Melanoma, also known as malignant melanoma, is a type of cancer that
develops from the pigment-containing cells known as melanocytes.
Melanomas typically occur in the skin, but may rarely occur in the
mouth, intestines, or eye. In women, they most commonly occur on
the legs, while in men they are most common on the back. Sometimes
they develop from a mole with concerning changes including an increase
in size, irregular edges, change in color, itchiness, or skin
The primary cause of melanoma is ultraviolet light (UV) exposure in
those with low levels of skin pigment. The UV light may be from
either the sun or from other sources, such as tanning devices.
About 25% develop from moles. Those with many moles, a history of
affected family members, and who have poor immune function are at
greater risk. A number of rare genetic defects such as xeroderma
pigmentosum also increase risk. Diagnosis is by biopsy of any
concerning skin lesion.
Using sunscreen and avoiding UV light may prevent melanoma.
Treatment is typically removal by surgery. In those with slightly
larger cancers, nearby lymph nodes may be tested for spread. Most
people are cured if spread has not occurred. For those in whom
melanoma has spread, immunotherapy, biologic therapy, radiation
therapy, or chemotherapy may improve survival. With treatment
the five-year survival rates in the United States is 98% among those
with localized disease and 17% among those in whom spread has
occurred. The likelihood that it will come back or spread depends
how thick the melanoma is, how fast the cells are dividing, and
whether or not the overlying skin has broken down.
Melanoma is the most dangerous type of skin cancer. Globally, in
2012, it newly occurred in 232,000 people. In 2015 there were 3.1
million with active disease which resulted in 59,800 deaths.
Australia and New Zealand have the highest rates of melanoma in the
world. There are also high rates in
Northern Europe and North
America, while it is less common in Asia, Africa, and Latin
Melanoma is more common in men than women.
become more common since the 1960s in areas which are mostly populated
with white people.
1 Signs and symptoms
2.1 UV radiation
4.2 Ugly duckling
5.1 Avoiding ultraviolet radiation
6.2 Add on treatment
Chemotherapy and immunotherapy
6.5 Radiation therapy
8.2 United States
10.1 Targeted therapies
10.2 BRAF inhibitors
10.4 Surveillance methods
10.5 Oncolytic virotherapy
12 External links
Signs and symptoms
Early signs of melanoma are changes to the shape or color of existing
moles or, in the case of nodular melanoma, the appearance of a new
lump anywhere on the skin. At later stages, the mole may itch,
ulcerate or bleed. Early signs of melanoma are summarized by the
Borders (irregular with edges and corners)
Diameter (greater than 6 mm (0.24 in), about the size of a
Evolving over time
These classifications do not, however, apply to the most dangerous
form of melanoma, nodular melanoma, which has its own classifications:
Elevated above the skin surface
Firm to the touch
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. It can
also spread to the liver, bones, abdomen or distant lymph nodes.
Melanomas are usually caused by
DNA damage resulting from exposure to
ultraviolet light from the sun. Genetics also plays a role.
Having more than fifty moles indicates an increased risk melanoma
might arise. A weakened immune system makes it easier for cancer to
arise due to the body’s weakened ability to fight cancer cells.
The ultraviolet radiation from tanning beds increases the risk of
melanoma. The International Agency for Research on
that tanning beds are "carcinogenic to humans" and that people who
begin using tanning devices before the age of thirty years are 75%
more likely to develop melanoma.
Those who work in airplanes also appear to have an increased risk,
believed to be due to greater exposure to UV.
UVB light (wavelengths between 315 – 280 nm) from
the sun is absorbed by skin cell
DNA and results in a type of direct
DNA damage called cyclobutane pyrimidine dimers (CPDs).
Thymine-thymine, cytosine-cytosine or cytosine-thymine dimers are
formed by the joining of two adjacent pyrimidine bases within a DNA
strand. Somewhat similarly to UVB, UVA light (longer wavelengths
between 400 – 315 nm) from the sun or from tanning beds can
also be directly absorbed by skin
DNA (at about 100 to 1000 fold lower
UVB is absorbed).
Studies suggest that exposure to ultraviolet radiation (UVA and
UVB) is one of the major contributors to the development of melanoma.
