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Malignant Melanoma

Malignant Melanoma

Definition

Malignant melanoma is a type of cancer arising from the melanocyte cells of the skin. Melanocytes are cells in the skin that produce a pigment called melanin. Malignant melanoma develops when the melanocytes no longer respond to normal control mechanisms of cellular growth. They may then invade nearby structures or spread to other organs in the body (metastasis), where again they invade and compromise the function of that organ.

Description

Melanocytes are derived from a structure in the human embryo called the neural crest. They are distributed in the epidermis and thus are found throughout the skin. They produce a brown pigment known as melanin and are responsible for racial variation in skin color as well as the color of moles. Malignant degeneration of the melanocyte gives rise to the tumor known as melanoma, which has four subtypes. These are: superficial spreading, nodular, lentigo maligna, and acral lentiginous melanomas, accounting for 70%, 15% to 30%, 4% to 10%, and 2% to 8% of cases, respectively. Malignant melanoma may develop anywhere on the body. In men, it is most common on the trunk. In women, it is most common on the back or legs. The subtype also may influence where the tumor develops; lentigo melanoma is more common on the face while acral lentiginous melanoma is more common on the palms of the hand, soles of the feet, or in the nail beds.

The locally invasive characteristic of this tumor involves vertical penetration through the skin and into the dermis and subcutaneous (under-the-skin) tissues of the malignant melanocytes. With the exception of the nodular variety of melanoma, there is often a phase of radial or lateral growth associated with these tumors. Since it is the vertical growth that characterizes the malignancy, the nodular variant of melanoma carries the worst prognosis. Fortunately, the superficial spreading type is most common.

The primary tumor begins in the skin, often from the melanocytes of a pre-existing mole. Once it becomes invasive, it may progress beyond the site of origin to the regional lymph nodes or travel to other organ systems in the body and become systemic in nature.

Lymph is the clear, protein-rich fluid that bathes the cells throughout our body. Lymph will work its way back to the bloodstream via small channels known as lymphatics. Along the way, the lymph is filtered through cellular stations known as nodes, thus they are called lymph nodes. Nearly all organs in the body have a primary lymph node group filtering the tissue fluid, or lymph, that comes from that organ. Different areas of the skin have different primary nodal stations. For the leg, they are in the groin. For the arm, the armpit or axilla. For the face, it is the neck. Depending where on the torso the tumor develops, it may drain into one groin or armpit, or both.

Cancer, as it invades in its place of origin, may also work its way into blood vessels. If this occurs, it provides yet another route for the cancer to spread to other organs of the body. When the cancer spreads elsewhere in the body, it has become systemic in extent and the tumor growing elsewhere is known as a metastasis.

Untreated malignant melanoma follows a classic progression. It begins and grows locally, penetrating vertically. It may be carried via the lymph to the regional nodes, known as regional metastasis. It may go from the lymph to the bloodstream or penetrate blood vessels, directly allowing it a route to go elsewhere in the body. When systemic disease or distant metastasis occur, melanoma commonly involves the lung, brain, liver, or occasionally bone. The malignancy causes death when its uncontrolled growth compromises vital organ function.

Of the anticipated new cases of cancer for the year 2003 in the United States, malignant melanoma will account for 5% of malignancies in men and 4% in women, being the sixth most common cancer in men and the seventh in women. It is estimated there will be 553,400 total cancer deaths in the United States in 2001. Malignant melanoma will account for 7,800 of these deaths, for an incidence of 1.5% of total deaths related to cancer.

The incidence of primary cutaneous malignant melanoma has been steadily increasing, possibly related to increase of sun exposure. Currently, the risk is about 13 per 100,000 of the population. It affects all age groups but is most commonly seen in patients between 30 and 60 years of age.

Sun exposure definitely increases the risk of developing melanoma, particularly in older males. The melanocytes are part of the integument's photoprotective mechanism; in response to sunlight, they produce melanin that has a protective role from the sun's ultraviolet rays. For Caucasians, the amount of melanin present in the skin is directly related to sun exposure. However, it is not so much the total sun exposure that seems important, rather it is the history of sunburn, (especially if severe or at an early age), that correlates with the increased risk. On this basis populations of fair-skinned people living in areas of high sun exposure such as the southwest United States or Australia are subject to increased risk. Malignant melanoma also affects non-Caucasiansthough sun exposure probably does not play a roleat a rate of 10% that of Caucasians. The most common form of melanoma in African Americans is acral lentiginous melanoma.

Malignant melanoma may arise in the skin anywhere on the body. It is estimated that 50%-70% develop spontaneously while the remainder start in a pre-existing mole.

Causes and symptoms

The predisposing causes to the development of malignant melanoma are environmental and genetic. The environmental factor is excessive sun exposure. There are also genetically transmitted familial syndromes with alterations in the CDKN2A gene, which encodes for the tumor-suppressing proteins p16 and p19. In 2003 a group of Swedish researchers reported that 63 out of a group of 71 melanoma patients, or 89% of the group, had mutations in either the NRAS or the BRAF gene. The researchers found that these mutations occur at an early point in the development of melanoma and remain as the tumor progresses.

As of early 2003, some researchers think there may be two pathways to malignant melanoma, one involving exposure to sunlight and the other with melanocyte proliferation triggered by other factors. This hypothesis is based on the difference in distribution of moles on the body between patients who develop melanomas on the face and neck, and those who develop melanomas on the trunk.

A small percentage of melanomas arise within burn scar tissue. As of 2003, researchers do not fully understand the relationship between deep burns and an increased risk of skin cancer.

As mentioned previously, melanin production in fair-skinned people is induced by sun exposure. An exposure substantial enough to result in a mild sunburn will be followed by melanin producing a tan that may last a few weeks. Both ultraviolet radiation and damaging oxygen radicals caused by sun exposure may damage cells, particularly their DNA. It is suspected that this damage induces mutations that result in the development of malignant melanoma. Though these mutations are alterations of the genome causing the melanoma, they are environmentally induced and account for sporadic or spontaneous cases of this disease.

A positive family history of one or two first-degree relatives having had melanoma substantially increases the risk on a genetic basis. A family tendency is observed in 8% to 12% of patients. There is a syndrome known as the dysplastic (atypical) nevus syndrome that is characterized by atypical moles with bothersome clinical features in children under age 10. Such individuals have to be observed closely for the development of malignant melanoma. Chromosome 9p has been identified as being involved in familial predisposition. There are mutations in up to 50% of familial melanoma patients of the tumor-suppressing gene CDKN2A. The actual number of moles increases risk, but the size of the moles needs be considered. Those with 10 larger moles of over 1 cm (0.4 in.) are at more risk than those with a higher number (50-99) of smaller moles. Finally, when a child is born with a large congenital mole, careful observation for change is appropriate because of increased risk.

