Malignant melanoma

Melanocytes are found throughout the lower part of the epidermis. They produce melanin, the pigment that gives skin its natural color. When skin is exposed to the sun, melanocytes produce more pigment, causing the skin to tan, or darken.

The skin is the body's largest organ. It protects against heat, sunlight, injury, and infection. The skin has 2 main layers: the epidermis (upper or outer layer) and the dermis (lower or inner layer).

When melanoma starts in the skin, the disease is called cutaneous melanoma. This PDQ summary is about cutaneous (skin) melanoma. Melanoma may also occur in the eye and is called intraocular or ocular melanoma. (Refer to the PDQ summary on Intraocular (Eye) Melanoma Treatment for more information.)

Melanoma is a cancerous tumour of melanocytes. Melanocytes predominantly occur in the skin but can be found elsewhere, particularly the eye. The vast majority of melanomas originate in the skin.

Causes

Epidemiologic studies suggest that exposure to ultraviolet radiation is one of the major contributors to the development of melanoma. Other candidates are mutations in or total loss of tumor suppressor genes. Use of tanning booths has been linked to the development of skin cancers, including melanoma.

Important factors in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation (see skin types).

Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult.

Fair and red-headed people are at greater risk for developing melanoma. A person with multiple atypical nevi or dysplastic nevi are at a significant risk. Eventhough constant exposure to sun can cause melanoma, it is a larger risk factor for other less serious skin cancers, such as basal cell carcinoma and squamous cell carcinoma. Individuals with blistering or peeling sunburns (particularly in the first twenty years of life) have a significantly greater risk for melanoma.

A family history of melanoma greatly increases a person's risk. It is critical that individuals with family members who have been diagnosed with melanoma be checked regularly for skin cancer.

Prevention

Primary

To prevent or detect melanomas (and increase survival rates), it is recommended that the public:

• Learn what they look like (see "ABCDE" mnemonic below.)
• Are aware of moles and check for changes (shape, size, color, itching or bleeding)
• Show any suspicious moles to a doctor (preferably a dermatologist).
• Minimize exposure to sources of ultraviolet radiation (the sun and tanning booths.)
• Follow sun protection measures such as wearing sunscreen with an SPF rating of 15 or better, as well as wearing protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats.)

A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCDE":

• Asymmetrical skin lesion.
• Border of the lesion is irregular.
• Color: melanomas are often black or dark brown but can be multicolored; any change in color should prompt a visit to a dermatologist.
• Diameter: any mole that increases in size or any large mole should be evaluated by a dermatologist.
• Elevation:The elevation of a mole or lesion may be a hint for the lesion being cancerous.

If you have a personal or family history of skin cancer or of dysplastic nevus syndrome (multiple atypical moles) you should see a dermatologist at least once a year.

Diagnosis

The diagnosis of melanoma requires expert knowledge, as early stages may look identical to harmless moles or not have any color at all. Beyond this expert knowledge a biopsy performed under local anesthesia is often mandatory to assist in making or confirming the diagnosis and in defining the severity of the melanoma.

The preferred biopsy method is a punch biopsy, using a surgical punch (an instrument similar to a tiny cookie cutter with a handle, with an opening ranging in size from 1 to 6 mm). The punch is used to remove a plug of skin (down to the subcutaneous layer) from a portion of a large suspicious lesion, or to completely remove a smaller lesion. Alternatively, an excisional biopsy can be performed, where the suspect lesion is removed by cutting an ellipse of tissue around it. With either method, the surgical wound is closed with sutures to accelerate healing, to minimize bleeding and the risk of infection, and also for cosmetic purposes.

Both methods will include the epidermal, dermal, and subcutaneous layers of the skin in the biopsy specimen, enabling the pathologist to determine the depth of penetration of the melanoma by microscopic examination. This is described by Clark level (involvement of skin structures) and Breslow depth (measured in millimeters).

Lactate dehydrogenase (LDH) tests are often used to screen for metastases, eventhough a number of patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH often indicates metastatic spread of the disease to the liver. It is common for patients diagnosed with melanoma to have chest X-rays and an LDH test, and in some cases CT, MRI, PET and/or PET/Computerized axial tomography scans. Sentinel lymph node biopsies and examination of the lymph nodes are also performed in patients to assess spread to the lymph nodes.

