticulous surgical removal of skin tissue. This procedure involves the following:

• Very thin layers are removed one at time, with each layer examined immediately under a microscope.
• When the layers are shown to be cancer free, the surgery is complete.

Because the doctor needs to be certain that all cancer cells are removed, in some cases the surgical area required is very wide and requires plastic surgical techniques. The amount of tissue removed depends on the size, depth, and degree of invasion:

• Stage I lesions that are less than one millimeter deep require the smallest excisions, usually about one centimeter (2/5 inch) off each side and downward from the original lesion.
• For melanomas 2 mm or more in thickness, a margin of 3 cm is important for reducing the risk of recurrence.
• Thicker lesions require wider excisions.

It used to be customary to remove a large area, regardless of the stage of cancer. This potentially disfiguring approach has been abandoned because studies have shown that excising wider margins does not improve survival. Nevertheless, sometimes skin grafts may need to be taken from other body sites to help cover the wound.

Of note: recurrence rates are very high with lentigo maligna (LM) after conservative surgery. Although this is a very slowly progressive condition, LM can develop into melanoma. Most of these lesions appear on the face and neck, so extensive surgery can be disfiguring. Patients should discuss with their doctor carefully staged surgery to remove all diseased tissue with as little cosmetic harm as possible.

Lymph Node Removal. If there is evidence that melanoma has spread to nearby lymph nodes but has not spread beyond, removing them may improve local disease control and might even improve survival in selected patients, although this is an ongoing area of investigation. At this time, Australian guidelines recommend lymph node removal only for patients younger than 60 years of age with 1 to 4 mm thick primary melanomas on the trunk.

Surgery for Metastatic Melanoma. In some cases, surgical removal of distant tumors may be possible and prolong survival, since often in melanoma the cancer spreads first only to a single site, such as the lung or the brain.

Cryosurgery. Cryosurgery freezes skin tissue and destroys it. This procedure is not useful for most melanomas, but it might have some value in specific situations. For example, it may be effective for smaller melanomas in the eye, a location that is difficult to treat with traditional surgery. It may be useful to eliminate residual cancer cells after standard surgery for lentigo maligna melanomas, an atypical form of melanoma that has a wide surface and is difficult to treat.

Chemotherapy

Chemotherapy is often used to treat recurrent or metastatic melanomas. The drugs are not intended as a cure but can prolong life and improve its quality.

Drugs Used. The following are some of the agents used to treat melanoma. They may be used alone or in combination under specific situations.

• Methylating agents, which impair the ability of cancer cells to divide, include dacarbazine (DTIC), temozolomide (TMZ), and procarbazine. To date, dacarbazine is the only drug approved for melanoma.
  • Temozolomide, an oral drug, may be comparable and improve quality of life. Because it can cross the blood-brain barrier (unlike dacarbazine), temozolomide is showing promise in preventing metastasis to the brain. It may also have some benefits in treating cancers that have already spread to the brain.
  • In a 2004 study, patients had a significantly higher response rate to fotemustine than to DTIC. Compared to DTIC, fortemustine was also associated with a slightly greater survival and longer time before brain metastases developed.
• Nitrosoureas, which include carmustine (BCNU) and lomustine (CCNU) are often used.
• Taxanes, such as docetaxel (Taxotere) and paclitaxel (Taxol), are showing some low-level activity against melanoma. Docetaxel is being studied in combination with other drugs.

Many other drugs and combinations used to boost drug effectiveness or minimize toxicity are under study. They include, vincristine, vinblastine, cisplatin, and tamoxifen.

Side Effects. Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include the following:

• Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting.
• Diarrhea.
• Temporary hair loss.
• Weight loss.
• Fatigue.
• Anemia. Erythropoetin stimulates red blood cell production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). Aranesp persists longer in the blood than epoetin alfa and so requires fewer injections.
• Depression.

