Throughout this booklet, words that may be new to readers are printed in italics. Definitions of these and other terms related to melanoma begin on page 23.
Melanoma is a type of cancer that usually occurs in the skin (cutaneous melanoma) but can also form in the eye and various other parts of the body, such as the anus, esophagus, central nervous system, and vulva. Ocular (of the eye) melanoma sometimes behaves differently than melanoma of the skin and other parts of the body. In this publication, melanomas are discussed in two sections, "Cutaneous Melanoma" and "Ocular Melanoma."
Knowledge about melanoma is increasing steadily. Up-to-date information on this and other cancer-related subjects is available from the toll-free Cancer Information Service at 1-800-4-CANCER.
Description and Function of the Skin
The skin is the body's outer covering. It protects the body from heat and light, injury, infection, and many chemicals. The largest organ of the body, the skin also regulates body temperature, stores water and fat, and helps to make vitamin D. The skin also acts as a sensor of the environment, sending information to the brain about temperature, pressure and vibration, pain, and touch.
The skin has two main layers--the inner dermis and the outer epidermis. The dermis contains cells, connective tissue, blood and lymph vessels, sweat and sebaceous glands, and follicles in which hair grows. Blood vessels in the dermis reach up toward the epidermis to supply it with nutrients. Sweat produced by glands is secreted onto the skin surface, where it evaporates, thereby cooling the skin and regulating body temperature. The sebaceous glands produce sebum, an oily substance that keeps the skin from drying out. Sweat and sebum reach the skin's surface through tiny openings called pores.
The epidermis, the outermost layer of the skin, is made up mostly of flat, scalelike cells called squamous cells. Squamous cells are formed from round basal cells, which are found in the lowest part of the epidermis. This part of the epidermis also contains melanocytes, cells that produce a pigment called melanin. The amount and type of melanin in the skin accounts for the variations in skin color found among different races and individuals.
Types of Skin Cancer
Skin cell growth begins deep in the epidermis, where basal cells divide. New cells formed through division push mature cells upward to the skin's surface, where they die and flake off. In this way, the skin constantly repairs itself, as new cells grow and multiply in a controlled, orderly manner to replace dying ones.
Sometimes, though, cell growth becomes uncontrolled, and a mass of tissue known as a tumor develops. Tumors can be either benign (not cancerous) or malignant (cancerous). Benign tumors do not invade nearby tissue, do not spread to other parts of the body, and are seldom a threat to life. Benign tumors usually can be removed by surgery and are not likely to return.
In contrast, malignant tumors invade and destroy nearby tissues and organs. Cancer cells can spread not only by extension into neighboring tissues but also by breaking away from the primary (original) tumor in the skin and traveling through the blood and lymph systems to other parts of the body, where they can form secondary tumors (metastasis). When melanoma spreads, it most commonly affects new locations in the skin, lymph nodes, lungs, liver, brain, or bones. Although another organ is affected, these secondary tumors retain many of the characteristics of the original melanoma. The secondary tumors are called "metastatic melanoma" (rather than lung, liver, or bone cancer) to indicate that they are part of a single disease and are not new cancers originating in these organs. Treatment for cancer that has spread must take into account the site and type of the primary tumor, the location and extent of the metastatic tumors, and other factors.
The two most common types of skin cancer are basal cell carcinoma, which arises in basal cells, and squamous cell carcinoma, which begins in squamous cells. These cancers, called nonmelanoma skin cancers, are often diagnosed and treated in the same way and are almost always curable. They are discussed in What You Need To Know About Skin Cancer.
Melanoma, the subject of this Research Report, develops in melanocytes. It is less common but more serious than basal cell or squamous cell carcinoma and is treated differently. Other, much less common types of cancer that can develop in the skin include Kaposi's sarcoma and cutaneous T-cell lymphoma (also called mycosis fungoides). These cancers are not discussed in this Research Report.
Incidence and Mortality
It is estimated that 32,000 new cases of cutaneous melanoma and 6,500 deaths from this disease occurred in the United States in 199 1. The incidence of melanoma in this country is increasing at the rate of 4.3 percent per year. This rate of increase is greater than that of any other type of cancer, except for lung cancer among women.
Whites develop melanoma much more frequently than people with more pigmented skin (such as blacks, Hispanics, or Asians), and many more of them die of the disease as well. In the United States, the incidence among whites increased by almost 75 percent from 1973 to 1988. The current annual incidence among whites is approximately 10 per 100,000 individuals; in blacks, the rate is about 1 per 100,000.
Fortunately, most new cases of melanoma are diagnosed early and can be cured by surgery. The overall 5-year relative survival rate is 81 percent. The 5-year survival rate for patients with localized melanoma is 91 percent. For patients whose disease has spread to other sites in the region of the original cancer, the 5-year survival rate is 50 percent, and for those whose cancer has spread to distant sites in the body, the rate is 14 percent.
Causes and Risk Factors
Scientists do not know exactly what causes melanoma, but several causes and risk factors have been identified.
Ultraviolet Radiation--Exposure to ultraviolet (UV) radiation from the sun and other sources is the major cause of melanoma and other cancers of the skin. UV radiation, which is invisible, is composed of wavelengths shorter than 400 nanometers (nm). (A nanometer is one-billionth of a meter.) Only a small amount of the sun's UV radiation (solar radiation) reaches the Earth's surface, and most of it is absorbed by the atmosphere's ozone layer. The amount of UV radiation reaching the Earth increases at higher altitudes and decreases with distance (latitude) from the Equator. Other related factors influencing exposure to solar UV radiation include heat, wind, humidity, season, time of day, and physical surroundings (snow, sand, or water can greatly increase exposure because they reflect UV radiation).
A number of epidemiologic observations support the conclusion that UV radiation causes melanoma.
* People who are protected from UV radiation by naturally dark skin have the lowest rates of melanoma.
* People who have red or blond hair, fair skin, freckles, and blue eyes and who sunburn easily but rarely tan are at greater risk for developing melanoma. The incidence is highest among fair-skinned people living close to the Equator, where the UV radiation exposure is greatest.
* The incidence of melanoma in the United States has risen steadily over the past 50 years, during which time Americans have increased their sun exposure through lifestyle changes--more outdoor recreational activities, more emphasis on tanning, scantier clothing, and a population shift to warm, sunny climates.
* The risk is higher than average for people who were severely sunburned as children.
* People with xeroderma pigmentosum, a rare hereditary disease in which the skin and eyes are extremely sensitive to light, are much more likely than the general population to develop melanoma.
