Uveal melanoma
Encyclopedia
Uveal melanoma is a cancer (melanoma
) of the eye
involving the iris
, ciliary body
, or choroid
(collectively referred to as the uvea
). Tumors arise from the pigment cells (melanocyte
s) that reside within the uvea
giving color to the eye. These melanocytes are distinct from the Retinal pigment epithelium cells underlying the retina
that do not form melanomas.
), are common and pose no health risks, unless they show signs of malignancy, in which case they are classified as iris melanomas. Though derived from uveal melanocytes, iris melanomas share more in common with cutaneous (skin) melanomas, in that they frequently harbor BRAF
mutations associated with ultraviolet
damage. Iris melanomas are much less likely to metastasize
than other uveal melanomas, and less likely to impair vision if detected and treated early.
, are very common and pose no health risks, unless they show signs of malignancy, in which case they are considered melanomas. Uveal melanoma is distinct from most skin melanomas associated with ultraviolet
exposure; however, it shares several similarities with non-sun-exposed melanomas, such as acral melanomas and mucosal melanomas. BRAF
mutations are extremely rare in posterior uveal melanomas; instead, uveal melanomas frequently harbor GNAQ/GNA11
mutations, a trait shared with blue nevi, Nevus of Ota
, and Ocular melanosis
. As seen in BRAF
, mutations in GNAQ/GNA11
are early events in tumorigenesis and are not prognostic for tumor stage or later metastatic spread. In contrast, mutations in the gene BAP1
are strongly linked to metastatic spread and patient survival. Incidence of posterior uveal melanoma is highest among people with light skin and blue eyes. Other risk factors, such as blue light exposure and arc welding have been put forward, but are still debated in the field. Mobile phone
use is not a risk factor for uveal melanoma.
, in which a small disc-shaped shield (plaque) encasing radioactive seeds (most often Iodine-125
, though Ruthenium-106 and Palladium-103 are also used) is attached to the outside surface of the eye, overlying the tumor. The plaque is left in place for a few days and then removed. The risk of metastasis after plaque radiotherapy is the same as that of enucleation, suggesting that micrometastatic spread occurs prior to treatment of the primary tumor. Other modalities of treatment include transpupillary thermotherapy, external beam proton therapy
, resection of the tumor, Gamma Knife stereotactic radiosurgery or a combination of different modalities. Different surgical resection techniques can include trans-scleral partial choroidectomy, and transretinal endoresection.
involvement, presence of orange pigment
overlying the tumor, and older patient age. Likewise several histological and cytological factors are associated with higher risk of metastasis including presence and extent of cells with epithelioid
morphology, presence of looping extracellular matrix patterns, increased infiltration of immune cells
, as well as staining with several immunohistochemical
markers.
The most important genetic alteration associated with poor prognosis in uveal melanoma is inactivation of BAP1
, which most often occurs through mutation of one allele
and subsequent loss of an entire copy of Chromosome 3
(Monosomy
3) to unmask the mutant copy. Because of this function in inactivation of BAP1, monosomy 3 correlates strongly with metastatic spread Where BAP1 mutation status is not available, gains on chromosomes 6
and 8
can be used to refine the predictive value of the Monosomy 3 screen, with gain of 6p indicating a better prognosis and gain of 8q indicating a worse prognosis in disomy
3 tumors. In rare instances, monosomy 3 tumors may duplicate the BAP1-mutant copy of the chromosome to return to a disomic state referred to as isodisomy. Thus, isodisomy 3 is prognostically equivalent to monosomy 3, and both can be detected by tests for chromosome 3 loss of heterozygosity
. Monosomy 3, along with other chromosomal gains, losses, amplifications, and LOH, can be detected in fresh or paraffin embedded samples by virtual karyotyping
.
The most accurate prognostic factor is molecular classification by gene expression profiling
of uveal melanomas. This analysis has been used to identify two subclasses of uveal melanomas: class 1 tumors that have a very low risk of metastasis and class 2 tumors that have a very high risk of metastasis. Gene expression profiling
outperforms all of the above-mentioned factors at predicting metastatic spread of the primary tumor, including monosomy 3.
for uveal melanoma is the liver
in most patients, less likely the lungs. Approximately 50% of patients will develop metastases within 15 years after treatment of the primary tumor. The average survival time after diagnosis of liver metastases is 8 to 10 months.