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 mutations in or total loss of tumor
suppressor genes. Use of sunbeds (with deeply penetrating UVA rays)
has been linked to the development of skin cancers, including
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.
Melanoma rates tend to be
highest in countries settled by migrants from northern Europe that
have a large amount of direct, intense sunlight that the skin of the
settlers is not adapted to, most notably Australia. Exposure during
childhood is a more important risk factor than exposure in adulthood.
This is seen in migration studies in Australia.
Having multiple severe sunburns increases the likelihood that future
sunburns develop into melanoma due to cumulative damage. The sun
and tanning beds are the main sources of UV radiation that increase
the risk for melanoma and living close to the equator increases
exposure to UV radiation.
A number of rare mutations, which often run in families, greatly
increase melanoma susceptibility. Several genes increase risks. 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 lower elevated risk.
Genetic testing can be used to search
for the 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 increase melanoma susceptibility.
Scattered throughout the genome, these mutations reduce a cell's
ability to repair DNA. Both CDKN2A and XP mutations are highly
penetrant (the chances of a carrier to express the phenotype is high).
Familial melanoma is genetically heterogeneous, and loci for
familial melanoma appear on the chromosome arms 1p, 9p and 12q.
Multiple genetic events have been related to melanoma's pathogenesis
(disease development). 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 common 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.
MC1R mutations are very
common; in fact, all red-haired people have a mutated copy. Mutation
MDM2 SNP309 gene is associated with increased risks for younger
Fair- and red-haired 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 several genes have been found in melanoma-prone
families. People with a history of one melanoma are at increased
risk of developing a second primary tumor.
Fair skin is the result of having less melanin in the skin, which
means there is less protection from UV radiation. A family history
could indicate a genetic predisposition to melanoma.
Where melanoma is most likely to develop
Molecular basis for melanoma cell motility: actin-rich podosomes
(yellow), along with cell nuclei (blue), actin (red), and an actin
The earliest stage of melanoma starts when melanocytes begin
Melanocytes are found between the outer layer
of the skin (the epidermis) and the next layer (the dermis). This
early stage of the disease is called the radial growth phase, when the
tumor is less than 1 mm thick. Because the cancer cells have not
yet reached the blood vessels deeper in the skin, it is very unlikely
that this early-stage melanoma 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 tumor cells start to move in a different direction —
vertically up into the epidermis and into the papillary dermis —
cell behaviour changes dramatically.
The next step in the evolution is the invasive radial growth phase,
which is a confusing term; however, it explains the process of the
radial growth, in which individual cells start to acquire invasive
potential. From this point on the melanoma is capable of spreading.
Breslow's depth of the lesion is usually less than 1 mm
(0.04 in), while the
Clark level is usually 2.
The vertical growth phase (VGP) following is the invasive melanoma.
The tumor becomes able to grow into the surrounding tissue and can
spread around the body through blood or lymph vessels. The tumor
thickness is usually more than 1 mm (0.04 in), and the tumor
involves the deeper parts of the dermis.
The host elicits an immunological reaction against the tumor during
the VGP, which is judged by the presence and activity of the tumor
infiltrating lymphocytes (TILs). These cells sometimes completely
destroy the primary tumor; this is called regression, which is the
latest stage of development. In certain cases, the primary tumor is
completely destroyed and only the metastatic tumor is discovered.
About 40% of human melanomas contain activating mutations affecting
the structure of the B-Raf protein, resulting in constitutive
signaling through the Raf to
MAP kinase pathway.
In general, cancers are caused by damage to DNA. UVA light mainly
causes thymine-thymine dimers. UVA also produces reactive oxygen
species and these inflict other
DNA damage, primarily single-strand
breaks, oxidized pyrimidines and the oxidized purine
DNA change) at 1/10th, 1/10th and 1/3rd the frequencies of
UVA-induced thymine-thymine dimers, respectively.
If unrepaired, CPD photoproducts can lead to mutations by inaccurate
translesion synthesis during
DNA replication or repair. The most
frequent mutations due to inaccurate synthesis past CPDs are cytosine
to thymine (C>T) or CC>TT transition mutations. These are
commonly referred to as UV fingerprint mutations, as they are the most
specific mutation caused by UV, being frequently found in sun-exposed
skin but rarely found in internal organs. Errors in
DNA repair of
UV photoproducts, or inaccurate synthesis past these photoproducts,
can also lead to deletions, insertions and chromosomal translocations.
