Melanoma

Melanoma is a malignant tumor of melanocytes which are found predominantly in skin but also in the bowel and the eye (see uveal melanoma). It is one of the rarer types of skin cancer but causes the majority of skin cancer related deaths.^[1][2] Despite many years of intensive laboratory and clinical research, the sole effective cure is surgical resection of the primary tumor before it achieves a thickness greater than 1 mm.

Around 160,000 new cases of melanoma are diagnosed worldwide each year, and it is more frequent in males and caucasians.^[3] It is more common in caucasian populations living in sunny climates than other groups.^[4] According to the WHO Report about 48,000 melanoma related deaths occur worldwide per annum.^[5]

The treatment includes surgical removal of the tumor; adjuvant treatment; chemo- and immunotherapy, or radiation therapy.

Melanomas also occur in horses, see equine melanoma, below.

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History

Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather scarce. However, one example lies in a 1960s examination of nine Peruvian Inca mummies, radiocarbon dated to be approximately 2400 years old, which showed apparent signs of melanoma: melanotic masses in the skin and diffuse metastases to the bones.^[6]

John Hunter is reported to be the first to operate on metastatic melanoma in 1787. Although not knowing precisely what it was, he described it as a "cancerous fungous excrescence". The excised tumor was preserved in the Hunterian Museum of the Royal College of Surgeons of England. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma.^[7]

The French physician René Laennec was the first to describe melanoma as a disease entity. His report was initially presented during a lecture for the Faculté de Médecine de Paris in 1804 and then published as a bulletin in 1806.^[8] The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820.^[9] In his later work in 1857 he remarked that there is a familial predisposition for development of melanoma (Eight Cases of Melanosis with Pathological and Therapeutical Remarks on That Disease).

The first formal acknowledgement of advanced melanoma as untreatable came from Samuel Cooper in 1840. He stated that the '... only chance for benefit depends upon the early removal of the disease ...'^[10] More than one and a half centuries later this situation remains largely unchanged.

In 1956, Australian professor Henry Oliver Lancaster discovered that melanomas were directly associated with latitude (ie, intensity of sunlight); and that exposure to the sun was a very high factor in the development of the cancer^{[citation needed]}.

Epidemiology and causes

Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental.^[11] "Intrinsic" factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure.

Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA^[12] and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in oncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor. Occasional extreme sun exposure (resulting in "sunburn") is causally related to melanoma.^[13] Those with more chronic long term exposure (outdoor workers) may develop protective mechanisms. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure) and is more common in indoor workers than outdoor workers (in a British study^[14]). Other factors are mutations in or total loss of tumor suppressor genes. Use of sunbeds (with deeply penetrating UVA rays) has been linked to the development of skin cancers, including melanoma.

Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Exposure during childhood is a more important risk factor than exposure in adulthood. This is seen in migration studies in Australia^[15] where people tend to retain the risk profile of their country of birth if they migrate to Australia as an adult. Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma.

Fair and red-headed people, persons with multiple atypical nevi or dysplastic nevi and persons born with giant congenital melanocytic nevi are at increased risk.^[16]

A family history of melanoma greatly increases a person's risk because mutations in CDKN2A, CDK4 and several other genes have been found in melanoma-prone families.^[17] Patients with a history of one melanoma are at increased risk of developing a second primary tumour.^[18]

The incidence of melanoma has increased in the recent years, but it is not clear to what extent changes in behavior, in the environment, or in early detection are involved.^[19]

Genetics

Familial melanoma is genetically heterogeneous,^[20] and loci for familial melanoma have been identified on the chromosome arms 1p, 9p and 12q. Multiple genetic events have been related to the pathogenesis of melanoma.^[21] The multiple tumor suppressor 1 (CDKN2A/MTS1) gene encodes p16INK4a - a low-molecular weight protein inhibitor of cyclin-dependent protein kinases (CDKs) - which has been localised to the p21 region of human chromosome 9.^[22]

Today, melanomas are diagnosed only after they become visible on the skin. In the future, however, physicians will hopefully be able detect melanomas based on a patient’s genotype, not just his or her phenotype. Recent genetic advances promise to help doctors to identify people with high-risk genotypes and to determine which of a person’s lesions have the greatest chance of becoming cancerous.

