Malignant melanoma is a type of cancer arising from the melanocyte cells of the skin. The melanocytes are cells in the skin that produce the pigment melanin. Malignant melanoma develops when the melanocytes no longer respond to normal control mechanisms of cellular growth and are capable of invasion locally or spread to other organs in the body (metastasis ), where again they invade and compromise the function of that organ.
Melanocytes, embryologically derived from the neural crest, 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 and also the color of moles. Malignant degeneration of the melanocyte gives rise to the tumor, melanoma, of which there are 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 sub-type 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.
The 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 occurs, 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 2001 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 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 risk of developing melanoma. 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-Caucasians—though sun exposure probably does not play a role—at a rate of 10% that of Caucasians.
Malignant melanoma may arise in the skin anywhere on the body. It is estimated that 50% to 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.
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 dysplasic (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 ABCD rule:
- Border irregularity
- Color variegation
- Diameter exceeding 6 mm (0.24 in.)
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
- crusting and bleeding
- sensory change
- diameter more 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 are diagnosed 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.
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.
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 doesn't 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 doesn't 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.
The treatment of malignant melanoma is primarily surgical. Newer, more effective protocols involving the medical oncologist are being developed for the patient with systemic disease. Radiation therapy has a limited role in the treatment of melanoma, primarily that of helping to ease the effects of metastasis to the brain or sometimes the skeleton.
Clinical staging, treatments, and prognosis
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.
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 mm to 1.5 mm penetration. Stage IIa is 1.5 mm to 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 or not the patient needs to 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 doesn't 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 lymph 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 exam 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 (also called interleukin-2), 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 interleukin is produced naturally in the body, its therapeutic form is developed via biotechnology in a laboratory setting. In some patients, this medication has helped shrink tumors. 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. 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.
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% to 47%, depending on the size and number of regional nodes involved. Stage IV malignant melanoma is almost always a fatal disease.
Alternative and complementary therapies
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 areas such as the brain or the bone.
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.
Clinical trials are studies of new modes of therapy in an effort to improve results of treatment. For those wishing to find a trial related to their particular situation, the National Cancer Institute lists those available at: <http://cancernet.nci.nih.gov/trialsrch.shtml>.
In an attempt to develop a new type of immunotherapy, melanoma-specific vaccines are being developed. Antigens specific to melanoma cells and other tumor-associated antigens are being used to stimulate the body's own natural immune system to attack and kill the cells of malignant melanoma. Though experimental, this type of therapy offers hope and clinical trials are underway.
Though it is difficult to prove that sunscreens statistically reduce the frequency of malignant melanoma at this time, most authorities recommend use as protection from ultraviolet light (considered a major factor in the development of melanoma.) Avoidance of severe sunburns is recommended.
Sub-ungal melanoma is a type of acral lentiginous melanoma that occurs in the nail beds. Any pigmented lesion in these areas needs evaluation. They are commonly mistaken for bruises or infection. The main concern is to know they exist so that proper evaluation is performed as early as possible.
Malignant melanoma may also involve the eye, as melanin-producing cells exist there also. Again, familiarity with these spots is important so that pigmented growths are not ignored but evaluated early.
Rarely, a patient presents with regional lymph node involvement, but the primary site of the tumor cannot be identified. The primary may not be producing pigment and is known as an amelanonic melanoma. Because these patients present with stage III disease, they do less well as a group overall.
Abeloff, Armitage, Lichter, and Niederhuber. Clinical Oncolo gy Library, 2nd ed. London: Churchill Livingstone, 1999.
Schwartz, Shires, Daly, et al, ed. Principles of Surgery New York: McGraw Hill, 1999.
Agarwala, Sanjiv S., and John M. Kirkwood. "Adjuvant Thera py of Melanoma." Seminars in Surgical Oncology 14, no. 4 (June 1998): 302-10.
Averbrook, Bruce J., Leo J. Russo, and Edward G. Mansour. "A Long-Term Analysis of 620 Patients with Malignant Melanoma at a Major Referral Center." Surgery 124 (October 1998): 739
Cascinelli, Natale. "Margin of Resection in the Management of Primary Melanoma." Seminars in Surgical Oncology 14, no. 4 (June 1998): 272-75.
Karakousis, Constantine P. "Therapeutic Node Dissections in Malignant Melanoma." Seminars in Surgical Oncology 5, no. 6 (Sept. 1998): 473-82.