The entire genomes of 25 melanomas were sequenced. On average,
about 80,000 mutated bases (mostly C>T transitions) and about 100
structural rearragements were found per melanoma genome. This is much
higher than the approximately 70 mutations across generations (parent
to child). Among the 25 melanomas, about 6,000 protein-coding
genes had missense, nonsense or splice site mutations. The
transcriptomes of over 100 melanomas has also been sequenced and
analyzed. Almost 70% of all human protein coding genes are expressed
in melanoma. Most of these genes are also expressed in other normal
and cancer tissues, with some 200 genes showing a more specific
expression pattern in melanoma compared to other forms of cancer.
Examples of melanoma specific genes are tyrosinase,
UV radiation causes damage to the
DNA of cells, typically thymine
dimerization, which when unrepaired can create mutations in the cell's
genes. When the cell divides, these mutations are propagated to new
generations of cells. If the mutations occur in protooncogenes or
tumor suppressor genes, 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.
Cancer stem cells may also be involved.
ABCD rule illustration: On the left side from top to bottom: melanomas
showing (A) Asymmetry, (B) a border that is uneven, ragged, or
notched, (C) coloring of different shades of brown, black, or tan and
(D) diameter that had changed in size. The normal moles on the right
side do not have abnormal characteristics (no asymmetry, even border,
even color, no change in diameter).
Melanoma in skin biopsy with H&E stain — this case may represent
superficial spreading melanoma.
Lymph node with almost complete replacement by metastatic melanoma.
The brown pigment is focal deposition of melanin.
Visual inspection is the most common diagnostic technique. Moles
that are irregular in color or shape are typically treated as
candidates. To detect melanomas (and increase survival rates), it is
recommended to learn to recognize them (see "ABCDE" mnemonic above),
to regularly examine moles for changes (shape, size, color, itching or
bleeding) and to consult a qualified physician when a candidate
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
However, many melanomas present as lesions smaller than 6 mm in
diameter; and all melanomas are malignant when they first appear as a
small dot. Physicians typically examine all moles, including those
less than 6 mm in diameter.
Seborrheic keratosis may meet some or
all of the ABCD criteria, and can lead to false alarms. Doctors can
generally distinguish seborrheic keratosis from melanoma upon
examination, or with dermatoscopy.
Some advocate replacing enlarging with evolution. Certainly moles that
change and evolve will be a concern. Alternatively, some practitioners
prefer elevation. Elevation can help identify a melanoma, but lack of
elevation does not mean that the lesion is not a melanoma. Most
melanomas in the US are detected before they become elevated. By the
time elevation is visible, they may have progressed to the more
dangerous invasive stage.
Nodular melanomas do not fulfill these criteria, having their own
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 is the "ugly duckling sign". It is
simple, easy to teach, and highly effective. Correlation of common
lesion characteristics is made. Lesions that greatly deviate from the
common characteristics are labeled an "Ugly Duckling", and a 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 is
required 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's
clothing". These fair-skinned individuals often have lightly
pigmented or amelanotic melanomas that do not present easy-to-observe
color changes and variations. Their borders are often indistinct,
complicating visual identification without a dermatoscope.
Amelanotic melanomas and melanomas arising in fair-skinned individuals
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 hard to distinguish from acne scarring, insect bites,
dermatofibromas, or lentigines.
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. A skin biopsy performed under local
anesthesia is often required to assist in making or confirming the
diagnosis and in defining severity. Elliptical excisional biopsies may
remove the tumor, followed by histological analysis and Breslow
scoring. Incisional biopsies such as punch biopsies are usually
contraindicated in suspected melanomas, because of the possibility of
sampling error or local implantation causing misestimation of
tumour thickness. However, fears that such biopsies may
increase the risk of metastatic disease seem unfounded.
Total body photography, which involves photographic documentation of
as much body surface as possible, is often used during follow-up for
high-risk patients. The technique has been reported to enable early
detection and provides a cost-effective approach (with 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) dermoscopic imaging,
with a combination of both methods appearing to give extremely high
rates of detection.