An excellent way of identifying changes of significance in a mole is the ABCDE rule:

  • Asymmetry
  • Border irregularity
  • Color variegation
  • Diameter greater than 6 mm (0.24 in)
  • Elevation above surrounding tissue.

Notice that three of the criteria refer to variability of the lesion (color variegation refers to areas of light color and black scattered within the mole). Thus small, uniform regular lesions have less cause for concern. It is important to realize that change in a mole or the rapid development of a new one are very important symptoms.

Another summary of important changes in a mole is the Glasgow 7-point scale. The symptoms and signs below can occur anywhere on the skin, including the palms of the hands, soles of the feet, and also the nail beds:

  • Change in size
  • Change in shape
  • Change in color
  • Inflammation
  • Crusting and bleeding
  • Sensory change
  • Diameter greater than 7 mm (0.28 in.

In this scheme, change is emphasized along with size. Bleeding and sensory changes are relatively late symptoms.

Symptoms related to the presence of regional disease are mostly those of nodules or lumps in the areas containing the lymph nodes draining the area. Thus nodularity can be found in the armpit, the groin, or the neck if regional nodes are involved. There is also a special type of metastasis that can occur regionally with malignant melanoma; it is known as an in-transit metastasis. If the melanoma is spreading through the lymph system, some of the tumor may grow there, resulting in a nodule part way between the primary site and the original lymph node. These in-transit metastasis are seen both at the time of original presentation or later after primary treatment has been rendered, the latter being a type of recurrence.

Finally, in those who either present with or progress to widespread or systemic disease, symptoms and signs are related to the affected organ. Thus neurologic problems, lung problems, or liver problems develop depending on the organ involved.

Diagnosis

None of the clinical signs or symptoms discussed above are absolute indications that a patient has malignant melanoma. The actual diagnosis is accomplished by biopsy, a procedure that removes tissue to examine under a microscope. It is important that the signs and symptoms are used to develop a suspicion of the diagnosis because the way the biopsy is performed for melanoma may be different than for other lesions of the skin.

The doctor may also use a dermatoscope to examine the mole prior to removal. The dermatoscope, which can be used to distinguish between benign moles and melanomas, is an instrument that resembles an ophthalmoscope. An immersion oil is first applied to the mole to make the outer layers of skin transparent.

When dealing with an early malignant melanoma, it is very important to establish the exact thickness of penetration of the primary tumor. Any biopsy that does not remove the full vertical extent of the primary is inadequate. Therefore, if a skin lesion is suspicious, full thickness excisional biopsy is the approach recommended. Shave biopsies and biopsies that remove only a portion of the suspect area are inappropriate. Often, in an early case, the excision involves just the suspicious lesion with minimal normal skin, but it should be a full vertical excision of the skin. If a melanoma is diagnosed, further treatment of this area will often be necessary but does not compromise outcome (prognosis). In some special areas of the body, minor modifications may be necessary about initial total excision, but full thickness excision should always be the goal. (See staging, below.)

Once the diagnosis is obtained, careful examination of the patient for regional lymph node involvement should be done. A careful review to uncover any symptoms of widespread disease is also appropriate.

The more common patient has an early melanoma, and extensive testing is not usually warranted. Routine testing in this situation involves a complete blood count, a chest x ray, and determinations of blood enzymes including lactic dehydrogenase and alkaline phosphatase.

If the patient has signs or symptoms of more advanced disease, or if the lesion's depth of penetration is sizeable, further imaging studies may be appropriate. These would involve CAT scans of the abdomen, the chest, or regional nodal areas, or a CT or MRI of the brain.

Treatment

The key to successful treatment is early diagnosis. Patients identified with localized, thin, small lesions (typified by superficial spreading subtype) nearly always survive. For those with advanced lesions, the outcome is poor in spite of progress in systemic therapy.

Clinical staging

Malignant melanoma is locally staged based on the depth of penetration through the skin and its appendages. There are two ways of looking at the depth of penetration. The Clarke system utilizes the layers of the dermis and the skin appendages present at that layer to identify the depth of penetration. The Breslow system uses the absolute measurement of depth. Though useful conceptually, the Clarke system is used less frequently because of the fact that skin is of different thickness in different regions of the body. The depth of penetration is much greater when the tumor reaches the subcutaneous fat when the skin involved is the back as opposed to the face. It turns out that the Breslow measurement is more reproducible and thus more useful; therefore, for purposes here, depth of penetration by absolute measurement (Breslow) is used in local staging.

Stage I and stage II have no involvement of the regional lymph nodes and are thus localized to the site of origin. These stages are subdivided on the basis of penetration. Stage Ia is 0.75 mm or less (1 mm = 0.04 in), and Stage Ib is 0.75-1.5 mm penetration. Stage IIa is 1.5-4.0 mm and Stage IIb is over 4.0 mm or into the subcutaneous fat. In stage III and IV, there is disease beyond the primary site. Stage III is defined by the presence of in-transit or regional nodal metastasis or both. Stage IV is defined by the presence of distant metastasis.

Once the diagnosis of malignant melanoma has been established by biopsy and the stage has been identified using the results of the examination and studies, a treatment plan is developed. Melanoma is not cured unless it is diagnosed at a stage when it can be isolated and removed surgically. Considerations revolve around the extent of the local and regional nodal surgery for stages I through III. For stage IV patients, or those that are treated and then develop recurrence at distant sites, chemotherapy or immunotherapy is planned. Studies are in progress to improve the results from traditional chemotherapeutic regimens. Adjuvant therapy (auxiliary drug treatment used to make possibility of relapse less for those at high risk) is also considered.

Surgical therapy for the primary site is that of wide local removal of the skin including subcutaneous tissue surrounding the lesion. In the past, wide excisions were large and encompassed 2 in. of tissue in all directions wherever feasible. It has been shown that such wide local excisions are not necessary and the issue has become: how wide is enough? Studies from the World Health Organization Melanoma Group and by the Melanoma Intergroup Committee in the United States have provided general guidelines based on the depth of penetration of the melanoma. These guidelines and anatomic considerations need to be kept in mind by the surgeon.