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
) of the eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
involving the iris
Iris (anatomy)
The iris is a thin, circular structure in the eye, responsible for controlling the diameter and size of the pupils and thus the amount of light reaching the retina. "Eye color" is the color of the iris, which can be green, blue, or brown. In some cases it can be hazel , grey, violet, or even pink...
, ciliary body
Ciliary body
The ciliary body is the circumferential tissue inside the eye composed of the ciliary muscle and ciliary processes. It is triangular in horizontal section and is coated by a double layer, the ciliary epithelium. This epithelium produces the aqueous humor. The inner layer is transparent and covers...
, or choroid
Choroid
The choroid, also known as the choroidea or choroid coat, is the vascular layer of the eye, containing connective tissue, and lying between the retina and the sclera. The human choroid is thickest at the far extreme rear of the eye , while in the outlying areas it narrows to 0.1 mm...
(collectively referred to as the uvea
Uvea
The uvea , also called the uveal layer, uveal coat, uveal tract, or vascular tunic, is the pigmented middle of the three concentric layers that make up an eye. The name is possibly a reference to its reddish-blue or almost black colour, wrinkled appearance and grape-like size and shape when...
). Tumors arise from the pigment cells (melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s) that reside within the uvea
Uvea
The uvea , also called the uveal layer, uveal coat, uveal tract, or vascular tunic, is the pigmented middle of the three concentric layers that make up an eye. The name is possibly a reference to its reddish-blue or almost black colour, wrinkled appearance and grape-like size and shape when...
giving color to the eye. These melanocytes are distinct from the Retinal pigment epithelium cells underlying the retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
that do not form melanomas.
Types
Uveal melanomas may arise from any of the three parts of the uvea, and are sometimes referred to by their location, as Choroidal melanoma, ciliary body melanoma, or iris melanoma. Large tumors often encompass multiple parts of the uvea and can be named accordingly. True iris melanomas, originating from within the iris as opposed to originating elsewhere and invading the iris, are distinct in their etiology and prognosis, such that the other tumors are often referred to collectively as Posterior uveal melanomas.Iris melanoma
Uveal tumors can originate from melanocytes residing within the iris. Benign melanocytic tumors, such as iris freckles and moles (neviMelanocytic nevus
A melanocytic nevus is a type of lesion that contains nevus cells .Some sources equate the term mole with "melanocytic nevus". Other sources reserve the term "mole" for other purposes....
), are common and pose no health risks, unless they show signs of malignancy, in which case they are classified as iris melanomas. Though derived from uveal melanocytes, iris melanomas share more in common with cutaneous (skin) melanomas, in that they frequently harbor BRAF
BRAF (gene)
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...
mutations associated with ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
damage. Iris melanomas are much less likely to metastasize
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
than other uveal melanomas, and less likely to impair vision if detected and treated early.
Posterior uveal melanoma
Benign melanocytic tumors of the choroid, such as choroidal freckles and neviMelanocytic nevus
A melanocytic nevus is a type of lesion that contains nevus cells .Some sources equate the term mole with "melanocytic nevus". Other sources reserve the term "mole" for other purposes....
, are very common and pose no health risks, unless they show signs of malignancy, in which case they are considered melanomas. Uveal melanoma is distinct from most skin melanomas associated with ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
exposure; however, it shares several similarities with non-sun-exposed melanomas, such as acral melanomas and mucosal melanomas. BRAF
BRAF (gene)
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...
mutations are extremely rare in posterior uveal melanomas; instead, uveal melanomas frequently harbor GNAQ/GNA11
Gq alpha subunit
Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway...
mutations, a trait shared with blue nevi, Nevus of Ota
Nevus of Ota
Nevus of Ota is a blue hyperpigmentation that occurs on the face. It was first reported by Dr. M. T. Ota of Japan in 1939.Nevus of Ota is caused by the entrapment of melanocytes in the upper third of the dermis...
