FitSugar

Don't Let Your SPF 30 Turn into SPF 20

FitSugar — Tue, 15 May 2007 14:30:00 -0700

Did you know that if applied incorrectly, an SPF 30 sunscreen is actually SPF 20?

SPF 30 sunscreen may provide significantly less protection when not enough is used. To get the most out of your sunscreen, use one ounce, enough to fill a shot glass (or your palm). This is the amount needed to cover the exposed areas of the body (arms, legs, neck and face of the average adult) properly. So stock up, use it liberally and reapply often (especially after you towel off).

Sunscreen Review: Badger 30 SPF

FitSugar — Mon, 13 Jul 2009 14:30:01 -0700

After reading the Environmental Working Group's sunscreen list, I decided to try a chemical free sunscreen and opt for mineral sunblock protection. I picked up a tube of Badger 30 SPF ($16) for face and body, which ranked really well on EWG list as being an effective sunscreen without creating health hazards with repeated use.

Learn what I think of Badger sunblock.

Melanoma and other skin cancers

FitSugar — Wed, 08 Oct 2008 17:35:01 -0700

In This Report

Highlights
Introduction
Melanoma
Nonmelanoma Skin Cancer
Precancerous Skin Condition...
Causes
Risk Factors
Prevention
Screening
Diagnosis
Staging
Treatment for Melanoma
Treatment for Nonmelanoma S...
Prognosis
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Risk factors

According to a report in the Archives of Dermatology, marathon runners are more likely than the general population to develop skin changes that increase the risk for melanoma.

Prevention

A study published in The Lancet indicates that the best ways to avoid sun damage are to reduce the time you spend in the sun and to wear a hat and clothing to protect as much of your skin as possible. Fabrics that are thick and tightly woven offer the best protection.

The U.S. Food and Drug Administration has approved a new type of sunscreen that may more effectively block UVA than products currently available in the United States. UVA light penetrates the skin deeper than other forms of sunlight. Exposure to UVA is believed to contribute to skin cancers. The new sunscreen, called Anthelios SX, is available over the counter.

Screening

A study published in CANCER has shown that older men are more likely to undergo a whole body skin exam if they understand their personal risk factors for melanoma and know where to go to have such an exam. The study emphasizes the importance of skin cancer awareness and education.

One-time melanoma screening for adults over age 50 seems to be as cost-effective as other nationally recommended cancer screening programs, according to a report in the Archives of Dermatology. The study authors also found that screening brothers and sisters of someone with melanoma every 2 years may also be cost-effective.

Diagnosis

Dermatologists detect melanoma earlier than other health care providers, according to an article in the Archives of Dermatology. The earlier melanoma is diagnosed and treated, the greater your chances of survival.

Introduction

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

Nonmelanoma, which includes basal cell cancer and squamous cell cancer
Melanoma, the deadliest form of skin cancer

Different skin cancers start in different layers or cells of the skin. To understand how skin cancer develops, 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 is called the epidermis. It is only about 20 cells deep, roughly as thick as a sheet of paper.
The dermis ranges in thickness from 1 - 4 millimeters (about 1/32 - 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. 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 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.
Sometimes, however, pigment cells grow out of control and become a cancerous and life-threatening melanoma.

Click the icon to see an image of melanin.

Melanoma

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. The thicker the melanoma, the greater the likelihood that it could spread to distant sites.

Removal of the lesion before it reaches the deeper layers of the skin is important for achieving a cure.

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 5 - 15 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 in mucous membranes.

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

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 1 - 5 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.

Common sites of melanoma in men include:

Head
Middle of the body (trunk)
Neck

Common sites of melanoma in women include:

Arms
Legs

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

Less common sites for melanoma include:

Fingers
Palms
Soles of the feet
Genitals
Lips
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.

Nonmelanoma Skin Cancer

The two other types of skin cancers are called basal cell cancer and squamous cell cancer. These are nonmelanoma skin cancers.

Basal cell cancer starts in the lowest part of the epidermis in round cells called basal cells. Basal cell is the most common form of skin cancer. It occurs in about 800,000 - 900,000 people every year.

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:

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 cancers 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 cancer resembles a scar with a hard base. This type is more likely to spread and must be treated very aggressively.

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 prove the diagnosis of 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 mimic an ordinary mole, cyst, or pimple. They may be particularly difficult to distinguish from benign cysts when they occur near the eyes.

Usually, basal cells grow slowly. They are rarely deadly. Most basal cell cancers need not be treated as an emergency, although late treatment can cause disfigurement, so 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, and kidney, and non-Hodgkin's lymphoma. Those at higher risk for such cancers appear to be men and anyone diagnosed before 60 with basal cell cancer.

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.

Types of squamous cell cancer:

Squamous cell carcinoma in situ (also called Bowen's disease) is the earliest form of this type of cancer. The cancer has not spread. Cancer areas appear as large reddish patches (often over 1 inch) that are scaly and crusted.
Invasive squamous cell carcinoma is highly likely to spread (metastasize). The skin cancer lesions can grown rapidly (over months) or slowly (over years). Eventually they become ulcerated.

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

Prompt treatment is desirable because squamous cell cancers are more likely to spread to local lymph nodes than basal cell cancer. Squamous cell cancers most likely to spread include:

Deep lesions, those larger than 2 cm in diameter, or patches with poorly defined margins
Recurrent lesions
Squamous cell cancer on neck, earlobe, eyelid, lips, or temple
Squamous cell cancer that develops in ulcers
Squamous cell cancer that develops on skin areas that have been previously treated with radiation or exposed to cancer-killing chemicals

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

Precancerous Skin Conditions

Actinic (Solar) Keratosis. Actinic keratosis (also called solar keratosis) is a precancerous skin lesion caused by too much sun exposure. Such lesions can turn into cancer, but not always.

Actinic keratoses occur after years of sun exposure. They appear 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; 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 cancers, but they are not malignant. The majority 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:

In the early stages, keratoacanthomas are smooth, red, and dome shaped.
Within a few weeks, they can grow rapidly, usually to 1 or 2 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 a surrounding outer rim of tissue and sometimes have a crusty interior.

Most will spontaneously get better 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

You cannot overestimate the role of the sun as the most important cause of prematurely aging skin (called photoaging ) and skin cancers.

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 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.

UVB is the main type of radiation responsible for sunburns. It primarily affects the outer skin layers. This type of ultraviolet light is most intense at midday when sunlight is brightest.
UVA penetrates more deeply and efficiently. Unlike UVB, window glass does not filter out UVA rays.

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. Free radicals are unstable molecules produced by normal chemical processes in the body that, in excess, can damage the body's cells and even alter the DNA. This contributes to the aging process and sometimes to cancer.
Defective DNA Repair and Protective Enzymes. Some skin cancers are caused by a breakdown in the body's mechanisms that help repair DNA damage. For example, xeroderma pigmentosum (XP) is a rare genetic disease in which the body cannot repair damage caused by ultraviolet light. Normally, a number of enzymes in the skin help protect against this damage.
Breakdown of Immune Protection. Specific immune factors protect the skin, including white blood cells called T lymphocytes and specialized skin cells called Langerhans cells. These immune system cells attack developing cancer cells at the very earliest stages. However, certain substances in the skin, particularly a chemical called urocanic acid, can suppress such immune factors when exposed to sunlight.

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 interfere with apoptosis. If this occurs, damaged cells can continue to spread, resulting in skin cancer.

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 block 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 apoptosis goes awry in melanoma cells, proliferation can become rampant.

CDKN2A Mutations. Mutations in a gene regulator called CDKN2A are the most common causes of inherited melanoma, which is 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 may weaken the body's ability to fend off impending cancers, including melanomas. As a person ages, they lose Langerhans cells that help fight off early skin cancers. The number of these immune cells decreases with age, possibly setting the stage for skin cancers in later life.

Risk Factors

In the United States, the rate of melanoma is rising more rapidly than any other cancer. According to the American Cancer Society, about 59,940 persons will be diagnosed with melanoma in 2007. More than 8,000 people will die from the cancer.

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.

A risk factor is anything that increases your chance of getting a disease. The following factors increase your risk for skin cancer:

Age over 40
Being male
Fair skin
Too much exposure to sunlight and ultraviolet radiation
Personal history of skin cancer
Family history of skin cancer
Smoking
Certain chronic or severe skin problems
Certain medical conditions or treatments that affect your immune system
Exposure to chemicals or radiation

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 - 14 the incidence is only 0.3 per 100,000. Between ages 14 - 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.

Skin cancer is associated with both duration and intensity of sun exposure. Risk of melanoma increases with excessive sun exposure during the first 10 - 18 years of life. Sunburns are also dangerous, with five or more sunburns doubling the risk of developing cancer. Cancer typically arises many years later.

Marathon runners are more likely than the general population to develop skin changes that increase your risk for melanoma. That's because marathon runners spend a lot of time outdoors. The study findings are published in the Archives of Dermatology.

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.

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 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.


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.

Australia has the highest melanoma rate in the world. In the United States the rate 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.

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 5 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.

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).

Psoriasis. 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.

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.

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

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.
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). The risk for those with atypical moles and no family history of melanoma is less clear.
Large birthmarks (giant congenital nevi). Very large birthmarks more than 8 inches across 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. Whenever possible, very large birthmarks should be removed during infancy. Experts disagree, however, about whether small birthmarks need to be removed. Parents should 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 3,164 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.

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

They 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.

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 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.

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.

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.

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

Immunosuppression. Skin cancer risk is increased in persons 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 heart transplants from donors who had the disease. Immune-suppressing drugs used to treat autoimmune disorders may also increase the risk of skin cancer. Potential skin cancer risks have been associated with the eczema drugs pimecrolimus (Elidel) and tacrolimus (Protopic).

Rheumatoid arthritis. Despite previous concerns, the rheumatoid arthritis drug etanercept (Enbrel) does not raise the risk for developing squamous cell skin cancer. The findings are reported in the Archives of Dermatology. Etanercept works by blocking tumor necrosis factor (TNF), an immune system chemical messenger that is involved in inflammatory processes and diseases.

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.

Prevention

The best way to lower the risk your risk of skin cancer is to protect your skin from the sun and UV light.

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. Adolescents are at special risk for sun-related cancers because, according to a 2002 study, most of them do not take protective measures when out in the sun. According to the study, boys are less likely to use sunscreen than girls, but girls are more likely to get sunburn and use tanning salons more often.

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. Do not rely on sunscreen alone for sun protection. Also wear protective clothing and sunglasses.
Avoid exposure particularly during the hours of 10 a.m. to 4 p.m., when UV rays are the strongest.
Clouds and haze do not protect you from the sun and in some cases may intensify UVB rays.
Avoid reflective surfaces such as water, sand, concrete, and white-painted areas.
UV intensity depends on the angle of the sun, not heat or brightness. The dangers are greater the closer to the start of summer.
Skin burns faster at higher altitudes. One study suggested that an average complexioned person burns in 6 minutes at 11,000 feet at noon compared to 25 minutes at sea level.
Avoid sun lamps, tanning beds, and tanning salons. The machines use mostly high-output UVA rays. Some experts believe that 15 - 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.

Wear protective clothing, sunglasses, and a hat to shield your face from the sun's rays. Special clothing can block out UV rays and is rated using sun protection factor (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.

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 1 should wear sunglasses that block all UVA and UVB rays when in the sun.

Click the icon to see a depiction of 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:

Organic formulas contain UV-filtering chemicals such as octocrylene, octyl salicylate, homosalate, and octyl methoxycinnamate (block UVB), avobenzone-Parsol 1789 (blocks UVA), cinoxate, ethylhexyl p-methoxycinnamate (blocks UVB and small amounts of UVA), oxybenzone, and benzophenone-3 (blocks UVA/UVB). People should look for a wide-spectrum sunscreen that contains combinations of these ingredients and filter both UVA and UVB. Of note: para-amino benzoic acid (PABA), once a popular ingredient, is now used infrequently. PABA may actually break down in the presence of UV exposure and release harmful oxidants. And many people have an allergic reaction to it. Some products contain PABA derivatives, such as padimate O or octyl dimethyl PABA.
Inorganic formulas contain the UV-blocking pigments zinc oxide or titanium dioxide. Zinc and titanium oxides lie on top of the skin and are not absorbed. They prevent nearly all UVA and UVB rays from reaching the skin. Older sunblocks are white, pasty, and unattractive, but current products use so-called microfine oxides, either zinc (Z-Cote) or titanium. They are transparent and nearly as protective as the older types. Microfine zinc oxide may be more protective and less pasty-colored than microfine titanium oxide.

Calculating the 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. 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:

Minimal: SPF 2 to 11
Moderate: SPF 12 through 29
High: 30+

Although some sunscreens claim SPFs higher than 30, the added protection at such higher levels is insignificant.

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. Children should be kept 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 on the face and 15 on the body.

Adults who burn easily instead of tanning and anyone with risk factors for skin cancer should use at least SPF 30.

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

Adults should include sunscreen every day, even if going outdoors for only a short time.
Apply a large amount to all exposed areas, including ears and feet. To achieve protection as indicated by the sunscreen's SPF, experts recommend half a teaspoon each for the head, neck, and each arm and a teaspoon each for the chest area, the back, and each leg.
Apply initially 30 minutes before venturing outdoors for best results. This allows time for the sunscreen to be absorbed. Then reapply every 15 - 30 minutes while being in the sunlight.
Also reapply each time after exercise or swimming. Choose a waterproof or water-resistant formula even if activities don't include swimming. Waterproof formulas last for about 40 minutes in the water, whereas water-resistant formulas last half as long.
Insect repellents reduce sunscreen SPFs by up to one-third. Use higher SPFs and very liberal application when applying both.

Possible Hazards of Sunscreens, Sun Avoidance, or Both. 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 provide protection against melanoma and some basal cell cancers. In fact, some studies have reported a higher association with sunscreen use and these skin malignancies, though not all studies report such negative results.

The reasons for this possible increased risk are unclear, though some theories include:

Until recently, many sunscreens blocked only or predominantly blocked UVB rays and not UVA, the more deeply penetrating rays now known to be especially dangerous. Studies then may not have reflected the effects of the broad-spectrum sunscreens now available, which block both UVA and UVB.
People who apply sunscreens may 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.
People may not put on enough sunscreen. A 2002 study found that people generally apply only 20 - 60% of the recommended amount, which can provide significantly less protection than the given SPF. A later study reported that when applied at the recommended amount, a broad-screen sunscreen prevents DNA damage from UV exposure.

Underexposure to sunlight. There is some major concern that underexposure to sunlight, due to the use of sunscreens or sun-avoidance measures, may produce other health problems such as:

Vitamin D deficiency. The body makes vitamin D through a chemical reaction to UVB sunlight. Too many sun-protection measures may increase the risk for developing vitamin D deficiency. Vitamin D helps prevent rickets, osteoporosis, and some cancers, including melanoma. People who need to avoid sunlight and whose diet is low in foods that contain vitamin D should check with their doctor about taking supplements. (Warning: Vitamin D is poisonous when taken in high doses.) People with darker skin are at higher risk for deficiencies from sun protection than those with whiter skin.
Other Cancers. Although sunlight is implicated in skin cancers, it is also associated with lower risks for breast, prostate, ovarian, and colon cancers. Some protection against these cancers may be related to vitamin D production by sunlight.
Depression. Many people suffer from seasonal affective disorder (SAD), a form of depression that generally occurs in winter and is associated with exposure to less sunlight.

The bottom line is that some sunlight is important and even necessary.

A study published in 1994 in the New England Journal of Medicine found that persons with a history of nonmelanoma skin cancer who ate a low-fat diet were much less likely to develop actinic keratosis, a precancerous skin condition.

However, the low-fat diet did not appear to have any effect on the development of basal cell cancer.

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. For example, a medicine called imiquimod is approved to prevent skin cancer in certain individuals. This medicine prompts the immune system to fight off foreign substances, including cancer cells. Chemopreventive agents under investigation and showing promise for skin cancer include:

Nonsteroidal anti-inflammatory drugs
Difluoromethylornithine (DFMO)
Catechins (phytochemicals found in certain foods)
Anti-aging drugs called retinoids (vitamin A derivatives)

Retinoids have been shown to prevent nonmelanoma skin cancer in patients with basal cell nevus syndrome, xeroderma pigmentosum, and transplanted organs. Oral retinoids include isotretinoin and acitretin. They may also prevent the development of squamous cell carcinoma in patients who are taking such medicines to treat psoriasis.

Early animal studies had suggested that cholesterol-lowering statins or fibrates may reduce the risk of skin cancer, but human studies have produced inconsistent results. A review of several studies has concluded that such drugs do not decrease your risk of melanoma. The findings are published in the Journal of the National Cancer Institute.

Researchers are also studying chemopreventative compounds that target genetic mechanisms in the skin. They may prove to be beneficial ingredients in creams or lotions used to prevent skin cancers on a molecular level. They include cytokine interleukin-12 and T4 endonuclease 5 (T4N5).

Studies have shown that mice with round-the-clock access to an exercise wheel developed skin cancer more slowly when exposed to UVB. Their tumors were also fewer in number and smaller. Analysis of the data suggested that exercise might trigger the death of the developing cancer cells faster than they can grow. Exercise also made the mice lose weight, and the number of tumors decreased as fat disappeared.

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

Studies suggest that vitamin E creams, particularly those made from a type of Vitamin E called alpha tocopherol, decreased skin roughness, length of facial lines, and wrinkle depth. Studies on mice have also shown that such creams reduce UV-related skin cancer.

Vitamin C is a very potent antioxidant. It is also called ascorbic acid. 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.

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.

Click the icon to read about the antioxidant selenium.

Antioxidant Skin Creams. There are wide claims about the benefits of antioxidants for wrinkles when used in skin creams. However, to date, only vitamin E, C, and selenium-based skin products have been shown to help reduce sun damage to the skin. However, most available brands contain very low concentrations of these antioxidants. In addition, the antioxidants are also not well absorbed by the skin, so the effect may be short-term.

Antioxidant Pills. One small study found that taking a combination of vitamins C and E supplements by mouth may help reduce sunburn reactions, although the protection is much less than from sunscreens. Taking the vitamins alone 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 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. Green tea skin care products are now available, but their quality is unregulated.
Ginger also appears to have some sun protective qualities.
Silymarin, a substance found in the milk thistle family (which includes artichokes), may prevent UVB-promoted cancers in animals.
Garlic has been shown to protect animals against UVB damage. 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 may contribute to dermatological 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 irritation in reaction to sunlight (photosensitivity). 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. For example, a study published in CANCER has shown that older men are more likely to undergo a whole body skin exam if they were aware of personal risk factors and where they could go to have an exam performed.

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.

A mnemonic device, ABCDE, is used to describe several features that help to distinguish skin cancer from noncancerous growths.

Asymmetry (A). Skin cancers usually grow in an irregular, asymmetric fashion. That means one half of the abnormal skin area is different than the other half.
Border Irregularity (B). Noncancerous lesions generally have clearly defined borders. Melanoma lesions often have 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.
- 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. A doctor should examine any suspicious lesion, no matter what size it is.
Evolution (E). A lesion that is growing or changing deserves evaluation.

The ABCDE plan is a general guide. It will not help detect the early stages of nodular melanoma and may also miss amelanotic melanoma, which is not pigmented.

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

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

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, they should compare their body to the map to check for new lesions, lumps, or moles and for changes in shape, color, and size.

Some experts have defined three specific body areas to look for skin cancers, including melanomas:

Areas visible to anyone, such as the arms or face -- about 60% of melanomas are found on such areas.
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 such as the scalp, buttock folds, and mouth -- about 6% of melanomas, usually more advanced, are found here.

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

Some experts recommend that everyone, especially those with a high risk of developing melanoma, have a dermatologist perform a whole body skin exam. Dermatologists detect melanoma earlier than other health care providers, according to an article in the Archives of Dermatology.

High-risk people include those with a 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 3 - 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.

Examinations for Patients Previously Treated for Melanoma. People who have had melanoma and have 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: Yearly exam
Stage II patients: Every 6 months for years 1 and 2 and annually thereafter
Stage III patients: Every 3 months for the first year, every 4 months for year 2, and every 6 months for years 3 to 5

All patients should be checked annually after year 5. These are guidelines only and may be changed, depending on individual patient characteristics.

Some studies also suggest that regular screening of family members of people with melanoma could prevent a number of serious cases. A 2007 report in the Archives of Dermatology has called for expanded melanoma screening programs. The study found that one-time melanoma screening for adults over age 50 seems to be as cost-effective as other recommended cancer screenings. The study authors also found that screening brothers and sisters of someone with melanoma every 2 years may also be cost-effective.

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, called a myxoid melanoma, may be mistaken for a benign skin disorder known as a myxoid fibrohistiocytic lesion. Other opinions from a second pathologist, computerized image processing or advanced staining techniques, may help to confirm the diagnosis.

A study published in the Archives of Internal Medicine has found that melanoma tends to be diagnosed at a later stage in persons who are not light-skinned. The study involved nearly 50,000 patients with melanoma, and included Caucasians, Hispanics, Asian/Pacific Islanders, African-Americans, and American Indians.

Some doctors now use dermoscopy (also called dermatoscopy or epiluminescence microscopy). This technique uses a handheld 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 the lesion and compare it for changes with later images taken at subsequent check ups. The device is not yet used in the United States. It still requires FDA approval. Testing is under way to confirm its accuracy.

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.

Shave biopsy uses a thin surgical blade to shave off the top layers of skin. The doctor may use this type of biopsy to diagnose basal cell cancer.
Punch biopsy uses a round, cookie-cutter-like tool. It is used to take a deeper sample skin.
Incisional and excisional biopsies remove tumors that have grown deep into the skin. An incisional biopsy cuts out part of the tumor. An excisional biopsy removes the entire tumor. These biopsies are used to diagnose melanoma.

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

A lymph node biopsy helps the doctor determine whether 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 and generally unnecessary for those thinner than 0.75 millimeter, 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 outlook in persons with melanoma.

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 which is closest to the cancer site. Sentinel node biopsy is used to stage many kinds of cancer, including 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 through the lymph system into the sentinel node, 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 or not to remove other lymph nodes:

If the sentinel node and others shows signs of cancer then the nearby lymph nodes are removed.
If they do not, then the remainder of the lymph nodes will likely be cancer-free, and further surgery is not needed.

If melanoma has been diagnosed, the doctor will perform other tests to see if the cancer has spread, such as a chest x-ray.

Blood tests that show high levels of lactate dehydrogenase suggest that the cancer has spread. Blood tests to assess liver function and other factors to help determine specific sites where the cancer may appear.

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.

Biomarkers are specific substances that are linked to cancer. Blood tests to detect biomarkers may be used to identify microscopic cancers if sentinel node biopsy results are uncertain. Researchers are continually investigating other biomarkers that may indicate whether the cancer had spread or how severe it is, 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.

Staging

Staging is the process used to determine the size of the tumor and where and how far it has spread. When a cancer spreads, it’s said to have metastasized. Staging helps the health care team plan for appropriate treatment.

Basal cell cancer is rarely staged, because it doesn't usually spread to other organs. However, it may be staged if it's very, very large.
Squamous cell cancer may be staged in persons who have a high risk of the cancer spreading.
Melanoma is always staged.

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

T = tumor. T is followed by a number to indicate thickness.
N = node. N is followed by numbers to indicate the number of lymph nodes involved.
M = metastasis. Metastasis is the spread of cancer to far away sites.

In addition a stage will include whether the melanoma is ulcerated or not, an indication of severity. Ulceration is determined 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 assigned stage. The higher the stage, the worse the long-term outlook.

The earliest melanomas, which do not penetrate beneath the surface of the skin and are known as melanoma in situ, are highly curable and are called stage 0 or not given a stage.
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 spread.

Specific stages are as follows:

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

Stage 1A. Tumor has not spread to the nodes. It is less than 1 mm and is not ulcerated.
Stage IB. Tumor has not spread to the nodes. It is less than 1 mm, but is ulcerated, or the tumor is between 1.01 and 2 mm but is not ulcerated.

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

Stage IIA. Tumor has not spread to the nodes. It is between 1.01 and 2 mm and is ulcerated, or it is 2.01 to 4 mm without ulceration.
Stage IIB. Tumor has not spread to the nodes. It is between 2.01 and 4 mm and is ulcerated or greater than 4 mm without ulceration.

Stage III. Survival rate is lower than earlier stages.

Stage IIIA. Tumor has spread to 1 node and it is up to 4 mm without ulceration. Sentinel biopsy has detected microscopic evidence of tumor cells in the node (micrometastasis).
Stage IIIB. Tumor is up to 4 mm without ulceration and has spread to one node or there is evidence of micrometastasis in two nodes.
Stage IIIC. Tumor is any thickness and ulceration may or may not be present. It has spread to 2 or 3 nodes. Additional "satellite" melanomas on the skin more than 2 cm (about an inch) from the original lesion may be present; these are sometimes called "metastases in transit."

Treatment for Melanoma

Treatment for melanoma depends on various factors, including:

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

Treatment options include:

Surgery to remove the melanoma cancer cells
Chemotherapy
Immunotherapy
Radiation therapy
Palliative therapy

Surgery is the primary treatment for all stages of melanoma. Some or all of the melanoma is often removed during the diagnosis 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.

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:

Stage I lesions that are less than 1 mm deep require the smallest surgical cuts, usually about 1 cm off each side and downward from the original lesion.
For melanomas that are 2 mm or thicker, a margin of 3 cm is important for reducing the risk of recurrence.
Thicker lesions require wider surgical cuts.

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.

Lymph Node Removal. If there is evidence that melanoma has spread to nearby lymph nodes but has not spread beyond, removing them 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 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.

Recurrence rates are very high with lentigo maligna after conservative surgery. Although this is a very slowly progressive condition, lentigo maligna 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.

Chemotherapy is often used to treat recurrent or metastatic melanomas. This type of therapy is not intended as a cure but can prolong life and improve its quality.

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.

Methylating agents impair the ability of cancer cells to divide. Dacarbazine (DTIC) and temozolomide (Temodar) are the ones most often used.
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.

Researchers continue to investigate other chemotherapy drugs and combinations of drugs to see which works 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:

Nausea and vomiting
Diarrhea
Temporary hair loss
Weight loss
Fatigue
Anemia
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.

Treating Side Effects

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

Erythropoietin stimulates red blood cell production and can help reduce or prevent anemia related to chemotherapy. 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.

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 metastasized or recurrent melanoma that occurs on the arm or leg. It does not appear to be useful for preventing metastasis after a first occurrence of melanoma in one of these locations.

This technique involves the following:

The blood supply to the limb with melanoma is temporarily interrupted using a tourniquet and then rechanneled through a heart-lung machine.
Anticancer drugs are added to the blood in doses up to 10 times the standard doses.
The blood is then heated to enhance the drug's potency.
The chemo-infused blood is then sent directly to the melanoma site, minimizing the likelihood of drug toxicity.
Adverse effects occur in less than 1% of cases and include severe problems in the treated limb (rarely leading to amputation) and drug leakage into the bloodstream. This can severely reduce white blood cells and lead to serious infection.

In addition to arms and legs, perfusion techniques have 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 persons with melanoma.

Cytokines. Cytokines are small proteins that play an important role in the body's immune response. Certain cytokines called interferons are used as a therapy for metastatic melanoma. These medicines are usually given along with chemotherapy or other immunotherapies, or both.

A number of cytokines and combinations are being investigated. They include:

Interferon alpha-2b (Intron) is the only FDA approved immunotherapy for late stage melanoma. 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.
Pegylated interferon and natural human interferon are long-acting forms are under investigation. One study showed that low-dose natural interferon after chemotherapy increased the 5-year relapse-free survival rate.
Interleukin-2 (Proleukin) is a hormone-like substance that stimulates the growth of cancer-fighting white blood cells. High-dose interleukin-2 has been shown to help patients with metastatic melanoma. The drug can cause significant side effects, including very low blood pressure, heart rhythm abnormalities, severe infections, and shortness of breath. The side effects are manageable and nearly always reversible.
Granulocyte-macrophage colony stimulating factor (GM-CSF, Leukine, Sargramostim) is an injectable cytokine under study. The drug boosts production of immune cells in the blood and bone marrow. An inhaled form of the drug is being tested for melanoma that has spread to the lungs.
T-cell therapy uses white blood cells, called tumor-infiltrating lymphocytes (TIL), that taken from the patient. The cells are modified so they better fight cancer and are then reinjected back into the patient. T-cell therapy is showing promising results, especially for patients with advanced melanoma who have failed to respond to other treatments.

A chemical called histamine is a powerful inhibitor of reactive oxygen species, ROS, which may inactivate immune cells that fight cancer. Researchers are investigating to see if it can be used along 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.

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 uniquely expressed by melanoma cells.

Many therapeutic melanoma vaccines are in advanced stages of development, but none is approved for use in the United States.

There are two basic types of therapeutic vaccines:

Autologous vaccines
Allogenic vaccines

Sometimes a combination of the two are used. In this case, it's called a hybrid.

Autologous vaccines are made from the patient's own cancer cells. This produces a very specific immune response that can target the patient's cancer precisely. Oncophage (HSPPC-96) and M-Vax are autologous vaccines for melanoma that have shown promise in early clinical trials. 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.

Allogenic vaccines are made in a laboratory using cells from someone other than the patient. They may be made from proteins from tumor cells, genetic material, or even bacteria. One such vaccine is Canvaxin. Early studies showed this vaccine increased survival rates in some patients with Stage 3 melanoma. However, a later trial was halted because the vaccine did not appear to improve make such patients live any longer.

Vaccine immunotherapy 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. Antisense compounds can prevent defective cancer genes from being translated into proteins that cause abnormal cell proliferation.

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.

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.

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 surgical removal of metastatic tumors may provide some benefit by easing pain, increasing the general quality of life, and lengthening survival.

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

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. An anti-angiogenesis drug is one that blocks the formation of new blood vessels. The growth of new blood vessels helps cancer cells grow and spread. The anti-angiogenesis drug thalidomide (Thalomid) is approved for treatment of melanoma but requires special prescribing precautions. This drug had gained notoriety in the 1960s because of devastating birth defects in the children of women who took it during pregnancy. Scientists are investigating drugs that are chemically similar to thalidomide but have fewer side effects.

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.

Treatment for Nonmelanoma Skin Cancer

A number of options are available for treating nonmelanoma skin cancer, including surgery, cryosurgery, phototherapy, radiation, and topical 5-fluorouracil.

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 Electrodesiccation. 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. 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. A human skin substitute (Apligraf) is applied to the surgical area. It helps speed up wound healing to achieve a better cosmetic effect.

Good candidates for Mohs surgery include:

Persons with squamous cell cancer
Persons with basal cell cancer greater than 1 cm (about half an inch)
Persons with basal cell cancer on the face, ear, or neck
Young people with skin cancer

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 cancers.

Cryosurgery removes skin cancer cells or actinic keratoses by freezing the affected tissue with liquid nitrogen. Studies have shown that cyrosurgery 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.

A head-to-head comparison of a freezing technique with Mohs micrographic surgery in patients with basal cell cancer 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%.

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.

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 recurred multiple times, radiation therapy may be indicated. Radiation is directed at the tumor. It may take 1 - 4 weeks with treatments performed 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 that 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.

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 and irritation, including stinging, itching, and burning, but in one study only 3% of patients stopped using it for these reasons. 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 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 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 and basal cell cancer, phototherapy has been equal to cryotherapy, with superior healing and appearance afterward. A 2003 study reported that it was more effective than topical 5-fluorouracil for patients with Bowen's disease, and there were fewer side effects.

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.

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.

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.


Medication	Skin Conditions Affected	Oral or Topical		Comments
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 if 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. A 10-year 2003 study of patients with Bowen's disease reported that 5-FU was safe and effective, with only 2 out of 26 cancers recurring.
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.
Imiquimod (Aldara)	FDA approved for the treatment of superficial basal cell cancer. Previously approved for treating actinic keratoses. Investigated for Bowen's disease and squamous cell cancer.		Imiquimod is a topical cream.	Imiquimod triggers the production of immune factors that help fight cell proliferation. Aldara should be used only when surgery for basal cell cancer is inappropriate. It is not approved for use on the face.
Alpha-Interferons	Basal cell cancer, squamous 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 reported to be good or very good by 83% of patients.

Prognosis

Virtually all basal and squamous type skin cancers can be cured if treated early.

The outlook for melanoma depends on when it is diagnosed.

If melanoma is detected in its earliest form, the 5-year survival rate is 99%. Other localized forms of melanoma have very favorable outlooks.

If the cancer is found after the melanoma has spread, the 5-year survival rate drops.

If melanoma spreads to nearby areas (regional metastatic), the rate is 65%.
If melanoma has spread to distant areas of the body, the survival rate is 15%.

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.

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.

Resources

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

References

Ambros-Rudolph CM, Hofmann-Wellenhof R, Richtig E, et al. Malignant melanoma in marathon runners. Arch Dermatol. 2006;142:1471-1474.

American Cancer Society. Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society; 2007.

Chemotherapy for Inoperable Liver Metastases from Ocular Melanoma. NCI Cancer Bulletin. November 30, 2004;1(46):7.

Dale KM, Coleman CI, Henyan NN et al. Statins and Cancer Risk: A Meta-Analysis. JAMA. 2006;295:74-80.

