What is Melanoma?

Melanoma, also called "Malignant Melanoma" is a cancer of the melanocytes, which are the pigment-forming cells in the skin, producing melanin. Interestingly, in early womb life, the melanocytes develop from the same cells which ultimately form the brain and nervous system. The skin is the most common site for melanoma to develop, since it contains the most melanocytes. Besides being found in the skin, melanocytes are also found in the anal/rectal region, in the linings of the mouth and vagina, and in the eye. Some are even found in the gut and central nervous system (brain and spinal cord). Any of these areas can develop melanoma, but much less commonly than the skin. It is quite common, however, for a melanoma starting in the skin to spread ("metastasize") to the aforementioned areas. The area where a cancer first starts is called the "primary site", as distinguished from later areas of spread. The "primary site" is usually apparent for most cancers, but not uncommonly it remains "occult" in melanoma - the first sign of disease being distant metastasis. Thus, it is common to first detect metastatic melanoma in the lung, bone or brain, although its occult primary site was probably the skin.

The skin is a tissue, meaning that it is a collection of cells organized as a unit. Cells are the smallest level of animal life, and are controlled by the genetic material called "genes" within them. Initially all human cells start out from the fusion of the sperm and egg cells; at the time of fertilization there is only one type of cell ("zygote") containing genetic information for constructing the entire human body. As the body is formed, cells specialize ("differentiate") into all sorts of specific subtypes, such as nerve, muscle, liver and heart cells. As they do so, part of the genetic material in them is "masked" so that it becomes unavailable; we do not need information on how to form a bone cell when we are making a stomach cell! However, every cell still retains, at some level in its genes, the total information necessary ("totipotential") for constructing an entirely new body. This is how scientists are able to clone a cheek cell, for instance, into a whole new animal.

Normally, skin cells divide very quickly in womb life, early childhood and through puberty to form the covering surface ("integument") of our bodies. In adulthood, they divide more slowly to replace cells that have died either from old age or injury. New skin cells arise at the deepest level of the skin, and gradually push their way upwards toward the surface as they mature. The main types of cells found within the skin are basal cells, which form the bottom layer, squamous cells, which push toward the surface to form the skin we see, and melanocytes, which produce melanin pigment that colors the skin. If specific types of gene damage occurs in a cell, it can start dividing out of control. When cells divide quickly, they tend to pile up to form a lump, called a "tumor". A tumor merely means an abnormal swelling; it can be caused by infection, inflammation, or just about anything and is usually not cancer. A "benign" tumor only grows in its local area (albeit quite large), it cannot spread distantly and is not cancer. In contrast, a "malignant" tumor has the ability to spread to anywhere in the body, and this is cancer. This process of spread is called "metastasis", and is what makes cancer so dangerous. Ultimately, cancer starts in a single cell and and is a disease of its genes. Any type of skin cell can give rise to skin cancer, when their reproduction goes out of control, and they divide in a disorganized way. When basal or squamous cells become cancerous, they are called carcinomas, while when the melanocytes become cancerous, this is called melanoma, which has such a different character that it is a different topic from other skin cancers.

How Common is Melanoma?

In 1997 in the United States 38,000 new cases of melanoma were diagnosed, and 7,300 deaths were attributed to the disease. The number of new cases of melanoma has tended to rise each year. In 1935, the lifetime risk of getting melanoma was only 1 in 1500, but had increased to 1 in 135 by 1990. It is expected to effect 1 in 90 people by the year 2000. While it is rare in young children, it begins to occur in puberty, and then increases each year through age 70, afterwhich it decreases. The more fair skinned a person is, the higher their risk to develop melanoma, of any body area. Conversely, it is very rare in dark black individuals. It is more common in predominantly fair-skinned countries, such as Australia.

What Causes or Increases the Risk for Melanoma?

Like any cancer, no one knows exactly why one individual gets melanoma and another does not. The exact cause of any cancer is currently unknown. However, several risk-factors have been discovered by studying groups of patients, it is vanishingly rare in people with none of the following factors:

Sun Exposure increases the risk of all skin cancers, including melanoma. One of the reasons that melanoma has increased over the years is thought to be people spending more time "sun worshiping" on the beach. More melanoma is noted in people living in sunny climates (i.e. Florida) than weak-sun areas (i.e. Alaska). Ocular (eye) melanoma is also more common in sunny areas, but not melanomas occurring deeper within the body.

Heredity - People with a family history of certain conditions make up about 10% of melanoma patients. These "melanoma families" have genes of "dominant" heredity, which means that if one parent has it, it will most likely be passed to their children. However, it is "incompletely penetrant", which means it won't necessarily be expressed in the offspring, even if they have it. Family members of those with these hereditary genes will tend to get melanoma at a younge age than the other 90% of individuals who develop melanoma sporadically. They are also more likely to have multiple sites of melanoma, which occurs in 5% of all patients. Particular syndromes associated with high risk for melanoma are "Dysplastic Nevus Syndrome" and "Atypical Mole Syndrome". A "nevus" is a pigmented area of skin, which may be raised, often called a "mole". Patients may have hereditary conditions where they have large or unusually shaped moles, which are filled with melanocytes. The odder shaped ("dysplastic") or

more abnormal ("atypical") they appear, the more likely to become cancerous. Also, the more the moles are irritated by sunlight or chemicals, the greater the chance that they will undergo "malignant degeneration" to become cancerous.

