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Melanoma and other skin cancers

Highlights

Overview

Risk Factors

New Drugs

Experimental Treatments

Risk Factors

Prevention

Introduction

Skin cancer is cancer that starts in the skin cells. Skin cancers are divided into two major groups:

Different skin cancers start in different cells of the skin. To understand how skin cancer develops, it is useful to understand the structure of the skin.

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

Skin layers
The skin is the largest organ of the body. The skin and its components (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 defense against ultraviolet light that can damage skin cells. The skin also helps control body temperature.

Melanocytes. A layer of cells between the epidermis and the dermis called melanocytes produces a brown-black skin pigment (melanin) that determines skin and hair color. Melanin also helps protect against the damaging rays of the sun.

As a person ages, melanocytes often multiply (proliferate). They form clusters that appear on the skin surface as small, dark, flat, or dome-shaped spots, which are usually harmless moles or “liver spots."

Melanin

Click the icon to view an image of melanin cells.

Melanoma

Melanoma accounts for less than 5% of all skin cancers, yet it results in most of the skin cancer deaths, according to the American Cancer Society (ACS). For the year 2013, the ACS estimates there will be about 76,690 new cases of melanoma in the U.S., and about 9,480 American deaths from the disease.

At first, melanoma cells are found in the epidermis and top layers of the dermis. However, once they grow downward into the dermis, the cancer can come into contact with lymph and blood vessels, and from there spread (metastasize) to other parts of the body. The thicker the melanoma, the greater the likelihood that it could spread to distant sites.

Removing the lesion before it reaches the deeper layers of the skin is important to achieve a cure.

Superficial Spreading Melanoma. Superficial spreading melanoma is the most common and most curable type of melanoma. It is flat, asymmetrical, unevenly colored, and usually grows outward across the surface of the skin. Superficial spreading melanoma accounts for about 70% of melanomas. In men, it occurs most often on the back. In women, it is most likely to be seen on the back of the leg.

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. Nodular melanoma accounts for about 5% of melanomas. It is usually seen on the trunk or limbs.

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 grow slowly for 5 - 15 years before cancer appears. Lentigo maligna melanoma accounts for 4 - 15% of melanoma cases.

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, or toes, under fingernails or toenails, or in mucus membranes.

Several other types of melanomas exist, but they are relatively uncommon.

Melanoma cells usually spread first through the lymph vessels or glands. Melanoma cells can also spread by way of blood vessels to various organs, carrying cancer to the liver, lungs, brain, or other sites.

Melanomas tend to grow in stages:

Have any suspicious lesion checked immediately, especially if it has grown quickly or is partially flat and partially raised.

Common sites of melanoma in men include:

Common sites of melanoma in women include:

However, melanoma can affect any area of the skin. You may not notice melanomas if they appear on areas that are difficult to examine, such as the scalp or back.

Less common sites for melanoma include:

A dark lesion under the nail that runs into the nearby skin and doesn't heal may be a sign of melanoma.

Rarely, melanomas appear in the mouth, iris of the eye, or retina at the back of the eye, where they may be found during dental or eye examinations. While quite rare, melanoma can also develop in the mucus membranes, such as the vagina, esophagus, anus, urogenital tract, and small intestines.

Melanoma

Click the icon to view an image of melanoma.

Nonmelanoma Skin Cancer

Other types of skin cancer are referred to as nonmelanoma skin cancers. The two most common types are called basal cell cancer and squamous cell cancer.

Basal cell cancer starts in the lowest part of the epidermis, in round cells called basal cells. Basal cell carcinoma is the most common form of skin cancer. However, this cancer is far less likely to be fatal than melanoma. The death rate from nonmelanoma skin cancers has dropped about 30% over the past 30 years.

Basal cell cancer usually develops later in life in areas that have received the most sun exposure, such as the head, neck, back, and especially the nose. However, some basal cell cancers appear in areas not exposed to the sun.

Basal cell cancers have many different appearances:

Basal cell cancer
Basal cell cancer is a cancerous (malignant) skin tumor involving 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 diagnose basal cell cancer. Treatment varies depending on the size, depth, and location of the cancer.

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

Usually, basal cells grow slowly. They are rarely deadly. Most basal cell cancers do not need to be treated as an emergency. However, because late treatment can cause disfigurement, they should be removed as early as possible.

Basal cell cancers that are most likely to spread include those that are larger than 1 centimeter, scar-like, and those located on the cheek, nose, neck, earlobe, eyelid, or temple.

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

Squamous cell cancer of the skin is even less common than basal cell cancers.

Squamous cell cancer develops from flat, scale-like skin cells called keratinocytes, which lie under the top layer of the epidermis. Most squamous cell cancers 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. Squamous cell cancers occur more often than basal cell cancers in African-Americans and Asians, and are more common in men than women.

Although squamous cell skin cancers usually can be removed completely with no risk of the cancer spreading, they are more likely, compared to basal cancers, to be invasive and to spread elsewhere in the body.

