MELANOMA OVERVIEW

Melanoma is a serious form of skin cancer that starts in the pigment-producing skin cells (melanocytes). Melanoma is the sixth most common cancer in the United States, and the number of melanoma cases diagnosed annually is increasing faster than for any other cancer. Although the explanation for this is unknown, it may be related to increased recreational sun exposure and global changes such as ozone depletion.

In contrast to other types of skin cancers (eg, squamous cell or basal cell cancers) that usually develop on sun-exposed areas of the body, melanomas can develop anywhere on the skin surface, as well as on the mucous membranes lining the mouth, nose, and genital areas. If left untreated, melanoma can spread (metastasize) to other parts of the body much more frequently than is typical for other types of skin cancers. Fortunately, when detected at an early stage, melanoma treatment is often effective in limiting the spread of the disease.

This topic reviews the diagnosis and treatment of localized melanoma. A separate topic discusses the treatment of advanced and metastatic melanoma. (See "Patient information: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)".)

MELANOMA DIAGNOSIS

Appearance of lesion — Similar to other types of skin cancer, melanoma is diagnosed based upon the appearance of a skin lesion. Melanomas can occur anywhere on the skin surface, but it frequently develops on the back and other areas that may be easy to miss with self-inspection. Abnormal findings can be described with an acronym, ABCDE (picture 1).

• A — Asymmetry (one side is different from opposite side) (picture 2)
• B — Border irregularities (jagged, uneven edge) (picture 3)
• C — Color variegation (ie, different colors within the same region) (picture 4)
• D — Diameter greater than 6 mm (if larger than a pencil eraser, evaluation recommended)
• E — Evolution (change) in color, shape, or symptoms over time (picture 5)

Other abnormal features include inflammation (swelling) and bleeding or crusting. The melanoma lesion frequently is described by patients as looking like a “blood blister” or a “tick bite”. A person who notices any of these changes should make an appointment with a healthcare provider as soon as possible. Referral to a dermatologist (physician who specializes in skin conditions) may be recommended.

Biopsy — To determine if the abnormality is a melanoma, a small piece of the area (or if it is small, the entire area) is removed and examined under a microscope to determine if precancerous or cancerous cells are present.

MELANOMA CLINICAL STAGING

After melanoma is diagnosed, the next step is to determine the clinical stage or extent of disease spread. Accurate staging is important to determine the most appropriate treatment.

The American Joint Committee on Cancer has defined a staging system for melanoma that takes into consideration the following characteristics:

• The thickness of the tumor
• Ulceration (loss of skin) over the surface of the melanoma
• Involvement of the draining lymphatics and/or "regional" lymph nodes
• Evidence of tumor spread beyond the lymph nodes (distant metastases)

A thorough physical examination, chest X-ray, and blood tests are typically performed to evaluate the possibility of lymph node or distant spread of the tumor.

Additional radiologic examinations (such as a CT scan) may also be recommended, particularly for patients with advanced melanoma, those with a previous melanoma, and those with signs or symptoms of metastasis. These scan are usually performed after the lymph nodes are evaluated and shown to be involved (see 'Evaluating the lymph nodes' below).

Surgery — In most patients, surgery is required to remove (or excise) the entire melanoma. Generally, one to two centimeters of normal skin surrounding the lesion must also be removed. This procedure is termed a wide local excision. This decreases the chance that the melanoma will recur at the same site.

The type of physician (eg, dermatologist or general surgeon) who will perform the surgery depends upon the location and size of the wide local excision. Most procedures are performed as a day surgery in a hospital or surgical center. Most patients are able to go home later the same day.

Occasionally, skin grafting may be necessary to promote healing and replace skin that has been removed. In some patients (such as those with a melanoma on the face or neck), it may be difficult to remove a sufficient amount of normal skin to ensure adequate margins. In this case, radiation therapy may be recommended after surgery.

If an enlarged lymph node (gland) is present, it may be biopsied at the time of the wide local excision. Even if enlarged lymph nodes cannot be detected, the lymph nodes may be evaluated during or after the surgical removal of the melanoma.

Evaluating the lymph nodes — The most common site of melanoma spread is the surrounding lymph nodes. Sometimes, lymph node involvement is obvious because an enlarged lymph node can be felt. In this case, removal of all the lymph nodes in that area (called a therapeutic node dissection) is the standard approach. Therapeutic node dissection provides an opportunity for cure the melanoma, particularly when used in conjunction with adjuvant systemic (body-wide) therapy (see 'Melanoma adjuvant therapy' below).

In the majority of cases, enlarged lymph nodes are not visible, and the only way to determine if lymph nodes are affected is to take a sample of the lymph node during surgery. This is typically accomplished with a surgical technique known as sentinel lymph node (SLN) biopsy.

Sentinel lymph node biopsy — The sentinel lymph node (SLN) technique is based upon the theory that when tumor cells migrate, they spread to one or a few lymph nodes before involving other nodes. These nodes can be identified by injecting a blue dye or radioactive material around the primary tumor before the wide local excision, and then searching for the node that has absorbed the dye or the radioactive tracer at the time of surgery. This is known as lymphatic mapping.

