Melanoma - Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Melanoma
Melanoma
From Wikipedia, the free encyclopedia
Melanoma i /ˌmɛləˈnoʊmə/ (from Greek
μέλας — melas, "dark")[1] is a malignant
tumor of melanocytes.[2] Melanocytes
produce the dark pigment, melanin, which
is responsible for the color of skin. These
cells 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 originate in
any part of the body that contains
melanocytes.
Melanoma
Classification and external resources
a melanoma
Melanoma is less common than other skin
cancers. However, it is much more
dangerous if it is not found early. It causes
the majority (75%) of deaths related to
skin cancer.[3] Worldwide, doctors
diagnose about 160,000 new cases of
melanoma yearly. In women, the most
common site is the legs and melanomas in
men are most common on the back.[4] It is
particularly common among Caucasians,
especially northwestern Europeans living
in sunny climates. There are high rates of
incidence in Oceania, Northern America,
Europe, Southern Africa, and Latin
America,[5] with a paradoxical decrease in
southern Italy and Sicily.[6] This
geographic pattern reflects the primary
cause, ultraviolet light (UV) exposure[7]
crossed with the amount of skin
pigmentation in the population.[8][9]
According to a WHO report, about 48,000
melanoma related deaths occur worldwide
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ICD-10
C43 (http://apps.who.int
/classifications/icd10/browse
/2010/en#/C43)
ICD-9
172.9 (http://www.icd9data.com
/getICD9Code.ashx?icd9=172.9)
ICD-O:
M8720/3 (http://www.progenetix.net
/progenetix/I87203/)
OMIM
155600 (http://omim.org/entry
/155600)
DiseasesDB 7947
(http://www.diseasesdatabase.com
/ddb7947.htm)
MedlinePlus 000850 (http://www.nlm.nih.gov
/medlineplus/ency/article
/000850.htm)
eMedicine
derm/257 (http://www.emedicine.com
/derm/topic257.htm)
med/1386
(http://www.emedicine.com
/med/topic1386.htm#)
ent/27
(http://www.emedicine.com
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per year.[10]
https://en.wikipedia.org/wiki/Melanoma
/ent/topic27.htm#)
plastic/456
(http://www.emedicine.com/plastic
The treatment includes surgical removal
/topic456.htm#)
of the tumor. If melanoma is found early,
MeSH
D008545 (http://www.nlm.nih.gov
while it is still small and thin, and if it is
/cgi/mesh/2013/MB_cgi?field=uid&
completely removed, then the chance of
cure is high. The likelihood of the
term=D008545)
melanoma coming back or spreading
depends on how deeply it has gone into the layers of the skin. For melanomas that come
back or spread, treatments include chemo- and immunotherapy, or radiation therapy.
Contents
1 Signs and symptoms
2 Cause
2.1 Genetics
2.2 UV radiation
3 Pathophysiology
4 Diagnosis
4.1 Classification
4.2 Laboratory
4.3 Staging
5 Prevention
6 Treatment
6.1 Surgery
6.2 Adjuvant treatment
6.3 Chemotherapy and immunotherapy
6.4 Lentigo maligna treatment
6.5 Radiation therapy
7 Prognosis
8 Epidemiology
9 History
10 Research
10.1 BRAF
10.2 Ipilimumab
10.3 Targeted therapies
10.4 Surveillance methods
11 See also
12 References
13 External links
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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 (such lesions should
be referred without delay to a dermatologist). At later stages, the mole may itch, ulcerate or
bleed.[11] Early signs of melanoma are summarized by the mnemonic "ABCDE":
Asymmetry
Borders (irregular)
Color (variegated)
Diameter (greater than 6 mm (0.24 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, 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 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.[12] It can also
spread to the liver, bones, abdomen or distant lymph nodes.
Cause
All cancers are caused by damage to the DNA 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.[13]
Genetics
See also: List of genes mutated in pigmented cutaneous lesions
A number of rare mutations, which often run in families, are known to greatly increase one’s
susceptibility to melanoma. Several different genes have been identified as increasing the
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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 lower elevated 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
(meaning that the chances of a person carrying the mutation to express the phenotype is very
high).
Familial melanoma is genetically heterogeneous,[14] 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.[15] 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.[16]
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. Mutation of the MDM2 SNP309 gene is associated with increased risk of melanoma in
younger women.[17]
UV radiation
The UV radiation from tanning beds increases the risk of melanoma.[18] The International
Agency for Research on Cancer finds that tanning beds are "carcinogenic to humans" with
people who begin using tanning devices before age 30 75% more likely to develop
melanoma.[19]
Pathophysiology
The earliest stage of melanoma starts when the melanocytes begin to grow out of control.