Scientists are concerned that the atmosphere's ozone layer is thinning and may eventually allow more UV radiation to reach the earth, thus increasing the risk of melanoma. The ozone layer is being depleted by synthetic products called chlorofluorocarbons, such as Freon[R]. In the past, these products served as propellants in aerosol sprays, and they are still used as cooling agents in refrigerators and air conditioners.
Other concerns are being raised by scientists studying the two types of solar UV radiation that reach the Earth's surface: UVA (320 to 400 nm) and UVB (290 to 320 nm) radiation. (Wavelengths below 290 nm, known as UVC radiation, do not reach the Earth.) For many years, health risks associated with UV radiation exposure have been attributed primarily to the shorter UVB wavelengths, which bum the skin more easily. Extensive laboratory studies support the cancer-causing potential of UVB radiation. However, recent studies suggest that UVA radiation, which penetrates the skin more deeply but takes longer to produce a bum, may also contribute to the development of melanoma and other conditions.
Although melanoma frequently develops in sun-exposed areas of the body, such as the arms and lower legs in women and the head, neck, and upper extremities in men, the risk associated with exposure to UV radiation does not account for all cases of melanoma. For example, melanoma also commonly occurs on the trunk of the body in men, a site that is not routinely exposed to UV radiation. In addition, melanoma risk is greater in people with intermittent intense sun exposure, such as office workers vacationing at the beach, than in outdoor workers with constant exposure. Thus, it appears that the relationship between UV radiation exposure and melanoma is not as clear cut as is the relationship between UV radiation and the development of nonmelanoma skin cancers. It seems likely that other risk factors also play a role in the development of melanoma.
Nevi-"Nevi" is the medical term for moles, which are clusters of melanocytes. Individuals with very large nevi (20 centimeters, or 7.8 inches, in diameter) that are present from birth have a higher-than-average risk of developing melanoma. In addition, people with certain types of atypical nevi may have an increased risk for this disease.
Atypical nevi are generally larger than ordinary moles and have irregular borders that fade into the surrounding skin. They may be totally flat, or parts may be raised above the skin surface. Their color--usually not uniform--may be dark brown, sometimes with pink or red areas. In addition, while the average adult has 10 to 40 moles, some people have more than 100 unusual moles on their skin. The initial diagnosis of atypical nevi is based on a physical exam by a physician, who may also remove several moles for examination with a microscope.
It is important to remember that although individuals with aytpical nevi may be at increased risk for melanoma, most do not develop this disease. The risk of developing melanoma is greatest for persons with many such nevi who are also from melanoma-prone families (i.e., in which two or more first-degree relatives--parents, children, brothers, sisters--have melanoma).
Reducing sun exposure is the easiest and most effective way to decrease the risk of developing melanoma, particularly for individuals in sun-sensitive, high-risk groups. The harmful effects of sun exposure begin in childhood. Severe sunburn in childhood or adolescence is associated with an increased risk of developing melanoma later in life.
The time of day and the time of year influence the extent of UV radiation exposure; the greatest exposure occurs during the summer. During the summertime, many people can be burned by the sun after only 20 to 30 minutes of continuous exposure. Throughout the summer months, daily UVB radiation exposure can be reduced at least 60 percent by avoiding the sun between 10 a.m. and 2 p.m. (11 a.m. and 3 p.m., daylight saving time).
People also can reduce their risk of sunburn by avoiding the sun when their shadow is shorter than they are. This "shadow method" works for any location and at any time of year. It is based on the principle that the closer the sun comes to being directly overhead, the stronger are its UV rays. However, it is also important to be aware that the harmful effects of UV radiation exposure are cumulative and that safe limits vary widely by individual.
When exposure to the midday sun is unavoidable, wearing protective clothing (such as a hat and long sleeves) and using an effective sunscreen are especially important. Sunscreens are rated in strength from 2 to 15 or higher. The U.S. Food and Drug Administration (FDA) requires that this rating, the sun protection factor (SPF), be printed on the container. The higher the SPF rating, the greater the blockage of UV radiation. (The FDA is reviewing data on sunscreens with SPF ratings higher than 15 to determine whether they afford any significant additional advantage.) A sunscreen should be applied about 30 minutes before each sun exposure and should be reapplied after swimming or perspiring heavily. These precautions should be followed even on overcast days, because a person can still be exposed to substantial UV radiation (about 80 percent as much as on a clear day). Furthermore, concrete, sand, ice, and snow reflect from 10 percent to more than 80 percent of these damaging rays.
One artificial source of UV radiation is tanning lamps, such as those used at home or in tanning salons. In particular, FDA warns that people whose skin always bums and never tans should stay away from these devices.
Some medications, such as antibiotics, antidepressants, and those given to cancer patients and organ transplant patients, can make the skin especially sensitive to sunlight. People taking such medications should check with their physician before tanning, either indoors or outside.
People with atypical nevi should avoid excessive sun exposure. They also should be examined by a doctor on a regular schedule, especially those from families with multiple cases of melanoma. Doctors may periodically take photographs of the nevi to help detect any changes in them. Changing moles should be surgically removed. Atypical nevi on the scalp may be removed, because it is difficult to see changes in nevi covered by hair. However, indiscriminate removal of large numbers of stable atypical nevi is not generally recommended because most of them do not develop into melanoma. In addition, removal of stable atypical nevi does not guarantee prevention of melanoma, which can develop in normal skin.
Detection and Diagnosis
Melanoma can begin in an existing mole or as a new, mole-like growth. If detected early, it can be effectively treated and usually cured. Moles that have or that develop any of the following characteristics should be examined by a physician as soon as they are noticed:
* Large size. Melanomas generally are at least 5 millimeters (mm) across (about 1/4 inch). If there is an increase (gradual or sudden) in the size of a mole, it may be a melanoma.
* Multiple colors. Melanomas tend to have a variety of colors--red, white, blue, and sometimes black or dark brown--within a single mole.
* Irregular border. Melanomas are likely to have uneven or notched borders.
* Abnormal surface. A mole may be a melanoma if it is scaly, flaky, oozing, or bleeding or has an open sore that does not heal.
* Unusual texture. If a mole feels hard or lumpy, it may be a melanoma.
* Abnormal skin around a mole. If pigment (color) from a mole has spread to surrounding skin, or if nearby skin is red or swollen or loses its pigmentation (becomes white or gray), a melanoma may be present.