Types of squamous cell cancer:

Squamous cell cancer

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

Getting prompt treatment is important, because squamous cell cancers are more likely than basal cell cancers to spread to local lymph nodes.

Squamous cell cancers most likely to spread include:

People who have had basal cell or squamous cell skin cancers face a two-fold increase in their risk of developing other types of cancer including:

The younger people are when they get nonmelanoma skin cancer, the higher their risk for developing other cancers.

Precancerous Skin Conditions

Actinic (Solar) Keratosis. Actinic keratosis (also called solar keratosis) is a skin lesion caused by too much sun exposure. There is some increased risk of skin cancer in patients who have these lesions, but the risk of one specific actinic keratosis turning into cancer is low. The increased risk of cancers may be due to the fact that heavy sun exposure has been linked to both actinic keratosis and nonmelanoma skin cancers.

Actinic keratosis occurs after years of sun exposure. It appears mostly on sun-exposed skin, such as the face, neck, back of the hands and forearms, upper chest, and upper back. Men may develop keratosis along the rim of the ear.

Actinic keratosis have the following characteristics:

Keratoacanthomas. Keratoacanthomas closely resemble squamous cell cancers, but they are not cancerous. Most of these occur in sun-exposed skin, usually on the hands or face. They are typically skin colored or slightly red when they first develop, but their appearance typically changes:

Most will get better on their own within 1 year, but they almost always scar after healing. Also about 25% develop into squamous cell cancers, 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 or injections.

Causes

The sun is the most important cause of prematurely aging skin (photoaging) and skin cancers.

Long-term, repeated exposure to sunlight appears to be responsible for most undesirable consequences of aging skin, including basal cell and squamous cell cancers.

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 (UVA or UVB) radiation strikes the DNA inside the skin cells and damages it.

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 actions the skin uses to defend itself against DNA damage.

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. However, some gene defects or other factors can interfere with apoptosis. If this occurs, damaged cells can continue to spread, resulting in skin cancer.

Risk Factors

According to the American Cancer Society the lifetime risk of getting melanoma is about 2% (1 in 50) for whites, 0.1% (1 in 1,000) for blacks, and 0.5% (1 in 200) for Hispanics. The number of melanoma cases has been increasing over the past 30 years.

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

The following factors increase your risk for skin cancer:

Aging may weaken the body's ability to fend off cancers, including melanomas. As a person ages, they lose Langerhans cells that help fight off early skin cancers, possibly setting the stage for skin cancers in later life.

Melanoma in Adults. Melanoma is most common in people over 40, although it also can affect young and middle-aged people. The average age at diagnosis is 57 years. Men are more likely to have invasive and fatal melanoma than women, although some research suggests that the higher rates are only because men fail to get suspicious skin changes diagnosed before they become dangerous. The rate in women levels off somewhat after age 50; researchers think menopause could have some sort of protective effect.

Melanoma in Children. Melanoma is rare in children under age 10. Among children ages 10 - 14 the incidence is only 0.3 per 100,000 children. Between ages 14 - 19, it is still very rare, with only 1.3 cases per 100,000 children. Parents should not be too alarmed by every minor skin imperfection in their children. However, melanoma is as serious in children as it is in adults, and early detection is still critical. It is also noteworthy that the incidence of melanoma in children and adolescents has been steadily increasing, by about 2% per year. 

Nonmelanoma skin cancers are rare in children and young adults, but they begin to increase significantly in middle age and older.

Skin cancer is associated with both the length and intensity of sun exposure. The risk of melanoma increases with excessive sun exposure during the first 10 - 18 years of life. Sunburns are also dangerous; having five or more sunburns doubles the risk of developing skin cancer. The cancer typically arises many years later.

Tanning Devices. Tanning beds and sun lamps increase the risk for developing melanoma, and the risk increases with frequency and length of use. Women in their 20s, as well as blondes and redheads, are especially at risk.

Phototherapy and Photochemotherapy with PUVA. There is some evidence that long-term treatment for psoriasis and other skin conditions using UVA radiation (PUVA) may increase the risk for melanoma.

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 for developing all types of skin cancers. The risk increases for those who easily sunburn and rarely tan, particularly if they live close to the equator where sunlight is most intense. However, people with darker complexions are not immune.

A classification system has been created for skin phototypes (SPTs) based on the sensitivity to sunlight. It ranges from SPT I (lightest skin plus other factors) to IV (darkest skin). 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.

Skin Type

Tanning and Burning Risk

I

Always burns, never tans, sensitive to sun exposure.

II

Burns easily, tans minimally.

III

Burns moderately, tans gradually to light brown.

IV

Burns minimally, always tans well to moderately brown.

V

Rarely burns, tans profusely to dark.

VI

Never burns, deeply pigmented, least sensitive.

Geography plays a role in skin cancer risk, primarily with regard to the intensity and length of sun exposure in certain locations. Studies show an increased incidence of melanomas in populations that previously had a lower incidence, but then migrated to Australia.