Gilchrest, B.A., et al. "The Pathogenesis of Melanoma Induced by Ultraviolet Radiation." New England Journal of Medi cine 340 (29 April, 1999): 17.
Grin, Caron M., and Marti Rothe. "Pigmented Lesions: Inno cent or Deadly?" Consultant 40 (February 2000): 304.
Joseph, Emmanuella, et. al. "Results of Complete Lymph Node Dissection in 83 Melanoma Patients with Positive Sentinel Nodes." Annals of Surgical Oncology 5, no. 2 (Mar. 1998): 119-25.
Langley, Richard G.B., and Arthur J. Sober. "Clinical Recogni tion of Melanoma and its Precursors." Hematology/Oncol ogy Clinics of North America 12, no. 4 (August 1998).
Nathan, Faith E., and Michael J. Mastrangelo. "Systemic Ther apy in Melanoma." Seminars in Surgical Oncology 14, no. 4 (June 1998): 319-27.
Weinstock, Martin A. "Early Detection of Melanoma." JAMA, The Journal of the American Medical Association 284 (16 August 2000): 886.
National Cancer Institute. 13 June 2001 <http://rex.nci.nih.gov/PATIENTS/INFO_PEOPL_DOC.html>.
Cancer Resource Center American Cancer Society. 20 June 2001 <http://www3.cancer.org/cancerinfo>.
Melanoma Patient's Information Page 20 June 2001 <http://www.mpip.org>.
Richard A. McCartney, MD
QUESTIONS TO ASK THE DOCTOR
- What stage of cancer do I have?
- Has the cancer spread? What tests will be used to determine this?
- What are my treatment options?
- Is adjuvant therapy really necessary in my case?
- What are the risks and side effects of these treatments?
- What medications can I take to relieve treatment side effects?
- Are there any clinical studies underway that would be appropriate for me?
- What effective alternative or complementary treatments are available for this type of cancer?
- How debilitating is the treatment? Will I be able to continue working?
- How will the treatment affect my sexuality?
- Are there any local support groups for melanoma patients?
- What is the chance that the cancer will recur?
- Is there anything I can do to prevent recurrence?
- How often will I have follow-up examinations?
—Therapy administered to patients who are at risk of having microscopic untreated disease present but have no manifestations
—The deeper portion or layer of the skin
Dysplastic nevus syndrome
—A familial syndrome characterized by the presence of multiple atypical appearing moles, often at a young age
—The superficial layer of the skin
—Composed of DNA, the genome is the genetic makeup of the cell
—Therapy using biologic agents that either enhance or stimulate normal immune function
Lymph node dissection
—Surgical removal of an anatomic group of lymph nodes
—Swelling of an extremity following surgical removal of the lymph nodes draining that extremity
—Cells derived from the neural crest that are in the skin and produce the protein pigment melanin
—A tumor growth or deposit that has spread via lymph or blood to an area of the body remote from the primary tumor
—The act of removing something surgically
—Structures related to the integument such as hair follicles and sweat glands
—Used to refer to a patient who has distant metastasis
Melanoma is a cancer that forms in the pigment cells (melanocytes) of the skin. There were approximately forty-seven thousand new cases in the United States in the year 2000, nearly eight thousand of which were fatal, mostly due to metastases. Reports of melanoma cases doubled in frequency during the last decade of the twentieth century. Solar exposure and genetic factors are responsible for the majority of cases.
Reduction in exposure to ultraviolet light, especially early in life, and regular screening of those at increased risk are the best approaches to reducing mortality from melanomas. The overall five-year survival rate is 85 percent, and surgical excision of early tumors is usually curative. More effective treatment for advanced malignant melanoma is needed, however.
Arthur J. Sober
(see also: Cancer; Skin Cancer; Ultraviolet Radiation )
Balch, C. M.; Houghton, A.; Sober, A. J.; and Soong, S. J., eds. (1998). Cutaneous Melanoma, 3rd edition. St. Louis, MO: Quality Medical Publishing.
mel·a·no·ma / ˌmeləˈnōmə/ • n. (pl. -no·mas or -no·ma·ta / -ˈnōmətə/ ) Med. a tumor of melanin-forming cells, typically a malignant tumor associated with skin cancer: melanomas can appear anywhere on the body | the incidence of melanoma is rising steadily.