Delavalle RP. Melanoma chemoprevention. Program presented at: Annual meeting of the American Academy of Dermatology. March 3, 2006; San Diego, CA.

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.

Early Detection and Surgery for Melanoma in Lymph Nodes May Increase Survival. NCI Cancer Bulletin. May 17, 2005;2(20):2.

Freeman SR, Drake AL, Heilig LF, et al. Statins, Fibrates, and Melanoma Risk: a Systematic Review and Meta-analysis. J Natl Cancer Inst. 2006;98:1538-46.

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

Lautenschlager S, Wulf HC, Pittelkow MR. Photoprotection. The Lancet [early online publication]. May 3, 2007.

Lebwohl M. Cutaneous oncology. Program presented at: Annual meeting of the American Academy of Dermatology; March 7, 2006; San Diego, CA.

Michna L, Wagner GC, Lou YR, XE JG, Peng QY, Lin Y, Carlson K, Shih WJ, Conney AH, Lu XP. Inhibitory effects of voluntary running wheel exercise on UVB-induced skin carcinogenesis in SKH-1 mice. Carcinogenesis. May 2006.

Pennie M, Soon S, Risser J, et al. Melanoma outcomes for medicare patients. Arch Dermatol. 2007; 143:488-494.

Response to Immunotherapy for Melanoma Tied to Autoimmunity. NCI Cancer Bulletin. February 21, 2006;3(: 4.

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.

Treatment for Metastatic Ocular Melanoma. NCI Cancer Bulletin. March 7, 2006;3(10):8.

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.

Weinstock MA. Cutaneous melanoma: public health approach to early detection. Dermatologic Therapy. 2006;19(1):26-31.

Review Date:
6/29/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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adam.com

Skin wrinkles and blemishes

FitSugar — Wed, 08 Oct 2008 17:34:59 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Smoking and Skin Damage

The skin of smokers ages more rapidly than the skin of non-smokers, even in areas of the body not exposed to sunlight, according to a 2007 study. Women in the study who smoked also had much lower levels of vitamin E secretions in their skin. Vitamin E may protect the skin from sun damage.
There may be an association between smoking and higher frequency of a type of acne (noninflammatory acne) in adult women, according to a European study.

Antioxidants and Your Skin

A study in the Journal of Nutrition found that a combination of antioxidants and trace elements supplementation raises the risk of skin cancer in women, but not in men.

Ultraviolet Radiation

Overall, exposure to ultraviolet radiation from sunlight (radiation referred to as UVA or UVB) accounts for about 90% of the symptoms of premature skin aging.
UVB primarily affects the outer skin layers. It is most intense when sunlight is brightest. People receive slightly over 70% of their yearly UVB dose during the summer.
UVA penetrates more deeply and efficiently. The intensity of UVA rays is less dependent on the time of day and season of the year than that of UVB rays.

Vitamin D

A report analyzing studies of vitamin D supplementation found that people who take vitamin D supplements live longer than those who do not. People who avoid sunlight are at risk for vitamin D deficiency.

Introduction

As you age, your skin undergoes progressive changes:

The cells divide more slowly, and the inner layer of skin (the dermis) starts to thin. Fat cells beneath the dermis begin to shrink. In addition, the ability of the skin to repair itself decreases with age, so wounds heal more slowly. The thinning skin becomes vulnerable to injuries and damage.
The deeper layer of the skin, which provides scaffolding for the surface skin layers, loosens and unravels. Skin then loses its elasticity (ability to stretch). When pressed, it no longer springs back to its initial position. Instead, older skin sags and forms furrows.
The sweat- and oil-secreting glands atrophy (waste away), leaving the skin without a protective layer of water and fat. The skin's ability to stay moisturized then decreases, and it becomes dry and scaly.
Frown lines (those between the eyebrows) and crow's feet (lines that spread from the corners of the eyes) appear to develop because of permanent small muscle contractions. Habitual facial expressions also form characteristic lines.
Gravity makes the situation worse, contributing to the formation of jowls and drooping eyelids. Eyebrows, surprisingly, move up as a person ages, possibly pulled up by forehead wrinkles.

Wrinkles can have a profound impact on self-esteem. The stigma attached to looking old is evidenced by the more than $12 billion Americans spend each year on cosmetics to hide the signs of aging. Our society places a premium on youthfulness, and age discrimination in the workplace, although illegal, has stalled many people's careers. Indeed, the emotional consequences of aging explain in large part why the cosmetics industry and plastic surgeons thrive.

The sun is the most important cause of prematurely aging skin (a process called photoaging) and skin cancers. Overall, exposure to ultraviolet radiation from sunlight (radiation referred to as UVA or UVB) accounts for about 90% of the symptoms of premature skin aging. Most of these effects occur by age 20:

Even small amounts of UV radiation trigger the processes leading to skin wrinkles.
Long-term repetitive exposure to sunlight adds up, and likely is responsible for the vast majority of unwanted consequences of aging skin, including basal cell and squamous cell cancers.
Intense exposure to sunlight in early life is an important cause of melanoma, a particularly aggressive type of skin cancer.

Initial Damaging Effects of Sunlight. Ultraviolet radiation penetrates the layers of the skin. Both UVA and UVB rays cause damage leading to wrinkles, lower immunity against infection, aging skin disorders, and cancer. They appear to damage cells in different ways, however.

UVB is the main cause of sunburns, and primarily affects the outer skin layers. UVB is most intense at midday when sunlight is brightest. People receive slightly over 70% of their yearly UVB dose during the summer. We receive only 28% during the remainder of the year. Window glass filters out UVB.
UVA penetrates more deeply and efficiently. The intensity of UVA rays is less dependent on the time of day and season of the year than that of UVB rays. For example, you receive only about half of your yearly UVA dose during the summer months, with the balance spread over the rest of the year. Window glass does NOT filter out UVA.

Both UVA and UVB rays cause damage to the body, including genetic injury, wrinkles, aging skin disorders, and skin cancers. Exactly how they cause this damage is not yet fully understood.

Processes Leading to Wrinkles. Even small amounts of UV radiation trigger the processes that can cause wrinkles:

Sunlight damages collagen fibers (the major protein that gives structure to the skin). Sunlight also causes damage to elastin, a protein in the skin that normally maintains springiness and strength of tissue beneath the skin.
In response to this sun-induced elastin accumulation, the body produces large amounts of enzymes called metalloproteinases. One study indicated that when people with light to moderate skin color are exposed to sunlight for just 5 - 15 minutes, the metalloproteinase levels in their body remain high for about a week.
The normal function of these metalloproteinases is generally positive -- to remodel the sun-injured tissue by producing and repairing collagen. This is an imperfect process, however, and some of metalloproteinases produced by sunlight actually degrade (break down) collagen. The result is an uneven formation (matrix) of disorganized collagen fibers called solar scars. Repetition of this imperfect skin rebuilding causes wrinkles.
An important event in this process is the over-production of oxidants, also called free radicals. These are unstable molecules that are normally produced by chemical processes in the body, a process called oxidation. Environmental damage, however, causes an overproduction of oxidants. Excessive amounts of oxidants damage the body's cells and even alter their genetic material. Oxidation may contribute to wrinkling by activating the specific metalloproteinases that degrade connective tissue.

In addition to sunlight, other factors may hasten the formation of wrinkles:

Cigarette Smoke. Smoking produces oxygen-free radicals, which accelerate wrinkles and aging skin disorders, and increase the risk for non-melanoma skin cancers. Studies also suggest that smoking and subsequent oxidation produce higher levels of metalloproteinases, the enzymes associated with wrinkles.

Air Pollution. Ozone, a common air pollutant, may be a particular problem for the skin. One study reported that it might deplete the amount of vitamin E in the skin. This vitamin is an important antioxidant.

Rapid Weight Loss. If weight loss occurs too rapidly, the volume of fat cells that cushion the face are also decreased before chemicals in the skin can react. This not only makes a person look gaunt, but can cause the skin to sag.

Blemishes

This report covers three types of blemishes: Liver spots, purpura, and seborrheic keratoses (or warts).

Liver spots (known as lentigos, or sun-induced or pigmented lesions) are flat brown spots on the skin. They are almost universal signs of aging. Occurring most noticeably on the hands and face, these blemishes tend to enlarge and darken over time. The extent and severity of the spots are determined by a combination of skin type, sun exposure, and age. These spots are harmless, but should be distinguished from lentigo maligna, which is an early sign of melanoma.

Liver spots or age spots are a type of skin change that are associated with aging. The increased pigmentation may be brought on by exposure to sun, or other forms of ultraviolet light, or other unknown causes.

Treating Liver Spots. Liver spots do not require treatment, although some people are distressed by their appearance. Treatments may include the following:

Trichloroacetic acid (a chemical peel).
Tretinoin (Retin A) alone or in a combination with Mequinol (Solagé). Tretinoin is related to vitamin A, and is also effective in treating wrinkles.
Gentle freezing with liquid nitrogen (cryotherapy).
Laser treatment. Specific lasers, such as the Nd:YAG, are effective in eliminating 80% of liver spots in one treatment. It may be more effective than cryotherapy and have fewer side effects.
Bleaching creams -- these are commonly available but are not as satisfactory as peels, and high concentrations can sometimes cause permanent loss of skin color.

Purpura occurs when tiny capillaries (blood vessels) break and leak blood into the skin. In older people, the condition (called senile or actinic purpura) is usually caused by fragile blood vessels. The capillaries appear as flat purplish patches. These patches are called petechiae when they are smaller than 3 mm (about a tenth of an inch). When they are greater than 3 mm, they are referred to as ecchymoses. Patients typically complain of a rash, which may appear reddish at first but gradually change color, turning brown or purple.

Treatment. Although there is no specific treatment for purpura, patients are advised to avoid trauma, including vigorous rubbing of the skin, which may be sufficient to damage the capillaries. Emollients that soften the skin may be helpful. Some doctors also recommend vitamin C, but its effectiveness is unproven.

Seborrheic keratoses, (also called seborrheic warts), are among the most common skin disorders in older adults. Their cause or causes are unknown. They usually appear on the head, neck, or trunk and can range in size from 0.2 - 3 cm (a little over an inch). They are well defined and appear to be pasted onto the skin, but their appearance can vary widely:

They can be smooth with tiny, round, pearl-like formations embedded in them.
They can be rough and warty.
They can be brown or black.

Seborrheic keratoses sometimes look like melanoma, since they can have an irregular border, but they are always benign. A dermatologist can tell the difference between them, although experts warn that melanomas may "hide" among these benign lesions and go unnoticed without close inspection. In general, seborrheic keratoses have a uniform appearance while melanomas often have a smooth surface that varies in height, color density, and shading. In some cases, keratoses may cause itching or irritation. They can be easily removed with surgery or freezing. Vitamin D3 ointment is also showing promise in clinical trials.

Risk Factors

Exposure to Sun in Childhood. It is estimated that 50 - 80% of skin damage occurs in childhood and adolescence from intermittent, intense sun exposure that causes severe sunburns. In spite of this now well-known effect, many people still believe that a tan in children signifies health. And even though many parents are concerned about sun exposure, they still rely too much on sunscreen and not enough on protective clothing.

The Elderly. Most people over 70 have at least one skin disorder. Many have three or four. Everyone experiences skin changes as they age, but a long life is not the sole determinant of aging skin. Family history, genetics, and behavioral choices all have a profound impact on the onset of aging-skin symptoms.

Of all the risk factors for aging skin, exposure to UV radiation from sunlight is by far the most serious. Indeed, the vast majority of undesirable consequences of aging skin occur in individuals who are repetitively exposed to the sun, including the following:

Outdoor workers, such as farmers, fishermen, construction workers, and lifeguards
Outdoor enthusiasts
Sunbathers
People who regularly attend tanning salons or use tanning beds (One study indicated that regular use significantly increases the risk for non-melanoma skin cancers. Fair-skinned women under age 50 may be at particular risk.)

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). 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 History
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

The common belief is that women are at greater risk for wrinkles than men. Some evidence suggests, however, that given the same risk factors, men and women in the same age groups have comparable risks for skin photoaging. In a French study, the evidence of moderate-to-severe photoaging was observed in the following:

Twenty two percent of women and 17% of men ages 45 - 49
Thirty six percent of women and 38% of men by age 54
Nearly half of both men and women by age 60

Some studies report that men are more likely to develop non-melanoma skin cancers.

Heavy smokers are almost five times more likely to have wrinkled facial skin than nonsmokers, according to one study. The skin of smokers in areas of their bodies not exposed to sunlight also seems to age more rapidly, compared to non-smokers in the same age group, according to a 2007 study. In fact, heavy smokers in their 40s often have facial wrinkles more like those of nonsmokers in their 60s.

Studies of identical twins have found smokers to have thinner skin (in some cases by as much as 40%), more severe wrinkles, and more gray hair than their non-smoking twins. Even worse, cigarette smokers are more prone to skin cancers, including squamous cell carcinoma and giant basal cell carcinomas. A European study found an association between smoking and higher frequency of a particular type of acne in adult women. The study also found that women who smoked had much lower levels of vitamin E secretions in their skin. Vitamin E is an antioxidant that may help protect the skin from sun damage. [See In-Depth Report #41: Smoking.]

Prevention

The best long-term prevention for overly wrinkled skin is a healthy lifestyle.

Eat Healthy. A diet with plenty of whole grains, fresh fruits and vegetables, and the use of healthy oils (such as olive oil) may protect against oxidative stress in the skin. One study reported that people over age 70 years had fewer wrinkles if they ate such foods. Diet played a role in improving skin regardless of whether the people in the study smoked or lived in sunny countries. Benefits from these foods may be due to high levels of anti-oxidants found in them.

Exercise. Daily exercise keeps blood flowing, which brings oxygen to the skin. Oxygen is an important ingredient for healthy skin.

Reduce Stress. Reducing stress and tension may have benefits on the skin.

Quit Smoking. Smoking not only increases wrinkles, but smokers have a risk for squamous cell cancers that is 50% higher than nonsmokers' risk. Smokers should quit smoking to prevent many health problems, not just unhealthy skin.

The following are some daily measures for skin protection:

Don't wash your face too often with tap water. (Once a day is enough.) It strips the skin of oil and moisture. In addition, chlorinated water, particularly at high temperatures, poses special risks for wrinkles.
Wash your face with a mild soap that contains moisturizers. Avoid alkaline soaps, especially with deodorant.
Pat the skin dry and immediately apply a water-based moisturizer.
Always apply sunscreen, even if going outdoors for short periods.
Avoid drinking alcohol within 3 hours of bedtime. Alcohol increases the risk for leaks in the capillaries, which allows more water in and causes sagging and puffiness. Capillary leakage increases when one is lying down.
Lie on the back when sleeping. This helps offset the effects of gravity.

One of the most important ways to prevent skin damage 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 only on sunscreen for sun protection. Wear protective clothing and sunglasses in addition.
Avoid exposure particularly from 10 a.m. to 4 p.m., 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 (2 months before summer starts) is equal to that in August (2 months after summer begins).
The higher the altitude the quicker one sunburns. One study suggested, for example, that an average complexion burns in 6 minutes at an altitude of 11,000 feet at noon, compared with 25 minutes at sea level in a temperate climate.
Avoid sun lamps and tanning beds or salons. They provide mostly high-output UVA rays. Some experts believe that 15 - 30 minutes at a tanning salon is 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 everyone:

Adults and 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 1 should wear sunglasses that block all UVA and UVB rays.

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 are therefore protective against sun damage More research is underway. A preliminary study funded by the National Cancer Institute found that people who received numerous daily injections of melanotan-1 (MT-1) before going in the sun or a tanning bed tanned more quickly and showed fewer signs of sun-related damage. MT-1 is a synthetic version of the hormone melanin, which helps produce the skin's natural pigment (color).

In 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:

Organic formulas contain UV-filtering chemicals such as octocrylene, octyl salicylate, homosalate, and octyl methoxycinnamate (block UVB), avobenzone-Parsol 1789 (blocks UVA), cinoxate, ethylhexyl p-methoxycinnamate (blocks UVB and small amounts of UVA), oxybenzone, benzophenone-3 (blocks UVA/UVB). People should look for a wide-spectrum sunscreen that contains combinations of these ingredients and filter both UVA and UVB. Of note: para-amino benzoic acid (PABA), once a popular ingredient, is now used infrequently. PABA may actually break down in the presence of UV exposure and release harmful oxidants. In addition, many people have an allergic reaction to it. Some products contain PABA derivatives, such as padimate O or octyl dimethyl PABA. It is not known if they have the same effects.
The Food and Drug Administration approved Anthelios SX in July 2006. This new sunscreen prevents sunburn and protects against ultraviolet A and B rays. The product contains ecamsule, an ingredient not previously marketed in the United States.
Inorganic formulas contain the UV-blocking pigments zinc oxide or titanium dioxide. Zinc and titanium oxides lie on top of the skin and are not absorbed. They prevent nearly all UVA and UVB rays from reaching the skin. Older sunblocks are white, pasty, and unattractive, but current products use so-called microfine oxides, either zinc (Z-Cote) or titanium. They are transparent and nearly as protective as the older types. Microfine zinc oxide may be more protective and less pasty-colored than microfine titanium oxide.

Inexpensive products work as well as expensive ones with the same ingredients. Unfortunately, there are still no standards for sunscreens, and even those claiming UVA protection may offer very little. In one study, the average UVA protection from a wide range of brands was only 23%. In fact, the average protection of brands not making the claim was 37%!

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. Inorganic sunscreens that protect against visible light and are still cosmetically acceptable are now available in Europe, but not yet in the US.

Calculating the SPF. The sun protection factor (SPF) on all sunscreen labels is a ratio based on the amount of UVB (not UVA) radiation required 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. 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:

Minimal: SPF 2 to 11.
Moderate: SPF 12 through 29.
High: 30+. (Although some sunscreens claim SPFs higher than 30, the added protection at such higher levels is insignificant.)

SPF Levels by Age Group. Certain groups should have higher or lower SPFs depending on age and other factors:

Although sunscreens are safe in most toddlers and children, they should not be the first and only lines of defense. In fact, experts are worrying that by relying too much on sunscreen and not providing other protective measures, parents may actually be increasing their children's risk for melanoma. All young children should be well covered with clothing, sunglasses, and hats as the first line of defense against sunburn. Children should be kept out of the sun during peak sunlight periods. Sunscreens should not be used 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 on the face and 15 on the body.
Adults who burn easily instead of tanning and anyone with risk factors for skin cancer should use at least SPF 30.

Timing and Amount of Application. You should apply sunscreen or sunblock liberally as follows:

Adults should include sunscreen with a daily skin regimen, even if going outdoors for only a short time.
Apply a large amount to all exposed areas, including ears and feet. To achieve protection as indicated by the sunscreen's SPF, experts recommend half a teaspoon each for the head, neck, and each arm and a teaspoon each for the chest area, the back, and each leg.
Apply initially 30 minutes before venturing outdoors for best results. (This allows time for the sunscreen to be absorbed. Then reapply every 15 - 30 minutes while being in the sunlight.
Also reapply each time after exercise or swimming. (Choose a waterproof or water-resistant formula even if activities don't include swimming. Waterproof formulas last for about 40 minutes in the water, whereas water-resistant formulas last half as long.)
Insect repellents reduce sunscreen SPFs by up to one-third. Use higher SPFs and very liberal application when applying both.

Sunscreen Use May Not Protect Against Basal Cell and Melanoma Cancers and May Even Increase the Risk. Although sunscreens help prevent squamous cell carcinomas and other skin disorders, sunscreens do not appear to provide protection against melanoma and some basal cell cancers. In fact, some studies have reported a higher association with sunscreen use and these skin malignancies, though not all studies report such negative results.

The reasons for this possible increased risk are unclear, though some theories include the following:

Until recently, many sunscreens blocked only or mostly UVB rays and not UVA, the more deeply penetrating rays now known to be especially dangerous. Past studies may not have reflected the effects of the broad-spectrum sunscreens now available, which block both UVA and UVB.
People who apply sunscreens may feel safe and stay out longer during high sun-exposure hours than is safe. Even if a person doesn't sunburn, UVA rays can still penetrate the skin and do harm.
People may not put on enough sunscreen. According to a 2002 study, people generally apply only 20 - 60% of the recommended amount, which can provide significantly less protection than the given SPF. (Of note, a 2003 study reported that when applied at the recommended amount, a broad-screen sunscreen prevents DNA damage from UV exposure. However, omitting it even once resulted in significant cell injury.)

Sunscreen Use May Increase the Risk for Health Problems Related to Sunlight Deficiencies. There is some major concern that underexposure to sunlight, due to the use of sunscreens or sun-avoidance measures, may produce other health problems, such as the following:

Vitamin D Deficiency. Vitamin D is found in only a few foods, such as fortified dairy products and fish, but it is produced in the skin in response to UVB sunlight. A medical literature review published in the journal Nutrition and Cancer reported that UVB rays may outshine dietary supplements for building the body's vitamin D reserves. Without an appropriate mix of diet and supplements, vigorous sun protection measures may increase a person's risk for developing vitamin D deficiency. Vitamin D is important for prevention of rickets, osteoporosis, and some cancers, including melanoma. People who need to avoid sunlight and whose diet is low in foods that contain vitamin D should check with their doctor about taking supplements. People with darker skin are at higher risk for deficiencies from sun protection than those with whiter skin. Note: vitamin D is toxic in high doses. Most doctors recommend 200 IU a day (for young adults) to 600 IU a day (above age 70). Doses up to 2,000 IU a day are considered safe. A report analyzing studies of vitamin D supplementation found that people who take vitamin D supplements live longer than those who do not. The researchers looked at 18 studies. They found that participants who received vitamin D supplements were, on average, 7% less likely to die during the study they were in, compared with those receiving "sugar pills."
Other Cancers. Although sunlight is implicated in skin cancers, it is also associated with lower risks for breast, prostate, ovarian, and colon cancers. Some protection against these cancers may be related to vitamin D production by sunlight.
Depression. Many people suffer from SAD (seasonal affective disorder), a form of depression that generally occurs in winter and is associated with exposure to less sunlight.

The bottom line is that some sunlight is important and even necessary for a healthful and high-quality life. Adults may benefit from daily moderate tanning (20 - 30 maximum minutes of exposure during lower-risk hours) over several days to slowly build up pigment in the skin.

Treatment

An increasing number of dermatology patients are looking for a way to improve the appearance of their skin. As a result, more and more products have become available to treat skin wrinkles and blemishes. From vitamins and supplements to exfoliants and chemical peels -- the options can be overwhelming. In some cases, more than one approach may be needed.

Antioxidants are substances that hunt oxygen-free radicals, the unstable particles that can damage cells. Free radicals may also cause sun damage and even skin cancers. Exposure to sunlight depletes antioxidants in the skin, and therefore they must be replaced.

Antioxidant ointments, creams, and lotions ("topical products") may help reduce the risk of wrinkles and protect against sun damage. Unlike sunscreens, they build up in the skin and are not washed away, so the protection may last. Selenium, coenzyme Q10 (CoQ10), and alpha-lipoic acid are types of antioxidants that come in topical form. Many are proving to be very beneficial for the skin.

Vitamin A. Vitamin A is important for skin health. UV radiation produces vitamin A deficiencies in the skin. Topical products containing natural forms of vitamin A (retinol, retinaldehyde) or vitamin A-related products called retinoids (tretinoin, tazarotene) may help repair skin damage due to sunburn and natural aging.

Tretinoin (Retin-A). Tretinoin (known commercially as Retin-A) is the only topical agent approved for treating photoaging and is available in prescription form (Avita, Renova, Differin). The June 2004 issue of Dermatology Surgery reported that tretinoin (0.25% concentration) was an effective and well-tolerated treatment for photodamaged facial skin. This drug produces a rosy glow and reduces fine and large wrinkles, liver spots, and surface roughness. It also may help prevent more serious effects of ultraviolet radiation. Patients may apply tretinoin to the face, neck, chest, hands, and forearms, and should do so at least twice a week. Noticeable improvement takes 2 - 6 months. Because Retin-A increases a person's sensitivity to the sun, patients should apply just a tiny amount at bedtime, and wear sunblock during the day. Patients should also avoid overexposure to the sun. Almost all patients experience redness, scaling, burning, and itching after 2 or 3 days that can last up to 3 months. In women who experience irritation, a daytime moisturizer or low-dose corticosteroid cream, such as 1% hydrocortisone, may help. There is some concern that overuse of high-dose tretinoin may cause excessive skin thinness over time. Studies now suggest that low concentrations (as low as .02%) of tretinoin can produce significant improvements in wrinkles and skin color, with less irritation than the higher doses.
Retinol. Retinol, a natural form of vitamin A, could not, until recently, be used in skin products because it was unstable and easily broken down by UV radiation. Stable preparations are now sold over the counter. In the right concentrations, retinol may be as effective as tretinoin, and studies indicate that it has fewer side effects. An animal study suggests that adding antioxidant creams (such as those containing vitamins C or E) may offer added protection against degradation of retinol, but not tretinoin. The Food and Drug Administration warns that over-the-counter retinol skin products are unregulated. The amount of active ingredients is unknown, and some preparations, in fact, may contain almost no retinol.
Tazarotene. Tazarotene (Tazorac, Zorac, Avage) is a retinoid used for acne and psoriasis. It has now been approved for treating wrinkles, skin discoloration, and blemishes due to photoaging. One short-term study suggested that it may be as effective as tretinoin and even slightly better at high doses. At such high doses, however, it can cause very severe irritation. Redness and peeling may be reduced by administering tretinoin first to get the skin acclimated. A randomized study of 562 patients with facial photodamage found that a daily application of tazarotene 0.1% cream resulted in a minimum 1 grade improvement in fine and coarse wrinkling, uneven skin color, pore size, skin roughness, and overall photodamage. More research is needed to determine if it produces any long-lasting significant benefits.

Warning: Pregnant women and those who may become pregnant should avoid any vitamin A derivative (a product related to vitamin A). For example, oral tretinoin causes birth defects, and women should avoid even topical Retin-A when pregnant or trying to conceive.

Vitamin C. Vitamin C, or ascorbic acid, is a very potent antioxidant. Most studies on the effects of antioxidants on the skin have used this vitamin. In laboratory studies, large amounts of vitamin C 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 (such as Cellex-C, Avon's Anew Formula C Treatment Capsules, Physician Elite, and others). More research is needed.

Antioxidants Under Investigation for Skin Care. Other antioxidants are also being investigated for their value in skin protection. Most available brands, however, contain very low concentrations of these antioxidants. In addition, they are also not well absorbed and 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 cream (a form of vitamin E), 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.
Both green and black tea may provide some protection against skin cancers and photoaging. There is also some evidence that pomegranate and soy extracts may help rejuvenate aging skin.
Aloe, ginger, grape seed extract, and coral extracts contain antioxidants and are promoted as being healthy for the skin, although evidence of their effects on wrinkles is weak.

A small study found that taking vitamin C and E supplements by mouth -- at the same time -- may help reduce sunburn, although it doesn't work as well as sunscreen. Taking the vitamins separately did not have any effect. Vitamin C and E are also antioxidants.

One of the basic methods for improving skin and eliminating small wrinkles is exfoliation (also called resurfacing), which is the removal of the top layer of skin to allow regrowth of new skin. Methods for doing this run from simple scrubs to special creams to intensive peeling treatments, including laser resurfacing. People with darker skin are at particularly higher risk for scarring or discoloration with the more powerful exfoliation methods.

Abrasive Scrubs. Scrub gently with a mildly abrasive material and a soap that contains salicylic acid to remove old skin so that new skin can grow. The motion should be perpendicular to the wrinkles. Use textured material or cleansing grains with microbeads. Organic materials, such as loofahs or sea sponges, may harbor bacteria. Avoid cleansing grains that contain pulverized walnut shells and apricot seeds, which can scratch skin on a microscopic level. Cleansing grains with microbeads don't have sharp edges and remove skin without cutting it. Exfoliation using scrubs, however, can worsen certain conditions, such as acne, sensitive skin, or broken blood vessels.

Topical Alpha Hydroxy Acid and Similar Substances. Alpha hydroxy acids (AHA) ease the shedding of dead skin cells and may even stimulate the production of collagen and elastin. Their natural forms are:

Lactic acid (milk)
Glycolic acid (sugar cane)
Malic acid (found in apples and pears)
Citric acid (oranges and lemons)
Tartaric acids (grapes)

Most alpha hydroxy acid products contain glycolic acid. Skin care products are also made from polyhydroxy acids (PHAs) and beta hydroxy acids (BHAs). Research suggests that PHA products may cause less skin irritation than AHA or BHA products.

Acid concentrations in over-the-counter AHA preparations are 2 - 10%. One clinical study suggested that 8% concentrations showed modest skin improvement Some examples include Avon's Anew Intensive Treatment (8% glycolic), Pond's Age Defying Complex (8%), Elizabeth Arden's Alpha-Ceramid Intensive Skin Treatment (3 - 7.5%), and BioMedic's home product (10%). Prescription strength creams contain at least 12% glycolic acid, and glycolic acid peels of 30 - 70% concentration may be administered in a doctor's office at weekly or monthly intervals.

Response to AHA varies, and the treatment is not without risk, particularly in high-concentration products. Side effects from over-the-counter creams, prescription products, and professional AHA peels can include burns, itching, pain, and possibly scarring. Studies also suggest that AHA may increase susceptibility to sun damage, even at concentrations as low as 4%. Such effects can persist up to a week after a person stops using the product. Experts advise that people purchase products with AHA concentrations of 10% or less. Chemical peels of up to 60% are available without prescription on the Internet. Such concentrations are not recommended, except under a doctor's supervision. If any adverse effects occur, stop using the product immediately. Always avoid sunlight or use proper sun protection when using these products.

Copper Peptides. Certain copper-containing compounds may protect skin and help repair it. Note: copper is a toxic metal. When using products containing copper, buy only those that contain peptides (small protein fragments) that bind to copper. Most studies have been conducted on the copper peptide glycyl-l-histidyl-l-lysine:copper (II) or GHK-Cu. It is currently used in a number of products (such as CP Serum, Neutrogena's Visibly Firm, ProCyte's Neova).

Furfuryladenine. Furfuryladenine (Kinetin, Kinerase) is a naturally occurring growth hormone found in plant and animal DNA. It has antioxidant and anti-aging properties. Some small laboratory studies suggest that furfuryladenine may delay the onset and decrease the effects of aging on skin. However, there are no well-conducted human studies to support this suggestion.

Vitamin K. Microsponge-based vitamin K is said to clear bruises spider veins, and other small blood vessel damage. Vitamin K is important for blood clotting.

Moisturizers help prevent dryness, bruising, and tearing. They have no effect on wrinkles by themselves. Moisturizers should be applied while the skin is still damp. These products retain skin moisture in various ways:

Occlusives, such as petroleum jelly, prevent water from evaporating.
Humectants, including glycerin, act by pulling water up to the surface of the skin from deep tissues. People with oily skin generally should use the humectant type.
More powerful compounds, such as monolaurin (Glylorin), contain mixtures of fatty molecules (lipids), which may help restore the skin's natural barriers against moisture loss and damage.

Most moisturizers contain combinations of these compounds. They usually have other ingredients as well, such as alpha hydroxy acids, sunscreens, collagen, and keratin. Collagen and keratin leave a protein film and temporarily stretch the skin. They range widely in price, and a major consumer organization found little difference in general between the more and less expensive products.

The skin under the eyes is very thin and does not produce as much of the protective oils that keep skin soft and supple. Manufacturers market their under-eye gels as being able to reduce puffiness and dark circles. The creams typically work in one of two ways:

By temporarily constricting blood vessels to prevent the build-up of fluids
By firming the skin with an invisible film

Never rub the creams under the eyes, as this may cause more wrinkles to form. Instead, apply these products with a light tapping motion to stimulate the skin.

Cosmetics, if properly applied, can be surprisingly effective in camouflaging the signs of aging skin, including wrinkles and age spots. Moreover, they offer additional benefits by retarding water loss and providing a physical barrier to UV radiation. However, as women age, less is more.

Here are some suggestions for older women:

Moisturizers. Apply moisturizers before foundation. If reddish discoloration is extensive or the skin is sallow, tinted moisturizers may be helpful and can be worn alone or under foundation.

Foundations. Caking on make-up will cause cracks at the wrinkle lines and only increase the appearance of aging. Try to cover large areas of the face with a moderate-coverage foundation that has a matte or semi-matte finish. Facial powder reflects light and thus minimizes wrinkles, but people with dry skin should avoid it.

Correcting Color. When blemishes are especially prominent, applying color correctors under the foundation can be very effective:

Green neutralizers mask red lesions.
Yellow will camouflage dark circles and bruises.
Mauve (a purplish-pink color) helps neutralize sallow skin or yellowish blemishes.
A white, pearled base helps to minimize wrinkles.

Blushes. Blushes and color washes can help conceal the spidery network of dilated capillaries on the nose and cheeks. Powder blushes are preferred because they blend easily on top of foundation.

Eyes. Powder eye shadows applied on top of a moisturizer are better than cream-based shadows. Light-colored shadow, applied along the upper eyelid crease and above the iris (the colored part of the eye) is best for offsetting the appearance of deep-set eyes. You should then apply a slightly deeper shade of the same color to the lower part of the eyelid, and draw it out to the corner.