The next issue in primary management is whether the patient should have the regional lymph nodes removed in addition to treatment of the primary tumor. The problems associated with the resection of regional lymph nodes are those of lifelong edema or swelling in the extremity. Though it does not occur in all patients (5% to 20%, depending on the extremity and extent of the dissection), it can be a disabling symptom. Certainly, if it could be ascertained that there was disease in the nodes, resection (removal) would be appropriate. However, if there was no disease, the risk of edema should be avoided. In patients with no signs of regional disease, depth of penetration of the primary tumor helps guide the decision. If the tumor penetrates less than 1mm, dissection is not usually done. If it is 1-2 mm, node dissection may be done at the time of primary treatment or the patient may be observed and only undergo lymph node dissection if the area later shows signs of disease. If the patient has enlarged lymph nodes or the depth of the tumor has led to the evaluation by CAT scan showing enlarged nodes, resection of the nodes will be considered. In the latter case, more extensive imaging of the lung, liver, or brain may be appropriate to be sure the patient does not already have stage IV disease.

Questions related to which patients should have resection of regional lymph nodes have led to an intermediary procedure known as sentinel node mapping and biopsy. Intermediate thickness melanomas between 1 and 4 mm deep (0.04 and 0.16 in.) may have nodal involvement even if the examination and any other studies done are normal. If a radioisotope tracer or blue dye is injected into the area of the primary tumor, very shortly it will travel to the lymph nodes draining that area. These sentinel nodes are thus identifiable and are the most likely to harbor any regional metastatic disease. If these nodes alone are biopsied and are normal, the rest of the lymph node group can be spared. If they show microscopic deposits of tumor, then the full resection of the lymph node group may be completed. This procedure allows selection of those patients with intermediate thickness melanoma who will benefit from the regional lymph node dissection.

Patients with metastatic melanoma who do not respond well to other therapies may be candidates for treatment with aldesleukin. Aldesleukin is a form of interleukin, a specific kind of biological response modifier that promotes the development of T-cells. These cells are part of the lymphatic system and can directly interact with and fight cancer cells. Although aldesleukin is produced naturally in the body, its therapeutic form is developed via biotechnology in a laboratory setting. Treatment is considered palliative, which means that it provides comfort but does not produce a cure. Side effects, however, can be severe, and range from flu-like symptoms to whole-body infection (sepsis ) and coma.

Some patients, such as those with IIb or stage III melanoma, are at high risk for the development of recurrence after treatment. Although these patients are clinically free of disease after undergoing primary treatment, they are more likely to have some microscopic disease in the body that studies have not yet been able to identify. In an effort to decrease the rate of relapse, adjuvant therapy may be considered. Interferon alpha 2a is an agent that stimulates the immune system. This adjuvant therapy may slightly increase the duration of a patient's disease-free state and lengthen overall survival. However, interferon alpha 2a has high toxicity and patients may not tolerate the side effects.

Unfortunately, treatment for those patients who present with or go on to develop systemic disease usually fails; melanoma that has metastasized to the brain is particularly difficult to treat. The chemotherapeutic agent dacarbazine, or DTIC, seems to be the most active agent. Overall responses are noted in about 20% of patients, and they last only two to six months. Combination therapy may be an option. The regimen of DTIC + BCNU (carmustine) + cisplatin + tamoxifen delivers a response rate of 40%. Combining biologic or immunologic agents such as interferon with standard chemotherapeutic agents is under study and showing improved response rates, though toxicity is substantial and only the healthier, younger patients tolerate the treatment.

Some researchers are investigating the reasons why melanomas are so resistant to chemotherapy. One suggestion as of late 2003 is that the genes ordinarily responsible for apoptosis (cell self-destruction) do not function normally in melanomas. The development of new drugs to treat melanoma depends on a better understanding of the complex processes involved in apoptosis.

Alternative treatment

Though radiation therapy has a minimal role in the primary treatment of malignant melanoma, for patients who have metastatic disease, radiation may be helpful. This is true in patients who have developed tumor deposits in such areas as the brain or bone.

Prognosis

Almost all patients survive stage Ia malignant melanoma, and the suvivorship for stage I overall is more than 90%. Survival drops in stage IIa to about 65% at five years and is worse yet for stage IIb at slightly over 50%. Stage III has a survival rate at 5 years of 10%-47%, depending on the size and number of regional nodes involved. Stage IV malignant melanoma is almost always a fatal disease.

Coping with cancer treatment

For those with familial tendencies for malignant melanoma, genetic counseling may be appropriate. Psychological counseling may be appropriate for anyone having trouble coping with a potentially fatal disease. Local cancer support groups may be helpful and are often identified by contacting local hospitals or the American Cancer Society.

Prevention

Though it is difficult to prove that sunscreens statistically reduce the frequency of malignant melanoma at this time, most authorities recommend their use as protection from ultraviolet light (considered a major factor in the development of melanoma.) Avoidance of severe sunburns is recommended.

KEY TERMS

Adjuvant therapy Treatment given to patients who are at risk of having microscopic untreated disease present but have no obvious symptoms.

Dermis The deeper portion or layer of the skin beneath the epidermis.

Dysplastic nevus syndrome A familial syndrome characterized by the presence of multiple atypical appearing moles, often at a young age.

Epidermis The uppermost layer of skin cells.

Genome The genetic makeup of a cell, composed of DNA.

Immunotherapy A form of treatment that uses biologic agents to enhance or stimulate normal immune function.

Integument The medical name for the skin.

Lymph node dissection Surgical removal of a group of lymph nodes.

Lymphedema Swelling of an arm or leg following surgical removal of the lymph nodes that drain the limb.

Melanocytes Skin cells derived from the neural crest that produce the protein pigment melanin.

Metastasis (plural, metastases) A tumor growth or deposit that has spread via lymph or blood to an area of the body remote from the primary tumor.

Nevus (plural, nevi) A medical term for mole.

Resection The act of removing something surgically.

Skin appendages Structures related to the integument such as hair follicles and sweat glands.

Variegation Patchy variation in color.

Resources

BOOKS

Abeloff, Armitage, Lichter, and Niederhuber. Clinical Oncology Library. 2nd ed. London: Churchill Livingstone, 1999.

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Dermatologic Disorders: Malignant Tumors." Section 10, Chapter 126. In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Dermatologic Disorders: Moles." Section 10, Chapter 125 In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Beers, Mark H., MD, and Robert Berkow, MD, editors. "Dermatologic Disorders: Reactions to Sunlight." Section 10, Chapter 119. In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

PERIODICALS

Brown, C. K., and J. M. Kirkwood. "Medical Management of Melanoma." Surgical Clinics of North America 83 (April 2003): 283-322.