A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. One class of mutations affects the gene CDKN2A. An alternative reading frame mutation in this gene leads to the destabilization of p53, a transcription factor involved in apoptosis and in fifty percent of human cancers. Another mutation in the same gene results in a non-functional inhibitor of CDK4, a [cyclin-dependent kinase] that promotes cell division. Mutations that cause the skin condition Xeroderma Pigmentosum (XP) also seriously predispose one to melanoma. Scattered throughout the genome, these mutations reduce a cell’s ability to repair DNA. Both CDKN2A and XP mutations are highly penetrant.

Other mutations confer lower risk but are more prevalent in the population. People with mutations in the MC1R gene, for example, are two to four times more likely to develop melanoma than those with two wild-type copies of the gene. MC1R mutations are very common; in fact, all people with red hair have a mutated copy of the gene. Two-gene models of melanoma risk have already been created, and in the future, researchers hope to create genome-scale models that will allow them to predict a patient’s risk of developing melanoma based on his or her genotype.

In addition to identifying high-risk patients, researchers also want to identify high-risk lesions within a given patient. Many new technologies, such as optical coherence tomography (OCT), are being developed to accomplish this. OCT allows pathologists to view 3-D reconstructions of the skin and offers more resolution than past techniques could provide. In vivo confocal microscopy and fluorescently tagged antibodies are also proving to be valuable diagnostic tools.

Detection and prevention

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),^[23] following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. Using a sunscreen with an SPF rating of 30 or better on exposed areas has been recommended.^[24] However, there are severe doubts about the ability of current sunscreen to prevent melanoma.^[25]

  To prevent or detect melanomas (and increase survival rates), it is recommended to learn what they look like (see "ABCDE" mnemonic below), to be aware of moles and check for changes (shape, size, color, itching or bleeding) and to show any suspicious moles to a doctor with an interest and skills in skin malignancy.^[26]

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 usually have multiple colors.
• Diameter: moles greater than 5 mm are more likely to be melanomas than smaller moles.
• Evolution: The evolution (ie change) of a mole or lesion may be a hint that the lesion is becoming malignant --or-- Elevation: The mole is raised or elevated above the skin.

The E is sometimes omitted, as in the ABCD guideline.

People with a personal or family history of skin cancer or of dysplastic nevus syndrome (multiple atypical moles) should see a dermatologist at least once a year to be sure they are not developing melanoma.

Diagnosis

Moles that are irregular in color or shape are suspicious of a malignant or a premalignant melanoma. Following a visual examination and a dermatoscopic exam (an instrument that illuminates a mole, revealing its underlying pigment and vascular network structure), the doctor may biopsy the suspicious mole. If it is malignant, the mole and an area around it needs excision. This will require a referral to a surgeon or dermatologist.

The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles or not have any color at all. Where any doubt exists, the patient will be referred to a specialist dermatologist. Beyond this expert knowledge a biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining the severity of the melanoma.

Excisional biopsy is the management of choice; this is where the suspect lesion is totally removed with an adequate ellipse of surrounding skin and tissue.^[27] The biopsy will include the epidermal, dermal, and subcutaneous layers of the skin, enabling the histopathologist to determine the depth of penetration of the melanoma by microscopic examination. This is described by Clark's level (involvement of skin structures) and Breslow's depth (measured in millimeters).

If an excisional biopsy is not possible in certain larger pigmented lesions, a punch biopsy may be performed by a specialist hospital doctor, 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, for histopathological examination.

Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many 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/CT scans. Although controversial, 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, although this is a very late sign. 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. Some patients with metastatic melanoma do not have an obvious detectable primary tumor.

Types of primary melanoma

The most common types of Melanoma in the skin:

• superficial spreading melanoma (SSM)
• nodular melanoma
• acral lentiginous melanoma
• lentigo maligna (melanoma)

Any of the above types may produce melanin (and be dark in colour) or not (and be amelanotic - not dark). Similarly any subtype may show desmoplasia (dense fibrous reaction with neurotropism) which is a marker of aggressive behaviour and a tendency to local recurrence.