Nevi ("moles") in themselves will increase the risk for skin melanoma. About 70% of skin melanoma have a pre-existing mole at the cancer site; this is one reason why one of the famous "7 signs of cancer" includes a change in a wart or mole. Interestingly, people continue to develop nevi throughout life. By age age 30, men have about 40 nevi that were not present at birth, mostly on the trunk and arms. This is one reason why the incidence of melanoma increases with age. Fortunately, only one of a million moles moles becomes malignant.

Chronic Irritation is a theme underlying the development of many types of cancer. Irritants include chemicals ("carcinogens"), ultraviolet light, radiation, and trauma causing scars to form in an area. Anything that damages cells over time will cause specific ones in damaged area to divide and try to repair damage. The more divisions, the more chance of something going awry in the division mechanism leading to uncontrolled growth - this is cancer and starts with a "screw-up" in just a single cell. Thus anything which is continuously irritating (i.e. cigarette smoke, strong sunlight) should be avoided to minimize the risk of developing any type of cancer over time.

Poor Immune System Function or "immunosuppression" raises the risk for many cancers, including melanoma. There is a theory called "immunosurveill- ance" which says that we are developing cancerous cells all the time, but that a healthy immune system recognizes and destroys them before they can start to divide, take root and spread. Many factors are associated with decreased immune system function, including viruses like HIV, EBV, CMV and Hepatitis, certain medications ("immunosuppressants"), poor nutrition, diabetes, and even feeling emotionally depressed over time. These conditions can "promote" the development of cancer, especially in genetically predisposed individuals.

What are the Signs and Symptoms of Melanoma?

A "sign" is something that the doctor can measure, such as the diameter of a mole, fever, or weight loss. A "symptom" is something felt by the patient, such as pain, nausea or fatigue. The way a patient appears when they first come to medical attention is called their "presentation". Early melanoma will have no symptoms and may just be a slightly abnormal skin mole which goes unnoticed. Tumor cells have to double 12 times to reach the 1 billion cells which make it just 1/2 inch across! Thus there is often a significant delay, from months to years, in making the diagnosis. When signs and symptoms do occur, they are likely to include the following:

1) A significant change in a pre-existing mole, such as enlargement, changes in it's borders (i.e. pushing into normal skin) or color (darker black or purple).

2) "Satellite Nodules" are little lumps of melanoma forming near the original site They result from the melanoma cells getting into the local lymphatics and then spreading into the nearby skin.

3) Swollen Lymph Nodes in the axilla (armpit) or groin from spread of the cancer through the lymph system. Lymph nodes are normally bean-shaped glands which help filter the blood; they are normally smaller than 1 cm. (1/2 inch). They can enlarge either from infection (common) or cancer (rare). Sometimes both infection and cancer simultaneously swell lymph nodes, in which case an antibiotic may result in partial (but incomplete) shrinkage. Enlargement of lymph nodes is called "lymphadenopathy" and it can presage the spread of cancer to distant sites, such as lung and brain.

4) Symptoms of Local Spread from other melanoma sites, like rectal bleeding from ano-rectal melanoma, or vulvar itching from growth there. Loss of vision will be the main symptom from ocular melanoma, and progressive digestive or respiratory problems from local growth in the intestines or lung.

5) Symptoms of Distant Spread, which can involve any organ in the body. Most commonly it spreads to liver, lung, bone and brain. It can cross the placenta in a pregnant woman and spread to her unborn baby. About 5% of melanomas are only discovered after they have spread, with their original site never known. The original site ("primary") may have spontaneously disappeared from immune processes, shedding, or have been removed years earlier and been long forgot- ten. Spread to the lung will tend to cause progressive wheezing if a lung tube (bronchi) is blocked, bleeding with coughing ("hemotysis") if a blood vessel is eroded into, chest wall ("pleuritic") pain as nerves are involved, and ultimate blockage and "collapse" of the affected lung with shortness of breath. Seconda- ry spread can occur to the lymph glands in the center of the chest, between the lungs, termed the "mediastinal" lymph nodes. This can result in hoarseness (since the recurrent laryngeal nerve which enervates the voicebox dips down into the mediastinum) and eventually progressive swelling of the neck, face and arms due to compromised blood return to the heart ("superior vena cava syn- drome") from mediastinal blockage. These problems tend to be treatable with emergent radiation therapy when caught early enough. Spread to the brain can result in no symptoms ("asymptomatic") growth until crucial structures become compromised. It is more likely for growth to be larger in the upper cerebral hemispheres or the brain than the lower cerebellar section, since their is more expansion room in the upper brain. Ultimately, some ramifications of brain metastasis are general, and others depend upon location.

Specifically, the most common general symptoms of brain metastasis are:

a) Seizures - any foreign body in the brain, including a tumor, can disturb it's normal electrical activity. The average brain runs on about 25 watts of electricity, enough to power a small bulb. In chronic epilepsy, doctors look for an abnormal area of the brain, called a "focus", and see if it can be safely removed to stop the seizures. Likewise, if a person comes to the doctor with new onset seizures, the first thing to check for is an abnormal area, or tumor, in the brain.

b) Headaches - There is limited room inside the skull; the brain and it's linings are insulated by a cushioning fluid that fills up the available space. If something starts growing inside the skull, it quickly increases the pressure within the skull.