People with certain genetic characteristics, such as blue or green eyes, or blonde or red hair, have an increased risk of skin cancers.

Patients diagnosed with melanoma, and who have a family history of melanoma or nevi, are considered to be at increased risk for more invasive cancers. A number of genetic factors are being investigated for their role in melanomas, including inherited genes and genetic defects that are acquired through the environment (particularly sunlight).

Your genetic makeup, and whether or not certain genes mutate in your body can increase your risk of developing melanoma and other skin cancers.

A genetic mutation in a gene called BRAF occurs in approximately 50% of patients with advanced melanoma.

Melanoma. Individuals who have been diagnosed with melanoma are at increased risk for a second primary melanoma. That risk may be as high as 5%, and is higher in older men and in those whose first melanoma was on the upper body and face.

People with family members who have or had melanoma have approximately a twofold risk of developing melanoma as those without a family history, and should be examined on a regular basis.

Nonmelanoma Skin Cancers. The evidence for an increased risk of nonmelanoma skin cancers with a family history of such cancers is increasing, but it is still weaker than the evidence for a familial connection to the risk of melanoma.

Moles (Nevi) and Other Dark Blemishes. Certain moles and dark blemishes increase the risk for skin cancer. Any mole (nevus) or other blemish that seems new, changing, or unusual in any way should be evaluated by a health care professional as an existing mole can become cancerous. Although 80% of melanoma cases develop from brand new lesions or moles, your risk of developing the condition increases if you have the tendency to develop moles.

Some specific moles or dark blemishes that are risk factors for melanoma include:

The more moles a person has, the higher the risk that one of those moles will become cancerous, although the danger is still very small. The risk is higher, however, with atypical moles.

Some skin blemishes can look like -- but are not -- melanoma. Noncancerous moles typically have the following characteristics:

Examples of moles or blemishes that may resemble skin cancer include:

Blue nevus. 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.

Liver Spots. Liver spots are usually evenly brown or tan spots caused by the sun. They are universal signs of aging. Occurring most noticeably on the hands and face, these harmless blemishes tend to enlarge and darken over time.

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 on the cheeks. It is not harmful, but it may be difficult to tell apart from a melanoma, even for experts.

Non-Hodgkin's Lymphoma. Survivors of either non-Hodgkin's lymphoma or melanoma face a higher risk for the other cancer. These diseases may have common causes, such as exposure to UV radiation or shared genetic factors.

Human papillomavirus (HPV). Genital warts (caused by human papillomavirus, or HPV) may also increase the risk of squamous cell cancer in the genital and anal areas and around fingernails.

Endometriosis. The condition in which cells that line the uterus also grow in other parts of the abdomen may be linked to a higher risk of melanoma. In one large study, women with a history of endometriosis had a 60% increased risk of developing melanoma. Those with uterine fibroids (benign tumors in the uterus) were also at increased risk.

Skin cancer risk is increased in people whose immune systems are suppressed because of certain medications, organ transplantation, or medical conditions such as AIDS. Melanoma has also developed in patients who received solid organ transplants from donors who had the disease.

Immune-suppressing drugs used to treat autoimmune disorders may also increase the risk of skin cancer. For example, patients who take TNF-alpha blockers to treat rheumatoid arthritis and other autoimmune diseases carry an increased risk for both melanoma and nonmelanoma skin cancers. Potential skin cancer risks have been associated with the eczema drugs pimecrolimus (Elidel) and tacrolimus (Protopic) in a small number of people. It is not known for sure whether these drugs, when used topically on the skin, actually cause cancer.

Occupational exposure to radiation and some chemicals (vinyl chloride, polychlorinated biphenyls, and petrochemicals) in health care or industrial settings may increase the risk for melanoma. However, the evidence for this increased risk is not very strong. Airline pilots have been found to have an 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.

Prevention

The best way to lower your risk of skin cancer is to protect your skin from the sun and UV light. That means avoiding excess sun exposure, especially in midday when the sun is strongest.

Wear sunscreen. The use of sunscreens is complex, and everyone should understand how and when to use them. Follow instructions closely and reapply as directed after swimming or sweating. 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.

Many parents are now taking effective steps to protect their children, although experts worry that they are relying too much on sunscreen and less on other protective measures.

The following are some specific guidelines for avoiding excessive sun exposure:

Wear protective clothing, sunglasses, and a hat to shield your face from the sun's rays. Special clothing can block out UV rays. This clothing is rated using sun protection factor (SPF) or a system called the ultraviolet protection factor (UPF) index, with 50 UPF being the highest. (According to one study, this is a very reliable indicator of protection.) The clothing is expensive, however.

Sun protection

Click the icon to view an image about sun protection.

When choosing a sunscreen, look at the ingredients. Preparations that help block UV radiation are sometimes classified as sunscreens or sunblocks, according to the substances they contain. In general, sunscreens contain organic formulas and sunblocks inorganic formulas. However, the term sunblock is used less and less as sunscreens increasingly contain both kinds of ingredients:

Inexpensive products with the same ingredients work as well as expensive ones.