Sentinel lymph node biopsy and lymphatic mapping are usually done at the time of the wide local excision. Most procedures are performed in a hospital after the patient is given general anesthesia to induce sleep and prevent pain. The patient may go home later the same day or the following day.

The status of this first draining (sentinel) lymph node accurately predicts the status of the remaining regional lymph nodes. Because only one, or at most, a few lymph nodes, is removed, the risk of this procedure is lower and the accuracy is greater than a full lymph node dissection.  After the lymph node is removed, it is then examined under a microscope to determine if abnormal cells are present.

The success of SLN biopsy is dependent upon the skill of the surgeon and the other physicians involved with the procedure. If later tests reveal that the cancer has spread to the SLN, a second procedure, termed a completion node dissection, is performed to remove the remaining lymph nodes. If the SLN is negative for tumor involvement, further lymph node dissection is usually not performed since the likelihood of finding tumor involvement is 5 percent or less.

When is SLN biopsy recommended? — SLN biopsy has become the standard technique for assessing the regional lymph nodes and is recommended for staging of most people with newly diagnosed melanomas. However, people whose melanomas are less than 1 mm in thickness (thin melanomas) may not require SLN, since the likelihood of tumor spread to the regional lymph nodes is less than 10 percent.

MELANOMA PATHOLOGIC STAGING

Once the staging work-up is complete, a pathologic disease stage between I and IV is assigned. A higher stage indicates more extensive disease.

• Stage I or IIA disease — The tumor is less than 4 millimeters thick without ulceration, or less than 2 millimeters thick if ulceration is present. This is considered to be localized disease. Surgery alone is curative in 70 to 90 percent of cases.
• Stage IIB or IIC disease — The tumor is 2.1 to 4 millimeters thick with ulceration, or 4 or more millimeters thick with or without ulceration. This is considered to be localized disease. Patients are at a higher risk of recurrence, even after the tumor has been completely surgically removed. Adjuvant (additional) therapy is often recommended, especially for tumors that are 4 or more millimeters thick. (See 'Melanoma adjuvant therapy' below.)
• Stage III disease — There is evidence of melanoma spread in the lymphatic channels surrounding the tumor (called satellites) or nearby lymph nodes. The tumor may be any thickness. Adjuvant therapy is strongly recommended.
• Stage IV disease — The melanoma has metastasized to more distant locations in the body, which may or may not include the lymph nodes. The tumor may be any thickness. This is referred to as advanced disease. For a full discussion of treatment of advanced disease, (see "Patient information: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)").

Based upon the pathologic disease stage, the optimal treatment is chosen. For patients with localized disease who have no evidence of distant metastases, the goals of treatment are:

• Complete surgical removal of the primary melanoma
• Evaluation of regional lymph nodes for evidence of tumor involvement
• Preventing further spread or disease recurrence

In patients with involved sentinel lymph nodes following the staging the standard of care is to completely remove all the remaining regional lymph nodes with a completion lymphadenectomy. The benefit of this standard procedure has been questioned, especially for patients with thin primary melanomas and very few tumor cells in their sentinel lymph node biopsy. Consequently, there is an ongoing international trial comparing completion lymph node biopsy to regional ultrasound evaluation of the lymph node basin on a scheduled basis. The study is determining whether survival is better with completion lymph node dissection.

MELANOMA ADJUVANT THERAPY

The term adjuvant therapy refers to any additional anticancer treatment that is given after a cancer is surgically removed. The objective of adjuvant treatment is to stop or slow the growth of any remaining cancer cells that were not removed during surgery.

Immunotherapy — Interferon alpha (IFNa) is the agent most commonly used to treat patients with melanoma who are at high risk for recurrence. Research has shown that IFNa, a form of immunotherapy, can help to decrease the chance of melanoma recurrence and improve a person's chance of survival [1]. Immunotherapy may boost the patient's immune response so that it can more effectively fight the cancer.

Treatment with IFNa begins after surgery and may continue for up to 12 months. The best way of giving adjuvant IFNa is not clear. The following IFNa regimen is the standard for people with high-risk melanoma. It includes two parts, which are given for up to 12 months.

• High dose intravenous therapy is given five days per week for four weeks.
• A lower dose of IFNa is given by injection under the skin (subcutaneously) three times weekly for up to 11 additional months. This injection can be given by the patient or a family member.

Although other regimens and doses have been studied, none has been shown to be as effective as this regimen. Because adjuvant IFNa therapy helps only a minority of patients at risk for melanoma recurrence and is frequently associated with significant side effects, patients are encouraged, whenever possible, to enroll in clinical trials testing adjuvant strategies aimed at improving the outcomes of treatment with IFNa (see 'Clinical trials' below).

Benefits — In one trial [1], benefit from IFNa seemed to be limited to patients who had lymph node involvement (stage III disease). In this group of patients, there was an approximately twofold increase in the number of patients who were free of disease recurrence at five years (called recurrence free survival).