This is called "increased intracranial pressure" or "ICP" for short. While the brain itself has no nerve endings, and so feels no pain, the linings of the brain are rich in sensory nerves and quickly detect an increase in pressure on them, causing headache. Brain tumor headaches tend to be worse in the morning, awaking, and furthermore they get worse each day.

c) Nausea and Vomiting are also possible signs of increased pressure within the brain, especially when accompanied by headache. The nausea is more common than actual vomiting.

d) Imbalance and stumbling can indicate a brain tumor, either because they are a symptom of increased pressure within the skull or because the tumor presses on the delicate areas controlling coordination, in the midbrain or cerebellum.

Some particular symptoms of brain cancer, depending on it's location:

Weakness in just one portion of the body, such as the right arm and leg or just the left hand. Generalized weakness, or fatigue, is itself not suspicious for brain tumors. Specific areas of the brain "represent" and control the movement and sensation of each part of the body, and a tumor there will disrupt that exact part. This can localize a tumor to the "motor cortex" in the upper brain.

Sensation changes in a particular part of the body, for the above reason. Numbness or a burning sensation in a limb may localize a tumor to the "sensory cortex" in the upper brain. There is a whole represenatation of the human body mapped out in the upper brain, called the "sensori-motor representation" which ramifies to each specific body area. With any disturbance of this area, it will seem to the patient as if the sensation (or lack thereof) is coming from that body area.

Visual problems - double vision is common and may occur from increased pressure within the skull pressing on the nerves controlling the eyes (espec- ially number VI, called the abducens nerve which is the longest in the skull). Partial blindness can occur from pituitary tumors in the midbrain pressing on the optic nerves, or from tumors at the very back of the brain (occipital lobe) where the the "visual cortex", which controls sight, is located. Of course, any melanoma can also start in or spread to the retinal area of the eye itself, leading to a "curtain like" loss of vision which is progressive.

Judgment or personality changes occur especially with tumor located near the front of the brain, in the "frontal cortex" which helps control personality. The changes typically get very obvious and don't improve with counseling.

Growth disturbance, breast enlargement, or changes in sex drive.

An insatiable desire to drink water, with frequent urination, is called SIADH and results from compressing of the midbrain structures controlling the body's fluid balance.

Hallucinations in vision or hearing arise from a tumor where these senses are processed. This often involves seeing bright objects or hearing music.

Paraneoplastic Syndromes are collections of symptoms caused by special chemicals and hormones manufactured by some melanoma cells. The cancer cells in the body, the more likely they are to produce enough chemicals to produce a paraneoplastic syndrome. Some examples are gynecomastia (breast swelling), vitiligo (patchy whiteness of the skin), acanthosis (black patches forming on the trunk) and ectopic Cushing's syndrome (truncal obesity, limb thinning, easy bruising, fat pad on back of neck, facial swelling, hairiness).

Signs of Advanced Disease include "melanosis" is a slate-gray discoloration of the skin caused by saturation of the blood from melanin pigments, produced by billions of melanoma cells. Even the urine can turn dark black. Patients with melanoma spread to the lungs can develop black sputum. Life-threatening spread to the heart can cause abnormal heart rhythms, and fluid around the heart ("pericardial effusion") can acutally progress to sqeezing it to the point of dangerously lowering blood pressure ("pericardial tamponade"). Intestinal blockage may necessitate emergent surgery for relief, and spread the spinal column can impinge the spinal cord and threaten paralysis ("epidural spinal cord compression") if not emergently relieved with surgery or irradiation. The propensity of malignant melanoma to spread to these other crucial areas are what makes it so dangerous.

How Does Melanoma Spread?

Normally melanoma starts from just one abnormal melanocyte, 70% of which are found in the skin. Commonly, it grows in "phases". Initially, it grows radially, which means it spreads horizontally along the surface of the skin. The cancer stays in it's local area during the radial growth phase. This "radial phase" can last 5 to over 20 years, depending upon the type of melanoma. At some point, the melanoma starts it's "vertical growth" phase, meaning it dives down to invade deep into the tissue. When the melanoma grows downward, it invades the lymph and blood vessels, and can then spread to the surrounding skin causing satellite nodules, to the local lymph nodes, and to distant organs via the bloodstream. Spread through the lymph system is called "lymphogenous" metastasis, and spread through the bloodstream is called"hematogenous" metastasis. It is this capacity for distant spread that makes cancer so dangerous.

What are the Types of Melanoma?

There are four basic types of melanoma which occur in any of many body areas:

"Superficial Spreading Melanoma" is the most common type (70% of cases). It appears as a thin plaque on the skin surface that can be black, brown, red tan or white, or a combination of colors ("variegated"). It is more common in women, especially on the back. Irregular borders are suspicious for cancer. It grows radially for a long time, often 20 years. Sometimes it shows areas of spontaneous regression that appear white. Then it starts growing vertically and spreads through the lymph system and bloodstream.

"Lentigo Melanoma" is about 15% of cases and looks like a large, flat, plaque up to about 2 inches in diameter. It is black to tan, and develops in on areas exposed to the sun (face and arms) especially in light-skinned people. It is equally common in men and women. It starts as a freckle ("Hutchinson's" and, like the "superficial spreading" type, grows radially for a long time. It then enters it's vertical growth phase, and can spread.