Under new FDA guidelines proposed in 2011, sunscreen products will carry a 4-star rating for UVA protection levels (1 star being the weakest protection, no stars meaning no UVA protection). In addition, sunscreens will carry the normal SPF rating, but it will be specific to UVB protection. The new sunscreen labels will also stress the importance of protective clothing for complete sun protection.

The safety and effectiveness of combination sunscreen and insect repellant products remain unclear. While sunscreen should be re-applied frequently, insect repellant applied too often could be toxic.

Organic formulas and inorganic microfine oxides do not protect against visible light, which is a problem for people who have light-sensitive skin conditions, including actinic prurigo, porphyria, and chronic actinic dermatitis.

Calculating SPF. SPF is a ratio based on the amount of UVB radiation needed to turn sunscreen- or sunblock-treated skin red compared to non-treated skin. For instance, people who sunburn in 5 minutes and who want to stay in the sun for 150 minutes might use an SPF 30 sunscreen. The formula would be: 30 (the SPF number) times 5 (minutes to burn) = 150 minutes in the sun.

Protection offered by sunscreens may be classified as follows:

Under the new FDA guidelines proposed in 2011, the maximum UVB protection factor would be raised from SPF 30 to 50.

SPF Levels by Age Group. Although sunscreens are safe in most toddlers and children, they should not be the first and only lines of defense. All young children should be well-covered with clothing, sunglasses, and hats. Keep children out of the sun during peak sunlight periods. Do not use sunscreens on babies younger than 6 months without consulting a doctor.

Older children and adults (even those with darker skin) benefit from using SPFs of 15 and over. Some experts recommend that most people should use SPF 30 or higher on the face and 15 or higher on the body. Adults who burn easily instead of tanning and anyone with risk factors for skin cancer should use SPF 30 or higher.

Timing and Amount of Application. Apply sunscreen or sunblock liberally as follows:

Possible Hazards of Relying on Sunscreens. When used generously and appropriately, sunscreen products and sun avoidance help reduce the severity of many aging skin disorders, including squamous cell cancers. There are certain concerns, however. Sunscreens do not appear to protect against melanoma and some basal cell cancers. It is also important to remember that even with the use of sunscreens, people should not stay out too long during peak sunlight hours. Even if a person doesn't sunburn, UVA rays can still penetrate the skin and do harm. In addition, some people use too little sunscreen, therefore unknowingly increasing their risk of aging skin disorders.

Chemoprevention is the use of a substance to prevent or reduce your risk of cancer. Certain drugs have been used to help block the development of skin cancers, including melanoma. These include a medicine called imiquimod, which is approved to prevent skin cancer in certain people. This medicine prompts the immune system to fight off foreign substances, including cancer cells.

Chemopreventive drugs under investigation that show promise for skin cancer include:

Antioxidants are chemicals or drugs that help prevent cell damage from unstable molecules called free radicals. Antioxidants promoted to protect the skin include vitamins C and E, and coenzyme Q10 (CoQ10).

Selenium - antioxidant

Click the icon to view an image about the antioxidant selenium.

There are wide claims about the benefits of antioxidants for wrinkles when used in skin creams. To date, only skin products containing selenium and vitamins E and C have been shown to help reduce sun damage to the skin. However, most available brands contain very low concentrations of these antioxidants. In addition, antioxidants are not well absorbed by the skin, so the effect may be short-term. There is also no evidence that they prevent skin cancer.

Warning: A wide range of herbal products may contribute to skin problems. Some Chinese herbal creams have been found to contain corticosteroids. Mercury or arsenic contaminants have been found in some Ayurvedic therapies. In addition, several oral herbal remedies used for medical or emotional conditions may produce photosensitivity (irritation in reaction to sunlight). They include, but are not limited to, St. John's wort, kava, and yohimbe.

Screening

Education and prevention programs have led to improved screening for skin cancer, which in turn has improved diagnosis and survival rates for melanoma.

Skin cancers may have many different appearances. They can be small, shiny, or waxy, scaly and rough, firm and red, crusty or bleeding, or have other features. Itching, tenderness, scaling, bleeding, crusting, or sores can signal potentially cancerous changes in any mole.

There are a number of factors to look for, which can serve as a general guide. They fall under the skin cancer ABCDE rule:

Keep in mind that the most important warning sign of melanoma is a new or changing skin lesion, regardless of its size or color. Changes that occur over a short period of time (particularly over a few weeks) are most concerning.

Anyone with risk factors for skin cancer should check their entire body about once a month. People who regularly check moles on their skin may have a lower risk of developing advanced melanoma.

It helps to draw a map of the body, indicating locations of moles, areas of discoloration, lumps, or other blemishes. Whenever you do a self-examination, compare your body to the map to check for new lesions, lumps, or moles and for changes in shape, color, and size.

There are three specific body areas to look for skin cancers, including melanomas:

Ask a partner to help you check these areas. Turn on a hair dryer to separate your hair and examine the scalp.