* Unusual sensation. A mole may be a melanoma if it itches or is painful or tender.
* Change in appearance of the skin. Melanomas may develop as new pigmented spots in a skin area that had been normal.
Although an experienced physician, especially a dermatologist, can often identify a melanoma on sight, a biopsy is the only sure way to make a diagnosis. A biopsy is surgical removal of all or part of the mole or suspicious-looking tissue for microscopic examination by a pathologist (a doctor who specializes in the diagnosis of disease by studying cells and tissues removed from the body). The pathologist determines whether cancer is present, and, if so, whether it is a basal or squamous cell carcinoma or a melanoma. A biopsy usually can be done in the doctor's office under local anesthesia.
If melanoma is diagnosed, the physician conducts additional tests to determine the stage of the disease. The staging of melanoma provides information about the depth to which the cancer has penetrated the skin and subcutaneous tissue, how widely it has grown, and whether it has metastasized. Staging procedures include a thorough physical examination, chest x-rays, blood tests, liver function tests, and pathological examination of tissue removed during surgery. Doctors use staging information to plan appropriate treatment.
Microstaging--The microstage of melanoma is determined by the thickness of the tumor and the level of skin that the tumor invaded. Researchers have noted that a patient's microstage is related to his or her prognosis (probable outcome of the disease). Dr. Alexander Breslow, of The George Washington University School of Medicine, grouped melanomas by thickness. He found that the thicker the growth, the greater the likelihood of metastasis. He also found that the rate of survival ranged from nearly 100 percent for patients with growths equal to or thinner than 0.75 millimeters (about 1/32 inch) to no greater than 20 percent for those with melanomas equal to or thicker than 4.0 mm (slightly greater than 1/8 inch).
Dr. Wallace Clark, Jr., of The University of Pennsylvania Medical School, classified melanomas according to the deepest layer of skin they had invaded. He found that the deeper the level of invasion, the poorer the prognosis.
Clark's classification system groups melanomas into five levels:
Level I The cancer involves only the epidermis (outer skin layer). Characterized by the abnormal growth of cells, it is sometimes called melanoma in situ. Level II Melanoma reaches into the papillary dermis (upper portion of the dermis). Level III Cancer extends to the bottom of the papillary dermis. Level IV Melanoma has invaded the reticular dermis (lower part of the dermis). Level V Cancer has penetrated through the layers of the skin into the underlying tissue.
Clinical Staging--In this original staging system, melanomas are classified into three. stages: localized disease (stage 1), regional metastasis (stage 11), and distant metastasis (stage 111). However, many doctors believe that melanoma can be more accurately staged to reflect a patient's prognosis by incorporating tumor thickness and level of invasion as well as the extent of the disease.
TNM Staging--The American Joint Committee on Cancer has developed a staging system based on Clark's levels, Breslow's categories of tumor thickness, and the extent of the disease. Specifically, it uses coded descriptions of primary tumor size (T), lymph node involvement (N), and degree of metastasis (M). The amount of skin invasion determines the extent of the primary tumor. Cutaneous melanoma is classified as TX, when the primary tumor cannot be assessed; TO, when there is no evidence of a primary tumor; Tis, when the growth contains abnormal but not cancerous cells; or T with a number from 1 to 4, depending on the degree of skin invasion. Lymph nodes are classified NX, if they cannot be assessed; NO, if no cancer cells are found in the node(s); or N with the number 1 or 2, depending on the size and location of the node(s) containing cancer cells. Distant metastases are classified as MX, when the presence of metastases cannot be determined; M0, when no distant disease is found; or M1, when there are metastases in skin, subcutaneous tissue, or lymph nodes distant from the primary tumor or in any internal organs.
The TNM stages are as follows:
In Situ Precancerous cells; Clark's level I. (Tis, N0, M0) Stage IA Melanoma thinner than 0.75 mm (1/32 inch); Clark's level II. (T1, N0, M0) Stage IB Melanoma 0.76 mm to 1.5 mm (1/32 to 1/16 inch) in thickness; Clark's level 111. (T2, N0, M0) Stage II Melanoma 1.51 mm to 4.0 mm (1/16 to 1/8 inch) in thickness; Clark's level IV. (T3, N0, M0) Stage IIIA Melanoma 4.1 mm (1/8 inch) thick or greater; Clark's level V; and/or metastasis to the skin or subcutaneous tissue within 2 cm (3/4 inch) of the primary tumor. (T4, N0, M0) Stage IIIB Melanoma of any size that has spread to only one group of nearby lymph nodes or to skin or subcutaneous tissue more than 2 cm from the primary tumor. (Any T, N1 or N2, M0) Stage IV Melanoma that involves one enlarged and fixed lymph node group, more than one lymph node group, or another organ or area of skin. (Any T, any N, M1)
Treatment of melanoma that has not spread beyond the original area of growth (especially if it is thin and has not invaded the papillary dermis) is highly effective, and most of these cancers can be cured. In some cases, melanoma that has spread to nearby lymph nodes also can be treated effectively. At present, however, therapy for melanoma that has spread to distant parts of the body is unsatisfactory, and many scientists are conducting basic research and clinical trials (treatment studies) to find better forms of treatment. (Additional information about clinical trials is found on pages 22 and 23.)
A number of factors affect the choice of treatment for a person who has melanoma. These include the location of the primary tumor, the stage of the cancer, and the person's age and general health. In developing a treatment plan to meet an individual patient's needs, doctors may recommend one or a combination of several treatment approaches: surge , chemotherapy, biological therapy, and radiation therapy.
Surgery--About 95 percent of patients with melanoma are treated with surgery. When the tumor is thin and has not spread beyond the initial area of growth (stage 1), it is usually curable with surgery alone. Generally, the doctor removes the growth and a border of normal tissue around it to eliminate any cancer cells that may have spread from the tumor. Researchers have found that removing some healthy tissue surrounding the cancer is necessary to prevent recurrence. A recent study by the World Health Organization Melanoma Group showed that a narrow border (1 cm, or 3/8 inch) of healthy tissue is adequate for thin (less than 1 mm thick) melanomas (stage IA and some stage IB tumors). Because it is likely that larger tumors have begun to spread, wide excision (the removal of a large margin of tissue around a melanoma) is used to treat some stage IB melanomas as well as all stage 11 and stage Ill melanomas. A skin graft may be necessary following wide surgical excision.