"Nodular Melanoma" is 15% of cases looks like a dark black or blue bump, with a regular border. It is more common in men. They occur in middle age and grow rapidly. It is a dangerous type since it grows vertically right from the outset, so can spread early to lymph nodes and through the bloodstream. About 5% of nodular melanomas lack pigment altogether ("amelenotic") and can be diagnoses by special laboratory methods to be discussed.

"Acral Melanoma" occurs on palms, soles, fingers, toes, or under nailbeds. Other types of melanoma can also occur in these locations, but the Acral type is most common there. Acral melanoma is mostly seen on the sole of the foot and is more common in dark-skinned persons. The average age is 60 years old, and the average size is 3 cm. They tend to grow quickly, with an average of 2 years before they enter their vertical growth phase.

How is Melanoma Diagnosed and Evaluated?

Typically, a patient will come to their doctor with a worrisome skin lesion that is suspicious for cancer. The only way to conclusively diagnose any cancer is to get a piece of it ("biopsy") and have a pathologist examine it under a microscope. Pathologists are physicians specializing in making diagnoses from tissue samples. Certain procedures are appropriate in the diagnosis of melanoma (and other cancers):

Physical Examination is mandatory to record the size, texture, color and descriptive characteristics of the melanoma. Melanomas usually don't have skin creases. The existence of any satellite lesions are noted. Local lymph glands are examined for enlargement (> 1 cm.). The entire skin surface of the body, including scalp, should be examined, as the original melanoma may metastasize. Furthermore, if a person has one melanoma the risk is over 900 times higher for them to develop another one in a different area. Full exam will include a rectal exam and pelvic exam for women, with special attention paid to any abnormalities.

Routine Blood Tests - there are no special blood tests ("tumor markers") now available for melanoma. However, all patients with suspected disease spread will get standard Complete Blood Count (CBC) to look for infections, anemia, and other blood cells abnormalities. Blood Chemistry Panel (SMA) tells about sodium, potassium, blood sugar, cholesterol, and liver and kidney function. Urinalysis (UA) looks for blood, protein, crystals and signs of infection. If major surgery is contemplated, special tests for blood clotting ability (PT and PTT) are routine. 3) Radiology Tests include standard Chest X-ray to look for signs of spread to heart and lungs. If anything suspicious is seen on Chest X-ray, it is common to order a CT scan of the chest and abdomen, which shows these areas in 1 cm. sections. MRI scans use magnetism instead of radiation and show the soft tissues with incredible resolution. MRI can help determine how deeply a large tumor has spread, and if it has contacted bone or nerves.

Other tests will be ordered according to symptoms. If there is suspicious of spread to the brain, a CT scan or MRI of the brain can check for this. CT scans are good for detecting lesions over 1 cm. in the upper brain (cerebral hemispheres), but MRI is better for imaging lower brain (cerebellar) and brainstem (pons and medulla) lesions and the extent of local metastasis. Either CT or MRI can be given in conjunction with radio-opaque contrast material injected into an arm vein; this helps highlight abnormal blood vessels around the tumor and helps to define the extent of the tumor for either pre-treatment or post-treatment (after treatment) scans. The type of contrast recommeded for CT is "omnipaque", which is safer and more comfortable than older agents, and the type used for MRI scans is "gadolinium".

These scans can also be used for meticulously planning radiation therapy in three dimensions. When there is new bone pain, a bone-scan can help determine whether the melanoma has spread to bone. For urinary or bowel problems, cytoscopy and sigmoidoscopy look into these areas, respectively, with a visualization tube. Unfortunately no test can as yet determine whether there is microscopic spread to a body area, but can only reveal the disease when it is large enough to be seen.

Biopsy (sampling) of the tumor is the only way to absolutely establish the diagnosis. This may also be therapeutic, as when the entire tumor is cut out (excisional biopsy). Alternatively, it may just take a piece of a larger tumor to see what it is (incisional biopsy). Great care must be taken with the biopsy procedure to ensure it's done properly. A careless biopsy may actually spread the tumor around, and lose valuable information as to how deep it penetrated and whether it was completely removed (has "clear margins"). Gauging the extent and further treatment requirements for a melanoma relies heavily on information from the biopsy, as will be seen. If the cancer has apparently al- ready spread, it may be easier to take a biopsy from an area of metastasis. Melanomas of the eye are generally not biopsied, but are diagnosed by exam.

The biopsy specimen is examined by a pathologist, who determines if it is cancer and if so what type. The pathologist may perform special stains on the tissue sample to look for melanin, and may look at the specimen under an electron microscope to help confirm the diagnosis by looking for small pigment packets called "melanosomes" in the cells. Sometimes, malignant melanoma doesn't even produce any pigment at all ("amelanotic melanoma") and so needs special stains ("immunohistochemistry") to identify it. These stains are S-100 and HMB-45. The pathologist must carefully measure the "depth of invasion" (if the whole tumor has been removed, and not just a piece of it's surface) so that the disease can be "staged" (see below).

How is the Extent of Melanoma Gauged?

The depth of invasion of melanoma into the skin and underlying fat has long been recognized to predict how the patient will do for skin melanomas. There are 2 widely used systems for defining the depth of melanoma invasion, and each assigns the melanoma to a particular "stage". Like all cancers, the extent of melanoma is defined by it's stage. Different information is used to stage different cancers. For melanoma, the two ways of measuring depth of invasion are the "Clark's Level" and the "Breslow System". While the Clark's level is only for skin melanomas, the Breslow system can check the depth in other tissues such as vulva and gut, as well as skin. The specifics of each system are below, the survivals are averages, not absolutes!