Everyone, but especially those with a high risk of developing melanoma, may benefit from a whole body skin exam performed by a dermatologist. People in the high-risk group include those with a personal or family history of melanoma, and individuals with atypical nevi (irregular moles that are larger than normal).

Such people should protect themselves from overexposure to sunlight and have a medical examination of the entire skin surface every 3 - 12 months (the frequency depends on your risk factors). The doctor may take photographs of specific moles, or your entire body, at each visit and compare them with previous photos to look for any changes.

Examinations for Patients Previously Treated for Melanoma. People who have had melanoma and have been treated successfully are at risk for the cancer returning (recurrence) or for developing another primary melanoma. Based on recurrence rates by cancer stage, doctors suggest the following guidelines for being reexamined by a doctor after treatment:

All patients should be checked annually after year 5. These are guidelines only and may depend on the individual patient.

Diagnosis

An experienced doctor should first rule out noncancerous (benign) conditions that resemble melanoma, such as a mole called a melanocytic nevus.

In rare instances, a melanoma will be difficult to detect. For example, an uncommon form called a myxoid melanoma may be mistaken for a benign skin disorder known as a myxoid fibrohistiocytic lesion. Additional diagnostic procedures such as a biopsy (see below), computerized image processing, or advanced staining techniques may help to confirm or rule out the diagnosis of melanoma.

Melanoma also tends to be diagnosed at a later stage in people with darker skin.

A combination of imaging approaches should be considered for early melanoma detection and diagnosis, since each technique alone has limitations. Some doctors now use various handheld scope-like devices (dermoscopy, dermatoscopy, or epiluminescence microscopy) that enhance the visualization of the suspected lesion.

A skin biopsy is the removal of skin tissue for examination under a microscope. The exact type of biopsy depends on how deep the lesion has penetrated the skin.

All of the above-mentioned biopsies can be done using local anesthesia.

A lymph node biopsy may be needed for patients with recently diagnosed melanoma, to help determine whether the cancer has spread to one or more lymph nodes.

A procedure called sentinel lymph node (SLN) biopsy is now recommended for cancers that are thicker than 1 millimeter. It is usually not necessary for cancers thinner than 0.75 millimeter, unless they have opened (ulcerated). Although some evidence suggests an SLN biopsy may improve survival, no clinical trials to date have proven that it improves the outlook in people with thin melanoma.

Sentinel node biopsy
Sentinel node biopsy is a technique that helps determine if a cancer has spread. 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 that is closest to the cancer site. Sentinel node biopsy is used to stage many kinds of cancer, including melanoma.

An SLN biopsy involves the following:

The results of the biopsy can help doctors decide whether or not to remove other lymph nodes:

Patients with nom-melanoma skin cancers generally require no further workup.

Those with melanoma may need the following:

Staging

Staging is the process used to determine the size of the tumor and where and how far it has spread (metastasized). Staging helps the health care team plan for appropriate treatment.

A number of factors may be used to identify melanoma that is likely to spread and may be hard to treat, including:

Health professionals have come up with various methods for staging cancer. This report uses the TNM staging system recommended by the American Joint Committee on Cancer.

The melanoma is considered ulcerated if skin layers over the tumor appear indistinct under the microscope.

In general, the thicker the lesion and the farther the cancer has spread, the higher the stage. Survival rates decrease with increasing stage.

Specific stages are as follows:

Stage I. Cure rates are excellent with surgical removal, since they are least likely to have spread.

Stage II. Melanomas can be cured, but the success rate lags behind that of Stage I because a small number of undetected cancer cells may have spread to distant sites. In addition to surgery, other forms of therapy may be recommended.

Stage III. Survival rate is lower than earlier stages.

Stage IV. Stage IV tumors have spread under the skin or to distant organs, including distant parts of the skin. Survival rates are very low.

Treatment for Melanoma

Treatment for melanoma depends on various factors, including:

Treatment options include:

Surgery is the primary treatment for all stages of melanoma. Some or all of the melanoma is often removed during the first biopsy. If cancerous tissue still remains after such a biopsy, a surgeon will cut away additional tissue from the surrounding area to remove any stray cancer cells.

Surgical management of melanoma that develops in rare sites, such as the vagina, cervix and ovaries, is becoming less aggressive. Studies have shown that wide local removal is equal to radical surgery in many of these cases. Melanoma of the urethra, bladder, and ureter usually requires extensive surgery, however.

Mohs micrographic surgery is a technique used to remove very thin layers of skin, one at a time. Each layer is examined immediately under a microscope. When the layers are shown to be cancer-free, the surgery is complete.

The amount of tissue removed depends on the size, depth, and degree of invasion:

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

Lymph Node Removal. If there is evidence that melanoma has spread to nearby lymph nodes but has not spread beyond them, removing those lymph nodes may reduce the chance of recurrence and help patients live longer.