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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, and the tumor
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 tumor 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.[20]
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 (0.04 in),
the Clark level is usually 2.
The following step in the process is the invasive melanoma — the vertical growth phase
(VGP). The tumor attains invasive potential, meaning it can 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),[21] 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 the melanoma development. In certain cases, the primary tumor is completely
destroyed and only the metastatic tumor is discovered. ~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.[22]
Diagnosis
Visual diagnosis of melanomas is still the most common method employed by health
professionals.[23] Moles that are irregular in color or shape are often treated as candidates of
melanoma. The diagnosis of melanoma requires experience, as early stages may look
identical to harmless moles or not have any color at all. 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. There is no
blood test for detecting melanomas.
To detect melanomas (and increase survival rates), it is recommended to learn what they look
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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.
[24][25]
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
may meet some or all of the ABCD criteria, and can lead
to false alarms among laypeople and sometimes even
physicians. An experienced doctor can generally
distinguish seborrheic keratosis from melanoma upon
examination, or with dermatoscopy.
Some advocate the system "ABCDE",[26] with E for
evolution. Certainly moles that change and evolve will be
a concern. Alternatively, some 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.
Nodular melanomas do not fulfill these criteria, having
their own mnemonic, "EFG":
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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).
A dermatoscope
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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".[27][28] 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[28] 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".[29] These
fair-skinned individuals often have lightly pigmented or
amelanotic melanomas which will not present easy-toobserve color changes and variation in colors. The
borders of these amelanotic melanomas are often
indistinct, making visual identification without a
dermatoscope very difficult.
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
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.
Following a visual examination and a dermatoscopic exam,[29] 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 the severity of the melanoma. If the mole is malignant, the mole
and an area around it need excision. Elliptical excisional biopsies may remove the tumor,
followed by histological analysis and Breslow scoring. Punch biopsies are contraindicated in
suspected melanomas, for fear of seeding tumor cells and hastening the spread of the
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malignant cells.
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.[23] 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.
Classification
Melanoma is divided into the following types:[30]
Lentigo maligna
Lentigo maligna melanoma
Superficial spreading melanoma
Acral lentiginous melanoma
Mucosal melanoma
Nodular melanoma
Polypoid melanoma
Desmoplastic melanoma
Amelanotic melanoma
Soft-tissue melanoma
An anal melanoma
See also:[31]
Melanoma with small nevus-like cells
Melanoma with features of a Spitz nevus
Uveal melanoma
Laboratory
Lactate dehydrogenase (LDH) tests are often used to screen for metastases, although many
patients with metastases (even end-stage) have a normal LDH; extraordinarily high LDH
often indicates metastatic spread of the disease to the liver. It is common for patients
diagnosed with melanoma to have chest X-rays and an LDH test, and in some cases CT,
MRI, PET and/or PET/CT scans. Although controversial, sentinel lymph node biopsies and
examination of the lymph nodes are also performed in patients to assess spread to the lymph
nodes. A diagnosis of melanoma is supported by the presence of the S-100 protein marker.
HMB-45 is a monoclonal antibody that reacts against an antigen present in melanocytic
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tumors such as melanomas, and stands for Human Melanoma Black. 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).
Staging
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.[32]
Melanoma stages:[33] 5 year survival rates:
Stage 0: 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
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 ulceration
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 metastasis
N3: Four positive lymph nodes or one lymph node and regional skin/in-transit
metastases
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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 LDH
Based upon AJCC five-year survival from initial
melanoma diagnosis with proper treatment.
Prevention
F18-FDG PET/CT in a
Minimizing exposure to sources of ultraviolet radiation
melanoma patient showing
[34]
(the sun and sunbeds),
following sun protection
multiple lesions, most likely
measures and wearing sun protective clothing (longmetastases
sleeved shirts, long trousers, and broad-brimmed hats)
can offer protection. 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.[35] 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.[36] This controversy is well discussed in numerous review articles, and is
rejected by most dermatologists.[37] 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. Using artificial light for tanning was once believed to help prevent skin cancers,
but it can actually lead to an increased incidence of melanomas.[38] 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.
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Treatment
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.[39]
Treatment of advanced malignant melanoma is
performed from a multidisciplinary approach.
Surgery
Extensive malignant melanoma
Excisional biopsies may remove the tumor, but further
on a patient's chest
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.[40] Many surgeons consider 0.5 cm the standard of
care for standard excision of melanoma-in-situ,[41] 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.[42]
Mohs surgery has been reported with cure rate as low as 77%[43] and as high as 98.0% for
melanoma-in-situ.[44] 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.[45]
Although controversial and without prolonging survival[citation needed], sentinel lymph node
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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.[46] 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.