Serious short- and long-term complications can also occur and may vary depending on the specific agents used. They include the following:

• Increased chance for infection from suppression of the immune system.
• Severe drops in white blood cells (neutropenia). Certain agents, such as taxanes, pose a higher risk for this than other chemotherapeutic drugs. White blood cell count may be improved with the addition of a drug called granulocyte colony-stimulating factor (either filgrastim or lenograstim).
• Liver and kidney damage.
• Abnormal blood clotting (thrombocytopenia).
• Allergic reaction.
• Menstrual abnormalities and infertility in women. A natural hormone medication called a gonadotropin-releasing hormone analogue that puts women in a temporary pre-pubescent state during chemotherapy may preserve fertility in some women.
• Rarely, secondary cancers such as leukemia.
• Problems in concentration, motor function, and memory, which may be long-term.

Benefits of Chemotherapy. About 20% of cancers shrink in response to one or more of these drugs, but the effects last only between three and six months. If the tumors completely disappear, the cancer may stay in remission much longer, but in virtually all cases it returns.

Immunotherapy

Immunotherapy uses drugs to boost the patient's own immune system. This treatment was developed after experts observed that in some melanoma patients, the tumor temporarily stopped growing and shrank, apparently in response to a very effective natural immune response. This phenomenon is very rare, though it appears more often in melanoma than in other cancers. Adjuvant immunotherapy (used after surgery) is proving to be helpful in melanoma patients at high risk of recurrence.

Cytokines. Specific powerful immune factors called cytokines, particularly those known as interferons, are being used to develop therapies for metastatic melanoma. These agents are typically administered with chemotherapy agents, with other immunotherapies, or both. (If cytokines are prescribed as single-agent therapy they are ineffective at lower doses while at higher, effective doses they become very toxic.) The results of one 2002 report, for example, reported that adding interferons and interleukins to chemotherapy doubled the five-year survival for advanced melanoma, from 5 - 10%. Side effects are greater with this approach but they are manageable. A number of other cytokines and combinations are being investigated.

• A 2004 study showed that long-term, low-dose interferon alpha-2a was not beneficial to patients who had undergone surgery to remove high-risk malignant melanoma.
• Interferon alpha-2b (Intron) is a genetically engineered agent (called a recombinant drug). It is given by injection and is the only FDA approved immunotherapy for late stage melanoma. A 2004 randomized clinical trial showed that neither interferon alpha-2b nor interferon gamma was beneficial in patients with high-risk melanoma. However, future trials of different interferon alpha-2b schedules, doses, or combinations with other agents may demonstrate some advantages. The most common side effects are fatigue, depression, and flu-like symptoms, which can be severe. (Starting an antidepressant, such as paroxetine (Paxil), several weeks before interferon therapy may help prevent depression.) Some patients have reported eye problems in the retina.
• Different forms of interferons, such a long-acting formulation called pegylated interferon and natural human interferon are under investigation. In one 2002 study of patients with Stage IIB or III melanoma who were first treated with two rounds of dacarbazine chemotherapy, low-dose natural interferon led to five-year relapse-free survival in 42%, compared to only 17% in those who did not receive any adjuvant interferon immunotherapy.
• Interleukin-2 (Proleukin) is a hormone-like substance that stimulates the growth of cancer-fighting white blood cells. High-dose interleukin-2 has obtained regression of metastatic melanoma in 15 - 17% of patients. In addition, a 2004 study showed a 35% response rate in patients with metastatic melanoma, including a complete response in 12% of patients. The drug, which is injected, can have significant side effects, including very low blood pressure, heart rhythm abnormalities, severe infections, and shortness of breath, but they are manageable and nearly always reversible.
• Another injectable cytokine under study is granulocyte-macrophage colony stimulating factor (GM-CSF, Leukine, Sargramostim), which boosts production of immune cells in the blood and bone marrow. An inhaled form of the drug is also being tested for melanoma that has spread to the lungs.

There is some concern that these treatments may actually produce substances called reactive oxygen species (ROS), which in turn inactivate immune cells that fight cancer. Histamine (Maxamine) is a powerful inhibitor of ROS, and researchers are testing it in combination with interleukin-2 cytokine therapy. In one study, the added benefits of histamine were modest except in patients with liver metastatic; in these patients, survival improved by 129 days, which was significant.