Surgery for Metastatic Melanoma. In some cases, surgical removal of distant tumors may be possible. This may extend 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 cancer cells that remain after standard surgery for lentigo maligna melanomas, an unusual form of melanoma that has a wide surface and is difficult to treat.

Recurrence rates are very high with lentigo maligna after conservative surgery. Although this cancer grows very slowly, lentigo maligna can develop into melanoma. Most of these lesions appear on the face and neck, so extensive surgery can be disfiguring. Patients should carefully discuss with their doctor having surgery to remove all diseased tissue while causing as little cosmetic harm as possible.

Chemotherapy is often used to treat melanomas that return or spread. This type of therapy is not intended as a cure, but it can prolong life and improve its quality. Chemotherapy tends to work better than radiotherapy for advanced stage cancers and tumors.

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

Researchers continue to investigate other chemotherapy drugs and combinations of drugs to see which ones work best.

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

Common side effects include the following:

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

Treating Side Effects

Drugs known as serotonin antagonists, especially ondansetron (Zofran) can relieve nausea and vomiting in nearly all patients given moderate drugs, and in most patients who take more powerful drugs.

Benefits of Chemotherapy. About 20% of cancers shrink in response to one or more of these drugs, but the effects last only 3 - 6 months. If the tumors completely disappear, the cancer may stay in remission much longer, but in virtually all cases it returns.

Chemotherapeutic regional perfusion (also called isolated limb perfusion) is a technique used to give a person very high-dose chemotherapy. It is often used effectively for melanoma that returns or spreads and that occurs on the arm or leg. It does not appear to be useful for preventing cancer spread after a first occurrence of melanoma in one of these locations.

This technique involves the following:

In addition to its use in the arms and legs, perfusion techniques have also been tested for the pelvis, head, neck, skin of the breast, and even the abdomen.

Immunotherapy uses drugs to boost the patient's own immune system. Immunotherapy after surgery may help prevent recurrence in certain people with melanoma. These medicines are usually given along with chemotherapy, other immunotherapies, or both.

Immunotherapy drugs being used include:

Vaccine Immunotherapy. Vaccine immunotherapy is the use of a specific vaccine to treat an existing cancer. In this case, the vaccine targets one or more proteins that are produced by melanoma cells.

Vaccine immunotherapy requires the body to build up its own defenses. It can take months before benefits occur, but when they do, tumor reduction is more lasting than with chemotherapy. Vaccines also seem to have fewer side effects than interleukin and interferon.

Many therapeutic melanoma vaccines are in the advanced stages of testing, but none is approved for use in the United States at this time. A combination of an experimental melanoma vaccine and interleukin-2 has shown very promising results compared to interleukin-2 alone in late phase testing of patients with advanced stage III or stage IV melanoma. Patients receiving the combination treatment lived longer and their tumors stopped growing for longer periods compared to patients receiving only interleukin-2. The vaccine is only suitable for people with a particular class of immune proteins known as HLA*A0201.

Monoclonal antibodies. A recent development in the fight against melanoma is the use of the new monoclonal antibody ipilimumab (Yervoy). This antibody allows the immune cells to attack tumors more effectively by blocking a regulator gene of the immune system. In March 2011, it was approved by the FDA for use in adult patients with late stage, inoperable melanoma. This drug, however, carries with it the risk of potentially fatal side effects that include intestinal inflammation (colitis) and inflammation of the liver (hepatitis).

An experimental promising monoclonal antibody treatment is called anti-PD1, or anti-PD1L.

Vemurafenib (Zelboraf) is an inhibitor of the mutated BRAF protein, which is found in approximately 50% of metastatic melanoma cases. Vemurafenib is approved by the FDA for treating metastatic or inoperable melanoma in patients with the BRAF mutation, and has proven superior to chemotherapy. A newer agent, dabrafenib, seems equally effective but with fewer skin side effects.

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 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 the following cases:

The goal of palliative therapy is to improve the patient's quality of life and relieve symptoms. It is not a cure. Advanced melanoma that has spread to distant sites often cannot be cured, although surgery to remove tumors that have spread may provide some benefit by easing pain, increasing the general quality of life, and lengthening survival.

Patients should ask their doctors about clinical trials, studies that examine new immunotherapies (vaccines, cytokines), gene therapies, chemotherapy combinations, or other treatments.

Treatment for Nonmelanoma Skin Cancer

Many options are available for treating nonmelanoma skin cancer, including:

Most basal and squamous cell cancers are treated with surgery or radiation. Research has found that surgery has the best results, but because it can have cosmetic effects, many patients opt for radiation.

The first step in nonmelanoma skin cancers is to determine the risk of aggressive types of these tumors. Basal cell tumors are considered high-risk.

Squamous cell cancers of the skin are considered to be high-risk if any of the following are present:

For any skin cancer and for some keratoses that need to be removed, surgery is the first treatment. One of the following surgeries is usually used:

Excisional Surgery. Cutting out the tumor and then assessing the tumor borders (margins).