Elsewhere:

• clear cell sarcoma (Melanoma of Soft Parts)
• mucosal melanoma
• uveal melanoma

Prognostic factors

See also: Breslow's depth

  Features that affect prognosis are tumor thickness in millimeters (Breslow's 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.^[28]

Certain types of melanoma have worse prognoses but this is explained by their thickness. 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 similarly 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 only microscopic 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 polymerase chain reaction (PCR), the prognosis is better. 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 still worse.

When there is distant metastasis, the cancer is generally considered incurable. The five year survival rate is less than 10%.^[29] The median survival is 6 to 12 months. Treatment is palliative, focusing on life-extension and quality of life. In some cases, patients may live many months or even years with metastatic melanoma (depending on the aggressiveness of the treatment). Metastases to skin and lungs have a better prognosis. Metastases to brain, bone and liver are associated with a worse prognosis.

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), although 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.

Also of importance are the "Clark level" and "Breslow depth" which refer to the microscopic depth of tumor invasion.^[30]

Melanoma stages:^[29]

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

• 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

Surgery is the first choice therapy for localized cutaneous melanoma. Depending on the stage a sentinel lymph node biopsy is done as well. Treatment of advanced malignant melanoma is performed from a multidisciplinary approach.

Surgery

  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 to 2 cm margins. The wide excision aims to reduce the rate of tumour recurrence at the site of the original lesion. This is a common pattern of treatment failure in melanoma. Considerable research has aimed to elucidate appropriate margins for excision with a general trend toward less aggressive treatment during the last decades. There seems to be no advantage to taking in excess of 2 cm margins for even the thickest tumors.^[31]

Mohs micrographic surgery is not well accepted in the treatment of melanoma. In this surgery, performed by specially-trained dermatologists, 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.^[32] However, the usefulness of Moh's surgery in melanoma is limited because of the difficulty of identifying melanocytic atypia on a frozen section, which may lead to incomplete resection of the melanoma.^[32][33]

Other issues to consider with Moh's technique are risks of tumor implantation and possible false negative margins due to suboptimal melanocytic staining.^[34] Deviation from recommended 1-2 cm margins of excision should thus be approached carefully.

Melanomas which spread usually do so to the lymph nodes in the region of the tumour before spreading elsewhere. Attempts to improve survival by removing lymph nodes surgically (lymphadenectomy) were associated with many complications but unfortunately no overall survival benefit. Recently the technique of sentinel lymph node biopsy has been developed to reduce the complications of lymph node surgery while allowing assessment of the involvement of nodes with tumour.^{[citation needed]}

Although controversial and without prolonging survival, "sentinel lymph node" biopsy is often performed, especially for T1b/T2+ tumors, mucosal tumors, ocular melanoma and tumors of the limbs. A process called lymphoscintigraphy is performed in which a radioactive tracer is injected at the tumor site in order to localize the "sentinel node(s)". Further precision is provided using a blue tracer dye and surgery is performed to biopsy the node(s). Routine H&E staining, and immunoperoxidase staining will be adequate to rule out node involvement. PCR (Polymerase Chain Reaction) tests on nodes, usually performed to test for entry into clinical trials, now demonstrate that many patients with a negative SLN actually had a small number of positive cells 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. If the disease is completely resected the patient will be considered for adjuvant therapy.