An anal melanoma
Melanoma is divided into the following types:
Lentigo maligna melanoma
Superficial spreading melanoma
Acral lentiginous melanoma
Melanoma with small nevus-like cells
Melanoma with features of a Spitz nevus
Lactate dehydrogenase (LDH) tests are often used to screen for
metastases, although many patients with metastases (even end-stage)
have a normal LDH; extraordinarily high LDH often indicates metastatic
spread of the disease to the liver.
It is common for patients diagnosed with melanoma to have chest X-rays
and an LDH test, and in some cases CT, MRI, PET and/or PET/CT scans.
Although controversial, sentinel lymph node biopsies and examination
of the lymph nodes are also performed in patients to assess spread to
the lymph nodes. A diagnosis of melanoma is supported by the presence
S-100 protein marker.
HMB-45 is a monoclonal antibody that reacts against an antigen present
in melanocytic tumors such as melanomas. It is used in anatomic
pathology as a marker for such tumors. The antibody was generated to
an extract of melanoma. It reacts positively against melanocytic
tumors but not other tumors, thus demonstrating specificity and
sensitivity. The antibody also reacts positively against junctional
nevus cells but not intradermal nevi, and against fetal melanocytes
but not normal adult melanocytes.
HMB-45 is nonreactive with almost all non-melanoma human malignancies,
with the exception of rare tumors showing evidence of melanogenesis
(e.g., pigmented schwannoma, clear cell sarcoma) or tumors associated
with tuberous sclerosis complex (angiomyolipoma and lymphangiomyoma).
Further context on cancer staging 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:
T stages of melanoma
Melanoma in situ (Clark Level I), 99.9% survival
Stage I / II: Invasive melanoma, 89–95% survival
T1a: Less than 1.0 mm primary tumor thickness, without
ulceration, and mitosis < 1/mm2
T1b: Less than 1.0 mm primary tumor thickness, with ulceration or
mitoses ≥ 1/mm2
T2a: 1.01–2.0 mm primary tumor thickness, without ulceration
F18-FDG PET/CT in a melanoma patient showing multiple lesions, most
Stage II: High risk melanoma, 45–79% survival
T2b: 1.01–2.0 mm primary tumor thickness, with ulceration
T3a: 2.01–4.0 mm primary tumor thickness, without ulceration
T3b: 2.01–4.0 mm primary tumor thickness, with ulceration
T4a: Greater than 4.0 mm primary tumor thickness, without
T4b: Greater than 4.0 mm primary tumor thickness, with ulceration
Stage III: Regional metastasis, 24–70% survival
N1: Single positive lymph node
N2: Two to three positive lymph nodes or regional skin/in-transit
N3: Four positive lymph nodes or one lymph node and regional
Stage IV: Distant metastasis, 7–19% survival
M1a: Distant skin metastasis, normal LDH
M1b: Lung metastasis, normal LDH
M1c: Other distant metastasis or any distant metastasis with elevated
Based upon AJCC five-year survival from initial melanoma diagnosis
with proper treatment.
Avoiding ultraviolet radiation
Minimizing exposure to sources of ultraviolet radiation (the sun and
sunbeds), following sun protection measures and wearing sun
protective clothing (long-sleeved shirts, long trousers, and
broad-brimmed hats) can offer protection.
Using artificial light for tanning was once believed to help prevent
skin cancers, but it can actually lead to an increased incidence of
The body uses UV light to generate vitamin D so there is a need to
balance getting enough sunlight to maintain healthy vitamin D levels
and reducing the risk of melanoma; it takes around a half hour of
sunlight for the body to generate its vitamin D for the day and this
is about the same amount of time it takes for fair-skinned people to
get a sunburn. Exposure to sunlight can be intermittent instead of all
at one time.
Sunscreen appears to be effective in preventing melanoma. In
the past, use of sunscreens 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 oxide, and titanium dioxide)
effectively block both UVA and
UVB even at lower SPFs.
protects against squamous cell carcinoma, another skin cancer.
Concerns have been raised that sunscreen might create a false sense of
security against sun damage.
Extensive malignant melanoma on a person's chest
Confirmation of the clinical diagnosis is done with a 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.