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

Mohs Micrographic Surgery. Mohs surgery is a procedure used for skin cancers at high risk for returning or becoming invasive. The technique removes very thin layers of skin one at a time. Each layer is examined immediately under a microscope. When the layers are shown to be cancer-free, the surgery is complete.

Good candidates for Mohs surgery include:

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 cancers that return. 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 cancers.

Cryosurgery removes skin cancer cells or actinic keratoses by freezing the affected tissue with liquid nitrogen. Studies have shown that cryosurgery can be used to remove even wide areas of actinic keratoses, and that it may be more successful over the long term than treatment with 5-fluorouracil, the standard drug. Cryosurgery also appears to reduce the risk for squamous cell cancer in these patients.

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.

The disadvantage of cryosurgery is that no tissue is taken to examine under a microscope to show that the cancer was completely removed.

In unusual cases where the skin cancer may be in an inoperable position (such as the eyelid or the tip of the nose) or if cancer has come back multiple times, radiation therapy may be indicated. Radiation therapy is more often used in the elderly.

Radiation is directed at the tumor. It may take 1 - 4 weeks, with treatments done several times a week. One technique being investigated for basal and squamous cell cancer uses radiation implants (brachytherapy) and custom-made molds to specifically target the radiation to the cancer site. Studies suggest that this treatment is very effective with few complications.

Topical phototherapy with the drug aminolevulinic acid (ALA) is a nonsurgical method that is proving to be a good choice for treating actinic keratoses and nonmelanoma skin cancers. The technique involves shining blue light onto the cancer area after the patient has taken ALA. ALA accumulates in the skin cells. When the cells are exposed to intense light, the chemical causes them to die. This approach allows precise targeting of one or more lesions, leaving healthy skin unaffected.

Topical phototherapy with ALA 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. However, it can cause pain and irritation, including stinging, itching, and burning.

ALA Phototherapy for Actinic Keratoses. Phototherapy works best on flat lesions when it is 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 one after another, as in cryotherapy. Studies suggest that it may work as well 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 cancer in situ, Bowen disease, and superficial basal cell cancer, phototherapy has been equal to cryotherapy, with better healing and appearance afterward.

Some studies have shown that about 10% of patients using phototherapy have a recurrence within 1 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.

Several 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.

MedicationSkin Conditions AffectedOral or TopicalComments

5-Fluorouracil

Actinic keratoses,

Bowen's disease and small nonmelanoma skin cancers.

Topical cream (Efudex, Fluoroplex) or injected gel containing 5-FU and epinephrine (AccuSite).

5-Fluorouracil (5-FU) removes actinic keratoses and is useful for some patients with a large number of lesions. It requires twice daily application for 3 - 4 weeks. It can cause significant redness, irritation, swelling, and crusting, which takes 2 - 4 weeks to heal. Newer preparations are reducing these side effects. It is still unclear whether this medication protects against recurrent keratoses or future skin cancer. Of concern is the possibility that 5-FU will clear the top of a skin cancer and obscure the rest of the cancer that lies beneath the surface of the skin.

Diclofenac and hyaluronan (Solaraze)

Actinic keratoses (approved). Investigated for basal cell.

Topical gel applied twice a day.

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID). When used to treat actinic keratoses, it is delivered to the skin with hyaluronan, a water-seeking molecule that helps maintain skin tension. It has modest effects and when healing occurs, it may not be evident for at least a month after treatment ends. However, it causes less irritation than 5-FU and may be useful for some people. Sun avoidance is necessary during treatment.

Imiquimod (Aldara)

FDA approved for the treatment of superficial basal cell cancer and actinic keratoses. Investigated for Bowen's disease and squamous cell cancer.

Imiquimod is a topical cream. Frequency and duration of application continues to be studied.

Applied 2 times per week for 16 weeks for AK.

Imiquimod triggers the production of immune factors that help fight cell proliferation. It should be used only when surgery for basal cell cancer is inappropriate.

Alpha-Interferons

Basal cell cancer

Require injections administered three times a week.

Interferons are immune factors that are being used to treat a number of serious conditions. Alpha-interferon injections may be effective against skin cancers that are hard to treat using conventional surgical measures. Cosmetic results are reported by 83% of patients to be good or very good.

Prognosis

Virtually all basal and squamous type skin cancers can be cured if treated early. These cancers are more likely to recur if they develop on the head and neck area, or if they are thicker. Most of the time, the recurrence will be local (at the same location as the original tumor).

The outlook for melanoma depends on when it is diagnosed and where it forms on the body.

Certain factors indicate melanoma is more likely to have spread or return after treatment:

In general, after patients are treated for melanoma, the longer they go without the cancer returning after treatment, the better their chance of remaining disease-free. However, relapses are not uncommon in those whose first melanoma was larger.

Anyone who has recovered from melanoma should carefully follow preventive guidelines and remain vigilant for suspicious lesions, because the risk for developing a new melanoma is increased even if the first one was successfully cured. Such relapses may occur even years after the original diagnosis.

Resources

References

American Cancer Society. Skin Cancer Facts. Available online. Last accessed September 8, 2013.