Lips. A lip-setting cream or facial foundation should be applied before lipstick to help prevent it from bleeding into surrounding wrinkles. Try using a stiff bristle brush instead of a lip pencil. The brush will help keep the lipstick on and prevent bleeding. (Some women use the pencil itself for the full lip, which gives color but appears natural.) Some make-up artists recommend cream lipsticks instead of matte.

The Food and Drug Administration (FDA) does not regulate herbal remedies and dietary supplements. In other words, the manufacturers and distributors of such products do not need FDA approval to sell their products. In addition, any substance that affects the body's chemistry can, like any drug, produce side effects that may be harmful. There have been numerous reported cases of serious and even deadly side effects from herbal products.

Overexposure to sunlight can damage skin. The following natural remedies may cause extra sensitivity to light (photosensitivity):

St. John's wort (Hypericum perforatum) is a popular herbal remedy for depression. People who are sensitive to light should not use it. A case report suggests that St. John's wort may cause skin reactions in patients who have laser treatment.
Kava (Piper methysticum) is an herb used to calm nerves and reduce stress. In addition to photosensitivity, it can cause liver damage.
Yohimbe (Pausinystalia yohimbe) is used to treat erectile dysfunction. Both the herb and the pharmaceutical drug (yohimbine) can cause sensitivity to light.
Essential oils in many botanical aromatherapy products can trigger photosensitivity. Avoid citrus oils (grapefruit, lemon, lime, and orange) as well as bergamot, cumin, ginger, and angelica root oils.

Resurfacing Treatments

There are many choices for skin resurfacing (also called exfoliation), and the patient must consider several different factors that affect the choice. Resurfacing can achieve the following:

Removal of abnormal tissue and rough skin
Stimulation of new skin growth
Stimulation of collagen and elastin production

In addition to determining the skill of the surgeon and the safety of the procedure, the patient must discuss the desired depth of the resurfacing and the capability of each procedure to reach this depth safely. All resurfacing procedures require a healing period afterward, during which the skin is red and sensitive. The deeper the procedure, the higher the risk for complications, including delayed healing, infection, loss of pigment (skin color), and scarring.

If you make the decision to pursue intensive treatments, consider the following factors, among others, and discuss them with your dermatologist or plastic surgeon:

The ability of the procedure to safely reduce wrinkles
The ease and safety record of the procedure
The skill of the doctor
The length of recovery
Possible complications
How long the benefits will last

A person's age also helps determine the procedure:

For people in their 30s, a simple chemical peel is sufficient.
After age 40, people may benefit from collagen or fat implants.
At age 50 and over, plastic surgeons recommend laser resurfacing and customized treatments for individual needs.

In older individuals, combination procedures may be beneficial. Some examples include the following:

Laser surgery may be used for deep lines (such as those around the mouth) and chemical peels used over the rest of the face.
For enhancing the eye by correcting droopy eyelids, bags, and a "sinking" brow, combinations of eyelift (blepharoplasty), Botox, and laser resurfacing may be used.

Chemical peels, also known as chemosurgery, help restore wrinkled, lightly scarred, or blemished facial skin. Much like chemical paint strippers, chemical peels strip off the top layers of skin, and new, younger-looking skin grows back. The procedure is very effective for the upper lip but cannot be performed around the eyes. Partial peels are often done in conjunction with a face-lift. Combinations of the topical antioxidants, such as tretinoin and vitamin C, along with a chemical peel, may be particularly effective.

The Procedure.

A dermatologist applies chemicals to the skin. They include trichloroacetic acid, high concentrations of alpha hydroxy or beta hydroxy acids, or combinations of all three.
In some cases, tretinoin or alpha hydroxy is applied 4 - 6 weeks before, and starting one day after, the peel. Such treatments can enhance the effects of a peel and reduce the risk of discoloration in people at risk for this complication. Tretinoin is being tested as a chemical peel.
A crust or scab generally forms within 24 hours after surgery. You can remove this scab by gently cleansing with soap and water.
The skin takes 6 - 7 days to heal.
After the scab disappears, the visible skin is deep red but gradually lightens as it regenerates.

Complications. Complications include white heads, cold sores, infection, scarring, numbness, and permanent discoloration, particularly in people with darker skin. Refinement of chemical peel techniques are now permitting doctors to reach deeper skin, improvements which make it easier to apply peels to non-facial skin and to individuals with darker skin.

Dermabrasion affects deeper layers of skin than chemical peels, and may be useful for removing disfiguring marks, such as deep acne scars or deep wrinkles. As with chemical peels, it is effective for wrinkles on the upper lip and chin, and cannot be used around the eyes. Some doctors prefer dermabrasion to lasers for skin surfacing of people with darker skin colors.

Standard Dermabrasion. Standard dermabrasion uses a rotating brush that removes the top layers of a person's skin. As with chemical peels, dermabrasion selectively strips away the upper layers of skin, leaving the underlying skin layers exposed. Similar to chemical peels, after the procedure, the treated skin oozes and forms a scab, a reaction that looks and feels uncomfortable, but only temporary. Postoperative care is similar for both procedures.

Microdermabrasion. A gentler variation called microdermabrasion uses very tiny crystals to polish the skin and a vacuum technique to remove them. It has largely replaced the older dermabrasion, and, in fact, was the fourth most common non-surgical cosmetic procedure performed in 2005, with over a million done. Results are similar to light chemical peels. Patients can have this procedure done on their lunch hour and return to work. Only mild redness occurs after treatment, although for best results five or six repetitive treatments are needed every 1 - 2 weeks. To date, overall patient satisfaction has been very high.

Lasers are currently the most effective exfoliation tools for eliminating wrinkles. Their unique advantages over other resurfacing methods are their ability to tighten the skin. A successful procedure can make patients look 10 - 20 years younger, and the results can last up to 10 years.

The procedure is most beneficial for the following areas:

It is best around the mouth and eyes. Recent evidence suggests CO₂ lasers may be even better than dermabrasion for the upper lip.
It is slightly less beneficial for the area around the nose.

Used alone, current laser therapy does not eliminate crow's feet, broken blood vessels, or dark circles under the eye. The evidence of the effects of lasers on acne scars is incomplete.

Standard laser dermabrasion is too harsh for thinner skin layers, such as on the neck. Newer and gentler laser techniques, however, stimulate collagen without removing skin layers, and may prove to be useful for necklines.

The Laser Resurfacing Procedure. In general the procedure works in the following way:

Laser pulses penetrate the skin quickly, vaporizing water and surface skin without damaging the deeper layers, allowing new top skin to grow.
In addition, the laser delivers enough heat to shorten collagen fibers, restoring some elasticity to the skin.

Choice of Lasers. The lasers used depend on skin type and severity of the condition. Some of the more common laser types are:

The carbon dioxide (CO₂) laser. This is the most powerful laser treatment and is used for deep wrinkles and skin imperfections. People who have had silicone injections should not have CO₂ procedures, which can burn and scar the skin over the implanted area.
The erbium: YAG (Er:YAG). This laser is gentler than the CO₂ laser, and is effective for mild wrinkles and for providing a smooth skin texture. It has a shorter recovery time. Some experts have even found the YAG laser as effective in removing deep wrinkles as CO₂ when used to sufficient depth. A variable pulse YAG laser can shift between pulses that destroy skin tissue to those that heat the skin. This process effectively resurfaces the skin with fewer side effects than CO₂ laser therapy.
Pulsed dye laser. Pulsed dye laser uses yellow light, which is easily absorbed by hemoglobin, the molecule that gives blood its red color. Pulsed dye laser treatments are used to treat skin blemishes that are due to blood vessel abnormalities, such as port-wine stains.

A gentle laser procedure called non-ablative laser resurfacing (NLite), also called photorejuvenation, is now approved for the treatment of all facial wrinkles. The procedure uses light energy to gently stimulate new collagen, and possibly elastin production, without removing the skin tissue itself. Its effects are less pronounced than those of other laser procedures. However, because it does not injure the external layers of skin, it can be used on delicate skin areas, such as the neck and around the eyes. It also causes very little irritation afterward.

Some surgeons are using combination techniques that employ more than one laser technology in one session, to achieve different effects. For example, one combination technique uses CO₂, YAG, pulsed-dye laser, and one other laser technology to both improve wrinkles and clear under-eye dark circles and acne scarring. Pretreatment with botulinum (Botox) injections before laser resurfacing significantly improved the treatment of crow's feet in one study.

Post-Procedure Recovery. The procedure itself is relatively painless, but the redness and irritation that occur during the healing process can be severe. Non-ablative laser resurfacing does not have the same severe after-effects as other laser treatments. For 8 - 9 days, the face looks skinned and swollen, and requires continuous moisturizing. Some doctors suggest that people with very sensitive skin, who cannot tolerate the necessary medications and lubricants, should avoid laser resurfacing. Redness and sensitivity can persist for 1 - 4 months. The patient must stay out of the sun as much as possible during this time, and should always avoid sunbathing and damaging their skin again. Early research suggests that silicone dressings may reduce post-procedure pain and crusting.

Complications. Scarring and infections can occur in about 1% of procedures. The risk of complications depends on the experience of the surgeon. People with a history of herpes simplex may experience flare-ups of fever, facial pain, and flu-like symptoms for 5 or 6 days after the procedure. In addition, people with darker skin may wish to avoid the procedure, because it can cause unpredictable and dramatic lightening of the skin.

A new skin rejuvenation technology, called Plasma Skin Resurfacing, or Portrait Plasma, was introduced in February 2005. The technology uses plasma energy (heat and light energy) to rejuvenate the skin from the deeper layers outwards. While new skin regenerates, the outer layers of the skin act as a natural bandage. When the outer layers peel off in the week after treatment, the new skin emerges. The process prevents or minimizes the raw appearance that follows laser treatments. This system uses radio waves to "excite" nitrogen gas, resulting in the release of energy. According to the manufacturer, skin regeneration using the Portrait Plasma system is rapid, and satisfaction with the procedure appears high. Long-term follow-up studies are not available yet for this new method. In 2006, the Food and Drug Administration approved this method for the treatment of wrinkles on other areas of the body, besides the face.

Cold Ablation. Cold ablation, called coblation for short, delivers saline (salt water) to the skin, through which a cool electric current is passed. A subsequent reaction heats and vaporizes the top shallow layer of skin. The procedure is very specific and appears to minimize any damage to other areas of the skin.

Radiofrequency Resurfacing. A promising technique uses low radiowave energy to resurface the skin. Preliminary research indicates that this procedure may eventually be as effective as laser surgery in reducing severe wrinkles around the eyes and mouth, with minimal pain and a shorter recovery time. In one study, one radiofrequency treatment with only a skin anesthetic resulted in tighter facial skin for 14 out of 15 patients within 12 weeks. All but one patient returned to normal activity immediately afterward. A small clinical trial published in Dermatology Surgery found that a noninvasive radiofrequency technique called NARF safely and effectively improved drooping lower eyelids.

Intense Pulsed Light. Intense pulsed light (IPL) uses filters to deliver different wavelengths of light. Doctors use it to treat a number of photoaging skin problems, and it appears to have long-term effects. Typically, four to six treatments are performed over a four-month period. Each treatment takes 15 - 20 minutes. Unlike laser light, which uses one color wavelength (such as green or red), intense pulsed light starts with a full spectrum of light. It then allows the doctor to selectively block off specific wavelengths, depending on how shallow or deep the procedure should go. IPL machines are less expensive and safer than lasers.

Implant Procedures

Implants, also called injectable fillers, are becoming a common means of erasing wrinkles and folds. Several materials are being used for deep wrinkles, depression under the eyes, lip enhancements, and acne scars.

After being banned from the market in 1992, silicone is making a comeback in research settings as a potential permanent wrinkle eraser. Scientists are looking into a new microdroplet technique (the use of very small drops) combined with purified silicone as a way to eliminate any danger. The past problems with silicone occurred when it was mixed with a foreign substance, like mineral oil, or when it was injected in large doses.

Most implants to date, however, are not completely satisfactory. Collagen implants and biologic fillers from animal, bacterial, or human sources do not provide long-lasting benefits. Synthetic fillers are permanent but may cause an allergic reaction, which can lead to chronic problems. Such reactions are rare, but they can be painful and unattractive.

The U.S. Food and Drug Administration (FDA) approved the Juvéderm product line in June 2006. Juvéderm is an injectable treatment of moderate-to-severe facial wrinkles and folds. Juvéderm products are gels made from hyaluronic acid. They are injected into the face. Doctors report good results after a single treatment with Juvéderm, and the results last for at least 6 months.


Name and Material Used	Procedure	Specific Areas Affected	Benefits	Drawbacks
Collagen implants. Collagen is the protein that forms the structures in the body (such as skin, bones, cartilage). The implant procedure has typically used bovine (cow) collagen. A form of human collagen (CosmoDerm, CosmoPlast) has now been approved.	Injected into target wrinkles with needle and syringe. Several weeks after injection, cow collagen breaks down and is replaced by newly created human collagen.	Wrinkles around the eyes and mouth. It is used to give lips greater fullness.	Very simple with faster recovery than many other implant techniques.	Wrinkles form again, and require repeat treatments 3 - 12 months later. Rarely, severe allergic reactions occur. Should not be used by children, pregnant women, and people with a history of autoimmune disease.
Microlipoinjection. Fat tissue from the patient's own thigh or abdomen.	Injected into target wrinkles with needle and syringe.	Deep wrinkles around the nose and mouth, folds in the forehead, and wrinkles on the hands.	No allergic or immune reaction because substance is patient's own fat.	Body eventually absorbs the fat, resulting in a need for multiple injections. Some studies suggest that 70% of the fat may still be in place after at least a year.
Gore-Tex. Highly porous (full of tiny holes) and inert (not chemically active) synthetic material.	Requires some surgery. Tiny patches are inserted under the skin to fill out wrinkles. Skin cells and blood vessels pass through the porous material easily, reducing the risk of severe irritation.	Deep wrinkles.	Material does not break down.	Possible scarring from surgical procedure. Allergic reactions are rare but can occur even with chemically inactive materials.
Artecoll. Contains PMMA, or polymethylmethacrylate, an inert substance, enclosed in tiny droplets of natural collagen.	Material is injected. Body absorbs collagen. PMMA remains and stimulates new collagen growth.	Deep wrinkles.	Although part of the implant is a natural collagen implant, it does not degrade as quickly as a full collagen implant.	Repeat treatments may still be needed. Possible allergic reaction.
Hyaluronic acid. Natural (non-animal) substance acts like a molecular sponge to absorb water. The FDA approved Restylane in 2003, Captiva, Hylaform-Plus, and Hylaform in 2004, and Juvéderm in 2006.	Gel is injected under the skin.	Moderate-to-severe wrinkles.	Low risk for allergic reaction. May last longer than cow collagen.	Repeat treatments needed.
Poly-L-lactic acid. Synthetic polymer. Approved in US as Sculpta. Approved in other countries as New-Fill.	Material is injected under the skin.	Approved in U.S. only for patients with facial fat loss due to HIV. Approved in other countries for wrinkles.	Low risk of allergies. Treatment effects can last 18 - 24 months.	Doctors require special training.

The popularity of Botox injections has skyrocketed in the United States. Between 2004 and 2005, the number of procedures performed jumped 16 percent. Botox injection was the number one non-surgical cosmetic procedure in 2005, with more than 3.2 million injections. Botulinum, the deadly toxin found in uncooked foods, is also a powerful muscle-relaxant. Tiny amounts of a purified form (Botox) are injected into wrinkles to relax the surrounding muscles. It may benefit forehead and frown lines, crow's feet, lower eyelids, lines on the side of the nose, and the area between the upper lip and the nose. It is also useful for treating involuntary muscle movements that can occur after a face-lift.

The injections need to be repeated every few months, since the effects wear off. The treatment decreases the ability to frown or squint and may cause the corners of the mouth to turn down. When used for areas around eyes, it produces a rounder appearance afterward, which patients should be aware of before they undertake the procedure.

The drug does not cross the blood-brain barrier, and, to date, the only side effects are temporary muscle weakness near the injection site. Although there have been some reports that Botox can reduce migraine and tension headaches, Botox also causes headaches in about 1% of cases. In some cases, the headaches can be very severe and long lasting (from 8 days to a month). Some researchers suggest that either a contaminated batch of Botox or a specific injection technique may be the cause, but additional investigation is needed.

Plastic Surgery

In 2005, there were over 2.1 million cosmetic surgeries, up 1% from the year before. Most of these surgeries were liposuction and breast surgeries. However, over 200,000 each of eyelid and nose surgeries were performed. Facial plastic surgeries range from being fairly minimal, such as a brow lift, to a full face-lift.

Several face-lift procedures (called rhytidectomies) are available. Face-lifts can provide individuals with a more youthful look. The degree of improvement, however, depends on many factors, including age, bone structure, skin type, and personal habits, such as smoking and sunbathing.

The Procedure. When a face-lift is a relatively simple procedure, it can take about 2 hours under local anesthetic in a doctor's office. Complicated face-lifts are done under general anesthesia in a hospital and can take 3 - 6 hours. The face-lift procedure may be one of the following:

Superficial musculoaponeurotic system (SMAS) is the most common face-lift procedure. The surgeon makes an incision at the hairline and separates the skin from the underlying tissue and muscles. The muscles are tightened and excess fat and tissue, such as fat under the chin and neck, are removed.
The endoscopic subperiosteal or subgaleal face-lift is a less invasive surgical technique. The surgeon raises facial structures rather than cutting away flaps of skin. Only a few half-inch incisions are made, and scarring is minimal. Not all individuals are candidates for this procedure, however.

Neither SMAS nor the endoscopic version is effective for the middle part of the face, particularly the deep lines (naso-labial folds) that run down from the nose beside the mouth. Some time after the SMAS face-lift, the upper face begins to age again while the lower area keeps its shape, causing the face to look imbalanced. Researchers are looking at other approaches, such as one called composite face-lift, that lift most muscles in the face.

Recovery Process. Recovery normally lasts from several weeks to several months. Swelling and discoloration are common. Some patients report tingling or numbing sensations after surgery. These sensations generally decrease as damaged nerves regenerate.

Complications. A face-lift is not without risks. A postsurgical hematoma is a collection of blood that can occur after a face-lift. In one study, major hematomas occurred in 2.2% of patients and minor hematomas in 6.65% of patients. They generally develop within 2 weeks of the surgery and require draining. Even minor hematomas need fast treatment to prevent greater complications. Such complications can include infection, changes in skin color, fluid buildup, and prolonged recovery time.

Other less common complications may include the following:

Infection
Excessive bleeding
Imbalanced facial muscles
Delayed healing
Scarring
Permanent injury to the nerves that control facial movements

These complications are rare, particularly with a skilled surgeon, but the more complex the face-lifts, the greater the risk.

Blepharoplasty. Blepharoplasty is the primary surgical procedure for eye lifts. Results usually last 5 -10 years. Although simple, it has potential complications, including permanent difficulty in closing the eyes or making a stern expression. Newer techniques, however, are preventing this complication. Assuming the surgeon is experienced, laser surgery is now preferred to the standard surgical scalpel approach. Laser surgery reduces bleeding and bruising, and both the operation and recovery are faster. Temporary blurred or double vision is common. More serious complications include infection, bleeding, dry eyes, difficulty in closing the eyes, and pulling down of the lower lids. Rare cases of blindness have been reported.

Transconjunctival Upper Blepharoplasty. An innovative procedure called transconjunctival upper blepharoplasty removes fat from the membrane that lines the eyelids (the conjunctiva) and is an effective technique for treating both the upper and lower eyelids. Unlike traditional blepharoplasty, this procedure does not cause scarring in the nasal area. In patients who have scars from previous surgeries, transconjunctival removal of fat can also make existing scars less obvious. Long-term side effects and effectiveness of this procedure have not been studied.

Laser Liposculpture and Platysma Resurfacing. A procedure called laser neck and jowl liposculpture and platysma resurfacing may prove to be an alternative to face-lifts. The procedure requires only a one-inch incision under the chin and removing excess fat. After the fat is removed, the surgeon tightens the platysma, the thin muscular sheet under the skin of the neck, which improves the shape of the neck. Only local anesthetic is needed, and the patient can return to normal activities in 2 days. The patient's skin should be elastic enough to be able to reform without sagging.

Resources

www.aad.org -- American Academy of Dermatology
www.asds.net -- American Society for Dermatologic Surgery
www.plasticsurgery.org -- American Society of Plastic and Reconstructive Surgeons
www.surgery.org -- American Society for Aesthetic Plastic Surgery
www.skincarephysicians.com/agingskinnet -- Aging Skin Net

References

Autier P, Gandini S. Vitamin D Supplementation and Total Mortality : A Meta-analysis of Randomized Controlled Trials. Arch Intern Med. 2007;167:1730-1737.

Cho HS, Lee MH, Lee JW, et al. Anti-wrinkling effects of the mixture of vitamin C, vitamin E, pycnogenol and evening primrose oil, and molecular mechanisms on hairless mouse skin caused by chronic ultraviolet B irradiation. Photodermatol Photoimmunol Photomed. 2007;23(5):155-62.

Edison BL, Green BA, Wildnauer RH, Sigler ML. A polyhydroxy acid skin care regimen provides antiaging effects comparable to an alpha-hydroxyacid regimen. Cutis. 2004;73(2 Suppl):14-17.

Gordon, ML. A conservative approach to the nonsurgical rejuvenation of the face. Dermatol Clin. 2005 Apr;23(2):365-71.

Helfrich YR, Yu L, Ofori A, et al. Effect of smoking on aging of photoprotected skin: evidence gathered using a new photonumeric scale. Arch Dermatol. 2007;143(3):397-402.

Hercberg S, Ezzedine K, Guinot C, et al. Antioxidant supplementation increases the risk of skin cancers in women but not in men. J Nutr. 2007;137(9):2098-105

Kang S. A multicenter, randomized, double-blind trial of tazarotene 0.1% cream in the treatment of photodamage. J Am Acad Dermatol. 2005; 52(2): 268-274.

Mitsuhashi Y, Kawaguchi M, Hozumi Y, Kondo S. Topical vitamin D3 is effective in treating senile warts possibly by inducing apoptosis. Dermatol. 2005;32(6):420-423.

Rubino C, Farace F, Dessy LA, Sanna MP, Mazzarello V. A prospective study of anti-aging topical therapies using a quantitative method of assessment. Plast Reconstr Surg. 2005;115(4):1156-1162.

Samuel M, Brooke RC, Hollis S, Griffiths CE. Interventions for photodamaged skin. Cochrane Database Syst Rev. 2005;(1):CD001782.

Sudel KM, Venzke K, Mielke H, et al. Novel aspects of intrinsic and extrinsic aging of human skin: beneficial effects of soy extract. Photochem Photobiol. 2005;81(3):581-587.

Thornfeldt C. Cosmeceuticals containing herbs: fact, fiction, and future. Dermatol Surg. 2005;31(7 Pt 2):873-880.

Vochelle D. The use of poly-L-lactic acid in the management of soft-tissue augmentation: a five-year experience. Semin Cutan Med Surg. 2004;23(4):223-226.

Yarosh D, Klein J, O'Connor A, Effect of topically applied T4 endonuclease V in liposomes on skin cancer in xeroderma pigmentosum: a randomised study. Xeroderma Pigmentosum Study Group. Lancet. 2001;357(9260):926-9.

Review Date:
10/23/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Sunscreen (On the skin)

admin — Thu, 04 Sep 2008 19:55:54 -0700

Overview

Introduction
Brand Name(s)
When This Medicine Should Not Be Used
How to Use This Medicine
How to Store and Dispose of This Medicine
Drugs and Foods to Avoid
Warnings While Using This Medicine
Possible Side Effects While Using This Medicine

HEALTH GUIDE REFERENCE FROM A.D.A.M

Introduction

May help protect your skin from sunburn, skin cancer, and other damage caused by the sun.

Brand Name(s)

Sport Sunscreen, Rite Aid Baby Sunscreen SPF 45, Rite Aid Sunscreen SPF 30, Rite Aid Sport Sunscreen SPF 48, Rite Aid Sport Sunscreen SPF 30, Rite Aid Sunscreen SPF 45 Oil Free Essential Defense, Rite Aid Sunscreen Sheer, Ti-Screen Moisturizing Sunscreen, Chap Stick Ultra, Rite Aid Kids Sunscreen

There may be other brand names for this medicine.

When This Medicine Should Not Be Used

Talk with your doctor if you have had an allergic reaction to a sunscreen. Even if you have had an allergic reaction to one sunscreen, you still may be able to use another sunscreen that contains different ingredients.

How to Use This Medicine

Cream, Stick, Gel/Jelly, Lotion, Spray

Most sunscreens are applied about 15 to 30 minutes before you go out into the sun. Sunscreens that contain PABA should be used about 1 to 2 hours before sun exposure. There are many different kinds of sunscreens, so instructions may change with each product. Always read and follow the instructions on the package label.
Use the sunscreen on your skin only. Do not get it in your eyes, nose, or mouth. Do not use the spray on your face. A sunscreen stick or lip balm especially made for your face is easy to use.
Apply a thick layer of sunscreen to all skin areas exposed to the sun. Reapply the sunscreen about every 2 hours, or after swimming, towel drying, or heavy sweating.
If the sunscreen contains alcohol, you should not use it near a fire or if you are smoking.

How to Store and Dispose of This Medicine

Store the sunscreen at room temperature away from heat and direct light. Do not freeze.
Keep all medicine out of the reach of children.

Drugs and Foods to Avoid

Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.

Talk with your doctor before using a sunscreen on the same skin areas you are treating with other skin medicines.

Warnings While Using This Medicine

You should not use sunscreens on children younger than 6 months of age unless you have first talked with your child's doctor. Children younger than 6 months old may absorb sunscreen through their skin into their bodies. It is best to keep infants younger than 6 months old out of the sun. If this cannot be avoided, lightweight clothes and a hat may help protect an infant from the sun.
Sunscreens work by either absorbing or reflecting the sun's ultraviolet radiation (UVR). UVR causes skin cancer, sunburns, and premature aging of skin (wrinkles and dry, thinning skin). Clouds will filter some UVR, but not all. You will still need to use sunscreen even when it is cloudy.
UVR can reflect off of light surfaces such as sand and snow. Wear a sunscreen when are out in the snow to keep from getting a sunburn.
Sunscreens are rated by SPFs (sun protection factors). Use a sunscreen with an SPF of at least 15. Children older than 6 months of age should wear a sunscreen of SPF 15 or higher when outdoors. If you need more protection or have fair skin, an SPF of 20 to 30 (or higher) can be used. You can also protect your skin by wearing a hat and lightweight clothes.
To prevent skin damage, avoid being in the sun between the hours of 10 AM and 3 PM, when the sun's rays are strongest.
Sunscreens that contain PABA may permanently stain your clothing yellow.

Possible Side Effects While Using This Medicine

If you notice these less serious side effects, talk with your doctor:

Rash

Review Date: 8/4/2008

A.D.A.M. Copyright

adam.com

Source Doc: 45_0824

Sunscreen (On the skin)

admin — Thu, 04 Sep 2008 20:05:13 -0700

Overview

Introduction
Brand Name(s)
When This Medicine Should Not Be Used
How to Use This Medicine
How to Store and Dispose of This Medicine
Drugs and Foods to Avoid
Warnings While Using This Medicine
Possible Side Effects While Using This Medicine

HEALTH GUIDE REFERENCE FROM A.D.A.M

Introduction

May help protect your skin from sunburn, skin cancer, and other damage caused by the sun.

Brand Name(s)

Esoterica Facial, Esoterica Sunscreen, Dermatone Skin Protector, Sportz Bloc, Dermatone UVA/Uvb Sunblock, Vanicream Lip Protectant, Sponix Sunscreen, Solbar Shield Sunscreen, Vanicream SPF 60, Vanicream SPF 30, NAVA-SC, Vanicream Sunscreen, Solbar Zinc SPF38, A-Fil, Rosula CLK

There may be other brand names for this medicine.

When This Medicine Should Not Be Used

How to Use This Medicine

Cream, Lotion, Gel/Jelly, Stick, Liquid, Ointment

Most sunscreens are applied about 15 to 30 minutes before you go out into the sun. Sunscreens that contain PABA should be used about 1 to 2 hours before sun exposure. There are many different kinds of sunscreens, so instructions may change with each product. Always read and follow the instructions on the package label.
Use the sunscreen on your skin only. Do not get it in your eyes, nose, or mouth. Do not use the spray on your face. A sunscreen stick or lip balm especially made for your face is easy to use.
Apply a thick layer of sunscreen to all skin areas exposed to the sun. Reapply the sunscreen about every 2 hours, or after swimming, towel drying, or heavy sweating.
If the sunscreen contains alcohol, you should not use it near a fire or if you are smoking.

How to Store and Dispose of This Medicine

Store the sunscreen at room temperature away from heat and direct light. Do not freeze.
Ask your pharmacist, doctor, or health caregiver about the best way to dispose of any outdated medicine or medicine no longer needed.
Keep all medicine out of the reach of children.

Drugs and Foods to Avoid

Ask your doctor or pharmacist before using any other medicine, including over-the-counter medicines, vitamins, and herbal products.

Talk with your doctor before using a sunscreen on the same skin areas you are treating with other skin medicines.

Warnings While Using This Medicine

You should not use sunscreens on children younger than 6 months of age unless you have first talked with your child's doctor. Children younger than 6 months old may absorb sunscreen through their skin into their bodies. It is best to keep infants younger than 6 months old out of the sun. If this cannot be avoided, lightweight clothes and a hat may help protect an infant from the sun.
Sunscreens work by either absorbing or reflecting the sun's ultraviolet radiation (UVR). UVR causes skin cancer, sunburns, and premature aging of skin (wrinkles and dry, thinning skin). Clouds will filter some UVR, but not all. You will still need to use sunscreen even when it is cloudy.
UVR can reflect off of light surfaces such as sand and snow. Wear a sunscreen when are out in the snow to keep from getting a sunburn.
Sunscreens are rated by SPFs (sun protection factors). Use a sunscreen with an SPF of at least 15. Children older than 6 months of age should wear a sunscreen of SPF 15 or higher when outdoors. If you need more protection or have fair skin, an SPF of 20 to 30 (or higher) can be used. You can also protect your skin by wearing a hat and lightweight clothes.
To prevent skin damage, avoid being in the sun between the hours of 10 AM and 3 PM, when the sun's rays are strongest.
Sunscreens that contain PABA may permanently stain your clothing yellow.

Possible Side Effects While Using This Medicine

If you notice these less serious side effects, talk with your doctor:

Rash

Review Date: 8/4/2008

A.D.A.M. Copyright

adam.com

Source Doc: 45_4962

Non-Hodgkin's lymphoma

FitSugar — Wed, 08 Oct 2008 17:35:06 -0700

In This Report

Highlights
Introduction
Risk Factors
Symptoms
Diagnosis
Outlook
Staging and Treatment Guide...
Chemotherapy
Biologic Therapy (Immunothe...
Radiation
Transplantation
Surgery
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

Chemotherapy can cause anemia, a drop in red blood cell (hemoglobin) levels. Erythropoiesis-stimulating drugs, which boost the production of red blood cells, are administered to counteract this complication. However, these drugs, which include epoietin alfa (Epogen, Procrit) and darbepoietin alfa (Aranesp), can also cause serious side effects and adversely affect survival when hemoglobin levels are raised too high.

In 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. The new labels have stronger warnings and updated dosing-related safety information.

The FDA advises that for treating anemia associated with chemotherapy, dosing should increase hemoglobin levels to no more than 12 g/dL. Treatment with these drugs should stop as soon as the chemotherapy course is completed. Erythropoiesis-stimulating drugs are not safe or appropriate for all patients undergoing chemotherapy. Patients should discuss the risks and benefits with their oncologists. The FDA is currently reviewing additional data concerning the safety of these drugs.

Positron Emission Tomography (PET) Scans and Lymphoma

PET scans are used to help diagnose and stage lymphoma, and they may also be helpful in assessing treatment outcomes for some types of lymphoma. In 2007, an international team of cancer specialists drew up new guidelines for evaluating how well lymphoma responds to treatment in clinical trials. The guidelines now recommend that PET scans be used to help determine if a patient has achieved remission.

Introduction

Lymphomas are malignancies of the lymph system that are generally subdivided into two groups, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Hodgkin's disease accounts for about 15% of all lymphomas. [For more information, see In-Depth Report #83: Hodgkin's disease.]

Non-Hodgkin's lymphomas is a term for malignancies that range from a very slow disease to an extremely aggressive but curable condition. They have certain features in common.

The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people refer to swollen glands in the neck, they are usually referring to swollen lymph nodes. Common areas where lymph nodes can be easily felt, especially if they are enlarged include the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).

Lymphomas, such as non-Hodgkin's lymphomas and Hodgkin's disease, represent tumors of the lymphatic system. This system is a network of organs, ducts, and nodes. The system interacts with the blood's circulatory system to transport a watery clear fluid called lymph throughout the body. The lymphatic system contains lymphocytes, important cells involved in defending the body against infectious organisms. This system also restores 60% of the fluid that leaks out from blood capillaries back into circulation, and its ducts provide transportation for fats, proteins, and other substances collected from the body's tissues.