However, in subsequent trials, an improvement in recurrence-free survival (approximately 20 to 40 percent better) was also seen in people with a lower risk of disease recurrence (stage IIB) as well [2].

We recommend adjuvant IFNa therapy for people at high risk of relapse (stage IIB, IIC, and III) who have no serious underlying medical problems and who have a life expectancy of 10 years of more.

Side effects — IFNa can have potentially toxic side effects, although the type and severity of side effects varies from one person to another. Because people have differing tolerances for side effects and differing ideas about the importance of quality versus quantity of life, the decision to undergo treatment with adjuvant IFNa is an individual one, especially for people who have node-negative but otherwise high-risk melanoma.

Side effects may include flu-like symptoms (low grade fever, muscle and joint aches, chills, fatigue), depression, a drop in the number of white blood cells, and temporary liver enzyme abnormalities. The majority of these effects can be managed with supportive care and/or a temporarily reduced dose of IFNa. Most reactions are completely reversible when treatment is stopped.

Future directions — Research is ongoing to identify other therapies that are effective in treating melanoma. It is hoped that combining interferon with a melanoma vaccine, radiation therapy, or other agents will result in a treatment that is more or equally effective and less toxic. As noted above, everyone with melanoma is encouraged, when possible, to enroll in a clinical trial (see 'Clinical trials' below).

MELANOMA MONITORING

Clinician monitoring — Because melanoma can recur in the same location or in new sites, routine follow-up and monitoring are very important. Seeing a healthcare provider regularly is the most important aspect of follow-up since most recurrences are discovered when the patient is seen and examined at regular intervals after treatment.

Blood tests and a chest X-ray may be performed at periodic intervals to evaluate the possibility of distant spread of melanoma. Other imaging studies (eg, CT or PET scans) are usually recommended only if new symptoms develop.

Self-examination — In addition to visits with a healthcare provider, monthly self-examination is recommended to identify any new or changing skin lesions. If a new or changing lesion is detected, contact a healthcare provider to determine if further evaluation is needed.

• To perform self-examination, stand in an area that is brightly lit. Use a hand-held mirror to examine the face, including the nose, lips, mouth, and ears. Face away from a full-length mirror and hold up the hand-held mirror to see the back of the head, ears, and neck.
• Examine both sides of the hands and arms, including between the findings and under the fingernails. Use the full-length mirror to examine the undersides and back of the arms and armpits. Examine the neck, chest, and abdomen. Women should lift the breasts to examine underneath.
• Using both mirrors, examine the shoulders, upper back, and upper arms. Scan the lower back, buttocks (including between the buttocks), and backs of both legs.
• Sit down, and rest one foot on a chair. Examine the legs, including the ankles, top and bottom of the feet, between the toes, and under the toenails. Switch legs and repeat. Use a hand-held mirror to examine the genitals.

Prevention of future melanoma — People who have had melanoma are at increased risk of developing melanoma again. Ways to reduce exposure to UV radiation from sunlight are discussed separately. (See "Patient information: Sunburn prevention (Beyond the Basics)".)

CLINICAL TRIALS

Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

• http://www.cancer.gov/clinicaltrials/education/main/Page1
• www.cancer.gov/clinicaltrials
• http://clinicaltrials.gov/

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Melanoma skin cancer (The Basics)
Patient information: Sunburn (The Basics)
Patient information: Seborrheic keratosis (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)
Patient information: Sunburn prevention (Beyond the Basics)

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Adjuvant immunotherapy for melanoma
Approach to the patient with macular skin lesions
Cutaneous melanoma: Management of in transit metastases
Cutaneous melanoma: Management of local recurrence
Evaluation and treatment of regional lymph nodes in melanoma
Imaging studies in melanoma
Inherited susceptibility to melanoma
Initial surgical management of melanoma of the skin and unusual sites
Management of brain metastases in melanoma
Ocular melanoma
Pathologic characteristics of melanoma
Primary prevention of melanoma
Risk factors for the development of melanoma
Role of radiation therapy in the management of melanoma
Screening and early detection of melanoma
Staging work-up and surveillance after treatment of melanoma
Surgical management of metastatic melanoma
Molecularly targeted therapy for metastatic melanoma

The following organizations also provide reliable health information.

• National Cancer Institute

      1-800-4-CANCER
      (www.cancer.gov)

• American Society of Clinical Oncology

     (www.cancer.net/portal/site/patient)

• National Comprehensive Cancer Network

     (www.nccn.com)

• American Cancer Society

      1-800-ACS-2345
     (www.cancer.org)

• National Library of Medicine

     (www.nlm.nih.gov/medlineplus/healthtopics.html)

• The Melanoma Center, University of Pittsburgh Cancer Institute

      (www.melanomacenter.org)

• Skin Cancer Foundation

      (www.skincancer.org)

• Melanoma Research Foundation

     (www.melanoma.org)

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