, and Ocular melanosis
Ocular melanosis
Ocular melanosis , also known as ocular melanocytosis or melanosis oculi, is a congenital disease of the eye which affects about 1 in every 5000 people and is a risk factor for uveal melanoma. In dogs is found almost exclusively in the Cairn Terrier, where until recently it was known as pigmentary...
. As seen in BRAF
BRAF (gene)
Serine/threonine-protein kinase B-Raf or simply B-Raf, also known as proto-oncogene B-Raf or v-Raf murine sarcoma viral oncogene homolog B1, is a protein that in humans is encoded by the BRAF gene...
, mutations in GNAQ/GNA11
Gq alpha subunit
Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway...
are early events in tumorigenesis and are not prognostic for tumor stage or later metastatic spread. In contrast, mutations in the gene BAP1
BAP1
Ubiquitin carboxyl-terminal hydrolase BAP1 is an enzyme that in humans is encoded by the BAP1 gene.-Further reading:...
are strongly linked to metastatic spread and patient survival. Incidence of posterior uveal melanoma is highest among people with light skin and blue eyes. Other risk factors, such as blue light exposure and arc welding have been put forward, but are still debated in the field. Mobile phone
Mobile phone
A mobile phone is a device which can make and receive telephone calls over a radio link whilst moving around a wide geographic area. It does so by connecting to a cellular network provided by a mobile network operator...
use is not a risk factor for uveal melanoma.
Treatment
The treatment protocol for uveal melanoma has been directed by many clinical studies, the most important being "The Collaborative Ocular Melanoma Study" (COMS). The treatment varies depending upon many factors, chief among them, the size of the tumor. Primary treatment can involve removal of the affected eye (enucleation); however, this is now reserved for cases of extreme tumor burden or other secondary problems. Advances in radiation therapies have significantly decreased the number of patients treated by enucleation in developed countries. The most common radiation treatment is plaque brachytherapyBrachytherapy
Brachytherapy , also known as internal radiotherapy, sealed source radiotherapy, curietherapy or endocurietherapy, is a form of radiotherapy where a radiation source is placed inside or next to the area requiring treatment...
, in which a small disc-shaped shield (plaque) encasing radioactive seeds (most often Iodine-125
Iodine-125
Iodine-125 is a radioisotope of iodine which has uses in biological assays, nuclear medicine imaging and in radiation therapy as brachytherapy to treat prostate cancer and brain tumors. It is the second longest-lived radioisotope of iodine, after iodine-129.Its half-life is around 59 days and it...
, though Ruthenium-106 and Palladium-103 are also used) is attached to the outside surface of the eye, overlying the tumor. The plaque is left in place for a few days and then removed. The risk of metastasis after plaque radiotherapy is the same as that of enucleation, suggesting that micrometastatic spread occurs prior to treatment of the primary tumor. Other modalities of treatment include transpupillary thermotherapy, external beam proton therapy
Proton therapy
Proton therapy is a type of particle therapy which uses a beam of protons to irradiate diseased tissue, most often in the treatment of cancer. The chief advantage of proton therapy is the ability to more precisely localize the radiation dosage when compared with other types of external beam...
, resection of the tumor, Gamma Knife stereotactic radiosurgery or a combination of different modalities. Different surgical resection techniques can include trans-scleral partial choroidectomy, and transretinal endoresection.
Prognostic factors
Several clinical and pathological prognostic factors have been identified that are associated with higher risk of metastasis of uveal melanomas. These include large tumor size, ciliary bodyCiliary body
The ciliary body is the circumferential tissue inside the eye composed of the ciliary muscle and ciliary processes. It is triangular in horizontal section and is coated by a double layer, the ciliary epithelium. This epithelium produces the aqueous humor. The inner layer is transparent and covers...
involvement, presence of orange pigment
Lipofuscin
Lipofuscin is the name given to finely granular yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, adrenals, nerve cells, and ganglion cells...
overlying the tumor, and older patient age. Likewise several histological and cytological factors are associated with higher risk of metastasis including presence and extent of cells with epithelioid
Epithelioid
An epithelioid cell is a cell that resembles epithelial cells in that it directly contacts its neighboring cells via cell surface molecules or junctions. Unlike epithelial cells, however, epithelioid cells make contacts over their entire surface, rather than at restricted portions. The term...
morphology, presence of looping extracellular matrix patterns, increased infiltration of immune cells
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
, as well as staining with several immunohistochemical
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
markers.