Lymphocytes. The lymphatic system is involved in the production and transportation of lymphocytes, white blood cells that are a primary component of the immune system. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign proteins (antigens). To understand the lymphatic system, it is helpful to track part of the life cycle of these lymphocytes:

Lymphocytes develop in the bone marrow or thymus gland and are therefore categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).
B cells complete their structural growth and definition (known as differentiation) and mature in the bone marrow.
T cells also start out in the bone marrow but differentiate and mature in the thymus gland, located beneath the breastbone (sternum). This small gland is active mostly in the fetal stage through the first 10 years of life, after which it atrophies (shrinks).
B-cell and T-cell lymphocytes leave these organs through the bloodstream, which eventually branches out into the tiny blood vessels called capillaries.
Some lymphocytes, along with fluid, proteins, and other substances, migrate out of the capillaries into the surrounding tissues. A proportion of these lymphocytes and other substances then enter the lymphatic vessels.
Lymphatic vessels begin as tiny, blind-ended tubes and lead to larger lymphatic ducts and branches until they drain into two ducts in the neck, where the fluid re-enters the bloodstream.
Along the way, the fluid passes through lymph nodes, oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or added to the contents of the node.

Lymph Nodes. In the lymph node, lymphocytes receive their initial exposure to foreign substances (antigens), such as bacteria or other microorganisms, activating the lymphocytes to perform their immune functions. The size of a lymph node varies generally from that of a pinhead to a bean. Most nodes are in clusters located throughout the system. Important node clusters are found in the neck, lower arm, armpit, and groin.

Other Structures in the Lymphatic System. The tonsils and adenoids are secondary organs composed of masses of lymph tissue that also play a role in the lymphatic system. The spleen is another important organ that processes lymphocytes from incoming blood.

Click the icon to see an animation about lymph nodes.

Click the icon to see an image of lymph nodes in the head and neck.

Click the icon to see an image of the immune system structures.

Non-Hodgkin's lymphomas occur most often in lymph nodes in the chest, neck, abdomen, tonsils, and the skin. NHLs may also develop in sites other than lymph nodes such as the digestive tract, central nervous system, and around the tonsils.

About 85% of non-Hodgkin's lymphomas (NHLs) arise in B cells; the rest occur in T cells. Activation of a gene called BCL-2 is believed to be partly responsible for many B-cell lymphomas. This defect prevents apoptosis (a natural process whereby cells self-destruct) in the lymphoma cells.

There are more than 20 distinct types of non-Hodgkin's lymphomas. Most first arise in the lymph nodes, but about 20 - 30% of cases are now found outside the nodes, most often in the stomach, small intestine, skin, and brain.

Even experts disagree about the exact groupings. Lymphomas are categorized in a number of ways.

Classification by Cell Type, Appearance, and Genetic Make-up: The REAL System. Different classification systems for lymphoma have been proposed. The system used in this report is called REAL (Revised European-American Lymphoma Classification). It classifies all lymphomas by appearance, cell type, and genetic make-up:

Non-Hodgkin's lymphomas are first grouped as B cell or T cell.
Next, they are categorized by whether the B-cell and T-cell lymphomas were derived from immature (precursor) cells or mature (peripheral) cells.
The peripheral B and T cells are then classified by their appearance, genetic make-up, and specific chemical "markers," which further identify them.

T-cell lymphomas, Hodgkin's disease, and certain leukemias and aggressive lymphomas are covered in the REAL classification but are not discussed in any depth in this report.

Groups by Slow or Fast Growth. Each non-Hodgkin's lymphoma is further defined by its grade, or how aggressive it is:

Indolent (slow-growing), also called low-grade
Aggressive (fast-growing), also called intermediate- or high-grade

According to one report, half of new cases are now intermediate-grade lymphomas. Low-grade makes up 30%, while high-grade makes up 10% of all lymphomas.

Groups by Properties. Lymphomas are also grouped by certain properties:

Size (large versus small)
Shape (round versus irregular)
Whether they are or resemble blood plasma cells
Whether they are follicular (organized in round clusters) or diffuse (spread evenly throughout the lymph node)

Staging. Staging the disease is the next important step in classifying lymphomas. The stage (I - IV) of an NHL is determined by the number of tumors and whether they are still localized or have spread beyond the lymph node. In general, the higher the stage, the poorer the outcome, but other factors are important for a precise prognosis.

Indolent (Slow-Growing) Lymphomas (also Called Low-Grade Lymphomas)

Follicular lymphomas (FLs). Follicular small cleaved cell lymphoma (grade I) and follicular mixed small and large cell lymphoma (grade II). FLs account for 70% of indolent tumors and 20% of all NHLs in industrialized countries. It is very rare in developing countries and in Asia.

Lymphoplasmacytoid/Waldenstrom's macroglobulinemia. Often found in bone marrow, lymph nodes, and spleen. Can cause blood to become viscous and "sticky."

Marginal zone lymphomas (MZL). MZLs often occur as a result of a pre-existing disorder such as hepatitis C, bacterial infection in the stomach (H. pylori ), or an autoimmune disorder (Sjögren syndrome in the salivary glands or Hashimoto's thyroiditis in the thyroid gland). They may be classified as:

Monocytoid B-cell lymphoma, which involves only lymph nodes
Splenic marginal zone lymphoma, which affects the spleen, blood, and bone marrow
Mucosa-associated lymphoid tissue (MALT) lymphoma, which usually involves the gastrointestinal tract, thyroid, lung, breast, or skin

There is some controversy over whether MALT is a variation of MZL or a completely separate type of lymphoma that is more suitably classified as a separate low-grade lymphoma. At this time, it is classified as an MZL.

Aggressive Lymphomas (also Called Intermediate- and High-Grade Lymphomas)

Diffuse large-cell lymphomas (DL). DLs are the most common NHLs, accounting for about 40% of all cases. Subtypes include the following:

Primary mediastinal large B-cell lymphoma
Follicular large cell lymphoma
Anaplastic large cell lymphoma
T-cell lymphomas (not covered in this report)

In about 40% of cases, these DL lymphomas appear in areas outside lymph nodes, including digestive tract, skin, bone, thyroid, and testes.

Burkitt's lymphoma/diffuse, small noncleaved cell lymphoma. This is the most common childhood NHL. In African children, it often involves facial bones and is associated with Epstein-Barr infection.

Mantle cell lymphoma. Mantle cell lymphomas are found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). This lymphoma is similar to indolent lymphomas at the time of diagnosis, but it is more aggressive.

Lymphoblastic lymphoma. This lymphoma often occurs in young people. It is associated with a large mediastinal mass (occurring in chest cavity between the lungs) and carries a high risk for spreading to bone marrow and central nervous system.

Risk Factors

About 63,000 Americans were diagnosed with non-Hodgkin's lymphomas in 2007, and nearly 19,000 people died of the disease. For the past 25 years, the incidence in NHL has increased continuously. Most of this increase has occured in people over age 65.

Part of the reason for the dramatic rise was AIDS, which increases the risk for high-grade lymphomas. However, even after eliminating changes in diagnosing NHLs and known causes (such as AIDS), the incidence over the past 40 years is 40% higher. The number of cases in which lymphomas first occur outside the lymph nodes has also increased compared to those limited to the nodes. (This observed increase, however, may in large part be due to different methods of diagnosing lymphomas).

The cancer can develop in people at all ages, including children, although it is most common in those ages of 45 - 60. In general, the incidence of NHL is 50% higher in men than in women. This higher rate has been observed in many countries. Nevertheless, recent reports suggest that the rate is leveling off or even declining in men, but is increasing in women, particularly African-American women. Overall, the risk is slightly higher in Caucasians than in African-Americans.

The risks for NHL among men versus women and among African-Americans versus Caucasians may vary by lymphoma subtype. For example, follicular lymphomas were significantly higher in Caucasians than in African-Americans, and there was little gender difference. High-grade lymphomas were the most rapidly increasing type, particularly among men, with follicular lymphomas increasing most rapidly in African-American men.

Other studies have also reported ethnic differences by specific lymphoma subtypes. For example, follicular lymphomas constitute 20% of all NHLs in Western nations but are very uncommon in Asia and in developing countries.

The brother or sister of a person with the disease has more than twice the risk of developing NHL than the general population. Some cases of NHL in such cases are due to inherited disorders of the immune system. Studies suggest, however, that such family clusters are more likely to be due to environmental conditions that trigger the genetic factors.

Because of the rapid rise in NHL, investigators are looking for lifestyle factor that may contribute to this increase. No real association between lymphomas and body weight or shape or amounts of exercise has been found.

A number of reports suggest an influence of diet in the development of non-Hodgkin's involvements. However, for the most part a strong association remains speculative. Some of the possible dietary risk factors include:

A number of studies have observed an association between an increased risk for non-Hodgkin's lymphomas and high consumption of red meat (beef, pork, and lamb).
A higher risk for lymphoma has also been suggested for trans fatty acids (hydrogenated polyunsaturated fats, which are contained in hard margarines and commercial baked goods and fast foods). There appears to be no higher risk with natural polyunsaturated fats (found in most vegetable and fish oils).
Fish may be protective.
Some evidence suggests that milk may also be protective.
One major study observed a reduction in risk with high intake of vegetables. Another found no protection from vegetables, but did with diets rich in fruit.
Vitamin supplements have no effect on NHL.

Despite these kinds of reports, the influence of diet on the development of non-Hodgkin's lymphomas remains speculative.

Alcohol Use. Studies on alcohol have been mixed, with some showing a higher risk, some a lower risk, and some no difference at all.

Smoking. There is no evidence that smoking increases the risk for NHL itself, although it has been linked with high-grade and follicular NHLs in people with lymphomas.

Viruses or other microorganisms also play a role in some lymphomas. A number are being investigated:

Epstein-Barr virus, the cause of mononucleosis, is highly associated with Burkitt's disease and NHLs associated with immunodeficiency diseases. It is also a risk factor for Hodgkin's disease
Adult T-cell leukemia-lymphoma, which appears to be caused by a virus known as HTLV-I, has been found in southwestern Japan, the Caribbean, and the southeastern United States.
People who have stomach inflammation due to Helicobacter pylori or H. heilmannii bacteria are at increased risk for mucosa-associated lymphoid tissue lymphomas (MALT). (The use of antibiotics to get rid of the bacteria may cause remission in some patients who have an early stage form of lymphoma in an early stage.)
Human herpes virus 8 has been associated with NHL.
Borrelia burgdorferi, the bacteria that causes Lyme disease, has been associated with primary B-cell lymphoma.
Heavy antibiotic use during adulthood may increase risk. A 2005 study found that adults who used antibiotics more than 10 times had 1.8 times the risk of developing NHL than nonusers. However, researchers were not certain if antibiotics themselves, or the underlying infections they treated, were responsible for the increased risk.

Click the icon to see an image of Lyme disease.

Studies are reporting a higher prevalence of viral hepatitis C and B in patients with lymphomas, although such viruses do not appear to play a major role in triggering lymphoma.

Patients with diseases or conditions that affect the immune system may be at higher risk for lymphomas:

HIV-positive patients and those with full-blown AIDS are at higher risk for NHL, and the disease is more likely to be widespread in these patients than in those without the immune disease. Most AIDS-related NHLs are high-grade lymphomas. Burkitt's lymphoma is often seen in patients with AIDS. Although these patients have had a very poor prognosis, advances in antiviral therapy for HIV now allow better management of NHL with some success in achieving favorable outcomes. Part of the dramatic increase in NHL incidence over the past decades can be traced to AIDS.
Patients with a history of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, Hashimoto's thyroiditis, Crohn's disease, and Sjögren syndrome, are at an increased risk for certain NHLs, such as marginal zone lymphomas.
People who have organ transplants are at higher risk for NHL, probably due to multiple factors, including the drugs used to suppress the immune system and the transplanted organ itself.
Patients who have had high-dose chemotherapy with stem-cell transplantation are at higher risk.
Other immunodeficiency syndromes that put people at risk for NHL include Chediak-Higashi syndrome, ataxia-telangiectasia, B-cell lymphoproliferative syndrome, Bruton agammaglobulinemia, common variable immunodeficiency, and Wiskott-Aldrich syndrome.

Note on Allergies: There appears to be no association between NHL and allergies, overactive responses of the immune system. Allergies are the most common immune disorder.

Overexposure to a number of industrial and agricultural chemicals has been frequently linked to an increased risk for lymphomas. The data, however, are not consistent.

Organochlorines are chemicals produced when solid waste is burned. These by-product chemicals include dioxin, polychlorinated biphenyls (PCBs), and furans. Many studies have indicated that exposure to these chemicals increases the risk of developing NHL.
A number of studies have found an association between NHL and certain pesticides and herbicides, although more research is needed to confirm any definitive risk.
White spirits, thinners, phenoxy herbicides, wood preservative, aviation gasoline, plastic, and rubber chemicals have been associated with a higher risk for lymphomas. Specifically, in one study, painters and lumberjacks had a higher risk for NHL, while office and house workers had a lower risk.
Some studies have found an association with long duration and early use of permanent dark hair dyes. There is no consistent evidence, however, that hair dye increases the risk for lymphomas.

Symptoms

The most common first sign of lymphomas is painless enlargement of one or more lymph node, usually in the neck, armpits, or groin. Patients should see their doctors if these symptoms do not go away within 2 - 3 weeks.

The most common lumps or swellings in the neck are enlarged lymph nodes. They can be caused by bacterial or viral infections, cancer, and other rare causes.

Lymphomas sometimes cause systemic symptoms -- symptoms that affect the whole body, rather than a specific location. Some systemic symptoms are referred to as B symptoms. Patients who have B symptoms have a more severe condition than asymptomatic patients with the same cancer stage or tumor location or size.

B systemic symptoms include:

Drenching night sweats and weight loss
Fever (may occur sporadically and only at night)

Other systemic symptoms include:

Itching all over the body caused by the release of histamines, substances ordinarily triggered by an allergic response. In the case of NHL, this is due to abnormalities in the immune system. Although this is a systemic symptom, it is not usually considered a B symptom if other systemic symptoms are not also present.
In late stages, some patients develop a skin rash.
Tumor masses in the chest can cause coughing or breathlessness.
Lymphomas in the stomach can cause nausea and vomiting.

Many patients seek medical help for abnormally swollen lymph nodes (commonly referred to as "swollen glands"). Swollen glands can be caused by many conditions, most often infections, and are rarely serious.

Infections. In the great majority of cases, swollen glands are caused by an infection:

Enlarged lymph nodes in the neck are much more likely to be a sign of strep or other throat infection than NHL.
Infectious mononucleosis (caused by the Epstein Barr virus) is a common cause of swollen lymph nodes in young people.
Travel, particularly to countries with a high incidence of tropical diseases, can trigger similar symptoms.
Other infections that cause swollen glands include cat scratch fever, Lyme or other tick-borne disease, HIV, tularemia, tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, and hepatitis.

Hodgkin's Disease. Although both Hodgkin's disease and non-Hodgkin's lymphomas are malignancies of the lymph nodes, they can usually be distinguished by certain characteristics. It is extremely important to differentiate between Hodgkin's lymphomas and non-Hodgkin's lymphomas, since the treatments for these two conditions differ. In particular, a subtype of lymphoma called anaplastic large-cell lymphoma (ALCL) might be confused with Hodgkin's disease under some circumstances. [For more information, see In-Depth Report #83: Hodgkin's disease.]


Characteristics	Hodgkin's Disease	Non-Hodgkin's Lymphomas
Age and Prevalence	Average age is 28 with two age peaks, the major one occuring between 15 - 24, anda lesser peak after age 55. It is less common than NHL.	Average age is about 67. It is more common than HD.
Location	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. However, in HD it is also more likely to appear in the chest cavity between the lungs (the mediastinum), particularly in younger patients. Only about 15 - 20% of cases are found in areas below the diaphragm. Disease occurs outside the nodes in about 4% of cases.	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. In NHL, however, it is also more likely to appear in the nodes in the abdomen (called the mesenteric nodes). The disease occurs in the chest cavity in less than 40% of patients. (An exception, lymphoblastic lymphoma, which is seen most often in young people, is likely to first appear in the chest.) Disease occurs outside the nodes in about 23% of patients. Slow-growing lymphomas are common in the liver and bone marrow.
Symptoms	More likely than NHL (40%) to have systemic symptoms (such as fever and night sweats) at the time of diagnosis.	Less likely to have systemic symptoms (27%) at the time of diagnosis.
Progression	Less likely than NHL to be diagnosed in stage IV (10%). Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site. If it spreads below the diaphragm, it usually reaches the spleen first; the disease then may spread to the liver and bone marrow. If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.	More likely than HD to be diagnosed in stage IV (36%). The lymphomas are less predictable in their course than Hodgkin's disease and they are more apt to spread.

Other Cancers or Serious Conditions in the Lymphatic System. Other cancers that can travel to lymph nodes include breast cancer and leukemia.

Very serious causes of enlarged lymph nodes include disorders of the lymph system, such as Castleman's disease, lymphomatoid granulomatosis, and angioimmunoblastic lymphadenopathy. These lymph system disorders, although noncancerous, involve abnormal lymph cells. They are often fatal and can be very difficult to distinguish from lymphomas. Many of the other serious illnesses involving diseased lymph nodes develop simultaneously at multiple sites, while Hodgkin's nearly always starts at one location before spreading to nearby nodes. [For more information, see In-Depth Report #83: Hodgkin's disease or Report #86: Acute lymphocytic leukemia.]

Exposure to Medications. Exposure to certain medications such as phenytoin (Dilantin) may cause enlarged nodes. Other drugs, such as cephalosporins, penicillins, or sulfonamides, can cause enlarged nodes and other symptoms, including fever and rash, which may resemble Hodgkin's disease.

Diagnosis

The doctor will first ask questions about the patient's medical history and perform a physical examination to detect any node enlargements. If these steps point to lymphoma, additional tests will be done to rule out other diseases or to confirm the diagnosis and extent of the lymphoma.

It is sometimes reasonable to wait a little while for the swelling and symptoms to go away before deciding that additional testing is necessary. In some cases, lymph node swelling may be due to a temporary infection. However, some lymphomas cause off and on lymph node swelling. This is particularly true with small cleaved cell lymphoma (the most common NHL). Lymph nodes should be checked periodically for any return of swelling.

The doctor will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node sometimes indicates certain conditions. For example, a stony, hard node is often a sign of cancer, usually one that has metastasized (spread to another part of the body). A firm, rubbery node may indicate lymphoma. Soft nodes suggest infection or inflammatory conditions.

Blood tests help rule out infection and other diseases. Such tests include those blood counts and blood chemistries for kidney and liver function, uric acid, calcium, and phosphate levels. In a patient already diagnosed with lymphoma, blood tests that measure the enzyme lactate dehydrogenase are important in determining the prognosis. High levels indicate bulkier tumors. The presence of anemia may indicate specific NHLs, such as diffuse, small lymphocytic lymphoma.

A biopsy is the most important test for diagnosing lymphomas and can be used to tell the difference between non-Hodgkin's and Hodgkin's disease. A biopsy has risks and should be performed only by a qualified and experienced doctor. Sometimes a doctor may choose to wait and observe the involved lymph nodes, which will usually go away on their own if a temporary infection is causing the swelling. (However, some lymphomas may go away and appear to be benign, only to reappear at a later time.)

The Procedure. The doctor removes the node and checks the surrounding areas. The tissue in the node is then examined under a microscope for signs of infection and abnormalities indicating cancer or other conditions.

Results. Even if biopsies do not show any problems, disease may still be present in some cases. The doctor should continue to observe the patient until swelling or other signs of disease are gone. Biopsied tissue samples should be frozen in case special tests are later required. Such tests may include detection of particular antibodies, genetic and immune factors, and certain markers (substances that may indicate disease) located on the surface of the cells. If lymphoma has been diagnosed, the tissue will be examined for its histology, the cellular structures that will determine the lymphoma type.

Bone marrow aspirate and biopsy are routinely performed to determine whether the disease has spread. With bone marrow aspirate, bone marrow cells are sucked out through a special needle. A biopsy may be performed before or after the aspiration. In this procedure, a special needle removes a core of the marrow that is structurally intact.

Click the icon to see an image of bone marrow aspiration.

Chest X-Ray. A chest x-ray shows the lymph nodes in the chest and neck area. It is particularly useful in detecting Hodgkin's disease and enlarged lymph nodes.

Click the icon to see an image of an x-ray machine.

Computer Tomography. Computed tomography (CT) scans are more accurate than x-rays. They can detect abnormalities in the chest and neck area, as well as revealing the extent of the cancer and whether it has spread. CT scans are used to evaluate symptoms and help diagnose lymphomas, help with staging of the disease, monitor response to treatment, and evaluate when the symptoms occur. A CT scan is also often used in detecting lymphomas in the abdominal and pelvic areas, the brain, and chest area.

Click the icon to see an image of a CT machine.

Magnetic Resonance Imaging (MRI). MRIs may be used to detect the spread of the disease to the brain, spine, chest, pelvis, and abdomen.

Click the icon to see an image of a MRI machine.

Positron Emission Tomography (PET). PET scans can help tell whether or not an enlarged lymph node is benign or cancerous. PET scans are more accurate than CT scans or other imaging tests for staging lymphomas. PET scans may also help doctors determine how well a patient has responded to treatment, if any residual cancer exists, and if a patient has achieved remission.

Tests of lymphoma's DNA are in use or are being developed to detect particular genetic abnormalities that help determine outlook and may eventually lead to new treatments. Examples of such abnormal genetic arrangements are those that affect normal cell death, resist chemotherapy, or trigger aggressive cancer growth.

An advanced approach called the microarray technique uses chips that contain up to thousands of DNA sequences that represent specific normal and abnormal genes. Such sequences have been compiled for lymphomas. Eventually, experts may be able to match a patient's DNA to these patterns and identify specific subtypes.

Biologic markers, also called biomarkers, are high levels of substances released by tumors. They indicate the level of cancer activity. Biomarkers can be found in sputum, blood, and tissue samples. Biomarkers can be enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), and growth factors. Some under investigation include:

CD44. This molecule binds to the surface of cells and may be involved in metastasis. High levels of this molecule may suggest a more aggressive disease.
BCL-6. This cancer gene is implicated in diffuse large B-cell lymphoma. High levels of this gene in these patients indicate a better outlook after treatment.

Outlook

Five-year survival rates for NHL range from 20 - 95%, depending on the lymphoma type, stage, age of the patient, and other variables. Because the outlook varies so widely, making a definite prognosis is very difficult. For example, patients with very slow growing (indolent) lymphomas can live many years. However, they are usually diagnosed at a late stage, after the cancer has spread, thus reducing the survival rate. Aggressive lymphomas are more likely to cause rapid death, but they are also often curable. New drugs that target specific factors in the tumor cells are improving survival rates.

Follicular lymphomas, the most common indolent (slow-growing) NHLs, are potentially curable in early stages I and II. Unfortunately, however, these slow-growing malignancies produce no symptoms until they are in advanced stages. In most cases, these lymphomas are not diagnosed until they have spread to other sites, including the spleen and bone marrow. In such cases, they are difficult to cure. Predicting outcome for indolent follicular lymphomas is more difficult than for aggressive lymphomas. Even if treatment achieves a response, these tumors almost always recur. Even after relapse, however, the tumors can be treated again if they are still very slow-growing.

In general, the average survival rate for follicular lymphoma is 7 - 10 years, depending on other risk factors. New drug treatments, particularly monoclonal antibodies, have significantly improved survival rates. According to a 2005 study, 91% of patients with follicular lymphoma now survive the first 4 years after diagnosis, compared with 69% of patients treated in the past with older types of drugs. The research team found the best 4-year survival rates for patients treated with the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy regimen followed by monoclonal antibody biologic drugs (rituximab or iodine-131 tositumomab).

Factors for Predicting Outlook in Indolent Lymphomas. Six risk factors are proving to be useful for predicting outlook:

Being male
Being older
Having stage III or IV disease
Elevated levels of the enzyme lactate dehydrogenase (LDH)
The presence of B symptoms
Erythrocyte sedimentation rate over 30

Patients with a good chance for a positive outcome (65% chance for survival rates of 10 years or greater) have one or none of these factors. Those with intermediate risk (23%) have two factors, and those likely to have a poor outcome (11%) have three or more factors. MALT lymphomas generally have a good prognosis. Primary gastric lymphomas have a 3-year survival rate of 89%.

High-grade aggressive lymphomas are often symptomatic early on and are potentially curable with aggressive treatments. Diffuse large-cell lymphomas, the most common aggressive non-Hodgkin's lymphomas, while fatal if not treated, are often curable with intensive chemotherapy combinations. If relapse occurs after chemotherapy, it usually does so within 2 years.

Most other aggressive lymphomas respond to aggressive chemotherapy. Mantle cell lymphoma is less responsive to chemotherapy. The average survival time is 3 - 5 years.

Factors for Predicting Outlook in Aggressive Lymphomas: A scoring system called the International Prognostic Index has proved to be fairly accurate for predicting outcome in patients with most aggressive B-cell lymphomas. It uses five risk factors to help predict whether the disease will be aggressive:

Being older than 60 -- this age group tends to have other medical conditions, which contribute to the poorer prognosis
Having a disseminated tumor (stage III or IV)
Disease that has spread to more than one site beyond the lymph nodes
A poor performance status
Having elevated levels of lactate dehydrogenase (LDH)

Having one or none of these risk factors indicates the best outlook. Two factors indicate a low-to-intermediate likelihood of a poor outlook. Three factors predict an intermediate-to-high likelihood of poor outlooks. Finally, four or five factors pose the highest likelihood of poor survival.

Lymphoma can spread to the central nervous system, or it can appear there first. Called primary CNS lymphomas (PCNSL), this condition is a very serious, particularly if it occurs at relapse.

The central nervous system is comprised of the brain and spinal cord. The peripheral nervous system includes all peripheral nerves.

Risk Factors for CNS Involvement After a Diagnosis of NHL. AIDS-related lymphomas often involve the central nervous system (CNS), including the brain and spinal column. CNS involvement also occurs with aggressive lymphomas, such as Burkitt’s lymphoma.

Risk Factors of Primary CNS Lymphomas. PCNSL used to account for only about 2% of lymphomas, but the incidence is on the rise in all age groups and in both. The reason for the increase is not known.

Medical Problems. The radiation and chemotherapies used in treating NHL can have long-term effects on many organs in the body and can increase the risk for serious illnesses, including heart disease and certain cancers.

Negative Emotional Problems. Depression and anxiety are common in survivors, particularly those who suffer additional medical conditions. Many patients also suffer from fatigue and aches and pains, called somatic symptoms, which have no apparent physical basis. In one study, such symptoms were more highly associated with intensive chemotherapy. Women and people in lower social and economic groups are at higher risk for depression and somatic symptoms -- just as they are in the general population.

Staging and Treatment Guidelines

Treatment for non-Hodgkin's lymphoma is highly specific for each patient and is determined by the tumor classification. It includes the following factors:

Stage
Grade
Histologic type (cellular structure)
Location
Other factors, such as blood levels of lactate dehydrogenase

Treatment for lymphomas has been primarily dependent on chemotherapy (particularly intensive regimens using several drugs) or a combination of chemotherapy and radiation. For advanced or refractory lymphomas and for relapse, patients may undergo bone marrow or stem cell transplantation. New treatments, especially those known as immunotherapies, or biological response modifier (BRM) therapies, are showing promise. Some experts recommend that patients ask their doctors about getting into well-designed clinical trials as early as possible.

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

In assessing the success of a clinical trial, experts often refer to the tumor response. A complete response, for example, means that there is no longer any evidence at all of the disease by examination, blood tests, or x-ray studies. It does not necessarily mean, however, that the disease is cured. It may still recur later on.

In judging the success of a treatment for NHL, the most important criteria are overall survival and the duration of time until the disease progresses or the patient dies.

In Stage I, lymphoma is found in only one lymph node area or in only one area or organ outside the lymph nodes. Either of the following indicates stage II:

Lymphoma is found in two or more lymph node areas on the same side of the diaphragm.
Lymphoma is found in only one area or organ outside the lymph nodes and in the lymph nodes around it. Other lymph node areas on the same side of the diaphragm may also have lymphoma.

Early Stage Indolent (Low-Grade) Lymphoma. Below are the general treatment options:

Radiation therapy. Radiation to local areas can achieve a cure in 40 - 50% of patients.
Chemotherapy. Chemotherapy uses drugs to kill cancer cells.
Watchful waiting. Patients who choose watchful waiting must be aware of signs and conditions indicating the need for treatment. These include B symptoms, endangered organs, massive bulky tumors, or a steady progression that lasts at least 6 months.
Investigative treatments, such as conjugated and unconjugated monoclonal antibodies or radiation plus chemotherapy. In one study, a combination of therapies worked better than radiation alone.

The following are treatment options for some specific low-grade lymphomas:

Mucosa-associated lymphoid tissue (MALT) lymphoma. When disease is in the stomach (gastric MALT) and the patient is infected with H. pylori bacteria, antibiotics can cause regression in a significant number of patients with stage I lymphoma. In certain patients where antibiotics fail, or are not appropriate, radiation alone can achieve significant cure rates. Surgery with or without radiation, or chemotherapy with or without radiation, are possible options. Treatment options for patients with MALT localized in other sites depend on the location of the specific disease and range from radiation to chemotherapy to biologic therapies, such as interferon.
Primary gastric lymphoma (indolent). Radiation is the typical treatment for this lymphoma, which is located only in the stomach, small intestine, or other nearby regions. Surgery is being reconsidered since it seems to offer no advantage.

Click the icon to see an image of the digestive system.

Early Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options include:

Chemotherapy alone
Combinations of chemotherapy (usually CHOP) plus radiation therapy
Radiation alone (rarely)
Chemotherapy alone or with surgery for lymphoma in the gastrointestinal region
Immunotherapies (rituximab, Bexxar) with or without chemotherapy (usually CHOP), or high dose chemotherapy and bone marrow or stem cell transplantation

In stage III, lymphoma is found in lymph node areas on both sides of the diaphragm (for instance, in both the chest and the abdomen). The lymphoma may also have spread to the spleen. In stage IV, lymphoma has spread via the bloodstream to organs outside the lymph system, such as the bone marrow or brain. Lymphoma cells may or may not be in the lymph nodes near these organs.

Advanced Stage Indolent (Low-Grade Lymphomas). Treatment options are controversial because of the low-cure rate and yet slow-growing nature of these lymphomas. Patients without symptoms are often managed by watchful waiting, in which the disease is monitored closely for development of symptoms or bulky tumor masses, particularly if they threaten major organs. At such times, treatment is started. Treatment may include:

Chemotherapy combinations (CHOP, CVP, CMOPP)
Nucleoside analogs (for example, fludarabine) alone or with chemotherapy
Oral alkylating chemotherapy drugs such as cyclophosphamide or chlorambucil with or without steroids
Monoclonal antibodies (MAbs) such as rituximab alone or in combinations with CHOP or nucleoside analogs
Chemotherapy plus interferon
Clinical trials involving intensive chemotherapy and radiation followed by bone marrow or stem cell transplantation

Advanced Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options may include:

Doxorubicin-based combination chemotherapy with or without rituximab
Chemotherapy plus radiation therapy
Immunotherapies with or without chemotherapy
Treatments to prevent disease from spreading to the central nervous system in high-risk patients
Clinical trials for patients at high risk for relapse, involving intensive chemotherapy, high dose chemotherapy, and bone marrow or stem cell transplantation

Indolent-Lymphomas Relapses. Nearly all patients with indolent lymphomas relapse after initial treatment, with length of remission after a first treatment averaging 18 - 50 months. Successful retreatment is often possible, but disease-free periods become increasingly shorter with each subsequent treatment.

Older patients may choose watchful waiting. Other treatment options may include:

Radiation alone or with chemotherapy -- in one study low-dose involved-field radiotherapy was very effective in recurring indolent lymphoma
Chemotherapy
High-dose chemotherapy with autologous stem cell transplant
Clinical trials involving monoclonal antibodies, radioimmunotherapy, nucleoside analogues alone or in combination with other drugs, or stem cell transplantation followed by biologic therapies

Aggressive Lymphomas Relapse. After initial treatment, more than half of patients with aggressive lymphomas are cured, while about 20% progress, and the other 30% relapse after a disease-free period. Among those who relapse, many can still be cured with aggressive treatments.

Treatment options:

Bone marrow or peripheral stem cell transplantation
Bone marrow transplantation with radiation
Clinical trials that involve continuous infusion chemotherapy, biologic therapies (monoclonal antibodies) alone or in combination with transplantation

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Treating Lymphoma Restricted to the Central Nervous System. Treatment options may include:

High-dose methotrexate regimens alone or in combination with radiation
Corticosteroids and radiation
Clinical trials that involve biologic therapies, such as rituximab or interferon alpha administered directly into the spinal fluid (intrathecal administration) for meningitis related to central nervous system lymphoma

Preventing (Prophylactic Treatment) Lymphomas in High-Risk Patients. Treatment to prevent the spread of NHL to the central nervous system may be appropriate in some patients. It is not recommended for patients with low-grade NHL. Preventive treatment may be appropriate for certain patients with high-grade NHL, such as those with lymphoblastic and Burkitt's lymphoma or if they have 4 - 5 of the following risk factors: Elevated levels in the blood of the enzyme acetate dehydrogenase and albumin (a common protein), being older than 60, and having lymph nodes beyond the peritoneum (the lining of the abdomen) and involvement of more than one site outside a lymph node.