Depending upon the location of the melanoma and results of the staging evaluation, surgeons sometimes recommend removing regional lymph nodes with a stage IB or stage 11 tumor. Because regional lymph nodes are often the first sites to which melanomas spread, removing the nodes may reduce the risk of recurrence. To date, however, no study has shown that removing regional lymph nodes makes a statistically significant difference in the length of time stage IB and stage 11 patients remain disease free or in the length of their survival.
Regional lymph nodes, or those affected by disease, are removed following wide excision for stage Ill melanoma. For more advanced disease (stage IV), surgical removal of metastatic tumors and affected lymph nodes may help relieve symptoms such as pain.
Chemotherapy--Some melanoma patients treated with surgery face a high risk of disease recurrence. To improve the outlook for these patients, researchers are evaluating the use of adjuvant chemotherapy to kill undetectable cancer cells that remain in the body after surgery.
A new method of administering adjuvant chemotherapy is under investigation to determine whether it is effective for patients with stage 11 or stage Ill melanoma in an arm or leg. Known as isolated limb perfusion or arterial perfusion, this method enables patients to receive high doses of anticancer drugs to only the affected limb. As a result, the patient does not experience many of the side effects that are common with systemic chemotherapy. In isolated limb perfusion, blood circulation to and from the limb is temporarily stopped with a tourniquet. Blood is withdrawn from the patient and pumped through a machine that adds oxygen and anticancer drugs. The blood is then pumped back into the major artery supplying the limb being treated. Often, the blood is heated to enhance the effects of the drugs. The drug most commonly used for perfusion is melphalan.
A similar technique, intra-arterial regional infusion, also is being studied in patients whose disease is limited to an arm or a leg. Again, normal blood circulation to and from the limb is stopped for a period of time. In this procedure, anticancer drugs are infused directly into the main artery of the limb. The drugs most commonly used for intra-arterial regional infusion are dacarbazine (DTIC) and cisplatin.
Researchers are also evaluating chemotherapy in the treatment of melanoma that has spread to the lymph nodes or to distant parts of the body. At this time, DTIC is the most effective single drug in treating metastatic melanoma. However, no drug or drug combination has produced long-term survival for patients with widespread disease. Therefore, clinical trials with anticancer drugs and biological agents are continuing, and patients with advanced disease should consider participating in these trials to evaluate new treatments. Most clinical trials involve combinations of drugs, because none alone has proven to be effective.
Hormone-blocking compounds, including the drug tamoxifen, are being tried in combination with chemotherapy or biological therapies. Some melanoma cells are dependent upon the hormone estrogen for growth. By blocking these cells' ability to absorb estrogen, researchers hope to slow or stop tumor growth.
Biological Therapy--Biological therapy, also known as biotherapy or immunotherapy, is another important cancer treatment. It is based on the knowledge and tools of modem molecular biology, immunology, and genetics. Biological therapy works either directly against the cancer or indirectly to change the way the patient's body reacts to a tumor. It may enhance the ability of a cancer patient's immune system to fight the growth of cancer cells, eliminate or suppress body responses that permit cancer growth, or make a cancer cell more sensitive to destruction by the patient's immune system. Researchers are conducting clinical trials to explore the potential of various types of biological therapy, such as those described below, both alone and combined with other forms of treatment.
Researchers are studying the effectiveness of adjuvant therapy for melanoma that involves the use of certain kinds of bacteria, proteins, and synthetic agents that stimulate the immune system. A vaccine composed of irradiated, inactivated melanoma cells, either alone or in combination with the bacterium known as BCG (bacillus Calmette-Guerin), is one form of adjuvant immunotherapy under investigation. The goal of this treatment is to sensitize the immune system, thereby increasing its ability to destroy melanoma cells.
Another adjuvant immunotherapy for melanoma involves interferons, proteins formed by human cells to help regulate certain cell processes. Interferons also have shown some effectiveness in the treatment of metastatic melanoma. These proteins appear to work both by boosting the body's immune reaction to invading cancer cells and by acting directly on cancer cells. Interferons may inhibit the growth of cancer cells or promote their development into cells with more normal behavior. In clinical trials, they are being tested alone and combined with other biological agents or with anticancer drugs.
Interleukin-2 (IL-2) is a hormone-like substance produced by blood cells. It stimulates the growth of lymphocytes, white blood cells that are an important part of the immune system. Scientists have found that some advanced melanoma patients respond to treatment with IL-2. Researchers also have used IL-2 to stimulate the growth of white blood cells in the laboratory. In one form of treatment, white blood cells are removed from blood taken from the patient. These cells are treated with IL-2 and returned to the patient along with more IL-2.
In similar research, scientists have begun studying the cancer-fighting potential of a specific type of white blood cell. These cells, commonly called tumor-infiltrating lymphocytes (TIL), can, after leaving the bloodstream, invade tumors and kill cancer cells. These white blood cells can be isolated from tumor tissue removed during surgery. In some studies, TIL were treated with IL-2 to increase their numbers and activity and then transferred, along with more IL-2, back into the patient. Some patients also have been given cyclophosphamide, an anticancer drug that reduces the body's ability to reject the new lymphocytes.
Researchers have also tested the ability of genetically altered white blood cells or cancer cells to boost the immune system's response to melanoma. These are very early studies, and researchers do not yet know what role these therapies will play in the future treatment of melanoma.
Radiation Therapy--Radiation therapy may be used to treat local recurrences of melanoma that cannot be surgically removed. Radiation therapy has also been tested for its effectiveness in preventing local recurrences. However, such treatment does not appear to improve long-term survival. In cases in which the disease has spread to the lung, gastrointestinal tract, bone, or brain (stage IV), radiation may provide relief from such symptoms as pain.
Recurrent Disease--Treatment for recurrent melanoma depends on prior therapy, the location and extent of recurrence, the patient's age and general health, and other factors. Tumors that recur locally (within 5 cm of the scar from the previous melanoma surgery) may be treated with additional surgery alone. Isolated limb perfusion or radiation therapy may be used to treat multiple local recurrences. Researchers are testing new methods of chemotherapy and biological therapy for melanoma that has metastasized to distant parts of the body. Clinical trials should be considered for patients with recurrent disease.
Followup Care--Because melanoma patients are at high risk for the development of new melanomas and sometimes for recurrence, they should be examined by a physician on a regular basis. Depending on the stage of the original growth, followup exams may include x-rays. Patients should also regularly examine their own skin.
