Melanoma
Encyclopedia
Melanoma is a malignant
tumor
of melanocyte
s. Melanocytes are cells that produce the dark pigment, melanin
, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye
(see uveal melanoma
). Melanoma can occur in any part of the body that contains melanocytes.
Melanoma is less common than other skin cancer
s. However, it is much more dangerous and causes the majority (75%) of deaths related to skin cancer. Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. The diagnosis is more frequent in women than in men and is particularly common among Caucasians
living in sunny climates, with high rates of incidence in Australia, New Zealand, North America, Latin America, and northern Europe.
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
. The chance of a cure is greatest when the tumor is discovered while it is still small and thin, and can be entirely removed surgically.
or, in the case of nodular melanoma
, the appearance of a new lump anywhere on the skin (such lesions should be referred without delay to a dermatologist). At later stages, the mole may itch
, ulcerate or bleed. Early signs of melanoma are summarized by the mnemonic
"ABCDE":
These classifications do not, however, apply to the most dangerous form of melanoma, nodular melanoma
, which has its own classifications:
Metastatic melanoma may cause nonspecific paraneoplastic symptoms, including loss of appetite, nausea, vomiting and fatigue. Metastasis
of early melanoma is possible, but relatively rare: less than a fifth of melanomas diagnosed early become metastatic. Brain metastases are particularly common in patients with metastatic melanoma.
inside cells. This damage can be inherited in the form of genetic mutations, but in most cases, it builds up over a person's lifetime and is caused by factors in their environment. DNA damage causes the cell to grow out of control, leading to a tumor
. Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.
). This early stage of the disease is called the radial growth phase, and the tumour is less than 1mm thick. Because the cancer cells have not yet reached the blood vessels lower down in the skin, it is very unlikely that this early-stage cancer will spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely removed with surgery.
When the tumour cells start to move in a different direction — vertically up into the epidermis and into the papillary dermis — the behaviour of the cells changes dramatically.
The next step in the evolution is the invasive radial growth phase, which is a confusing term; however, it explains the next step in the process of the radial growth, when individual cells start to acquire invasive potential. This step is important – from this point on the melanoma is capable of spreading. The Breslow's depth
of the lesion is usually less than1 mm (0.0393700787401575 in), the Clark level is usually 2.
The following step in the process is the invasive melanoma — the vertical growth phase (VGP). The tumour attains invasive potential, meaning it can grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumour thickness is usually more than 1 mm (0.0393700787401575 in), and the tumour involves the deeper parts of the dermis.
The host elicits an immunological reaction against the tumour (during the VGP), which is judged by the presence and activity of the tumour infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary tumour, this is called regression, which is the latest stage of the melanoma development. In certain cases, the primary tumour is completely destroyed and only the metastatic tumour is discovered.
have been identified as increasing the risk of developing melanoma. Some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene called MC1R that causes red hair, have a relatively low risk. Genetic testing
can be used to determine whether a person has one of the currently known mutations.
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 nonfunctional 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.
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 (disease development) 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
.
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 (typical unaffected 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 want to identify high-risk lesions (abnormal area of tissue) within a given patient. Many new technologies, such as optical coherence tomography
(OCT), are being developed to accomplish this. OCT allows pathologists to view three-dimensional 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.
released a report that categorized tanning beds as “carcinogenic to humans”. The agency, which is part of the World Health Organization
(WHO), previously classified tanning beds as “probably carcinogenic”. The change comes after an analysis of more than 20 epidemiological studies indicating that people who begin using tanning devices before age 30 are 75% more likely to develop melanoma.
In December 2009, Julie Morgan, Labour MP for Cardiff North, introduced a Private Member's Bill before Parliament aimed at preventing under-18s using sunbeds. MPs considered the evidence, including research from a UK cancer charity. The research found that a quarter of a million children in England between the ages of 11 and 17 regularly used sunbeds. The bill was passed in April 2011; the Sunbed (Regulation) Bill restricts the use of sunbeds to over-18s in England and Wales (Scotland already had this legislation). All sunbed salons will have to be staffed and provide accurate health information on the dangers of sunbeds.
There is no blood test for detecting melanomas. Visual diagnosis of melanomas is still the most common method employed by health professionals. To 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.
A popular method for remembering the signs and symptoms of melanoma is the mnemonic "ABCDE":
A weakness in this system is the diameter. Many melanomas present themselves as lesions smaller than 6 mm in diameter; and 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 6 mm in diameter. Seborrheic keratosis
may meet some or all of the ABCD criteria, and can lead to false alarm
s among laypeople and sometimes even physicians. An experienced doctor can generally 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. Alternatively, 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.
However, nodular melanoma
s do not fulfill these criteria, having their own mnemonic "EFG":
A recent and novel method of melanoma detection is the "ugly duckling sign" It 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 amelanotic 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.
Moles that are irregular in color or shape are often treated as candidates of melanoma. Following a visual examination and a dermatoscopic exam
, or in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. If the mole is malignant, the mole and an area around it need 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, break the "Ugly Duckling" sign, and are very hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines
.
Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up of high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (being possible with the use of any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes. The diagnosis method should be used in conjunction with (and not as a replacement for) dermscopic imaging, with a combination of both methods appearing to give extremely high rates of detection. Similarly, there is a web-based technology for mole screening, which evaluates customers’ images against a ‘bank’ of known clinical results. The online-screening test
is not a substitute for existing medical services, but rather, the technology uses very sophisticated state-of-the-art analysis of a digital image of a suspect mole to screen out any benign moles (the vast majority cases – over 90%), reducing the pressure on healthcare services. The standard approach to the diagnosis of Melanoma is to encourage people to look for any change in colour, size and shape of a mole following the A-B-C-D-E guidelines mentioned previously. The use of digital image analysis and structure recognition provides a machine interpretation to classify moles based on risk, and provides additional advice and support to users - both patient and professional.
See also:
(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.
is available at TNM.
Also of importance are the "Clark level" and "Breslow's depth
", which refer to the microscopic depth of tumor invasion.
Melanoma stages:
5 year survival rates:
Stage 0: Melanoma in situ (Clark Level I), 99.9% survival
Stage I/II: Invasive melanoma, 85–99% survival
Stage II: High risk melanoma, 40–85% survival
Stage III: Regional metastasis, 25–60% survival
Stage IV: Distant metastasis, 9–15% survival
Based upon AJCC five-year survival with proper treatment
(long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past, use of sunscreen
s with a sun protection factor (SPF) rating of 50 or higher on exposed areas were recommended, 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 rejected by most dermatologists. 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 an increased 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 one's shadow is shorter than one's height. These are rough rules, however, and can vary depending on locality and individual skin cancer risk.
Almost all 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 can be difficult to distinguish between a 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.