Adjuvant treatment

High risk melanomas may require referral to a medical or surgical oncologist for adjuvant treatment. In the United States most patients in otherwise good health will begin up to a year of high-dose interferon treatment, which has severe side effects, but may improve the patients' prognosis.^[35] This claim is not supported by all research at this time and in Europe interferon is usually not used outside the scope of clinical trials.^[36][37]

Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.^[38]

Chemotherapy and immunotherapy

Various chemotherapy agents are used, including dacarbazine (also termed DTIC), immunotherapy (with interleukin-2 (IL-2) or interferon (IFN)) 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.^[39] IL-2 (Proleukin®) is the first new therapy approved for the treatment 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, although only in a small percentage of patients.^[40] A number of new agents and novel approaches are under evaluation and show promise.^[41]

Lentigo maligna treatment

Some superficial melanomas (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara®) topical cream, an immune enhancing agent. Application of this cream has been shown to decrease tumor size prior to surgery, reducing the invasiveness of the procedure. This treatment is used especially for smaller melanoma in situ lesions located in cosmetically sensitive regions. Several published studies demonstrate a 70% cure rate with this topical treatment. With lentigo maligna, surgical cure rates are no higher. Some dermasurgeons are combining the 2 methods: surgically excise the cancer, then treat the area with Aldara® cream post-operatively for 3 months.

Radiation and other therapies

Radiation therapy is often used after surgical resection for patients with locally or regionally advanced melanoma or for patients with unresectable distant metastases. It may reduce the rate of local recurrence but does not prolong survival.^[42]

In research setting other therapies, such as gene therapy, may be tested.^[43] Radioimmunotherapy of metastatic melanoma is currently under investigation.

Experimental treatment developed at the National Cancer Institute (NCI), part of the National Institutes of Health in the US was used in advanced (metastatic) melanoma with moderate success. The treatment, adoptive transfer of genetically altered autologous lymphocytes, depends on delivering genes that encode so called T cell receptors (TCRs), into patient's lymphocytes. After that manipulation lymphocytes recognize and bind to certain molecules found on the surface of melanoma cells and kill them.^[44]

Future thought

One important pathway in melanin synthesis involves the transcription factor MITF. The MITF gene is highly conserved and is found in people, mice, birds, and even fish. MITF production is regulated via a fairly straightforward pathway. UV radiation causes increased expression of transcription factor p53 in keratinocytes, and p53 causes these cells to produce melanoctye stimulating hormone (MSH), which binds to melanocortin 1 receptors (MC1R) on melanocytes. Ligand-binding at MC1R receptors activates adenyl cyclases, which produce cAMP, which activates CREB, which promotes MITF expression. The targets of MITF include p16 (a CDK inhibitor) and Bcl2, a gene essential to melanocyte survival. It is often difficult to design drugs that interfere with transcription factors, but perhaps new drugs will be discovered that can impede some reaction in the pathway upstream of MITF.

Studies of chromatin structure also promise to shed light on transcriptional regulation in melanoma cells. It has long been assumed that nucleosomes are positioned randomly on DNA, but murine studies of genes involved in melanin production now suggest that nucleosomes are stereotypically positioned on DNA. When a gene is undergoing transcription, its transcription start site is almost always nucleosome-free. When the gene is silent, however, nucleosomes often block the transcriptional start site, suggesting the nucleosome position may play a role in gene regulation.

Finally, given the fact that tanning helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce tanning in individuals who would otherwise get sunburns. Redheads, for example, do not tan because they have MC1R mutations. In mice, it has been shown that the melanin-production pathway can be rescued downstream of MC1R. Perhaps such a strategy will eventually be used to protect humans from melanoma.

References

Patient information

• What You Need To Know About Moles and Dysplastic Nevi - patient information booklet from cancer.gov (PDF)
• MPIP: Melanoma patients information page
• Melanoma Support Organisation (Victoria, Australia) - Ran by Melanoma Sufferers with strong links to Cancer Institutes in Victoria, Australia
• Melanoma Patients Australia
• Mikes Page - The Melanoma Resource Center
• MEL-L - Melanoma e-mail list for patients, caregivers and healthcare professionals - Supporting the Melanoma Patient since 1996

Images, photographs

• Melanoma photo library at Dermnet
• DermAtlas: Melanoma images
• Photographs of melanoma
• Skin imaging methods for melanoma diagnosis(commercial advertising)
• Pictures of melanomas
• Pictures of amelanotic melanomas

Videos

• Health Video: Melanoma and Non-Melanoma Skin Cancers - Overview, Prevention, and Treatment
• Health Video: How to Perform a Skin Self Exam