Description and Function of the Eye
The eye is composed of three tissue regions and two inner cavities. The outer tissue group (fibrous tunic) surrounds the entire eyeball and consists of the cornea, the clear covering over the iris, and the sclera, which covers the rest of the eye and is responsible for its white color. The middle group (vascular tunic, also called the uvea), consists of the choroid, the ciliary body, and the iris. The inner coat (nervous tunic) is the retina. The interior of the eyeball is divided into two cavities by the lens. The anterior and posterior cavities are filled with a watery fluid and a jelly-like substance, respectively, which help give the eye its shape.
The iris is a circular group of muscles that contract or relax to control the amount of light entering the pupil. The ciliary body is located at the edges of the iris, to which it is attached. It contains a muscle that alters the shape of the lens, which sits behind the iris and focuses light. At the side of the eye, the ciliary body connects with the choroid layer, which nourishes the retina.
Like melanoma of the skin, melanoma of the eye originates in melanocytes, the pigmented cells that give the eye its color. Sometimes, pigmented cells found in the vascular tunic grow in a disordered and abnormal way, giving rise to a cancerous tumor, or melanoma. Ocular melanoma may develop in any of the uveal structures.
Incidence and Causes
Although ocular melanoma is the most common primary eye cancer in white adults, it is still very rare, with approximately seven new cases per million people diagnosed each year. This form of melanoma is even rarer in blacks and Asians.
The causes of this disease are not well understood. One study suggests that sunlight plays a role in the development of some ocular melanomas. Based on animal studies, some scientists believe that viruses and certain chemicals, including nicotine, may be involved in the formation of ocular melanoma.
Nevi can occur in the eye as they do on the skin. A person who has a condition known as ocular melanocytosis, in which a number of nevi are present in the eye, has an increased risk for ocular melanoma.
Detection and Diagnosis
Signs and Symptoms--Signs of ocular melanoma depend on where in the eye the cancer develops. Melanoma that develops in the iris may produce a pigmented spot, often noticed by the patient. Other signs include distortion of the pupil, presence of new blood vessels, curling of the iris near the pupil, and cataract formation.
Tumor in the choroid and ciliary body may be diagnosed during a routine eye examination before they produce any symptoms. However, if the tumors reach a large size, symptoms such as loss or deterioration of vision and the presence of floating spots may be observed. Cataracts, secondary glaucoma, and inflammation also may occur.
Diagnosis--Diagnostic procedures for ocular melanoma also depend upon where the disease begins. The doctor may suspect melanoma of the iris if he or she detects a changing spot that varies in color from velvety brown to translucent or pink. Diagnostic procedures for ocular melanoma that starts in the iris include:
* Slit lamp examination, in which light is projected into the eye through a slit, allowing the doctor to use a microscope to study the surface of the eye, the inside of the eye, and the lens, iris, and cornea. The doctor may take pictures at successive appointments to see whether the tumor is growing; this procedure is called serial slit lamp photography.
* Gonioscopy, a procedure in which the doctor examines the angle of the front portion of the eye with a slit lamp and a special lens called a gonioscope lens. An obstruction of this angle may signal the presence of glaucoma and possibly melanoma.
Diagnosis of melanomas that begin in the choroid and ciliary body usually include the examination techniques mentioned above, as well as several others:
* Ophthalmoscopy, the visual examination of the eye's interior, in which the doctor uses drops to dilate the pupil and a special instrument called an ophthalmoscope to view the inner eye, including the retina.
* Fundus photography, the process of taking pictures using an ophthalmoscope, is helpful in locating and characterizing an ocular melanoma. Photos may be taken at several appointments to allow the doctor to detect any changes in the eye.
* Ultrasonography, a procedure in which high-frequency sound waves are projected into the eye and the echoes converted by a computer into a picture showing the shape, location, and tissue characteristics of a tumor inside the eye. The ultrasound test is important in helping to confirm the diagnosis of ocular melanoma.
* Fluorescein angiography, in which the eye's blood vessels, including those that supply a tumor, are highlighted with a dye. This procedure can help distinguish an ocular melanoma from other types of eye tumors or conditions.
When a diagnosis of ocular melanoma is made, it is necessary to determine the extent of the disease in order to plan treatment. The patient has a full medical examination, which includes blood tests, x-rays, and sometimes scans of different organs to determine whether the cancer has spread to other parts of the body. In about 2 percent of patients with ocular melanoma, metastases to other areas are detected at the time of initial diagnosis. When ocular melanoma spreads, it most often appears in the liver. It can also spread to the brain, lungs, and areas directly under the skin. Metastasis to other sites is less common.
Melanomas are classified by where they begin in the eye (iris, ciliary body, or choroid) and by their size. Small melanomas are 10 mm (about 3/8 inch) or less in diameter and 2 mm (1/12 inch) or less in thickness. Medium-size melanomas are between 10 and 15 mm (about 3/8 to 5/8 inch) in diameter and from 2 to 8 mm (1/12 to 1/3 inch) in thickness, and large melanomas are more than 15 mm (over 5/8 inch) in diameter or more than 8 mm in thickness. In addition, ocular melanomas are classified by the microscopic appearance of the cells. Most melanomas of the iris and some melanomas in the choroid and ciliary body are made up of spindle-shaped cells. Spindle cell tumors are less likely to metastasize than nonspindle cell types. More aggressive melanomas include those composed of several nonspindle cell types and tumors in which spindle cells are mixed with nonspindle types.
When ocular melanoma is detected and treated at an early stage, it may be curable, and vision can be preserved in some cases. The selection of treatment depends, in part, on tumor size, location, site of origin (iris, ciliary body, or choroid), and growth rate. Other factors affecting the choice of treatment are the degree to which the tumor has invaded nearby structures of the eye, the presence of distant metastases, the patient's age and general health, eyesight in the affected and the unaffected eye, and the patient's preferences.
Small ocular melanomas that are not growing and do not interfere with vision may not be treated, but they require close observation. Those ocular melanomas that do require treatment usually are managed with surgery to remove either the tumor (resection) or the entire eye (enucleation) or with radiation therapy.
Doctors do not always know what treatment will offer patients the best chance of a cure. Decisions about treatment are made on a case-by-case basis. Several doctors, including an ophthalmologist (eye specialist) and an oncologist (cancer specialist), may be consulted to develop the treatment plan. Patients should discuss the possible side effects of their treatment options with their doctor. Side effects accompany each form of treatment. For example, surgery can result in serious visual impairment. Radiation therapy can cause bleeding within the eye (hemorrhage), cataract formation, glaucoma, inflammation, and other conditions.