Balch CM, Gershenwald JE, Soong S-j, et al. Final Version of 2009 AJCC Melanoma Staging and Classification. J Clin Oncol. 2009;27:6199-6206

Brantsch KD, Meisner C, Schonfisch B, Trilling B, Wehner-Caroli J, Rocken M, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: a prospective study. The Lancet Oncology. 2008;9:713-720.

Bristol-Myers Squibb. Yervoy web site. Available online. Last accessed September 8, 2013.

Chapman PB. Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAFV600E-mutated melanoma. J Clin Oncol. 2012;30(suppl; abstr 8502^)

Eggermont AM, Suciu S, Santinami M, et al: EORTC Melanoma Group. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final result of EORTC 18991, a randomised phase III trial. Lancet. 2008;372(9633):117-26.

Flaherty KT, Robert C, Hersey P, et al. Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. New England Journal of Medicine. 2012;367:107-114.

Fayter D, Corbett M, Heirs M, Fox D, Eastwood A. A systematic review of photodynamic therapy in the treatment of pre-cancerous skin conditions, Barrett's oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin. Health Technol Assess. 2010;14(37):1-288.

Garcia C, Polette E, Crowson AN. Basosquamous carcinoma. J Am Dermatol. 2009;60(1):137-43.

Genentech USA, Inc. Zelboraf Prescribing Information. Available online. Last accessed September 8, 2013.

Gershenwald JE, Ross MI. Sentinel-lymph-node biopsy for cutaneous melanoma. NEngl J Med. 2011;364(18):1738-1745.

Goodson AG, Grossman D. Strategies for early melanoma detection: Approaches to the patient with nevi. J Am Acad Dermatol. 2009;60(5):719-35: quiz 736-8. Review.

Guadagnolo BA, Zagars GK. Adjuvant radiation therapy for high-risk notal metastases from cutaneous melanoma. Lancet Oncol. 2009;10(4):409-16.

Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med.
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Hauschild A, Grob J-J, Demidov L. et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet. 2012; 380(9839): 358 - 365.

Hodi FS, McDermott DF. Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Eng J Med. ePub June 5, 2010. Available online.

Kirby JS, Miller CJ. Intralesional chemotherapy for nonmelanoma skin cancer: a practical review. J Am Acad Dermatol. 2010;63(4):689-702.

Lansbury L, Leonardi-Bee J, Perkins W, Goodacre T, Tweed JA, Bath-Hextall FJ. Interventions for non-metastatic squamous cell carcinoma of the skin. CochraneDatabase Syst Rev. 2010;(4):CD007869.

Lange JR, Fecher LA, Sharfman WH, et al. Melanoma. In: Abeloff MD, Armitage JO, Nierderhuber JE, Kastan MB, McKenna WG, eds. Abeloff's Clinical Oncology. 4th ed. Philadelphia, Pa: Churchill Livingstone; 2008:chap 73.

Lazovich D, Vogel RI, Berwick M, Weinstock MA, Anderson KE, Warshaw EM. Indoor tanning and risk of melanoma: a case-control study in a highly exposed population. Cancer Epidemiol Biomarkers Prev. 2010;19(6):1557-1568.

Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol. 2009;145(12):1431-1438.

Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102(7):493-501.

Morton CA, Szeimies R-M, Sidoroff A, Braathen LR. European guidelines for topical photodynamic therapy part 1: treatment delivery and current indications – actinic keratoses, Bowen’s disease, basal cell carcinoma. Journal of the European Academy of Dermatology and Venereology. 2013;27(5): 536–544. First published online November 26, 2012.

National Comprehensive Cancer Network. Basal cell and squamous cell cancers: NCCN Medical Practice Guidelines and Oncology;V.2. 2013. Available online. Last accessed September 8, 2013.

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PharmaDerm. Solaraze Prescribing Information. Available online. Last accessed September 8, 2013.

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Savel MS, Wong SI. Review of evidence-based support for pretreatment imaging in melanoma. J Natl compr Canc netw. 2009;7(3):281-9. Review.

Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364(22):2119-2127.

Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol. 2010;62(4):582-590.

Telfer NR, Colver GB, Morton CA. Guidelines for the Management of Basal Cell Carcinoma. BJD. 2008;159:35-48.

Tran KT, Wright NA, Cockerell CJ. Biopsy of the pigmented lesion-when and how. J Am Acad Dermatol. 2008;59(5):852-71. Review.

Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics. 2013;131(5):846-854.

Wood GS, Gunkel J, Stewart D, et al. Nonmelanoma skin cancers: basal and squamous cell carcinomas. In: Abeloff MD, Armitage JO, Nierderhuber JE, Kastan MB, McKenna WG, eds. Abeloff's Clinical Oncology. 4th ed. Philadelphia, Pa: Churchill Livingstone; 2008:chap 74.



Review Date: 9/28/2013
Reviewed By: Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M. Health Solutions, Ebix, Inc.
The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997- A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.
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