“Melanoma Monday” is the kick-off of May Melanoma Month, with special activities nationally and locally. Also known as National Skin Self-Examination Day, it is when people are encouraged to examine their skin for skin cancer. Since 1985, this program has helped to detect more than 188,000 suspicious lesions, including more than 21,500 suspected melanomas.
or a small, full-thickness sampling with a punch skin biopsy
. This is usually followed up with a wider excision of the scar or tumor. 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.
Complete surgical excision with adequate surgical margin
s 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 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margin
s, usually 0.2 to 0.5 cm. Many surgeons consider 0.5 cm the standard of care for standard excision of melanoma-in-situ, but 0.2 cm 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. CCPDMA
and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this "intra-epithelial" type of melanoma.
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 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.
Excisional skin biopsy
is the management of choice. Here, the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue. To avoid disruption of the local lymphatic drainage, the preferred surgical margin for the initial biopsy should be narrow (1 mm). The biopsy should include the epidermal, dermal, and subcutaneous layers of the skin. This enables 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 (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. A large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram-directed lymphnode dissection. A small punch biopsy can be used 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.
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. 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.
Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.
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. 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.
is used, distances from sections should approach 0.1 mm 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.
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. Radioimmunotherapy
of metastatic melanoma is currently under investigation.
Radiotherapy has a role in the palliation of metastatic melanoma.
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 lymphocyte
s (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 node
s, 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.
, while the most relevant environmental factor is sun exposure.
Epidemiologic studies suggest that exposure to ultraviolet
radiation (UVA 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 mutation
s in the cell's gene
s. When the cell divides
, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor gene
s, the rate of mitosis
in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor
. Data from patients suggest that aberrant levels of Activating Transcription Factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells; studies from mice on skin cancer tend to confirm a role for Activating Transcription Factor-2 in cancer progression. Occasional extreme sun exposure (resulting in "sunburn
") is causally related to melanoma. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers. Other factors are mutation
s in or total loss of tumor suppressor gene
s. Use of sunbed
s (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
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. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that sunscreen
— while preventing the sunburn — does not protect mice, injected with melanoma cells a day after UV exposure, from developing 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.
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. Patients with a history of one melanoma are at increased risk of developing a second primary tumour.
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.
To understand how sunscreen can reduce sunburn and at the same time cause melanoma it is necessary to distinguish between direct DNA damage
and indirect DNA damage
. Genetic analysis has shown that 92% of all melanoma are caused by the indirect DNA damage.
Although some people believe that dark-skinned people such as those of African descent cannot get sunburns, they are in fact susceptible, and should use sunscreen accordingly, as sunscreen has been proven to protect against other cancers such as squamous cell carcinoma and basal cell carcinoma.
vian 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.
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.
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.
The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820. 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 acknowledgment 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 ...' More than one and a half centuries later this situation remains largely unchanged.
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 melanocyte-stimulating hormone
(MSH), which binds to melanocortin 1 receptor
s (MC1R) on melanocytes. Ligand-binding at MC1R receptors activates adenylate cyclase
s, which produce cAMP
, which activates CREB
, which promote 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 that nucleosome position may play a role in gene regulation.
Finally, given the fact that melanin helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce melanin synthesis 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.
A study published on January 27, 2011, by M. Raza Zaidi et al. shows that interferon-γ links ultraviolet radiation to melanomagenesis in mice. Using a mouse model that allowed the visual tracking and purification of melanocytes using a green fluorescent dye, data showed that UVB-induced, macrophage-enhanced interferon-γ release results in melanoma growth, proliferation and immunoevasion. Based on these results, the interferon-γ pathway can potentially serve as part of new therapeutic measures to treat patients suffering from malignant melanoma, as well as a potential preventive strategy against UV-induced radiation.
. Early clinical trials suggested that B-Raf inhibitors including Plexxicon(R)'s vemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation. In June 2011, a large clinical trial confirmed the positive findings from those earlier trials.
. The study found an increase in median survival from 6.4 to 10 months in patients with advanced melanomas treated with the monoclonal ipilimumab
, versus an experimental vaccine. It also found a one year survival rate of 25% in the control group using the vaccine, 44% in the vaccine and ipilimumab group, and 46% in the group treated with ipilimumab alone. However, some have raised concerns about this study for its use of the unconventional control arm, rather than comparing the drug against a placebo or standard treatment. Meaning that the drug performed better than the vaccine, although the vaccine has not been tested before and may be causing toxicity — making the drug appear better by comparison.
In June 2011, a clinical trial of ipilimumab plus dacarbazine, combined this immune system booster with the standard chemotherapy drug that targets cell division. It showed an increase in median survival for these late stage patients to 11 months instead of the 9 months normally seen. Researchers were also hopeful that perhaps 10-20% of patients could live a long time. Some serious side-effects of revving up the immune system were seen in some patients. A course of treatment costs $120,000. The drug's brandname is Yervoy.
, may be tested.
Two kinds of experimental treatments developed at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the US have been used in advanced (metastatic) melanoma with high success rates in terms of melanoma treatments.
The first treatment involves Adoptive Cell Therapy (ACT) using TILs immune cells (Tumor Infiltrating Lymphocytes) isolated from a patient's own melanoma tumor. These cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily reduces normal T cells in the patient's body. TIL Therapy following lymphodepletion can result in durable complete response in a variety of setups. Up to date, the only medical center outside the USA managed to successfully implement this technology is Sheba Medical Center through "Ella Institute of Melanoma", found in Israel (objective response rates of 50%). The second 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.
Sutent may be effective for patients with metastatic melanoma.
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
of melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s. Melanocytes are cells that produce the dark pigment, melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
(see uveal melanoma
Uveal melanoma
Uveal melanoma is a cancer of the eye involving the iris, ciliary body, or choroid . Tumors arise from the pigment cells that reside within the uvea giving color to the eye...
). Melanoma can occur in any part of the body that contains melanocytes.
Melanoma is less common than other skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
s. However, it is much more dangerous and causes the majority (75%) of deaths related to skin cancer. Worldwide, doctors diagnose about 160,000 new cases of melanoma yearly. The diagnosis is more frequent in women than in men and is particularly common among Caucasians
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
living in sunny climates, with high rates of incidence in Australia, New Zealand, North America, Latin America, and northern Europe.
According to a WHO
Who
Who may refer to:* Who , an English-language pronoun* who , a Unix command* Who?, one of the Five Ws in journalism- Art and entertainment :* Who? , a 1958 novel by Algis Budrys...
report, about 48,000 melanoma related deaths occur worldwide per year.
The treatment includes surgical removal of the tumor, adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
treatment, chemo-
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and immunotherapy
Cancer immunotherapy
Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease...
, or radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
. The chance of a cure is greatest when the tumor is discovered while it is still small and thin, and can be entirely removed surgically.