The depths are measured with a micrometer. You can see how accuracy is important. The actual staging system used by the American Joint Committee on Cancer (AJCC) takes into account the Breslow level, whether lymph nodes are involved, and whether the cancer has spread to distant organs.

The above survivals (from textbooks) are based upon conventional treatment and do not reflect progress from the latest effective treatments of melanoma. Furthermore, they include demise from all causes, including heart attacks, accidents, or other cancers. No one can predict just how well any particular patient with melanoma will do; many patients live many productive years with "incurable" cancer. We are only M.D.s. not "M.Dieties"! The best predictor for how well a patient will do tomorrow is how well they are doing today.

What is the Conventional Treatment for Melanoma?

Surgery is the conventional treatment for localized melanoma. "A chance to cut, a chance to cure" has been the surgeon's motto. For very early melanoma, surgery is curative. Unfortunately, surgery is seldom curative once the disease has spread. The biopsy is the first surgery performed to diagnose the tumor, and an excisional biopsy is all that is needed to treat early stage I cancers. If the cancer has invaded less than 0.85 mm, the risk of spread to lymph nodes or distant organs is remote (1%). The entire cancer should be removed with a safety margin. The size of this safety margin depends upon the size of the tumor. For tumors 1 cm. or less, a 2 cm. safety margin is adequate. For tumors over 1 cm., a 4 - 5 cm. safety margin is appropriate. Cutting out large amounts of nearby tissue for larger tumors has not improved survival, since the cancer has by then already spread to more distant sites. In general, for a tumor on a limb, incisions are made along direction of limb length for better healing and less scaring. Tumors ofthe trunk or face are removed along "Langer's Lines", which is the direction of the "grain" of the skin learned by plastic surgeon's. For tumors deep within the body, the cosmetic appearance is not important, but organ function shouldn't be compromised unless absolutely necessary. That is again because heroic operations to remove large cancers have not improved survival due to co-existing distant spread. However, palliative operations (such as to clear a bowel or lung blockage) or for a brain metastasis causing neurological compromise are appropriate asimmediate results can be seen.

A controversial area is the approach to local lymph nodes, which is a frequent site of cancer spread. Firstly, there is universal agreement that if local lymph nodes are enlarged (> 1 cm.) they should be removed. This is because the chance of local lymph node involvement is higher than the risk of distant spread, so the cancer may still all be removed even if the local lymph nodes are involved. Therefore, theoretically patients might also do better if lymph nodes in the region were removed whether they were enlarged or not, on the chance the cancer may have spread to them (and only be visible with a microscope). This procedure is called an "elective lymph node dissection" and, while logical, has failed to increase survival when done routinely. Thus, it is controversial whether these apparently non-involved lymph nodes should be removed. Generally lymph node removals ("lymphadenectomies") are safte procedures, with an operative death rate ("mortality") of less than 0.1%. There is some drawback ("morbidity") to removing lymph nodes, such as a greater chance for limb swelling ("edema") , infection and scarring. The general consensus from the National Cancer Institute is that if the original melanoma is less than 1 mm. thick, regional nodes should not be removed as the chance of spread to them is very small (1%), and just complete removal of the tumor should be curative.

If the cancer is between 1 and 3 mm. in patients less than 60 years old, there may be a small increase in cure rate when an "elective lymph node dissection" is done, so it should be considered. For patients with cancers greater than 4 mm., there is no increase in cure rates for elective lymph node dissection, and so it should not be recommended.

This is because even if the lymph nodes are found to be involved by the pathologist, the cancer has nearly always spread distantly by this time, so local measures are no longer effective at cure. However, again obviously involved or suspicious lymph nodes should always be removed at surgery, especially if there is no other evidence of distant spread ( "therapeutic dissection"). This is because not all swollen lymph nodes are cancerous, they may have been swollen from infection or some other reason, so it is important to check that they are actually involved to properly stage the cancer. Also, involved lymph nodes can continue to grow, cause pain, ulceration and limb swelling, and are much harder to control with surgery as they get larger. Thus removing them early can save a lot of unsightly and uncomfortable problems later on. It is also useful to check whether unsuspicious nodes are "microscopically involved".

An interesting approach to the problem of whether to remove normal appearing ymph nodes is the "sentinal lymph node biopsy". This means that only the lymphnode most likely to be involved is removed, if it is not cancerous, then there is a 96% chance that other lymph nodes are similarly not involved. Thus, if the sentinal lymph node biopsy is negative (nothing there), no further lymph nodes are removed. If, on the other hand it is positive (cancerous), then a full local lymph node removal is done.The sentinal lymph node can actually be identified by an experienced surgeon in 80% of cases. If the groin or armpit have involved lymph nodes, a complete dissection is done. If the neck has involved lymph nodes, a "modified" dissection (not as radical) is done, since is preserves appearance and neck function without sacrificing completeness of the operation. Since lymph nodes may be very small and deep in the tissue, they are seldom "all removed", and how far to go with the operation is left to the judgment of the surgeon.