Excisional biopsies may remove the tumor, but further surgery is often
necessary to reduce the risk of recurrence. Complete surgical excision
with adequate surgical margins and assessment for the presence of
detectable metastatic disease along with short- and long-term followup
is standard. Often this is done by a wide local excision (WLE) with 1
to 2 cm margins. Melanoma-in-situ and lentigo malignas are
treated with narrower surgical margins, 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 tumor 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 98.0% 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 that spread usually do so to the lymph nodes in the area of
the tumor before spreading elsewhere. Attempts to improve survival by
removing lymph nodes surgically (lymphadenectomy) were associated with
many complications, but 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.
Biopsy of sentinel lymph nodes is a widely used procedure when
treating cutaneous melanoma.
Neither sentinel lymph node biopsy nor other diagnostic tests should
be performed to evaluate early, thin melanoma, including melanoma in
situ, T1a melanoma or T1b melanoma ≤ 0.5mm. People with these
conditions are unlikely to have the cancer spread to their lymph nodes
or anywhere else and already have a 97% 5-year survival rate.
Because of these things, sentinel lymph node biopsy is unnecessary
health care for them. Furthermore, baseline blood tests and
radiographic studies should not be performed only based on identifying
this kind of melanoma, as there are more accurate tests for detecting
cancer and these tests have high false-positive rates. To
potentially correct false positives, gene expression profiling may be
used as auxiliary testing for ambiguous and small lesions.
Sentinel lymph node
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 hematoxylin and eosin (H&E) and immunoperoxidase staining
will be adequate to rule out node involvement. Polymerase chain
reaction (PCR) tests on nodes, usually performed to test for entry
into clinical trials, now demonstrate that many patients with a
negative sentinel lymph node actually had a small number of positive
cells in their nodes. Alternatively, a fine-needle aspiration biopsy
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.
Add on treatment
High-risk melanomas may require adjuvant treatment, although attitudes
to this vary in different countries. 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 slightly. However, the British Association
of Dermatologists guidelines on melanoma state that interferon is not
recommended as a standard adjuvant treatment for melanoma. A 2011
meta-analysis showed that interferon could lengthen the time before a
melanoma comes back but increased survival by only 3% at 5 years. The
unpleasant side effects also greatly decrease quality of life.
In Europe, interferon is usually not used outside the scope of
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 chemotherapy agents, including temozolomide, 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) was the first new therapy approved (1990 Europe, 1992
USA) 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. Intralesional IL-2 for in-transit
metastases has a high complete response rate ranging from 40 to
By 2005 a number of new agents and novel approaches were under
evaluation and showed promise.
Clinical trial participation was considered the standard of
care for metastatic melanoma.
Therapies for metastatic melanoma include biologic immunotherapy
agents ipilimumab, pembrolizumab, and nivolumab; BRAF inhibitors,
such as vemurafenib and dabrafenib; and a MEK inhibitor
Ongoing research is looking at treatment by adoptive cell
transfer. For this purpose, application of prestimulated or
modified T cells or dendritic cells is possible.
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 loafing 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.
Radiation therapy is often used after surgical resection for patients
with locally or regionally advanced melanoma or for patients with
unresectable distant metastases. Kilovoltage x-ray beams are often
used for these treatments and have the property of the maximum
radiation dose occurring close to the skin surface. 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
A diagram showing the most common sites for melanoma to spread
Features that affect prognosis are tumor thickness in millimeters
(Breslow's depth), depth related to skin structures (Clark level),
type of melanoma, presence of ulceration, presence of
lymphatic/perineural invasion, presence of tumor-infiltrating
lymphocytes (if present, prognosis is better), location of lesion,
presence of satellite lesions, and presence of regional or distant
metastasis. Certain types of melanoma have worse prognoses but
this is explained by their thickness. Interestingly, less invasive
melanomas even with lymph node metastases carry a better prognosis
than deep melanomas without regional metastasis at time of staging.
Local recurrences tend to behave similarly to a primary unless they
are at the site of a wide local excision (as opposed to a staged
excision or punch/shave excision) since these recurrences tend to
indicate lymphatic invasion.