Iris--Melanomas of the iris are generally smaller, slower growing, and less aggressive than melanomas in the choroid or ciliary body. A doctor may recommend only careful monitoring of a melanoma in the iris if it does not appear to be growing and doesn't interfere with vision. Surgical resection of the tumor may be suggested for slow-growing tumors. If the tumor has grown over a large portion of the iris, has impaired the patient's vision, or is too large to be excised, the eye may be enucleated. In the rare cases in which the tumor has spread beyond the eye, orbital exenteration (removal of the eye plus the surronding tissues) may be necessary.
Choroid and Ciliary Body--Until fairly recently, enucleation was the usual treatment for choroidal and ciliary melanomas. However, patients with melanoma in these areas of the eye now have more treatment options. Patients may simply be observed by a doctor, especially if the tumor is small and appears to be slow growing or inactive. If the size, location, or other factors make treatment advisable, the doctor may recommend localized radiation or enucleation with or without external radiation.
Localized radiation is given in the form of a radioactive plaque, made by placing radioactive pellets in a plastic disk covered on one side with a gold plate. The disk is sewn to the eye over the tumor. The radiation released by the plaque is directed to the tumor, while the gold plate protects the surrounding tissues and the brain from receiving radiation. A few specialized radiation treatment centers are treating ocular melanomas with charged particle beam radiation. These charged particles are protons or ions that are supercharged, or excited, to enhance their radioactive effect.
The amount of radiation needed to destroy a large melanoma, whether given by plaque or by other means, is often so great that the eye itself is severely injured or destroyed. Therefore, enucleation (or exenteration, in the case of extraocular tumor extension) is still the recommended treatment for large tumors of the ciliary body and choroid. It is not known, however, whether external radiation given to shrink a tumor prior to enucleation improves the effectiveness of surgery.
Because little is known about the comparative effectiveness of the treatment options for medium and large choroidal melanomas, the National Eye Institute is sponsoring the Collaborative Ocular Melanoma Study to develop a standard treatment for these tumors. In this study, patients with large melanomas undergo either external beam radiation followed by enucleation or enucleation alone. Those with medium-sized tumors receive either treatment with radioactive plaques or enucleation surgery.
The NCI is supporting an investigational study comparing external treatment using radioactive, charged helium particles with radioactive iodine implants for localized ocular melanoma. This study will compare the results of each treatment, the long-term effects of treatment on vision, patients' relative risk of developing distant metastases, and long-term patient survival.
Doctors are looking at several other investigational techniques to treat certain patients with ocular melanoma. Small melanomas of the choroid and ciliary body may be removed by surgical resection, in which the tumor and underlying tissue are removed. One experimental procedure that reduces the amount of radiation necessary for treatment combines external radiation with hyperthermia, a technique in which the tumor is heated. However, hyperthermia may result in complications, including pain, inflammation, detachment of the retina, loss of vision, and blindness.
Photocoagulation has been used with some success in the treatment of certain small tumors. In this procedure, the blood vessels entering the tumor are destroyed with a laser, thereby depriving the tumor of nutrients. Photocoagulation may be used in combination with radiation to treat small (under 10 mm) and medium-sized (10-15 mm) tumors. In addition, photodynamic therapy with hematoporphyrin derivative (HPD) may be useful in treating these melanomas. Photodynamic therapy uses an interaction between light and a substance that makes cells more sensitive to light (photosensitizing agent) to destroy tumor tissue. When injected into the body, HPD collects in tumor cells, sensitizing them to light. Doctors then expose the cancer to a laser beam. This activates the photosensitizer and produces a toxic reaction that destroys the tumor.
Patients with advanced ocular melanomas may also be eligible to participate in treatment studies with interferons. (For a discussion of interferons, see page 14.)
Rehabilitation and Followup--Treatment results, side effects, and evidence of metastatic disease may not appear for several months to years following the initial therapy. It is therefore important that patients have regular followup examinations. Patients may also undergo some type of reconstructive surgery after treatment. For a patient who undergoes enucleation, a silicone ball is sewn inside the eye socket; the area around the implant usually heals within 4 to 8 weeks. The patient is then fitted with an artificial eye, or prosthesis, which fits over the front of the silicone ball. The artificial eye looks like a real eye, but it does not move as well nor, of course, does it restore vision. Patients should discuss this and other reconstructive options with their doctor before therapy.
Clinical Trials and PDQ
To improve the outcome of treatment for patients with melanoma, NCI supports clinical trials at many hospitals throughout the United States. Patients who take part in this research make an important contribution to medical science and may have the first chance to benefit from improved treatment methods. Physicians are encouraged to inform their patients about the option of participating in such studies. To help patients and doctors learn about current trials, NCI has developed PDQ, a computerized system designed to give quick and easy access to:
* descriptions of current clinical trials that are accepting patients, including information about the objectives of the studies, medical eligibility requirements, details of the treatment programs, and the names and addresses of physicians and facilities conducting the studies;
* up-to-date information about the standard treatments for most types of cancer; and
* names of physicians and organizations involved in cancer care.
To access PDQ, doctors may use a computer with a telephone hookup and a PDQ access code or the services of a medical library with online searching capability. Cancer Information Service offices (1-800-4-CANCER) provide PDQ searches to callers and can tell doctors how to obtain regular access to the database. Patients may ask their doctors to use PDQ or may call 1-800-4-CANCER to request a search themselves. Information specialists at this toll-free number use a variety of sources, including PDQ, to answer questions about cancer prevention, diagnosis, treatment, and research.
Adjuvant chemotherapy: Treatment with drugs that is given to patients after they have completed their primary treatment.
Arterial perfusion: Treatment with anticancer drugs in which blood is withdrawn from a patient, pumped through a machine that adds anticancer drugs, and returned to the major artery supplying the limb being treated.
Atypical nevi: Moles whose appearance is different from common moles. Atypical nevi are generally larger than ordinary moles and have irregular borders. Their color is usually not uniform and they may be flat, or parts may be raised above the skin surface.
Basal cells: Cells found in the lowest part of the epidermis. These cells divide to produce new skin cells, replacing those that die and slough off the surface of the skin.
Biological therapy: Treatment that uses natural or laboratory-made substances to stimulate or restore the ability of the body's immune system to fight disease more effectively. Also called immunotherapy.
Biopsy: The surgical removal of a small piece of tissue for microscopic examination.
Cataract: A painless condition in which the lens of the eye becomes clouded, resulting in loss of vision that often can be relieved surgically.