Signs and symptoms
Early signs of melanoma are changes to the shape or color of existing molesMole (skin marking)
A melanocytic nevus is a type of lesion that contains nevus cells .Some sources equate the term mole with "melanocytic nevus". Other sources reserve the term "mole" for other purposes....
or, in the case of nodular melanoma
Nodular melanoma
Nodular melanoma is the most aggressive form of melanoma. It tends to grow more rapidly in thickness than in diameter. Instead of arising from a pre-existing mole, it may appear in a spot where a lesion did not previously exist...
, the appearance of a new lump anywhere on the skin (such lesions should be referred without delay to a dermatologist). At later stages, the mole may itch
Itch
Itch is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to classify it as any one type of sensory experience. Modern science has shown that itch has many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response...
, ulcerate or bleed. Early signs of melanoma are summarized by the mnemonic
Mnemonic
A mnemonic , or mnemonic device, is any learning technique that aids memory. To improve long term memory, mnemonic systems are used to make memorization easier. Commonly encountered mnemonics are often verbal, such as a very short poem or a special word used to help a person remember something,...
"ABCDE":
- Asymmetry
- Borders (irregular)
- Color (variegated), and
- Diameter (greater than 6 mm (0.236220472440945 in), about the size of a pencil eraser)
- Evolving over time
These classifications do not, however, apply to the most dangerous form of melanoma, nodular melanoma
Nodular melanoma
Nodular melanoma is the most aggressive form of melanoma. It tends to grow more rapidly in thickness than in diameter. Instead of arising from a pre-existing mole, it may appear in a spot where a lesion did not previously exist...
, which has its own classifications:
- Elevated above the skin surface
- Firm to the touch
- Growing
Metastatic melanoma may cause nonspecific paraneoplastic symptoms, including loss of appetite, nausea, vomiting and fatigue. Metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
of early melanoma is possible, but relatively rare: less than a fifth of melanomas diagnosed early become metastatic. Brain metastases are particularly common in patients with metastatic melanoma.
Cause
All cancers are caused by damage to the DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
inside cells. This damage can be inherited in the form of genetic mutations, but in most cases, it builds up over a person's lifetime and is caused by factors in their environment. DNA damage causes the cell to grow out of control, leading to a tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
. Melanoma is usually caused by damage from UV light from the sun, but UV light from sunbeds can also contribute to the disease.
Natural history
The earliest stage of melanoma starts when the melanocytes begin to grow out of control. Melanocytes are found between the outer layer of the skin (the epidermis) and the next layer (the dermisDermis
The dermis is a layer of skin between the epidermis and subcutaneous tissues, and is composed of two layers, the papillary and reticular dermis...
). This early stage of the disease is called the radial growth phase, and the tumour is less than 1mm thick. Because the cancer cells have not yet reached the blood vessels lower down in the skin, it is very unlikely that this early-stage cancer will spread to other parts of the body. If the melanoma is detected at this stage, then it can usually be completely removed with surgery.
When the tumour cells start to move in a different direction — vertically up into the epidermis and into the papillary dermis — the behaviour of the cells changes dramatically.
The next step in the evolution is the invasive radial growth phase, which is a confusing term; however, it explains the next step in the process of the radial growth, when individual cells start to acquire invasive potential. This step is important – from this point on the melanoma is capable of spreading. The Breslow's depth
Breslow's depth
In medicine, Breslow's depth is used as a prognostic factor in melanoma of the skin. It is a description of how deeply tumor cells have invaded.-History:...
of the lesion is usually less than1 mm (0.0393700787401575 in), the Clark level is usually 2.
The following step in the process is the invasive melanoma — the vertical growth phase (VGP). The tumour attains invasive potential, meaning it can grow into the surrounding tissue and can spread around the body through blood or lymph vessels. The tumour thickness is usually more than 1 mm (0.0393700787401575 in), and the tumour involves the deeper parts of the dermis.
The host elicits an immunological reaction against the tumour (during the VGP), which is judged by the presence and activity of the tumour infiltrating lymphocytes (TILs). These cells sometimes completely destroy the primary tumour, this is called regression, which is the latest stage of the melanoma development. In certain cases, the primary tumour is completely destroyed and only the metastatic tumour is discovered.
Genetics
A number of rare mutations, which often run in families, are known to greatly increase one’s susceptibility to melanoma. Several different genesGênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
have been identified as increasing the risk of developing melanoma. Some rare genes have a relatively high risk of causing melanoma; some more common genes, such as a gene called MC1R that causes red hair, have a relatively low risk. Genetic testing
Genetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
can be used to determine whether a person has one of the currently known mutations.
One class of mutations affects the gene CDKN2A
CDKN2A
CDKN2A can refer to:* P16 * p14arf...
. An alternative reading frame
Reading frame
In biology, a reading frame is a way of breaking a sequence of nucleotides in DNA or RNA into three letter codons which can be translated in amino acids. There are 3 possible reading frames in an mRNA strand: each reading frame corresponding to starting at a different alignment...
mutation in this gene leads to the destabilization of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
involved in apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and in fifty percent of human cancers. Another mutation in the same gene results in a nonfunctional inhibitor of CDK4, a [cyclin-dependent kinase] that promotes cell division. Mutations that cause the skin condition xeroderma pigmentosum
Xeroderma pigmentosum
Xeroderma pigmentosum, or XP, is an autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet light is deficient. In extreme cases, all exposure to sunlight must be forbidden, no matter how small. Multiple basal cell carcinomas and other skin...
(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.
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 (disease development) of melanoma. The multiple tumor suppressor
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
1 (CDKN2A/MTS1) gene encodes p16INK4a — a low-molecular weight protein inhibitor of cyclin-dependent protein kinases
Cyclin-dependent kinase
thumb|350px|Schematic of the cell cycle. outer ring: I=[[Interphase]], M=[[Mitosis]]; inner ring: M=Mitosis; G1=[[G1 phase|Gap phase 1]]; S=[[S phase|Synthesis]]; G2=[[G2 phase|Gap phase 2]]...
(CDKs) — which has been localised to the p21 region of human chromosome 9
Chromosome 9 (human)
125px|rightChromosome 9 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome, as they normally do with all chromosomes...
.
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 (typical unaffected type) copies of the gene. MC1R
Melanocortin 1 receptor
The melanocortin 1 receptor , also known as melanocyte-stimulating hormone receptor , melanin-activating peptide receptor, or melanotropin receptor, is a G protein-coupled receptor which binds to a class of pituitary peptide hormones known as the melanocortins, of which include adrenocorticotropic...
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
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
.
In addition to identifying high-risk patients, researchers want to identify high-risk lesions (abnormal area of tissue) within a given patient. Many new technologies, such as optical coherence tomography
Optical coherence tomography
Optical coherence tomography is an optical signal acquisition and processing method. It captures micrometer-resolution, three-dimensional images from within optical scattering media . Optical coherence tomography is an interferometric technique, typically employing near-infrared light...