T-Cell Therapy. Immunotherapy that uses T cells is showing promising results, especially for patients with advanced melanoma who have failed to respond to other treatments. T-cell therapy extracts white blood cells, (tumor-infiltrating lymphocytes, or TILs), from the patient. The TILs are treated with a drug that improves their tumor-fighting capabilities, and then injected back into the patient. Patients also receive chemotherapy to help increase the tumor-fighting cells. In a 2005 study of 35 patients with advanced melanoma, half of patients who received T-cell therapy showed substantial improvement.

Vaccine Immunotherapy. Vaccine immunotherapy uses melanoma-associated cells to serve as antigens (foreign proteins that antibodies in the immune system specifically seek out and attack). Part of the problem in developing a vaccine is that scientists are still unsure exactly which antigens are most likely to elicit an immune response that effectively kills cancer cells. Furthermore, antigens that are effective in one person may not be effective in another.

Many vaccines are now in advanced stages of development. Some are promising, but to date, none has yet emerged as an important weapon in treating advanced melanoma. In 2004, a long-term study of the bacillus Calmette-Guerin (BCG) vaccine reported the disappointing result that BCG provided no benefit in patients with stage I-III melanoma.

Some vaccines employ one or a few antigens (so-called monovalent vaccines); others consist of a "cocktail" of antigens (so-called polyvalent vaccines), which may be more likely to contain the right antigen targets.

Vaccines are often enhanced by substances or procedures called adjuvants (e.g., SAF-M, viruses, dendritic cells) to further boost effectiveness.

Most use one of two basic approaches, autologous and allogeneic, or a combination of the two (called a hybrid):

• Autologous vaccines are made from the patient's own cancer cells or parts of them. This produces a very specific immune response that can target the patient's cancer precisely. Some, such as Oncophage (HSPPC-96) and M-Vax, are showing promise in early trials and are undergoing additional testing. One problem with the autologous approach is that there is no way to scientifically assess outcome or even guarantee repeated success since each vaccine is unique to the individual patient. This approach is also appropriate only for select patients.
• Allogeneic vaccines purify and use antigens that may be derived from proteins from tumor cells, genetic material, or even bacteria. Such antigens are anchored on melanoma cells and stimulate an immune attack by powerful antibodies. A number of investigative vaccines (e.g., Melacine, Canvaxin) use multiple antigens (called allogeneic polyvalent vaccines) to reduce the risk for eventual tumor resistance to a single antigen. Studies are suggesting that the polyvalent vaccines may improve long-term survival rates in some patients. For example, Canvaxin achieved five year survival rates of 39% compared to 20% for unvaccinated patients. It is not yet clear if they are superior to high-dose interferon, but research continues.

Unlike chemotherapy, in which the drugs directly attack the tumor and shrinkage occurs quickly, the use of vaccines requires the body to build up its own defenses. It can take months before beneficial effects occur, but when they do, tumor reduction is much more lasting than with chemotherapy. Vaccines also seem to have fewer side effects than interleukin and interferon.

Antisense Compounds. Of interest is therapy that employs antisense compounds, which can prevent defective cancer genes from being translated into proteins that cause abnormal cell proliferation. Compounds are being investigated for use against mutations in bcl-xL and bcl-2 genes that block apoptosis, a natural process by which cells self-destruct and so do not become cancerous. A 2000 study using a combination of dacarbazine with oblimersen (G3139, Genasense), an antisense agent that turns off bcl-2 produced, achieved complete remission in one patient and partial responses in 43%. Late phase trials are in process.

Monoclonal Antibodies (MAb). Antibodies are natural substances produced by immune cells that home in and destroy cancer cells. Scientists are identifying specific antibodies that may attack melanoma cells and cloning them to create monoclonal antibodies. MAbs have shown promise for other cancers and are now being tested for melanoma, often in combination with vaccines and other forms of immunotherapy.

Other Experimental Therapies

Tetracyclines. Chemically modified tetracyclines, a common antibiotic, have been shown to modify metalloproteinase, an enzyme in the skin that promotes skin cancers, including melanoma.

Anti-Angiogenesis Agents. A number of trials are studying agents that block angiogenesis, which is the formation of new blood vessels. A tumor can fuel its own growth with angiogenesis. Thalidomide (Thalomid) is one of the most important anti-angiogenesis agents under investigation for melanoma. This agent had gained notoriety in the 1960s because of devastating birth defects in the children of women who took it during pregnancy. It not only has anti-angiogenic activity but also other anti-tumor effects when given concurrently with chemotherapy (e.g., temozolomide, dacarbazine). Several studies indicate that some cases of advanced melanoma may respond to thalidomide. A thalidomide derivative (Revimid) and Endostatin, another anti-angiogenesis drug, is also undergoing testing.