Chemotherapy: Treatment with anticancer drugs.
Chlorofluorocarbons: Synthetic chemicals used as cooling agents in refrigerators and air conditioners. Chlorofluorocarbons break down ozone, a form of oxygen in the atmosphere that absorbs ultraviolet radiation from the sun.
Choroid: Part of the vascular tunic, the middle layer, of the eyeball. The choroid nourishes the retina, or inner layer.
Ciliary body: Part of the vascular tunic, the middle layer, of the eyeball. The muscle in the ciliary body focuses the lens of the eye.
Clinical trial: Research conducted with patients, usually to evaluate a new treatment. Each trial is designed to answer scientific questions and to find better ways to treat patients.
Computed tomography (CT or CAT) scan: An x-ray procedure that uses a computer to produce detailed pictures of areas inside the body.
Cornea: The clear portion of the outer layer of the eyeball; it covers the iris, the colored part of the eye.
Cutaneous: Referring to the skin.
Dermatologist: A doctor specializing in the treatment of skin disorders.
Dermis: The inner layer of the skin. The dermis contains connective tissue, blood and lymph vessels, sweat- and oil-producing glands, and hair follicles.
Enucleation: The surgical removal of the eyeball.
Epidemiologic: Relating to epidemiology, the study of the incidence and spread of disease in a population.
Epidermis: The outer layer of the skin. Melanocytes, basal cells, and squamous cells are found in the epidermis.
Fibrous tunic: The outer layer covering the eyeball. It is composed of the sclera and the cornea.
5-year relative survival rate: The likelihood that a patient will not die from causes associated specifically with his or her cancer for at least 5 years after diagnosis.
Fluorescein angiography: The process of taking pictures of blood vessels that have been injected with a special dye. The dye allows the blood vessels to show up on the photograph.
Fundus photography: The process of taking pictures of the eye through a special camera used to view the inner eye.
Glaucoma: A disease of the eye in which there is a buildup of pressure in the eye. If not treated, glaucoma can lead to the loss of vision.
Gonioscopy: Examination of part of the interior of the eye using an instrument called a gonioscope.
Helium: A gas. Charged, radioactive particles of helium are sometimes used in radiation therapy.
Hematoporphyrin derivative: A photosensitizing agent, a substance that makes cells more sensitive to light.
Hemorrhage: The escape of blood from vessels; bleeding.
Immune system: The complex group of organs and cells that defend the body against infection and disease.
Incidence: The rate at which a disease occurs within a population. Cancer incidence is usually expressed in terms of the number of newly diagnosed cases per 100,000 people per year.
Interferons: Proteins produced by a variety of cells in the body to help regulate certain cell processes. Large quantities of different interferons may be produced in the laboratory using special techniques. These proteins are used in the treatment of some forms of cancer, including melanoma.
Interleukin-2: A hormone-like substance produced by certain blood cells. It stimulates the growth of those blood cells that are an important part of the body's immune system.
Intra-arterial regional infusion: Treatment with anticancer drugs in which the drugs are put directly into the artery that supplies blood to a region of the body, usually an arm or a leg.
Iodine: An element. Radioactive forms of iodine are sometimes used in radiation therapy.
Iris: The colored portion of the eye. The iris is part of the middle layer of the eye. It is a muscle that controls the amount of light entering the eye.
Isolated limb perfusion: Treatment with anticancer drugs in which blood is withdrawn from a patient, pumped through a machine that adds anticancer drugs, and returned to the major artery supplying the limb being treated.
Laser: An instrument producing a powerful beam of light that can develop intense heat when focused at close range.
Lens: The portion of the eye through which light passes as it is focused onto the retina.
Lymph nodes: Small, bean-shaped organs located along the lymphatic system. Also called lymph glands.
Lymphocytes: White blood cells that are an important part of the immune system.
Melanin: The pigment, or color, produced by melanocytes. Melanin gives the skin and irises their color and helps to protect skin from the damaging effects of ultraviolet radiation.
Melanocytes: Special cells in the epidermis of the skin or the uvea of the eye that produce the pigment called melanin. Clusters of melanocytes appear on the skin as moles.
Melanoma: Cancer that begins in metanocytes. Melanoma appears on the skin as a new or changing mole.
Metastasis: The spread of cancer cells from one part of the body to another through the lymphatic system or bloodstream.
Microstage: The extent of a cancer determined by measuring the thickness of a melanoma and by noting the deepest level of skin invaded by the tumor.
Monoclonal antibody: A laboratory-produced antibody that can target a specific antigen. They can be made in large quantities in the laboratory. Monoclonal antibodies are being studied in clinical trials to determine their effectiveness in cancer detection, diagnosis, and treatment.
Nervous tunic: See Retina.
Nevi: The medical term for clusters of melanocytes. Nevi on the skin are commonly called moles.
Ocular: Referring to the eye.
Ocular melanocytosis: A condition in which a number of nevi are seen in the eye as dark spots caused by the clustering of melanocytes.
Oncologist: A doctor who specializes in treating cancer.
Ophthalmologist: A doctor who specializes in the treatment of diseases of the eye.
Ophthalmoscopy: Examination of the inner eye. The doctor first dilates the pupil with special eye drops and then uses an instrument called an ophthalmoscope to view the eye.
Orbital exenteration: Surgical removal of the eyeball and some surrounding tissue.
Ozone layer: Part of the Earth's atmosphere in which there is a concentration of ozone, a form of oxygen, which absorbs a large portion of the sun's ultraviolet radiation.
Pathologist: A specialist who diagnoses disease by studying how tissues and cells look under a microscope.
Photocoagulation: A process using a laser to destroy blood vessels entering a tumor in order to deprive the tumor of its nutrients.
Photodynamic therapy: Therapy that uses the interaction between laser light and a substance that makes cells more sensitive to this light. The light causes a chemical reaction that destroys cancer cells.
Radiation therapy: Treatment with high-energy x-rays or other rays to kill cancer cells.
Resection: Surgical removal of an organ or area of tissue.
Retina: The inner layer of the eyeball, also called the nervous tunic. The retina detects the light entering the eye and produces signals that are translated by the brain into images.
Sclera: Part of the outer layer of the eye, or fibrous tunic. It covers all of the eyeball except for the area over the iris and gives the eye its white color.
Slit lamp: An magnifying instrument used to examine the eye. In a slit lamp, an intense beam of light is projected through a narrow slit in the instrument.