The most important genetic alteration associated with poor prognosis in uveal melanoma is inactivation of BAP1
BAP1
Ubiquitin carboxyl-terminal hydrolase BAP1 is an enzyme that in humans is encoded by the BAP1 gene.-Further reading:...
, which most often occurs through mutation of one allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
and subsequent loss of an entire copy of Chromosome 3
Chromosome 3 (human)
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs and represents about 6.5 percent of the total DNA in cells....
(Monosomy
Monosomy
Monosomy is a form of aneuploidy with the presence of only one chromosome from a pair. Partial monosomy occurs when only a portion of the chromosome has one copy, while the rest has two copies.-Human monosomy:...
3) to unmask the mutant copy. Because of this function in inactivation of BAP1, monosomy 3 correlates strongly with metastatic spread Where BAP1 mutation status is not available, gains on chromosomes 6
Chromosome 6 (human)
Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans more than 170 million base pairs and represents between 5.5 and 6% of the total DNA in cells...
and 8
Chromosome 8 (human)
Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 145 million base pairs and represents between 4.5 and 5.0% of the total DNA in cells....
can be used to refine the predictive value of the Monosomy 3 screen, with gain of 6p indicating a better prognosis and gain of 8q indicating a worse prognosis in disomy
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
3 tumors. In rare instances, monosomy 3 tumors may duplicate the BAP1-mutant copy of the chromosome to return to a disomic state referred to as isodisomy. Thus, isodisomy 3 is prognostically equivalent to monosomy 3, and both can be detected by tests for chromosome 3 loss of heterozygosity
Loss of heterozygosity
Loss of heterozygosity in a cell is the loss of normal function of one allele of a gene in which the other allele was already inactivated. This term is mostly used in the context of oncogenesis; after an inactivating mutation in one allele of a tumor suppressor gene occurs in the parent's germline...
. Monosomy 3, along with other chromosomal gains, losses, amplifications, and LOH, can be detected in fresh or paraffin embedded samples by virtual karyotyping
Virtual Karyotype
Virtual karyotype detects genomic copy number variations at a higher resolution level than conventional karyotyping or chromosome-based comparative genomic hybridization .-Background:...
.
The most accurate prognostic factor is molecular classification by gene expression profiling
Gene expression profiling in cancer
Cancer is a disease characterized by uncontrolled cell growth and proliferation. For cancer to develop, genes regulating cell growth and differentiation must be altered; these mutations are then maintained through subsequent cell divisions and are thus present in all cancerous cells...
of uveal melanomas. This analysis has been used to identify two subclasses of uveal melanomas: class 1 tumors that have a very low risk of metastasis and class 2 tumors that have a very high risk of metastasis. Gene expression profiling
Gene expression profiling in cancer
Cancer is a disease characterized by uncontrolled cell growth and proliferation. For cancer to develop, genes regulating cell growth and differentiation must be altered; these mutations are then maintained through subsequent cell divisions and are thus present in all cancerous cells...
outperforms all of the above-mentioned factors at predicting metastatic spread of the primary tumor, including monosomy 3.
Metastasis
The primary site of metastasisMetastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
for uveal melanoma is the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
in most patients, less likely the lungs. Approximately 50% of patients will develop metastases within 15 years after treatment of the primary tumor. The average survival time after diagnosis of liver metastases is 8 to 10 months.
External links
- The Tumori Foundation
- The Ocular Melanoma Foundation. A cancer nonprofit foundation.
- The Ocular Oncology Service at Washington University St. Louis
- The Eye Cancer Network
- Ocular Oncology - Bascom Palmer Eye Institute
- OCU-MEL - Ocular Melanoma e-mail list for patients, caregivers and healthcare professionals
- All NCI-approved clinical trials for uveal melanoma that has spread to the liver
- A phase III clinical trial for uveal melanoma that has spread to the liver