Carlson, J. A., A. Slominski, G. P. Linette, et al. "Malignant Melanoma 2003: Predisposition, Diagnosis, Prognosis, and Staging." American Journal of Clinical Pathology 120 , Supplement (December 2003): S101-S127.

Eigentler, T. K., U. M. Caroli, P. Radny, and C. Garbe. "Palliative Therapy of Disseminated Malignant Melanoma: A Systematic Review of 41 Randomised Clinical Trials." Lancet Oncology 4 (December 2003): 748-759.

Halder, R. M., and C. J. Ara. "Skin Cancer and Photoaging in Ethnic Skin." Dermatologic Clinics 21 (October 2003): 725-732.

Horig, H., and H. L. Kaufman. "Local Delivery of Poxvirus Vaccines for Melanoma." Seminars in Cancer Biology 13 (December 2003): 417-422.

Jellouli-Elloumi, A., L. Kochbati, S. Dhraief, et al. "Cancers Arising from Burn Scars: 62 Cases." [in French] Annales de dermatologie et de venereologie 130 (April 2003): 413-416.

McWilliams, R. R., P. D. Brown, J. C. Buckner, et al. "Treatment of Brain Metastases from Melanoma." Mayo Clinic Proceedings 78 (December 2003): 1529-1536.

Omholt, K., A. Platz, L. Kanter, et al. "NRAS and BRAF Mutations Arise Early During Melanoma Pathogenesis and Are Preserved Throughout Tumor Progression." Clinical Cancer Research 9 (December 15, 2003): 6483-6488.

Rockmann, H., and D. Schadendorf. "Drug Resistance in Human Melanoma: Mechanisms and Therapeutic Opportunities" Onkologie 26 (December 2003): 581-587.

Weinstock, Martin A. "Early Detection of Melanoma." JAMA, The Journal of the American Medical Association 284 (August 16, 2000): 886.

Whiteman, D. C., P. Watt, D. M. Purdie, et al. "Melanocytic Nevi, Solar Keratoses, and Divergent Pathways to Cutaneous Melanoma." Journal of the National Cancer Institute 95 (June 4, 2003): 806-812.

ORGANIZATIONS

American Academy of Dermatology. 930 N. Meacham Road, P.O. Box 4014, Schaumburg, IL 60168-4014. (847) 330-0230. Fax: (847) 330-0050. http://www.aad.org.

American Cancer Society. 1599 Clifton Road NE, Atlanta, GA 30329. (800) ACS-2345.

National Cancer Institute (NCI). NCI Public Inquiries Office, Suite 3036A, 6116 Executive Boulevard, MSC8332, Bethesda, MD 20892-8322. (800) 4-CANCER or (800) 332-8615 (TTY). http://www.nci.nih.gov.

OTHER

Cancer Resource Center. American Cancer Society. June 20, 2001. http://www3.cancer.org/cancerinfo.

Melanoma Patient's Information Page. June 20, 2001. http://www.mpip.org.

National Cancer Institute. June 13, 2001. http://rex.nci.nih.gov/PATIENTS/INFO_PEOPL_DOC.html.

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malignant melanoma

malignant melanoma n. see melanoma.

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Malignant Melanoma

Malignant Melanoma

Definition

Melanoma is an illness in which cancer cells form in melanocytes, the cells that give skin its color. In malignant melanoma, melanocytes become cancerous and may spread throughout the body and invade other organs and tissues. Initially melanoma begins on the surface of the skin. If left untreated, melanoma can cause illness that may be fatal; however, if caught early, melanoma may be treatable with surgery, chemotherapy , radiation therapy, and immunotherapy.

Description

The epidermis, the outermost and upper layer of the skin, contains melanocytes, the skin cells that make melanin, the pigment that gives skin its hue. Melanin is responsible for the color of a person's skin, hair, and eyes. When a cancerous tumor develops in the melanocytes, a person has malignant melanoma.

Most cases of melanoma occur in the skin, but sometimes melanoma can also occur in the colored part of the eye, a condition known as intraocular melanoma.

Sometimes melanoma arises out of normal skin, but it can also develop in a mole (also called a nevus). Moles are benign growths or collections of melanocytes on the skin. According to the American Academy of Dermatology, individuals have typically about 30 moles on their skin.

The number and type of moles individuals have may increase the risk of developing melanoma. People with more than 50 moles or with moles that are unusual and irregular looking (doctors call these dysplastic or atypical moles) are at increased risk of developing melanoma.

There are four major types of melanoma:

Superficial spreading melanoma accounts for 70% of all cases of melanoma and typically occurs in younger people. This type of melanoma takes a long time to penetrate the top layer of skin, and the first sign of it is a flat or slightly raised skin lesion. The lesion may be discolored with irregular borders and may develop out of a previously benign mole. It is most likely to occur on the trunk in men, the legs in women, and the upper back in men and women.

Lentigo maligna melanoma is another form of melanoma that is most often found in older adults. It begins as a flat or slightly raised tan, brown, or dark brown skin discoloration that remains close to the skin's surface. Once the malignancy spreads, it is referred to as lentigo maligna melanoma.

Acral lentiginous melanoma is the most common type of melanoma in African Americans and Asians and is least common among Caucasians. The black or brown discoloration of acral letiginous melanoma first spreads on the surface of the skin, often under the nails or on the soles of the feet or palms of the hands.

Nodular melanoma, which accounts for 10 to 15% of all melanoma cases, is the most aggressive form of melanoma, and by the time it is diagnosed, it may have spread to other areas of the body. This type of melanoma starts as a bump that is usually black. Most frequently nodular melanoma is found on the trunk, legs, and arms, and most often affects older people.

Superficial spreading melanoma, lentigo maligna melanoma, and acral lentiginous melanoma begin as

in situ malignancies, which means they only affect the top layers of skin. Eventually, these forms of melanomas may become invasive and spread to other areas of the body. Nodular melanoma is often invasive by the time it is diagnosed, however.

Invasive melanomas are more severe and more difficult to treat.

Demographics

In the United States, one in 85 people are expected to develop melanoma during their lifetime. According to American Cancer Society (ACS) estimates, 68,480 cases of melanoma were expected to be newly diagnosed in the United States in 2008.

Malignant melanoma occurs in people of all ages and ethnicities. However, certain factors put people at greater risk for developing this disease, including the following:

  • having fair skin
  • having red or blond hair
  • having blue or green eyes
  • being older than 20 years
  • having excessive sun exposure, exposure to artificial ultraviolet light (such as in tanning beds), or a history of sunburns
  • having a close relative with melanoma
  • having lots of moles
  • having moles that are unusual or irregular-looking

Because the development of melanoma is usually related to sun exposure, people with less melanin and lighter skin, hair, and eyes are at greater risk. The disease is 10 times more common in whites than in African Americans.