Curcumin. The yellow spice found in turmeric and curry powders may contain cancer-fighting properties. In a preliminary laboratory study, curcumin stopped the growth of melanoma cells. It is far too early, however, to recommend curcumin for clinical use

Radiation

In general, radiation is used to help relieve pain and discomfort caused by cancer that has spread or recurred. Radiation is not used as often for treating melanoma as it is for other forms of cancer because melanoma cells tend to be more resistant to its effects. It may be useful in some cases, however.

• In some patients with tumors less than 3 cm deep, however, radiation may help slow down metastasis when combined with a super-heating process using microwaves.
• Brachytherapy, in which radioactive seeds are implanted close to the tumor, has also been used with success for melanoma of the eye.
• Lentigo maligna may sometimes be treated successfully with specific radiation treatments called soft, or Grenz, x-rays.
• Radiotherapy using a so-called gamma knife (very focused gamma radiation) is also effective for cancer that has metastasized to the brain, in some cases halting the growth and, in rare situations, even eliminating it.

Treatment for Other Skin Cancers

Although any diagnosis of cancer is frightening, very few people die of nonmelanoma skin cancers. They are generally slow growing and very curable. A number of options are available for treating these skin problems, including surgery, cryosurgery, phototherapy, radiation, and topical 5-fluorouracil. Few comparison studies have been performed to see which procedures are most effective for these skin problems.

Surgery

For any skin cancer and for some keratoses that require removal, surgery is the first treatment. It is usually one of the following:

Excisional Surgery. This is the surgical removal of the cancerous lesion.

Curettage and Electrodessication. This procedure involves scraping away of the cancerous tissue followed by electric cauterization to stop the bleeding.

Mohs Micrographic Surgery. Mohs surgery is a meticulous procedure used for skin cancers at high risk for recurrence or becoming invasive. Studies indicate patients with the following skin cancers are among the good candidates for this procedure:

• Squamous cell carcinomas.
• Basal cell carcinomas greater than 1 cm (about half an inch).
• Basal cell carcinomas on the face, ear, or neck.
• Skin cancer that occurs in young people.

This procedure involves the following:

• Very thin layers are removed one at time, with each layer examined immediately under a microscope.
• When the layers are shown to be cancer free, the surgery is complete.
• Because the doctor needs to be certain that all cancer cells are removed, in some cases the surgical area required is very wide and requires plastic surgical techniques. Human skin substitute (Apligraf) is a living biological dressing that is being investigated. It is applied to the surgical area to achieve a better cosmetic effect.

Mohs surgery saves more healthy tissue than other procedures and is highly effective. It results in a 99% cure rate for primary tumors and a 95% cure rate for recurrent ones. It can be safely performed in the doctor's office. Complications are uncommon but can include bleeding and infection.

Lasers. Laser surgery may be useful for certain basal cells and for keratoses that appear on the lips, although it is not clear whether lasers offer any advantages over other surgical treatments. Lasers do not appear to be very effective for thick or tough squamous cell carcinomas.

Cryosurgery

Cryosurgery removes skin cancer cells or actinic keratoses by freezing the affected tissue with liquid nitrogen (a technique known as cryosurgery). Studies report the following:

• It can remove even wide areas of actinic keratoses and may be more effective over the long term than treatment with 5-fluorouracil, the standard drug. Cryosurgery also appears to reduce the risk for squamous cell carcinoma in these patients.
• A head-to-head comparison or a freezing technique with Mohs micrographic surgery in patients with basal cell carcinomas (BCCs) reported similar recurrence rates with each approach. Over 85% of the patients with the freezing technique were satisfied with the appearance of the area afterwards. Five-year recurrence rates were only 2.1%. (Mohs surgery is still the treatment of choice for high-risk BCCs.)

Cryotherapy achieves good cosmetic results for many patients. However, it may cause blistering and ulceration, leading to pain and infection, as well as harmless, but undesirable, skin-color changes.