The results of surgery alone closely follow the survivals given on pages 6 and 7. This is because, in general, complete surgical removal of a strictly local cancer has been the only curative procedure for melanoma. If the cancer recurs at only the local site after surgery, a second surgery ("salvage surgery") results in about 30% long-term survival. Balanced judgment must be used in performing surgery, since heroic operations for locally advanced cancer seldom improve survival, owing to the likelihood that the disease has already spread distantly. Similarly, several centimeters of "safety margin" around the tumor is adequate, since drastic removal of neighboring tissue doesn't help cure

Radiation Treatment has been used for nearly a century to treat many cancers, including melanoma. Interestingly, the first therapeutic use of radiation was noted with the "disappearance of a hairy mole" treated with a radiation beam. Melanoma is not considered highly "radiosensitive", meaning that high doses must be administered to kill it. Unfortunately, these high doses also damage neighboring normal tissues, so this limits the amount of radiation which can be safely given. In other words, enough radiation will certainly destroy the tumor, but at the cost of overdosing the patient. Nonetheless, radiation therapy does have a place in treatment of melanoma today. Radiation is commonly used for palliative (comfort) therapy in patients with spread of the disease causing clinical problems. These include bone pain, bowel blockage, and spread to the brain causing neurologic symptoms. Large local tumors and areas of uncontrolled lymph node spread which are ulcerated and bleeding can often be helped with a course of radiation treatment. Radiation is excellent at "cauterizing" bleeding and reducing pain from spread into bone and nerves. In fact, it is better for cancer pain than any narcotic, and doesn't have the narcotic side effects of sedation and constipation. Radiation is administered by a "Radiation Oncologist", a cancer doctor who specializes in it's administration. Prior to starting treatments, the area is marked out on a replica machine and positioning X-rays are taken; this process is called "Simulation" and takes less than one hour. Watercolor marks, and eventually pinpoint tattoo marks, are placed on the patient's skin to designate the area to get treated. Often, information from the simulation and previous scans are put into a "Treatment Planning Computer" which generates a "Plan".

A "plan" tells how much radiation is going into the tumor, and how much into adjacent normal tissues. If the are treated is very straightforward (i.e. a melanoma metastasis to hip bone) a plan may not be done, the are can be treated directly after simulation. External Beam radiation is given with a machine called a "linear accelerator" or "LINAC" for short. The patient lies on a hard table and is aligned with laser lights. Patients are often treated from several different directions, but the machine head pivots around the patient so that they simply lie still on the table. Treatment is normally given Monday through Friday, and takes about 15 minutes of being in the department per day. The dose to "cure" an area (appreciating that radiation therapy is local treatment) is about 80 Gray (units of irradiation) given over 8 weeks. The sid-effects (see below) of high dose radiation generally makes it unusual to be recommended for curative intent ("definitive therapy"). More commonly symptom relieving ("palliative therapy") is given, those dose is usually 30 to 40 Gray at a rate of 2 - 3 Gray per treatment, so it takes about 2 - 4 weeks of treatment. If a day is missed, it is simply added at the end so the whole prescribed dose is given. If the intent of the treatment is curative, high doses must be given, reaching perhaps 80 Gray over 8 weeks, but the aggressiveness of this treatment makes it unusual to be recommended.

Radiation is generally an easy treatment to receive; patients do not get radioactive or "radiation poisoning" The side-effects of radiation are generally only in the area treated. For the low doses given for palliation of brain metastasis, most patients will get local skin redness and fatigue; other side effects are quite rare but mimic those below when considering high dose treatment. Amazingly, the brain tolerates radiation very well, and tolerates much higher doses that the lung or kidney. For many "primary brain cancers" Usual doses are 45 - 60 Gray are given at about 2 Gray per day. Curative intent for melanoma requires higher doses so side effects ("toxicity") of therapy will be more profound. Side effects of radiation are divided into "acute" and "late" reactions. Acute reactions occur during the treatment period, while late reactions may occur months to years later. Expected acute reactions include fatigue, hair loss (which is only permanent for doses of > 50 Gray) and scalp redness and irritation. This can progress to frank peeling of the skin and is treated with ointments like acemannan and topical steroids. Patients may get stuffiness or even pain in their ears from eardrum irritation from radiation. It is also possible to have some temporary swelling of the brain when first starting treatments, which may worsen neurological symptoms. To help prevent this, patients are often started on oral steroids, like decadron, prior to radiation therapy. All of the acute reactions from radiation take at least several treatments before they appear, and they are short-term and resolve within several weeks after completing treatment.

Possible later side-effects are long term fatigue, memory loss, mental ability deterioration, hormonal deficiencies, and the worst complication, radiation necrosis. This is when part of the brain dies from radiation, and it can cause headaches, seizures, and eventual death. Of course, the brain may not fill in a gap where a previous tumor was with new tissue, and a persistant defect should not be confused with radiation necrosis. Brain necrosis can also spread, but it should not be confused with growing tumor. The best test to differentiate persistant tumor form radiation necrosis is a Positron Emission Tomography ("PET") scan; it uses radioactively labeled glucose to check the metabolic area at the suspicious site. It can moreover image the whole body and see tiny metastasis elsewhere with very little side effects (except high cost!) with a "total body" PET scan. Necrotic (that is dead) brain is first treated with steroids, but often must be removed surgically. The greater the amount of brain irradiated, and the higher the dose, increases the risk of radiation necrosis, as well as the other late effects. Therefore, radiation oncologists try to limit the volume of brain treated, and only treat the whole brain if absolutely necessary, and never to more than 50 Gray. Smaller areas can be treated safely to over 70 Gray, if the treatment is given as many small doses or "fractions". A small further concern about radiation, especially in low-grade melanomas is that they may become even more aggressive from the radiation treatment. This is called "malignant degeneration" but is commoner for brain tumors which originate in the brain as their "primary site". In general, however, radiation is safe and effective for melanoma metastasis to the brain.