Rates of melanoma increase with age and are highest in those in their 80s, according to the ACS.

Having certain procedures or health conditions that weaken the immune system may also predispose a person to developing melanoma. Compared to people in the general population, those who have undergone organ transplants have a threefold risk of melanoma. Having human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS ), other forms of cancer, or autoimmune diseases that require immunosuppressive treatments can also increase a person's risk of developing malignant melanoma.

Causes and symptoms

As of 2008 physicians did not know exactly why melanoma develops in some people but not others. What they do know is that excessive exposure to the sun, especially as a child or young adult (such as having an outdoor summer job for several years), and having severe, blistering sunburns increase the likelihood that a person will develop melanoma.

The development of melanoma is also thought to have a strong genetic link, since many people who develop melanoma also have family members with the disease. In fact, researchers discovered a gene called BRAF that may play a role in the development of melanoma. A mutated form of BRAF, found in two-thirds of melanoma samples analyzed in one study, is thought to switch on the malignant cells, allowing them to grow and divide. Another gene mutation, called p53, has also been associated with melanoma cases among families.

The first sign of melanoma is a mole, sore, lump, or growth found on the skin. Melanoma can occur anywhere on the body, but it is most often found on the backs of men and the legs of women. Generally, melanomas are black or brown, but may be red, skin-colored, or white.

Changes in a mole's appearance over time may also indicate malignant melanoma. Sometimes, a growth or mole may bleed, ooze, or itch, which indicates malignancy. Having satellite moles, new moles that grow near an existing mole, may also point to this form of skin cancer .

People with moles, lumps, or growths that fit these criteria should be checked by a doctor.

Diagnosis

For older adults who find an abnormal mark or mole on the skin, the first step should be to contact their healthcare providers for a skin examination. The doctor or nurse will carefully examine all moles, birthmarks, and pigmented areas over the person's entire body, including the back, legs, hands, feet, and scalp.

Doctors often use the “ABCDEs” when making a diagnosis of melanoma. They include:

  • Asymmetry: Melanomas are usually asymmetrical, with one half different than the other.
  • Border irregularity: The edges of a melanoma may be ragged or blurred.
  • Color: A malignant melanoma often has several colors or shades, whereas benign moles are typically one color.
  • Diameter: Cancerous moles are usually larger than a pencil eraser (about 6 millimeters).
  • Evolving: An area of skin that has recently undergone changes.

If the healthcare provider finds a spot that has one or more of these criteria, he or she will remove cells from the abnormal area so they can be examined by a pathologist, a procedure called a biopsy. The doctor may remove as much as possible of the suspicious area so that the pathologist can check the entire sample for cancer cells.

After a person has been diagnosed with melanoma, doctors may use additional tests and procedures to determine the stage of the cancer, a process referred to as staging. Staging helps identify whether and to what extent cancer has spread throughout the body and helps guide the type of treatment the patient will receive. In the earlier melanoma stages (Stage I and Stage II), the tumor is smaller and remains in the top layers of the skin. In later melanoma stages (Stages III and IV), the melanoma is thicker and has spread to other parts of the body.

Chest x rays, computed tomography (CT or CAT) scans, magnetic resonance imaging (MRI) scans, and positron emission tomography (PET) scans are tests that doctors use to determine the spread of melanoma throughout the patient's organs and tissues. In addition, surgeons may remove additional tissue from around the melanoma (a procedure called wide local incision) so it can be checked by a pathologist for additional cancer cells. The lymph nodes may also be biopsied to determine if the cancer has spread to these tissues.

Treatment

Most thin melanomas in the early stages are treated by removing the cancerous cells and a portion of surrounding skin tissue. If a biopsy shows that cancer has spread to the lymph nodes, then they may need to be removed as part of treatment. Sometimes people undergoing surgical treatment for melanoma may also need skin grafts to cover the surgical wound.

In addition to surgery, doctors may recommend treating the melanoma with radiation therapy, chemotherapy, or immunotherapy.

In radiation therapy, ionizing radiation is aimed directly at the tumor, thereby killing cancerous cells.

In chemotherapy treatment, a patient takes potent drugs designed to kill cancer cells or stop them from dividing. Melanoma patients may also undergo a particular type of chemotherapy treatment called hyperthermic isolated limb perfusion. In this procedure, a tourniquet is used to stop blood flow to the arm or leg that has the melanoma. Chemotherapy drugs are then injected into the bloodstream, allowing the medication to stay primarily in the area where the cancer is.

Immunotherapy involves taking medications that stimulate the immune system, causing the body to destroy the melanoma cells or slow the progression of the disease throughout the body. A specific type of immunotherapy called biologic therapy involves administering interferon-alpha to melanoma cancer patients. This drug, a chemical that is already produced by the body in smaller amounts, has potent side effects but can kill tumor-producing cancer cells.

Nutrition/Dietetic concerns

Some research suggests that eating a diet rich in antioxidants , folic acid , fats, and proteins and whole, unprocessed foods may aid in the prevention of skin cancer such as melanoma. Specific plant flavonoids have also been studied for their skin-protective properties, including apigenin (found in vegetables, fruits, tea, and wine), curcumin (found in the spice turmeric), resveratrol (found in grape skins, red wine, and peanuts), and quercetin (found in apples and onions).

Prognosis

Melanoma is less common than other forms of skin cancer, but it is the most deadly type of this disease. In 2008, the American Cancer Society estimated that 8,420 people might die because of melanoma in 2008. However, the majority of people with melanoma are diagnosed in the early stages. Early detection of melanoma is linked to higher rates of survival.

Whether the melanoma has spread to the body's organs and the thickness of the lesion at the time of diagnosis have significant impact on the prognosis. The thicker the melanoma and the greater the spread, the worse the prognosis.

Other factors may also influence survival rates. For example, although melanoma among African Americans is rare, it is more lethal. Melanomas also tend to be thinner in females, so women have more favorable survival rates.

QUESTIONS TO ASK YOUR DOCTOR

How does my sun/ultraviolet light exposure history affect my risk of melanoma?

  • How often do I need skin examinations for melanoma?
  • Do I have any moles or lesions that I should watch carefully?
  • How far has my melanoma spread beneath the skin?
  • What is my prognosis, based on the stage of melanoma I have?
  • Are there risks and side effects associated with cancer treatment?
  • How should I care for my skin after melanoma treatment?
  • What steps should I take to avoid sun exposure now that I have been treated for melanoma?