Chemotherapy

Chemotherapy plays a role in the treatment of nearly all lymphoma patients and has achieved remarkable results, even in late stages. It uses drugs to kill cancer cells. Such drugs are called cytotoxic drugs. Chemotherapy is referred to as bodywide or systemic therapy because the drugs travel throughout the bloodstream to the entire body.

Studies indicate that chemotherapy as sole treatment is adequate for most children and young adults in early, and perhaps in many advanced, stages. (Radiation has been commonly used for these patients but can be particularly dangerous for children.)

A chemotherapy cycle is usually 21 - 28 days. Patients take the drugs for a few days, then have a period of rest. The drugs may be taken by mouth or given by injection. Chemotherapy is injected into the spinal fluid if the cancer has spread to the brain. This is called intrathecal chemotherapy. Intrathecal chemotherapy is also used as a preventive measure in patients at high risk for central nervous system involvement. Chemotherapy may be administered at a medical center or in a doctor's office. Some patients receiving chemotherapy need to remain in the hospital for several days so the effects of the drug can be monitored. Patients with lymphoblastic lymphoma may need long-term maintenance chemotherapy. Such therapy does not seem to benefit patients with small-noncleaved-cell and large-cell lymphomas.

CHOP. The current standard chemotherapy regimen for NHL is CHOP. CHOP is a combination of cyclophosphamide, doxorubicin hydrochloride (Adriamycin), vincristine (Oncovin), and prednisone. It is proving to be particularly effective for many stages of lymphoma when used in combination with rituximab (Rituxan), a monoclonal antibody. (See Biologic Therapy section.) Some studies of this combination in low-grade lymphomas have reported response rates of 70 - 100%. CHOP alone is still preferred for HIV patients, who tend to have a toxic response to rituximab.

CVP. This stands for cyclophosphamide, vincristine, and prednisone. It may be used with CHOP in certain cases.

Fludarabine and Nucleoside Analogues. Fludarabine (Fludara) is a type of drug called a nucleoside analogue. It is one of the most active drugs for treating low-grade lymphomas and may be effective for other NHLs, including mantle cell lymphomas. Promising regimens containing fludarabine are under investigation. For example, FND (fludarabine, mitoxantrone, and dexamethasone) may be helpful in combination with rituximab for certain patients, including those with indolent NHL. Other nucleoside analogues include gemcitabine and cladribine. Toxicities and infection rates from high dose nucleoside analogues have been high. Fludarabine also has been associated with a risk for leukemia.

Bendamustine. This potent drug has shown to be effective for indolent NHLs and possibly aggressive lymphomas. One study suggested that a single dose of low-dose etoposide, taken by mouth, may be beneficial for elderly patients.

Antibiotics. Antibiotics, such as doxycycline, may cure or put into complete remission about half of mucosa-associated lymphoid tissue (MALT) lymphoma cases. MALT lymphoma is a type of lymphoma that sometimes affects the eyes. It is associated with the bacterium Helicobacter pylori (H. pylori ), which also causes stomach ulcers. Recent studies indicate that antibiotics are a good alternative to chemotherapy or radiation for patients with this type of lymphoma. Patients most likely to respond positively to antibiotics are those with MALT lymphoma in its early stages.

Vorinostat. Vorinostat (Zolinza) was approved in 2006 for treatment of cutaneous T-cell lymphoma (CTCL), a rare form of NHL.

Side effects and complications of any chemotherapeutic regimen are common. They are more severe with higher doses. Side effects may increase over the course of treatment.

Common Side Effects. Common side effects include:

Nausea and vomiting -- Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and in most patients who take more powerful drugs.
Diarrhea
Hair loss
Weight loss
Depression

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps a few days a month.

Serious Side Effects. Serious chemotherapy side effects can also occur and may vary depending on the specific drugs used. They include:

Neutropenia is a severe drop in white blood cells. Neutropenia increases the chance for infection from suppression of the immune system and is a potentially life-threatening condition. Drugs known as granulocyte colony stimulating factor (G-CSF) are used to help boost white blood cell count. These drugs, which include filgrastim (Neupogen) and pegfilgrastim (Neulasta), can help lessen the risk for neutropenia occurrence and, if neutropenia does occur, to reduce its length and severity.
Anemia is a lack of red blood cells. Erythropoietin stimulates red blood cell (hemoglobin) production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). In 2007, the FDA released strict dosing guidelines for these drugs. In patients with cancer, they should be used to treat only anemia associated with chemotherapy and to increase hemoglobin levels to no more than 12 g/dL. Treatment should stop as soon as chemotherapy is complete. These drugs may not be safe or appropriate for all patients.
Liver and kidney damage
Abnormal blood clotting (thrombocytopenia)
Allergic reaction

Long-Term Complications.

Fatigue and Somatic Symptoms. Chemotherapy has been associated with long-term somatic symptoms, which are general conditions, such as fatigue and aches and pains that have no apparent physical basis. Fatigue is especially common after chemotherapy and can even last for years.
The most serious long-term complications from chemotherapy are secondary cancers, particularly in people over age 40.
Infertility is a risk, particularly with the use of cyclophosphamide.
Some patients get osteoporosis (bone thinning) and damage in bone cells.
Regimens containing certain drugs, particularly doxorubicin or mitoxantrone, increase the risk for future heart failure.

Click the icon to see an image of the uterus and ovaries.

In general, these serious late side effects are dependent on the cumulative drug dose and rate of administration.

Doctors are particularly concerned about the effects of combinations of chemotherapy with radiation, especially leukemia and heart problems. Interestingly, in one study on patients with intermediate- and high-grade NHL, those on chemotherapy alone had more toxic effects than those on combined modality, most likely because it employed fewer cycles of chemotherapy. Better radiation techniques are also reducing the risks of combined modality treatments.

Biologic Therapy (Immunotherapy)

Biological response modifier therapy, also called immunotherapy, uses the body's own immune system to fight cancer using natural or laboratory-developed factors. These drugs are often combined with other treatments.

Monoclonal antibodies (MAbs) are designed in the laboratory to produce the same effects as natural antibodies and are exciting new weapons in the anti-cancer armament. They bind to specific proteins called antigens and make them vulnerable to attack by other factors in the immune system. Lymphomas carry antigens that provoke strong immune responses and so are believed to be particularly good candidates for MAb therapy.

MAbs are called either unconjugated or conjugated, depending on how they are designed to destroy the cancer cell.

Unconjugated monoclonal antibodies rely on a strong natural immune system. The antibody builds up at the tumor site until it is able to trigger an immune response against the cancer. A possible downside to this form is the potential development of tolerance to the antibody so that it loses its effectiveness. Rituximab is an unconjugated form and the first MAb to be approved for any cancer.
Conjugated monoclonal antibodies are linked to a plant or bacterial toxin or radioisotope. The antibody specifically attacks the antigen on the lymphoma cell, and the toxin or radioactive material from the isotope kills it.

Unconjugated MAbs (Rituximab). Rituximab (Rituxan) was the first monoclonal antibody approved for cancer. This drug targets the CD-20 antigen, which is found on most B-cell lymphomas.

First approved in 1997 for treatment of relapsed or refractory NHL, rituximab has received several expanded indications since that time. As of 2006, rituximab is approved for:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, NHL
First-line treatment of diffuse large B-cell (DLBC), CD20-positive, NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens
First-line treatment of follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy
Low-grade, CD20-positive, B-cell NHL in patients with stable disease or patients who have been partially or completely helped by first-line treatment with CVP chemotherapy

Rituximab in combination with CHOP (a regimen called R-CHOP, or CHOP-R) is used for first-line treatment for aggressive lymphomas, with studies reporting 3-year event-free survival of 53% compared to 35% with CHOP alone. A 2006 study also indicated that rituximab provides benefits when used as maintenance treatment after CHOP or R-CHOP induction therapy. Rituximab plus CHOP is also showing promise as a first-line treatment for mantle cell lymphoma.

Rituximab is given by infusion. The treatment has mild-to-moderate short-term side effects, including nausea, fever, chills, hives, dizziness, and headache. Uncommon and more serious side effects are severe allergic reactions, very low blood pressure, blood abnormalities, wheezing, infections, and sudden heart events.

Rituximab has also been associated with cases of progressive multifocal leukoencephalopathy (PML), a rare and potentially deadly brain infection. Patients who experience any of the following symptoms should immediately contact their doctors:

Vision problems or unusual eye movements
Confusion
Dizziness or loss of balance
Difficulty talking or walking

Patients who have previously had hepatitis B, or who are at high-risk for this viral infection, should be tested before taking rituximab because the drug has been linked to reactivation of the hepatitis B virus. Patients who are HIV-positive may experience more adverse effects from rituximab than with CHOP.

Conjugated Monoclonal Antibodies with Radioimmunotherapy. Conjugated MAbs with radioimmunotherapy contain tiny amounts of radioactive materials. When the drug is injected, the monoclonal antibody targets an antigen (protein) on the surface of the tumor. The radioisotope is then delivered directly into the tumor where it kills the cancer. Ibritumomab and tositumomab both target the CD-20 antigen. Treatment with these drugs takes about 7 - 9 days to complete, compared to several months for traditional chemotherapy treatments.

Ibritumomab (Zevalin) is approved for patients with relapsed or refractory low-grade, follicular or transformed B-cell NHL. It is also approved for patients with follicular NHL who have not responded to rituximab (Rituxan). Research indicates it may also be safe for patients with advanced NHL who have had stem cell transplantation. Zevalin uses an yttrium-90 (90-Y) radioactive isotope.
Tositumomab and Iodine I-131 (Bexxar) combines the monoclonal antibody tositumomab with the radioisotope I-131. The Bexxar treatment is approved for treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Overall response rates of 56% have been reported with Bexxar, with up to 30% being complete responses (no evidence of cancer). Recent studies suggest that when Bexxar is used as a first treatment, it may produce long-term complete remission in patients with advanced stage follicular lymphoma. In a 2005 New England Journal of Medicine study, 95% of previously untreated patients with advanced follicular lymphoma responded to Bexxar, and 75% had complete responses. Seventy percent who had complete responses from Bexxar treatment were still disease-free 4 - 7 years later.

In general, these drugs cause fewer side effects than traditional chemotherapy. However, serious complications may include skin infections, severe allergic reactions, and temporary lowering of blood counts.

Other Monoclonal Antibodies. Other MAbs are being developed that target other antigens on lymphomas. For example, epratuzumab targets CD-22 and is showing promise in early studies. Some are being studied in both conjugated and unconjugated forms and also in combination with MAbs that target different antigens.

Interferon alpha (Intron A) is used as an antiviral drug that also has properties that are effective against some common forms of NHL, particularly low-grade, follicular NHL in advanced stages. It is usually combined with chemotherapy regimens such as CHOP that contain an anthracycline drug (usually doxorubicin). The combination is toxic, however, and outcomes vary. Interferon is also being studied for lymphomas in the central nervous system. It may be useful after autologous stem cell transplantation.

Side Effects. Side effects of interferon include flu-like symptoms, severe depression, irritability, weight loss, vomiting, general weakness and loss of strength, and fever. About a third of patients have a severe drop in white blood cells. About 10% of patients cannot tolerate the drug's side effects.

Cytotoxic Deoxyguanosine Analogue Prodrugs. Nelarabine (Arranon) is approved for treating T-cell lymphoblastic lymphoma (T-LBL). T-LBL is a rare form of lymphoma that accounts for less than 2% of all cases of NHL.

Proteasome Inhibitors. In 2006, bortezomib (Velcade) was approved for treatment of mantle cell lymphoma in patients who have received at least one prior therapy.

Cyclin-Dependent Kinase Inhibitors. Flavopiridol, a drug known as a cyclin-dependent kinase inhibitor, is showing some effect in patients with mantle-cell lymphoma. This drug is designed to block enzymes that regulate cell cycles and help block their growth.

Vaccines. Although still experimental, lymphoma vaccines are used to treat -- not prevent -- cancer. They are part of an immunotherapy approach called personalized medicine; each vaccine is individually tailored to the genetic composition of the patient’s tumor. The vaccine is usually given a few months after a patient receives chemotherapy. Several different vaccines, including the BiovaxID and MYVax, are in late-stage clinical trials.

Radiation

Radiation is commonly used to treat indolent lymphomas. The dose administered ranges from 35 - 50 Gy and depends on a number of factors: The type of lymphoma, the age of the patient, whether the intent is to cure or relieve symptoms, how close sensitive organs are to the diseased area, and whether radiation is being combined with chemotherapy.

Radiation is tailored to the individual and usually limited to the diseased areas and possibly nearby regions:

If the lymphoma is confined to tissues above the diaphragm, radiation is delivered to the neck, chest, and under arms (called the mantle-field) and sometimes to lymph nodes in the upper abdomen or spleen or both.
If the lymphoma is below the diaphragm, subtotal nodal radiation may be used, which is directed to other regions, including lymph nodes in the upper abdomen, spleen, and pelvis, in addition to the mantle-field.
Radiation to the brain is called cranial radiation.
Total body irradiation is sometimes performed, although it is not clear whether its high toxicity outweighs any advantages.

Devices called planning simulators allow doctors to plan x-ray treatments that accurately conform to the patient's anatomy so that protective shields can be created to precisely protect the regions outside the treatment areas.

Side effects and complications of radiation generally depend on the target site in the body. They include:

Dental problems
Inflammation in the lungs -- with carefully conducted therapy, the risks for lung complications are small. Lung impairment may not even be evident, and the lungs usually recover after 2 - 3 years.
Hypothyroidism
Infections
Long-term risk for heart disease
Long-term risk for certain cancers -- of particular concern is a possible increased risk for breast cancer. Studies indicate that young women and adolescent girls are at highest risk, with the incidence increasing significantly 15 years after treatment. The risk is greater in those who had higher radiation doses. Radiation may also increase the risk over time for other cancers, including lymphoma and thyroid, lung, and colon cancers, although the risk is still low. Smoking, of course, increases the risk for lung cancer. Radiation of bone marrow increases the risk for leukemia.
Impaired bone growth -- children and adolescents are at special risk for bone problems caused by radiation. Experts are finding that radiation for many children and young adults in early stages or NHL is no more effective and has more serious long-term effects than chemotherapy. Some believe that radiation should play no role in the treatment of young people, except in special cases, such as lymphomas that require radiation to the brain.
Infertility -- the negative effects on fertility may be worse in women than in men; sperm usually recover within 5 years. To protect the ovaries, a technique called ovarian transposition is sometimes used. Transposition may sometimes be performed through a laparoscope, a thin tube containing tiny instruments and cameras, which is introduced through a small incision. The doctor uses the laparoscope to move the ovaries out of the range of areas being treated with radiation.

Click the icon to see an image of the lungs.

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of the uterus and ovaries.

Transplantation

Stem cell procedures have proven to produce long-term survival and even cures in some patients with intermediate- and high-grade non-Hodgkin's lymphomas.

Stem cell transplantation involves removing and replacing stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Sources of Cells. Stem cells must first be collected in one of the following ways:

Directly from blood, called peripheral blood stem cell transplantation
From bone marrow, called bone marrow transplantation
From umbilical cords or placentas -- this procedure uses donor cells, but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, so it is generally used for children and sometimes adults with low weight.

Some evidence suggests that both stem cell and bone marrow procedures produce similar benefits in terms of response rates and duration of remission. However, in one study, stem cell transplantation was associated with better overall survival rates. It also seems to be superior in terms of cost, quality of life, and the need for less supportive care.

Donor or Patient Cells. The marrow or blood stem cells can be taken from the patient (autologous) or from a matched donor (allogeneic):

In an autologous transplant, the marrow or blood cells used for replacement are taken from the patient. There is some danger, however, that these cells may contain tumor cells, and that the cancer can regrow. It is unclear if this approach improves survival compared to standard chemotherapy for newly diagnosed disease. However, it clearly has benefits in the treatment of some forms of relapsed non-Hodgkin's lymphomas. There is also a higher risk for leukemia. (This risk is lower in peripheral stem cells transplants than in bone marrow transplants.)
In an allogeneic transplant, bone marrow or stem cells are taken from a donor. Siblings are the best donors. Relapse rates can be very low with this approach, and cure may be possible in some cases. However, it is highly toxic and donor and recipient must be matched as closely as possible to avoid rejection by the immune system, a serious complication called graft-versus-host disease. Advances in techniques are reducing the toxicities associated with this approach. Older patients who cannot tolerate the preparatory treatment required for a standard allogeneic transplant may be able to receive a non-myeloblative transplant (“mini-transplant), which uses lower doses of chemotherapy and radiation.

The Blood Stem Cell Collection Procedure. With peripheral blood stem cell transplantation:

The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim, pegfilgrastim) to stimulate stem cell growth.
The patient (or donor in an allogeneic procedure) then undergoes apheresis. With this process the blood is withdrawn from one of the patient's veins, then passes through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes 3 - 4 hours but needs to be repeated several times.
The stem cells are treated to remove contaminants and then are frozen to keep them alive until the patient is ready to receive them back.

Blood is the only fluid tissue in the body. Blood transports oxygen and nutrients to body tissues, and returns waste and carbon dioxide. Blood distributes nearly everything that is carried from one area in the body to another place within the body. For instance, blood helps transport hormones from the endocrine organs to their target organs. Blood also helps maintain body temperature. The protective functions of blood include clot formation and the prevention of infection.

Allogeneic transplants are preceded by chemotherapy treatment known as conditioning. The point of this treatment is to inactivate the immune system and to kill any residual malignant cells. It is extremely toxic since it also destroys non-malignant marrow cells. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning to reduce toxicity includes total-body radiation plus drugs. Monoclonal antibodies, such as rituximab, are promising drugs, since they have low toxicity and may add benefits for all stages of transplantation.
A few days after treatment, the patient given the stored stem cells, which are administered through a vein. This may take several hours. Patients may have a fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
The patient may be treated with granulocyte colony-stimulating factor after chemotherapy. The goal is to stimulate the growth of infection-fighting white blood cells. Adding thrombopoietin may help enhance stem cell production.
The patient is kept in a protected environment to minimize infection. Patients who have received an allogeneic transplant may need blood cell replacement, nutritional support, and drugs to treat graft-versus host disease. They usually can leave the hospital within 3 - 5 weeks.

Candidates. These procedures are typically used for patients with relapsed aggressive lymphoma who are still sensitive to the effects of chemotherapy. The procedures do not work for patients whose tumors are not responsive to drugs. Some evidence suggests that certain primary (non-relapsed) lymphomas initially unresponsive to a first round of chemotherapy but who respond to a second round may benefit from combination of high-dose chemotherapy and radiation followed by transplantation. Transplantation is also being investigated as first-line therapy for patients with aggressive lymphomas, although at this time evidence does not support its use.

Success Rates. Success rates vary depending on many factors. The following are survival rates reported by a few studies of patients with different lymphomas:

In patients with refractory or relapsed intermediate grade NHL who received autologous transplantation, 5-year survival rates averaged 34%.
In a study of allogeneic bone marrow transplantation, 58% of patients with late-stage low-grade lymphoma had survived after an average of 29 months.
Patients with anaplastic large-cell lymphoma were treated with autologous stem cell transplantation with intensified chemotherapy as first line-therapy. Survival rates were 87% at 5 and more years afterward. (Survival was much lower with other lymphomas.)
Patients with diffuse aggressive NHL who did not achieve a first remission but who are still sensitive to chemotherapy achieved a 5-year survival rate of up to 37% after autologous stem cell transplantation.
In one study, 35% of patients with an initial poor prognosis were still alive 5 years after an allogeneic stem cell transplantation, although mortality probability from the treatment itself was very high (48%).

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now mortality rates are below 5%.

Infection resulting from a weakened immune system is the most common side effect. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. The risk for infection is most critical during the first 6 weeks following the transplant, but it takes 6 - 12 months post-transplant for a patient’s immune system to fully recover. Immune systems of patients with graft-versus-host disease can take even longer to function normally.

Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis carinii (a protozoan) are among the most important life-threatening infections.

It is very important that patients take precautions to avoid infections. Guidelines for post-transplant infection prevention include:

Discuss with your doctor what vaccinations you need and when you should get them.
Avoid crowds, especially during cold and flu season.
Be diligent about handwashing and make sure that visitors wash their hands.
Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
Boil tap water before drinking it.
Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
Do not sleep with pets. Avoid contact with pets’ excrement.
Avoid fresh flowers and plants as they may carry mold. Do not garden.
Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
Report to your doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection. Some of these symptoms can also indicate graft-versus-host disease.
Report to your ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. Mild cases of GVHD can actually be helpful as they can cause graft-versus-lymphoma where the immune system kills remaining lymphoma cells. Still, severe GVHD can pose serious complications.

To reduce the risk for GVHD, doctors remove some immune T-cells from the donor’s stem cells before the transplant. Researchers are investigating new techniques to refine this process of T-cell depletion.

Acute GVHD occurs in 30 - 50% of allogeneic transplants, usually within 25 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older patients). The first sign of acute GVHD is a rash, which typically develops on the palms of hands and soles of feet and can then spread to the rest of the body. Other symptoms may include nausea, vomiting, stomach cramps, diarrhea, loss of appetite and jaundice (yellowing of skin and eyes). To prevent acute GVHD, doctors give patients immune-suppressing drugs such as steroids, methotrexate, cyclosporine, tacrolimus, and monoclonal antibodies.

Chronic GVHD can develop 70 - 400 days after the allogeneic transplant. Initial symptoms include those of acute GVHD. Skin, eyes, and mouth can become dry and irritated, and mouth sores may develop. Chronic GVHD can also sometimes affect the esophagus, gastrointestinal tract and liver. Bacterial infections and chronic low-grade fever are common. Chronic GVHD is treated with similar medicines as acute GVHD.

Too much sun exposure can trigger GVHD. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.

Secondary cancers. There is a small long-term risk for leukemia after transplantation in young people. Use of newer chemotherapeutic drugs, however, may not pose as high a danger as older treatments.

Other potentially serious complications include:

Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
Infertility
Organ complications to the liver, heart, kidney, or lungs
Failure of the transplant
Muscle problems including stiffness, cramps, and joint pain
Frequent urination and bladder control problems
Older patients should be screened for osteoporosis (bone thinning) and hypothyroidism (underactive thyroid)

Surgery

Surgery is sometimes used to remove as much malignant tissue as possible before administering chemotherapy. This is particularly useful for bulky tumors that occur in the stomach.

Surgery is sometimes performed for primary gastric lymphoma, but its advantages are uncertain. Some studies indicate that chemotherapy alone or with radiation may be sufficient and could spare many patients from surgery.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.leukemia.org -- The Leukemia and Lymphoma Society
www.canceradvocacy.org -- National Coalition for Cancer Survivorship
www.marrow.org -- National Marrow Donor Program
www.asco.org -- American Society of Clinical Oncology
www.lymphoma.org -- Lymphoma Research Foundation
www.plwc.org -- People Living with Cancer
www.oncolink.org -- Cancer information
www.fhcrc.org/science/clinical/ltfu/patient -- Fred Hutchinson Cancer Research Center -- Transplant Infection Guidelines for Patients
www.lymphomainfo.net -- Lymphoma Information Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Boffetta P, de Vocht F. Occupation and the risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007: 16(3):369-72.

Ferrara JL. Novel strategies for the treatment and diagnosis of graft-versus-host-disease. Best Pract Res Clin Haematol. 2007. 20(1):91-7.

Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007 Feb 10;25(5):571-8. Epub 2007 Jan 22.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. V.3.2007.

Seam P, Juweid ME, Cheson BD. The role of FDG-PET scans in patients with lymphoma. Blood. 2007 Nov 15;110(10):3507-16. Epub 2007 Aug 20.

Review Date:
1/21/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Susan Posnick Cosmetics: Serious Protection Against Skin Cancer

FitSugar — Mon, 29 Sep 2008 10:00:00 -0700

Mineral powders for your face are all the rage now. Not only are they all natural, but they're a great weightless foundation that makes your skin look even and shine-free. The best part is these minerals also contain SPF, which protects your skin from the sun's harmful rays. Bare Escentuals was the pioneer in mineral powders, and now many other companies have come up with their own versions. My favorite is one made by Susan Posnick Cosmetics.

I absolutely love her minerals known as Coloflo ($64), and prefer them to Bare Escentuals bareMinerals. To find out why read more.

The reason I love Susan Posnik's minerals over Bare Escentuals is because this powder offers more sun protection. Colorflo contains SPF 26 while bareMinerals only offers SPF 15 (big difference). This sun protection even lasts in water, and the powder is anti-bacterial, sweatproof, and enriched with vitamins A and E . Another great feature is that Susan Posnick's powder comes in a self-dispensing refillable container with a washable brush attached. All you do is sweep the brush on your skin and the powder is already in the bristles. It's very convenient for sticking in your purse and the fact that you can purchase refills for $32 makes the environmentalist in me smile.

I also learned that Susan Posnick was a professional make-up artist for over 20 years, and she is a skin cancer survivor. She left her work in the film and fashion industry to develop a product with substantial sun protection that wouldn't feel heavy on your skin. Yet another reason to love Coloflo.

Fit's Tips: The blush featured in the photo is called Colorme ($32) in the shade, Peony. If you purchase it in October - so wait a couple of days, the proceeds will benefit the National Breast Cancer Foundation since October is National Breast Cancer Awareness Month.

Psoriasis

FitSugar — Wed, 08 Oct 2008 17:35:27 -0700

In This Report

Highlights
Introduction
Types of Psoriasis
Causes
Risk Factors
Diagnosis
Treatment
Topical Medications
Systemic Medications
Phototherapy
Managing Psoriasis
Outlook
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Treatment

Psoriasis that develops on the hands or feet is often very difficult to treat. However, an advanced clinical trial showed that a medication called efalizumab (Raptiva) effectively cleared or nearly cleared moderate-to-severe symptoms in adults after 12 weeks.

Several studies have shown that most people with severe psoriasis who are treated with infliximab (Remicade) have significant improvement in symptoms by week 10. The findings were presented at the 2007 annual meeting of the American Academy of Dermatology.

Continuing etanercept (Enbrel) after 12 weeks improves disease severity without an increase in infections or side effects, according to a study published in the Archives of Dermatology.

Disease classification

The National Psoriasis Foundation has proposed a new way to classify psoriasis. Instead of being grouped as mild, moderate, or severe, the group suggests a new two-tiered system that classifies patients as needing either local or body-wide (systemic) treatment.

Coexisting conditions

Studies from Newfoundland and Germany have revealed increased cases of diabetes, obesity, arthritis, and cancer in patients with psoriasis. Previous research has found an increased risk of heart disease in psoriasis patients. Research is underway to determine if there are genetic links between psoriasis and these conditions.

Severe psoriasis has been linked to a significant increase in a patient's risk of death. A study of more than 713,000 patients showed that severe psoriasis increased mortality by 50%. Such patients should receive comprehensive health examinations to reduce the risk, the authors recommended. Study participants were considered to have severe psoriasis if they required systemic treatment.

Smoking and psoriasis

Introduction

Psoriasis is a chronic skin disorder marked by periodic flare-ups of sharply defined red patches, covered by a silvery, flaky surface. The main disease activity leading to psoriasis occurs in the epidermis, the top five layers of the skin.

The process starts in the basal (bottom) layer of the epidermis, where keratinocytes are made. Keratinocytes are immature skin cells that produce keratin, a tough protein that helps form hair, nails, and skin. In normal cell growth, keratinocytes grow and move from the bottom layer to the skin's surface and shed unnoticed. This process takes about a month.

In persons with psoriasis, the keratinocytes multiply very rapidly and travel from the basal layer to the surface in about 4 days. The skin cannot shed these cells quickly enough, so they build up, leading to thick, dry patches, or plaques. Silvery, flaky areas of dead skin build up on the surface of the plaques before being shed. The underlying skin layer (dermis), which contains the nerves and blood and lymphatic vessels, becomes red and swollen.

Types of Psoriasis

Various forms of psoriasis exist. Some can occur alone or at the same time as other types, or one may follow another. The most common type is called plaque psoriasis, also known as psoriasis vulgaris.

Plaque psoriasis leads to skin patches that start off in small areas, about one-eighth of an inch wide. They usually appear in the same areas on opposite sides of the body.

The patches slowly grow larger and develop thick, dry plaque. If the plaque is scratched or scraped, bleeding spots the sizes of pinheads appear underneath. This is known as the Auspitz sign.

Some patches may become ring shaped (annular), with a clear center and scaly raised borders that may appear wavy and snake-like.

As the disease progresses, eventually separate patches may join together to form larger areas. In some cases, the patches can become very large and cover wide areas of the back or chest. This is known as geographic plaques because the skin lesions resemble maps.

Plaque psoriasis may persist for long periods. More often it flares up periodically, triggered by certain factors such as cold weather, infection, or stress.

Patches most often occur on the:

Elbows
Knees
Lower back

The may also be seen on the:

Upper pelvic bone area
Bottom of the feet
Calves and thighs
Genital areas
Palms of hands

Psoriasis of the scalp affects about 50% of patients. In some cases, the psoriasis may cover the scalp with thick plaques that extend down from the hairline to the forehead.

Psoriasis patches rarely affects the face in adulthood. In children, psoriasis is most likely to start in the scalp and spread to other parts of the body. Unlike in adults, it also may occur on the face and ears.

Psoriatic arthritis (PsA) is an inflammatory condition characterized by stiff, tender, and inflamed joints. Estimates on its prevalence among those with psoriasis range from 2 - 42%. AIDS patients and those with severe psoriasis are at higher risk for developing PsA.

About 80% of PsA patients have psoriasis in the nails. Arthritic and skin flare-ups tend to occur at the same time. It is not clear whether psoriatic arthritis is a unique disease or a genuine variation of psoriasis, although evidence suggests they are both caused by the same immune system problem.

Although patients with psoriatic arthritis tend to have mild skin symptoms, the disease affects the entire body. PsA, therefore, is more serious than the more common plaque psoriasis. Infrequently, the course of PsA has been associated with a syndrome known by the acronym SAPHO, which stands for:

Synovitis (inflammation in the joints)
Acne
Pustule eruptions
Hyperostosis (abnormal bony growths)
Osteolysis (bone destruction)

Some experts group PsA into five forms. The forms differ according to the location and severity of the affected joint:

Symmetric PsA: Symptoms occur in the same location on both sides of the body. It usually affects multiple joints. In about half of the cases, the condition will get worse. The condition is very similar to, but less disabling than, rheumatoid arthritis. The psoriasis itself is often severe.
Asymmetric PsA: This form involves periodic joint pain and redness, usually in only one to three joints, which can be the knee, hip, ankle, wrist, or one or more fingers. The pain does not occur in the same location on both sides of the body.
Distal interphalangeal predominant (DIP): DIP involves the joints of the fingers and toes closest to the nail. It occurs in about 5% of PsA cases.
PsA in the spine: Inflammation in the spinal column (spondylitis) is the primary symptom in about 5% of PsA cases. Such patients may have stiffness and burning sensations in the neck, lower back, sacroiliac, or spinal vertebrae. The spine can be involved in many patients with PsA, even though stiffness and burning sensations in these areas are not the primary symptoms. When it affects the spine, psoriatic arthritis most frequently targets the sacrum (the lowest part of the spine). Movement is difficult.
Arthritis mutilans: This is a severe, deforming, and progressive form of arthritis. It affects less than 5% of PsA cases. It mainly affects the small joints of the hands and feet, but it can also be found in the neck and lower back. Arthritic and skin flares and remissions tend to coincide.

People who start to smoke after developing psoriasis may delay the onset of psoriatic arthritis, according to research presented at the 2007 annual meeting of the Society for Investigational Dermatology. Researchers found that in nonsmokers, the time between psoriasis diagnosis and psoriatic arthritis development was 13 years, compared to 23 among those who started smoking after the onset of psoriasis. Study participants who smoked before developing psoriasis had psoriatic arthritis occur in about 8 years. However, smoking causes serious health problems and should not be considered as a way to delay this type of psoriasis.