Surgery and Radiation Together

Studies from the Brain Tumor Study Group in the 1960's showed that when both surgery and radiation are both used for aggressive brain cancers, that the survival results were better than using either treatment alone. This data can be extrapolated to high grade tumors metastatic to the brain. It was found that patients did better if they had a total resection of the tumor, and if the radiation dose to the tumor area was taken up to 60 Gray. Furthermore, studies done purely for brain metastasis of other primary cancers showed that survival (on average) was increased from 15 to 40 weeks if a craniotomy (brain surgery) was done in conjunction with External Beam radiation therapy to a moderate dose (e.g. 40 Gray). There was no benefit, in these early studies, to higher dose radiation- just more side-effects. However, newer techniques of precisely targeting the radiation using 3-dimensional localization techniques in the computer plan, stereotactic radiosurgery which meticulously targets the radiation beam, and using multiple treatments of radiation ("hyperfractionation") per day all justify using higher doses with similar side effects to lower doses.

Typically, a patient diagnosed brain metastasis is first taken to surgery where it's total removal is attempted by neurosurgeons, so long as the primary site is adequately controlled by local therapy. Afterward, an MRI scan helps to tell how much tumor is left, but typically is not accurate for at least 2 months after the surgery while swelling ("edema") and bruising ("ecchymosis") resolve. The patient heals for 2 - 3 weeks and is then simulated for radiation treatments, based upon the volume of tumor as was seen on the scans prior to surgery. The patient is on steroids to help prevent swelling and antiseizure medicines, and they are told not to drive or operate dangerous machinery. They get 5 - 7 weeks of External Beam irradiation, and afterwards see the radiation oncologist 2 - 4 weeks later. Usually an MRI scan is gotten 2- 4 months after radiation is completed, to check the tumor's response. The tumor should continue to shrink after radiation is completed, since cells damaged by radiation die when they try to divide. A sooner scan might show a mass that had no living tumor cells left in it, but this would be confusing to the doctor and worrisome to the patient, as nothing could be done about it anyway.

Thus some time is allowed to pass for the tumor to shrink after radiation before a scan is gotten, unless the symptoms get dramatically worse. Later scans may show residual or growing tumor that can get further treatment, as is discussed in "latest treatments". In general, combination treatment has been, and remains, safe and effective for symptom therapy, and may cure selected subsets of individuals with "mono-metastasis" or "pauci-metastasis" - that is to one or few distant sites respectively. A metastatic melanoma is not necessarily a "death sentence", the important factor is how well the metastasis responds to treatment. Chemotherapy has not been shown to improve survival (so far) when given as an adjunct to surgery ("adjuvant therapy"). It is difficult to interpret the results of chemotherapy for disease which has spread, since amazingly some melanomas (even advanced ones) will spontaneously disappear without any therapy. this is thought to to immunological mechanism stimulated within the body, especially after a virus or other fever-causing infection. Unfortunately, this spontaneous disappearance is unusual (<2%) so a search has been made for ways to treat the melanoma once it has spread. Surgery and radiation therapy are only local treatments, they cannot treat the whole body ("systemic treatment").

Since the cancerous cells may have escaped to, and be lurking in, any part of the body, it makes sense to treat the whole body with something that will kill melanoma. This is the same rationale for using chemotherapy for any cancer. Some cancers, however, are much more sensitive to our current chemotherapy agents than others, and so far melanoma has not responded well to our available agents. The most effective current single drug is Dacarbazine and it gives a response rate of 20% for skin and lymph node disease, but less than 5% when the disease has spread to other organs. When dacarbazine is combined with other agents (i.e. cisplatinum or vincristine) this is then "combination chemotherapy", and the response rate increases to about 40%. This is at a cost of greater side-effects (anemia, infection, nerve and kidney damage). The most depressing fact about chemotherapy for metastatic melanoma is that response tends to be short-lived, averaging just 5 months. In fact, out of 500 patients who got chemotherapy in a Mayo clinic trial, only 10 out of 500 patients survived for 5 years. This demonstrates that far better chemotherapy, or other treatments such as gene therapy and immune therapy, are required to make a difference for the vast majority of those patients who's disease has spread.

The conclusion of conventional therapy is that surgery is effective for those patients with early disease, and radiation is good for relieving symptoms of late disease.Unfortunately, those patients with distant spread almost inevitably have disease progression in spite of all available conventional treatments.

What is the Latest Effective Treatment for Melanoma?

For early melanoma, 2 mm. or less in depth, excisional surgery produces excellent results and remains the procedure of choice. With increasing depth, a sentinal lymph node biopsy can indicate with over 95% accuracy whether regional lymph nodes are involved and should be removed; recall that any suspiciously enlarged lymph nodesare always removed. If lymph nodes are involved, there is a 70% chance the patient will develop distant disease. Fortunately, there have been some modest advances in chemotherapy to treat microscopically seeded and overtly disseminated disease.