Squamous cells: Flat, scale-shaped cells found in the epidermis of the skin.
Stage: A description of cancer that includes the size of the tumor and the extent of spread, if any, to lymph nodes or other parts of the body from the original site.
Surgery: An operation.
Tumor-infiltrating lymphocytes: Special cancer-fighting cells of the immune system that are found in tumors. In an experimental cancer treatment, scientists remove these cells from a patient's tumor, grow them in the laboratory, and return them to the patient along with interleukin-2, a hormone-like substance that stimulates the growth of these cells.
Ultrasonography: The process of using sound waves to produce pictures of internal organs. Sound waves are directed into tissues and produce echoes, which in turn are changed into pictures (sonograms) that appear on a monitor screen. Because different types of tissue reflect sound waves differently, it is possible to see abnormal growths.
Ultraviolet (UV) radiation: Invisible light next to visible violet light in the spectrum of energy produced by the sun. UV radiation is shorter in wavelength and higher in energy than visible light.
Uvea: The middle layer of the eyeball, which is composed of the choroid, ciliary body, and iris. Also called the vascular tunic. Ocular melanocytes are located in the uvea.
Vaccine: A preparation of a disease-causing agent or a similar substance that is given to patients to stimulate the immune system to fight disease or to prevent subsequent disease. For example, scientists are conducting studies to determine whether a vaccine composed of irradiated melanoma cells can help prevent the return of the cancer.
Vascular tunic: See Uvea.
Xeroderma pigmentosum: A rare, inherited disease in which the skin and eyes are extremely sensitive to the sun. Many spots similar to freckles appear on the skin, and the skin tends to thin and become glossy white. People with this condition have a greatly increased risk of skin and eye cancers, including melanoma.
The materials marked with an are distributed free of charge by NCI. Ordering information is provided on page 49. The other items are not available from NCI; they can be found in medical libraries, many college and university libraries, and some public libraries.
Balch, C.M. "The Role of Elective Lymph Node Dissection in Melanoma: Rationale, Results, and Controversies," Journal of Clinical Oncology, Vol.6(1), 1988, pp. 163-172.
(*) "Biological Therapies: Newest Form of Cancer Treatment." Office of Cancer Communications, National Cancer institute, 1988.
(*) Chemotherapy and You: A Guide to Self-Help During Treatment. Office of Cancer Communications, National Cancer Institute. NIH Publication No. 91-1136.
Coleman, D.J., et al. "Ultrasonic Hyperthermia and Radiation in the Management of Intraocular Melanoma," American Journal of Ophthalmology, Vol. 10 1 (6), 1986, pp. 635-642.
DeVita, V.T., et al., eds. Cancer: Principles and Practice of Oncology. 3rd ed. Philadelphia: J.B. Lippincott Co., 1989.
Friedman, Robert J., et al. "Early Detection of Malignant Melanoma: The Role of Physician Examination and Self-Examination of the Skin," Ca--A Cancer Journal for Clinicians, Vol. 35(3), 1985, pp. 130-151.
Garretson, B.R., et al. "Choroidal Melanoma Treatment with Iodine 125 Brachytherapy," Archives of Ophthalmology, Vol. 105(10), 1987, pp. 1394-1397.
Gragoudas, E.S., et al. "Long-Term Results of Proton Beam Irradiated Uveal Melanomas," Ophthalmology, Vol. 94(4), 1987, pp. 349-353.
(*) Greene, M.H., et al. "Acquired Precursors of Cutaneous Malignant Melanoma--The Familial Dysplastic Nevus Syndrome," New England Journal of Medicine, Vol. 312(2), 1985, pp. 91-97.
Haskell, C.M. Cancer Treatment. 3rd ed. Philadelphia: W.B. Saunders Co., 1990.
Legha, S. "Current Therapy for Malignant Melanoma," Seminars in Oncology, Vol. 16(1), Supplement 1, 1989, pp. 34-44.
Manschot, W.A. and Van Strik, R. "Is Irradiation a Justifiable Treatment of Choroidal Melanoma? Analysis of Published Results," British Journal of Ophthalmology, Vol. 71(5), 1987, pp. 348-352.
(*) Radiation Therapy and You: A Guide to Self-Help During Treatment. Office of Cancer Communications, National Cancer Institute. NIH Publication No. 91-2227.
Rosenberg, S.A., et al. "Gene Transfer into Humans--Immunotherapy of Patients With Advanced Melanoma, Using Tumor-Infiltrating Lymphocytes Modified by Retroviral Gene Transduction," New England Journal of Medicine, Vol. 323(9), 1990, pp. 570-578.
Rosenberg, S.A., et al. "Use of Tumor-Infiltrating Lymphocytes and Interleukin-2 in the Immunotherapy of Patients With Metastatic Melanoma: A Preliminary Report," New England Journal of Medicine, Vol. 319(23), 1988, pp. 1676-1680.
Scotto, J. and Fears, T.R. "The Association of Solar Ultraviolet and Skin Melanoma Incidence Among Caucasians in the United States," Cancer Investigation, Vol. 5(4), 1987, pp. 275-283.
Straatsma, B., et al. "Enucleation Versus Plaque Irradiation for Choroidal Melanoma," Ophthalmology, Vol. 95(7), 1988, pp. 1000-1004. (*) Sunlight, Ultraviolet Radiation, and the Skin. Consensus Development Conference Statement, National Institutes of Health, Vol. 7(8), 1989.
Veronesi, U., et al. "Thin Stage I Primary Cutaneous Malignant Melanoma: Comparison of Excision with Margins of 1 or 3 Cm," New England Journal of Medicine, Vol. 318(18), 1988, pp. 1 159-1162.
(*) What Are Clinical Trials All About? Office of Cancer Communications, National Cancer Institute. NIH Publication No. 90-2706.
(*) "What You Need To Know About Cancer Treatment Using Interleukin-2." Office of Cancer Communications, National Cancer Institute, 1988.
For more information on this subject or to obtain other NCI publications, write to the Office of Cancer Communications, National Cancer Institute, Bethesda, MD 20892, or call the Cancer Information Service toll-free at
Spanish-speaking staff members are available.
This Research Report has been approved by National Institutes of Health scientists. Please direct questions or comments to the Research Reports Editor, National Cancer Institute, Office of Cancer Communications, Bethesda, MD 20892.
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|Title Annotation:||Research Report|
|Publication:||Pamphlet by: U.S. Department of Health and Human Services|
|Date:||Feb 1, 1992|
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