Psoriasis Form	Description of Skin Patches	Comments
Guttate Psoriasis	The patches are teardrop-shaped and appear suddenly, usually over the trunk and often on the arms, legs, or scalp. They often disappear without treatment.	Guttate psoriasis can occur as the initial outbreak of psoriasis, often in children and young adults 1 - 3 weeks after a viral or bacterial (usually streptococcal) respiratory or throat infection. A family history of psoriasis and stressful life events are also highly linked with the start of guttate psoriasis. Guttate psoriasis can also develop in patients who have already had other forms of psoriasis, most often in people treated with widely-applied topical (rub-on) products containing corticosteroids.
Inverse Psoriasis	Patches usually appear as smooth inflamed patches without a scaly surface. They occur in the folds of the skin, such as under the armpits or breast, or in the groin.	Inverse psoriasis may be especially difficult to treat.
Seborrheic Psoriasis	Patches appear as red scaly areas on the scalp, behind the ears, above the shoulder blades, in the armpits or groin, or in the center of the face.	Seborrheic psoriasis may be especially difficult to treat.
Nail Psoriasis	Tiny white pits are scattered in groups across the nail. Toenails and sometimes fingernails may have yellowish spots. Long ridges may also develop across and down the nail. The nail bed often separates from the skin of the finger and collections of dead skin can build up underneath the nail.	Over half of patients with psoriasis have abnormal changes in their nails, which may appear before other skin symptoms. In some cases, nail psoriasis is the only symptom.
Generalized Erythrodermic Psoriasis (also called psoriatic exfoliative erythroderma)	This is a rare and severe form of psoriasis, in which the skin surface becomes scaly and red. The disease covers all or nearly all of the body.	About 20% of such cases evolve from psoriasis itself. The condition may also be triggered by certain psoriasis treatments, and other medications such as corticosteroids or synthetic antimalarial drugs.
Pustular Psoriasis	Patches become pus-filled and blister-like. The blisters eventually turn brown and form a scaly crust or peel off. Pustules usually appear on the hands and feet. When they form on the palms and soles, the condition is called palmar-plantar pustulosis.	Pustular psoriasis may erupt as the first occurrence of psoriasis, or it may evolve from plaque psoriasis. A number of conditions may trigger pustular psoriasis, including infection, pregnancy, certain drugs, and metal allergies. It can also accompany other forms of psoriasis and be very severe.

Causes

The precise causes of psoriasis are unknown. It is generally believed to be due to damage in factors in the immune system, enzymes, and other materials that control skin cell division. This prompts an abnormal immune response, which causes rapid production of immature skin cells and inflammation.

The Normal Immune System Response. The inflammatory process is the result of the body's immune response, which fights infection and heals wounds and injuries:

When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign invaders, such as bacteria or viruses.
The masses of blood cells that gather at the injured or infected site produce factors to repair wounds, clot the blood, and fight infections.
In the process, the surrounding area becomes inflamed (red and swollen), and some healthy tissue is injured.

The Infection Fighters. The primary infection-fighting units are two types of white blood cells: lymphocytes and leukocytes.

Lymphocytes include two subtypes known as T cells and B cells. Both types of cells are designed to recognize foreign substances (antigens) and launch an offensive or defensive action against them:

B cells produce antibodies, which are designed to attack the antigens. Antibodies can either ride along with a B cell or travel on their own.
T cells have special receptors attached to their surface that recognize the specific antigen.

T cells are further categorized as killer T cells or helper T cells (TH cells).

Killer T cells directly attack antigens found on bacteria or other cells.
Helper T stimulate B cells and other white cells to attack the antigen.

The actions of the helper T cells are of special interest. Researchers have found high numbers of helper T cells in psoriatic plaques. Helper T cells normally stimulate B cells to produce antibodies. In psoriasis, however, they appear to direct the B cells to produce autoantibodies ("self" antibodies), which attack skin cells. In psoriatic arthritis, cells in the joints also come under attack.

Helper T cells also release or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are very important for healing. If overproduced, however, they can cause serious damage, including inflammation and injury during the psoriasis disease process. In psoriasis, researchers are particularly interested in cytokines known as GRO-alpha, tumor necrosis factor, and certain interleukins.

Cytokines attract large numbers of other large white blood cells known as neutrophils. Neutrophils stimulate the production of arachidonic acid, producing two key players in the inflammatory process:

Leukotrienes: These chemicals attract even more white blood cells to the inflamed area.
Prostaglandins: These chemicals widen blood vessels and increase blood flow.

A combination of genes is involved with increasing a person's susceptibility to the conditions leading to psoriasis.

HLA Molecules. The processes leading to all autoimmune diseases involve the human leukocyte antigen (HLA) system. HLA molecules pick off parts of antigens and present them on the surface of a cell so that the various infection-fighting factors in the immune system can recognize and destroy them. Most immune disorders, including psoriatic arthritis, are due to problems with this system. For example, psoriasis patients with an HLA genetic factor called HLA-CW6 tend to develop psoriasis at an earlier than average age. However, only 10% of people who have this gene develop psoriasis. Other genetic and environmental factors are required to actually trigger the disease.

PSORs. Researchers have now identified four key genes (named PSOR 1 - 4) that are involved with psoriasis. Of particular interest are the genes located in regions on specific chromosomes that are linked to HLA and tumor necrosis factor, another immune factor strongly associated with psoriasis.

Weather, stress, injury, infection, and medications, while not direct causes, are often important in triggering the disease process leading to the start and worsening of psoriasis.

Weather. Cold, dry weather is a common trigger of psoriasis flare-ups. Hot, damp, sunny weather helps relieve the problem in most patients. However, some people have photosensitive psoriasis, which actually improves in winter and worsens in summer when skin is exposed to sunlight.

Stress and Strong Emotions. Stress, unexpressed anger, and emotional disorders, including depression and anxiety, are strongly associated with psoriasis flare-ups. In one study, nearly 40% of patients remembered a specific stressful event that occurred within a month of a psoriasis flare. Other research has suggested that stress can trigger specific immune factors associated with psoriasis flares.

Infection. Infections caused by viruses or bacteria can trigger some cases of psoriasis. For example:

Streptococcal infections in the upper respiratory tract, such as tonsillitis, sinusitis, and strep throat, are known to trigger guttate psoriasis in children and young adults. The infections may make ordinary plaque psoriasis worse.
Human immunodeficiency virus (HIV) is also associated with psoriasis.
An uncommon form of human papillomaviruses (HPV) called EV-HPV has been associated with psoriasis. Although EV-HPV is probably not a direct cause, it may play a role in the continuation of psoriasis. This HPV form is not the virus associated with cervical cancer and genital warts.

Skin Injuries and the Köbner Response. The Köbner response is a delayed response to skin injuries, in which psoriasis develops later on at the site of the injury. In some cases, even mild abrasions can cause an eruption, which may be a factor in the frequency of psoriasis on the elbows or knees. It should be noted that psoriasis can develop in areas with no history of skin injury.

Medications. Drugs that can trigger the onset of the disease, worsen symptoms, or cause a flare-up include:

Angiotensin-converting enzyme (ACE) inhibitors, drugs used to treat high blood pressure and heart problems
Beta-blockers, drugs used to treat high blood pressure and heart problems
Chloroquine, a medicine used to treat malaria
Lithium for bipolar disorder treatment
Indomethacin, a nonsteroidal anti-inflammatory drug (NSAIDs) -- Note: Other NSAIDs, such as meclofenamate, may actually improve the condition.
Progesterone, used in female hormone therapies

Flare-ups of severe psoriasis may occur in persons who stop taking steroids taken by mouth, or who discontinue use of very strong steroid ointments that cover wide skin areas. The flare-ups may be of various psoriatic forms, including guttate, pustular, and erythrodermic psoriasis. Because these drugs are also used to treat psoriasis, this rebound effect is of particular concern.

Medications that cause rashes, a side effect of many drugs, can trigger psoriasis as part of the Köbner response.

Risk Factors

Between 5.8 and 7.5 million Americans have psoriasis. Risk factors for psoriasis include:

Age under 20. About 40% develop the condition before age 20. Psoriasis (most often plaque psoriasis) can even occur in infants.
Climate. Some studies have found that the disorder develops earlier and more frequently in colder climates. For example, psoriasis occurs more frequently in African-Americans and in Caucasians who live in colder climates than in people of any ethnicity who live in Africa.
Ethnicity. Psoriasis is uncommon in Native Americans of either North or South American descent.
Family history of the disease. About 35% of those with psoriasis have one or more family members with the disorder.
Male gender. Some studies have indicated that more men than women have psoriasis.

Diagnosis

A microscopic examination of tissue taken from the affected skin patch is needed to make a definitive diagnosis of psoriasis and to distinguish it from other skin disorders. Usually in psoriasis, the examination will show a large number of dry skin cells, but without many signs of inflammation or infection. Specific changes in the nails are often strong signs of psoriasis.

Several conditions produce symptoms that resemble those of psoriasis. For example:

Seborrheic psoriasis is hard to distinguish from seborrheic dermatitis (dandruff is one form of this condition). Seborrheic dermatitis patches are usually greasy, yellowish, and crusty. Nail involvement may also help differentiate psoriasis.
Generalized erythrodermic psoriasis may be confused with drug allergic reactions, atopic eczema, and symptoms of lymphomas.
Fungal infections, other skin conditions, or circulation problems may also cause nail changes typical of psoriasis.

Symptoms of psoriatic arthritis may also resemble the following:

Rheumatoid arthritis (RA). As in rheumatoid arthritis, psoriatic arthritis can cause pain or tenderness in one or more joints, and morning stiffness is common. People with psoriatic arthritis, however, lack a particular antibody, called rheumatoid factor, which is found in the blood of many people with rheumatoid arthritis.
Systemic lupus erythematosus (SLE). Symptoms of SLE may include both a psoriasis-like rash and arthritis, which could make the diagnosis difficult.
Reiter's disease. Reiter's disease is a syndrome that includes arthritis and inflammation in the eyes and urinary tract. It also causes skin lesions that are very similar to psoriasis, which are usually raised patches on the lips, penis, palms, and soles.
Gout. Gout causes pain, often in the fingers and toes.

Some evidence now indicates that inflammation in psoriatic arthritis may be distinguished from other arthritic conditions by its occurrence in sites where muscle tissue inserts into the bone (called enthesitis) rather than in the joint, which is a common site in other inflammatory arthritic conditions.

Severity of psoriasis itself ranges from one or two flaky inflamed patches to widespread pustular psoriasis that, in rare cases, can be life threatening. To help determine the best treatment for a patient, doctors usually classify the disease as mild to severe. The classification depends on how much of the skin is affected:

Mild psoriasis affects less than 3% of the body surface. Most cases of psoriasis are limited to less than 2% of the skin.
Moderate psoriasis covers 3 - 10% of the skin.
If more than 10% of the body is affected, the disease is considered severe.

The palm of the hand equals 1% of the body. The severity of the disease is also measured by its effect on a person’s quality of life.

However, the National Psoriasis Foundation has proposed a new classification method. The group suggests a new two-tiered system that classifies patients as needing either local or body-wide (systemic) treatment.

While disease severity impacts treatment success, some forms of psoriasis can be very resistant to treatment even though they are not categorized as severe. They include:

Any psoriasis on the palms and soles (hand and foot psoriasis)
Inverse psoriasis (which occurs in the folds of the skin)
Scalp psoriasis
Psoriatic arthritis

Treatment

Many creams, ointments, lotions, and pills are available for the treatment of psoriasis. Many patients require only over-the-counter treatment, or even none at all during relapses.

About a third of patients with psoriasis, however, do not respond to over-the-counter remedies and lifestyle changes, and require aggressive treatments. In some cases, such treatments need to be lifelong.

In general, there are three treatment options for patients with psoriasis.

Topical medications such as lotions, ointments, creams, and shampoos
Body-wide (systemic) medications, which involve pills or injections that affect the whole body, not just the skin
Phototherapy, which uses light to treat psoriasis lesions

Individual requirements vary widely, and treatment selection must be carefully discussed with the doctor.

Giving treatment in a particular order is a strategy for providing both quick relief of symptoms and long-term maintenance. It involves three main steps:

The quick fix, to clear the psoriatic lesions during an acute outbreak (for example, a high-strength topical steroid in mild-to-moderate psoriasis, or an oral immunosuppressant in more severe cases)
The transitional phase, intended to gradually introduce the maintenance drug
Ongoing maintenance therapy

Choices for transitional or maintenance treatments depend on the severity of the condition. Some examples are described in the following sections.

In severe chronic cases, a doctor may recommend rotational therapy. This approach alternates treatments. The goal is to prevent severe side effects or build-up of resistance from long-term use of a single medicine. An example of a rotational schedule may be the following:

The patient gets phototherapy for about 2 years.
The patient then takes one or two powerful body-wide drugs for 1 - 2 years and stops.
Phototherapy starts again, and the cycle repeats.

Some doctors use the Koo-Menter Psoriasis Instrument (KMPI) to decide which patients should receive a pill or an injection. The KMPI’s questions include:

Does psoriasis cover at least 5% of the patient’s body?
Is the patient disabled by psoriasis?
Does psoriasis affect the patient’s quality of life?

If the answer to these questions is "yes," three additional questions are considered:

Is light therapy inappropriate for the patient?
Is the patient’s psoriasis resistant to light therapy?
Does the patient have psoriatic arthritis?

If the answer to these questions is “yes,” a doctor may decide to prescribe a pill or injected drugs.

Doctors increasingly use combinations of pills, creams, ointments, and phototherapy instead of single medications. Combinations of oral treatments are particularly useful, since the doses of each drug can be reduced. This lowers the risk of severe side effects. Thousands of combinations are possible, and the patient and doctor should discuss the best treatment for individual needs.

Topical Medications

Topical medications are those applied only to the surface of the body. They come in the following forms:

Creams
Foams
Gels
Lotions
Occlusive tapes
Ointments
Shampoos
Solutions
Sprays

In general, topical treatments are the first line for mild-to-moderate psoriasis, but they may also be used, alone or in combination, with more powerful treatments for moderate-to-severe cases. Topical medicines rarely produce complete clearance, however.

Corticosteroid topical treatments are the mainstay of psoriasis treatments in the United States. They work for most patients. Such treatments:

Decrease inflammation
Block cell production
Relieve itching

Corticosteroids are available in a wide range of strengths, and are generally given as follows:

Less potent drugs are used for mild-to-moderate psoriasis.
Stronger drugs are reserved for more severe disease.

In the past, topical steroids have been used twice a day. Studies are reporting, however, that certain drugs may work just as well if taken once a day. Most studies have evaluated high-potency steroids, but one study suggested that those of medium strength, such as triamcinolone (Aureocort, Tri-Adcortyl), may be equally beneficial as a once-daily treatment. However, corticosteroids used alone clear psoriasis in only 4 - 36% of patients.

Combination therapy. Combinations with other drugs are often needed. For example, an effective, topical regimen uses the following combination for maintenance therapy:

A high-potency steroid (such as halobetasol) on the weekend
A vitamin D3 topical medication called calcipotriene, twice daily on weekdays

In one study, more than 75% of patients with mild-to-moderate psoriasis remained in remission for at least 6 months with this regimen.

Side Effects. The more powerful the corticosteroid, the more effective it is. But it also has a higher risk for severe side effects. Side effects may include:

Burning
Irritation
Dryness
Acne
Thinning of the skin; skin may become shiny, fragile, and easily cut
Dilated (widened) blood vessels
Loss of skin color

Loss of Effectiveness. In most cases, the patients become tolerant to the effects of the drugs, and the drugs no longer work as they should. Some experts recommend using intermittent therapy (also called weekend or pulse therapy). This type of treatment involves applying a high-potency topical medication for 3 full days each week.

Note: This list is not all inclusive.
Low potency (some are available over the counter)	Desonide (Tridesilon, DesOwen) Flumethasone pivalate (Locorten) Fluocinolone acetonide (Synalar, Derma-Smoothe) Hydrocortisone (Hytone, Penecort, Synacort, Cort-Dome, Nutracort, Westcort) Triamcinolone acetonide (Aristocort)
Low to medium potency	Alclometasone dipropionate (Aclovate) Hydrocortisone (Locoid, Pandel) Hydrocortisone valerate (Westcort) Prednicarbate (Dermatop)
Medium to upper-mid potency	Clocortolone pivalate (Cloderm) Fluticasone propionate (Cutivate) Mometasone furoate (Elocon) Triamcinolone acetonide (Aureocort, Tri-Adcortyl, Kenalog)
High potency	Betamethasone (Diprosone) Amcinonide (Cyclocort) Desoximetasone (Topicort) Diflorasone diacetate (Florone, Maxiflor) Fluocinonide (Lidex) Halcinonide (Halog)
Very high potency	Halobetasol propionate (Ultravate) Betamethasone (Diprolene, Luxiq) Clobetasol propionate (Temovate, Olux) Diflorasone diacetate (Florone, Maxiflor, Psorcon)

Coal tar preparations have been used to treat psoriasis for about 100 years, although their use has declined with the introduction of topical vitamin D3-related medicines. Crude coal tar stops the action of enzymes that contribute to psoriasis, and helps prevent new cell production. Tar is often used in combination with other drugs and with ultraviolet B (UVB) phototherapy.

Side Effects. Preparations have the following drawbacks:

Stains on clothing
Skin irritation
Sun sensitivity and increased risk of sunburn for up to 24 hours after use

Anthralin (Dritho-Scalp, Drithocreme, Micanol) is related to a medication called chrysarobin, in use since the early 1900s. Anthralin slows skin cell reproduction and can produce remissions that last for months. It is recommended only for chronic or inactive psoriasis, not for acute or inflamed eruptions. Persons with kidney problems should use anthralin with caution.

As with tar, its use has also declined with introduction of the topical vitamin D-related medicines, but newer formulations, such as Micanol, have made its use more tolerable. Micanol (Psoriatec) is an anthralin formulated in microcapsules, which dissolve and allow the drug to be delivered directly to the target skin areas. It is particularly useful for scalp psoriasis, and it is less likely to stain.

Side Effects. Anthralin may cause the following side effects:

Skin irritation and burning
Staining of clothes, hair, fabrics, plastics, and other household products

Patients should not use anthralin on their faces. Fair skinned people should generally avoid it. Triethanolamine (CuraStain) is a chemical that can neutralize anthralin and help reduce irritation from short-contact anthralin treatment. It should be applied 1 or 2 minutes before washing off the anthralin. It is then reapplied after drying the skin.

Washing stained items with hypochlorite (Clorox) detergents can help remove stains. Many people use disposable gloves while applying the treatment to avoid staining hands.

Application. Apply anthralin only to the psoriasis plaques. Rub the cream in well, and wipe off any excess. Wash off only with lukewarm water, not soap. Using hot water will trigger the staining action. A technique called short-contact anthralin therapy (SCAT), also called minute therapy, is useful for local areas of psoriasis. In such cases, anthralin is applied for only 10 minutes to an hour.

A topical form of vitamin D3, calcipotriene (Dovonex) is proving to be both safe and effective. It is now available in a foam preparation, which makes compliance even easier. Several other topical vitamin D3 related drugs showing promise include maxacalcitol (Oxarol), tacalcitol, and calcitriol (Silkis).

Calcipotriene appears to:

Block skin cell reproduction
Enhance the maturity of keratinocytes (the impaired skin cells in psoriasis)
Acts as an anti-inflammatory

It works just as well as moderate topical corticosteroids, short-term anthralin, and coal tar in improving mild-to-moderate plaque psoriasis. Unlike steroids, patients do not develop thinning of the skin or tolerance to the drug.

Using the drug in combination with other topical and systemic treatments may improve effectiveness. Calcipotriene doesn't work as well as the highest potency corticosteroids, but products or regimens that combine both medications are proving to be more effective than either one alone. Taclonex, an ointment containing both calcipotriol and betamethasone, was approved by the U.S. Food and Drug Administration (FDA) in January 2006 for the treatment of adults with psoriasis. Studies show the combination works better than either drug alone.

Combining vitamin D ointments with systemic medicines, notably methotrexate, acitretin, or cyclosporine, increases effectiveness and allows lower doses or either medication, thereby reducing side effects.

Studies also report success in some patients who use vitamin D ointments in combination with phototherapy treatment.

Side Effects. Calcipotriene may cause the following side effects:

A possible lowering of vitamin D levels, which may affect bone growth in some children
A possible increase in blood calcium levels (seen in some people who apply calcipotriene to large areas)
Skin irritation in about 20% of patients, particularly on the face and in skin folds

Calcipotriene appears to cause greater skin irritation than potent corticosteroids. Diluting the drug with petrolatum or applying topical corticosteroids to sensitive areas may prevent this problem.

Retinoids are related to vitamin A. They are used for various skin disorders. Tazarotene (Tazorac) is the first topical retinoid found to be effective for mild-to-moderate psoriasis. It is available in cream or gel form.

Unlike steroids, patients do not develop thinning of the skin or tolerance to the drug. Only a very small amount is needed on each lesion. It can be used on the scalp and nails, but it is not recommended for the genital areas or around the eyes. The gel should be used on only 20% of the body at anytime; the cream on up to 35%. (Note: The palm of the hand is about 1% of the body surface.)

Combining topical retinoids with other psoriasis treatments, such as with topical steroids, works better than using the drug by itself.

Side Effects. Tazarotene may cause dryness and irritation of healthy skin. Applying zinc oxide and moisturizer around the treated area can protect the healthy skin.

At levels high enough to be effective for psoriasis, tazarotene can cause severe skin irritation on treated areas. This medicine, then, is usually used in combination with other treatments, therefore allowing a lower dose. Mixing the drug in equal amounts with petroleum jelly (Vaseline) initially and then gradually increasing the amount of tazarotene may help the skin areas become less sensitive. It should be noted that the skin can become very red while it is actually improving.

Vitamin A derivatives (drugs related to vitamin A) have been associated with birth defects and should not be used by women who are pregnant, who wish to conceive, or who are nursing.

Salicylic acid applied to the skin helps remove scaly plaque and enhance the actions of other medications. It should not be used to cover wide areas of the body, since it can cause nausea and ringing in the ears. Combinations with high potency steroids, such as mometasone furoate (Combisor), clobetasol propionate, and betamethasone, are proving to be very helpful. Only Combisor is available in the United States.

Watertight (occlusive) tapes or wrappings may help heal psoriasis. Occlusive tapes are particularly useful for psoriatic cuts on the palms and soles. In such cases, the tape should be applied across the cuts until they heal.

Occlusive tapes retain sweat, which helps restore moisture to the outer skin layer and prevent scaling. They also protect against abrasion and irritation.

High-Potency Corticosteroid Tapes. Applying a corticosteroid beneath an occlusive tape, or using a tape that already has a potent corticosteroid (Cordran Tape) such as flurandrenolide may be especially beneficial. Studies are showing that high-potency corticosteroid-containing tapes are more effective than using high-potency corticosteroid ointments alone.

However, the tapes are expensive and are associated with a high rate of skin irritation, increased secondary infections, and a greater chance of symptoms relapse after treatment is stopped. Infection risk may be reduced by changing tapes every 12 hours.

The use of corticosteroids under occlusive tapes on large areas of psoriasis also increases the risk for adrenal insufficiency, a sometimes dangerous condition that occurs because the body loses its ability to produce natural steroids. Children are especially vulnerable to this effect.

Other Medications with Occlusive Tapes or Wrappings. The tapes may be used in combination with other medications, such as fluorouracil. Occlusive wrappings are not usually used with tazarotene (Tazorac) and should never be used without a doctor's recommendation.

Numerous topical medications are under investigation. One such medication, tacrolimus (Protopic), is an immunosuppressant that is proving to be useful in allergic skin disorders and is being studied for psoriasis. Studies have been mixed on its benefits, although new delivery methods may make it more effective. It may prove to be safe for sensitive areas, such as the face. Pimecrolimus (Elidel), a similar medication, is also being studied.

Systemic Medications

Systemic treatment uses various medications that affect the whole body, not just the skin. Many systemic drugs used for psoriasis are also used for other severe diseases, including autoimmune diseases (especially rheumatoid arthritis) and cancer.

Systemic treatments for psoriasis may be taken by mouth or injection. The medicines can have significant side effects and are generally reserved for severe psoriasis.

At this time, the only systemic medications specifically approved for psoriasis are:

Cyclosporine
Methotrexate
Retinoids

As with all medications for psoriasis, the patient should use the lowest strength medication first. The primary treatment is called a first-line treatment, the next is known as a second-line treatment, and so on. Combinations of medications are often used.

Methotrexate (Rheumatrex) is a biologic drug that interferes with cell reproduction and has anti-inflammatory properties. It is a first line, or primary, systemic drug used to treat adults with severe psoriasis. The medicine is one of the few systemic drugs proven to help patients with psoriatic arthritis.

The drug is taken weekly, not daily. (Deadly reactions have been reported in people who mistakenly took it once a day.)

Side Effects. Common side effects of methotrexate include:

Anemia
Headache
Mild hair loss
Mouth sores
Nausea
Possible muscle aches
Rash
Vomiting

Many of these side effects are due to folic acid deficiency. Patients should ask their doctor if folic acid supplements (generally recommended at 1 - 5 mg daily) are necessary.

More serious side effects include:

Increased risk for infections, particularly shingles and pneumonia. Methotrexate suppresses the immune system. Patients with active infections should avoid this drug.
Infertility, miscarriage, and birth defects. If used during pregnancy, the drug can cause miscarriages or birth defects in the baby. It may harm fertility in men.
Kidney complications.
Liver damage. In one study, 25% of patients taking methotrexate for 5 years developed scarring of the liver. Those with existing liver problems should not take this medicine, if possible. Regular monitoring for liver toxicity, including blood tests and liver biopsies, is important in patients who take the drug.
Lung disease. This side effect can be sudden and severe, and occurs in up to 5% of people who take methotrexate. Risk factors include diabetes, existing lung inflammation, protein in urine, and use of rheumatoid arthritis drugs called DMARDs.
Lymphomas. A few cases have been reported, which are most likely related to the drug's immune-suppressing (lowering) effects. In most instances, the disease has gone into remission when the drug was stopped. Most studies have found no significant risk for cancers in patients taking methotrexate.
Osteoporosis. Low doses of methotrexate do not appear to have any significant effect on bone loss, but long-term studies are needed to confirm this.
Radiation recall: An uncommon side effect in patients who have previously been burned by radiation cancer treatments or sunburns. In such cases, a flare-up of symptoms occurs in the previously affected skin areas.
Severe anemia. Folic acid supplements can offset this effect.
Toxic effects on bone marrow. This can cause reduced blood cell production.

Despite its side effects, some experts view methotrexate as the best therapy for widespread plaque psoriasis. It may also be effective for some patients with other severe forms of the disease, including psoriatic arthritis, generalized erythrodermic, and pustular psoriasis.

Methotrexate appears to be effective in children, but more safety research is needed.

Drug Interactions. Many drugs interact with methotrexate, occasionally with harmful results. For example, the antibiotic trimethoprim-sulfamethoxazole increases the toxicity of methotrexate.

A serious, harmful reaction can occur if methotrexate is taken with common, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen, or naproxen. Other NSAIDs, namely ketoprofen, flurbiprofen, and piroxicam, appear to be safe when given with methotrexate and may be used in patients with psoriatic arthritis. Rheumatoid arthritis (RA) patients who take methotrexate often take NSAIDs as well, but methotrexate doses in psoriasis patients are usually much higher than those in RA.

People Who Should Avoid Methotrexate. Pregnant and nursing mothers should never take methotrexate because it increases the risk for severe, even fatal, birth defects and miscarriage. The drug should be discontinued several months before planning a pregnancy. It may also cause temporary impairment of fertility in men.

Persons with the following conditions should also avoid taking methotrexate:

Alcoholism
Anemia or other blood abnormalities
Immunosuppression
Kidney problems
Liver problems (including hepatitis)
Rheumatoid arthritis
Peptic ulcers

Patients at risk for liver complications include those with diabetes and obesity. Anyone with a history of hepatitis should have a liver biopsy before taking methotrexate.

Oral retinoids are vitamin A-related medications taken by mouth. This group of medicines is also a first-line treatment for adults with severe psoriasis. Oral retinoids used for psoriasis include acitretin (Soriatane) and isotretinoin (Accutane).

Acitretin is the retinoid of choice and may be dramatically effective for severe psoriasis, particularly pustular or erythrodermic variants. When used alone, it is much less effective against more common forms, such as plaque or guttate psoriasis. However, combinations with PUVA phototherapy can markedly improve the response even in these patients.

Accutane, more commonly used to treat acne, is far less potent than acitretin, but may still be effective against pustular psoriasis and also be effective with phototherapy.

Oral retinoids help control cell reproduction and have anti-inflammatory properties. They may even improve arthritis that accompanies psoriasis.

Combination therapy. Acitretin may work the best when combined with other treatments, usually topical drugs and especially phototherapy. Combination therapy allows lower doses of oral retinoids to be used, which diminishes many skin and mucous membrane side effects. Acitretin combined with phototherapy has some of the highest clearance rates of any treatment.

Side Effects. All retinoids have the same potentially serious toxicities as do high doses of vitamin A. Side effects include:

Bone and joint pain
Bruising
Depression and possible suicide risk (with isotretinoin)
Eye problems, including blurred vision, cataracts, conjunctivitis, and a sudden deterioration in night vision
Fatigue
Headache
Increased bone growth, particularly in the ankles, pelvic area, and knees
Increased triglyceride levels
Liver damage
Nail problems
Skin and mucous membrane problems, including dry nose, nosebleeds, dry eyes, chapped lips, thinning hair, dry or "sticky" feeling skin, and peeling of the palms and soles

In rare cases, retinoids, particularly isotretinoin, may cause a condition called benign intracranial hypertension (pseudotumor cerebri), which occurs in the brain. Symptoms include headache, nausea, vomiting, and blurred vision. Patients experiencing these symptoms should call a doctor immediately and stop taking the drug.

Oral retinoids should not be taken during pregnancy.

Despite these side effects, oral retinoids remain among the safest systemic therapies for psoriasis. A low-fat diet, aerobic exercise, and fish oil supplements may help reduce the side effects. Certain cholesterol-lowering drugs, including gemfibrozil (Lopid) or certain statins, such as atorvastatin (Lipitor), may help control triglyceride levels.

Maintenance doses should be as low as possible and should be taken every second or third day.

Taking retinoids during pregnancy significantly increases the risk for severe birth defects in the unborn child. Pregnant or nursing women or those planning to become pregnant should not use these drugs. Women of childbearing age who take retinoids should have regular pregnancy tests.

Doctors recommend that acitretin should not be given to any woman who may become pregnant within 3 years of taking it. Drinking alcohol changes acitretin to a retinoid that is stored in fat cells for 3 years. It may have the potential for causing birth defects during that time. It's important to note that cooking products and over-the-counter preparations, such as cough syrup, may contain alcohol and be inadvertently consumed.
Women who are pregnant or plan to become pregnant should not use isotretinoin. As of December 31, 2005, everyone who takes, prescribes, or dispenses the drug must enroll in a national registry called iPLEDGE.

Cyclosporine (Neoral, Sandimmune, SangCya) blocks certain immune factors and may be effective for all forms of psoriasis. It is also a first line, or primary, systemic drug used to treat adults with severe psoriasis. Neoral is the preparation used most often for psoriasis and clears psoriasis in many patients within 8 - 12 weeks.

Side Effects. Cyclosporine has significant side effects if used for a long time, notably kidney problems and non-melanoma skin cancers. It should be reserved for patients who do not respond to phototherapy or less potent systemic medications (for example, methotrexate or acitretin).

Common and temporary side effects include:

Fatigue
Gingivitis
Gout
Hair growth
Headaches
Joint pain
Tremor

More serious complications may include:

Kidney damage
High blood pressure (Some doctors advise treating high blood pressure with calcium channel blockers, since other standard blood pressure drugs may worsen psoriasis. Calcium channel blockers also help prevent kidney problems.)
High cholesterol and lipid levels
High levels of calcium and low levels of magnesium
Increased risk for infections
Liver problems
Lymphomas
Skin cancers (Patients who have taken cyclosporine after PUVA therapy have a higher incidence of squamous cell skin cancer. According to a 2003 study, the risk is six times that of the general population. The risks are highest with long use and previous use of PUVA, methotrexate, or other immunosuppressants.)

To reduce complications of cyclosporine, the dosage is decreased after improvement occurs. Maintenance therapy is usually limited to a year, although some experts believe that a microemulsion form of Neoral (Neoral-Neo) may be safe for up to 2 years. Patients should be monitored regularly for high blood pressure and signs of kidney or liver problems and skin cancers.

Patients Who Should not Use Cyclosporine. Because the drug suppresses the immune system, people with active infections or cancer should avoid it. Patients with uncontrolled high blood pressure and impaired kidney function should also not use this medication. Cyclosporine therapy for children with psoriasis has not been well studied.

Drug and Food Interactions. Cyclosporine interacts with numerous drugs -- both prescription and over-the-counter preparations -- and also grapefruit and grapefruit juice.

Biological response modifiers, sometimes called "biologics," belong to a new class of drugs that are considered the most exciting development in psoriasis treatment. Biologics are genetically engineered drugs that interfere with specific components of the autoimmune response. Because of their precise targets, these drugs do not damage the entire immune system the way that general immunosuppressants do.

Biologics are considered second- or third-line treatments, and may be used alone or sometimes in combination with first-line systemic drugs.

There are different types of biologics used to treat psoriasis:

T cell blockers block immune cells linked to inflammation.
Tumor necrosis factor (TNF) blockers target the chemical messenger TNF-alpha, which is released during the inflammatory response.

Types of T-cell blockers:

Alefacept (Amevive). This drug is approved for the treatment of moderate-to-severe plaque psoriasis. Studies suggest that the drug produces 50 - 75% improvement in symptoms. Alefacept is given in a doctor's office or clinic. Patients receive weekly injections for 12 weeks. Patients need weekly blood tests to make sure T cell levels do not drop too low. Side effects are generally mild and include sore throat, dizziness, and cough. There have been a few reports of serious infection and cancer.
Efalizumab (Raptiva). This drug is approved for the treatment of moderate-to-severe plaque psoriasis. Many patients experience 50 - 75% improvement in symptoms within 4 - 6 weeks of starting the drug. Patients give themselves shots of this drug for 12 weeks. Some clinical trials suggest that a longer course of treatment (24 weeks) may also be safe and effective for patients with chronic plaque psoriasis. Some patients have flare-ups of psoriatic lesions after stopping efalizumab. Very serious, but rare, side effects include hemolytic anemia and antibiotic-resistant infections.