Radiation

In unusual cases where the carcinoma may be in an inoperable position (such as the eyelid or the tip of the nose) or if cancer has recurred multiple times, radiation therapy may be indicated. Radiation is directed at the tumor. It may take one to four weeks with treatments performed several times a week. One technique being investigated for basal and squamous cell carcinoma uses radiation implants (brachytherapy) and custom-made molds to specifically target the radiation. Studies suggest that this treatment is very effective with few complications.

Topical Phototherapy and Aminolevulinic Acid (ALA)

Topical phototherapy with aminolevulinic acid (ALA) is a nonsurgical method that is proving to be a good choice for treating actinic keratoses and some nonmelanoma skin cancers (Bowen's disease and basal cell carcinoma). It employs blue light administered after that patient has taken aminolevulinic acid (Levulan, Karastik). ALA accumulates in the skin cells and when exposed to intense light, the chemical causes these cells to die. This approach allows precise targeting of one or more lesions, leaving healthy skin unaffected.

It does not penetrate deeper than the epidermis (the top layer of the skin), so it does not produce scarring or changes in skin color, as cryotherapy or other more invasive treatments do.

It can cause pain, irritation, including stinging, itching, and burning, but in one study only 3% of patients stopped using it for this reason. In a 2002 study, the procedure was more painful for patients with actinic keratoses than for those with nonmelanoma skin cancers. It was also painful when large areas were affected, and men experienced more pain than women.

ALA Phototherapy for Actinic Keratoses. Phototherapy is showing very good results for actinic keratoses. It works best on flat lesions performed in two treatments, and is more effective for clearing lesions on the face than those on the scalp. Phototherapy can also treat multiple lesions at the same time instead of sequentially, as in cryotherapy. Studies to date suggest that it may be as effective as cryotherapy and achieve better cosmetic results. (More patients report burning and itching with phototherapy, however.) Phototherapy is also equal to topical 5-fluorouracil in effectiveness and achieving a satisfactory appearance.

ALA Phototherapy for Nonmelanoma Skin Cancers. In patients with squamous cell carcinoma-in-situ (Bowen's disease) and basal cell carcinoma, phototherapy has been equal to cryotherapy, with superior healing and appearance afterward. A 2003 study reported that it was more effective than topical 5-FU for patients with Bowen's disease and there were fewer side effects.

Nevertheless, two 2001 studies reported that despite initial good results, about 10% of patients using phototherapy experienced a recurrence within one year. These recurrence rates are higher than with surgery and other standard treatments. Longer-term studies are required before ALA phototherapy can be recommended for most patients with nonmelanoma skin cancers.

Exfoliation

Chemical peeling, or exfoliation, is useful for solar keratoses on the face, especially in people with fair, dry skin. Alpha-hydroxy acids, for example, are being investigated for keratoses. Dermabrasion, which "sands" the skin, may also be effective although scarring is possible. A 2002 study found laser resurfacing to treat severe sun damage on the face; however, it may not prevent nonmelanoma skin cancers.

Medications

A number of medications are being used for keratoses and some may be helpful for skin cancers as well. Besides cryotherapy, 5-fluorouracil is the other most commonly used treatment for actinic keratoses. Other medications are also available.

Resources

• www.skincancer.org -- The Skin Cancer Foundation
• www.aad.org -- American Academy of Dermatology
• www.asds-net.org -- American Society for Dermatologic Surgery
• www.cancer.org -- American Cancer Society
• www.cancer.gov -- National Cancer Institute
• www.nccn.org -- National Comprehensive Cancer Network
• www.asco.org -- American Society for Clinical Oncology
• www.epa.gov/sunwise/uvindex.html -- UV index information
• www.mpip.org -- Melanoma Patients' Information Page
• www.oncolink.com -- University of Pennsylvania cancer site

References

Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-2357.

Gallagher RP, Spinelli JJ, Lee TK. Tanning beds, sunlamps, and risk of cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prev. 2005;14(3):562-566.

Siwak DR, Shishodia S, Aggarwal BB, Kurzrock R. Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer. 2005;104(4):879-890.

Veierod MB, Weiderpass E, Thorn M, et al. A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst. 2003;95(20):1530-1538.

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