(OCT), are being developed to accomplish this. OCT allows pathologists to view three-dimensional reconstructions of the skin and offers more resolution than past techniques could provide. In vivo confocal microscopy
Confocal microscopy
Confocal microscopy is an optical imaging technique used to increase optical resolution and contrast of a micrograph by using point illumination and a spatial pinhole to eliminate out-of-focus light in specimens that are thicker than the focal plane. It enables the reconstruction of...
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.
UV radiation
In July 2009, the IARCInternational Agency for Research on Cancer
The International Agency for Research on Cancer is an intergovernmental agency forming part of the World Health Organisation of the United Nations....
released a report that categorized tanning beds as “carcinogenic to humans”. The agency, which is part of the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(WHO), previously classified tanning beds as “probably carcinogenic”. The change comes after an analysis of more than 20 epidemiological studies indicating that people who begin using tanning devices before age 30 are 75% more likely to develop melanoma.
In December 2009, Julie Morgan, Labour MP for Cardiff North, introduced a Private Member's Bill before Parliament aimed at preventing under-18s using sunbeds. MPs considered the evidence, including research from a UK cancer charity. The research found that a quarter of a million children in England between the ages of 11 and 17 regularly used sunbeds. The bill was passed in April 2011; the Sunbed (Regulation) Bill restricts the use of sunbeds to over-18s in England and Wales (Scotland already had this legislation). All sunbed salons will have to be staffed and provide accurate health information on the dangers of sunbeds.
Diagnosis
Melanocytic nevus
A melanocytic nevus is a type of lesion that contains nevus cells .Some sources equate the term mole with "melanocytic nevus". Other sources reserve the term "mole" for other purposes....
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":
- Asymmetrical skin lesion.
- Border of the lesion is irregular.
- Color: melanomas usually have multiple colors.
- Diameter: moles greater than 6 mm are more likely to be melanomas than smaller moles.
- Enlarging: Enlarging or evolving
A weakness in this system is the diameter. Many melanomas present themselves as lesions smaller than 6 mm in diameter; and 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 6 mm in diameter. Seborrheic keratosis
Seborrheic keratosis
A seborrheic keratosis is a noncancerous benign skin growth that originates in keratinocytes. Like liver spots, seborrheic keratoses are seen more often as people age. In fact they are sometimes humorously referred to as the "barnacles of old age". They appear in various colors, from light tan to...
may meet some or all of the ABCD criteria, and can lead to false alarm
False alarm
A false alarm, also called a nuisance alarm, is the fake report of an emergency, causing unnecessary panic and/or bringing resources to a place where they are not needed. Over time, repeated false alarms in a certain area may cause occupants to start to ignore all alarms, knowing that each time it...
s among laypeople and sometimes even physicians. An experienced doctor can generally distinguish seborrheic keratosis from melanoma upon examination, or with dermatoscopy
Dermatoscopy
Dermatoscopy is the examination of skin lesions with a dermatoscope...
.
Some will advocate the system "ABCDE", with E for evolution. Certainly moles which change and evolve will be a concern. Alternatively, 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.
However, nodular melanoma
Nodular melanoma
Nodular melanoma is the most aggressive form of melanoma. It tends to grow more rapidly in thickness than in diameter. Instead of arising from a pre-existing mole, it may appear in a spot where a lesion did not previously exist...
s do not fulfill these criteria, having their own mnemonic "EFG":
- Elevated: the lesion is raised above the surrounding skin.
- Firm: the nodule is solid to the touch.
- Growing: the nodule is increasing in size.
A recent and novel method of melanoma detection is the "ugly duckling sign" It 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 amelanotic 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
Dermatoscopy
Dermatoscopy is the examination of skin lesions with a dermatoscope...
) very difficult.
People with a personal or family history of skin cancer or of dysplastic nevus syndrome
Dysplastic nevus syndrome
Dysplastic nevus syndrome is a cutaneous condition described in certain families, and characterized by unusual nevi and multiple inherited melanomas.-Historical background:In 1820 Norris reported the first case of what is now recognized as FAMMM...
(multiple atypical moles) should see a dermatologist at least once a year to be sure they are not developing melanoma.
Moles that are irregular in color or shape are often treated as candidates of melanoma. Following a visual examination and a dermatoscopic exam
Dermatoscopy
Dermatoscopy is the examination of skin lesions with a dermatoscope...
, or in vivo diagnostic tools such as a confocal microscope, the doctor may biopsy the suspicious mole. If the mole is malignant, the mole and an area around it need excision.
The diagnosis of melanoma requires experience, as early stages may look identical to harmless moles
Mole (skin marking)
A melanocytic nevus is a type of lesion that contains nevus cells .Some sources equate the term mole with "melanocytic nevus". Other sources reserve the term "mole" for other purposes....
or not have any color at all. A skin biopsy
Skin biopsy
Skin biopsy is a biopsy technique in which a skin lesion is removed and sent to the pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 days. It is commonly performed by dermatologists. Skin...
performed under local anesthesia
Local anesthesia
Local anesthesia is any technique to induce the absence of sensation in part of the body, generally for the aim of inducing local analgesia, that is, local insensitivity to pain, although other local senses may be affected as well. It allows patients to undergo surgical and dental procedures with...
is often required to assist in making or confirming the diagnosis
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
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, break the "Ugly Duckling" sign, and are very hard to distinguish from acne scarring, insect bites, dermatofibromas, or lentigines
Lentigo
A lentigo is a small pigmented spot on the skin with a clearly-defined edge, surrounded by normal-appearing skin. It is a harmless hyperplasia of melanocytes which is linear in its spread. This means the hyperplasia of melanocytes is restricted to the cell layer directly above the basement...
.
Total body photography, which involves photographic documentation of as much body surface as possible, is often used during follow-up of high-risk patients. The technique has been reported to enable early detection and provides a cost-effective approach (being possible with the use of any digital camera), but its efficacy has been questioned due to its inability to detect macroscopic changes. The diagnosis method should be used in conjunction with (and not as a replacement for) dermscopic imaging, with a combination of both methods appearing to give extremely high rates of detection. Similarly, there is a web-based technology for mole screening, which evaluates customers’ images against a ‘bank’ of known clinical results. The online-screening test
Moletest
Moletest is a UK based company and the World’s first online remote mole screening service for the detection of non-melanoma and melanoma skin cancers in moles...
is not a substitute for existing medical services, but rather, the technology uses very sophisticated state-of-the-art analysis of a digital image of a suspect mole to screen out any benign moles (the vast majority cases – over 90%), reducing the pressure on healthcare services. The standard approach to the diagnosis of Melanoma is to encourage people to look for any change in colour, size and shape of a mole following the A-B-C-D-E guidelines mentioned previously. The use of digital image analysis and structure recognition provides a machine interpretation to classify moles based on risk, and provides additional advice and support to users - both patient and professional.