Adjuvant 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.[47] However British Association of Dermatologist guidelines
on melanoma state that interferon is not recommended as a standard adjuvant treatment for
melanoma. [48] 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
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effects also greatly decrease quality of life.[49]
In Europe, interferon is usually not used outside the scope of clinical trials.[50][51]
Metastatic melanomas can be detected by X-rays, CT scans, MRIs, PET and PET/CTs,
ultrasound, LDH testing and photoacoustic detection.[52]
Chemotherapy and immunotherapy
Various chemotherapy agents are used, including dacarbazine (also termed DTIC),
immunotherapy (with interleukin-2 (IL-2) or interferon (IFN)), as well as local perfusion, are
used by different centers. The overall success in metastatic melanoma is quite limited.[53]
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.[54] A
number of new agents and novel approaches are under evaluation and show promise.[55]
Clinical trial participation should be considered the standard of care for metastatic
melanoma.[56]
Other chemotherapy options include ipilimumab, vemurafenib and temozolomide.
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 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%,[43] and as high as
95% by another author.[44] 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.[57]
Some melanocytic nevi, and melanoma-in-situ (lentigo maligna) have resolved with an
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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
Radiation therapy is often used after surgical resection for patients with locally or regionally
advanced melanoma or for patients with unresectable distant metastases. It may reduce the
rate of local recurrence but does not prolong survival.[58] Radioimmunotherapy of metastatic
melanoma is currently under investigation. Radiotherapy has a role in the palliation of
metastatic melanoma.[59]
Prognosis
See also: Breslow's depth
Features that affect prognosis are tumor thickness in millimeters (Breslow's depth), depth
related to skin structures (Clark level), type of melanoma, presence of ulceration, presence of
lymphatic/perineural invasion, presence of tumor-infiltrating lymphocytes (if present,
prognosis is better), location of lesion, presence of satellite lesions, and presence of regional
or distant metastasis.[60] Certain types of melanoma have worse prognoses but this is
explained by their thickness. Interestingly, less invasive melanomas even with lymph node
metastases carry a better prognosis than deep melanomas without regional metastasis at time
of staging. Local recurrences tend to behave similarly to a primary unless they are at the site
of a wide local excision (as opposed to a staged excision or punch/shave excision) since
these recurrences tend to indicate lymphatic invasion.
When melanomas have spread to the lymph nodes, one of the most important factors is the
number of nodes with malignancy. Extent of malignancy within a node is also important;
micrometastases in which malignancy is only microscopic have a more favorable prognosis
than macrometastases. In some cases micrometastases may only be detected by special
staining, and if malignancy is only detectable by a rarely employed test known as the
polymerase chain reaction (PCR), the prognosis is better. Macrometastases in which
malignancy is clinically apparent (in some cases cancer completely replaces a node) have a
far worse prognosis, and if nodes are matted or if there is extracapsular extension, the
prognosis is still worse.
When there is distant metastasis, the cancer is generally considered incurable. The five year
survival rate is less than 10%.[33] 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
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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.
Epidemiology
Generally, an individual's risk for developing melanoma
depends on two groups of factors: intrinsic and
environmental.[63] "Intrinsic" factors are generally an
individual's family history and inherited genotype, while
the most relevant environmental factor is sun exposure.
Age-standardized incidence rate
Epidemiologic studies suggest that exposure to
of melanoma of the skin per
[64]
ultraviolet radiation (UVA
and UVB) is one of the
100,000 inhabitants in 2008.[61]
major contributors to the development of melanoma. UV
5.26–7.00
no
radiation causes damage to the DNA of cells, typically
data
14.01–15.75
thymine dimerization, which when unrepaired can create
7.01–8.75
less
mutations in the cell's genes. When the cell divides, these
than 1.75
15.76–17.50
mutations are propagated to new generations of cells. If
8.76–10.50
the mutations occur in protooncogenes or tumor
suppressor genes, the rate of mitosis in the mutation1.76–3.50
17.76–19.25
bearing cells can become uncontrolled, leading to the
10.51–12.25
formation of a tumor. Data from patients suggest that
3.51–5.25
more
aberrant levels of Activating Transcription Factor in the
12.26–14.00than
nucleus of melanoma cells are associated with increased
19.25
metastatic activity of melanoma cells;[65][66][67] studies
from mice on skin cancer tend to confirm a role for
Activating Transcription Factor-2 in cancer progression.[68][69] Occasional extreme sun
exposure (resulting in "sunburn") is causally related to melanoma.[70] 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.[71][72] Other factors are mutations in or total loss of tumor
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suppressor genes. Use of sunbeds (with deeply
penetrating UVA rays) has been linked to the
development of skin cancers, including melanoma.[73]
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[74] 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.[75]
Age-standardized death from
melanoma and other skin cancers
per 100,000 inhabitants in
2004.[62]
no
2.1–2.8
data
5.6–6.3
less
2.8–3.5
than 0.7
6.3–7
3.5–4.2
0.7–1.4
7–7.7
4.2–4.9
1.4–2.1
4.9–5.6
more
than 7.7
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.[76]
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.[77]
Patients with a history of one melanoma are at increased risk of developing a second primary
tumor.[78]
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.[79]
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.[80]
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.[81]
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History
Although melanoma is not a new disease, evidence for its occurrence in antiquity is rather
scarce. However, one example lies in a 1960s examination of nine Peruvian 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.[82]
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.[83]
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.[84] The first English language report of
melanoma was presented by an English general practitioner from Stourbridge, William
Norris in 1820.[85] 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 ...'[86] More than one and a half centuries later this situation remains largely
unchanged.