In addition, older adults generally have shorter survivals after melanoma diagnosis.

Prevention

To prevent melanoma from developing, avoiding or reducing the amount of sun and ultraviolet light exposure is critical.

Older adults should always apply a sunscreen with a sun protection factor (SPF) of 15 or higher every day during all seasons. In addition, wearing protective clothing and accessories, such as hats, sunglasses, and long sleeves, can reduce the amount of sun exposure to the skin.

The sun's rays are strongest between 10 a.m. and 2 p.m., so if possible, seniors should complete outdoor activities before or after these hours, especially during the summer. People should avoid lying in the sun or using tanning beds in order to further reduce sun exposure.

To identify melanoma in its earlier stages when it is easier to treat, the American Cancer Society recommends that all people older than 40 get professional skin examinations every year. In addition, older adults or their caregivers should examine the skin monthly to check for suspicious growths or moles and contact their healthcare providers if they have concerns.

KEY TERMS

Biopsy —Removal of cells or tissues so a pathologist can examine them for abnormalities or cancer cells.

Flavonoid —A plant-derived chemical compound thought to have antioxidant properties.

In situ —In place, not having invaded other sites.

Malignant —A tumor that is cancerous and may spread to nearby tissue and other parts of the body.

Mole —A benign group of pigmented cells on the surface of the skin. A mole is usually dark and is sometimes raised.

Ulceration —A break in the skin that occurs when cells die.

Caregiver concerns

Caregivers of those with malignant melanoma may find themselves helping to feed, dress, and bathe the patient during and after cancer treatment. They may need to help change bandages, drive the person to doctor appointments, or manage insurance or financial issues if the person is incapacitated by cancer treatments.

To get support, caregivers can talk to a nurse or social worker about recommendations for a local cancer support group. Involvement in support groups gives caregivers the chance to learn what to expect, share stories, and find support while they care for loved ones with cancer.

Resources

BOOKS

Eldridge, Lynne, and David Borgeson. Avoiding Cancer One Day at a Time: Practical Advice for Preventing Cancer. Edina, MN: Beaver's Pond Press, 2006.

Nouri, Keyvan. Skin Cancer. Columbus, OH: McGraw Hill, 2007.

ORGANIZATIONS

American Academy of Dermatology, PO Box 4014, Schaumburg, IL, 60168-4014, (847) 330-0230, (888) 462-DERM (426-3376), (847) 330-0050, www.aad.org.

American Cancer Society, 250 Williams Street NW, Atlanta, GA, 30303, (800) ACS-2345 (227-2345), www.cancer.org.

National Cancer Institute, 6116 Executive Blvd., Room 3036A, Bethesda, MD, 20892-8322, (800) 422-6237, [email protected], www.cancer.gov.

Skin Cancer Foundation, 149 Madison Ave., Suite 901, New York, NY, 10016, (212) 725-5176, 212-725-5751, [email protected], www.skincancer.org.

Amy Sutton

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Malignant Melanoma

Malignant melanoma

Definition

Malignant melanoma is a type of skin tumor that is characterized by the cancerous growth of melanocytes, which are cells that produce a dark pigment called melanin.

Description

Overview

Cancer of the skin is the most common type of cancer and continues to grow in incidence. Skin cancer starts in the top layer of skin (the epidermis) but can grow down into the lower layers, the dermis and the subcutaneous layer. There are three main types of cells located in the epidermis, each of which can become cancerous. Melanocytes are the pigmented cells that are scattered throughout the skin, providing protection from ultraviolet (UV) light. Basal cells rest near the bottom of the epidermis and the layer of cells that continually grow to replace skin. The third type of epidermal cell is the squamous cells which make up most of the cells in human skin.

Melanoma

Malignant melanoma is the most serious type of skin cancer. It develops from melanocytes. Although melanoma is the least common skin cancer, it is the most aggressive. It spreads (metastasizes) to other parts of the body—especially the lungs and liver—as well as invading surrounding tissues. Melanomas in their early stages resemble moles. In Caucasians, melanomas appear most often on the trunk, head, and neck in men and on the arms and legs in women. Melanomas in African Americans, however, occur primarily on the palms of the hand, soles of the feet, and under the nails. Melanomas appear only rarely in the eyes, mouth, vagina, or digestive tract. Although melanomas are associated with exposure to the sun, the greatest risk factor for developing melanoma may be genetic. People who have a first-degree relative (parent, sibling or child) with melanoma have an increased risk up to eight times greater of developing the disease.

Basal cell cancer

Basal cell cancer is the most common type of skin cancer, accounting for about 75% of all skin cancers. It occurs primarily on the parts of the skin exposed to the sun and is most common in people living in equatorial regions or areas of high ozone depletion. Light-skinned people are more at risk of developing basal cell cancer than dark-skinned people. This form of skin cancer is primarily a disease of adults; it appears most often after age 30, peaking around age 70. Basal cell cancer grows very slowly. If it is not treated, however, it can invade deeper skin layers and cause disfigurement. This type of cancer can appear as a shiny, translucent nodule on the skin or as a red, wrinkled and scaly area.

Squamous cell cancer

Squamous cell cancer is the second most frequent type of skin cancer. It arises from the outer keratinizing layer of skin, so named because it contains a tough protein called keratin. Squamous cell cancer grows faster than basal cell cancer; it is more likely to metastasize to the lymph nodes as well as to distant sites. Squamous cell cancer most often appears on the arms, head, and neck. Fair-skinned people of Celtic descent are at high risk for developing squamous cell cancer. This type of cancer is rarely life-threatening but can cause serious problems if it spreads and can also cause disfigurement. Squamous cell cancer usually appears as a scaly, slightly elevated area of damaged skin.

Other skin cancers

Besides the three major types of skin cancer, there are a few other relatively rare forms. The most serious of these is Kaposi's sarcoma (KS), which occurs primarily in persons who have AIDS or older males of Mediterranean descent. When KS occurs with AIDS it is usually more aggressive. Other types of skin tumors are usually nonmalignant and grow slowly. These include:

  • Bowen's disease. This is a type of skin inflammation (dermatitis) that sometimes looks like squamous cell cancer.
  • Actinic or solar keratosis. This is a sunlight-damaged area of skin that sometimes develops into cancer.
  • Keratoacanthoma. A keratoacanthoma is a domeshaped tumor that can grow quickly and appear like squamous cell cancer. Although it is usually benign, it should be removed.