Classification
Melanoma is divided into the following types:- Lentigo malignaLentigo malignaLentigo maligna is a melanoma in situ that consists of malignant cells but does not show invasive growth. Lentigo maligna is not the same as lentigo maligna melanoma, and should be discussed separately. It typically progresses very slowly and can remain in a non-invasive form for years...
- Lentigo maligna melanomaLentigo maligna melanomaLentigo maligna melanoma is a melanoma that has evolved from a lentigo maligna. They are usually found on chronically sun damaged skin such as the face and the forearms of the elderly. The nomenclature is very confusing to both patients and physicians alike....
- Superficial spreading melanomaSuperficial spreading melanomaSuperficial spreading melanoma is usually characterized as the most common form of cutaneous melanoma in Caucasians...
- Acral lentiginous melanomaAcral lentiginous melanomaAcral lentiginous melanoma is a kind of lentiginous skin cancer skin melanoma.Acral lentiginous melanoma is observed on the palms, soles, under the nails and in the oral mucosa. It occurs on non hair-bearing surfaces of the body which may or may not be exposed to sunlight. It is also found on...
- Mucosal melanomaMucosal melanomaMucosal melanoma is a rare cutaneous condition characterized by a melanoma of the mucous membranes....
- Nodular melanomaNodular melanomaNodular melanoma is the most aggressive form of melanoma. It tends to grow more rapidly in thickness than in diameter. Instead of arising from a pre-existing mole, it may appear in a spot where a lesion did not previously exist...
- Polypoid melanomaPolypoid melanomaPolypoid melanoma is a rare cutaneous condition, a virulent variant of nodular melanoma....
- Desmoplastic melanomaDesmoplastic melanomaDesmoplastic melanoma is a cutaneous condition characterized by a deeply infiltrating type of melanoma....
- Amelanotic melanomaAmelanotic melanomaAmelanotic melanoma is a type of skin cancer in which the cells do not make melanin.appearance: they can be pink,red,purple or of normal skin color, hence difficult to recognise...
- Soft-tissue melanoma
See also:
- Melanoma with small nevus-like cellsMelanoma with small nevus-like cellsMelanoma with small nevus-like cells is a cutaneous condition, a tumor that contains variably-sized, large nests of small melanocytes with hyperchromatic nuclei and prominent nucleoli....
- Melanoma with features of a Spitz nevusMelanoma with features of a Spitz nevusMelanoma with features of a Spitz nevus is a cutaneous condition characterized histologically with tissue similar to a spitz nevus and with overall symmetry and a dermal nodule of epithelioid melanocytes that do not mature with progressively deeper dermal extension....
- Uveal melanomaUveal melanomaUveal melanoma is a cancer of the eye involving the iris, ciliary body, or choroid . Tumors arise from the pigment cells that reside within the uvea giving color to the eye...
Laboratory
Lactate dehydrogenaseLactate dehydrogenase
Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
(LDH) tests are often used to screen for metastases
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
, 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
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
, MRI, PET
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
and/or PET/CT scans. Although controversial, sentinel lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
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
S-100 protein
S-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix conformation. There are at least 21 different types of S100 proteins...
marker.
Staging
Further context on cancer stagingCancer staging
The stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...
is available at TNM.
Also of importance are the "Clark level" and "Breslow's depth
Breslow's depth
In medicine, Breslow's depth is used as a prognostic factor in melanoma of the skin. It is a description of how deeply tumor cells have invaded.-History:...
", which refer to the microscopic depth of tumor invasion.
Melanoma stages:
5 year survival rates:
Stage 0: Melanoma in situ (Clark Level I), 99.9% survival
Stage I/II: Invasive melanoma, 85–99% survival
- T1a: Less than 1.00 mm primary tumor thickness, without ulceration, and mitosis < 1/mm2
- T1b: Less than 1.00 mm primary tumor thickness, with ulceration or mitoses ≥ 1/mm2
- T2a: 1.00–2.00 mm primary tumor thickness, without ulceration
Stage II: High risk melanoma, 40–85% survival
- T2b: 1.00–2.00 mm primary tumor thickness, with ulceration
- T3a: 2.00–4.00 mm primary tumor thickness, without ulceration
- T3b: 2.00–4.00 mm primary tumor thickness, with ulceration
- T4a: 4.00 mm or greater primary tumor thickness without ulceration
- T4b: 4.00 mm or greater primary tumor thickness with ulceration
Stage III: Regional metastasis, 25–60% survival
- N1: Single positive lymph node
- N2: Two to three positive lymph nodes OR regional skin/in-transit metastasis
- N3: Four positive lymph nodes OR one lymph node and regional skin/in-transit metastases
Stage IV: Distant metastasis, 9–15% survival
- M1a: Distant skin metastasis, normal LDHLactate dehydrogenaseLactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...
- M1b: Lung metastasis, normal LDH
- M1c: Other distant metastasis OR any distant metastasis with elevated LDH
Based upon AJCC five-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 clothingSun protective clothing
Sun protective clothing is clothing specifically designed for sun protection and is produced from a fabric rated for its level of ultraviolet protection. A novel weave structure and denier may produce sun protective properties...
(long-sleeved shirts, long trousers, and broad-brimmed hats) can offer protection. In the past, use of sunscreen
Sunscreen
Sunblock is a lotion, spray, gel or other topical product that absorbs or reflects some of the sun's ultraviolet radiation on the skin exposed to sunlight and thus helps protect against sunburn...
s with a sun protection factor (SPF) rating of 50 or higher on exposed areas were recommended, 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 rejected by most dermatologists. 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
Sunscreen controversy
Sunscreen protects against two common forms of skin cancer, squamous cell carcinoma and basal cell carcinoma , and several sunscreen ingredients protect against tumor development in photocarcinogenicity tests in mice...
for further references and discussions.
Tanning, once believed to help prevent skin cancers, actually can lead to an increased 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 one's shadow is shorter than one's height. These are rough rules, however, and can vary depending on locality and individual skin cancer risk.
Almost all 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 can be difficult to distinguish between a 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.
“Melanoma Monday” is the kick-off of May Melanoma Month, with special activities nationally and locally. Also known as National Skin Self-Examination Day, it is when people are encouraged to examine their skin for skin cancer. Since 1985, this program has helped to detect more than 188,000 suspicious lesions, including more than 21,500 suspected melanomas.
Treatment
Confirmation of the clinical diagnosis is either done with an excisional skin biopsySkin biopsy
Skin biopsy is a biopsy technique in which a skin lesion is removed and sent to the pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 days. It is commonly performed by dermatologists. Skin...
or a small, full-thickness sampling with a punch skin biopsy
Skin biopsy
Skin biopsy is a biopsy technique in which a skin lesion is removed and sent to the pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 days. It is commonly performed by dermatologists. Skin...