When melanomas have spread to the lymph nodes, one of the most
important factors is the number of nodes with malignancy. Extent of
malignancy within a node is also important; micrometastases in which
malignancy is only microscopic have a more favorable prognosis than
macrometastases. In some cases micrometastases may only be detected by
special staining, and if malignancy is only detectable by a rarely
employed test known as the polymerase chain reaction (PCR), the
prognosis is better. Macrometastases in which malignancy is clinically
apparent (in some cases cancer completely replaces a node) have a far
worse prognosis, and if nodes are matted or if there is extracapsular
extension, the prognosis is worse still. In addition to these
variables, expression levels and copy number variations of a number of
relevant genes may be used to support assessment of malignant melanoma
When there is distant metastasis, the cancer is generally considered
incurable. The five-year survival rate is less than 10%. The
median survival is 6–12 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. Survival is better with metastasis in which
the location of the primary tumor is unknown.
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.
About 200 genes are prognostic in melanoma, with both unfavorable
genes where high expression is correlated to poor survival and
favorable genes where high expression is associated with longer
survival times. Examples of unfavorable genes are
MCM6 and TIMELESS
and an example of a favorable gene is WIPI1.
Age-standardized new cases per year of melanoma of the skin per
100,000 inhabitants in 2008.
less than 1.75
more than 19.25
Deaths from melanoma and other skin cancers per million persons in
Globally, in 2012, melanoma occurred in 232,000 people and resulted in
Australia and New Zealand have the highest rates of
melanoma in the world. It has become more common in the last 20
years in areas that are mostly Caucasian.
The rate 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.
Australia has a very high — and increasing — rate of melanoma. In
2012, deaths from melanoma occurred in 7.3-9.8 per 100,000 population.
In Australia, melanoma is the third most common cancer in either sex;
indeed, its incidence is higher than for lung cancer, although the
latter accounts for more deaths. It is estimated that in 2012, more
than 12,000 Australians were diagnosed with melanoma: given
Australia's modest population, this is better expressed as 59.6 new
cases per 100,000 population per year; >1 in 10 of all new cancer
cases were melanomas.
Melanoma incidence in
Australia is matter
of significance, for the following reasons:
Australian melanoma incidence has increased by more than 30 per cent
between 1991 and 2009.
Australian melanoma age-standardised incidence rates were, as of 2008,
at least 12 times higher than the world average.
Australian melanoma incidence is, by some margin, the highest in the
Overall age-standardised cancer incidence in
Australia is the highest
in the world, and this is attributable to melanoma alone.
Age-standardised overall cancer incidence is similar to New Zealand,
but there is a statistically-significant difference between Australia
and all other parts of the developed world including North America,
Western Europe, and the Mediterranean.
In the United States about 9,000 people die from melanoma a year.
In 2011 it affected 19.7 per 100,000, and resulted in death in 2.7 per
71,943 people in the United States were diagnosed with melanomas of
the skin, including 42,430 men and 29,513 women.
9,394 people in the United States died from melanomas of the skin,
including 6,239 men and 3,155 women.
Cancer Society’s estimates for melanoma incidence in
the United States for 2017 are:
About 87,110 new melanomas will be diagnosed (about 52,170 in men and
34,940 in women).
About 9,730 people are expected to die of melanoma (about 6,380 men
and 3,350 women).
Melanoma is more than 20 times more common in whites than in African
Americans. Overall, the lifetime risk of getting melanoma is about
2.5% (1 in 40) for whites, 0.1% (1 in 1,000) for African Americans,
and 0.5% (1 in 200) for Hispanics.
The risk of melanoma increases as people age. The average age of
people when the disease is diagnosed is 63.
See also: Timeline of melanoma
Although melanoma is not a new disease, evidence for its occurrence in
antiquity is rather scarce. However, one example lies in a 1960s
examination of nine Peruvian 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). Norris was also a pioneer
in suggesting a link between nevi and melanoma and the possibility of
a relationship between melanoma and environmental exposures, by
observing that most of his patients had pale complexions. He also
described that melanomas could be amelanotic and later showed the
metastatic nature of melanoma by observing that they can disseminate
to other visceral organs.
The first formal acknowledgment of advanced melanoma as untreatable
came from Samuel Cooper in 1840. He stated that the only chance for a
cure depends upon the early removal of the disease (i.e., early
excision of the malignant mole) ...'
More than one and a half centuries later this situation remains
The word melanoma is from the Greek μέλας melas meaning
Pharmacotherapy research for unresectable or metastatic malignant
melanoma is ongoing.