Risk factors

SUN EXPOSURE. Most skin cancers are associated with the amount of time that a person spends in the sun and the number of sunburns received, especially if they occurred at an early age. Skin cancer typically does not appear for 10-20 years after the sun damage has occurred. Because of this time lag, skin cancer rarely occurs before puberty and occurs more frequently with age.

MOLES. The number of moles (nevi) on a person's skin is related to the likelihood of developing melanoma. There are three types of nevi: not cancerous (benign); atypical (dysplastic); or birthmark (congenital). All three types of nevi have been associated with a higher risk of developing melanoma. Sometimes the moles themselves can become cancerous. Usually, however, the cancer is a new growth that occurs on normal skin.

HEREDITY. The tendency to develop skin cancer also tends to run in families. As has already been mentioned, there appears to be a significant genetic factor in the development of melanoma.

Causes and symptoms

Skin cancer begins to develop when a change or mutation occurs in one of the cells of the skin, causing it to grow without control. This mutation can be caused by ultraviolet (UV) light; most skin cancers are thought to be caused by overexposure to UV light from the sun. The incidence of severe, blistering sunburns is particularly closely related to skin cancer, more so when these burns occur during childhood. Exposure to ionizing radiation, arsenic, or polycyclic hydrocarbons in the workplace also

appears to stimulate the development of skin cancers. The use of psoralen for treatment of psoriasis may be associated with the development of squamous cell cancer. Skin cancers are also more common in immunocompromised persons, such individuals with AIDS or those who have undergone organ transplants.

The first sign of skin cancer is usually a change in an existing mole, the presence of a new mole, or a change in a specific area of skin. Any change in a mole or skin lesion, including changes in color, size, or shape, tenderness, scaliness, or itching should be suspected of being skin cancer. Areas that bleed or are ulcerated may be signs of more advanced skin cancer. By doing a monthly self-examination, a person can identify abnormal moles or areas of skin and seek evaluation from a qualified health professional. The ABCD rule provides an easy way to remember the important characteristics of moles when one is examining the skin:

  • Asymmetry. A normal mole is round, whereas a suspicious mole is unevenly shaped.
  • Border. A normal mole has a clear-cut border with the surrounding skin, whereas the edges of a suspect mole are often irregular.
  • Color. Normal moles are uniformly tan or brown, but cancerous moles may appear as mixtures of red, white, blue, brown, purple, or black.
  • Diameter. Normal moles are usually less than 0.20 in (5 mm) in diameter. A skin lesion greater than 0.25 in (0.6 cm) across may be suspected as cancerous.

There are two systems used in staging melanomas. The first is Clark's, which bases staging on the level of invasion, or which tissues the tumor has penetrated (i.e. which skin layer). The other is the American Joint Committee on Cancer. The second system is sometimes called the TNM system, which stands for tumor-nodesmetastasis, after the three major phases in cancer progression. Most experts generally agree that the thickness of the tumor is more accurate than the level of invasion for predicting prognosis (the outcome of the disease and estimated chance of recovery) and choosing an appropriate treatment.

Diagnosis

A person who has a suspicious-looking mole or area of skin should consult a doctor. In many cases, the person's primary care physician will make a referral to a doctor who specializes in skin diseases (a dermatologist). The dermatologist will carefully examine the lesion for the characteristic features of skin cancer. If further testing seems necessary, the dermatologist will perform a skin biopsy by removing the lesion under local anesthesia . Because melanomas tend to grow in diameter, as well as downwards into the epidermis and fatty layers of skin, a biopsy sample that is larger than the mole will be taken. This tissue is then analyzed under a microscope by a specialist in diseased organs and tissues (a pathologist). The pathologist makes the diagnosis of cancer and determines how far the tumor has grown into the skin. The evaluation of the progression of the cancer is called staging. Staging refers to how advanced the cancer is and is determined by the thickness and size of the tumor. Additional tests will also be done to determine if the cancer has moved into the lymph nodes or other areas of the body. These tests might include chest x ray , computed tomography scan (CT scan), magnetic resonance imaging (MRI), and blood tests.

Treatment

Surgery

The primary treatment for skin cancer is to cut out (excise) the tumor or diseased area of skin. Surgery usually involves a simple excision using a scalpel to remove the lesion and a small amount of normal surrounding tissue. A procedure known as microscopically controlled excision can be used to examine each layer of skin as it is removed to ensure that the proper amount is taken. Depending on the amount of skin removed, the cut is either closed with stitches or covered with a skin graft. When surgical excision is performed on visible areas, such as the face, cosmetic surgery may also be performed to minimize the scar. Other techniques for removing skin tumors include burning, freezing with dry ice (cryosurgery), or laser surgery . For skin cancer that is localized and has not spread to other areas of the body, excision may be the only treatment needed.

Nonsurgical approaches

Although chemotherapy is the normal course of therapy for most other types of advanced cancer, it is not usually effective and not usually used for advanced skin cancer. For advanced melanoma that has moved beyond the original tumor site, the local lymph nodes may be surgically removed. Immunotherapy in the form of interferon or interleukin is being used more often with success for advanced melanoma. There is growing evidence that radiation therapy may be useful for advanced melanoma. Other treatments under investigation for melanoma include gene therapy and vaccination . Recent studies have shown that the use of a vaccine prepared from a person's own cancer cells may be useful in treating advanced melanoma. For people previously diagnosed with skin cancers, the chances of getting additional skin cancers are high. Therefore, regular monthly self-examination, as well as frequent examinations by a dermatologist, are essential.

Alternative treatment

There are no established alternative treatments for skin cancer. Immunotherapy, which strengthens the immune system , is an approach that may prove valuable in the future. Preventive measures that can be helpful include minimizing exposure to the sun and sunburn, eating a diet high in antioxidants and supplementation with antioxidant nutrients.

Prognosis

The prognosis for skin cancer depends on several factors, the most important of which are the invasiveness of the tumor and its location. The prognosis is good for localized skin cancers that are diagnosed and treated early. For basal cell cancer and squamous cell cancer, the cure rate is close to 100%, although most people with these forms will have recurrent skin cancer. For localized melanoma, the cure rate is approximately 95%. The prognosis worsens with larger tumors. Melanoma that has spread to the lymph nodes has a 5-year survival rate of 54%; advanced melanoma has a survival rate of only 13%. When melanoma has spread to other parts of the body, it is generally considered incurable. The median length of survival is six months.

Health care team roles

A physician makes an initial diagnosis. A dermatologist and pathologist may confirm the diagnosis. A surgeon removes most lesions. A plastic and reconstructive surgeon may repair or minimize surgical scars. Nurses and nurse practitioners will participate in prevention education with patients.