. This is usually followed up with a wider excision of the scar or tumor. Depending on the stage, a sentinel lymph node
Sentinel lymph node
The sentinel lymph node is the hypothetical first lymph node or group of nodes reached by metastasizing cancer cells from a primary tumor.-Physiology:...
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
Elliptical excisional biopsies are performed to excise (followed by histological analysis and Breslow scoring, and in some cases may indeed actually remove) the tumor, but further surgery is often necessary to reduce the risk of recurrence. Punch biopsies are contraindicated in suspected melanomas, for fear of seeding tumour cells and hastening the spread of the malignant cells.Complete surgical excision with adequate surgical margin
Surgical margin
Surgical margin, also known as tumor free margin, free margin, normal skin margin, and normal tissue margin, usually refers to the visible normal tissue or skin margin that is removed with the surgical excision of a tumor, growth, or malignancy.-Definition:Surgical margin in a surgery reports...
s 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
Wide local excision
A wide local excision is a surgical procedure to remove a small area of diseased or problematic tissue with a margin of normal tissue. This procedure is commonly performed on the breast and to skin lesions, but can be used on any area of the body....
(WLE) with 1 to 2 cm margins. Melanoma-in-situ and lentigo malignas are treated with narrower surgical margin
Surgical margin
Surgical margin, also known as tumor free margin, free margin, normal skin margin, and normal tissue margin, usually refers to the visible normal tissue or skin margin that is removed with the surgical excision of a tumor, growth, or malignancy.-Definition:Surgical margin in a surgery reports...
s, usually 0.2 to 0.5 cm. Many surgeons consider 0.5 cm the standard of care for standard excision of melanoma-in-situ, but 0.2 cm margin might be acceptable for margin controlled surgery (Mohs surgery
Mohs surgery
Mohs surgery, also known as chemosurgery, created by a general surgeon, Dr. Frederic E. Mohs, is microscopically controlled surgery used to treat common types of skin cancer. It is one of the many methods of obtaining complete margin control during removal of a skin cancer using frozen section...
, 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
Mohs surgery
Mohs surgery, also known as chemosurgery, created by a general surgeon, Dr. Frederic E. Mohs, is microscopically controlled surgery used to treat common types of skin cancer. It is one of the many methods of obtaining complete margin control during removal of a skin cancer using frozen section...
has been reported with cure rate as low as 77% and as high as 98% for melanoma-in-situ. CCPDMA
CCPDMA
CCPDMA is the acronym for "complete circumferential peripheral and deep margin assessment". It is the preferred method for the removal of certain cancers, especially skin cancers.A classical example of CCPDMA is Mohs surgery...
and the "double scalpel" peripheral margin controlled surgery is equivalent to Mohs surgery in effectiveness on this "intra-epithelial" type of melanoma.
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
Lymphadenectomy
Lymphadenectomy consists of the surgical removal of one or more groups of lymph nodes. It is almost always performed as part of the surgical management of cancer....
) were associated with many complications, but unfortunately, no overall survival benefit. Recently, the technique of sentinel lymph node
Sentinel lymph node
The sentinel lymph node is the hypothetical first lymph node or group of nodes reached by metastasizing cancer cells from a primary tumor.-Physiology:...
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 to localize the sentinel node(s). Further precision is provided using a blue tracer dye
Dye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....
, and surgery is performed to biopsy the node(s). Routine H&E staining, and immunoperoxidase
Immunoperoxidase
Immunoperoxidase is a type of immunostain used in molecular biology, medical research, and clinical diagnostics. In particular, immunoperoxidase reactions refer to a sub-class of immunohistochemical or immunocytochemical procedures in which the antibodies are visualized via a peroxidase-catalyzed...
staining will be adequate to rule out node involvement. PCR
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
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.
Excisional skin biopsy
Skin biopsy
Skin biopsy is a biopsy technique in which a skin lesion is removed and sent to the pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 days. It is commonly performed by dermatologists. Skin...
is the management of choice. Here, the suspect lesion is totally removed with an adequate (but minimal, usually 1 or 2 mm) ellipse of surrounding skin and tissue. To avoid disruption of the local lymphatic drainage, the preferred surgical margin for the initial biopsy should be narrow (1 mm). The biopsy should include the epidermal, dermal, and subcutaneous layers of the skin. This enables the histopathologist
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
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 (0.5 cm, 1.0 cm, or 2 cm), as a misdiagnosis can result in excessive scarring and morbidity from the procedure. A large initial excision will disrupt the local lymphatic drainage and can affect further lymphangiogram-directed lymphnode dissection. A small punch biopsy can be used 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.
Adjuvant treatment
High-risk melanomas may require adjuvantAdjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
treatment. In the United States, most patients in otherwise good health will begin up to a year of high-dose interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
treatment, which has severe side effects, but may improve the patient's prognosis. 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.
Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs, ultrasound, LDH testing and photoacoustic detection.
Chemotherapy and immunotherapy
Various chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agents are used, including dacarbazine
Dacarbazine
Dacarbazine is an antineoplastic chemotherapy drug used in the treatment of various cancers, among them malignant melanoma, Hodgkin lymphoma, sarcoma, and islet cell carcinoma of the pancreas.Dacarbazine is a member of the class of alkylating agents, which destroy cancer cells by adding an alkyl...
(also termed DTIC), immunotherapy
Cancer immunotherapy
Cancer immunotherapy is the use of the immune system to reject cancer. The main premise is stimulating the patient's immune system to attack the malignant tumor cells that are responsible for the disease...
(with interleukin-2 (IL-2) or interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
(IFN)), as well as local perfusion, are used by different centers. 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.
Lentigo maligna treatment
Standard excision is still being done by most surgeons. Unfortunately, the recurrence rate is exceedingly 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 control (peripheral margins) is necessary to eliminate the false negative errors. If bread loafingBread loafing
Bread loafing is a common method of processing surgical specimen for histopathology. The process involves cutting the specimen into 3 or more sections. The cut sections are mounted by embedding in paraffin or frozen medium. The cut edge is then thinly sliced with a microtome or a cryostat...
is used, distances from sections should approach 0.1 mm to assure that the method approaches complete margin control.
Mohs surgery
Mohs surgery
Mohs surgery, also known as chemosurgery, created by a general surgeon, Dr. Frederic E. Mohs, is microscopically controlled surgery used to treat common types of skin cancer. It is one of the many methods of obtaining complete margin control during removal of a skin cancer using frozen section...
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
Lentigo maligna
Lentigo maligna is a melanoma in situ that consists of malignant cells but does not show invasive growth. Lentigo maligna is not the same as lentigo maligna melanoma, and should be discussed separately. It typically progresses very slowly and can remain in a non-invasive form for years...