Sometimes the skin lesion may bleed, itch, or ulcerate. A slow-healing lesion should be watched closely, as that may be a sign of melanoma. Be aware also that in circumstances that are still poorly understood, melanomas may "regress" or spontaneously become smaller or invisible - however the malignancy is still present. Amelanotic (colorless or flesh-colored) melanomas do not have pigment and may not even be visible. Lentigo maligna, a superficial melanoma confined to the topmost layers of the skin (found primarily in older patients) is often described as a "stain" on the skin. A number of patients with metastatic melanoma do not have a detectable primary tumor.

Types of Primary Melanoma

In the skin:

• Superficial spreading cancerous melanoma (SSMM)
• Nodular melanoma
• Acral lentiginous melanoma
• Lentigo maligna melanoma
• Amelanotic melanoma
• Minimal deviation melanoma
• Desmoplastic melanoma

Elsewhere:

• Melanoma of soft parts
• Mucosal melanoma
• Ocular melanoma

Prognostic factors

Features that affect prognosis are tumor thickness in millimeters (Breslow depth), depth related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion, presence of tumor infiltrating lymphocytes (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant metastasis.

Certain types of melanoma have worse prognoses. For example, minimal deviation melanomas have a much better prognosis than superficial spreading melanomas or even lentigo maligna melanomas. Interestingly, less invasive melanomas even with lymph node metastases carry a better prognosis than deep melanomas without regional metastasis at time of staging. Local recurrences tend to behave similar to a primary unless they are at the site of a wide local excision (as opposed to a staged excision or punch/shave excision) since these recurrences tend to indicate lymphatic invasion.

When melanomas have spread to the lymph nodes, one of the most important factors is the number of nodes with malignancy. Extent of malignancy within a node is also important; micrometastases in which malignancy is microscopic only have a more favorable prognosis than macrometastases. In some cases micrometastases may only be detected by special staining, and if malignancy is only detectable by a rarely-employed test known as PCR, the prognosis is good. Macrometastases in which malignancy is clinically apparent (in some cases cancer completely replaces a node) have a far worse prognosis, and if nodes are matted or if there is extracapsular extension, the prognosis is worse.

When there is distant metastasis, the cancer is generally considered incurable, since there is a near 0% recovery rate from these cancers. Treatment is palliative, focusing on life-extension and quality of life. In some cases, patients may live a number of months or even years with metastatic melanoma (depending on the aggressiveness of the therapy.) Distant skin metastases, while painful, generally have a better prognosis than any other distant metastasis. Lung metastases have a worse prognosis than distant skin metastasis. An even worse prognosis applies for patients with metastases to other tissues, most usually the brain, liver, kidney, and pancreas.

There is not enough definitive evidence to adequately stage, and thus give a prognosis for ocular melanoma and melanoma of soft parts, or mucosal melanoma (e.g. rectal melanoma), eventhough these tend to metastasize more easily. Even though regression may increase survival, when a melanoma has regressed, it is impossible to know its original size and thus the original tumor is often worse than a pathology report might indicate.

Staging

Further context on cancer staging is available at TNM.

Stage 0: Melanoma in Situ (Clark Level I), 100% Survival

Stage I/II: Invasive Melanoma, 85-95% Survival

• T1a: Less than 1.00 mm primary, w/o Ulceration, Clark Level II-III
• T1b: Less than 1.00 mm primary, w/Ulceration or Clark Level IV-V
• T2a: 1.00-2.00 mm primary, w/o Ulceration

Stage II: High Risk Melanoma, 40-85% Survival

• T2b: 1.00-2.00mm primary, w/ Ulceration
• T3a: 2.00-4.00 mm primary, w/o Ulceration
• T3b: 2.00-4.00 mm primary, w/ Ulceration
• T4a: 4.00mm or greater primary w/o Ulceration
• T4b: 4.00mm or greater primary w/ Ulceration

Stage III: Regional Metastasis, 25-60% Survival

• N1: Single Positive Lymph Node
• N2: 2-3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis
• N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases

Stage IV: Distant Metastasis, 9-15% Survival (10-Year Survival ~0%)

• M1a: Distant Skin Metastasis, Normal LDH
• M1b: Lung Metastasis, Normal LDH
• M1c: Other Distant Metastasis OR Any Distant Metastasis with Elevated LDH

Based Upon AJCC 5-Year Survival With Proper Treatment

Treatment

Diagnostic punch or excisional biopsies may appear to excise (and in some cases may indeed actually remove) the tumor, but further surgery is often necessary to reduce the risk of recurrence.