Prevention

Prevention is the best way to approach skin cancer. Avoiding unnecessary sun exposure, from such sources as sun lamps and tanning salons, is relatively simple. Parents of small children should protect them against the risk of sunburn. Precautions include avoiding high sun, when the rays of the sun are most intense (between 11 a.m. and 1 p.m.). In addition, persons living at high elevations need to take extra precautions because the intensity of UV radiation increases by 4% with every 1,000-ft (305-m) rise above sea level. When outdoors protective clothing should be worn, covering exposed skin. Sunglasses with UV protective coating should also be worn.

There is presently some debate about the ability of sunscreen to protect against skin cancer. Some scientists believe that gradual exposure to the sun, in order to develop a mild tan, may offer the best protection from skin cancer. Skin cancer has also been related to diets that are high in fat. Decreasing the amount of fat consumed may also help to decrease the risk of skin cancer.


KEY TERMS


Biopsy —Removal of a small piece of tissue for examination. This is done under local anesthesia and removed by either using a scalpel or a punch, which removes a small cylindrical portion of tissue.

Cryosurgery —The use of extreme cold to destroy tissue in treating skin cancer.

Dermatologist —A doctor who specializes in skin diseases.

Epidermis —The outermost layer of skin.

Interferon —A group of proteins that have an effect on immune function and appear to have an anti-tumor effect in some persons.

Melanin —A dark pigment that is found in certain skin cells and helps to protect the skin from ultraviolet light.

Melanocyte —A specialized skin cell that produces melanin.

Metastasis —The movement of cancer cells from one area of the body to another through the blood or the lymph vessels.

Pathologist —A specialist in diseased organs and tissues.

Staging —The process of classifying and evaluating the progression of a cancer.

TNM staging —A staging system for classifying cancers developed by the American Joint Committee on Cancer. The initials stand for tumor, nodes, and metastasis.


Resources

BOOKS

Balch, Charles M. Cutaneous Melanoma, 3rd ed. St. Louis, Quality Medical Publishing, 1998.

Buchan, John and Roberts, Daffyd Lloyd. Pocket Guide to Malignant Melanoma. New York, Blackwell Science, 2000.

Darmstadt, Gary L. "Tumors of the skin." In Nelson Textbook of Pediatrics, 16th ed., edited by Richard E. Behrman et al. Philadelphia: W.B. Saunders, 2000, 2051-2053.

Parker, Frank. "Skin diseases of general importance." In Cecil Textbook of Medicine, 21st ed., edited by Goldman, Lee and Bennett, J. Claude. Philadelphia: W.B. Saunders, 2000, 2276-2298.

Poole, Catherine M. and Guerry, DuPont. New Haven, CT, Yale University Press, 1998.

Schofield, Jill R. and Robinson, William A. What You Really Need to Know About Moles and Melanoma. Baltimore: Johns Hopkins University Press, 2000.

Smithson, William A. "Cancer of the skin." In Nelson Textbook of Pediatrics, 16th ed., edited by Richard E. Behrman et al. Philadelphia: Saunders, 2000, 1566-1567.

Sober, Arthur J., Koh, Howard K., Tran, N-LT and Washington, Carl V. "Melanoma and other skin cancers." In Harrison's Principles of Internal Medicine, 14th ed., edited by Anthony S. Fauci, et al. New York: McGraw-Hill, 1998, 543-549.

PERIODICALS

Bedikian A.Y., Plager C., Stewart J.R., O'Brian C.A., Herdman S.K., Ross M., Papadopoulos N., Eton O., Ellerhorst J., Smith T. "Phase II evaluation of bryostatin1 in metastatic melanoma." Melanoma Research 11, no. 2(2001): 183-188.

Hillner B.E., Kirkwood J.M., Agarwala S.S. "Burden of illness associated with metastatic melanoma." Cancer 91, no. 9 (2001): 1814-1821.

Lucci A., Citro H.W., Wilson L. "Assessment of knowledge of melanoma risk factors, prevention, and detection principles in Texas teenagers." Journal of Surgical Research 97, no. 2 (2001): 179-183.

Naylor M.F. "Melanoma vaccines." Dermatology Online Journal 6, no. 1 (2000): 5-9.

Shore R.E. "Radiation-induced skin cancer in humans." Medical and Pediatric Oncology 36, no. 5 (2001): 549-554.

Taran J.M., Heenan P.J. "Clinical and histologic features of level 2 cutaneous malignant melanoma associated with metastasis." Cancer 91, no. 9 (2001): 1822-1825.

ORGANIZATIONS

American Academy of Dermatology, 930 N. Meacham Road, PO Box 4014, Schaumburg, IL 60168-4014. (847) 330-0230. Fax: (847) 330-0050. <http://www.aad.org>.

American Melanoma Foundation, 3914 Murphy Canyon Road, Suite A132, San Diego, CA 92123. (858) 277-4426. <http://www.melanomafoundation.org/homepage.html>. [email protected]

Melanoma Education Foundation, 7 Jones Road, Peabody, MA 01960. <http://www.skincheck.com/#Site%20Content>. [email protected]

Melanoma Research Foundation, 23704-5 El Toro Rd., #206, Lake Forest, CA 92630. Phone/Fax: (800) 673-1290. [email protected]

National Cancer Institute, Building 31, Room 10A31, 31 Center Drive, MSC 2580, Bethesda, MD 20892-2580.(800) 422-6237 or (301) 435-3848. http://www.nci.nih.gov/.

Skin Cancer Foundation, 245 5th Avenue Suite 1403, New York, NY 10016. (800) 754-6490. Fax: (212) 725-5751. <http://www.skincancer.org/melanoma/>, [email protected]

OTHER

American Academy of Dermatology. <http://www.aad.org/SkinCancerNews/WhatIsSkinCancer/ABCDMel.html>.

Melanoma Foundation of Australia. <http://www.med.usyd.edu.au/medicine/melanoma/>.

National Library of Medicine. <http://www.nlm.nih.gov/medlineplus/melanoma.html>.

National Melanoma Foundation. <http://www.nationalmelanoma.org/>.

University of California-Davis. <http://matrix.ucdavis.edu/tumors/new/tutorial-intro.html>.

University of Maryland. <http://umm.drkoop.com/conditions/ency/article/001442.htm>.

University of Pennsylvania. <http://cancer.med.upenn.edu/disease/melanoma/>.

L. Fleming Fallon, Jr., M.D., Dr.P.H.

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