) have resolved with an experimental treatment, imiquimod
Imiquimod
Imiquimod is a prescription medication that acts as an immune response modifier. It is marketed by Meda AB, Graceway Pharmaceuticals and iNova Pharmaceuticals under the trade names Aldara and Zyclara, and by Mochida as Beselna. It is also referred to as R-837.- History :The original FDA approval...
(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.
Radiation therapy
Radiation therapyRadiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
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. Radioimmunotherapy
Radioimmunotherapy
Radioimmunotherapy uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. In cancer therapy, an antibody with specificity for a tumor-associated antigen is used to deliver a lethal dose of radiation to the tumor cells...
of metastatic melanoma is currently under investigation.
Radiotherapy has a role in the palliation of metastatic melanoma.
Prognosis
Features that affect prognosisPrognosis
Prognosis is a medical term to describe the likely outcome of an illness.When applied to large statistical populations, prognostic estimates can be very accurate: for example the statement "45% of patients with severe septic shock will die within 28 days" can be made with some confidence, because...
are tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
thickness in millimeters (Breslow's depth
Breslow's depth
In medicine, Breslow's depth is used as a prognostic factor in melanoma of the skin. It is a description of how deeply tumor cells have invaded.-History:...
), depth related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of lymphatic/perineural invasion
Perineural invasion
In pathology, perineural invasion, abbreviated PNI, refers to cancer spreading to the space surrounding a nerve.-Significance:Cancers with PNI usually have a poorer prognosis, as PNI is thought to be indicative of perineural spread, which can make resection of malignant lesions more difficult....
, presence of tumor-infiltrating lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...
s (if present, prognosis is better), location of lesion, presence of satellite lesions, and presence of regional or distant metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. Certain types of melanoma have worse prognoses but this is explained by their thickness
Breslow's depth
In medicine, Breslow's depth is used as a prognostic factor in melanoma of the skin. It is a description of how deeply tumor cells have invaded.-History:...
. 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
Wide local excision
A wide local excision is a surgical procedure to remove a small area of diseased or problematic tissue with a margin of normal tissue. This procedure is commonly performed on the breast and to skin lesions, but can be used on any area of the body....
(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 node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s, 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
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
(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
Palliative care
Palliative care is a specialized area of healthcare that focuses on relieving and preventing the suffering of patients...
, focusing on life-extension and quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
. 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
Pathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
might indicate.
Epidemiology
Generally, an individual's risk for developing melanoma depends on two groups of factors: intrinsic and environmental. "Intrinsic" factors are generally an individual's family history and inherited genotypeGenotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
, while the most relevant environmental factor is sun exposure.
Epidemiologic studies suggest that exposure to ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
of cells, typically thymine
Thymine
Thymine is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nucleobase. As the name suggests, thymine may be derived by methylation of uracil at...
dimerization, which when unrepaired can create mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the cell's gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s. When the cell divides
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s, the rate of mitosis
Mitosis
Mitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
. Data from patients suggest that aberrant levels of Activating Transcription Factor in the nucleus of melanoma cells are associated with increased metastatic activity of melanoma cells; studies from mice on skin cancer tend to confirm a role for Activating Transcription Factor-2 in cancer progression. Occasional extreme sun exposure (resulting in "sunburn
Sunburn
A sunburn is a burn to living tissue, such as skin, which is produced by overexposure to ultraviolet radiation, commonly from the sun's rays. Usual mild symptoms in humans and other animals include red or reddish skin that is hot to the touch, general fatigue, and mild dizziness. An excess of UV...
") is causally related to melanoma. Melanoma is most common on the back in men and on legs in women (areas of intermittent sun exposure). The risk appears to be strongly influenced by socio-economic conditions rather than indoor versus outdoor occupations; it is more common in professional and administrative workers than unskilled workers. Other factors are mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in or total loss of tumor suppressor gene
Tumor suppressor gene
A tumor suppressor gene, or anti-oncogene, is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.-Two-hit hypothesis:Unlike...
s. Use of sunbed
Sunbed
A sunbed , tanning bed or sun tanning bed is a device which emits ultraviolet radiation to produce a cosmetic tan. Regular tanning beds use several fluorescent lamps that have phosphor blends designed to emit UV in a spectrum that is somewhat similar to the sun...
s (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
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
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. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated. The cause is the exaggerated UV-exposure. It has been shown that sunscreen
Sunscreen
Sunblock is a lotion, spray, gel or other topical product that absorbs or reflects some of the sun's ultraviolet radiation on the skin exposed to sunlight and thus helps protect against sunburn...
— while preventing the sunburn — does not protect mice, injected with melanoma cells a day after UV exposure, from developing melanoma.
Fair and red-headed people, persons with multiple atypical nevi or dysplastic nevi
Dysplastic nevus
A dysplastic nevus is an atypical melanocytic nevus; a mole whose appearance is different from that of common moles. Dysplastic nevi are generally larger than ordinary moles and have irregular and indistinct borders...
and persons born with giant congenital melanocytic nevi are at increased risk.
A family history of melanoma greatly increases a person's risk because mutations in CDKN2A
CDKN2A
CDKN2A can refer to:* P16 * p14arf...
, CDK4 and several other genes have been found in melanoma-prone families. Patients with a history of one melanoma are at increased risk of developing a second primary tumour.
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.
To understand how sunscreen can reduce sunburn and at the same time cause melanoma it is necessary to distinguish between direct DNA damage
Direct DNA damage
Direct DNA damage can occur when DNA directly absorbs the UV-B-photon. UVB light causes thymine base pairs next to each other in genetic sequences to bond together into thymine dimers, a disruption in the strand, which reproductive enzymes cannot copy...
and indirect DNA damage
Indirect DNA damage
Indirect DNA damage occurs when a UV-photon is absorbed in the human skin by a chromophore that does not have the ability to convert the energy into harmless heat very quickly. Molecules that do not have this ability have a long lived excited state. This long lifetime leads to a high probability...
. Genetic analysis has shown that 92% of all melanoma are caused by the indirect DNA damage.
Although some people believe that dark-skinned people such as those of African descent cannot get sunburns, they are in fact susceptible, and should use sunscreen accordingly, as sunscreen has been proven to protect against other cancers such as squamous cell carcinoma and basal cell carcinoma.
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 PeruPeru
Peru , officially the Republic of Peru , is a country in western South America. It is bordered on the north by Ecuador and Colombia, on the east by Brazil, on the southeast by Bolivia, on the south by Chile, and on the west by the Pacific Ocean....
vian 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.
John Hunter
John Hunter (surgeon)
John Hunter FRS was a Scottish surgeon regarded as one of the most distinguished scientists and surgeons of his day. He was an early advocate of careful observation and scientific method in medicine. The Hunterian Society of London was named in his honour...
