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Melanoma

Melanoma (pronounced /?m?l??no?m?/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 less common types of skin cancer but causes the majority (75%) of skin cancer related deaths.Melanocytes are normally present in skin, being responsible for the production of the dark pigment melanin.Despite many years of intensive laboratory and clinical research, the greatest chance of cure is in the early surgical resection of thin tumours. Around 60,000 new cases of melanoma invasive melanoma are diagnosed in the US each year, more frequently in males and in Caucasians.[3] It is more common in Caucasian populations living in sunny climates than in other groups, or in those who use tanning salons.According to a WHO report about 48,000 melanoma related deaths occur worldwide per year. The treatment includes surgical removal of the tumor, adjuvant treatment, chemo- and immunotherapy, or radiation therapy.

Classification

Melanoma may be divided into the following stereotypes:[6]:694-699
  1. Lentigo maligna
  2. Lentigo maligna melanoma
  3. Superficially spreading melanoma
  4. Acral lentiginous melanoma
  5. Mucosal melanoma
  6. Nodular melanoma
  7. Polypoid melanoma
  8. Desmoplastic melanoma
  9. Amelanotic melanoma
  10. Soft-tissue melanoma
  11. Melanoma with small nevus-like cells
  12. Melanoma with features of a Spitz nevus
  13. Uveal melanoma

[ Signs and symptoms

Early signs of melanoma are changes to the shape or color of existing moles. The mole may itch, ulcerate or bleed.[8] Metastatic melanoma may cause general symptoms like loss of appetite, nausea, vomiting and fatigue. Metastasis as the first symptom of melanoma is possible, however, fortunately less than a fifth of melanomas diagnosed yearly become metastatic.

Cause

Genetics

Familial melanoma is genetically heterogeneous,[ 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.[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. 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 patients 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 persons lesions have the greatest chance of becoming cancerous. A number of rare mutations, which often run in families, are known to greatly increase ones 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 cells 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 patients 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. Mutation of the MDM2 SNP309 gene is associated with increased risk of melanoma in younger women.