Complete surgical excision with adequate margins and assessment for the presence of detectable metastatic disease along with short and long term follow up is standard. Often this is done by a "wide local excision" (WLE) with 1.0 cm margins.

More recently, Mohs micrographic surgery is becoming increasingly popular for smaller melanomas, particularly of the face. In this surgery, performed by specially-trained dermatologists also qualified as dermatopathologists under local anesthesia, a small layer of tissue is excised and prepared as a frozen tissue section. This section can be prepared and examined by the dermatologist/dermatopathologist within one hour, and the patient will return for further stages of excision as needed, with each excised tissue layer being examined until clear margins are obtained. Eventhough the amount of stages mandatory can range from one to five or more, on average only two stages will be necessary to excise the tumor. If a tumor is found to be more invasive or widespread than previously thought, a WLE may on rare occasions be performed after Mohs surgery has begun. Eventhough the risk of recurrence is slightly higher, the procedure is much less invasive and patients undergoing Mohs surgery have a similar survival rate to patients undergoing WLE.

Some dermatologists have also successfully experimented with imiquimod (Aldara andreg;) topical cream. Application of this cream has been shown to decrease tumor size previous to surgery, reducing the invasiveness of the procedure. This therapy is used particularly for smaller melanoma in situ lesions located in cosmetically sensitive regions. Until this therapy is further understood, it is not recommended to use Aldara as the sole alternative to surgery. Eventhough difficult to determine (due to a lack of original biopsy reports for Aldara patients), initial findings indicate that Aldara may clear a tumor of malignancy before any biopsy or surgery is performed.

Melanomas with greater involvement may require referral to a medical or surgical oncologist. A "sentinel lymph node" biopsy is often performed, particularly for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. A process called "lymphoscintigraphy" is performed in which a mildly radioactive tracer is injected at the tumor site in order to localize the "sentinel node(s)". Surgery is performed to biopsy the node(s). Routine Handamp;E staining, and immunoperoxidase staining will be adequate to rule out node involvement. PCR (Polymerase Chain Reaction) tests on nodes, commonly performed to test for entry into clinical trials, now demonstrate that a number of patients with a negative SLN actually had a small amount of malignancy in their nodes. Alternatively, a fine-needle aspiration may be performed, and is often used to test masses. If a lymph node is positive, depending on the extent of lymph node spread, a radical lymph node dissection will often be performed, and most patients in otherwise good health will begin up to a year of high-dose interferon therapy, which despite side effects, greatly improves a patient's prognosis.

Metastatic melanomas can be detected by X-rays, Computerized axial tomography scans, MRIs, PET and PET/CTs, ultrasound, and LDH testing. Various chemotherapy agents are used, including dacarbazine (also termed DTIC), immunotherapy (with interleukin-2(IL-2) or interferon) as well as local perfusion are used by different centers. They can occasionally show dramatic success, but the overall success in metastatic melanoma is quite limited. IL-2 (Proleukinandreg;)is the first new treatment approved for the therapy of metastatic melanoma in 20 years. Studies have demonstrated that IL-2 offers the possibility of a complete and long-lasting remission in this disease.

Radiation treatment is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. In research setting other therapies, such as gene treatment, may be tested.

Treatment of cancerous melanoma is best performed from a multidisciplinary approach including dermatologists, medical oncologists, radiation oncologists, surgical oncologists, general surgeons, neurologists, neurosurgeons, otorynolaryngologists, radiologists, pathologists/dermatopathologists, research scientists, nurse practitioners and clinician assistants, and palliative care experts. Nurse practitioners (NPs) and clinician assistants (PAs) are qualified to evaluate and treat patients with their supervising physicians, so do not be surprised if you visit a dermatologist and see an NP or PA.