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
Royal College of Surgeons of England
The Royal College of Surgeons of England is an independent professional body and registered charity committed to promoting and advancing the highest standards of surgical care for patients, regulating surgery, including dentistry, in England and Wales...
. It was not until 1968 that microscopic examination of the specimen revealed it to be an example of metastatic melanoma.
The French physician René Laennec
René Laennec
René-Théophile-Hyacinthe Laennec was a French physician. He invented the stethoscope in 1816, while working at the Hôpital Necker and pioneered its use in diagnosing various chest conditions....
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.
The first English language report of melanoma was presented by an English general practitioner from Stourbridge, William Norris in 1820. 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 acknowledgment 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 ...' More than one and a half centuries later this situation remains largely unchanged.
Research
One important pathway in melaninMelanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
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
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
in keratinocytes, and p53 causes these cells to produce melanocyte-stimulating hormone
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(MSH), which binds to melanocortin 1 receptor
Melanocortin 1 receptor
The melanocortin 1 receptor , also known as melanocyte-stimulating hormone receptor , melanin-activating peptide receptor, or melanotropin receptor, is a G protein-coupled receptor which binds to a class of pituitary peptide hormones known as the melanocortins, of which include adrenocorticotropic...
s (MC1R) on melanocytes. Ligand-binding at MC1R receptors activates adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
s, which produce cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
, which activates CREB
CREB
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
, which promote MITF expression. The targets of MITF include p16
P16 (gene)
Cyclin-dependent kinase inhibitor 2A, also known as multiple tumor suppressor 1 , is a tumor suppressor protein, that in humans is encoded by the CDKN2A gene...
(a CDK inhibitor
CDK inhibitor
A CDK inhibitor is a chemical that inhibits the function of CDKs. It is used to treat cancers by preventing overproliferation of cancer cells...
) 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
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
structure also promise to shed light on transcriptional regulation in melanoma cells. It has long been assumed that nucleosomes are positioned randomly on DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
, 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 that nucleosome position may play a role in gene regulation.
Finally, given the fact that melanin helps protect skin cells from UV-induced damage, new melanoma prevention strategies could involve attempts to induce melanin synthesis 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.
A study published on January 27, 2011, by M. Raza Zaidi et al. shows that interferon-γ links ultraviolet radiation to melanomagenesis in mice. Using a mouse model that allowed the visual tracking and purification of melanocytes using a green fluorescent dye, data showed that UVB-induced, macrophage-enhanced interferon-γ release results in melanoma growth, proliferation and immunoevasion. Based on these results, the interferon-γ pathway can potentially serve as part of new therapeutic measures to treat patients suffering from malignant melanoma, as well as a potential preventive strategy against UV-induced radiation.
BRAF
About 60% of melanomas contain a mutation in the B-Raf geneBRAF (gene)
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...
. Early clinical trials suggested that B-Raf inhibitors including Plexxicon(R)'s vemurafenib could lead to substantial tumor regression in a majority of patients if their tumor contain the B-Raf mutation. In June 2011, a large clinical trial confirmed the positive findings from those earlier trials.
Ipilimumab
At the American Society of Clinical Oncology Conference in June 2010, pharmaceutical company reported the clinical findings of their drug ipilimumabIpilimumab
Ipilimumab , marketed as Yervoy, is a drug used for the treatment of melanoma, a type of skin cancer. It is a U.S...
. The study found an increase in median survival from 6.4 to 10 months in patients with advanced melanomas treated with the monoclonal ipilimumab
Ipilimumab
Ipilimumab , marketed as Yervoy, is a drug used for the treatment of melanoma, a type of skin cancer. It is a U.S...
, versus an experimental vaccine. It also found a one year survival rate of 25% in the control group using the vaccine, 44% in the vaccine and ipilimumab group, and 46% in the group treated with ipilimumab alone. However, some have raised concerns about this study for its use of the unconventional control arm, rather than comparing the drug against a placebo or standard treatment. Meaning that the drug performed better than the vaccine, although the vaccine has not been tested before and may be causing toxicity — making the drug appear better by comparison.
In June 2011, a clinical trial of ipilimumab plus dacarbazine, combined this immune system booster with the standard chemotherapy drug that targets cell division. It showed an increase in median survival for these late stage patients to 11 months instead of the 9 months normally seen. Researchers were also hopeful that perhaps 10-20% of patients could live a long time. Some serious side-effects of revving up the immune system were seen in some patients. A course of treatment costs $120,000. The drug's brandname is Yervoy.
Targeted therapies
In clinical research setting other therapies, such as adoptive cell therapy or gene therapyGene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
, may be tested.
Two kinds of experimental treatments developed at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in the US have been used in advanced (metastatic) melanoma with high success rates in terms of melanoma treatments.
The first treatment involves Adoptive Cell Therapy (ACT) using TILs immune cells (Tumor Infiltrating Lymphocytes) isolated from a patient's own melanoma tumor. These cells are grown in large numbers in a laboratory and returned to the patient after a treatment that temporarily reduces normal T cells in the patient's body. TIL Therapy following lymphodepletion can result in durable complete response in a variety of setups. Up to date, the only medical center outside the USA managed to successfully implement this technology is Sheba Medical Center through "Ella Institute of Melanoma", found in Israel (objective response rates of 50%). The second 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.
Sutent may be effective for patients with metastatic melanoma.
Surveillance methods
Advances in high resolution ultrasound scanning have enabled surveillance of metastatic burden to the sentinel lymph nodes. The Screening and Surveillance of Ultrasound in Melanoma trial (SUNMEL) is evaluating ultrasound as an alternative to invasive surgical methods.See also
- List of cutaneous conditions
- Seborrheic keratosisSeborrheic keratosisA seborrheic keratosis is a noncancerous benign skin growth that originates in keratinocytes. Like liver spots, seborrheic keratoses are seen more often as people age. In fact they are sometimes humorously referred to as the "barnacles of old age". They appear in various colors, from light tan to...
looks like melanoma but is benign - Spitz nevusSpitz nevusA Spitz nevus is a benign melanocytic nevus, a type of skin lesion, affecting the epidermis and dermis....
- Melanotropin receptorMelanotropin receptorMelanotropin receptor is a protein found in skin and eye cells that make melanin . People with certain changes in the gene for the melanotropin receptor have a higher risk of developing melanoma...
- Slip-Slop-SlapSlip-Slop-SlapSlip-Slop-Slap and wrap is the iconic and internationally recognised sun protection campaign prominent in Australia during the 1980s. Launched by Cancer Council Victoria in 1980, the Slip! Slop! Slap! campaign features a singing, dancing Sid Seagull encouraging people to reduce sun exposure and...
An Australian health campaign - Basal cell carcinomaBasal cell carcinomaBasal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
type of non-melanoma skin cancer - Squamous cell carcinomaSquamous cell carcinomaSquamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
type of non-melanoma skin cancer