] Diagnosis

ABCD rule illustration. On the left side from top to bottom: melanomas showing (A) Asymmetry, (B) a border that is uneven, ragged, or notched, (C) coloring of different shades of brown, black, or tan and (D) diameter that had changed in size. The normal moles on the right side do not have abnormal characteristics (no asymmetry, even border, even color, no change in diametry). To detect melanomas (and increase survival rates), it is recommended to learn what they look like (see ABCD 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. A popular method for remembering the signs and symptoms of melanoma is the mnemonic ABCDE:
  1. Asymmetrical skin lesion.
  2. Border of the lesion is irregular.
  3. Color: melanomas usually have multiple colors.
  4. Diameter: moles greater than 6mm are more likely to be melanomas than smaller moles.
  5. Enlarging: Enlarging or evolving
A weakness in this system is the D. Many melanomas present themselves as lesions smaller than 6mm in diameter; and likely all melanomas were malignant on day 1 of growth, which is merely a dot. An astute physician will examine all abnormal moles, including ones less than 6mm in diameter. Seborrheic keratosis may meet some or all of the ABCD criteria, and can lead to false alarms among laypeople. An experienced doctor can distinguish seborrheic keratosis from melanoma upon examination, or with dermatoscopy. Some will advocate the system ABCDE, with E for evolution. Certainly moles which change and evolve will be a concern. Alternately, some will refer to E as elevation. Elevation can help identify a melanoma, but lack of elevation does not mean that the lesion is not a melanoma. Most melanomas are detected in the very early stage, or in-situ stage, before they become elevated. By the time elevation is visible, they may have progressed to the more dangerous invasive stage. A recent and novel method of melanoma detection is the Ugly Duckling SignIt is simple, easy to teach, and highly effective in detecting melanoma. Simply, correlation of common characteristics of a person`s skin lesion is made. Lesions which greatly deviate from the common characteristics are labeled as an Ugly Duckling, and further professional exam is required. The Little Red Riding Hood sign suggests that individuals with fair skin and light colored hair might have difficult-to-diagnose melanomas. Extra care and caution should be rendered when examining such individuals as they might have multiple melanomas and severely dysplastic nevi. A dermatoscope must be used to detect ugly ducklings, as many melanomas in these individuals resemble non-melanomas or are considered to be wolves in sheep clothing. These fair skinned individuals often have lightly pigmented or amelanotic melanomas which will not present easy-to-observe color changes and variation in colors. The borders of these amelanotic melanomas are often indistinct, making visual identification without a dermatoscope (dermatoscopy) very difficult. 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. A dermatoscope. A modern polarized dermatoscope. 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, used routinely by one in 4 dermatologists in the United States,[or an examination using other in vivo diagnostic tools, such as a confocal microscope, the doctor may biopsy the suspicious mole. If it is malignant, the mole and an area around it needs excision. The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles or not have any color at all. A skin biopsy performed under local anesthesia is often required to assist in making or confirming the diagnosis and in defining the severity of the melanoma. Amelanotic melanomas and melanomas arising in fair skinned individuals (see the Little Red Riding Hood sign) are very difficult to detect as they fail to show many of the characteristics in the ABCD rule, and breaks the Ugly Duckling sign. These melanomas are often light brown, or pink in color - and very hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines. There is no blood test for detecting melanomas. Malignant melanoma in skin biopsy with H&E stain. This case may represent superficial spreading melanoma. Excisional skin biopsy is the management of choice; this is where the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2mm) ellipse of surrounding skin and tissue. The preferred surgical margin for the initial biopsy should be narrow (1mm) in order to prevent the disruption of the local lymphatic drainage. The biopsy will include the epidermal, dermal, and subcutaneous layers of the skin, enabling the histopathologist to determine the thickness of the melanoma by microscopic examination. This is described by Breslow`s thickness (measured in millimeters). However, for large lesions such as suspected lentigo maligna, or for lesions in surgically difficult areas (face, toes, fingers, eyelids), a small punch biopsy in representative areas will give adequate information and will not disrupt the final staging or depth determination. In no circumstances should the initial biopsy include the final surgical margin (0.5cm, 1.0cm, or 2cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. Large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram directed lymphnode dissection. A small punch biopsy can be utilized at any time where for logistical and personal reasons a patient refuses more invasive excisional biopsy. Small punch biopsies are minimally invasive and heal quickly, usually without noticeable scarring. 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. A diagnosis of melanoma is supported by the presence of the S-100 protein marker. 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.

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. Melanoma stages: Stage 0: Melanoma in Situ (Clark Level I), 99.9% Survival Stage I/II: Invasive Melanoma, 85-99% Survival
  1. T1a: Less than 1.00mm primary, w/o Ulceration, Clark Level II-III
  2. T1b: Less than 1.00mm primary, w/Ulceration or Clark Level IV-V
  3. T2a: 1.00-2.00mm primary, w/o Ulceration
Stage II: High Risk Melanoma, 40-85% Survival
  1. T2b: 1.00-2.00mm primary, w/ Ulceration
  2. T3a: 2.00-4.00mm primary, w/o Ulceration
  3. T3b: 2.00-4.00mm primary, w/ Ulceration
  4. T4a: 4.00mm or greater primary w/o Ulceration
  5. T4b: 4.00mm or greater primary w/ Ulceration
Stage III: Regional Metastasis, 25-60% Survival
  1. N1: Single Positive Lymph Node
  2. N2: 2-3 Positive Lymph Nodes OR Regional Skin/In-Transit Metastasis
  3. N3: 4 Positive Lymph Nodes OR Lymph Node and Regional Skin/In Transit Metastases
Stage IV: Distant Metastasis, 9-15% Survival
  1. M1a: Distant Skin Metastasis, Normal LDH
  2. M1b: Lung Metastasis, Normal LDH
  3. M1c: Other Distant Metastasis OR Any Distant Metastasis with Elevated LDH
Based Upon AJCC 5-Year Survival With Proper Treatment