Types of TNF blockers:

Etanercept (Enbrel) is approved for the treatment of psoriatic arthritis and moderate-to-severe plaque psoriasis. The drug is given either alone or in combination with methotrexate. Side effects include infections and lymphoma, a type of cancer. Patients inject themselves under the skin, once or twice a week for 12 weeks. However, a 2007 study published in the Archives of Dermatology found that continuing etanercept after 12 weeks lowers the severity of disease without increasing infections or side effects. Study participants randomly received 50 milligrams of the drug or a placebo biweekly up to 84 weeks. Strongest improvements were noted at 48 weeks among those who received the drug.
Infliximab (Remicade) is approved for the treatment of psoriatic arthritis. Patients receive three intravenous infusions during the first 6 weeks of treatment. After the initial treatment period, patients receive an infusion every 8 weeks. Therapy takes 2 hours and is given in a doctor’s office or clinic. Patients with a history of infection or heart failure should not take this drug. Several studies have shown that symptoms improve significiantly by week 10 in the majority of patients with severe psoriasis who are treated with infliximab.
Adalimumab (Humira) is being tested in clinical trials for treatment of psoriasis and psoriatic arthritis. Results from a Phase III (late-stage) study show that the drug works better than methotrexate in the treatment of moderate-to-severe psoriasis.
Efalizumab (Raptiva) appears to effectively clear or nearly clear moderate-to-severe hand and foot psoriasis after 12 weeks. This type of psoriasis is often very difficult to control and treat.

Interleukins (IL) being investigated as sources or targets of therapy include IL-4, IL-2, IL-8, IL-11, and IL-12. For example, in a 2003 study, 75% of patients with severe psoriasis who were treated with interleukin-4 (rhuIL-4) experienced improvement rates of more than 68%.

A study of 180 patients with moderate-to-severe plaque psoriasis has shown that an investigational medicine called ABT-874 greatly reduced symptoms in most patients. ABT-874 targets proteins that are responsible for psoriasis-related inflammation.

Leflunomide. Leflunomide (Arava) is a disease-modifying antirheumatic drug (DMARD), which blocks autoimmune antibodies and is a powerful anti-inflammatory medication. It is proving to be active against psoriatic arthritis. Reports of adverse effects are comparable to those with methotrexate. Common problems include nausea, diarrhea, hair loss, and rash. Potentially serious side effects include infections and liver injury.

Sulfasalazine. Sulfasalazine (Azulfidine) is sometimes used for psoriasis. In one major analysis, sulfasalazine and methotrexate were the only medications proven to help patients with psoriatic arthritis. Many people, however, stop taking the drug because of common side effects that include headaches, gastrointestinal complaints, and rash. Benefits, if any, should be apparent in 4 - 6 weeks.

Immunosuppressants. Some immunosuppressants being studied for psoriasis include tacrolimus (Prograf), pimecrolium, and sirolimus. In one study, for example, tacrolimus showed an 83% reduction in symptoms in patients with psoriasis who used the drug. Studies have been limited, however. Side effects of these medications are similar to those of cyclosporine. Pimecrolimus may specifically target the skin and so have fewer side effects. (Some are also being studied as topical treatments.)

Phototherapy

Phototherapy means to treat with light.

When sunlight penetrates the top layers of the skin, this ultraviolet radiation bombards the DNA inside skin cells and injures it. This can cause wrinkles, aging skin, and skin cancers. However, these same damaging effects can destroy the skin cells that form psoriasis patches.

Phototherapy for psoriasis can be given as ultraviolet A (UVA) light in combination with medications, or as variations of ultraviolet B (UVB) light with or without medications. Not everyone is a candidate. For example, it may not be appropriate for patients who should avoid sunlight or those with very severe psoriasis.

Ultraviolet A (UVA) is a main part of sunlight. UVA phototherapy uses a photosensitizing medication (usually psoralen) in combination with UVA radiation to be effective. A photosensitizing medication makes a person more sensitive to light. Treatment with psoralen and UVA is referred to as PUVA. This approach is very powerful and effective in more than 85% of patients who use it. However, it poses a higher risk for skin cancers than UVB.

PUVA treatments cause inflammation and redness in the skin to develop within 2 - 3 days after treatment. Such damage inhibits skin cell proliferation and reduces psoriasis plaque formation.

Forms of psoralen include methoxsalen, 8-methoxypsoralen (8-MOP), or bergapten (5-MOP). The effectiveness of the treatment is based on a chemical reaction in the skin between the psoralen and light, which creates redness and inflammation that prevents the psoriasis disease process.

People should avoid this treatment if they are taking drugs or have conditions that cause them to be light sensitive. They should also take protective measures before, during, and after each treatment.

Initial PUVA Treatment Phase. The initial phase typically follows these steps:

Psoralen is typically taken by mouth in the form of 8-methoxypsoralen (for example, Oxsoralen) 75 minutes to 2 hours before the treatment starts. Psoralen reaches the skin through the bloodstream, where it increases the skin's sensitivity to UVA radiation.
Topical preparations of psoralen are alternatives to pills. They can be "painted on" or applied to the affected areas by soaking or bathing in a psoralen solution. PUVA-bath therapy may be especially useful for persistent psoriasis on the palms and soles or for patients with liver disease or who get severe nausea from taking the pill form. UVA should be given within 15 minutes of using topical psoralen.
The patient enters and stands in a light box, a unit lined with ultraviolet lamps. The initial UVA exposure time is very short (seconds to several minutes), and then increases to 20 minutes or longer. The amount of time a person is exposed to UVA rays depends on the skin type, with the shortest times recommended for fair-skinned patients.
Treatments may be repeated two or three times a week. They should never be performed more frequently than once every other day, since the full effects of the treatments are not evident for 48 hours.

It takes an average of about 25 PUVA treatments for full effect, but during that period, treatment intensity may vary.

If there is no response after 10 treatments, the doctor may increase the UVA energy.
If there is still no response after 15 treatments, the psoralen dosage may be increased.
If a patient's skin does not improve at all or worsens after these changes, the treatment is temporarily stopped. PUVA may be causing a toxic response in such cases, and, often, the condition gradually improves over the following 2 weeks.
If the skin does not improve over the following 2 weeks, PUVA treatment has failed. If skin improves during this resting period, treatment resumes.

Maintenance Phase. Once the psoriasis has improved by about 95%, the patient may be put on a maintenance schedule. Often only one or two treatments a month are needed, but some people may need more frequent treatments. As maintenance continues and the interval between treatments lengthens, the patients may become more susceptible to tanning and sunburn. They should reduce exposure to natural sunlight during this time.

Success Rates. Nearly 90% of patients achieve marked improvement or clearing within 20 - 30 treatment sessions.

Combinations. Combining acitretin, calcipotriene, methotrexate, or tazarotene gel with PUVA may enhance effectiveness or increase response. In addition, combinations may allow for lower doses of radiation or medications to be used, minimizing side effects. Retinoids may also help protect against skin cancers, while methotrexate may increase the risk. In some cases, patients resistant to PUVA or UVB may respond when the phototherapies are combined.

Side Effects and Complications of PUVA.

The psoralen methoxsalen causes a general ill-feeling and nausea in 20% of patients. Dividing up the dose and taking it in 15-minute intervals with food, or taking ginger 20 minutes before taking the drug, may be helpful.
Skin reactions, including itching, sunburn, and blistering, are common. These can generally be avoided with careful administration of PUVA therapy and protective measures. Antihistamines, baths with special oatmeal preparations (Aveeno), and capsaicin ointment (Zostrix) may be helpful.
After treatment, white spots commonly develop where psoriasis plaques had been, particularly in people with naturally darker skin. If they are troublesome, tanning products may help darken them. Small, dark raised spots called PUVA lentigines may also develop in affected areas with long-term treatment
Prolonged standing may trigger fainting in people with certain heart or blood pressure problems.
People with liver disease should discuss using topical psoralens, since oral forms may have adverse effects on the liver.
UVA penetrates the skin more deeply than UVB, so there is a greater danger of deep skin damage, accelerated skin aging, and skin cancers. Anyone who needs to avoid sunlight should not get this treatment.
The procedure increases the risk for cataracts if eyes are not protected for up to 24 hours after treatment.

Special Warning on PUVA and Skin Cancers. It has been known for some time that PUVA can change DNA and cause genetic mutations. PUVA is known to increase the risk for squamous cell skin cancer and slightly increase the risk for basal cell skin cancer, both of which are nearly always curable. One study reported an increased risk of melanoma. The risk for skin cancers is higher in persons who have:

A family or personal history of skin cancer
Light skin and fair or red hair
Received radiation or x-ray treatments or taken immunosuppressant drugs
Received over 200 PUVA treatments

Discussions are under way about discontinuing PUVA for psoriasis. The arguments generally are as follows:

Opponents of PUVA argue that studies suggest a long-term risk for melanoma, starting about 15 years after treatment, particularly in people who receive more than 250 treatments. In one long-term study, only 9 out of 1,380 patients developed melanoma. However, 7 of these cases occurred in the last 5 years of the study, indicating that the danger persists and more patients in this study are likely to develop this serious skin cancer as time goes on.
Supporters of PUVA argue that it is not yet known if the people who developed melanoma experienced sunburn during the procedures or if they already had risk factors for skin cancers. If so, then properly given treatments could still be considered safe for patients without risk factors. They also argue that PUVA is still the most effective treatment for severe psoriasis, and the alternatives are usually very powerful and relatively new drugs that may have even more serious side effects. Furthermore, the addition of retinoids may protect against skin cancers while proving to be a very effective combination.

Side effects of UVA radiation can be severe. Protective measures are needed during, before, and after treatment. Patients should avoid prolonged exposure to the sun for 24 hours before the oral treatment starts.

Protective Measures During Treatment:

Patients should wear specially designed goggles to protect the eyes from UVA radiation.
Sensitive areas, such as genitals, abdominal skin, and breasts, should be covered until tanning occurs in the exposed areas, after about a third of the treatment period. Note that PUVA is associated with a high risk for genital skin cancers, so male genitals must be covered throughout the process.

The following safety features should be available in the PUVA chamber:

Lamps with protective shields
A viewing window for a health professional to check the patient periodically
A door that can be opened by the patient easily and with little pressure
A timer that terminates the session automatically
An accessible alarm device

Protective Measures After Treatment. The drugs used in PUVA increase susceptibility for a natural sunburn for hours after treatment. The patient should take the following precautions:

Patients should wear UVA absorbing wrap-around sunglasses that are designed to completely block out stray radiation. They should begin wearing them as soon as they take the drug, and for at least 12 hours after the treatment. This is important to prevent a PUVA reaction around the eyes that can cause cataracts. There is no need to wear these glasses after sundown.
For about 8 hours after taking the drug, patients must also avoid exposure to daylight, even if the day is cloudy or exposure occurs through windows.
Patients who must go out should wear heavy opaque clothing (clothes that do not let light through), including hats and gloves.
Patients should apply sunblock over all exposed areas, including the lips. The sunblock should have an SPF (sun protection factor) of more than 15 and include ingredients that block both UVB and UVA radiation.
No patient should spend a long time in sunlight for at least 2 days after the combined treatment.

Ultraviolet B is another main part of sunlight, and is the main cause of sunburn. It generally affects the outer skin layers. UVB radiation reduces the abnormally rapid skin cell growth that occurs with psoriasis.

Types of UVB therapy:

Broadband UVB
Narrowband UVB (NB-UVB)
Laser treatments

Broad spectrum or broad band UVB is radiation in the wavelength of 290 - 350 nanometers, and is the standard UVB phototherapy treatment in the United States. It is not as potent as the treatments that use narrow-band UVB or PUVA, and is not useful for chronic psoriasis.

Broadband UVB may be given with or without medications. When used without medication (known as selective ultraviolet phototherapy), UVB treatment generally is given as follows:

Treatment starts in the doctor's office or another medical setting. Once the disease has stabilized, the patient can obtain a prescription for equipment that can be used at home. Even at home, treatment must always be supervised.
In preparation, the patient fully undresses, although unaffected areas may be covered to avoid overexposure.
The initial session may last as little as a few seconds, depending on whether the patient has a lighter or darker skin, with the lightest skin exposed to the briefest session. The duration increases with each treatment until the skin clears or the patient experiences itching or irritation. It should be noted that the condition may worsen initially.
UVB therapy usually requires about 20 - 40 treatments (about three per week). Full results take about 3 weeks.

Use of Medication. UVB was commonly used with coal tar (the Goeckerman regimen) in past decades, and then with anthralin (the Ingram regimen). Other medications are being studied with some success, and may prove to be tolerated better.

The Goeckerman regimen requires daily treatments for up to 4 weeks. The coal tar or anthralin are applied once or twice each day and then washed off before the procedure. Studies indicate that a low-dose (1%) coal tar preparation is as effective as high dose (6%). Such regimens are unpleasant, but still useful for some patients with severe psoriasis, since they can achieve long-term remission (up to 6 - 12 months).

Some evidence suggests that using a simple emollient (such as Vaseline or mineral oil) that enhances UVB light penetration can be effective. This addition to the treatment increases the risk for sunburns, however, and patients must be careful to avoid sun exposure. Researchers are tring combinations of other topical and oral medications. For example, combining UVB with methotrexate, or retinoids such as a tazarotene gel or oral acitretin, is producing positive results. Combinations with any of these drugs, however, must be supervised carefully to avoid serious reactions.

Side Effects of UVB. The treatment can cause itching and redness. UVB radiation from sunlight is known to increase the risk for skin cancers. There is no strong evidence, however, that UVB treatments pose any risk for skin cancers except on male genitalia. This risk, however, can be significant (4.5%) at high doses.

Narrow band radiation may be safer than other approaches, and some experts now believe it should be the first option for patients with chronic plaque psoriasis.

NB-UVB is used without medications and is very strong. Whether it has any affect, however, on the disease process itself is unclear. The light wavelength is between 310 - 312 nanometers, which, theoretically, is the most beneficial part of sunlight.

Exposure times are shorter but of higher intensity than with broadband UVB. This therapy is probably less likely than PUVA to cause skin cancers.

Clearance of 75% typically occurs after 10 - 12 treatments. NB-UVB treatments performed three times a week achieve results that are equal to twice-weekly PUVA treatments. Weekly NB-UVB treatments are not effective. Studies so far are mixed on whether NB-UVB remission rates are equal to those of PUVA.

Patients prefer NB-UVB over other PUVA treatments because they do not have to wear protective eyewear, take medications, or experience unpleasant side effects, notably nausea. It is also safe for pregnant women and children.

Combinations with topical medications, such as tazarotene or psoralens, may help NB-UVB therapy work better.

Laser UVB Treatment. A recent variation of a device called an excimer laser (Xtrac) delivers a precise UVB wavelength of 308 nanometers. The laser is more effective than narrow-band UVB for localized psoriasis, since it allows very specific areas of skin to be targeted. (Note: The therapy is not suitable for the scalp.) Generally, 8 - 10 treatments given twice a week will clear psoriasis. Remission rates are similar to NB-UVB, but the excimer laser can clear the psoriasis faster and at lower doses. It also spares the healthy skin around it. Blistering is a common side effect. More comparison studies are needed to determine risk and benefits compared to NB-UVB, particularly any long-term risk for skin cancer.

Pulsed-Dye Lasers. Pulsed-dye lasers give off high-intensity yellow light, which destroys the tiny blood vessels that make up psoriatic plaques. This treatment has been used for years to remove birthmarks, such as port wine stains and unsightly blood vessels on the skin. Some studies have reported significant (but not complete) improvement, and remissions that have lasted up to 13 months. Treatment sessions last up to 30 minutes and can feel uncomfortable (similar to being repeatedly snapped with a rubber band). It typically takes up to six sessions to clear the target areas. Bruising is common, and there is a small risk for scarring.

Home tanning devices and tanning salons are not usually recommended, but they may be helpful for patients without access to a medical unit. In a 2003 study, many patients achieved a significant reduction in symptoms when taking acitretin and exposed to a UVB commercial tanning unit (specifically, a Wolff tanning bed).

However, UV outputs can vary widely among tanning beds and salons. Some units emit UVA radiation, which poses a higher risk for skin cancers. Adverse effects of tanning salons that use UVA or UVB radiation are the same as with any UV phototherapies, including a risk for skin cancer.

Managing Psoriasis

Although sunburn carries a risk for skin cancer and can make psoriasis worse, regular exposure to the sun helps clear psoriasis in people with mild-to-moderate conditions. People should cover non-affected areas with clothing or sunscreen and sun bath only until the skin starts to tan.

Vacations in sunny areas, such as Hawaii or the Caribbean, can offer relief. For those who can afford it, a prolonged stay of several weeks at the Dead Sea in Israel has proven to significantly improve or clear 88% of those with psoriasis who go there. The region offers a unique combination of intense but naturally filtered UVA radiation combined with minerals and salts from the sea.

Because of the association between negative emotions and psoriatic flare-ups, relaxation and anti-stress techniques may be helpful. A small 1999 study found that hypnosis aimed at reducing stress may relieve symptoms.

Another study found that some patients with psoriasis had a traumatic or stressful event coincide with the appearance of psoriasis. Talking to a psychiatrist about the issue resulted in significant symptom improvement in 62% of study patients who recalled such an event.

If skin becomes dry and itchy, the patient may try the following:

Soak in a warm bath for about 15 minutes.
Afterward, apply salicylic acid first, which removes scaly skin and may promote the penetration of both moisturizers and topical prescription medications.
Then, apply a thick moisturizer or emollient, such as Vaseline, Cetaphil cream, or Eucerin cream. Lotions are not good enough moisturizers.
Special gloves made of Gore-Tex (DermaPore) may be worn at night over a thick moisturizer cream. These gloves are protective but also allow moisture to escape.

Some experts suggest that many common moisturizers may actually increase water loss in psoriasis, but studies still have to confirm this. In the meantime, if moisturizers help relieve the condition, patients should use them.

Capsaicin (Zostrix) is an ointment prepared from the active ingredient in hot chili peppers. It is used to relieve arthritic pain and may help relieve psoriatic itching. Capsaicin should be handled using a glove and applied to affected areas three or four times daily. The patient will usually have a burning sensation when the drug is first applied, but this sensation lessens with use.

Folic Acid. Patients should be sure they get enough of the B vitamin folate (folic acid). Folate-rich foods include liver, asparagus, fruits, green leafy vegetables, dried beans and peas, orange juice, and yeast. Many types of bread and other commercial grain products now have added folic acid.

Omega-3 Fatty Acids. Omega-3 fatty acids, particularly those found in some fish oil, have anti-inflammatory properties that may benefit some patients with psoriasis and other autoimmune conditions.

Patients with persistent psoriasis may be tempted to try alternative or untested treatments, including herbs and other nontraditional therapies. Researchers at the Medical College of Georgia say green tea slowed the growth of skin cells in animal studies and may one day prove to be useful in treating psoriasis. More research is needed.

Several traditional remedies for psoriasis include various other herbal supplements, but to date no clinical studies have been reported on these substances. No one should use any unproven therapy without consulting a doctor to be sure such treatment is not harmful, and does not interfere with any standard medications they take.

Herbal remedies and dietary supplements are not regulated by the FDA. This means that manufacturers and distributors do not need FDA approval to sell their products. In addition, any substance that affects the body's chemistry can, like any drug, produce side effects that may be harmful. There have been many reported cases of serious and even deadly side effects from herbal products.

The following are special concerns for people taking natural remedies for psoriasis:

Zinc pyrithione is sometimes used, but its effectiveness is doubtful. A number of so-called natural psoriasis products (Skin-Cap, Blue Cap, Miralex) that contain this compound also contain prescription-strength corticosteroids. Such steroids have the same side effects as those in standard psoriasis agents. These products have been banned in the U.S. and Canada, but similar untested medications are available over the Internet.
Gotu Kola (Centella asiatica) is sometimes applied in a cream for psoriasis. The oral form of the herb has serious side effects, however, including increasing the risk for miscarriage in pregnant women.

Outlook

Psoriasis is lifelong and not curable. Although it is also marked by rapid cell growth, psoriasis is neither cancerous nor contagious.

In general, studies report the following features of its course:

The condition almost always relapses. In a few cases, large areas of plaque can persist for years.
Psoriasis nearly always goes into remission, however, often clearing on its own. In one study, 30% of patients reported untreated psoriasis going into remissions that lasted 1 - 54 years.
Psoriasis can improve during pregnancy, especially during the second and third months. Increased levels of estrogen may be responsible for this improvement. Relapse may occur after giving birth.

The emotional and social consequences of psoriasis should not be underestimated.

Many patients suffer severe humiliation and depression if plaques are visible. Some even withdraw from society and become isolated.
Some patients are forced to leave their jobs and go on disability if the condition becomes incapacitating.

Researchers have reported the following:

Surveys of patients with psoriasis report a negative mental and physical impact that is nearly equivalent to that of other major chronic conditions, including cancer, high blood pressure, diabetes, heart disease, and depression.
In one study, 75% of patients reported that psoriasis hurt their confidence.
Another study reported that 8% of people with psoriasis felt their life was not worth living.

Some patients, particularly men, use alcohol and smoking as self-medication to reduce the emotional consequences of psoriasis. In fact, studies have found that people with psoriasis have higher mortality rates, mostly from heavy drinking. Smoking has also been cited as a major risk, particularly for pustular psoriasis. Some experts believe that drinking and smoking may actually cause biological damage that contributes to psoriasis itself.

However, smoking may delay the onset of psoriatic arthritis in some patients, depending on when they started the habit. Psoriatic arthritis tends to occur about a decade after psoriasis develops. The review of 281 psoriasis patients showed that the condition appeared after about 13 years in nonsmokers, compared to 23 years in those who began smoking after the first onset of psoriasis. Psoriatic arthritis appeared after 8 years in people who smoked before developing psoriasis.

Folate Deficiency in Severe Psoriasis. Severe psoriasis can also cause folate deficiency. Folate is a B vitamin that is important for nerve function, preventing birth defects. It also prevents elevations of homocysteine, a factor that may play a critical role in heart disease.

Skin Cancers. In one study, patients with severe psoriasis (who receive medications that affect the whole body) were at higher than normal risk for developing cancers, primarily skin cancers and lymphomas. The risk was not any higher for patients with milder psoriasis. There is some indication, however, that patients with psoriasis have a higher risk for non-melanoma skin cancers regardless of treatments.

Heart Attacks. A study released in October 2006 shows an increased risk of heart attacks in people with psoriasis. The risk was highest in young patients with severe psoriasis.

Other Coexisting Conditions: Studies done in Newfoundland and Germany have also revealed increased cases of diabetes, obesity, arthritis, and cancer in patients with psoriasis. Research is underway to determine if there are genetic links between psoriasis and these conditions.

Increased Risk of Death. Severe psoriasis has been linked to a significant increase in a patient's risk of death. A study of more than 713,000 patients showed that severe psoriasis increased mortality by 50%. Study authors encourage patients to receive comprehensive health examinations to reduce the risk. Study participants were considered to have severe psoriasis if they required systemic treatment.

Impaired Temperature Regulation. Erythrodermic psoriasis, in which psoriasis covers the entire skin, can cause abnormalities in the body's ability to regulate temperature.

Zumbusch Psoriasis. A combination of erythrodermic and pustular psoriasis causes a serious condition called Zumbusch psoriasis:

The condition can develop abruptly.
Symptoms may include fever, chills, weight loss, and muscle weakness.
Patients may develop excessive fluid build-up, protein loss, and electrolyte imbalances. In such cases, hospitalization is required. Fluid and chemical balances must be restored and temperature stabilized as soon as possible.

Zumbusch psoriasis can be life threatening, particularly in the elderly. The condition is very rare in children and, if it occurs, tends to improve more quickly than in adults, possibly even without medication.

Most cases of psoriatic arthritis (PsA) are mild, but complications can occur:

Severe joint deformity and destruction (called arthritis mutilans) may develop, generally in the small joints of the hands and feet. Studies report this happens in about 5 - 16% of patients. Psoriasis patients with other arthritic conditions (osteoarthritis or rheumatoid arthritis) in the joints of the fingers tend to have a higher risk.
People with PsA may have a higher risk for respiratory illnesses.

Some earlier studies indicated that patients with psoriatic arthritis had a shorter lifespan than the general population, but more recent studies found no significant difference.

Resources

www.psoriasis.org -- National Psoriasis Foundation
www.aad.org -- American Academy of Dermatology
www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.clinicaltrials.gov -- Find clinical trials

References

Gelfand JM, Neimann AL, Shin DB, et al. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006 Oct 11;296(14):1735-41.

U.S. Food and Drug Administration. CDER Drug and Biologic Approvals for Calendar Year 2006 -- Updated through August 31, 2006. Last accessed on 15 October, 2006.

FDA Announces Strengthened Risk Management Program to Enhance Safe Use of Isotretinoin (Accutane) for Treating Severe Acne. US Food and Drug Administration. Rockville, MD: National Press Office; August 12, 2005.

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Review Date:
9/19/2007
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Acute lymphocytic leukemia

FitSugar — Wed, 08 Oct 2008 17:35:07 -0700

In This Report

Highlights
Introduction
Symptoms
Causes
Risk Factors
Diagnosis
Outlook
Treatment
Home Management
Treatment to Achieve Remiss...
Treatment During Remission...
Treatment After Relapse
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Acute Lymphocytic Leukemia (ALL)

There are four major types of leukemia. ALL is the most common type of leukemia diagnosed in children, and the least common type diagnosed in adults. About 5,200 people are diagnosed with ALL each year. Children account for two-thirds of these cases. In general, children with ALL have a better prognosis than adults. Most children with ALL can be cured of this cancer.

Symptoms and Diagnosis

Symptoms of ALL include fatigue, pale skin, recurrent infections, bone pain, bruising, and small red spots under the skin. Doctors use various tests, including blood counts and bone marrow biopsies, to diagnose ALL.

Treatment

ALL is treated with chemotherapy and, sometimes, radiation. Children receive different types of chemotherapy regimens than adults. Patients with advanced cancer that has not responded to these treatments may need a stem cell transplant.

Infection Prevention

Both chemotherapy and transplantation increase the risk for infection. Patients must take serious precautions to avoid exposure to germs. Ways to prevent infection include:

Practice good hygiene including regular handwashing and dental care (brushing, flossing)
Avoid crowds, especially during cold and flu season
Eat only well-cooked foods (no raw fruits or vegetables)
Boil tap water before drinking it
Do not keep fresh flowers or plants in your house as they may carry mold

Introduction

The word leukemia literally means "white blood" and is used to describe a variety of cancers that begin in the blood-forming cells of the bone marrow.

White blood cells (leukocytes) evolve from immature cells referred to as blasts. Malignancy in these blasts is the source of leukemias, which generally progresses as follows:

Normally, blasts constitute 5% or less of healthy bone marrow. In leukemia, however, these blasts remain abnormally immature and multiply continuously, eventually constituting between 30 - 100% of the bone marrow.
Eventually these malignant blast cells fill up the bone marrow and prevent production of healthy red cells, platelets, and mature white cells (leukocytes).

They spill out of the marrow into the bloodstream and lymph system and can travel to the brain and spinal cord (the central nervous system). As the number of normal cells decline, dangerous symptoms develop, which, if untreated, become lethal.

Leukemias are divided into two major types:

Acute (which progresses quickly with many immature white cells)
Chronic (which progresses more slowly and has more mature white cells)

Some blasts are called lymphoblasts (which become mature cells called lymphocytes) and others are called myeloblasts (which mature to myeloid cells). Acute leukemias are in turn subdivided into two classifications according to whether the malignant blasts are lymphocytes or myeloid:

Acute lymphocytic leukemia (ALL), which is the subject of this report
Acute myeloid leukemia (AML), which is not covered in this report

Acute lymphocytic leukemia (ALL) is also known as acute lymphoid leukemia or acute lymphoblastic leukemia. The majority of childhood leukemias are of the ALL type. Malignancies in this disease can arise either in T-cell or B-cell lymphocytes.

T cell ALL is diagnosed in 15% of children and adults with ALL.
About 85% of ALL cases are of the B-cell lymphocyte lineage (often referred to as "early" or "pre" B-cell lineage).

Blood Cell Lines

In adults, blood cells are produced by the bone marrow, the spongy material filling the body's bones. The bone marrow produces two blood cell groups, myeloid and lymphoid.

Myeloid Cell Line. The myeloid cell line includes the following:

Immature cells called erythrocytes that later develop into red blood cells
Blood clotting cells (platelets)
Some white blood cells, including macrophages (which act as scavengers for foreign particles), eosinophils (which trigger allergies and also defend against parasites), and neutrophils (the main defenders against bacterial infections)

Lymphoid Cell Line. The lymphoid cell line includes the lymphocytes, which are the body's primary infection fighters. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign substances (antigens).

Lymphocytes develop in the thymus gland or bone marrow and are therefore categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).

Lymphocytes and the Lymph System

Understanding how acute lymphocytic leukemia (ALL) arises requires knowledge of lymphocytic development and function:

B cells develop and mature in their final form (known as differentiation) in the bone marrow.
T cells also start out in the bone marrow but differentiate and mature in the thymus gland, located beneath the breastbone. This small gland is active mostly in the fetal stage through the first 10 years of life, after which it atrophies (shrinks).
B-cell and T-cell lymphocytes leave these organs through the bloodstream, which eventually branches out into the tiny blood vessels called capillaries.
Once they leave the capillaries, some lymphocytes migrate into the surrounding tissues. Some of these lymphocytes (along with fluid, proteins, and other substances) then enter the lymphatic vessels.
Lymphatic vessels begin as tiny, blind-ended tubes and lead to larger lymphatic ducts and branches. They drain into two ducts in the neck, where the fluid re-enters the bloodstream.
Along the way, the fluid passes through lymph nodes, which are oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or are added to the contents of the node.

Symptoms

The symptoms of ALL may be difficult to recognize. ALL usually begins abruptly and intensely, but in some cases symptoms may develop slowly. They may be present one day, and absent the next, particularly in children. Symptoms develop when:

There are not enough healthy mature white blood cells (leukocytes) to mount a defense against infection.
There are not enough healthy platelets to prevent bleeding.
The depleted oxygen-bearing red blood cells can't provide enough oxygen to organs.

Symptoms include:

Fatigue
Paleness -- patients may have poor coloring from anemia caused by insufficient red blood cells
Recurrent minor infections
Fevers
Bone pain
Bruising -- may result from only slight injury
Poor healing of minor cuts
Uncontrolled bleeding -- bleeding events increase as the bone marrow fails to produce enough platelets to make a normal blood clot, a condition called thrombocytopenia.
Small, red spots on the skin (petechiae)
Vision changes (rare)

Causes

Between 1973 - 1990, the number of acute lymphocytic leukemia cases in children under age 15 rose by 27%. The causes of the disease are not known, but experts believe that ALL develops from a combination of genetic, biologic, and environmental factors.

Advances in genetic technologies have allowed identification of a number of mutations associated with ALL. Missing or defective genes that suppress tumors are responsible for some of these cases. Identifying specific genetic allows doctors to determine how aggressive a specific case is and eventually could provide targets for developing highly specific treatments.

Translocations. Up to 65% of leukemias contain genetic rearrangements, called translocations, in which some of the genetic material (genes) on a chromosome may be altered, or shuffled, between a pair of chromosomes.

The most common genetic injury in ALL is t(12;21), which means a translocation with a genetic shift occurred between chromosome 12 and 21. This translocation is also referred to as TEL-AML1 fusion. It occurs in about 20% of patients with ALL. Researchers believe that this translocation may occur during fetal development in some patients.
About 20% of adults and about 5% of children with ALL have a genetic abnormality called the Philadelphia (Ph) chromosome [t(9;22)].
Another important chromosome translocation is t(4;11) involving the MLL gene, also called HRX or ALL-1.

Ikaros. A defective gene known as Ikaros, which regulates lymphocyte development, may play a major role in childhood ALL.

MTHFR. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism. Children with certain variations in the gene for MTHRF have a reduced risk of developing ALL. Variations in the MTHRF gene may also influence response to antifolate chemotherapy.

Risk Factors

ALL in Children. ALL is the most common type of cancer diagnosed in children. ALL accounts for about 75% of cases of childhood leukemia. Each year, about 2,400 American children and adolescents are diagnosed with ALL. ALL can strike children of all ages, but is most likely to occur when children are 2 - 3 years of age.

ALL in Adults. ALL is the least common type of leukemia among adults. About 1 in 3 cases of ALL occur in adults.

Caucasian and Hispanic children have a much higher risk for ALL than African-American children.

Certain inherited disorders can increase the risk for leukemia. For example, children with Down syndrome have a 20-times greater risk of developing ALL than the general population. Other rare genetic disorders associated with increased risk include Bloom syndrome, Fanconi's anemia, ataxia-telangiectasia, neurofibromatosis, Shwachman syndrome, IgA deficiency, and congenital X-linked agammaglobulinemia.