In clinical research setting other therapies, such as adoptive cell
therapy or gene therapy, are being tested.
Two kinds of experimental treatments developed at the National Cancer
Institute (NCI), have been used in metastatic melanoma with tentative
The first treatment involves adoptive cell therapy (ACT) using TILs
immune cells (tumor infiltrating lymphocytes) isolated from a person'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.
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 vaccine to train the immune system to fight cancer showed modest
benefit in late-stage testing in 2009 against melanoma.
About 60% of melanomas contain a mutation in the B-Raf gene. Early
clinical trials suggested that B-Raf inhibitors including Plexxicon'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.
In August 2011
Vemurafenib received FDA approval for the treatment of
late-stage melanoma. In May 2013 the US FDA approved dabrafenib as a
single agent treatment for patients with BRAF V600E mutation-positive
Some researchers believe that combination therapies that
simultaneously block multiple pathways may improve efficacy by making
it more difficult for the tumor cells to mutate before being
destroyed. In October 2012 a study reported that combining Dabrafenib
MEK inhibitor trametinib led to even better outcomes. Compared
Dabrafenib alone, progression-free survival was increased to 41%
from 9%, and the median progression-free survival increased to 9.4
months versus 5.8 months. Some side effects were, however, increased
in the combined study. 
In January 2014, the FDA approved the combination of dabrafenib and
trametinib for the treatment of patients with BRAF V600E/K-mutant
Eventual resistance to BRAF and MEK inhibitors may be due to a cell
surface protein known as EphA2 which is now being investigated.
At the American Society of Clinical
Oncology Conference in June 2010,
Bristol-Myers Squibb pharmaceutical company reported the clinical
findings of their drug ipilimumab. 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. The criticism was that
Ipilimumab performed better than the vaccine, the vaccine has
not been tested before and may be causing toxicity, making the drug
appear better by comparison.
Ipilimumab was approved by the FDA in March 2011 to treat patients
with late-stage melanoma that has spread or cannot be removed by
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.
Advances in high resolution ultrasound scanning have enabled
surveillance of metastatic burden to the sentinel lymph nodes.
The Screening and Surveillance of Ultrasound in
(SUNMEL) is evaluating ultrasound as an alternative to invasive
In some countries oncolytic virotherapy methods are studied and used
to treat melanoma. Oncolytic virotherapy is a promising branch of
virotherapy, where oncolytic viruses are used to treat diseases;
viruses can increase metabolism, reduce anti-tumor immunity and
disorganize vasculature. Talimogene laherparepvec (T-VEC) (which
is a herpes simplex virus type 1–derived oncolytic immunotherapy),
was shown to be useful against metastatic melanoma in 2015 with an
increased survival of 4.4 months.
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The dictionary definition of melanoma at Wiktionary
Media related to
Melanoma at Wikimedia Commons
Melanoma at Curlie (based on DMOZ)
Diseases of the skin and appendages by morphology
epidermal inclusion cyst
dermatofibroma (benign fibrous histiocytoma)
infantile digital fibromatosis
granular cell tumor
lichen simplex chronicus
langerhans cell histiocytosis
systemic lupus erythematosus
pityriasis rubra pilaris
acute contact dermatitis
porphyria cutanea tarda
epidermolysis bullosa simplex
insect bite reactions
transient acantholytic dermatosis
pityriasis lichenoides et varioliformis acuta
subcorneal pustular dermatosis
idiopathic guttate hypomelanosis
hypopigmented mycosis fungoides
systemic lupus erythematosus
fixed drug eruption
disseminated intravascular coagulation
lichen sclerosis et atrophicus
systemic lupus erythematosus
loose anagen syndrome
acne keloidalis nuchae
mucous membrane pemphigoid
Tumors: Skin neoplasm, nevi and melanomas (C43/D22, 172/216, ICD-O
Superficial spreading melanoma
Lentigo maligna melanoma
Acral lentiginous melanoma
Melanoma with features of a Spitz nevus
Melanoma with small nevus-like cells
Melanocytic tumors of uncertain malignant potential
Nevus of Ito/
Nevus of Ota
Pigmented spindle cell nevus
Congenital melanocytic nevus
Congenital melanocytic nevus (Giant
Balloon cell nevus
Dysplastic nevus syndrome
Benign melanocytic nevus