Prevention

Minimizing exposure to sources of ultraviolet radiation (the sun and sunbeds),[following sun protection measures and wearing sun protective clothing (long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past it was recommended to use sunscreens with an SPF rating of 30 or higher on exposed areas as older sunscreens more effectively blocked UVA with higher SPF. Currently, newer sunscreen ingredients (avobenzone, zinc, and titanium) effectively block both UVA and UVB even at lower SPFs. However, there are questions about the ability of sunscreen to prevent melanoma. This controversy is well discussed in numerous review articles, and is refuted by most dermatologists.[26][27] This correlation might be due to the confounding variable that individuals who used sunscreen to prevent burn might have a higher lifetime exposure to either UVA or UVB. See Sunscreen controversy for further references and discussions. Tanning, once believed to help prevent skin cancers, actually can lead to increase incidence of melanomas. Even though tanning beds emit mostly UVA, which causes tanning, it by itself might be enough to induce melanomas. A good rule of thumb for decreasing ultraviolet light exposure is to avoid the sun between the hours of 9 a.m. and 3 p.m. or avoid the sun when your shadow is shorter than your height. These are rough rules, however, and can vary depending on locality and individual skin cancer risk. Almost all malignant melanomas start with altering the color and appearance of normal-looking skin. This area may be a dark spot or an abnormal new mole. Other melanomas form from a mole or freckle that is already present in the skin. It is very hard to distinguish the difference between a malignant melanoma and a normal mole. When looking for danger signs in pigmented lesions of the skin a few simple rules are often used. The ABCDE list, the ugly duckling sign, and the red riding hood rule are defined and discussed under the heading Detection earlier in this article.

Management

Surgery is the first choice therapy for localized cutaneous melanoma. Depending on the stage a sentinel lymph node biopsy is done as well, although controversy exists around trial evidence for this procedure. 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 followup is standard. Often this is done by a wide local excision (WLE) with 1 to 2cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margins, usually 0.2 to 0.5cm.[ Many surgeons consider 0.5cm the standard of care for standard excision of melanoma-in-situ,[30] but 0.2cm margin might be acceptable for margin controlled surgery (Mohs surgery, or the double bladed technique with margin control). 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. Mohs surgery has been reported with cure rate as low as 77%and as high as 98% for melanoma-in-situ. Melanomas which spread usually do so to the lymph nodes in the region of the tumor 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 tumor. 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 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 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 patient`s 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.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. A number of new agents and novel approaches are under evaluation and show promise. Clinical trial participation should be considered the standard of care for metastatic melanoma. In 2005, a phase III clinical trial for a melanoma vaccine was halted after showing little benefit compared to placebo. On June 23, 2008, Israeli scientists from the Oncology Institute of the Hadassa Medical Center in Jerusalem announced they developed a vaccine that prevents recurrences of the disease among previous sufferers and increases chances of survival for current ones. One of the most promising current experimental treatment approaches, also an immunotherapy, is OncoVEX GM-CSF (BioVex Inc, Woburn, MA) which is currently in Phase 3 clinical trials following a very high level of efficacy having been observed in Phase 2.

Lentigo maligna treatment

Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceeding high (up to 50%). This is due to the ill defined visible surgical margin, and the facial location of the lesions (often forcing the surgeon to use a narrow surgical margin). The narrow surgical margin used, combined with the limitation of the standard bread loafing technique of fixed tissue histology - result in a high false negative error rate, and frequent recurrences. Margin controlled (peripheral margins) is necessary to eliminate the false negative errors. If breadloafing is utilized, distances from sections should approach 0.1mm to assure that the method approaches complete margin control. Mohs surgery has been done with cure rate reported to be as low as 77%,and as high as 95% by another author. The double scalpel peripheral margin controlled excision method approximates the Mohs method in margin control, but requires a pathologist intimately familiar with the complexity of managing the vertical margin on the thin peripheral sections and staining methods. Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an experimental treatment, imiquimod (Aldara) topical cream, an immune enhancing agent. Some dermasurgeons are combining the 2 methods: surgically excising the cancer and then treating the area with Aldara cream postoperatively for three months. Considering the very poor cure rate with standard excision, it might not be a bad idea to follow up all surgical excisions with topical imiquimod treatments.

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.[45] In research setting other therapies, such as gene therapy, may be tested.[46] 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. A new treatment that trains the immune system to fight cancer has shown modest benefit in late-stage testing against melanoma.

Prognosis

: 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. 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 the 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%.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.