Research
Pharmacotherapy research for unresectable or metastatic malignant melanoma offers new
treatment possibilities.[2] In addition to the advances with recently approved agents, ongoing
research into combination therapy, such as dabrafenib and trametinib, may reveal a more
effective and better-tolerated option for patients with metastatic melanoma. One important
pathway in melanin synthesis involves the transcription factor MITF. The MITF gene is
highly conserved and is found in people, mice, birds, and even fish. MITF production is
regulated via a fairly straightforward pathway. UV radiation causes increased expression of
transcription factor p53 in keratinocytes, and p53 causes these cells to produce melanocytestimulating hormone (MSH), which binds to melanocortin 1 receptors (MC1R) on
melanocytes. Ligand-binding at MC1R receptors activates adenylate cyclases, which
produce cAMP, which activates CREB, which promote MITF expression. The targets of
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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.[citation needed]
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.[87]
BRAF
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.[88] In
June 2011, a large clinical trial confirmed the positive findings from those earlier trials.
[89][90]
In June 2012 a study reported that patients taking a different B-Raf inhibitor, Dabrafenib, did
better than patients taking a chemotherapy agent. [91]
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
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before being destroyed. In October 2012 a study reported that combining Dabrafenib with a
MEK inhibitor trametinib led to even better outcomes. Compared to 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. [92] [93]
Ipilimumab
At the American Society of Clinical Oncology Conference in June 2010, the 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.[94]
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.
[95][96][97]
The criticism was that although 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.
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.[89][98]
Targeted therapies
In clinical research setting other therapies, such as adoptive cell therapy or gene therapy,
may be tested.[99] 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.[20] 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.[100][101] Up
to date, the only medical center outside the USA that has managed to successfully implement
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this technology is Sheba Medical Center through "Ella Institute of Melanoma", found in
Israel (objective response rates of 50%).[101] 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.[102]
A new treatment that trains the immune system to fight cancer has shown modest benefit in
late-stage testing against melanoma.[103] Sutent may be effective for patients with metastatic
melanoma.[104]
Surveillance methods
Advances in high resolution ultrasound scanning have enabled surveillance of metastatic
burden to the sentinel lymph nodes.[105] The Screening and Surveillance of Ultrasound in
Melanoma trial (SUNMEL) is evaluating ultrasound as an alternative to invasive surgical
methods.[106]
See also
Basal cell carcinoma - a type of non-melanoma skin cancer
Cutaneous conditions
Melanotropin receptor
Seborrheic keratosis - looks like melanoma but is benign
Slip-Slop-Slap - an Australian health campaign
Spitz nevus
Squamous cell carcinoma - a type of non-melanoma skin cancer
Uveal melanoma - melanoma of the eye
References
Notes
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Jeffrey" ignored (help); Text "Hamid, Omid" ignored (help); Text "Schuchter, Lynn" ignored
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"Kudchadkar, Ragini" ignored (help); Text "Burris, Howard A." ignored (help); Unknown
parameter |eprint= ignored (help)
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^ Forbes http://blogs.forbes.com/sciencebiz/2010/06/the-risk-for-bristol/ |url= missing title
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^ "Phase 3 clinical study: Ipilimumab boosts, sustains immune system responses against
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Melanoma - Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Melanoma
External links
Melanoma (http://www.dmoz.org/Health/Conditions_and_Diseases/Cancer
/Melanoma//) at the Open Directory Project
Melanomas and melanocytic hyperplasias (//pl.wikibooks.org
/wiki/Atlas_histopatologii_guz%C3%B3w_sk%C3%B3ry
/Rozrosty_i_nowotwory_melanocytarne) in: Atlas histopatologii guzów skóry
(pl.wikibooks.org)
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organization.
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