One agent that may make a significant difference is Cisplatin, an analogue which contains platinum, with standard doses (60 to 150 mg/m2). This can be combined with the newly available agent Ethiofos (WR2721), a "normal tissue protectant" which helps spare normal tissues from both radiation and chemotherapy. In small trials, responses have averaged 50%. While the median "response" is 6 months, some patients will do much better than that with this treatment. Using "regional therapy" (of say a limb, section of lung or liver) with Intraarterial (placed via a canula tumor into a small local artery) instillation of Cisplatin and an absorbing sponge are placed, and concomittant irradiation can be given to moderate dose (i.e. 40 Gray). Even without adding radiation, a 45% rate of response is seen for liver metastasis from ocular melanoma with this "intra-arterial instillation regional therapy". Other regional therapy (such as isolated limb perfusion) leads to 40% Complete Response with 50% lasting 2 years or more.

The most aggressive chemotherapy utilized high dose BCNU (Dacarbazine), Melphalan or Thiotepa in conjunction with autologous bone marrow transplant. Responses are seen in 60% of patients, but the toxicity is fatal in up to 1/3 of patients. The most depressing thing about this approach is the short term average response, just 3 to 6 months. However, ~10% of patients are long term responders, have successfully tolerated the transplant, and may be cured.

Immune therapy (melanoma vaccines) are the latest treatment for probable or definite distant disease. Extensive research has been conducted at the John Wayne Cancer Center in California. Melanoma vaccines attempt to stimulate the body's own defense mechanisms against the melanoma, and were developed with the observation that some patient's disease will disappear spontaneously, especially if the have gotten some type of other infection which stimulates the immune system. These vaccines are given after melanoma develops, unlike children's vaccines (i.e. polio) which are given to prevent a disease. Melanomas from different patients show common markers, called "antigens", which promote a response from the immune system - that is production of an "antibody" against the melanoma. There are various ways to stimulate the immune system to fight melanoma. One is to grind up cancer cells from other patients, and inject a suspension of them. Often multiple injections over time are required. Another method is to use "non-specific" immune stimulators, such as the BCG vaccine used to test for tuberculosis. Both of these methods require multiple injections to keep stimulating the immune system against the melanoma, and both can be used together. Chemotherapy response (when one occurs) is very soon, within 3 - 4 weeks; but vaccine responses (that is shrinkage of the tumor) often take 12 - 14 weeks, as the body slowly builds up antibody against the tumor.

"Cancervax" is the product developed by the John Wayne Cancer Center; it uses an irradiated mixture cancer cells from at least 3 other patients; it is a living whole cell vaccine. It has a medium survival of 2 years (compared to 6 months for standard therapy) and a 5-year survival rate of 25% for melanoma which has spread. Patients who do best are those whose sites of distant disease have been removed surgically, so there was no evident disease prior to starting the vaccine. These patients have a 5 - year survival rate of 33%, the best yet reported. Furthermore, Cancervax appears to help prevent new metastasis! This is critical since up to 95% of patients with spread to distant organ sites have melanoma cancer cells circulating in their bloodstreams. Another immune-modulating drug which can be given is Interferon alfa-2b. It is given under the skin 3 times per week, and has a response rate of about 40%. This agent has been proven in a large trial to increase overall survival for stage III melanoma patients (those with lymph nodes positive), so it can be given routinely following surgery for these patients. About 70% of patients with stage III disease can be seen to have melanoma cells circulating in their bloodstreams. The average increase in survival with Interferon alfa-2b is over 1 year, and this translates into more cures. It has side effects of fatigue, fever and headache. The best administration appears to be high to intermediate doses for 1 year. Overall, melanoma vaccines and other immune stimulators have been the first therapy since proven to increase survival in advanced melanoma.

A worthy note is the advancement of radiation therapy techniques for patients who develop spread to the brain. "Stereotactic Radiosurgery" is now offered in nearly all University Radiation Oncology Departments and localizes multiple fields of radiation directly upon brain metastasis in a single treatment taking several hours, it's painless
and the patient spends only 1 day in the hospital. It can be used as a "boost" after External Beam therapy to partial or whole brain, it adds about 20 Gray to the previous dose but in terms of effectiveness its more like 50-60 Gray (since it is "radiobiologically more effective" when given all at one time). Multiple areas of spread to brain, up to 3 cm each, can be treated this way. This treatment is usually combined with prior local surgery to debult the tumor, and/or regional whole-brain radiation, to kill residual (often microscopic) areas of disease before they have a chance to grow.

For the patient diagnosed with malignant melanoma, it is important not to rely on a single pill or ray, but utilize a "combination" approach. This means utilizing a program for improved nutrition, exercise and spiritual renewal. It is worthwhile to select a safe, affordable Alternative Therapy that the patient can believe in - and that doesn't interfere with getting the latest effective treatment. CancerAnswers.com has an In-Depth Transcript describing reasonable Alternative Therapies available via our Website. Overall, there is more hope than ever before for patient's with melanoma cancer, and the overall survival is now over 80% for the average patient. Patients with the poorer-risk types or widespread disease have the best chance for survival by combining treatment modalities. Continued advancements against metastatic malignant melanoma offer better hope than ever before for patients and families of those stricken, and effective therapy for this once often fatal disease looms on the horizon. Overall, the future has never looked brighter for patients with metastatic malignant melanoma.