Previous cancer treatment with high doses of radiation or chemotherapy can increase the risk for developing ALL. Prenatal exposure to x-rays also appears to increase risk in children. Lower levels of radiation (living near power lines, video screen emissions, small appliances, cell phones) are unlikely to pose any cancer risk.

Diagnosis

Laboratory tests provide the basis for diagnosing ALL.

Flow cytometry uses light to count blood cells in a stream of fluid. It is an important tool used to diagnose leukemia, determine its progress, and tell if any disease remains after treatment. It can also determine the components and structural features of individual cells. Flow cytometry can process thousands of cells in seconds.

A complete blood cell count (CBC) is the first step in diagnosing ALL. However, blood tests do not always detect leukemia. About 10% of patients with ALL have a normal blood cell count. A CBC may show various findings, including:

Presence of circulatory leukemic blast cells (may miss the cells on occasion)
Presence and severity of anemia
Count of a variety of blood cell types (a high white blood cell count indicates a more severe disease)

Click the icon to see an illustrated series detailing a complete blood cell count test.

If blood test results are abnormal or the doctor suspects leukemia despite normal cell counts, a bone marrow aspiration and biopsy are the next steps. These are very common and safe procedures. However, because this test can produce considerable anxiety, particularly in children, parents may want to ask the doctor if sedation is appropriate for their child.

A local anesthetic is given.
A needle is inserted into the bone, usually the rear hipbone. There may be brief pressure or pain. A small amount of marrow is withdrawn. Marrow looks like blood.
A larger needle is then inserted into the same place and pushed down to the bone. The health professional will wiggle the needle from side to side to loosen a larger specimen for the biopsy. The patient will feel some pressure.
The sample is then taken to the lab to be analyzed. All the results are completed within a couple of days.

Click the icon to see an image of bone marrow removal.

Normal bone marrow contains 5% or less of blast cells (the immature cells that ordinarily develop into healthy blood cells). In leukemia, abnormal blasts constitute between 30 - 100% of the marrow.

If bone marrow examination confirms ALL, a spinal tap may be performed, which uses a needle inserted into the spinal canal. The patient feels some pressure and usually must lie flat for about an hour afterward to prevent severe headache. This can be difficult, particularly for children, so parents should plan reading or other quiet activities that will divert the child during that time. Parents should also be certain that the professional administering this test is highly experienced.

Click the icon to see an image of a spinal tap.

A sample of cerebrospinal fluid with leukemia cells is a sign that the disease has spread to the central nervous system. In most cases of childhood ALL, leukemia cells are not found in the cerebrospinal fluid.

Once a diagnosis of leukemia has been made, further tests are performed to check:

Whether the cells are myeloid or lymphocytic
Stage of maturity of the ALL B cell
Specific markers, or immunologic features, on the surface of the cancer cell
The genetic makeup of the cells ( cytogenetics)
The physical characteristics of the cells ( morphology)

First, the doctors must determine the cell of origin. In other words, they want to determine if the cell is myeloid or lymphocytic. One method is to measure an enzyme called terminal deoxynucleotidyl transferase (TdT).

About 95% of all ALL types (except the subtype B cell) have elevated TdT.
Only about 20% of cases of acute myeloid leukemia (AML) express TdT, however, so its use in determining the cell line is limited.

The stage of maturity of the leukemic B cell helps determine prognosis. There are three stages:

Early precursor-B. About 80% of patients with ALL have the early precursor-B subtype, which is the least mature. It also offers the best prognosis.
Precursor-B. This is the intermediate stage.
B cell. This is the mature cell and ALL in this stage is identical to Burkitt's non-Hodgkin's lymphoma. It is therefore treated differently from other ALL cases.

A series of tests are used to determine the immunologic pattern of the leukemia cell (how it can be expected to interact with the immune system).

On the surface of malignant ALL cells are markers for certain antigens (molecules that set off a targeted attack by the immune system using antibodies). Such antigens are proving to be very helpful in predicting outcome.

An antigen is a substance that can provoke an immune response. Typically, antigens are substances not usually found in the body.

Important antigens associated with ALL include:

CD10, more frequently referred to as cALLa (common ALL antigen). This antigen occurs in about half of all ALL cases and in about 80% of ALL B-precursor patients. It is associated with a good prognosis.
CD95 (associated with a good prognosis)
CR19
DR

The surfaces of T-cell ALL cancer cells express several antigens as well. For example, the presence of one of these, CD2, suggests a favorable prognosis.

Genetic tests are useful for a number of important criteria:

Diagnosing a specific ALL subtype
Designing appropriate treatment
Deciding prognosis
Monitoring patients throughout treatment and beyond

Cytogenetics is a technique that researchers use to determine specific genetic abnormalities, which are found in nearly 65% of all leukemias. Detecting these genetic defects is helpful in making a full diagnosis of ALL and in planning the most appropriate therapy. Specific technologies called microarray chips are capable of checking up to 48,000 different genes in a single test, which holds promise for assessing prognosis and developing very targeted therapies in the future. Research on DNA microarray analysis continues to reveal different prognostic subgroups of ALL. As the precision, logistics, and cost effectiveness of DNA microarray assays improve, they may be used more commonly in the clinical setting.

MTHFR Variants. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism. Variations in the MTHRF gene may also influence response to antifolate chemotherapy. A 2004 study showed that patients with one of two specific variations of the MTHFR gene had a lower probability of survival following treatment with methotrexate.

Translocations. Genetic translocations (swapping of genes on chromosomes) may affect outlook. Examples include:

Patients with the t(12;21) genetic translocation (also referred to as TEL-AML1 fusion) have an excellent prognosis.
Patients who carry the defective gene called ETV6 often respond well to chemotherapy.
The t(4;11), sometimes referred to as MLL, is the most common translocation in children under age 1 year. Unfortunately, anyone with t(4;11) has a poor outlook. One study suggested that this genetic variant may actually be a unique leukemia and require treatments that differ from standard ALL.
The Philadelphia translocation t(9;22) also indicates a poor outlook. It represents about 20% of adult cases and about only 5% of childhood cases.
The t(1;19) location occurs in about 5% of ALL childhood cases and requires aggressive treatment.

Ploidy. Ploidy refers to the number of chromosomes. Additional copies (hyperdiploidy) or absence of copies (hypodiploidy) of chromosomes affect prognosis. For example, in children hyperdiploidy is associated with a more favorable outcome and hypodiploidy with a poorer outcome. (Hypodiploidy occurs in only 1% of children with ALL.)

The morphology of a cell includes its physical characteristics, such as shape and structure. To determine the morphology of the leukemia cells, samples of the bone marrow are taken and particular contents of the cells are stained with a dye. They are then examined under a microscope.

Acute lymphocytic leukemia cells are grouped, according to the French-American-British (FAB) classification system, into three ALL morphologic types. (It should be noted that this system is subjective and is now used to complement other diagnostic tests mentioned above):

L1 cells. These are small blasts with scant amounts of cytoplasm (the substance in a cell between its membrane and nucleus). L1 cells usually contain a round nucleus and there is little variation among them. L1 represents the most common ALL morphology and offers the best prognosis. It occurs in about 85% of children and 30% of adults with ALL.
L2 cells. These cells are larger than L1 and have more abundant cytoplasm. They vary significantly among each other and have an irregularly shaped nucleus. L2 morphology conveys a poorer prognosis than L1, although the two cells' types are treated similarly. Subtype L2 is the most common morphologic type in ALL adults; 64% of adults with ALL have this subtype compared with only 15% of children.
L3 cells. These are uncommon. They resemble another malignancy called Burkitt's lymphoma, and their treatments are now the same.

Assays that test for cancerous cells are improving, allowing doctors to detect smaller and smaller amounts of hidden disease. For example, flow cytometry assays can detect 0.01% leukemic cells, and PCR assays can detect 0.001% leukemic cells. A new concept called minimal residual disease (MRD) is becoming an important prognostic factor in ALL. A more precise measure of disease response, MRD may soon replace existing measures such as "complete response" and "partial response" when assessing the effectiveness of ALL treatment. Ongoing studies of MRD in ALL may help identify patients in remission who are at risk of relapse. In addition, early therapeutic intervention based on the presence of MRD may improve outcome and prolong survival.

Using the results of the tests described above, patients are classified into low-, average-, and high-risk groups. This information allows the doctor to diagnosis the type of leukemia and plan the best treatment. Each classification requires unique therapies.

Doctors attempt to make a prognosis and determine an optimal treatment plan by assessing all the cell characteristics plus the white blood cell count. As examples:

Patients who have an L1 or L2 morphology, a white blood cell count of less than 15,000 mm3, a t(12;21) genetic translocation, and a cALLa-positive antigen marker have an excellent outlook.
On the other hand, patients who have an L2 morphology, a white blood cell count greater than 30,000 mm3, and who lack the cALLa marker have a poorer prognosis and require more aggressive treatment

Outlook

Acute lymphocytic leukemia is responsible for about 1,400 deaths a year in the U.S., and it can progress quickly if untreated. However, ALL is one of the most curable cancers and survival rates are now at an all-time high. People who have Philadelphia chromosome-positive ALL tend to have a poorer prognosis, although new treatments are helping many of these patients achieve remission.

Outlook in Children with ALL. More than 95% of children with ALL attain remission.

Certain children are at higher risk for a poor outcome than others:

Infants and children age 10 years and older tend to have a poorer outcome than young children (ages 1 - 9 years).
Some studies indicate a better prognosis for girls than boys. This may be partly due to boys’ risks for testicular cancer.
Survival rates for African-American and Hispanic children are lower than Caucasian and Asian children, but this may be due to poorer access to treatment.

Responding well to early treatment is a good sign regardless of the risk category. Other positive predictors include:

Less than 5% of cells being blasts after 7 - 14 days of treatment
Less than 1,000 blasts per microliter on peripheral smear after 7 days

Outlook in Adults with ALL. Adults tend to have a more severe condition than children, even if they are carrying the same ALL genes. Still, 60 - 80% of adults with ALL can expect to achieve full remission with standard treatments, and 35 - 40% survive beyond 2 years with aggressive treatments. Younger adults with ALL have better long-term survival rates than older adults with the disease.

Treatment

The aim of initial treatment is to get rid of the leukemia cells in the body (achieve complete remission) and have 5% of lower levels of blasts in the bone marrow.

There are typically four treatment stages for the average-risk patient with ALL:

Induction therapy in order to achieve a first remission
Central nervous system prophylaxis (preventive treatment), usually given along with induction therapy
Consolidation, intensive therapy to prevent relapse after remission has been achieved
Maintenance treatment, lower intensity therapy given for several years to prevent relapse after remission

The following are specific treatments used for ALL:

Chemotherapy is the primary treatment for each stage.
Radiation to the brain and spinal cord is also administered in some cases.
A bone marrow transplant is often recommended for relapsed ALL or in cases that cannot be induced into remission (refractory disease). It is also sometimes considered after remission is achieved for certain high-risk ALL types. The timing of bone marrow transplantation can be controversial, particularly after a first remission, although it has produced excellent long-term survival rates in appropriate patients.
New drugs known as biological therapies are also being used.

Drugs Used to Prevent Infections During Treatment. Half of all patients with ALL develop fever in the early stages, especially if patients also have low levels of the white blood cells called neutrophils (a condition called neutropenia).

Blood is made of red blood cells, platelets, and various white blood cells.

Neutropenia, common in ALL, is a significant risk factor for serious infection. Doctors are increasingly concerned about fungal infections, which are becoming more common in these patients, particularly after transplant procedures.

Antibiotics and Antifungal Medications. The use and timing of antibiotics and antifungal medications depend on the particular organisms and severity of the infection. In some cases of neutropenia, patients may need preventive antibiotics.
Granulocyte Colony-Stimulating Factor. Granulocyte colony-stimulating factor (lenograstim, filgrastim) is often given to patients who receive chemotherapy in order to stimulate the growth of infection-fighting white blood cells. This helps prevent neutropenia.

Intravenous Fluids. Patients may also need to receive intravenous fluids and be treated for fluid imbalances, which can cause abnormal levels of sodium, potassium, calcium, and uric acid. Such treatments might include sodium bicarbonate, allopurinol, and aluminum hydroxide or calcium carbonate.

Transfusions. Red blood cell or platelet transfusions may be needed. (Patients who may need allogeneic transplantations should not receive transfusions from potential donors.)

Home Management

A parent should call the doctor if the child has any symptoms that are out of the ordinary, including (but not limited) to:

Any fever of 101°F or higher
Any signs of a flu or cold
Shortness of breath
Severe diarrhea
Blood in the urine or stools
Trouble urinating

Tracking Neutrophils. Parents should track their child's absolute neutrophil count. This measurement for the amount of white blood cells is an important gauge of a child's ability to fight infection.

Counts over 1,000 usually provide sufficient protection so that children can engage in normal activities, including school and other functions where they are exposed to other children.
If the count is between 500 - 1,000, the child should avoid large groups.
If it falls between 200 - 500, the child should stay at home and should see only healthy visitors who have washed their hands vigorously.
Neutrophil counts below 200 indicate that the child is at high risk for infection and should have no visitors.

Maintaining Strict Hygiene. Children with ALL and anyone exposed to them, not only friends and family members but also doctors and nurses, should maintain strict hygiene:

Frequent hand washing with antibacterial soap is particularly essential.
Everyone should wash their hands before and after meals, after being outside, before preparing food, and after going to the bathroom.
When visiting the doctor, a parent should ask about a side entrance or areas where the patient will not be exposed to other sick children.

Vaccinations. Studies now suggest that young survivors of leukemia have an increased risk for measles, mumps, and rubella (MMR), even if they have been previously vaccinated. Children may need reimmunization. Siblings of patients with ALL who require polio vaccinations should be given the killed virus (IPV), not the live polio vaccination (OPV).

Use a soft toothbrush when counts are low to prevent gum bleeding.
Avoid common pain relievers known as nonsteroidal anti-inflammatory drugs (NSAIDs). They increase the risk for bleeding and include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), and ketoprofen (Actron, Orudis KT).

Some of the drugs used for leukemia cause extreme sun sensitivity. Children should wear sunblock and be covered with sun-protective clothing when going outside to avoid sunburn, which can cause skin infection.

Treatment to Achieve Remission

The aim of induction therapy, the first treatment phase, is to reduce the number of leukemia cells to undetectable levels. The general guidelines for induction therapy are as follows:

Patients are given intensive chemotherapy that uses powerful multi-drug regimens. (Infants require special regimens not discussed here.)
For both children and adults, some of these therapies are administered orally, others intravenously.
Hospitalization is usually necessary at some point to help prevent infection and to administer blood products. However, much of this therapy can be given on an outpatient basis.
After the first cycle of induction, bone marrow tests are done to determine if the patient is in remission.
Another bone marrow test is sometimes done about a week later to confirm the first results.
A bone marrow transplant is considered for patients who do not respond at all to induction treatment.

Both children and adults typically start with a 3-drug regimen. Imatinib (Gleevec) or dasatanib (Sprycel) may be added for patients with Philadelphia chromosome-positive ALL.

For children, the standard drugs are:

Vincristine (Oncovin), a vinca alkaloid drug
Prednisone or dexamethasone. These drugs are corticosteroids. Dexamethasone may be more effective than prednisone, but it increases the risk for infections and other serious side effects.
Asparaginase. Generally provided as pegaspargase (Oncaspar) in place of L-asparaginase (Elspar) for treating newly diagnosed ALL in children. With pegaspargase, patients need only 3 injections over a 20-week period instead of the 21 injections required for L-asparaginase.

For adults, the standard drugs are:

Vincristine
Prednisone
Anthracycline drug, such as such as doxorubicin, daunorubicin, or epirubicin. Some adult chemotherapy regimens also add on an asparaginase drug or cyclophosphamide (Cytoxan).

The induction chemotherapy described above does not penetrate the blood-brain barrier sufficiently to destroy leukemic cells in the brain. CNS prophylaxis is critical for preventing disease that has spread to the brain, spine, and testes (called sanctuary disease sites). Although only 3% of children with ALL have evidence of leukemia in the central nervous system (CNS) at the time of diagnosis, leukemia will spread to this region in 50 - 70% of children who don't receive preventive (prophylactic) treatment. The brain is one of the first sites for relapsing leukemia.

For children, CNS prophylaxis uses intrathecal chemotherapy, in which a drug is injected directly into the spinal fluid. Intrathecal chemotherapy is given with methotrexate alone or a combination of methotrexate, cytarabine, and hydrocortisone.

Some high-risk children also receive radiation to the skull (cranial irradiation), radiation to the spine, or both at the same time. This combination can be very toxic and can cause later learning problems. It is generally used only in children who have evidence of the disease in the central nervous system at the time of diagnosis. Later complications can include learning and neurologic problems. Using lower-dose units of radiation, however, may significantly reduce the risk for mental impairment. Cranial radiation is also associated with increased risks for stroke and secondary cancers.

Adult CNS prophylaxis is performed in one of three ways:

Cranial radiation plus intrathecal chemotherapy with methotrexate
High-dose systemic infusion of methotrexate plus intrathecal methotrexate without cranial radiation
Intrathecal methotrexate chemotherapy alone

Survival in acute leukemia depends on complete remission. Although not always clear-cut, remission is indicated by the following:

All signs and symptoms of leukemia disappear.
There are no abnormal cells in the blood, bone marrow, and cerebrospinal fluid.
The percentage of blast cells in the bone marrow is less than 5%.
Blood platelet count returns to normal.

Induction can produce extremely rapid results, and the faster the time to remission the better the outlook:

A complete remission usually occurs within the first 4 weeks. Patients who show low disease levels within 7 - 14 days have an excellent outlook, particularly if they have favorable genetic factors, and may need less-intensive treatments afterward.
Patients with high disease levels at 14 days or who require more than 4 weeks to achieve remission are at higher risk for relapse and most likely need more aggressive treatment.

Side effects and complications of any chemotherapeutic regimen and radiation therapy are common, are more severe with higher doses, and increase over the course of treatment. Administering drugs for shorter duration can sometimes reduce toxicities without affecting the drugs' cancer-killing effects.

Common Side Effects. Typical side effects include:

Nausea and vomiting. Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs, and most patients who take more powerful drugs. In one study, nearly all patients who took a combination of dexamethasone (a steroid) in combination with ondansetron within 24 hours of chemotherapy experienced either a significant or complete reduction in nausea and vomiting.
Diarrhea
Hair loss
Weight loss
Depression

Serious Side Effects. Serious side effects can also occur and may vary depending on the specific drugs used.

Infection from suppression of the immune system or from severe drops in white blood cells is a common and serious side effect. Patients should make all efforts to prevent infection. The patient at high risk for infection may need very potent antibiotics and antifungal medications as well as granulocyte colony-stimulating factors or G-CSF (lenograstim, filgrastim) to stimulate the growth of infection-fighting white blood cells. Patients should make all efforts to minimize exposure to bacteria and viruses. (See “Infection Prevention” in the Transplant section of this report.)

Other serious side effects include:

Liver and kidney damage
Immediate and short-term risks of radiation therapy may include seizures, stroke, and paralysis
Very high levels of uric acid in the blood, which can damage the kidneys
Very high levels of calcium in the blood
Abnormal blood clotting
Allergic reaction
Low blood sugar (hypoglycemia) -- a rare complication in young, thin children who are taking purine analogues such as mercaptopurine and thioguanine
Suppression of adrenal glands in children who take short-term, high-dose corticosteroids such as prednisolone

Long-Term Complications.

Fatigue is very common after chemotherapy and can be significant and long-lasting.
Combinations of intrathecal chemotherapy plus brain radiation in children can cause some serious complications, including seizures and problems in learning and concentration. Methotrexate is particularly toxic. (The effects of intrathecal chemotherapy alone on mental functioning, however, did not seem significant.) Seizures can often be treated successfully with anti-epilepsy medications.
Delayed puberty. The effects of treatment in the brain can affect regions that regulate reproductive hormones, which may affect fertility later on. Chemotherapy, cranial radiation, or both can impair fertility in male and female patients. Cranial radiation can also result in impaired growth.
Bone loss can occur after chemotherapy, particularly with corticosteroids and after bone marrow transplantation. Drugs are available, particularly bisphosphonates, which may help reduce this risk.
Pancreatic beta-cell damage. A 2004 study reported that children who have been off treatment for at least 1 year have a higher risk of impaired insulin response. This suggests that chemotherapy-induced beta cell damage persists after therapy has been stopped.
Heart damage. Some of the treatments increase risk factors for future heart disease, including unhealthy cholesterol levels and high blood pressure. Anthracyclines (doxorubicin, daunorubicin, epirubicin) have been associated with later development of heart failure. Lower doses used for many ALL children may not pose a high risk to the heart. Some anthracyclines (DaunoXome, Myocet, Doxil) now come in tiny protective capsules that may reduce toxic effects. Patients with ALL should be sure to maintain a healthy lifestyle and be regularly monitored for heart risks to help reduce these effects.
Stroke. Survivors of childhood leukemia are at increased risk of later stroke, especially if they received treatment with cranial radiation.
Obesity. Children treated for ALL are at higher risk for obesity, possibly because the treatments trigger an earlier than normal occurrence in childhood weight gain. Corticosteroid drugs used in treatments also increase appetite, which contributes to the problem.
Central nervous system. Radiation and intrathecal MTX therapy may be associated with an increased risk of mood disturbances (such as depression) among adult survivors of childhood ALL. Patients with depression may benefit from psychosocial support. Cranial radiation and drugs used in chemotherapy, especially specific corticosteroids and spinal injection treatments, may also impair mental functioning and cause neurologic problems, such as movement problems.
Infections. Some children may be more vulnerable to infections after completing chemotherapy, although the immune system tends to improve over time. Patients who have had a bone marrow transplantation or lung damage from the treatments may be particularly vulnerable. Studies suggest that young survivors of leukemia have an increased risk for measles, mumps, and rubella (MMR), even if they have been previously vaccinated. Children, then, may need reimmunization.
Secondary Cancers. Studies indicate that survivors of childhood ALL are at increased risk of later developing other types of cancers, including brain and spinal cord tumors, basal cell skin carcinoma, and myeloid (bone marrow) malignancies. Radiation and older types of chemotherapy are mainly responsible for this risk. Newer types of ALL treatment may be less likely to cause secondary cancers.

Treatment During Remission

Consolidation and maintenance therapies follow induction and first remission. The goal of consolidation and maintenance therapies is to prevent a relapse. The specific treatment choices and degree of aggressiveness after induction therapy depend on a number of factors, particularly the risk factors for relapse.

Consolidation therapy is additional treatment that is administered after induction therapy and before maintenance therapy. This is an intense regimen that is designed to prevent the high relapse rates that occur with induction therapy alone. (The benefits of this therapy are clearer in children than in older adults, who may just be given maintenance.)

Consolidation therapy usually continues for about 6 months and uses 1 - 6 courses of chemotherapy, depending on risk factors for relapse.

Examples of consolidation regimens for children at standard risk:

A limited number of courses of intermediate- or high-dose methotrexate, one of the oldest drugs used for leukemia.
An anthracycline drug, such as daunorubicin (Cerubidine), used for reinduction followed by cyclophosphamide (Cytoxan, Neosar) 3 months after remission. These are very powerful drugs, but when used in this way toxicity is limited.
Extended use of an asparaginase drug.

More intense regimens are used for children at high-risk for relapse.

Instead of chemotherapy alone as consolidation therapy, some high-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone may undergo allogeneic stem cell or autologous stem cell bone marrow transplant after the intensive chemotherapy regimens. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission.

Allogeneic transplantation is an option when a well-matched donor is available. Although this treatment can be effective in keeping the leukemia away, significant complications -- such as graft versus host disease, blood clots, liver problems, and lung damage -- can occur and may be a cause of death even without a return of cancer.
Autologous stem cell bone marrow transplant (using the patient's own bone marrow cells) seems to be helpful also and may be as effective as allogeneic transplantation.

The last phase of treatment is maintenance, or continuation therapy:

Maintenance therapy typically uses weekly administration of methotrexate (usually in oral form) and daily doses of mercaptopurine. (Mercaptopurine should be given in the evening.)
Treatment continues for 2 - 3 years for most children with ALL (with the exception of those with mature B-cell leukemia). It is not yet clear if prolonged maintenance therapy benefits adults with ALL.
If children were not given CNS prophylaxis before, it may be given now.
Vincristine and a corticosteroid drug (generally dexamethasone) are often added to standard maintenance therapy, although some studies indicate that they do not provide additional benefit.

A maintenance regimen is usually less toxic and easier to tolerate than induction and consolidation. Some studies, however, indicate that overall survival could further be improved with more-aggressive maintenance therapies, including:

Vincristine and a corticosteroid added to the standard maintenance regimen
Longer term low-dose maintenance
Intense regimens similar to induction (called reinduction)

Maintenance is typically ongoing until complete remission has lasted 2 - 3 years.

Investigation is ongoing to determine the best drugs and schedules to use. For example, doctors have debated whether thioguanine is a better choice than mercaptopurine (a 2006 study recommended that mercaptopurine remain the standard thiopurine drug for treating childhood ALL). Researchers are also trying to pinpoint patients who would best benefit from aggressive maintenance treatments.

The following are factors that increase the risk for relapse after initial treatments:

Microscopic evidence of leukemia after 20 weeks of therapy (minimal disease)
Age over 30
A high white blood cell count at the time of diagnosis
Disease that has spread beyond the bone marrow to other organs
Certain genetic abnormalities, such as the presence of the Philadelphia chromosome or MLL gene translocations
Patients with high disease levels after 7 - 14 days of induction therapy
The need for 4 or more weeks of induction chemotherapy in order to achieve a first complete remission

Patients with one or more of these risk factors may be candidates for bone marrow transplantation once they are in first remission.

Treatment After Relapse

Between 50 - 70% of children and 40 - 50% of adults who achieve complete remission after initial therapy but then suffer a relapse may be able to go into a second complete remission.

Treatment for relapse after a first remission may be standard chemotherapy or experimental drugs, or more aggressive treatments such as stem cell transplants.

The decision depends on a number of factors:

Children who relapse 3 or more years after achieving a first complete remission have an excellent chance for a second remission without aggressive treatments.
Those who relapse fewer than 6 months following initial treatment, especially while on chemotherapy, have about a 20% chance of long-term freedom from disease. In such cases, remission is possible following another course of standard chemotherapy but the duration of remission is usually fewer than 6 months.

Treatment decisions also rely on prior treatments and where the relapse has occurred. Relapse can occur in the bone marrow, central nervous system, or sanctuary disease sites (brain, spine, or testicles). The incidence of relapse in sanctuary sites is about 10%.

Candidates for transplantation include:

Patients who relapse following initial remission with standard chemotherapy.
High-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission.
Patients who fail to achieve a complete remission during initial chemotherapy.

Transplantation procedures do not appear to offer any additional advantages for patients at low or standard risk.

Many different drugs are used to treat ALL relapses. These drugs include vincristine, asparaginase, anthracyclines (doxorubicin, daunorubicin), cyclophosphamide, cytarabine (ara-C), and epipodophyllotoxins (etoposide, teniposide). Corticosteroids, such as prednisone or dexamethasone, may also be used.

In 2004, the Food and Drug Administration (FDA) approved clofarabine (Clolar) for treatment of relapsed or refractory ALL in children. This drug was the first new leukemia treatment approved specifically for young patients in more than a decade. In 2005, nelarabine (Arranon) was approved to treat adults and children with relapsed or refractory T-cell acute lymphocytic leukemia (T-ALL). In 2006, the FDA approved imatinib (Gleevec) for treating patients with Philadelphia chromosome-positive ALL that has not responded to or has returned after treatment. Also in 2006, the FDA approved dasatinib (Sprycel) for patients who are not helped by imatinib.

Tyrosine kinase inhibitors. Tyrosine kinase is a growth-stimulating protein. Tyrosine kinase inhibitor drugs block the cell signals that trigger cancer growth. Several tyrosine kinase inhibitors, including imatinib (Gleevec) and dastinib (Sprycel), have recently been approved for treating Philadelphia chromosome-positive ALL. In 2006 clinical trials, Nilotinib (AMN-107) produced excellent results in patients with Philadelphia chromosome positive ALL who are resistant to imatinib.

Monoclonal antibodies (MAbs). Used alone or in combination with chemotherapy, MAbs target specific antigens on ALL blast cells. Although MAbs have been studied primarily in the treatment of B-cell non-Hodgkin's lymphoma, drugs demonstrating benefit in preliminary trials of ALL include anti-CD20 (rituximab) and anti-CD22 (epratuzumab). Alemtuzumab (MabCampath) is also showing promise in treating relapsed or refractory T-ALL. More studies are needed to determine the best MAb regimens in ALL.

In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. These procedures are based on removal and replacement of stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Sources of Cells. Stem cells must first be collected either from:

Bone marrow (bone marrow transplantation)
Blood (peripheral blood stem cell transplantation). Evidence suggests that peripheral blood stem cell transplantation may be the superior approach. Studies report survival rates of 45% in bone marrow transplant patients compared to 65 - 70% in stem cell transplant patients, with benefits being significant in those with more severe disease.
Fetal umbilical cord or placentas. This procedure uses donor cells but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, however, so at this time its use is limited to children and sometimes adults with low weight. (Some studies indicate success for adults with normal weights.)

Donor or Patient Cells. The sources of marrow or blood cells can be taken from the patient or a donor:

If the bone marrow or stem cells are taken from a donor, the transplant is referred to as allogeneic. Allogeneic transplants from genetically matched sibling donors offer the best results in ALL. With new techniques, donor bone marrow from unrelated but immunologically similar donors is proving to work as well as those from matched siblings. This approach is still reserved for patients in second remission or beyond. A 2006 study indicated that allogeneic transplant is also a good treatment option for patients with Philadelphia chromosome-positive ALL who are resistant to imatinib (Gleevec).
If the marrow or blood cells used are the patient's own, the transplant is called autologous. Autologous transplants in patients with ALL are generally not beneficial, since there is some danger that the cells used may contain tumor cells and the cancer can regrow. Treatment advances that reduce this risk, however, may make autologous transplantation feasible in patients without family donors.

The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim) to stimulate stem cell growth.
The donor (or patient in an autologous procedure) then undergoes apheresis. With this process, the blood is withdrawn from one of the patient's veins and passed through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes 3 - 4 hours but needs to be repeated several times.
The stem cells are then frozen.

The patient is given high-dose chemotherapy with or without radiation -- a treatment known as conditioning. The point is to inactivate the immune system and to kill any residual malignant cells. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning includes radiation with drugs.
A few days after treatment, the patient is rescued using the stored stem cells, which are administered through a vein. This may take several hours. Patients may experience fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
The patient is kept in a protected environment to minimize infection, and the patient usually needs blood cell replacement and nutritional support.

Two- to 5-year survival rates after transplantation plus chemotherapy range from 40 - 80%. Certain patients with the Philadelphia chromosome, which carries a poor prognosis, may achieve significant success with an allogeneic bone marrow transplant from a closely matched related donor.

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

Blood stem cell transplantation itself is fairly dangerous and has a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now, mortality rates are below 5%. Potentially serious complications include:

It is very important that patients take precautions to avoid infections. Guidelines for post-transplant infection prevention include:

Discuss with your doctor what vaccinations you need and when you should get them.
Avoid crowds, especially during cold and flu season.
Be diligent about hand washing and make sure that visitors wash their hands.
Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
Boil tap water before drinking it.
Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
Do not sleep with pets. Avoid contact with pets’ excrement.
Avoid fresh flowers and plants as they may carry mold. Do not garden.
Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
Report to your doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection. Some of these symptoms can also indicate graft-versus-host disease.
Report to your ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. To reduce the risk for GVHD, doctors remove some immune T cells from the donor’s stem cells before the transplant. Researchers are investigating new techniques to refine this process of T cell depletion.

Too much sun exposure can trigger GVHD. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.

Other potentially serious complications include:

Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
Infertility
Organ complications to the liver, heart, kidney, or lungs
Failure of the transplant
Muscle problems, including stiffness, cramps, and joint pain
Frequent urination and bladder control problems
Older patients should be screened for osteoporosis (thinning of bones) and hypothyroidism (underactive thyroid)

Resources

www.leukemia-lymphoma.org -- Leukemia and Lymphoma Society
www.cancer.org -- American Cancer Society
www.cancer.gov -- National Cancer Institute
www.bmtnews.org -- Blood and Marrow Transplant Information Network
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.aspho.org -- American Society of Pediatric Hematology/Oncology
www.candlelighters.org -- Candlelighters Childhood Cancer Foundation
www.clf4kids.com -- Childhood Leukemia Foundation

References

Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007 Jan;115(1):138-45. Campbell LK, Scaduto M, Sharp W, et al. A meta-analysis of the neurocognitive sequelae of treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer. 2007 Jul;49(1):65-73.

Hijiya N, Hudson MM, Lensing S, et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007 Mar 21;297(11):1207-15.

Ribera JM, Ortega JJ, Oriol A, et al. Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol. 2007 Jan 1;25(1):16-24.

Waber DP, Turek J, Catania L, et al. Neuropsychological outcomes from a randomized trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS treatment in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. J Clin Oncol. 2007 Nov 1;25(31):4914-21.

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